The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: methodological report phase I.
To apply a data-driven approach to investigate, in patients newly presenting with undifferentiated inflammatory synovitis, key variables that discriminate the subset of patients at sufficiently high risk of persistent or erosive disease for the purpose of developing new criteria for rheumatoid arthritis (RA). In this first phase of the collaborative effort of the American College of Rheumatology and European League Against Rheumatism to develop new criteria for RA, a pooled analysis of early arthritis cohorts made available by the respective investigators is presented. All the variables associated with the gold standard of treatment with methotrexate during the first year after enrolment were first identified. Principal component analysis was then used to identify among the significant variables those sets that represent similar domains. In a final step, from each domain one representative variable was extracted, all of which were then tested for their independent effects in a multivariate regression model. From the OR in that final model, the relative weight of each variable was estimated. The final domains and variables identified by this process (and their relative weights) were: swelling of a metacarpophalangeal joint (MCP; 1.5), swelling of a proximal interphalangeal joint (PIP; 1.5), swelling of the wrist (1.5), tenderness of the hand (ie, MCP, PIP or wrist (2)), acute phase reaction (ie, C reactive protein or erythrocyte sedimentation rate and weights for moderate or high elevations of either one (1 for moderate, 2 for high elevation)) and serological abnormalities (ie, rheumatoid factors or anti-citrullinated protein antibodies, again with separate weights for moderate or high elevations (2 and 4, respectively)). The results of this first phase were subsequently used in the second phase of the project, which is reported in a separate methodological paper, and for derivation of the final set of criteria.


Oligonucleotide probe for the visualization of Escherichia coli/Escherichia fergusonii cells by in situ hybridization: specificity and potential applications.
There are several occasions when enumeration of Escherichia coli cells is needed. These include examination of urine specimens and water or food samples. Present methods rely on growth in more or less selective media (colony-forming units on agar or the most probable number method using liquid media). Unfortunately, no really selective medium with 100% efficiency of plating is available for E. coli. A 24-mer oligonucleotide probe (Colinsitu), complementary to a piece of 16S ribosomal ribonucleic acid, has been tested for specifically visualizing E. coli cells by in situ hybridization and epifluorescence microscopy. The fluorescent dye-labeled probe was able to stain cells of E. coli, Shigella spp. and E. fergusonii. Shigella spp. are known to belong to the E. coli genomospecies and E. fergusonii is the nomenspecies closest to E. coli by DNA-DNA hybridization. The probe did not stain any strain of 169 other genomospecies of the family Enterobacteriaceae or of a few other species frequently encountered in the environment. Revivification without cell division allowed the visualization of E. coli cells in contaminated water. In situ hybridization using the Colinsitu probe is a potential tool for the confirmation of (atypical) E. coli in reference centers and the rapid (3-6 h) detection and enumeration of E. coli in urine specimens, contaminated water and food. More work is needed to include in situ hybridization in laboratory routine.


Combined Transcriptomic and Proteomic Approach to Identify Toxicity Pathways in Early Life Stages of Japanese Medaka (Oryzias latipes) Exposed to 1,2,5,6-Tetrabromocyclooctane (TBCO).
Currently, the novel brominated flame retardant 1,2,5,6-tetrabromocyclooctane (TBCO) is considered a potential replacement for hexabromocyclododecane (HBCD). Therefore, use of TBCO could increase in the near future. To assess potential toxicological risks to aquatic organisms, embryos of Japanese medaka (Oryzias latipes) were exposed to 10, 100, or 1000 μg/L TBCO from 2 h postfertilization until 1 day post-hatch. TBCO accumulated in embryos in the order of 0.43-1.3 × 10(4)-fold, and the rate constant of accumulation was 1.7-1.8 per day. The number of days to hatch and the hatching success of embryos exposed to the medium and the greatest concentrations of TBCO were impaired. Responses of the transcriptome (RNA-seq) and proteome were characterized in embryos exposed to 100 μg/L TBCO because this was the least concentration of TBCO that caused an effect on hatching. Consistent with effects on hatching, proteins whose abundances were reduced by exposure to TBCO were enriched in embryo development and hatching pathways. Also, on the basis of the responses of transcriptome and proteome, it was predicted that TBCO might impair vision and contraction of cardiac muscle, respectively, and these effects were confirmed by targeted bioassays. This study provided a comprehensive understanding of effects of TBCO on medaka at early life stages and illustrated the power of "omics" to explain and predict phenotypic responses to chemicals.


Daytime urinary incontinence in primary school children: a population-based survey.
To determine the prevalence and severity of, and risk factors for, daytime urinary incontinence in children starting primary school. Population-based cross-sectional survey of new entrant primary school children in Sydney, Australia. A random cluster sample of 2020 primary school children was surveyed by using a daytime incontinence questionnaire with known substantial repeatability (mean kappa = 0.70). The questionnaire was returned for 1419 (70%) children with a mean age of 5.9 years; 16.5% of children had experienced one or more episodes of wetting in the last 6 months (mild), 2.0% had wet twice or more per week (moderate), and 0.7% were wet every day (severe) (overall prevalence of 19.2%). On multivariate analysis, recent emotional stress (odds ratio 5.7), a history of daytime wetting along the paternal line (odds ratio 9.3), and a history of wetting among male siblings (odds ratio 5.3) were independent risk factors for moderate to severe daytime wetting. Expressed as population attributable risk, 59% and 28% of moderate-severe and mild daytime wetting, respectively, can be attributed to these 3 factors. Only 16% of families with affected children had sought medical help. Daytime urinary incontinence in the first year of primary school is more common than previously reported, and only a small proportion of affected children seek medical help. Emotional stress and family history are likely to be major causal factors.


Lipopolysaccharide signal transduction, regulation of tumor necrosis factor biosynthesis, and signaling by tumor necrosis factor itself.
In recent years, the chain of events that connects introduction of bacterial endotoxin (lipopolysaccharide; LPS) into a mammalian host, and the syndrome of organ damage and vascular collapse that ensues, have come into sharper focus. Several of the molecules that engage LPS, and a rough outline of the signaling cascade that leads to cytokine release from mononuclear cells, have been elucidated. The principal cytokines that mediate the untoward effects of LPS have also been identified. The most important of these is tumor necrosis factor (TNF), which elicits biologic responses from virtually every type of cell to which it binds. Two distinct receptors transduce the TNF signal. Mechanisms of TNF receptor action are becoming increasing clear, and there is reason to hope that, through intervention at many distinct levels, the devastating effects of LPS might be attenuated or averted.


'Lost' smear-positive pulmonary tuberculosis cases: where are they and why did we lose them?
Ntcheu District, rural Malawi. 1) To locate smear-positive pulmonary tuberculosis patients who were identified during the first 6 months of 2000 but did not start treatment ('lost cases'); 2) to describe these patients' pathways to diagnosis, health status and socio-demographic characteristics; and 3) to explore why these patients did not start treatment. Lost cases were traced from programme registers and interviewed using the qualitative research critical incidents narrative (CIN) interviews technique. Results were triangulated with responses from health care workers through focus group discussions. The laboratory registered 157 new smear-positive patients. Twenty three (15%) of these were 'lost' (did not appear in the treatment register). CIN interviews were conducted with five lost patients and 14 carers of lost patients who had died. Long pathways to diagnosis were the norm. Health system structural barriers were the main factors behind these pathways, including requirement for hospital attendance, delays in symptom recognition and receipt of sputum results, and the misconception that negative smears excluded tuberculosis. Some smear-positive cases experience very long pathways to diagnosis and are lost from this free public health system. The diagnostic process needs to become more responsive to patients' needs.


Metal-Organic Framework Encapsulated Whole-Cell Vaccines Enhance Humoral Immunity against Bacterial Infection.
The increasing rate of resistance of bacterial infection against antibiotics requires next generation approaches to fight potential pandemic spread. The development of vaccines against pathogenic bacteria has been difficult owing, in part, to the genetic diversity of bacteria. Hence, there are many potential target antigens and little a priori knowledge of which antigen/s will elicit protective immunity. The painstaking process of selecting appropriate antigens could be avoided with whole-cell bacteria; however, whole-cell formulations typically fail to produce long-term and durable immune responses. These complications are one reason why no vaccine against any type of pathogenic E. coli has been successfully clinically translated. As a proof of principle, we demonstrate a method to enhance the immunogenicity of a model pathogenic E. coli strain by forming a slow releasing depot. The E. coli strain CFT073 was biomimetically mineralized within a metal-organic framework (MOF). This process encapsulates the bacteria within 30 min in water and at ambient temperatures. Vaccination with this formulation substantially enhances antibody production and results in significantly enhanced survival in a mouse model of bacteremia compared to standard inactivated formulations.


[The prevalence of intestinal parasites according to the distribution of the patients' gender and parasite species for five years at the Osmangazi University Medical Faculty].
In this study, patients (outpatients and inpatients) with various gastrointestinal system complaints presenting at various clinics of the Eskisehir Osmangazi University Medical Faculty, from February 2003-December 2007 were investigated for the presence of intestinal parasites. The prevalence of intestinal parasites was evaluated according to parasite species, gender of the patients and the years, in which cases were seen. A total of 34,733 stool samples were prepared by formal-ethyl acetate concentration and examined in saline and iodine preparations microscopically with 10x and 40x magnifications. Also trichrome stained preparations of non-pathogenic amoebas and modi-fied Erlich-Ziehl-Nielsen stained preparations for Cryptosporidium spp were examined by oil-immersion objectives (100x). One or more parasites were found in 1252 of the 34,733 stool samples (including nonpathogenic protozoa).the overall prevalence of intestinal parasitic infection rate was 3.6%, of these patients, 52.5% were female and 47.5% male. Predominant parasites were Entamoeba histolytica/dispar group amoebas (31% (397/1252), followed by Giardia intestinalis 19% (236/1252), Blastocystis hominis 7% (108/1252), and Cryptosporid-ium parvum %4.5 (56/1252). Since the cellophane type method was only used in a few cases; the rates detected in helminth cases in this study were different from other studies. The ratio of E. vermicularis was found to be 2.3% (29/1252), Taenia saginata 0.8% (10/1252) and Strongyloides stercoralis 0.4% (5/1252). In comparison to a previous 10 year retrospective study which was performed in our hospital, we detected an important decrease in prevalence of parasites. But the presence of intestinal parasites is still an important problem.


