Control of transcription termination by an RNA factor in bacteriophage P4 immunity: identification of the target sites.
Prophage P4 immunity is elicited by a short, 69-nucleotide RNA (CI RNA) coded for within the untranslated leader region of the same operon it controls. CI RNA causes termination of transcription that starts at the promoter PLE and prevents the expression of the distal part of the operon that codes for P4 replication functions (alpha operon). In this work, we identify two sequences in the untranslated leader region of the alpha operon, seqA and seqC, that are the targets of the P4 immunity factor. seqA and seqC exhibit complementarity to a sequence internal to the CI RNA (seqB). Mutations in either seqA or seqC that alter its complementarity to seqB abolished or reduced P4 lysogenization proficiency and delayed the shutoff of the long transcripts originating from PLE that cover the entire operon. Both seqA and seqC single mutants were still sensitive to P4 prophage immunity, whereas P4 seqA seqC double mutants showed a virulent phenotype. Thus, both functional sites are necessary to establish immunity upon infection, whereas a single site appears to be sufficient to prevent lytic gene expression when immunity is established. A mutation in seqB that restored complementarity to both seqA and seqC mutations also restored premature termination of PLE transcripts, thus suggesting an important role for RNA-RNA interactions between seqB and seqA or seqC in P4 immunity.


FGF2 binding, signaling, and angiogenesis are modulated by heparanase in metastatic melanoma cells.
Heparanase (HPSE) and fibroblast growth factor-2 (FGF2) are critical regulators of melanoma angiogenesis and metastasis. Elevated HPSE expression contributes to melanoma progression; however, further augmentation of HPSE presence can inhibit tumorigenicity. HPSE enzymatically cleaves heparan sulfate glycosaminoglycan chains (HS) from proteoglycans. HS act as both low-affinity FGF2 receptors and coreceptors in the formation of high-affinity FGF2 receptors. We have investigated HPSE's ability to modulate FGF2 activity through HS remodeling. Extensive HPSE degradation of human metastatic melanoma cells (70W) inhibited FGF2 binding. Unexpectedly, treatment of 70W cells with low HPSE concentrations enhanced FGF2 binding. In addition, HPSE-unexposed cells did not phosphorylate extracellular signal-related kinase (ERK) or focal adhesion kinase (FAK) in response to FGF2. Conversely, in cells treated with HPSE, FGF2 stimulated ERK and FAK phosphorylation. Secondly, the presence of soluble HPSE-degraded HS enhanced FGF2 binding and ERK phosphorylation at low HS concentrations. Higher concentrations of soluble HS inhibited FGF2 binding, but FGF2 signaling through ERK remained enhanced. Soluble HS were unable to support FGF2-stimulated FAK phosphorylation irrespective of HPSE treatment. Finally, cell exposure to HPSE or to HPSE-degraded HS modulated FGF2-induced angiogenesis in melanoma. In conclusion, these effects suggest relevant mechanisms for the HPSE modulation of melanoma growth factor responsiveness and tumorigenicity.


Effectiveness of second-generation antipsychotics: a naturalistic, randomized comparison of olanzapine, quetiapine, risperidone, and ziprasidone.
No clear recommendations exist regarding which antipsychotic drug should be prescribed first for a patient suffering from psychosis. The primary aims of this naturalistic study were to assess the head-to-head effectiveness of first-line second-generation antipsychotics with regards to time until drug discontinuation, duration of index admission, time until readmission, change of psychopathology scores and tolerability outcomes. Patients >or= 18 years of age admitted to the emergency ward for symptoms of psychosis were consecutively randomized to risperidone (n = 53), olanzapine (n = 52), quetiapine (n = 50), or ziprasidone (n = 58), and followed for up to 2 years. A total of 213 patients were included, of which 68% were males. The sample represented a diverse population suffering from psychosis. At admittance the mean Positive and Negative Syndrome Scale (PANSS) total score was 74 points and 44% were antipsychotic drug naïve. The primary intention-to-treat analyses revealed no substantial differences between the drugs regarding the times until discontinuation of initial drug, until discharge from index admission, or until readmission. Quetiapine was superior to risperidone and olanzapine in reducing the PANSS total score and the positive subscore. Quetiapine was superior to the other drugs in decreasing the PANSS general psychopathology subscore; in decreasing the Clinical Global Impression - Severity of Illness scale score (CGI-S); and in increasing the Global Assessment of Functioning - Split version, Functions scale score (GAF-F). Ziprasidone was superior to risperidone in decreasing the PANSS positive symptoms subscore and the CGI-S score, and in increasing the GAF-F score. The drugs performed equally with regards to most tolerability outcomes except a higher increase of hip-circumference per day for olanzapine compared to risperidone, and more galactorrhoea for risperidone compared to the other groups. Quetiapine appears to be a good starting drug candidate in this sample of patients admitted to hospital for symptoms of psychosis. ClinicalTrials.gov ID; URL: http://www.clinicaltrials.gov/: NCT00932529.


Association between handling of pet treats and infection with Salmonella enterica serotype newport expressing the AmpC beta-lactamase, CMY-2.
Resistance to the extended-spectrum cephalosporins can occur in Salmonella species via the production of extended-spectrum and AmpC beta-lactamases. We describe human infections with Salmonella enterica serotype Newport phage type 14 strains resistant to ceftazidime (CAZ) and cefoxitin (FOX) related to the handling of pet treats containing dried beef. These strains were isolated from five patients in Calgary, Alberta, Canada, during 2002 and were compared to a strain cultured from a commercial pet treat present at the property of one of the patients. The strains were resistant to FOX, CAZ, cefpodoxime, ampicillin, and chloramphenicol; intermediate resistant to ceftriaxone and cefotaxime; and sensitive to the aminoglycosides, ciprofloxacin, cefepime, and imipenem. Isoelectric focusing, multiplex PCR, and sequencing of the amplicons showed that all strains produced the plasmid-encoded AmpC beta-lactamase, CMY-2. Restriction analysis of plasmid DNA following transformation demonstrated that bla(CMY-2) was encoded on an approximately 140-kb plasmid. Pulsed-field gel electrophoresis showed the human and pet treat Salmonella strains to be highly related. This study is the first to implicate the transfer of multidrug-resistant Salmonella species through the handling of commercial pet treats containing animal products. In addition to documenting the first cases of human infection caused by CMY-2-producing S. enterica serotype Newport strains in Canada, this study illustrates the necessity of rapid and accurate laboratory-based surveillance in the identification of novel types of antimicrobial resistance.


Evidence that binding site occupancy is necessary and sufficient for effective major histocompatibility complex (MHC) class II transport through the secretory pathway redefines the primary function of class II-associated invariant chain peptides (CLIP).
Invariant chain (Ii) associates with newly synthesized class II molecules in the endoplasmic reticulum (ER), an interaction that has been shown to interfere with peptide binding to class II molecules. The class II-associated invariant chain peptide (CLIP) region (residues 81-104) of Ii is believed to mediate this inhibition by engaging the binding domain of class II like an antigenic peptide. Together, these findings have given rise to a model in which CLIP association with the class II groove acts to prevent inappropriate presentation of peptides imported into the ER for association with major histocompatibility complex class I molecules. However, the properties of class II molecules synthesized by cells lacking coexpressed Ii are at least superficially inconsistent with this paradigm in that they do not show clear evidence of peptide acquisition. At the same time, we have previously shown the shortest form of Ii still containing CLIP to play an essential role in regulation of early class II molecule assembly and transport in the secretory pathway. Using covalent peptide technology, we now show that occupancy of the class II binding site in the ER regulates class II trafficking to the Golgi complex, an event that is the locus of the major defect in cells of Ii-deficient mice. These data argue that CLIP occupies the class II binding site, not to prevent interaction with short peptides meant for class I, but rather to maintain the structural integrity of class II molecules that are labile without engaged binding regions, and that would also associate with intact proteins in the ER if left unoccupied. By these means, CLIP occupancy of the class II binding site promotes effective export of useful class II molecules for endocytic peptide acquisition.