Robust G2 pausing of adult stem cells in Hydra.
Hydra is a freshwater hydrozoan polyp that constantly renews its two tissue layers thanks to three distinct stem cell populations that cannot replace each other, epithelial ectodermal, epithelial endodermal, and multipotent interstitial. These adult stem cells, located in the central body column, exhibit different cycling paces, slow for the epithelial, fast for the interstitial. To monitor the changes in cell cycling in Hydra, we established a fast and efficient flow cytometry procedure, which we validated by confirming previous findings, as the Nocodazole-induced reversible arrest of cell cycling in G2/M, and the mitogenic signal provided by feeding. Then to dissect the cycling and differentiation behaviors of the interstitial stem cells, we used the AEP_cnnos1 and AEP_Icy1 transgenic lines that constitutively express GFP in this lineage. For the epithelial lineages we used the sf-1 strain that rapidly eliminates the fast cycling cells upon heat-shock and progressively becomes epithelial. This study evidences similar cycling patterns for the interstitial and epithelial stem cells, which all alternate between the G2 and S-phases traversing a minimal G1-phase. We also found interstitial progenitors with a shorter G2 that pause in G1/G0. At the animal extremities, most cells no longer cycle, the epithelial cells terminally differentiate in G2 and the interstitial progenitors in G1/G0. At the apical pole ~80% cells are post-mitotic differentiated cells, reflecting the higher density of neurons and nematocytes in this region. We discuss how the robust G2 pausing of stem cells, maintained over weeks of starvation, may contribute to regeneration.


Can physical activity maintain normal grades of body mass index and body fat percentage?
A cross-sectional study was undertaken on 767 urban male volunteers performing physical activity and 469 age and socioeconomic status matched controls not doing any physical activity from the city limits of North India. Height and weight were recorded for each participant to determine their Body Mass Index (BMI). Body fat percentage and weight was measured using a body fat monitor. Fifty three percent of the physical activity performers showed normal BMI compared to 49% nonphysical activity performers. Overweight was observed in 43.3% physical activity performers compared to 44.7% nonphysical activity performers. Fifty two percent of physical activity performers had normal body fat percent compared to 48.5% nonphysical activity performers. Low body fat percent was observed in 23.4% physical activity performers compared to 2.7% nonphysical activity performers. High body fat percent was observed in 48.7% nonphysical activity performers compared to 45.8% physical activity performers. Overall, the study suggested that physical activity alone cannot maintain BMI and body fat percent, but it can reduce the risk of overweight and high body fat percent in the population.


Atrial and pulmonary endothelin mRNA is increased in a canine model of chronic low cardiac output.
Chronic thoracic inferior vena caval constriction (TIVCC) is a model of low-cardiac output congestive heart failure (CHF), in which pulmonary and atrial as well as circulating endothelin (ET) are increased. ET is a potent vasoconstrictor and mitogenic peptide whose circulating concentrations are increased in severe human and experimental CHF. To date, an increase in ET production at key sites in CHF remains controversial. Therefore, the current study was designed to determine cardiac and pulmonary ET-1 mRNA in an experimental model of CHF produced by TIVCC in which avid sodium retention, intense vasoconstriction, and elevation of circulating ET-1 occur as in human CHF. Experiments were conducted in normal dogs and dogs with 7 days of TIVCC. Cardiac and pulmonary ET-1 mRNA were measured by quantified densitometry of Northern blots. Plasma and tissue (cardiac and pulmonary) ET-1 immunoreactivity were determined by radioimmunoassay. Cardiac and pulmonary tissue localization of ET-1 were determined by immunohistochemical staining. Plasma ET-1 was significantly increased in TIVCC compared with normal dogs. ET-1 mRNA was detectable in normal canine atria, ventricle, and lung. ET-1 mRNA was significantly increased in TIVCC compared with normal dogs in both atrial and pulmonary tissues without alternations in ventricular ET mRNA. Atrial and pulmonary tissue concentrations of ET-1 also were markedly elevated in TIVCC compared with normal dogs. Immunohistochemical staining of atrial and pulmonary tissues for ET-1 demonstrated that the increased ET immunoreactivity was localized to atrial myocytes and pulmonary epithelial cells. These studies support a role for the heart and lung in the increased production of ET-1 in CHF. The current studies also suggest that ET-1 may have important autocrine and paracrine actions in cardiopulmonary regulation in experimental CHF.


The discordant pleasures of everyday eating: Reflections on the social gradient in obesity under neo-liberalism.
Despite widespread epidemiological evidence of a social gradient in obesity, there has been less attention focused on understanding this from a sociological perspective. Furthermore, whilst pleasure is an obvious feature of contemporary cultural representations of food and eating, this has not figured prominently in sociological understandings of the social gradient. Using qualitative data from biographical interviews conducted with adults living in materially deprived parts of South Yorkshire (UK) we introduce the idea of discordant pleasure in relation to everyday eating as a way of shedding light on the social gradient in obesity. We highlight in particular, the ways in which materially deprived individuals who were defined as obese described the tensions between the pleasures of eating and the struggles for bodily control, alongside the affective dimensions - frustration and shame - that this process engendered. We draw on Berlant's work on lateral and interruptive agency to make sense of these accounts, suggesting that classed agency and discordant pleasure are important dimensions in understanding the social gradient in obesity under neoliberalism.


3D Reconstruction of the Neurovascular Unit Reveals Differential Loss of Cholinergic Innervation in the Cortex and Hippocampus of the Adult Mouse Brain.
Increasing evidence supports a role for cerebrovasculature dysfunction in the etiology of Alzheimer's disease (AD). Blood vessels in the brain are composed of a collection of cells and acellular material that comprise the neurovascular unit (NVU). The NVU in the hippocampus and cortex receives innervation from cholinergic neurons that originate in the basal forebrain. Death of these neurons and their nerve fibers is an early feature of AD. However, the effect of the loss of cholinergic innervation on the NVU is not well characterized. The purpose of this study was to evaluate the effect of the loss of cholinergic innervation of components of the NVU at capillaries, arteries and veins in the hippocampus and cortex. Adult male C57BL/6 mice received an intracerebroventricular injection of the immunotoxin p75NTR mu-saporin to induce the loss of cholinergic neurons. Quadruple labeling immunohistochemistry and 3D reconstruction were carried out to characterize specific points of contact between cholinergic fibers and collagen IV, smooth muscle cells and astrocyte endfeet. Innate differences were observed between vessels of the hippocampus and cortex of control mice, including a greater amount of cholinergic contact with perivascular astrocytes in hippocampal capillaries and a thicker basement membrane in hippocampal veins. Saporin treatment induced a loss of cholinergic innervation at the arterial basement membrane and smooth muscle cells of both the hippocampus and the cortex. In the cortex, there was an additional loss of innervation at the astrocytic endfeet. The current results suggest that cortical arteries are more strongly affected by cholinergic denervation than arteries in the hippocampus. This regional variation may have implications for the etiology of the vascular pathology that develops in AD.


Generalization, similarity, and Bayesian inference.
Shepard has argued that a universal law should govern generalization across different domains of perception and cognition, as well as across organisms from different species or even different planets. Starting with some basic assumptions about natural kinds, he derived an exponential decay function as the form of the universal generalization gradient, which accords strikingly well with a wide range of empirical data. However, his original formulation applied only to the ideal case of generalization from a single encountered stimulus to a single novel stimulus, and for stimuli that can be represented as points in a continuous metric psychological space. Here we recast Shepard's theory in a more general Bayesian framework and show how this naturally extends his approach to the more realistic situation of generalizing from multiple consequential stimuli with arbitrary representational structure. Our framework also subsumes a version of Tversky's set-theoretic model of similarity, which is conventionally thought of as the primary alternative to Shepard's continuous metric space model of similarity and generalization. This unification allows us not only to draw deep parallels between the set-theoretic and spatial approaches, but also to significantly advance the explanatory power of set-theoretic models.


Surveillance for antimicrobial resistance profiles among Shigella species isolated from a semirural community in the northern administrative area of santiago, chile.
Variations in antibiotic resistance patterns were studied among 178 Shigella strains isolated from 1997 to 2001 in children less than five years of age with acute diarrhea from Colina, a semi-rural community in Santiago, Chile. The minimal inhibitory concentration of several commonly used antibiotics was determined by the agar dilution method. Shigella strains showed high rates of resistance to ampicillin (82%), cotrimoxazole (65%), tetracycline (53%), and chloramphenicol (49%). Furthermore, 51% of the strains showed resistance patterns to multiple antibiotics. Only 9% of the strains were resistant to amoxicillin-clavulanic acid and no resistance was observed to ciprofloxacin, nalidixic acid, or cefotaxime. Continuous monitoring of resistance patterns in Shigella is essential for establishing and updating guidelines for antibiotic treatment in shigellosis.


Using beryllium bonds to change halogen bonds from traditional to chlorine-shared to ion-pair bonds.
Ab initio MP2/aug'-cc-pVTZ calculations have been carried out to investigate the structures, binding energies, and bonding characteristics of binary complexes HFBe:FCl, R2Be:FCl, and FCl:N-base, and of ternary complexes HFBe:FCl:N-base and R2Be:FCl:N-base for R = H, F, Cl; N-base = NH3, NHCH2, NCH. Dramatic synergistic cooperative effects have been found between the Be···F beryllium bonds and the Cl···N halogen bonds in ternary complexes. The Cl···N traditional halogen bonds and the Be···F beryllium bonds in binary complexes become significantly stronger in ternary complexes, while the F-Cl bond weakens. Charge-transfer from F to the empty p(σ) orbital of Be leads to a bending of the XYBe molecule and a change in the hybridization of Be, which in the limit becomes sp(2). As a function of the intrinsic basicity of the nitrogen base and the intrinsic acidity of the Be derivative, the halogen-bond type evolves from traditional to chlorine-shared to ion-pair bonds. The mechanism by which an ion-pair complex is formed is similar to that involved in the dissociative proton attachment process. EOM-CCSD spin-spin coupling constants (1X)J(Cl-N) across the halogen bond in these complexes also provide evidence of the same evolution of the halogen-bond type.


Retinoic acid-induced glandular differentiation of the oesophagus.
Retinoic acid (RA) is a powerful differentiation agent. Barrett's oesophagus occurs when duodeno-gastro-oesophageal reflux causes squamous epithelium (SE) tissue to become columnar epithelium tissue by an unknown mechanism. The bile acid lithocholic acid (LCA) competes for the retinoid X receptor retinoid binding site. Hence, RA pathways may be implicated in Barrett's oesophagus. RA activity in tissues and cell lines treated with all-trans retinoic acid (ATRA) with or without LCA was assessed using a reporter. Expression of p21 was determined by real-time PCR in Barrett's oesophagus cell lines with or without LCA. SE and Barrett's oesophagus biopsy specimens were exposed to 100 muM of ATRA or 20 mM of a RA inhibitor, citral, in organ culture for >72 h. Characteristics of treated specimens, compared with untreated controls, were analysed by immunohistochemical analysis (cytokeratins (CKs), vimentin) and RT-PCR (CKs). Confocal microscopy assessed temporal changes in co-localisation of CK8/18 and vimentin. Cell proliferation was assessed by bromo-deoxyuridine incorporation and immunohistochemical analysis for Ki67 and p21. RA biosynthesis was increased in Barrett's oesophagus compared with SE (p<0.001). LCA and ATRA caused a synergistic increase in RA signalling as shown by increased p21 (p<0.01). Morphological and molecular analysis of SE exposed to ATRA showed columnar differentiation independent of proliferation. Metaplasia could be induced from the stromal compartment alone and vimentin expression co-localised with CK8/18 at 24 h, which separated into CK8/18-positive glands and vimentin-positive stroma by 48 h. Citral-treated Barrett's oesophagus led to phenotypic and immunohistochemical characteristics of SE, which was independent of proliferation. RA activity is increased in Barrett's oesophagus and is induced by LCA. Under conditions of altered RA activity and an intact stroma, the oesophageal phenotype can be altered independent of proliferation.


Caring for older people in the 21st century: 'notes from a small island'.
Drawing on carer narratives from research undertaken in New Zealand, this paper considers the interrelationship between place and the care-giving experience. In doing so, it considers: first, how informal carers of older people experience the transition in the place of care from the home to care homes; second, how they negotiate new identities for themselves as carers in these new care settings; and third, carers' views on how we might develop more inclusive models of care in care home settings. While much current work on care-giving in the home highlights the blurring of the boundaries between formal and informal care-giving, this paper suggests that the blurring of the boundaries of care may also be manifest in an increased penetration of informal care-giving within the semi-public space of the residential care home.


Tumour inflammasome-derived IL-1β recruits neutrophils and improves local recurrence-free survival in EBV-induced nasopharyngeal carcinoma.
Inflammasomes sense infection and cellular damage and are critical for triggering inflammation through IL-1β production. In carcinogenesis, inflammasomes may have contradictory roles through facilitating antitumour immunity and inducing oncogenic factors. Their function in cancer remains poorly characterized. Here we show that the NLRP3, AIM2 and RIG-I inflammasomes are overexpressed in Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC), and expression levels correlate with patient survival. In tumour cells, AIM2 and RIG-I are required for IL-1β induction by EBV genomic DNA and EBV-encoded small RNAs, respectively, while NLRP3 responds to extracellular ATP and reactive oxygen species. Irradiation and chemotherapy can further activate AIM2 and NLRP3, respectively. In mice, tumour-derived IL-1β inhibits tumour growth and enhances survival through host responses. Mechanistically, IL-1β-mediated anti-tumour effects depend on infiltrated immunostimulatory neutrophils. We show further that presence of tumour-associated neutrophils is significantly associated with better survival in NPC patients. Thus, tumour inflammasomes play a key role in tumour control by recruiting neutrophils, and their expression levels are favourable prognostic markers and promising therapeutic targets in patients.


Nonequilibrium molecular dynamics study of electric and low-frequency microwave fields on hen egg white lysozyme.
Nonequilibrium molecular dynamics simulations of various mutants of hen egg white lysozyme have been performed at 300 K and 1 bar in the presence of both external static electric and low-frequency microwave (2.45 GHz) fields of varying intensity. Significant nonthermal field effects were noted, such as marked changes in the protein's secondary structure relative to the zero-field state, depending on the field conditions, mutation, and orientation with respect to the applied field. This occurred primarily as a consequence of alignment of the protein's total dipole moment with the external field, although the dipolar alignment of water molecules in both the solvation layer and the bulk was also found to be influential. Substantial differences in behavior were found for proteins with and without overall net charges, particularly with respect to translational motion. Localized motion and perturbation of hydrogen bonds were also found to be evident for charged residues.


Introduction of guanidinium-modified deoxyuridine into the substrate binding regions of DNAzyme 10-23 to enhance target affinity: implications for DNAzyme design.
Deoxyribozymes (DNAzymes) are important catalysts for potential therapeutic RNA destruction and no DNAzyme has received as much notoriety in terms of therapeutic use as the Mg(2+)-dependent RNA-cleaving DNAzyme 10-23 (Dz10-23). As such, we have investigated the synthetic modification of Dz10-23 with a guanidinium group, a functionality that reduces the anionic nature and can potentially enhance the membrane permeability of oligonucleotides. To accomplish this, we synthesized a heretofore unknown phosphoramidite, 5-(N,N'-biscyanoethoxycarbonyl)-guanidinoallyl-2'-deoxyuridine and then incorporated it into oligonucleotides via solid phase synthesis to study duplex stability and its effect on Dz10-23. This particular modification was chosen as it had been used in the selection of Mg(2+)-free self-cleaving DNAzymes; as such this will enable the eventual comparison of modified DNAzymes that do or do not depend on Mg(2+) for catalysis. Consistent with antecedent studies that have incorporated guanidinium groups into DNA oligonucleotides, this guanidinium-modified deoxyuridine enhanced the thermal stability of resulting duplexes. Surprisingly however, Dz10-23, when synthesized with modified residues in the substrate binding regions, was found to be somewhat less active than its non-modified counterpart. This work suggests that this particular system exhibits uniform binding with respect to ground state and transition state and provides insight into the challenge of re-engineering a Mg(2+)-dependent DNAzyme with enhanced catalytic activity.


Combining evolutionary information and neural networks to predict protein secondary structure.
Using evolutionary information contained in multiple sequence alignments as input to neural networks, secondary structure can be predicted at significantly increased accuracy. Here, we extend our previous three-level system of neural networks by using additional input information derived from multiple alignments. Using a position-specific conservation weight as part of the input increases performance. Using the number of insertions and deletions reduces the tendency for overprediction and increases overall accuracy. Addition of the global amino acid content yields a further improvement, mainly in predicting structural class. The final network system has sustained overall accuracy of 71.6% in a multiple cross-validation test on 126 unique protein chains. A test on a new set of 124 recently solved protein structures that have no significant sequence similarity to the learning set confirms the high level of accuracy. The average cross-validated accuracy for all 250 sequence-unique chains is above 72%. Using various data sets, the method is compared to alternative prediction methods, some of which also use multiple alignments: the performance advantage of the network system is at least 6 percentage points in three-state accuracy. In addition, the network estimates secondary structure content from multiple sequence alignments about as well as circular dichroism spectroscopy on a single protein and classifies 75% of the 250 proteins correctly into one of four protein structural classes. Of particular practical importance is the definition of a position-specific reliability index. For 40% of all residues the method has a sustained three-state accuracy of 88%, as high as the overall average for homology modelling. A further strength of the method is greatly increased accuracy in predicting the placement of secondary structure segments.


Detection and phylogenetic characterisation of novel Anaplasma and Ehrlichia species in Amblyomma triguttatum subsp. from four allopatric populations in Australia.
Anaplasma and Ehrlichia spp. are tick-borne pathogens that can cause severe disease in domestic animals, and several species are responsible for emerging zoonoses in the northern hemisphere. Until recently, the only members of these genera reported in Australia (A. marginale, A. centrale, and A. platys) were introduced from other continents, through the importation of domestic animals and their associated ticks. However, unique Anaplasma and Ehrlichia 16S rRNA gene sequences were recently detected for the first time in native Australian ticks, particularly in Amblyomma triguttatum subsp. ticks from southwest Western Australia (WA). We used molecular techniques to survey Am. triguttatum subsp. ticks from four allopatric populations in southern and western Australia for Anaplasma and Ehrlichia species, and described here the phylogeny of these novel organisms. An A. bovis variant (genotype Y11) was detected in ticks from two study sites; Yanchep National Park (12/280, 4.3%) and Barrow Island (1/69, 1.4%). Phylogenetic analysis of 16S rRNA and groEL gene sequences concluded that A. bovis genotype Y11 is a unique genetic variant, distinct from other A. bovis isolates worldwide. Additionally, a novel Ehrlichia species was detected in Am. triguttatum subsp. from three of the four study sites; Yanchep National Park (18/280, 6.4%), Bungendore Park (8/46, 17.4%), and Innes National Park (9/214, 4.2%), but not from Barrow Island. Phylogenetic analysis of 16S, groEL, gltA, and map1 gene sequences revealed that this Ehrlichia sp. is most closely related to, but clearly distinct from, E. ruminantium and Ehrlichia sp. Panola Mountain. We propose to designate this new species 'Candidatus Ehrlichia occidentalis'. Anaplasma bovis genotype Y11 and 'Candidatus E. occidentalis' are the first Anaplasma and Ehrlichia species to be recorded in native Australian ticks.


Prevention and therapy of leg ischaemia in extracorporeal life support and extracorporeal membrane oxygenation with peripheral cannulation.
Extracorporeal membrane oxygenation (ECMO) and extracorporeal life support (ECLS) have been around for a long time, but it is only in recent years, with the advent of acute respiratory distress syndrome consecutive to influenza A (H1N1) infection, that these life-saving technologies have seen a broader application. Although the results of ECLS and ECMO are perceived as generally encouraging, there are still disturbing complications related to peripheral cannulation in general and, more specifically, to cannulation in the groin. The present review was designed to assess the magnitude of this latter problem, i.e. leg ischaemia related to ECLS and ECMO, in the literature and to identify strategies for possible therapies and, more importantly, prevention. The search strategy selected identified seven original articles with more than twenty patients, totalling 407 patients who underwent veno-arterial ECMO, and one large review dealing with all kinds of complications. For the original reports, the number of cases with veno-arterial support ranged from 21 to 143, with, as far as available, frequency of ischaemic complications between 11% and 52%, a reported range of surgical intervention between 9% and 22%, and a leg amputation rate from 2% to 10%. It appears that the number of reports dealing with lower extremity ischaemia during ECMO increases in parallel with the number of reports about ECMO. Strategies for early detection of peripheral ischaemia, interventions for efficient reperfusion, and measures for prevention including new concepts with smaller and eventually bidirectional arterial cannulas are discussed.