The effect of Nigella sativa L. supplementation on serum C-reactive protein: A systematic review and meta-analysis of randomized controlled trials.
Evidence on the efficacy ofNigella sativa supplementation is equivocal, thus the aim of this systematic review and meta-analysis of randomized clinical trials (RCTs) was to examine the effect of Nigella sativa (N. sativa) supplementation on plasma C-reactive protein (CRP) concentrations. PubMed, Scopus, ISI Web of Science, Cochrane library, and Google Scholar databases were searched (up to April 2019) to identify RCTs investigating the effects of N. sativa seed and seed oil supplementation on CRP. Weighted mean differences (WMD) was pooled using a random-effects model. Standard methods were also used for assessment of heterogeneity, sensitivity analysis, and publication bias. Eventually only five articles which reported data of interest entered for data analysis. The meta-analysis showed a significant reduction in serum CRP (WMD: -0.55 mg/L, 95% CI: -1.02, -0.08, P = 0.02), with significant heterogeneity between selected studies (I2 = 77.3%). Between-study heterogeneity disappeared following subgroup analysis, stratified by baseline BMI (≥30 kg/m2: I2 = 2.8%). However, the effect of N. sativa seed and seed oil supplementation on CRP was only significant in studies that were conducted on participants with BMI ≥ 30 kg/m2 (WMD: -0.50 mg/L, 95% CI: -0.85, -0.15). This meta-analysis suggests thatN. sativa seed and seed oil supplementation can significantly reduce serum CRP level. However, RCTs with a larger sample size and longer follow-up periods should be conducted for future investigations to confirm the veracity of these results.


Detection of acute kidney injury with hyperpolarized [13 C, 15 N]Urea and multiexponential relaxation modeling.
To assess the utility of Laplacian fitting to describe the differences in hyperpolarized [13 C, 15 N]urea T2 relaxation in ischemic and healthy rodent kidneys. Six rats with unilateral renal ischemia were investigated. [13 C, 15 N]Urea T2 mapping was undertaken with a radial fast spin echo method, with subsequent postprocessing performed with regularized Laplacian fitting. Simulations showed that Laplacian fitting was stable down to a signal-to-noise ratio of 20. In vivo results showed a significant increase in the mono- and decrease in biexponential pools in ischemia reperfusion injury kidneys, in comparison to healthy (14 ± 10% versus 4 ± 2%, 85 ± 10% versus 95 ± 3%; P < .05). We demonstrate, for the first time, the differences in multiexponential behavior of [13 C, 15 N]urea between the healthy and ischemic rodent kidney. The distribution of relaxation pools were found to be both visually and numerically significantly different. The ability to improve the information level in hyperpolarized MR, by using the relaxation contrast mechanisms is an appealing option, that can easily be adopted in large animals and even in clinical studies in the near future.


[Excise taxes on sugar-sweetened beverages in Latin America and the CaribbeanImposto especial de consumo sobre bebidas açucaradas na América Latina e no Caribe].
To characterize the design of excise taxes on sugar-sweetened beverages (SSBs) in Latin America and the Caribbean and assess opportunities to increase their impact on SSB consumption and health. A comprehensive search and review of the legislation in effect as of March 2019, collected through existing Pan American Health Organization and World Health Organization monitoring tools, secondary sources, and surveying ministries of finance. The analysis focused on the type of products taxed, and the structure and base of these excise taxes. Out of the 33 countries analyzed, 21 apply excise taxes on SSBs. Seven countries also apply excise taxes on bottled water and at least four include sugar-sweetened milk drinks. Ten of these excise taxes are ad valorem with some tax bases set early in the value chain, seven are amount-specific, and four have either a combined or mixed structure. Three countries apply excise taxes based on sugar concentration. While the number of countries applying excise taxes on SSBs is promising, there is great heterogeneity in design in terms of structure, tax base, and products taxed. Existing excise taxes could be further leveraged to improve their impact on SSB consumption and health by including all categories of SSBs, excluding bottled water, and relying more on amount-specific taxes regularly adjusted for inflation and possibly based on sugar concentration. All countries would benefit from additional guidance. Future research should aim to address this gap.


Breast cancer in systemic lupus erythematosus.
Evidence points to a decreased breast cancer risk in systemic lupus erythematosus (SLE). We analyzed data from a large multisite SLE cohort, linked to cancer registries. Information on age, SLE duration, cancer date, and histology was available. We analyzed information on histological type and performed multivariate logistic regression analyses of histological types according to age, SLE duration, and calendar year. We studied 180 breast cancers in the SLE cohort. Of the 155 cases with histology information, 11 were referred to simply as 'carcinoma not otherwise specified'. In the remaining 144 breast cancers, the most common histological type was ductal carcinoma (n = 95; 66%) followed by lobular adenocarcinoma (n = 11; 8%), 15 cancers were of mixed histology, and the remaining ones were special types. In our regression analyses, the independent risk factors for lobular versus ductal carcinoma was age [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.01-1.14] and for the 'special' subtypes it was age (OR 1.06, 95% CI 1.01-1.10) and SLE duration (OR 1.05, 95% CI 1.00-1.11). Generally, up to 80% of breast cancers are ductal carcinomas. Though our results are not definitive, in the breast cancers that occur in SLE, there may be a slight decrease in the ductal histological type. In our analyses, age and SLE duration were independent predictors of histological status.


Indole-3-carbinol in women with SLE: effect on estrogen metabolism and disease activity.
Estrogen metabolism in women with SLE is weighted towards 16alpha-hydroxyestrone, an estrogenic compound that might fuel disease activity. Indole-3-carbinol (I3C) is a nutritional compound that can shift estrogen metabolism towards less estrogenic metabolites. However, the effects of I3C in women with SLE have not been studied. Open-label 1-week metabolic study of 375 mg/day I3C was carried out in women with SLE, followed by a 3-month observational period for disease activity. The primary outcome measure was the change in ratio of urinary 2:16alpha hydroxyestrone levels. Secondary measures included the SLE Disease Activity Index. Seventeen clinically premenopausal women fulfilling ACR criteria for probable/definite SLE (mean age 37.9 y, range 20-49 y, mean disease duration 4.3 y, range 0.5-15) completed the 1-week metabolic study; 12 took I3C for 3 months. The mean 2:16alpha hydroxyestrone ratio increased by 1.84 to 3.15 (P = 0.0001). Mean SLEDAI scores were 10.0 (baseline); 6.25 (3 months); and 8.8 (3 months after withdrawal; P = NS). Women with SLE can manifest a metabolic response to I3C and might benefit from its antiestrogenic effects. We did not observe any striking effects on SLE disease activity during the 3-month observational period.


Seeking medical help to conceive.
The demand for therapies to assist conception is growing in a number of countries including Canada. This study provides estimates of the number and characteristics of couples who sought medical help for conception and identifies the interventions and/or techniques they used. The data are from the Infertility Component of the 2009/2010 Canadian Community Health Survey. The analysis examines couples in which the woman was aged 18 to 44, resulting in 3,656 respondents. Percentages, means and confidence intervals were calculated. Two logistic regression models were run to estimate associations between socio-demographic characteristics and seeking medical help to conceive. About three in four couples reported having tried to become pregnant. Of these, 15% had sought medical help for conception. Among those who had sought help for conception, 68% reported tracking the menstrual cycle and ovulation; 42% reported using fertility-enhancing drugs; 19% reported using assisted reproductive techniques; and 29% reported "other" medical treatment. Given the trend toward delayed childbearing, the demand for medical help to conceive may be greater in the future.


Relationship Among Concentrations of Sphaerotheca macularis Conidia in the Air, Environmental Conditions, and the Incidence of Powdery Mildew in Strawberry.
Atmospheric concentrations of Sphaerotheca macularis conidia were monitored for 2 years on a strawberry crop in Huelva (southwestern Spain). The presence of airborne conidia was determined to assess the role of weather conditions on conidial release. The relationship between airborne conidia and incidence of powdery mildew on fruit was also studied. Concentrations of conidia were estimated with a Burkard volumetric spore sampler. The presence of conidia was related to temperature, relative humidity, and rainfall, with a positive correlation for the first factor and a negative correlation with the other two. The presence of conidia in the air was positively correlated with disease incidence. A diurnal pattern of conidia release was observed.


Effect of time on biomechanics during exercise on the functional re-adaptive exercise device.
Mechanistic studies of the Functional Re-adaptive Exercise Device (FRED) have shown it automatically recruits Lumbar Multifidus (LM) and Transversus Abdominis (TrA) - two deep-spinal muscles that are atrophied and show altered motor control in low back pain (LBP). No studies have investigated the time required to familiarise to FRED exercise, which is required to inform future FRED based clinical trial protocols. This study therefore determined the effect of time, during FRED exercise, on biomechanical outcome measures, to establish the familiarisation period, and assess for loss of technique throughout a ten minute trial. A cohort comparison study of 148 participants, 70 experiencing low back pain, had lumbopelvic kinematics, exercise frequency and movement variability measured during a 10 minute trial. Magnitude-based inference was used to assess for familiarisation, using plots of variation over time with familiarised reference ranges. The no pain group took 170 seconds, and the back pain group took 150 seconds, to familiarise. A familiarisation period of at least 170 seconds (2.8 minutes) is recommended. This justifies, and provides a familiarisation time for use of the FRED as a motor control intervention.