MMP-9 and CXCL8/IL-8 are potential therapeutic targets in epidermolysis bullosa simplex.
Epidermolysis bullosa refers to a group of genodermatoses that affects the integrity of epithelial layers, phenotypically resulting in severe skin blistering. Dowling-Meara, the major subtype of epidermolysis bullosa simplex, is inherited in an autosomal dominant manner and can be caused by mutations in either the keratin-5 (K5) or the keratin-14 (K14) gene. Currently, no therapeutic approach is known, and the main objective of this study was to identify novel therapeutic targets. We used microarray analysis, semi-quantitative real-time PCR, western blot and ELISA to identify differentially regulated genes in two K14 mutant cell lines carrying the mutations K14 R125P and K14 R125H, respectively. We found kallikrein-related peptidases and matrix metalloproteinases to be upregulated. We also found elevated expression of chemokines, and we observed deregulation of the Cdc42 pathway as well as aberrant expression of cytokeratins and junction proteins. We further demonstrated, that expression of these genes is dependent on interleukin-1 β signaling. To evaluate these data in vivo we analysed the blister fluids of epidermolysis bullosa simplex patients vs. healthy controls and identified matrix metalloproteinase-9 and the chemokine CXCL8/IL-8 as potential therapeutic targets.


HRE-type genes are regulated by growth-related changes in internal oxygen concentrations during the normal development of potato (Solanum tuberosum) tubers.
The occurrence of hypoxic conditions in plants not only represents a stress condition but is also associated with the normal development and growth of many organs, leading to adaptive changes in metabolism and growth to prevent internal anoxia. Internal oxygen concentrations decrease inside growing potato tubers, due to their active metabolism and increased resistance to gas diffusion as tubers grow. In the present work, we identified three hypoxia-responsive ERF (StHRE) genes whose expression is regulated by the gradual decrease in oxygen tensions that occur when potato tubers grow larger. Increasing the external oxygen concentration counteracted the modification of StHRE expression during tuber growth, supporting the idea that the actual oxygen levels inside the organs, rather than development itself, are responsible for the regulation of StHRE genes. We identified several sugar metabolism-related genes co-regulated with StHRE genes during tuber development and possibly involved in starch accumulation. All together, our data suggest a possible role for low oxygen in the regulation of sugar metabolism in the potato tuber, similar to what happens in storage tissues during seed development.


Peroxiredoxin-6--a potential protein marker for meat tenderness in bovine longissimus thoracis muscle.
The muscle sarcoplasmic proteins from bovine M. longissimus thoracis muscle were studied using proteomics to identify possible protein markers for meat tenderness. This study included 3 experiments: A1, A2, and B. From a collection of biopsies from the bovine M. longissimus thoracis muscle, excised 4 d before slaughter from 178 Norwegian Red young bulls, 26 biopsies were studied in Exp. A1. Based on Warner-Bratzler shear force (WBSF) values at 7 d postmortem, the biopsies were separated into a tender and a tough group of 13 bulls each and analyzed by 2-dimensional gel electrophoresis (2-DE) and Western blotting. The 2-DE experiments identified 4 different proteins: stress-70 protein, protein DJ-1, peroxiredoxin-6, and malate dehydrogenase, which were different in abundance in the tender and tough groups. However, only peroxiredoxin-6 was confirmed by quantification from Western blots. Peroxiredoxin-6 is an antioxidant enzyme that plays a role in protecting cells from oxidative stress. Peroxiredoxin-6 was identified through 3 spots of the same molecular weight, but with different pI on the Western blots. Only one of the spots was more abundant in the biopsies from the tender group. In Exp. A2, samples collected 1 h postmortem from the same animals and muscles as in Exp. A1 were analyzed by Western blotting. In these postmortem samples, the same spot from peroxiredoxin-6 as in Exp. A1 was more abundant in the tender group. In addition, one of the other peroxiredoxin-6 spots was also more abundant in the tender group. To verify the results from Exp. A, biopsies from 14 additional animals were analyzed in Exp. B by Western blotting against stress-70 protein, protein DJ-1, peroxiredoxin-6, and malate dehydrogenase. No significant differences between the tough and tender groups could be observed in these biopsies. However, for peroxiredoxin-6, the tendencies pointed in the same direction as in Exp. A. In conclusion, peroxiredoxin-6 might be a potential protein marker for meat tenderness detectable in biopsies and in samples collected shortly after slaughter. However, more animals are needed to verify the findings in the present study.


Broad-host-range Yersinia phage PY100: genome sequence, proteome analysis of virions, and DNA packaging strategy.
PY100 is a lytic bacteriophage with a broad host range within the genus Yersinia. The phage forms plaques on strains of the three human pathogenic species Yersinia enterocolitica, Y. pseudotuberculosis, and Y. pestis at 37 degrees C. PY100 was isolated from farm manure and intended to be used in phage therapy trials. PY100 has an icosahedral capsid containing double-stranded DNA and a contractile tail. The genome consists of 50,291 bp and is predicted to contain 93 open reading frames (ORFs). PY100 gene products were found to be homologous to the capsid proteins and proteins involved in DNA metabolism of the enterobacterial phage T1; PY100 tail proteins possess homologies to putative tail proteins of phage AaPhi23 of Actinobacillus actinomycetemcomitans. In a proteome analysis of virion particles, 15 proteins of the head and tail structures were identified by mass spectrometry. The putative gene product of ORF2 of PY100 shows significant homology to the gene 3 product (small terminase subunit) of Salmonella phage P22 that is involved in packaging of the concatemeric phage DNA. The packaging mechanism of PY100 was analyzed by hybridization and sequence analysis of DNA isolated from virion particles. Newly replicated PY100 DNA is cut initially at a pac recognition site, which is located in the coding region of ORF2.


Genetic similarity between adenoid tissue and middle ear fluid isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis from Iranian children with otitis media with effusion.
Otitis media with effusion (OME) is a common disease among children, in the pathogenesis of which bacterial infections play a critical role. It was suggested that adenoid tissue could serve as a reservoir for bacterial infection, the eustachian tubes being the migration routes of bacteria into the middle ear cavity. The aim of this study was to investigate the genetic similarity between isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, obtained from adenoid tissue and middle ear fluid. A total of 60 specimens of middle ear fluids (MEFs) and 45 specimens of adenoid tissue were obtained from 45 children with OME. All the samples were inoculated on culture media for bacterial isolation and identification. The genetic similarity between bacterial isolates was determined by pulsed-field gel electrophoresis (PFGE). The same bacterial species were simultaneously isolated from adenoid tissue and MEFs of 14 patients, among which, 6 pairs of M. catarrhalis, 5 pairs of S. pneumoniae and 3 pairs of H. influenzae were identified. Based on the genetic similarities between isolate pairs, found by PFGE analysis, this study suggested that M. catarrhalis, S. pneumoniae and H. influenzae colonize the adenoid tissue, then migrate to the middle ear cavity and, hence, contribute to the total pathogenesis of OME.


Coronary sinus pH during percutaneous transluminal coronary angioplasty: early development of acidosis during myocardial ischaemia in man.
Coronary sinus pH was measured continuously in eight patients undergoing angioplasty to the left anterior descending coronary artery. A catheter tip pH sensitive electrode with a response time of less than 300 ms and an output of greater than or equal to 57 mV/pH unit was placed high in the coronary sinus. Recordings were obtained during a total of 24 balloon occlusions of the left anterior descending coronary artery varying in duration from 5 to 45 s. Continuous 12 lead surface electrocardiograms were recorded. During or after balloon inflation of greater than or equal to 12 s (n = 4) there was no change in coronary sinus pH or the electrocardiogram. During balloon inflation of greater than or equal to 15 s (n = 20) coronary sinus pH was unaltered but between 4 and 6 s after balloon deflation coronary sinus pH fell transiently by between 0.010 and 0.120 pH units before returning to the control value within 65 s. Ischaemic changes were seen on the electrocardiogram during 15 balloon occlusions. In individual patients the peak fall in coronary sinus pH was related to the duration of occlusion of the left anterior descending coronary artery. A rise in coronary sinus pH (alkalosis) was never seen. In man acidosis occurs in the myocardium after short periods (greater than or equal to 12 s) of ischaemia. The fall of pH precedes ischaemic changes on the surface electrocardiogram and occurs concurrently with the earliest reported changes in contractile function.


Blood pressure, blood flow, and oxygenation in the clipped kidney of chronic 2-kidney, 1-clip rats: effects of tempol and Angiotensin blockade.
Angiotensin II maintains renal cortical blood flow and renal oxygenation in the clipped kidney of early 2-kidney, 1-clip Goldblatt hypertensive (2K,1C) rats. The involvement of Ang II is believed to decline, whereas oxidative stress increases during the progression of 2K,1C hypertension. We investigated the hypothesis that the acute administration of drugs to inhibit reactive oxygen species (Tempol), angiotensin II type 1 receptors (candesartan), or angiotensin-converting enzyme (enalaprilat) lowers mean arterial pressure and increases kidney blood flow and oxygenation in the clipped kidney of chronic 2K,1C rats in contrast to sham controls. Twelve months after left renal artery clipping or sham, mean arterial pressure, renal cortical blood flow, and renal cortical and medullary oxygen tension were measured after acute administration of Tempol followed by enalaprilat or candesartan followed by enalaprilat. The mean arterial pressure of the 2K,1C rat was reduced by candesartan (-9%) and, more effectively, by Tempol (-35%). All of the applied treatments had similar blood pressure-lowering effects in sham rats (average: -21%). Only Tempol increased cortical blood flow (+35%) and cortical and medullary oxygen tensions (+17% and +94%, respectively) in clipped kidneys of 2K,1C rats. Administration of enalaprilat had no additional effect, except for a modest reduction in cortical blood flow in the clipped kidney of 2K,1C rats when coadministered with candesartan (-10%). In conclusion, acute administration of Tempol is more effective than candesartan in reducing the mean arterial blood pressure and improving renal blood perfusion and oxygenation in the clipped kidney of chronic 2K,1C rats.