Determining the chemical exchange saturation transfer (CEST) behavior of citrate and spermine under in vivo conditions.
To estimate the exchange rates of labile (1) H in citrate and spermine, metabolites present in prostatic secretions, to predict the size of the citrate and spermine CEST effects in vivo. CEST z-spectra were acquired at high-field [11.7 Tesla (T)] from citrate and spermine solutions at physiological pH (6.5) using saturation power 6 μT. CEST was performed at different temperatures to determine exchange regimes (slow, intermediate or fast). For low pH solutions of spermine, exchange rates were estimated from resonance line width, fitting z-spectra using the Bloch equations incorporating exchange, and using quantifying exchange using saturation time experiments (QUEST). These rates were extrapolated to physiological pH. Citrate showed little CEST effect at pH 6.5 and temperature (T) = 310 K (maximum 0.001% mM(-1) ), indicating fast exchange, whereas spermine showed greater CEST effects (maximum 0.2% mM(-1) ) indicating intermediate-to-fast exchange. Extrapolating data acquired from low pH spermine solutions predicts exchange rates at pH 6.5 and T of 310 K of at least 2 × 10(4) s(-1) . Citrate and spermine show minimal CEST effects at 11.7T even using high saturation power. These effects would be much less than 2% at clinical field-strengths due to relatively faster exchange and would be masked by CEST from proteins. Magn Reson Med 76:742-746, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.


Pain management: physiopathology, future research and endpoints.
In this article, first, the different stages of acquisition and processing of nociceptive information from peripheral receptor to brain are reviewed and the plastic changes that accompany tissue injury are underlined. For instance, the subclassification of peripheral receptors in nociceptors and non-nociceptors (e.g., mechanoreceptors, thermoreceptors) must be understood in the light of peripheral sensitization. This phenomenon is the probable explanation for primary hyperalgesia, the decrease in pain threshold at the site of injury. The observation that substance P enhances N-methyl-D-aspartate (NMDA)-elicited responses suggests that these two receptors may operate in concert to prolong and amplify the afferent input generated by peripheral tissue injury. Such afferent barrage induces a state of central sensitization. Second, the major problems in the management of cancer pain, i.e. the development of tolerance to opioids and opioid-insensitive pain, are discussed. The loss of drug effect observed after chronic exposure of the opioid receptor (tolerance) may be the consequence of the down-regulation or desensitization phenomenon (where the total number of receptors coupled to the second messenger is reduced). The agonist dose-response begins to shift to the right. The dramatic analgesic improvement obtained with subanaesthetic doses of ketamine, an NMDA receptor antagonist, in those of our cancer patients who have become resistant to morphine is intriguing. As shown for tolerance, insensitivity to opioids may represent a rightward shift in the opioid dose-response curve and the analgesic effect of ketamine the reversal of that shift.


Novel 1,2,3-triazolium-based dicationic amphiphiles synthesized using click-chemistry approach for efficient plasmid delivery.
Herein, we report the synthesis, characterization and evaluation of the transfection efficiencies of a series of dicationic amphiphiles designed to construct quaternary ammonium ion-based cationic lipids varying in chain length of the hydrophobic back bone connected individually through head group to a 1,2,3-triazolium cation consisting of 2-hydroxy ethyl chain as substitution. Accordingly, three dicationic amphiphiles were synthesized by "click chemistry" approach and formulated to bilayered vesicles using DOPE as a co-lipid. The transfection efficacies of these novel lipid formulations were measured and correlated with the results obtained from various physicochemical techniques. Importantly, the observed gradient in the activity profile, where the transfection potential increased with decreasing chain length of the lipid hydrophobic back bone, highlights the synergistic interplay of the lipid alkyl chain length in coordination with charge delocalization in modulating the transfection potency of these 1,2,3-triazolium-based lipids.


Simple fluorescent sensors engineered with catalytic DNA 'MgZ' based on a non-classic allosteric design.
Most NAE (nucleic acid enzyme) sensors are composed of an RNA-cleaving catalytic motif and an aptameric receptor. They operate by activating or repressing the catalytic activity of a relevant NAE through the conformational change in the aptamer upon target binding. To transduce a molecular recognition event to a fluorescence signal, a fluorophore-quencher pair is attached to opposite ends of the RNA substrate such that when the NAE cleaves the substrate, an increased level of fluorescence can be generated. However, almost all NAE sensors to date harbor either NAEs that cannot accommodate a fluorophore-quencher pair near the cleavage site or those that can accept such a modification but require divalent transition metal ions for catalysis. Therefore, the signaling magnitude and the versatility of current NAE sensors might not suffice for analytical and biological applications. Here we report an RNA-cleaving DNA enzyme, termed 'MgZ', which depends on Mg(2+) for its activity and can accommodate bulky dye moieties next to the cleavage site. MgZ was created by in vitro selection. The selection scheme entailed acidic buffering and ethanol-based reaction stoppage to remove selfish DNAs. Characterization of MgZ revealed a three-way junction structure, a cleavage rate of 1 min(-1), and 26-fold fluorescence enhancement. Two ligand-responsive NAE sensors were rationally designed by linking an aptamer sequence to the substrate of MgZ. In the absence of the target, the aptamer-linked substrate is locked into a conformation that prohibits MgZ from accessing the substrate. In the presence of the target, the aptamer releases the substrate, which induces MgZ-mediated RNA cleavage. The discovery of MgZ and the introduction of the above NAE sensor design strategy should facilitate future efforts in sensor engineering.


Tucunarella n. Gen. and other dactylogyrids (Monogenoidea) from cichlid fish (Perciformes) from Peruvian Amazonia.
During parasitological research on cichlid fish from the tributaries of the Amazon River around Iquitos, Peru, the following gill monogenoidean species were found: Tucunarella cichlae n. gen. and n. sp. from Cichla monoculus Spix and Agassiz; Gussevia alioides Kritsky, Thatcher, and Boeger, 1986 from Heros severus Heckel; Gussevia asota Kritsky, Thatcher, and Boeger, 1989 from Astronotus ocellatus (Agassiz); Gussevia disparoides Kritsky, Thatcher, and Boeger, 1986 from H. severus (all new geographical records) and Cichlasoma amazonarum Kullander (new host record); Gussevia longihaptor (Mizelle and Kritsky, 1969) Kritsky, Thatcher, and Boeger, 1986 and Gussevia undulata Kritsky, Thatcher, and Boeger, 1986 from C. monoculus ; Sciadicleithrum satanopercae Yamada, Takemoto, Bellay, and Pavanelli, 2008 from Satanoperca jurupari Heckel; and Sciadicleithrum variabilum (Mizelle and Kritsky, 1969) Kritsky, Thatcher, and Boeger, 1989 from C. amazonarum (new host and geographical records). Tucunarella n. gen. is proposed to accommodate a new species, Tucunarella cichlae , which is its type and only known species in the genus. The new genus is characterized by, besides a very large body size (about 1.5 mm vs. much less than 1 mm in other ancyrocephaline genera in Amazonia), a thickened tegument, 1 pair of eyes, overlapping gonads (testis dorsal to the germarium), nonarticulated male copulatory organ (MCO) and accessory piece, a coiled (counterclockwise) MCO, a dextral vaginal aperture, a haptor armed with 2 pairs of anchors (each with broad base and subequal roots, which are marginally folded), and dorsal and ventral bars and 14 hooks with protruding blunt thumbs and 2 different shapes (slender vs. slightly expanded shanks). Illustrations and data on morphological and biometric variability of individual species from different hosts are provided. The present data provide evidence of a relatively wide host specificity of gill monogenoideans parasitic in South American cichlids.


Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. Muse cells are endogenous reparative pluripotent-like stem cells distributed in various tissues. They can selectively home to damaged sites after intravenous injection by sensing sphingosine-1-phosphate produced by damaged cells, then exert pleiotropic effects, including tissue protection and spontaneous differentiation into tissue-constituent cells. In G93A-transgenic ALS mice, intravenous injection of 5.0 × 104 cells revealed successful homing of human-Muse cells to the lumbar spinal cords, mainly at the pia-mater and underneath white matter, and exhibited glia-like morphology and GFAP expression. In contrast, such homing or differentiation were not recognized in human mesenchymal stem cells but were instead distributed mainly in the lung. Relative to the vehicle groups, the Muse group significantly improved scores in the rotarod, hanging-wire and muscle strength of lower limbs, recovered the number of motor neurons, and alleviated denervation and myofiber atrophy in lower limb muscles. These results suggest that Muse cells homed in a lesion site-dependent manner and protected the spinal cord against motor neuron death. Muse cells might also be a promising cell source for the treatment of ALS patients.