Adaptive omnivory and species coexistence in tri-trophic food webs.
The commonness of omnivory in natural communities is puzzling, because simple dynamic models of tri-trophic systems with omnivory are prone to species extinction. In particular, the intermediate consumer is frequently excluded by the omnivore at high levels of enrichment. It has been suggested that adaptive foraging by the omnivore may facilitate coexistence, because the intermediate consumer should persist more easily if it is occasionally dropped from the omnivore's diet. We explore theoretically how species permanence in tri-trophic systems is affected if the omnivore forages adaptively according to the "diet rule", i.e., feeds on the less profitable of its two prey species only if the more profitable one is sufficiently rare. We show that, compared to systems where omnivory is fixed, adaptive omnivory may indeed facilitate 3-species persistence. Counter to intuition, however, facilitation of 3-species coexistence requires that the intermediate consumer is a more profitable prey than the basal resource. Consequently, adaptive omnivory does not facilitate persistence of the intermediate consumer but enlarges the persistence region of the omnivore towards parameter space where a fixed omnivore would be excluded by the intermediate consumer. Overall, the positive effect of adaptive omnivory on 3-species persistence is, however, small. Generally, whether omnivory is fixed or adaptive, 3-species permanence is most likely when profitability (=conversion efficiency into omnivores) is low for basal resources and high for intermediate consumers.


ACGME Duty Hour Requirements: Perceptions and Impact on Resident Training and Patient Care.
In 2003, the Accreditation Council for Graduate Medical Education (ACGME) created national guidelines for resident work hours to promote safe care and high-quality learning. However, some reports suggested that the 2003 rules did not reduce resident fatigue or improve patient care. Since July 2011, further restrictions have been in effect. The changes have been the source of much controversy regarding their impact on resident education and patient safety. We reviewed existing literature on the effects of the new and old rules, with a focus on the field of orthopaedics. In addition, we conducted a national survey of orthopaedic residents and residency directors to assess the general opinions of the orthopaedic community. Overall, only 19.7% of all respondents were satisfied with the new 2011 regulations, whereas 58.9% believe the 80-hour work week averaged over 4 weeks is appropriate. The results will inform discussions and decisions related to changing residency education in the future.


Longitudinal model predicting partner violence among white, black, and Hispanic couples in the United States.
A limited amount of information pertaining to ethnic-specific risk factors associated with intimate partner violence across time currently exists. The current study examines ethnic-specific longitudinal predictors of male-to-female and female-to-male partner violence (MFPV and FMPV) in white, black, and Hispanic couples in the U.S. general population. In 1995, a total of 1635 married or cohabitating couples 18 years of age or older living in households in the 48 contiguous states participated in a national survey that used a multistage probability sampling procedure with 100 primary sampling units and included oversamples of blacks and Hispanics. In 2000, the follow-up survey had an overall response rate of 72% and included 406 white, 232 black, and 387 Hispanic intact couples.Ethnic-specific regression models predicting MFPV and FMPV at follow-up were developed. The risk factors of interest included male and female reports of history of childhood abuse, exposure to parental violence, impulsivity, alcohol problems, frequency of drinking five or more drinks per occasion, volume of alcohol consumed per week in average standard drinks, approval of marital aggression and male-to-female and female-to-male partner violence at baseline. MFPV and FMPV in 1995 and 2000 were based on the Conflict Tactics Scale Form R. Black and Hispanic couples were at approximately three times greater risk of MFPV and two times greater risk of FMPV at follow-up in comparison to white couples even after controlling for sociodemographic characteristics, alcohol consumption, and psychosocial variables. Extreme specific models indicated that among blacks, MFPV was a significant predictor of MFPV and FMPV at follow-up. In contrast, among Hispanics, FMPV was a significant predictor of FMPV and MFPV at follow-up. Ethnic-specific multivariate logistic regression models indicated that the predictors of MFPV and FMPV including psychosocial variables, alcohol use, and alcohol-related problems varied by ethnicity. These findings contribute to our continually growing knowledge base regarding ethnic differences associated with the development of intimate partner violence and have important implications for prevention and intervention.


Incidence of Heart Failure Observed in Emergency Departments, Ambulatory Clinics, and Hospitals.
Reports on the burden of heart failure (HF) have largely omitted HF diagnosed in outpatient settings. We quantified annual incidence rates ([IR] per 1,000 person years) of HF identified in ambulatory clinics, emergency departments (EDs), and during hospital stays in a national probability sample of Medicare beneficiaries from 2008 to 2014, by age and race/ethnicity. A 20% random sample of Medicare beneficiaries ages ≥65 years with continuous Medicare Parts A, B, and D coverage was used to estimate annual IRs of HF identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes. Of the 681,487 beneficiaries with incident HF from 2008 to 2014, 283,451 (41%) presented in ambulatory clinics, 76,919 (11%) in EDs, and 321,117 (47%) in hospitals. Overall, incidence of HF in ambulatory clinics decreased from 2008 (IR 22.2, 95% confidence interval [CI] 22.0, 22.4) to 2014 (IR 15.0, 95% CI 14.8, 15.1). Similarly, incidence of HF-related ED visits without an admission to the hospital decreased somewhat from 2008 (IR 5.5, 95% CI 5.4, 5.6) to 2012 (IR 4.2, 95% CI 4.1, 4.3) and stabilized from 2013 to 2014. Similar to previous reports, HF hospitalizations, both International Classification of Diseases, Ninth Revision, Clinical Modification code 428.x in the primary and any position, decreased over the study period. More than half of all new cases of HF in Medicare beneficiaries presented in an ambulatory clinic or ED. The overall incidence of HF decreased from 2008 to 2014, regardless of health-care setting. In conclusion, consideration of outpatient HF is warranted to better understand the burden of HF and its temporal trends.


Unique device identification system. Final rule.
The Food and Drug Administration (FDA) is issuing a final rule to establish a system to adequately identify devices through distribution and use. This rule requires the label of medical devices to include a unique device identifier (UDI), except where the rule provides for an exception or alternative placement. The labeler must submit product information concerning devices to FDA's Global Unique Device Identification Database (GUDID), unless subject to an exception or alternative. The system established by this rule requires the label and device package of each medical device to include a UDI and requires that each UDI be provided in a plain-text version and in a form that uses automatic identification and data capture (AIDC) technology. The UDI will be required to be directly marked on the device itself if the device is intended to be used more than once and intended to be reprocessed before each use.


Optimization of the signal-to-noise ratio of frequency-domain instrumentation for near-infrared spectro-imaging of the human brain.
Frequency-domain near-infrared spectro-imaging offers significant advantages over the continuous-wave method in human brain applications. However, the drawback of existing instruments is a low signal-to-noise ratio for measured phase and modulation depth changes caused by cerebral activation. In this paper we show that in the case of the geometry specific for the activated area in the human brain, the SNR can be significantly improved by increasing the modulation frequency. We present the results of two studies: one performed experimentally using a subnanosecond pulsed light source and a spherical absorbing inhomogeneity immersed in a highly scattering solution, and the other performed numerically using Monte Carlo simulations of light transport in an MRI based digital phantom of the adult human head. We show that changes caused by the absorbing inhomogeneity in both phase and modulation depth increase with frequency and reach maximum values at frequencies between 400 and 1400 MHz, depending on the particular source-detector distance. We also show that for the human head geometry an increase of the modulation frequency from 100 to 500 MHz can increase the phase SNR 2-3 times, and the modulation depth SNR up to 10 times.


Short-Term Plasticity in a Computational Model of the Tail-Withdrawal Circuit in Aplysia.
The tail-withdrawal circuit of Aplysia provides a useful model system for investigating synaptic dynamics. Sensory neurons within the circuit manifest several forms of synaptic plasticity. Here, we developed a model of the circuit and investigated the ways in which depression (DEP) and potentiation (POT) contributed to information processing. DEP limited the amount of motor neuron activity that could be elicited by the monosynaptic pathway alone. POT within the monosynaptic pathway did not compensate for DEP. There was, however, a synergistic interaction between POT and the polysynaptic pathway. This synergism extended the dynamic range of the network, and the interplay between DEP and POT made the circuit responded preferentially to long-duration, low-frequency inputs.


Studies on the effect of solvents on self-assembled monolayers formed from organophosphonic acids on indium tin oxide.
The preparation of self-assembled monolayers (SAMs) of organophosphonic acids on indium tin oxide (ITO) surfaces from different solvents (triethylamine, ethyl ether, tetrahydofuran (THF), pyridine, acetone, methanol, acetonitrile, dimethyl sulfoxide (DMSO), or water) has been performed with some significant differences observed. Cyclic voltammetry (CV), X-ray photoelectron spectroscopy (XPS), scanning tunneling microscopy (STM), and contact angle measurement demonstrated that the quality of SAMs depends critically on the choice of solvents. Higher density, more stable monolayers were formed from solvents with low dielectric constants and weak interactions with the ITO. It was concluded low dielectric solvents that were inert to the ITO gave monolayers that were more stable with a higher density of surface bound molecules because higher dielectric constant solvents and solvents that coordinate with the surface disrupted SAM formation.


Partnering with Private Providers to Promote Long-Acting Contraceptives in Urban Bangladesh: A Mixed-Methods Feasibility Study.
Bangladesh's pluralistic health system has diversified opportunities for clients to obtain family planning, but public-private partnerships could improve access to services, particularly in urban areas. Sixteen providers, clients and program managers were interviewed to assess perspectives on a family planning orientation and demand-side financing referral program tested in Mirpur, Bangladesh. The 15-month program, conducted in 2015-2016, was designed to encourage private providers to identify non-family planning clients with unmet contraceptive needs, promote choice of a broader contraceptive mix and refer clients to one of three public or nonprofit clinics for provision of their preferred method. Use of the system was assessed by tracking referral slips. Most stakeholders reported that it was acceptable and feasible to discuss fertility intentions with clients presenting for non-family planning matters. Providers were able to alleviate clients' misconceptions and fears concerning long-acting contraceptive methods, but were unable to address patriarchal and religious barriers. The majority of referrals were done by private providers who had a pre-existing relationship with one of the family planning clinics and referred clients to that clinic; overall, documented referrals accounted for 13% of provision of reversible and permanent methods at that clinic during the study period. Providing private practitioners with appropriate training on contraceptives and referral could improve Bangladeshi women's access to long-acting and other contraceptive methods in urban areas, and may be useful for other types of health workers. Further study of suitable referral systems is warranted.