Challenge of Using Passive Acoustic Monitoring in High-Energy Environments: UK Tidal Environments and Other Case Studies.
The use of passive acoustic monitoring (PAM) around marine developments is commonplace. A buffer-based PAM system (e.g., C-POD) is a cost-effective method for assessing cetacean acoustic presence. Devices have been deployed by Sea Mammal Research Unit (SMRU) Marine around the United Kingdom, allowing an examination of the performance of C-PODs with respect to background noise, tilt angle, and environmental factors. C-PODs were found to often only monitor for a few seconds of each minute, resulting in significant loss of monitoring time. Issues were likely driven by environmental and deployment factors. The practical limitations of buffer-based PAM systems in high-energy/noisy environments are indicated here.


Screening of chemical libraries in pursuit of kallikrein-5 specific inhibitors for the treatment of inflammatory dermatoses.
Background Aberrant kallikrein activity is observed in a number of inflammatory dermatoses. Up-regulation of kallikrein-5 (KLK5) activity leads to uncontrolled skin desquamation and cleavage of proteinase-activated receptor-2 (PAR2), causing the release of pro-inflammatory cytokines and disruption of epidermal barrier function. This study aimed to identify KLK5-specific small molecule inhibitors which can serve as the foundation of a novel therapeutic for inflammatory skin disorders. Methods Five chemical libraries (13,569 compounds total) were screened against recombinant KLK5 using a fluorogenic enzymatic assay. Secondary validation was performed on the top 22 primary hits. All hits were docked in the KLK5 crystal structure to rationalize their potential interactions with the protein. Results A naturally occurring compound derived from the wood of Caesalpinia sappan (Brazilin) was identified as a novel KLK5 inhibitor (IC50: 20 μM, Ki: 6.4 μM). Docking suggests that the phenolic moiety of Brazilin binds in the S1-pocket of KLK5 and forms a H-bond with S195 side chain. KLK14 was also found to be susceptible to inhibition by Brazilin with a calculated IC50 value of 14.6 μM. Conclusions Natural KLK5 small molecule inhibitors such as Brazilin, are ideal for topical skin disease drug design and remain a promising therapeutic for severe cases of inflammatory skin disorders. Optimized KLK inhibitors may have increased efficacy as therapeutics and warrant further investigation.


Rivaroxaban for Thromboprophylaxis After Nonelective Orthopedic Trauma Surgery in Switzerland.
This study investigated the effectiveness and the outcomes of rivaroxaban vs the standard of care for venous thromboembolic prophylaxis in patients undergoing fracture-related surgery. A total of 413 patients undergoing fracture-related surgery from 9 Swiss orthopedic and trauma centers were enrolled. The authors selected the type of venous thromboembolic prophylaxis according to standardized medical practice at the participating centers before the inclusion of patients: 208 patients received rivaroxaban and 205 received the standard of care. Data on symptomatic thromboembolic and bleeding events, surgery-related complications, death, adverse events, time to mobilization, and hospital discharge were collected. Symptomatic thromboembolic events were reported in 1 patient (0.5%) and 2 patients (1.0%) and treatment-emergent major bleeding events were reported in 1 patient (0.5%) and 2 patients (1.0%) receiving rivaroxaban and the standard of care, respectively. The durations of hospital stay and venous thromboembolic prophylaxis were similar in the 2 groups. In both groups, adverse events related to venous thromboembolic prophylaxis were reported in 12 patients. The proportion of patients with minor and major fracture surgery was 74.3% and 25.7%, respectively. In patients undergoing minor fracture surgery receiving rivaroxaban (n=167) and the standard of care (n=140), no symptomatic thromboembolic events and no major bleeding events were reported. Outcomes of this study indicate that rivaroxaban might be an appropriate oral alternative for venous thromboembolic prophylaxis in routine medical care after fracture-related major and minor surgery. Reported results were comparable to those from other large-scale, noninterventional and randomized controlled studies. [Orthopedics. 2017; 40(2):109-116.].


Structure-activity correlations for beta-phenethylamines at human trace amine receptor 1.
A cell line in which RD-HGA16 cells were stably transfected with the hTAAR 1 receptor was created and utilized to carry out a systematic evaluation of a series of beta-phenethylamines. Fair agreement was observed with data obtained for aryl and ethylene chain substituted analogs in an AV12-664 cell line in which hemagglutinin-tagged hTAAR 1 was stably co-expressed with rat G alpha(s). Analogs with multiple substituents as well as analogs with bulky groups were found to be partial agonists. Analogs in which the primary amino group was converted to a secondary or a tertiary amino group by N-methylation were also partial agonists. Comparative Molecular Field Analysis (CoMFA) using the potency data yielded a regression coefficient r(2) of 0.824. The steric field contribution to the model was 61% with the balance (39%) contributed by the electrostatic field. The collective results suggest that increasing steric bulk both at the amino nitrogen, particularly by N-dimethylation, and at the 4-position of the aromatic ring leads to low efficacy ligands.


Electronic quantum fluxes during pericyclic reactions exemplified for the Cope rearrangement of semibullvalene.
The outcome of a pericyclic reaction is typically represented by arrows in the Lewis structure of the reactant, symbolizing the net electron transfer. Quantum simulations can be used to interpret these arrows in terms of electronic fluxes between neighboring bonds. The fluxes are decomposed into contributions from electrons in so-called pericyclic orbitals, which account for the mutation of the Lewis structure for the reactant into that for the product, in other valence and in core orbitals. Series of time-integrated fluxes of pericyclic electrons can be assigned to the arrows, for example 0.09-0.23 electrons for Cope rearrangement of semibullvalene, with hysteresis-type time evolutions for 27.3 fs. This means asynchronous electronic fluxes during synchronous rearrangement of all the nuclei. These predictions should become observable by emerging techniques of femto- to attosecond time-resolved spectroscopy.


The evolution of cooperative breeding through group augmentation.
Some individuals (helpers) in cooperatively breeding species provide alloparental care and often suppress their own reproduction. Kin selection is clearly an important explanation for such behaviour, but a possible alternative is group augmentation where individuals survive or reproduce better in large groups and where it therefore pays to recruit new members to the group. The evolutionary stability of group augmentation is currently disputed. We model evolutionarily stable helping strategies by following the dynamics of social groups with varying degrees of subordinate help. We also distinguish between passive augmentation, where a group member benefits from the mere presence of others, and active augmentation, where their presence as such is neutral or harmful, but where helping to recruit new group members may still be beneficial if they in turn actively provide help for the current reproductives ('delayed reciprocity'). The results show that group augmentation (either passive or active) can be evolutionarily stable and explain costly helping by non-reproductive subordinates, either alone or leading to elevated help levels when acting in concert with kin selection. Group augmentation can thus potentially explain the weak relationships between relatedness and helping behaviour that are observed in some cooperatively breeding species. In some cases, the superior mutualistic performance of cooperatively behaving groups can generate an incentive to stay and help which is strong enough to make ecological constraints unnecessary for explaining the stability of cooperatively breeding groups.


Mindfulness-based interventions in schools-a systematic review and meta-analysis.
Mindfulness programs for schools are popular. We systematically reviewed the evidence regarding the effects of school-based mindfulness interventions on psychological outcomes, using a comprehensive search strategy designed to locate both published and unpublished studies. Systematic searches in 12 databases were performed in August 2012. Further studies were identified via hand search and contact with experts. Two reviewers independently extracted the data, also selecting information about intervention programs (elements, structure etc.), feasibility, and acceptance. Twenty-four studies were identified, of which 13 were published. Nineteen studies used a controlled design. In total, 1348 students were instructed in mindfulness, with 876 serving as controls, ranging from grade 1 to 12. Overall effect sizes were Hedge's g = 0.40 between groups and g = 0.41 within groups (p < 0.0001). Between group effect sizes for domains were: cognitive performance g = 0.80, stress g = 0.39, resilience g = 0.36, (all p < 0.05), emotional problems g = 0.19 third person ratings g = 0.25 (both n.s.). All in all, mindfulness-based interventions in children and youths hold promise, particularly in relation to improving cognitive performance and resilience to stress. However, the diversity of study samples, variety in implementation and exercises, and wide range of instruments used require a careful and differentiated examination of data. There is great heterogeneity, many studies are underpowered, and measuring effects of Mindfulness in this setting is challenging. The field is nascent and recommendations will be provided as to how interventions and research of these interventions may proceed.


Divalent cations regulate connexin hemichannels by modulating intrinsic voltage-dependent gating.
Connexin hemichannels are robustly regulated by voltage and divalent cations. The basis of voltage-dependent gating, however, has been questioned with reports that it is not intrinsic to hemichannels, but rather is derived from divalent cations acting as gating particles that block the pore in a voltage-dependent manner. Previously, we showed that connexin hemichannels possess two types of voltage-dependent gating, termed V(j) and loop gating, that in Cx46 operate at opposite voltage polarities, positive and negative, respectively. Using recordings of single Cx46 hemichannels, we found both forms of gating persist in solutions containing no added Mg(2+) and EGTA to chelate Ca(2+). Although loop gating persists, it is significantly modulated by changing levels of extracellular divalent cations. When extracellular divalent cation concentrations are low, large hyperpolarizing voltages, exceeding -100 mV, could still drive Cx46 hemichannels toward closure. However, gating is characterized by continuous flickering of the unitary current interrupted by occasional, brief sojourns to a quiet closed state. Addition of extracellular divalent cations, in this case Mg(2+), results in long-lived residence in a quiet closed state, suggesting that hyperpolarization drives the hemichannel to close, perhaps by initiating movements in the extracellular loops, and that divalent cations stabilize the fully closed conformation. Using excised patches, we found that divalent cations are only effective from the extracellular side, indicative that the binding site is not cytoplasmic or in the pore, but rather extracellular. V(j) gating remains essentially unaffected by changing levels of extracellular divalent cations. Thus, we demonstrate that both forms of voltage dependence are intrinsic gating mechanisms in Cx46 hemichannels and that the action of external divalent cations is to selectively modulate loop gating.


Prevalence of Noncardiac and Genetic Abnormalities in Neonates Undergoing Cardiac Operations: Analysis of The Society of Thoracic Surgeons Congenital Heart Surgery Database.
Among patients with congenital heart disease (CHD), the coexistence of noncardiac congenital anatomic abnormalities (NC), genetic abnormalities (GA), and syndromes (S) may influence therapeutic strategies and outcomes. The appreciated prevalence of these abnormalities has risen because increased screening and improved diagnostic precision enable identification of these comorbidities in a larger fraction of neonates with CHD. We examined the contemporary prevalence and distribution of NC/GA/S across diagnostic groups among neonates undergoing cardiac operations using a large nationally representative clinical registry. The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) was queried to identify neonates (≤30 days) who underwent index cardiac operations from 2010 to 2013. The fundamental cardiac diagnosis was used to identify 10 diagnostic groups. The prevalence of NC/GA/S was reported across each group. The cohort included 15,376 index neonatal operations from 112 centers. Overall, 18.8% (2,894 of 15,376) of operations were performed in neonates with NC/GA/S. Patients with atrioventricular septal defect (212 of 357 [59.4%]), interrupted aortic arch (248 of 567 [43.7%]), truncus arteriosus (204 of 554 [36.8%]), and tetralogy of Fallot (417 of 1,383 [30.2%]) had the highest prevalence of NC/GA/S abnormalities, whereas those with transposition of the great arteries (111 of 2,778 [4.0%]) had the lowest prevalence. The most commonly identified NC/GA/S included heterotaxy (597 of 15,376 [3.9%]), DiGeorge syndrome or 22q11 deletion (550 of 15,376 [3.6%]), Down syndrome or trisomy 21 (318 of 15, 376 [2.1%]), intestinal malrotation (220 of 15,376 [1.4%]), and Turner syndrome or 45XO (189 of 15,376 [1.2%]). The prevalence of NC/GA/S varies widely across CHD diagnostic groups. This information may be useful for patient counseling, recommendations for screening for anomalies and genetic disorders, and perioperative management.


Appropriate and inappropriate imaging rates for prostate cancer go hand in hand by region, as if set by thermostat.
Policy makers interested in containing health care costs are targeting regional variation in utilization, including the use of advanced imaging. However, bluntly decreasing utilization among the highest-utilization regions may have negative consequences. In a cross-sectional study of prostate cancer patients from 2004 to 2005, we found that regions with lower rates of inappropriate imaging also had lower rates of appropriate imaging. Similarly, regions with higher overall imaging rates tended to have not only higher rates of inappropriate imaging, but also higher rates of appropriate imaging. In fact, men with high-risk prostate cancer were more likely to receive appropriate imaging if they resided in areas with higher rates of inappropriate imaging. This "thermostat model" of regional health care utilization suggests that poorly designed policies aimed at reducing inappropriate imaging could limit access to appropriate imaging for high-risk patients. Health care organizations need clearly defined quality metrics and supportive systems to encourage appropriate treatment for patients and to ensure that cost containment does not occur at the expense of quality.


Origins of the Indo-Europeans: genetic evidence.
Two theories of the origins of the Indo-Europeans currently compete. M. Gimbutas believes that early Indo-Europeans entered southeastern Europe from the Pontic Steppes starting ca. 4500 B.C. and spread from there. C. Renfrew equates early Indo-Europeans with early farmers who entered southeastern Europe from Asia Minor ca. 7000 BC and spread through the continent. We tested genetic distance matrices for each of 25 systems in numerous Indo-European-speaking samples from Europe. To match each of these matrices, we created other distance matrices representing geography, language, time since origin of agriculture, Gimbutas' model, and Renfrew's model. The correlation between genetics and language is significant. Geography, when held constant, produces a markedly lower, yet still highly significant partial correlation between genetics and language, showing that more remains to be explained. However, none of the remaining three distances--time since origin of agriculture, Gimbutas' model, or Renfrew's model--reduces the partial correlation further. Thus, neither of the two theories appears able to explain the origin of the Indo-Europeans as gauged by the genetics-language correlation.


Higher adenoma detection rate with the endocuff: a randomized trial.
Background and study aim Different techniques have been introduced to improve the endoscopist's view and enhance the detection of polyps. The endocuff is a polymer sleeve cap that is connected to the tip of the colonoscope in order to improve visualization of the mucosa during colonoscopy. The aim of the study was to compare adenoma detection rates (ADR) of endocuff-assisted colonoscopy and conventional colonoscopy. Patients and methods Patients 50 years or older were randomized into two groups: an endocuff-assisted colonoscopy group and a conventional colonoscopy group without the endocuff. Results A total of 337 patients were included: 174 in the endocuff group and 163 in the conventional group. The median age was 61 years (interquartile range 55 - 70 years), and 74 % were women. The ADR was higher in the endocuff group than in the conventional group (22.4 % vs. 13.5 %; P = 0.02). The mean number of adenomas was 0.30 (SD 0.25) in the endocuff group and 0.21 (SD 0.26) in the conventional group (P = 0.02). The rate of ileal intubation was lower in the endocuff group (73 % vs. 87 %; P < 0.001). No serious adverse events occurred with the use of the endocuff. Conclusions Endocuff colonoscopy achieved a greater ADR than conventional colonoscopy.Trial registered at ClinicalTrials.gov (NTC02387593).


Methylation of the Tumor Suppressor Genes HIC1 and RassF1A Clusters Independently From the Methylation of Polycomb Target Genes in Colon Cancer.
Methylation changes within tumor suppressor (TS) genes or polycomb group target (PcG) genes alter cell fates. Chromatin associated with PcG targets is bivalent in stem cells, while TS genes are not normally bivalent. PcG target methylation changes have been identified in tumor stem cells, and abnormal methylation is found in TS genes in cancers. If the epigenetic states of genes influence DNA methylation, then methylation of PcG targets and TS genes may evolve differently during cancer development. More importantly, methylation changes may be part of a sequence in tumorigenesis. Chromatin and methylation states of 4 PcG targets and 2 TS genes were determined in colon cancer cells. The methylation states were also detected in 100 pairs of colon cancer samples. Principle component analysis (PCA) was used to reveal whether TS methylation or PcG methylation was the main methylation change associated with colon cancers. Chromatin and methylation states differ in colon cancer cell lines. The methylation states within PcG targets clustered independently from the methylation states in TS genes, a finding we previously reported in liver cancers. PCA in colon cancers revealed the strongest association with methylation changes in 2 TS genes, HIC1 and RassF1A. Loss of HIC1 methylation correlated with decreased tumor migration. PcG and TS methylation states cluster independently from each other. The deduced principle component correlated better with TS methylation than PcG methylation in colon cancer. Abnormal methylation changes may represent a sequential biomarker profile to identify developing colon cancer.


NACA deficiency reveals the crucial role of somite-derived stromal cells in haematopoietic niche formation.
The ontogeny of haematopoietic niches in vertebrates is essentially unknown. Here we show that the stromal cells of the caudal haematopoietic tissue (CHT), the first niche where definitive haematopoietic stem/progenitor cells (HSPCs) home in zebrafish development, derive from the caudal somites through an epithelial-mesenchymal transition (EMT). The resulting stromal cell progenitors accompany the formation of the caudal vein sinusoids, the other main component of the CHT niche, and mature into reticular cells lining and interconnecting sinusoids. We characterize a zebrafish mutant defective in definitive haematopoiesis due to a deficiency in the nascent polypeptide-associated complex alpha subunit (NACA). We demonstrate that the defect resides not in HSPCs but in the CHT niche. NACA-deficient stromal cell progenitors initially develop normally together with the sinusoids, and HSPCs home to the resulting niche, but stromal cell maturation is compromised, leading to a niche that is unable to support HSPC maintenance, expansion and differentiation.