The partial dehydrogenation of aluminium dihydrides.
The reactions of a series of β-diketiminate stabilised aluminium dihydrides with ruthenium bis(phosphine), palladium bis(phosphine) and palladium cyclopentadienyl complexes is reported. In the case of ruthenium, alane coordination occurs with no evidence for hydrogen loss resulting in the formation of ruthenium complexes with a pseudo-octahedral geometry and cis-relation of phosphine ligands. These new ruthenium complexes have been characterised by multinuclear and variable temperature NMR spectroscopy, IR spectroscopy and single crystal X-ray diffraction. In the case of palladium, a series of structural snapshots of alane dehydrogenation have been isolated and crystallographically characterised. Variation of the palladium precursor and ligand on aluminium allows kinetic control over reactivity and isolation of intermetallic complexes that contain new Pd-Al and Pd-Pd interactions. These complexes differ by the ratio of H : Al (2 : 1, 1.5 : 1 and 1 : 1) with lower hydride content species forming with dihydrogen loss. A combination of X-ray and neutron diffraction studies have been used to interrogate the structures and provide confidence in the assignment of the number and position of hydride ligands. 27Al MAS NMR spectroscopy and calculations (DFT, QTAIM) have been used to gain an understanding of the dehydrogenation processes. The latter provide evidence for dehydrogenation being accompanied by metal-metal bond formation and an increased negative charge on Al due to the covalency of the new metal-metal bonds. To the best of our knowledge, we present the first structural information for intermediate species in alane dehydrogenation including a rare neutron diffraction study of a palladium-aluminium hydride complex. Furthermore, as part of these studies we have obtained the first SS 27Al NMR data on an aluminium(i) complex. Our findings are relevant to hydrogen storage, materials chemistry and catalysis.


Isoprostane-induced airway hyperresponsiveness is dependent on internal Ca2+ handling and Rho/ROCK signaling.
We previously reported the ability of isoprostanes to induce airway hyperresponsiveness (AHR). In this study, we examined the signaling mechanisms underlying that phenomenon with the standard muscle bath technique. Responses to a threshold concentration of carbachol (CCh, 3 x 10(-9) M) were significantly augmented by pretreatment for 20 min with 8-isoprostaglandin E(2) (15-E(2t)-IsoP, 10(-6) M): this AHR was obliterated in tissues pretreated with the selective Rho kinase (ROCK) inhibitor Y-27632 added 20 min before isoprostane, but not by cyclopiazonic acid (CPA). Increasing the CCh concentration to 3 x 10(-8) M (still considerably less than the half-maximally effective concentration of CCh) evoked larger contractions that were also augmented significantly by 15-E(2t)-IsoP: this AHR was completely abolished in tissues pretreated with CPA as well as those pretreated with Y-27632. We noted, however, that Y-27632 and CPA profoundly effect baseline tone and the cholinergic response per se, which confounds the interpretation of the data summarized above. We therefore modified the protocol by using combinations of CCh and blocker (CPA, Y-27632, or nifedipine) that were equieffective. In this way, we found that AHR could not be demonstrated under conditions in which Rho/ROCK signaling or Ca(2+) release was abolished (by Y-27632 and CPA, respectively). Likewise, other autacoids that act through G protein-coupled receptors via Rho/ROCK and Ca(2+) release (serotonin, histamine) mimicked this effect of isoprostane, whereas bradykinin did not. We conclude that isoprostane-induced AHR is mediated in part through an action on Rho/ROCK signaling. This novel finding may contribute to a better understanding of the mechanisms underlying AHR and asthma.


Morphometry of the amusic brain: a two-site study.
Congenital amusia (or tone deafness) is a lifelong disability that prevents otherwise normal-functioning individuals from developing basic musical skills. Behavioural evidence indicates that congenital amusia is due to a severe deficit in pitch processing, but very little is known about the neural correlates of this condition. The objective of the present study was to investigate the structural neural correlates of congenital amusia. To this aim, voxel-based morphometry was used to detect brain anatomical differences in amusic individuals relative to musically intact controls, by analysing T1-weighted magnetic resonance images from two independent samples of subjects. The results were consistent across samples in highlighting a reduction in white matter concentration in the right inferior frontal gyrus of amusic individuals. This anatomical anomaly was correlated with performance on pitch-based musical tasks. The results are consistent with neuroimaging findings implicating right inferior frontal regions in musical pitch encoding and melodic pitch memory. We conceive the present results as a consequence of an impoverished communication in a right-hemisphere-based network involving the inferior frontal cortex and the right auditory cortex. Moreover, the data point to the integrity of white matter tracts in right frontal brain areas as being key in acquiring normal musical competence.


Descriptive Epidemiology of Adolescent Clavicle Fractures: Results From the FACTS (Function after Adolescent Clavicle Trauma and Surgery) Prospective, Multicenter Cohort Study.
The majority of previous investigations on operative fixation of clavicle fractures have been related to the adult population, with occasional assessments of the younger, more commonly affected adolescent population. Despite limited prospective data for adolescents, the incidence of operative fixation of adolescent diaphyseal clavicle fractures has increased. To detail the demographic features and descriptive epidemiology of a large pooled cohort of adolescent patients with diaphyseal clavicle fractures presenting to pediatric tertiary care centers in the United States through an observational, prospective, multicenter cohort study (Function after Adolescent Clavicle Trauma and Surgery [FACTS]). Cross-sectional study; Level of evidence, 4. Patients aged 10 to 18 years who were treated for a diaphyseal clavicle fracture between August 2013 and February 2016 at 1 of 8 geographically diverse, high-volume, tertiary care pediatric centers were screened. Treatment was rendered by any of the pediatric orthopaedic providers at each of the 8 institutions, which totaled more than 50 different providers. Age, sex, race, ethnicity, fracture laterality, hand dominance, mechanism of injury, injury activity, athletic participation, fracture characteristics, and treatment decisions were prospectively recorded in those who were eligible and consented to enroll. A total of 545 patients were included in the cohort. The mean age of the study population was 14.1 ± 2.1 years, and 79% were male. Fractures occurred on the nondominant side (56%) more frequently than the dominant side (44%). Sport was the predominant activity during which the injury occurred (66%), followed by horseplay (12%) and biking (6%). The primary mechanism of injury was a direct blow/hit to the shoulder (60%). Overall, 54% were completely displaced fractures, defined as fractures with no anatomic cortical contact between fragments. Mean shortening within the completely displaced group was 21.9 mm when measuring the distance between fragment ends (end to end) and 12.4 mm when measuring the distance between the fragment end to the corresponding cortical defect (cortex to corresponding cortex) on the other fragment (ie, true shortening). Comminution was present in 18% of all fractures. While 83% of all clavicle fractures were treated nonoperatively, 32% of completely displaced fractures underwent open reduction and internal fixation. Adolescent clavicle fractures occurred more commonly in male patients during sports, secondary to a direct blow to the shoulder, and on the nondominant side. Slightly more than half of these fractures were completely displaced, and approximately one-fifth were comminuted. Within this large cohort, approximately one-third of patients with completely displaced fractures underwent surgery, allowing for future prospective comparative analyses of radiographic, clinical, and functional outcomes.


Design of dual drug-loaded dendrimer/carbon dot nanohybrids for fluorescence imaging and enhanced chemotherapy of cancer cells.
Design of powerful nanosystems to overcome multidrug resistance (MDR) for effective chemotherapy of cancer currently remains a great challenge. Herein, we report the development of a poly(amidoamine) (PAMAM) dendrimer/carbon dot nanohybrid for dual drug loading to overcome MDR and simultaneously monitor cancer cells via fluorescence imaging. First, blue-emitting carbon dots (CDs) were synthesized using sodium citrate as a carbon source via the hydrothermal method and used as a carrier to load the anticancer drug doxorubicin (DOX) through non-covalent interactions, thus forming CDs/DOX complexes. In parallel, PAMAM dendrimers of generation 5 (G5) were covalently modified by the targeting ligand cyclic arginine-glycine-aspartic (RGD) peptide and the drug efflux inhibitor d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). Then, through electrostatic interaction, functional dendrimers (G5-RGD-TPGS) were complexed with CDs/DOX complexes to form a dual drug-loaded nanohybrid system. The dual drug-loaded dendrimer/CD nanohybrids were well characterized. We showed that the nanohybrids possessed good colloidal stability and enabled significant inhibition of cancer cells due to the presence of TPGS, which can inhibit P-glycoprotein (P-gp) by decreasing ATP levels and increasing ROS levels; simultaneously, fluorescence imaging of cancer cells could be achieved in vitro due to the luminescence of CDs. In addition, the attached RGD ligands rendered the nanohybrid with targeting specificity to cancer cells expressing αvβ3 integrin receptors. The developed dual drug-loaded dendrimer/CD nanohybrid may be used as a promising theranostic platform to overcome MDR for enhanced chemotherapy as well as for fluorescence imaging of cancer cells.


Environmental and Psychophysical Heat Stress in Adolescent Tennis Athletes.
We investigated the environmental conditions in which all outdoor International Tennis Federation (ITF) junior tournaments (athlete ages: <18 y) were held during 2010-2019. Thereafter, we performed a crossover trial (ClinicalTrials.gov: NCT04197375) assessing the efficacy of head-neck precooling for mitigating the heat-induced psychophysical and performance impacts on junior athletes during tennis match play. ITF junior tournament information was collected. We identified meteorological data from nearby (13.6 [20.3] km) weather stations for 3056 (76%) tournaments. Overall, 30.1% of tournaments were held in hot (25°C-30°C wet-bulb globe temperature [WBGT]; 25.9%), very hot (30°C-35°C WBGT; 4.1%), or extremely hot (>35°C WBGT; 0.1%) conditions. Thereafter, 8 acclimatized male junior tennis athletes (age = 16.0 [0.9] y; height = 1.82 [0.04] m; weight = 71.3 [11.1] kg) were evaluated during 2 matches: one with head-neck precooling (27.7°C [2.2°C] WBGT) and one without (27.9°C [1.8°C] WBGT). Head-neck precooling reduced athletes' core temperature from 36.9°C (0.2°C) to 36.4°C (0.2°C) (P = .001; d = 2.4), an effect reduced by warm-up. Head-neck precooling reduced skin temperature (by 0.3°C [1.3°C]) for the majority of the match and led to improved (P < .05) perceived exertion (by 13%), thermal comfort (by 14%), and thermal sensation (by 15%). Muscle temperature, heart rate, body weight, and urine specific gravity remained unaffected (P ≥ .05; d < 0.2). Small or moderate improvements were observed in most performance parameters assessed (d = 0.20-0.79). Thirty percent of the last decade's ITF junior tournaments were held in hot, very hot, or extremely hot conditions (25°C-36°C WBGT). In such conditions, head-neck precooling may somewhat lessen the physiological and perceptual heat strain and lead to small to moderate improvements in the match-play performance of adolescent athletes.


Close structural resemblance between putative polymerase of a Drosophila transposable genetic element 17.6 and pol gene product of Moloney murine leukaemia virus.
We have made a computer-assisted search for homology among polymerases or putative polymerases of various viruses and a transposable element, the Drosophila copia-like element 17.6. The search revealed that the putative polymerase (second open reading frame) of the copia-like element 17.6 bears close resemblance in overall structural organization to the pol gene product of Moloney murine leukaemia virus (M-MuLV): they show significant homology to each other at both the N- and C-terminal portions, suggesting that the 17.6 putative polymerase carries two enzymatic activities, related to reverse transcriptase and DNA endonuclease. The putative polymerase of cauliflower mosaic virus (CaMV) shows striking homology with the putative polymerase of 17.6 over almost its entire length, but it lacks the DNA endonuclease-related sequence. Furthermore, it was shown that the N-terminal ends of the M-MuLV pol product and the CaMV and 17.6 putative polymerases exhibit strong sequence homology with the gag-specific protease (p15) of Rous sarcoma virus (RSV) as well as the amino acid sequence predicted from the gag/pol spacer sequence of human adult T-cell leukaemia virus (HTLV). These p15-related sequences contain a highly conserved stretch of amino acids which show a close similarity with sequences around the active site amino acids Asp-Thr-Gly of the acid protease family, suggesting that they have an activity similar to acid protease. On the basis of the alignment of reverse transcriptase-related sequences, a dendrogram representing phylogenetic relationships among all the viruses compared together with 17.6 was constructed and its evolutionary implication is discussed.


Acetate production from lactose by Clostridium thermolacticum and hydrogen-scavenging microorganisms in continuous culture--effect of hydrogen partial pressure.
The effect of the addition of hydrogen-consuming microorganisms on the metabolism of Clostridium thermolacticum was studied. By growing this bacterium in continuous culture at 58 degrees C, on 29 mmol lactose l(-1) (10 gl(-1)) in the feed, with the H2-consuming microorganisms Methanothermobacter thermoautotrophicus and Moorella thermoautotrophica, the volumetric productivity of acetate was increased up to 3.9 mmol l(-1)h(-1) at a dilution rate of 0.058 h(-1). This was about three times higher than the maximal acetate volumetric productivity quantified when C. thermolacticum was cultivated alone. In the consortium, C. thermolacticum was the only species able to metabolize lactose; it produced not only acetate, but also hydrogen, carbon dioxide and lactate. The other species of the consortium were growing on these by-products. Meth. thermoautotrophicus played an important role as a very efficient hydrogen scavenger and decreased the hydrogen partial pressure drastically: hydrogen was converted to methane. Moor. thermoautotrophica converted lactate as well as hydrogen and carbon dioxide into acetate. As a consequence, lactose was efficiently consumed and the only organic product in the liquid phase was acetate.


Paleomagnetism. Solar nebula magnetic fields recorded in the Semarkona meteorite.
Magnetic fields are proposed to have played a critical role in some of the most enigmatic processes of planetary formation by mediating the rapid accretion of disk material onto the central star and the formation of the first solids. However, there have been no experimental constraints on the intensity of these fields. Here we show that dusty olivine-bearing chondrules from the Semarkona meteorite were magnetized in a nebular field of 54 ± 21 microteslas. This intensity supports chondrule formation by nebular shocks or planetesimal collisions rather than by electric currents, the x-wind, or other mechanisms near the Sun. This implies that background magnetic fields in the terrestrial planet-forming region were likely 5 to 54 microteslas, which is sufficient to account for measured rates of mass and angular momentum transport in protoplanetary disks.


Polymicrobial Amniotic Fluid Infection with Mycoplasma/Ureaplasma and Other Bacteria Induces Severe Intra-Amniotic Inflammation Associated with Poor Perinatal Prognosis in Preterm Labor.
To study the relationship between perinatal prognosis in cases of preterm labor (PTL) and polymicrobial infection in amniotic fluid (AF) and intra-amniotic (IA) inflammation using a highly sensitive and reliable PCR-based method. To detect prokaryotes using a nested PCR-based method, eukaryote-made thermostable DNA polymerase without bacterial DNA contamination was used in combination with bacterial universal primers. We collected AF aseptically from 118 PTL cases and 50 term subjects. The prevalence of microorganisms was 33% (39/118) by PCR and only 7.6% (9/118) by culture. PTL caused by a combination of positive Mycoplasma/Ureaplasma and other bacteria had significantly higher AF IL-8 levels and a significantly shorter amniocentesis-to-delivery interval. Our newly established PCR method is useful for detecting IA microorganisms. Polymicrobial infection with Mycoplasma/Ureaplasma and other bacteria induces severe IA inflammation associated with poor perinatal prognosis in PTL.


A weighted angiographic scoring model (W-CTO score) to predict success of antegrade wire crossing in chronic total occlusion: analysis from a single centre.
The aim of this study was to derive a weighted score model predicting success/failure of antegrade wire crossing in chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Four hundred and four consecutive CTO cases (408 lesions) undergoing CTO-PCI between January 2009 and March 2015 were included. Data were divided into two sets, namely "derivation" and "validation", in a 70:30 ratio. The score was derived using multivariate analysis to identify independent predictors of wire crossing failure from the derivation set (n=285 lesions) and validated on the remaining 123 lesions (validation set). The overall procedural success rate was 83.6%. Independent predictors of CTO-PCI failure and their contribution to the weighted score were a blunt stump (beta coefficient 2.12), length of occlusion >20 mm (beta coefficient 1.71), presence of calcification (beta coefficient 0.72), presence of tortuosity (beta coefficient 1.06) and collateral with Rentrop grade <2 (beta coefficient 1.06). The respective scores allotted were +2.0, +1.5, +1, +1, +1 (total 6.5), rounding the coefficient to the nearest 0.5. Score values of 0-2, >2-4 and >4 were classified as low, intermediate and high levels of difficulty for CTO-PCI success and were associated with 98%, 74.2%, and 42.5% (p<0.0001), respectively, of antegrade wire crossing success in the derivation set. This was also validated on the validation set with CTO success in the three derived difficulty levels being 100%, 82.4% and 48.4%, respectively. Our weighted angiographic CTO score is a strong predictor of final antegrade wire crossing success and could be used in day-to-day clinical practice of CTO interventions.


Transfer learning enables the molecular transformer to predict regio- and stereoselective reactions on carbohydrates.
Organic synthesis methodology enables the synthesis of complex molecules and materials used in all fields of science and technology and represents a vast body of accumulated knowledge optimally suited for deep learning. While most organic reactions involve distinct functional groups and can readily be learned by deep learning models and chemists alike, regio- and stereoselective transformations are more challenging because their outcome also depends on functional group surroundings. Here, we challenge the Molecular Transformer model to predict reactions on carbohydrates where regio- and stereoselectivity are notoriously difficult to predict. We show that transfer learning of the general patent reaction model with a small set of carbohydrate reactions produces a specialized model returning predictions for carbohydrate reactions with remarkable accuracy. We validate these predictions experimentally with the synthesis of a lipid-linked oligosaccharide involving regioselective protections and stereoselective glycosylations. The transfer learning approach should be applicable to any reaction class of interest.


Attenuated total reflection (ATR) Fourier transform infrared (FT-IR) spectroscopy of oxidized polymer-modified bitumens.
Oxidative age hardening of bitumen results in increasing fatigue susceptibility of bituminous mixtures, thus reducing the service life of asphalt pavements. Polymer additives to bitumen have been shown to improve its viscoelastic properties and, in some cases, reduce the level of bitumen hardening. Fourier transform infrared (FT-IR) spectroscopy enables evaluation of oxidation levels in bitumen by measuring the concentration of oxygen-containing chemical functionalities. This paper summarizes the results of the investigation of oxidative age hardening of polymer-modified bitumens (PMB) caused by accelerated aging in laboratory conditions. The PMB samples are prepared with different concentrations of styrene-butadiene-based co-polymers. Next, the PMB samples are aged using standard procedures that employ air blowing at 163 °C for 85 min followed by conditioning the samples at 100 °C and 2.1 MPa pressure for 20 to 48 hours. The resultant changes in their chemical composition are evaluated by portable attenuated total reflection (ATR) spectrometer. Measurements of ketone, sulfoxide, and hydroxyl content in PMB samples indicated similar oxidation pathways to those of non-modified bitumens. In addition, no evidence of polymer degradation due to accelerated aging of PMB was found in this study.


Juvenile probation officers' evaluation of traumatic event exposures and traumatic stress symptoms as responsivity factors in risk assessment and case planning.
Juvenile probation officers (JPOs) are increasingly using risk/needs assessments to evaluate delinquency risk, identify criminogenic needs and specific responsivity factors, and use this information in case planning. Justice-involved youth are exposed to traumatic events and experience traumatic stress symptoms at a high rate; such information warrants attention during the case planning process. The extent to which JPOs identify specific responsivity factors, in general, and trauma history, specifically, when scoring risk/need assessments is understudied. In the current study, 147 JPOs reviewed case vignettes that varied by the adolescents' gender (male vs. female), traumatic event exposure (present vs. absent), and traumatic stress symptoms (present vs. absent), and then scored the YLS/CMI and developed case plans based on that information. JPOs who received a vignette that included trauma information identified a higher number of trauma-specific responsivity factors on the YLS/CMI. Despite an overall high needs match ratio (57.2%), few JPOs prioritized trauma as a target on case plans. The findings underscore the importance of incorporating trauma screening into risk/needs assessment and case planning. (PsycINFO Database Record


SCADA data and the quantification of hazardous events for QMRA.
The objective of this study was to assess the use of on-line monitoring to support the QMRA at water treatment plants studied in the EU MicroRisk project. SCADA data were obtained from three Catchment-to-Tap Systems (CTS) along with system descriptions, diary records, grab sample data and deviation reports. Particular attention was paid to estimating hazardous event frequency, duration and magnitude. Using Shewart and CUSUM we identified 'change-points' corresponding to events of between 10 min and >1 month duration in timeseries data. Our analysis confirmed it is possible to quantify hazardous event durations from turbidity, chlorine residual and pH records and distinguish them from non-hazardous variability in the timeseries dataset. The durations of most 'events' were short-term (0.5-2.3 h). These data were combined with QMRA to estimate pathogen infection risk arising from such events as chlorination failure. While analysis of SCADA data alone could identify events provisionally, its interpretation was severely constrained in the absence of diary records and other system information. SCADA data analysis should only complement traditional water sampling, rather than replace it. More work on on-line data management, quality control and interpretation is needed before it can be used routinely for event characterization.