Untargeted metagenomic sequencing identifies Toscana virus in patients with idiopathic meningitis, southern Spain, 2015 to 2019.
BackgroundVarious pathogens, including bacteria, fungi, parasites, and viruses can lead to meningitis. Among viruses causing meningitis, Toscana virus (TOSV), a phlebovirus, is transmitted through sandfly bites. TOSV infection may be suspected if patients with enterovirus- and herpesvirus-negative aseptic (non-bacterial) meningitis recall recent insect bites. Other epidemiological factors (season, rural area) may be considered. The broad range of possible meningitis aetiologies poses considerable diagnosis challenges. Untargeted metagenomic next-generation sequencing (mNGS) can potentially identify pathogens, which are not considered or detected in routine diagnostic panels.AimIn this retrospective, single-centre observational study, we investigated mNGS usefulness to understand the cause of meningitis when conventional approaches fail.MethodsCerebrospinal fluid (CSF) samples from patients hospitalised in southern Spain in 2015-2019 with aseptic meningitis and no aetiology found by conventional testing, were subjected to mNGS. Patients' demographic characteristics had been recorded and physicians had asked them about recent insect bites. Obtained viral genome sequences were phylogenetically analysed.ResultsAmong 23 idiopathic cases, TOSV was identified in eight (all male; median age: 39 years, range: 15-78 years). Five cases lived in an urban setting, three occurred in autumn and only one recalled insect bites. Phylogenetic analysis of TOSV segment sequences supported one intra-genotype reassortment event.ConclusionsOur study highlights the usefulness of mNGS for identifying viral pathogens directly in CSF. In southern Spain, TOSV should be considered regardless of recalling of insect bites or other epidemiological criteria. Detection of a disease-associated reassortant TOSV emphasises the importance of monitoring the spread and evolution of phleboviruses in Mediterranean countries.


Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism.
Septic encephalopathy is a severe brain dysfunction caused by systemic inflammation in the absence of direct brain infection. Changes in cerebral blood flow, release of inflammatory molecules and metabolic alterations contribute to neuronal dysfunction and cell death. To investigate the relation of electrophysiological, metabolic and morphological changes caused by SE, we simultaneously assessed systemic circulation, regional cerebral blood flow and cortical electroencephalography in rats exposed to bacterial lipopolysaccharide. Additionally, cerebral glucose uptake, astro- and microglial activation as well as changes of inflammatory gene transcription were examined by small animal PET using [18F]FDG, immunohistochemistry, and real time PCR. While the systemic hemodynamic did not change significantly, regional cerebral blood flow was decreased in the cortex paralleled by a decrease of alpha activity of the electroencephalography. Cerebral glucose uptake was reduced in all analyzed neocortical areas, but preserved in the caudate nucleus, the hippocampus and the thalamus. Sepsis enhanced the transcription of several pro- and anti-inflammatory cytokines and chemokines including tumor necrosis factor alpha, interleukin-1 beta, transforming growth factor beta, and monocot chemoattractant protein 1 in the cerebrum. Regional analysis of different brain regions revealed an increase in ED1-positive microglia in the cortex, while total and neuronal cell counts decreased in the cortex and the hippocampus. Together, the present study highlights the complexity of sepsis induced early impairment of neuronal metabolism and activity. Since our model uses techniques that determine parameters relevant to the clinical setting, it might be a useful tool to develop brain specific therapeutic strategies for human septic encephalopathy.


Velocimetric third-harmonic generation microscopy: micrometer-scale quantification of morphogenetic movements in unstained embryos.
We demonstrate the association of third-harmonic generation (THG) microscopy and particle image velocimetry (PIV) analysis as a novel functional imaging technique for automated micrometer-scale characterization of morphogenetic movements in developing embryos. Using a combined two-photon-excited fluorescence and THG microscope, we characterize the optical properties of Drosophila embryos and show that sustained THG imaging does not perturb sensitive developmental dynamics. Velocimetric THG imaging provides a quantitative description of the dynamics of internal structures in unstained wild-type and mutant embryos.


Spectroscopic study of ablation in guided surface discharge plasmas.
A spectroscopic study of gliding ablative discharges has been carried out on N(2), CO(2), and lasing mixtures of TEA CO(2) lasers. By spectroscopic plasma diagnosis techniques (local thermodynamic equilibrium assumed) we observed an inhomogeneous transversal distribution of the ablated elements. Electronic temperature and density transversal distributions are, however, fairly homogeneous. We also found a different ablation threshold for two ablated substrate elements. The ablation threshold seems to be related to the plasma current density. The results are of practical interest in the UV preionization of TEA CO(2) lasers.


Frailty and functional decline indices predict poor outcomes in hospitalised older people.
admission to a Geriatric Evaluation and Management Unit (GEMU) can optimise a patient's chance of functional recovery. to evaluate the ability of several commonly used frailty and functional decline indices to predict GEMU outcomes, both at discharge and at 6 months. prospective, observational study. consecutive GEMU patients aged ≥70 years. patients were classified as 'frail' or 'at high risk of functional decline' using several frailty and functional decline instruments. Predictive ability was evaulated using logistic regression and area under receiver operator characteristic (ROC) curves (auROC). a total of 172 patients were included. Frailty prevalence varied from 24 to 94% depending on the instrument used. Several instruments predicted patients at risk of poor outcome, including the Frailty Index of Accumulative Deficits (FI-CD), Fried's Cardiovascular Health Study index, the Study of Osteoporotic Fractures index, an adapted Katz score of activities of daily living (ADL), Instrumental ADL, the Score Hospitalier d'Evaluation du Risque de Perte d'Autonomie (SHERPA) and grip strength [odds ratio (OR) range of 2.06-6.47]. Adequate discriminatory power for discharge outcome was achieved by the FI-CD (auROC = 0.735, P < 0.001) and an adapted Katz score (auROC = 0.704, P = < 0.001). The FI-CD also showed adequate discriminatory power for a poor 6-month outcome (auROC = 0.702, P < 0.001). frailty and functional decline instruments can predict older patients at risk of poor outcome. However, only the FI-CD showed adequate discriminatory power for outcome prediction at both follow-up time-points.


Novel anthropomorphic hip phantom corrects systemic interscanner differences in proximal femoral vBMD.
Quantitative computed tomography (QCT) is increasingly used in osteoporosis studies to assess volumetric bone mineral density (vBMD), bone quality and strength. However, QCT is confronted by technical issues in the clinical research setting, such as potentially confounding effects of body size on vBMD measurements and lack of standard approaches to scanner cross-calibration, which affects measurements of vBMD in multicenter settings. In this study, we addressed systematic inter-scanner differences and subject-dependent body size errors using a novel anthropomorphic hip phantom, containing a calibration hip to estimate correction equations, and a contralateral test hip to assess the quality of the correction. We scanned this phantom on four different scanners and we applied phantom-derived corrections to in vivo images of 16 postmenopausal women scanned on two scanners. From the phantom study, we found that vBMD decreased with increasing phantom size in three of four scanners and that inter-scanner variations increased with increasing phantom size. In the in vivo study, we observed that inter-scanner corrections reduced systematic inter-scanner mean vBMD differences but that the inter-scanner precision error was still larger than expected from known intra-scanner precision measurements. In conclusion, inter-scanner corrections and body size influence should be considered when measuring vBMD from QCT images.


Cytosolic nucleotides block and regulate the Arabidopsis vacuolar anion channel AtALMT9.
The aluminum-activated malate transporters (ALMTs) form a membrane protein family exhibiting different physiological roles in plants, varying from conferring tolerance to environmental Al(3+) to the regulation of stomatal movement. The regulation of the anion channels of the ALMT family is largely unknown. Identifying intracellular modulators of the activity of anion channels is fundamental to understanding their physiological functions. In this study we investigated the role of cytosolic nucleotides in regulating the activity of the vacuolar anion channel AtALMT9. We found that cytosolic nucleotides modulate the transport activity of AtALMT9. This modulation was based on a direct block of the pore of the channel at negative membrane potentials (open channel block) by the nucleotide and not by a phosphorylation mechanism. The block by nucleotides of AtALMT9-mediated currents was voltage dependent. The blocking efficiency of intracellular nucleotides increased with the number of phosphate groups and ATP was the most effective cellular blocker. Interestingly, the ATP block induced a marked modification of the current-voltage characteristic of AtALMT9. In addition, increased concentrations of vacuolar anions were able to shift the ATP block threshold to a more negative membrane potential. The block of AtALMT9-mediated anion currents by ATP at negative membrane potentials acts as a gate of the channel and vacuolar anion tune this gating mechanism. Our results suggest that anion transport across the vacuolar membrane in plant cells is controlled by cytosolic nucleotides and the energetic status of the cell.


Management of Daylily Rust with Different Fungicides and Application Methods.
The objectives of this study were to assess the efficacy of various fungicides applied as root dips, soil drenches, or foliar sprays to daylily plants grown in containers and planted in the field to manage rust caused by Puccinia hemerocallidis. Soil drenches and foliar sprays were evaluated in field experiments in Griffin, GA in 2010 and 2011. Dipping bare-root daylily plants for 5 min in azoxystrobin, tebuconazole, or thiophanate-methyl significantly reduced lesion development compared with nontreated control plants. Drenches with azoxystrobin, fluoxastrobin, or tebuconazole, each at three rates (0.06, 0.12, and 0.24 g of active ingredient [a.i.]/container), significantly reduced development of rust lesions on container-grown daylily plants for up to 9 weeks after treatment and 6 weeks after inoculation. One early-season drench of azoxystrobin at 0.12 g a.i‥/plant provided season-long reduction in disease incidence and disease progress that was comparable with foliar sprays with azoxystrobin or chlorothalonil applied at 14-day intervals. Dip or drench applications of fungicides would allow growers to diversify rust management options and could reduce the number of foliar fungicide applications.


More active pre-school children have better motor competence at school starting age: an observational cohort study.
Almost half of young children do not achieve minimum recommendations of 60 daily minutes in physical activity. Physical activity is potentially an important determinant of the development of motor competence in children. This study is one of very few longitudinal studies in this area and the first to investigate early childhood physical activity as a predictor of subsequent motor skill competence. Children were assessed as part of the Melbourne InFANT Program longitudinal cohort study at 19 months, 3.5 years and 5 years. Moderate-to-vigorous physical activity (MVPA) (accelerometry) was assessed at each time point. At age 5, children were also assessed in actual (Test of Gross Motor Development-2) and perceived motor competence (Pictorial Scale of Perceived Movement Skill Competence). General linear models were performed with all 12 skills (six object control and six locomotor skills), both actual and perceived, at age 5 as the respective outcome variables. Predictor variables alternated between MVPA at 19 months, 3.5 years and 5 years. Based on standardized TGMD-2 scores most children were average or below in their skill level at age 5. MVPA at 19 months was not a predictor of actual or perceived skill at age 5. MVPA at 3.5 years was associated with actual locomotor skill (B = 0.073, p = 0.033) and perceived total skill at 5 years of age (B = 0.059, p = 0.044). MVPA was not a predictor of actual or perceived object control skill at any age. Parents and preschool staff should be informed that more time in MVPA as a preschool child contributes to locomotor skill and to perceptions of skill ability in a child of school starting age. Understanding this relationship will assist in intervention development.


IR action spectroscopy of glycosaminoglycan oligosaccharides.
Glycosaminoglycans (GAGs) are a physio- and pharmacologically highly relevant class of complex saccharides, possessing a linear sequence and strongly acidic character. Their repetitive linear core makes them seem structurally simple at first glance, yet differences in sulfation and epimerization lead to an enormous structural diversity with only a few GAGs having been successfully characterized to date. Recent infrared action spectroscopic experiments on sulfated mono- and disaccharide ions show great promise. Here, we assess the potential of two types of gas-phase action spectroscopy approaches in the range from 1000 to 1800 cm-1 for the structural analysis of complex GAG oligosaccharides. Synthetic tetra- and pentasaccharides were chosen as model compounds for this benchmark study. Utilizing infrared multiple photon dissociation action spectroscopy at room temperature, diagnostic bands are largely unresolved. In contrast, cryogenic infrared action spectroscopy of ions trapped in helium nanodroplets yields resolved infrared spectra with diagnostic features for monosaccharide composition and sulfation pattern. The analysis of GAGs could therefore significantly benefit from expanding the conventional MS-based toolkit with gas-phase cryogenic IR spectroscopy. Graphical abstract.


Predictors of lower-extremity amputation in patients with an infected diabetic foot ulcer.
Infection commonly complicates diabetic foot ulcers and is associated with a poor outcome. In a cohort of individuals with an infected diabetic foot ulcer, we aimed to determine independent predictors of lower-extremity amputation and the predictive value for amputation of the International Working Group on the Diabetic Foot (IWGDF) classification system and to develop a risk score for predicting amputation. We prospectively studied 575 patients with an infected diabetic foot ulcer presenting to 1 of 14 diabetic foot clinics in 10 European countries. Among these patients, 159 (28%) underwent an amputation. Independent risk factors for amputation were as follows: periwound edema, foul smell, (non)purulent exudate, deep ulcer, positive probe-to-bone test, pretibial edema, fever, and elevated C-reactive protein. Increasing IWGDF severity of infection also independently predicted amputation. We developed a risk score for any amputation and for amputations excluding the lesser toes (including the variables sex, pain on palpation, periwound edema, ulcer size, ulcer depth, and peripheral arterial disease) that predicted amputation better than the IWGDF system (area under the ROC curves 0.80, 0.78, and 0.67, respectively). For individuals with an infected diabetic foot ulcer, we identified independent predictors of amputation, validated the prognostic value of the IWGDF classification system, and developed a new risk score for amputation that can be readily used in daily clinical practice. Our risk score may have better prognostic accuracy than the IWGDF system, the only currently available system, but our findings need to be validated in other cohorts.


Predicting the timing of cherry blossoms in Washington, DC and Mid-Atlantic States in response to climate change.
Cherry blossoms, an icon of spring, are celebrated in many cultures of the temperate region. For its sensitivity to winter and early spring temperatures, the timing of cherry blossoms is an ideal indicator of the impacts of climate change on tree phenology. Here, we applied a process-based phenology model for temperate deciduous trees to predict peak bloom dates (PBD) of flowering cherry trees (Prunus×yedoensis 'Yoshino' and Prunus serrulata 'Kwanzan') in the Tidal Basin, Washington, DC and the surrounding Mid-Atlantic States in response to climate change. We parameterized the model with observed PBD data from 1991 to 2010. The calibrated model was tested against independent datasets of the past PBD data from 1951 to 1970 in the Tidal Basin and more recent PBD data from other locations (e.g., Seattle, WA). The model performance against these independent data was satisfactory (Yoshino: r(2) = 0.57, RMSE = 6.6 days, bias = 0.9 days and Kwanzan: r(2) = 0.76, RMSE = 5.5 days, bias = -2.0 days). We then applied the model to forecast future PBD for the region using downscaled climate projections based on IPCC's A1B and A2 emissions scenarios. Our results indicate that PBD at the Tidal Basin are likely to be accelerated by an average of five days by 2050 s and 10 days by 2080 s for these cultivars under a mid-range (A1B) emissions scenario projected by ECHAM5 general circulation model. The acceleration is likely to be much greater (13 days for 2050 s and 29 days for 2080s) under a higher (A2) emissions scenario projected by CGCM2 general circulation model. Our results demonstrate the potential impacts of climate change on the timing of cherry blossoms and illustrate the utility of a simple process-based phenology model for developing adaptation strategies to climate change in horticulture, conservation planning, restoration and other related disciplines.


Bistability and self-pulsation phenomena in silicon microring resonators based on nonlinear optical effects.
Bistability (BS) and self-pulsation (SP) phenomena in silicon microring resonators (MRR) with intense CW light injection are studied. Several nonlinear optical effects including Kerr effect, two-photon absorption, free carrier absorption and free carrier dispersion are taken into account. The threshold optical intensity of BS and SP is derived from the coupled mode theory and a linear stability analysis method. The influences of MRR's parameters (carrier lifetime, linear loss and radius) and light injection conditions (input power, wavelength detuning) on the characteristics of SP (modulation depth and oscillating frequency) are analyzed and discussed. It is shown that, SP occurs only if the carrier lifetime ranges from several ps to several-hundred ps and the input light intensity is higher than 10⁶W/cm². The modulation depth of SP can be as large as 8dB and the associated oscillating frequency is in the range from several GHz to beyond 10 GHz.