International comparability of reference unit costs of education services: when harmonizing methodology is not enough (PECUNIA project).
Health problems can lead to costs in the education sector. However, these costs are rarely incorporated in health economic evaluations due to the lack of reference unit costs (RUCs), cost per unit of service, of education services and of validated methods to obtain them. In this study, a standardized unit cost calculation tool developed in the PECUNIA project, the PECUNIA RUC Template for services, was applied to calculate the RUCs of selected education services in five European countries. The RUCs of special education services and of educational therapy were calculated using the information collected via an exploratory gray literature search and contact with service providers. The RUCs of special education services ranged from €55 to €189 per school day. The RUCs of educational therapy ranged from €6 to €25 per contact and from €5 to €35 per day. Variation was observed in the type of input data and measurement unit, among other. The tool helped reduce variability in the RUCs related to costing methodology and gain insights into other aspects that contribute to the variability (e.g. data availability). Further research and efforts to generate high quality input data are required to reduce the variability of the RUCs.


Safety and Efficacy of Budesonide Oral Suspension Maintenance Therapy in Patients With Eosinophilic Esophagitis.
We aimed to determine the safety and efficacy of budesonide oral suspension (BOS) maintenance therapy in patients with eosinophilic esophagitis (EoE). We performed an open-label extension study of a 12-week, multicenter, randomized, double-blind, placebo-controlled trial. Patients with EoE (11-40 years old) who completed double-blind BOS (n = 45) or placebo therapy (n = 37) received 24 weeks' open-label BOS (2.0 mg once daily for 12 weeks, with optional dose increase [1.5-2.0 mg twice daily] for 12 weeks thereafter). Predefined efficacy outcomes included: proportion of patients with a histologic response (≤6 eosinophils/high-power field [eos/hpf]) and change in mean peak eosinophil counts after 24 weeks. Analyses were stratified by patients who received placebo (placebo/BOS) or BOS (BOS/BOS) during the double-blind trial. BOS was well tolerated and drug-related adverse events were uncommon (placebo/BOS, 19% [7/37]; BOS/BOS, 4% [2/45]). Incidence of oral candidiasis (1 per group) and esophageal candidiasis (placebo/BOS group, n = 4) remained low. Changes in morning serum cortisol levels were not clinically relevant. A histologic response was observed in 49% (16/33) of patients receiving placebo/BOS and 23% (9/39) receiving BOS/BOS. Mean peak eosinophil counts (baseline vs week 24 or early termination) were: placebo/BOS, 118.8 vs 29.1; P < .001 and BOS/BOS, 38.1 vs 72.4; P = .01. Of the patients who responded to double-blind therapy, 42% maintained a histologic response during the open-label extension; 4% of nonresponders gained response. In an open-label extension study of patients with EoE, BOS was well tolerated and drug-related adverse events were uncommon. BOS maintained a histologic response in some initial responders, but few initial nonresponders had a response. ClinicalTrials.gov no: NCT01642212.


Social factors and overweight: evidence from nine Asian INDEPTH Network sites.
Overweight/obesity increases the risk of morbidity and mortality from a number of chronic conditions, including heart disease, stroke, diabetes and some cancers. This study examined the distribution of body mass index (BMI) in nine Health and Demographic Surveillance System (HDSS) sites in five Asian countries and investigated the association between social factors and overweight. This cross-sectional study was conducted in nine HDSS sites in Bangladesh, India, Indonesia, Thailand and Vietnam. The methodology of the WHO STEPwise approach to Surveillance with core risk factors (Step 1) and physical measurements for weight, height and waist circumference (Step 2) were included. In each site, about 2,000 men and women aged 25-64 years were selected randomly using the HDSS database. Weight was measured using electronic scales, height was measured by portable stadiometers and waist circumference was measured by measuring tape. Overweight/obesity was assessed by BMI defined as the weight in kilograms divided by the square of the height in metres (kg/m(2)). At least 10% people were overweight (BMI >/= 25) in each site except for the two sites in Vietnam and WATCH HDSS in Bangladesh where few men and women were overweight. After controlling for all the variables in the model, overweight increases with age initially and then declines, with increasing education, and with gender with women being heavier than men. People who eat vegetables and fruits below the recommended level and those who do high level of physical activity are, on the whole, less heavy than those who eat more and do less physical activity. As the proportion of the population classified as being overweight is likely to increase in most sites and overweight varies by age, sex, and social and behavioural factors, behavioural interventions (physical exercise, healthy diet) should be developed for the whole population together with attention to policy around nutrition and the environment, in order to reduce the adverse effects of overweight on health.


Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype.
Triple-negative breast cancer (TNBC) is an aggressive subtype with no targeted therapeutics. The luminal androgen receptor (LAR) subtype constitutes 15% of TNBC and is enriched for androgen receptor (AR) and AR target genes. Here, we show that a cohort of TNBC not only expresses AR at a much higher rate (∼80%) but also expresses AR splice variants (AR-SVs) (∼20%), further subclassifying LAR-TNBC. Higher AR and AR-SV expression and corresponding aggressive phenotypes are observed predominantly in specimens obtained from African American women. LAR TNBC specimens are enriched for interferon, Janus kinase (JAK)-signal activator and transducer (STAT), and androgen signaling pathways, which are exclusive to AR-expressing epithelial cancer cells. AR- and AR-SV-expressing TNBC cell proliferation and xenograft and patient-tumor explant growth are inhibited by AR N-terminal domain-binding selective AR degrader or by a JAK inhibitor. Biochemical analysis suggests that STAT1 is an AR coactivator. Collectively, our work identifies pharmacologically targetable TNBC subtypes and identifies growth-promoting interaction between AR and JAK-STAT signaling.


Patient-centered, direct-access online care for management of atopic dermatitis: a randomized clinical trial.
New models of health care delivery for dermatological care have the potential to increase access and improve patient-centered outcomes. To compare effectiveness of a direct-access, online model for follow-up dermatologic care in pediatric and adult patients with atopic dermatitis with that of in-person office visits. This was a 1-year, randomized controlled equivalency clinical trial in medically underserved areas, outpatient clinics, and the general community. Participants included children and adults with atopic dermatitis with access to the Internet, computers, and digital cameras. After an initial in-person visit, patients were randomized 1:1 to direct-access online or usual in-person care for follow-up management of atopic dermatitis. In the direct-access online group, patients captured and transmitted clinical images and history asynchronously to dermatologists online; dermatologists evaluated the clinical information, provided recommendations and education, and prescribed medications online asynchronously. In the in-person group, patients visited dermatologists in their offices for follow-up care. Atopic dermatitis disease severity as assessed by patient-oriented eczema measure (POEM) and investigator global assessment (IGA). A total of 156 children and adults were randomized. Between baseline and 12 months, the mean (SD) within-group difference in POEM score in patients in the direct-access online group was -5.1 (5.48) (95% CI, -6.32 to -3.88); in the in-person group, the within-group difference was -4.86 (4.87) (95% CI, -6.27 to -3.46). The difference in the change in POEM scores between the 2 groups was 0.24 (6.59) (90% CI, -1.70 to 1.23), which was contained within the predetermined 2.5 equivalence margin. The percentage of patients achieving clearance or near-clearance of their disease (IGA score of 0 or 1) was 38.4% (95% CI, 27.7% to 49.3%) in the direct-access online group and 43.6% (95% CI, 32.6%-54.6%) in the in-person group. The difference in the percent of patients achieving clearance or near-clearance between the 2 groups was 5.1% (90% CI, 1.7%-8.6%), which was contained within the predetermined 10% equivalence margin. The direct-access online model results in equivalent improvements in atopic dermatitis clinical outcomes as in-person care. Direct-access online care may represent an innovative model of delivering dermatological services to patients with chronic skin diseases. clinicaltrials.gov Identifier: NCT00985894.


Targeted alpha therapy with 212Pb or 225Ac: Change in RBE from daughter migration.
Targeted α-therapy (TAT) could be delivered early to patients who are at a high-risk for developing brain metastases, targeting the areas of the vasculature where tumor cells are penetrating into the brain. We have utilized a Monte Carlo model representing brain vasculature to calculate physical dose and DNA damage from the α-emitters 225Ac and 212Pb. The micron-scale dose distributions from all radioactive decay products were modeled in Geant4, including the eV-scale interactions using the Geant4-DNA models. These interactions were then superimposed on an atomic-scale DNA model to estimate strand break yields. In addition to 225Ac having a higher dose per decay than 212Pb, it also has a double strand break yield per decay that is 4.7 ± 0.5 times that of 212Pb. However, the efficacy of both nuclides depends on retaining the daughter nuclei at the target location in the brain vasculature. The relative biological effectiveness (RBE) of 225Ac and 212Pb are similar when the entire decay chains are included, with maxima of 2.7 ± 0.6 and 2.5 ± 0.5 (respectively), and RBE values of about 2 to a depth of 80 μm. If the initial daughter is lost, the RBE of 212Pb is completely reduced to 1 or lower and the RBE of 225Ac is approximately 2 only for the first 40 μm.


Stem Cells in Neurological Disorders: Emerging Therapy with Stunning Hopes.
Neurodegenerative diseases are still a challenge for researchers and clinicians due to its complexity. Traditional medicines usually do not provide sufficient protection against these diseases due to drug resistance and relapse. The discovery of the therapeutic potential of stem cells offers new opportunities for the treatment of incurable neurological diseases. Based on their biological properties, stem cells can differentiate into specific tissue type and maintain the cellular tissue/organ homeostasis in physiological and pathological conditions. Recently, it has been demonstrated that somatic cells of patients can be reprogrammed to a pluripotent state from which neural lineage cells can be derived. Potential strategies such as cell replacement therapy and gene transfer to the diseased or injured brain have opened a new line of therapeutic approach for a broad spectrum of human neurological diseases. Thus, stem cell replacement therapy for central and peripheral nervous system disorders aims at repopulating the affected neural tissue with new neurons. However, the limiting factors that have hampered the development of this promising therapeutic approach are the lack of suitable cell types for cell replacement therapy in patients suffering from neurological disorders. In this review, we have discussed the recent advances in stem cell replacement therapy with particular emphasis to neurological disorders.