Effect of water content in a canned food on voluntary food intake and body weight in cats.
To determine whether water content in a canned food diet induces decreases in voluntary energy intake (EI) or body weight (BW) in cats fed ad libitum. 16 sexually intact male domestic shorthair cats. Maintenance EI was determined for 2 months in 10 weight-stable cats consuming a control diet (typical colony diet). Cats were allocated into 2 groups of equal BW and fed a canned diet (with-water [WW] diet) or a freeze-dried version of the canned diet (low-water [LW] diet) twice daily. Diets were identical in nutrient profile on a dry-matter basis. Each dietary treatment period of the crossover experiment lasted 3 weeks, with a 3-week washout period between diets. Body composition measurements were determined by use of deuterium oxide at the end of each dietary treatment. Daily food intake was measured for determination of dry-matter intake and EI. Six other cats were used in preference tests for the 3 diets. EI was significantly decreased for the WW diet (mean ± SD, 1,053.0 ± 274.9 kJ/d), compared with EI for the LW diet (1,413.8 ± 345.8 kJ/d). Cats had a significant decrease in BW during consumption of the WW diet. Body composition was unaltered by diet. In short-term preference tests, cats ate significantly more of the WW than the LW diet. Bulk water in the WW diet stimulated decreases in EI and BW in cats. The impact of water content on energy density and food consumption may help promote weight loss in cats.


[Arborescent species of the genus Blechnum (Blechnaceae: Pteridophyta)].
Although the genus Blechnum has been largely studied, problems of species characterization, nomenclature, classification and taxonomy remain unsolved. For these reasons, in this study we intend to deepen in the characterization of the arborescent group of Blechnum with a review of eight species: B. brasiliense, B. columbiense, B. cycadifolium, B. magellanicum, B. moritzianum, B. schomburgkii, B. tabulare and B. werckleanum.Type material and several collections from diverse herbaria were studied. For morphological studies we used both herbarium and fresh material collected by the authors in fieldwork between 2005 and 2010. Rhizomes, stipes, vascularization of costae, as well as several characters of the lamina, such as outline, division, venation, margin structure, epidermal patterns, stomata, presence and types ofhypodermis, and mesophyll ofpinnae were studied. Important aspects of the morphology of the sporophyte have been analyzed, and external characters have been correlated with internal diagnostic ones to use the most reliable external traits in keys and descriptions. Taxonomy has been updated, and corrections have been introduced to the species nomenclature and comments were included to summarize the current knowledge of the geographical distribution and ecology. The presence of B. tabulare in America is confirmed, and the taxonomy of the species is updated, since external and internal morphology indicated that other related, American and African species, such as B. spannagelii and B. madagascariense must be included under that name. Similar studies carried out on B. schomburgkii indicated that the name is a synonym of B. auratum subsp. auratum, while B. auratum subsp. columbiense is treated here as a well characterized species. Detailed study of numerous specimens allowed to characterize B. moritzianum, being the correct name to apply to the recently described B. yungense. A refreshed description of the species is presented together with a list of new, selected materials to illustrate current known geographical distribution. Expanded data on ecology, geographical distribution and affinities are given, and a key for species identification is presented.


Exploring inequities in skilled care at birth among migrant population in a metropolitan city Addis Ababa, Ethiopia; a qualitative study.
Ethiopia records high levels of inequity in skilled birth care (SBC), where the gaps are much wider among urban migrant women. An intervention project has been conducted in Addis Ababa, intending to improve quality and to ensure equitable access to maternal and newborn care services. As part of the project, this study explored the inequities in maternal health care among migrant women in Addis Ababa, Ethiopia. A qualitative community based study was conducted from April to May 2014 among 45 purposefully selected internal migrant women. Eleven women who give birth at home and eight who gave birth at health facility in the last year preceding the study participated in in-depth interviews. Four primiparas' young women, 18 women who have children and four grandmothers participated in focus group discussions. Guides were used for data collection. Using framework and content analysis three themes and four sub-themes emerged. According to the informants, patterns of service utilization varied widely. Antenatal care and infant immunization were fairly equally accessed across the different age groups of informants in their most recent birth irrespective of where they gave birth, yet obvious access gaps were reported in SBC and postpartum care. There were missed opportunities to postpartum care. Only few women had received postpartum care despite, some of the women delivering in the health facility and many visiting the health facilities for infant immunization. The four emerged sub-themes reportedly influencing access and utilization of SBC were social influences, physical access to health facility, risk perceptions and perceived quality of care and disrespect. Of these social, structural and health system factors, informants presented experiences of disrespectful care as a powerful deterrent to SBC. Migrant women constitute disadvantaged communities in Addis Ababa and have unequal access to SBC and postpartum care. This happens in the backdrop of fairly equitable access to antenatal care, infant immunization, universal health coverage and free access to maternal and newborn care. Addressing the underlying determinants for the inequities and bridging the quality gaps in maternal and newborn services with due emphasis on respectful care for migrant women need tailored intervention and prioritization.


Path following control of planar snake robots using virtual holonomic constraints: theory and experiments.
This paper considers path following control of planar snake robots using virtual holonomic constraints. In order to present a model-based path following control design for the snake robot, we first derive the Euler-Lagrange equations of motion of the system. Subsequently, we define geometric relations among the generalized coordinates of the system, using the method of virtual holonomic constraints. These appropriately defined constraints shape the geometry of a constraint manifold for the system, which is a submanifold of the configuration space of the robot. Furthermore, we show that the constraint manifold can be made invariant by a suitable choice of feedback. In particular, we analytically design a smooth feedback control law to exponentially stabilize the constraint manifold. We show that enforcing the appropriately defined virtual holonomic constraints for the configuration variables implies that the robot converges to and follows a desired geometric path. Numerical simulations and experimental results are presented to validate the theoretical approach.


Choosing to live with home dialysis-patients' experiences and potential for telemedicine support: a qualitative study.
This study examines the patients' need for information and guidance in the selection of dialysis modality, and in establishing and practicing home dialysis. The study focuses on patients' experiences living with home dialysis, how they master the treatment, and their views on how to optimize communication with health services and the potential of telemedicine. We used an inductive research strategy and conducted semi-structured interviews with eleven patients established in home dialysis. Our focus was the patients' experiences with home dialysis, and our theoretical reference was patients' empowerment through telemedicine solutions. Three informants had home haemodialysis (HHD); eight had peritoneal dialysis (PD), of which three had automated peritoneal dialysis (APD); and five had continuous ambulatory peritoneal dialysis (CAPD). The material comprises all PD-patients in the catchment area capable of being interviewed, and all known HHD-users in Norway at that time. All of the interviewees were satisfied with their choice of home dialysis, and many experienced a normalization of daily life, less dominated by disease. They exhibited considerable self-management skills and did not perceive themselves as ill, but still required very close contact with the hospital staff for communication and follow-up. When choosing a dialysis modality, other patients' experiences were often more influential than advice from specialists. Information concerning the possibility of having HHD, including knowledge of how to access it, was not easily available. Especially those with dialysis machines, both APD and HHD, saw a potential for telemedicine solutions. As home dialysis may contribute to a normalization of life less dominated by disease, the treatment should be organized so that the potential for home dialysis can be fully exploited. Pre-dialysis information should be unbiased and include access to other patients' experiences. Telemedicine may potentially facilitate a communication-based follow-up and improve safety within the home setting, making it easier to choose and live with home dialysis.


SU-E-T-442: Assessing Vertex Beam with its Dosimetric Relevance for Intracranial Tumours: A Computational Exploration.
To assess the selection of the minimal vertex beam angle for the avoidance of organs at risk (OARs) in radiotherapy planning of brain tumors. Seventy patients with intracranial tumors were studied. Three field conformal plans with co-planar or non co-planar beam arrangements with an anterior vertex beam were used. Two methods were studied for determining the vertex angle for avoidance of eye as organ at risk. In the standard technique, the beam's eye view (BEV) was used to determine need of vertex beam. For the vertex beam, the angle was approximated to avoid eyes. In the second method, the angle from the baseplate to the posterior surface of the head and the angle from the posterior surface of the head to the inferior-most extent of the head were measured from sagital view. The minimum vertex angle required was calculated as the complement of the sum of these angles. The dose volume histogram parameters were maintained. Depending on the spatial location of the planning target volume with reference to the eyes, patients were classified into 4 types: no overlap; overlap with eye anteriorly; overlap with eye posteriorly, overlap with eye anteriorly and posteriorly. No additional angulation, positive vertex and negative vertex angles were needed for type 1, 2 and 3 respectively. The angle subtended by the isocenter to the neck rest apex was the required vertex angle for type 4. Of the 36 type 2, 3 and 4 patients the planned vertex angle was more than the calculated vertex angle by over 5 degrees in 10 patients, and less by over 5 degrees in 4 patients. A simple method for deriving the minimal vertex beam angle for OAR avoidance in radiotherapy planning of intracranial tumors was described and validated.


Chronic medical conditions among jail detainees in residential psychiatric treatment: a latent class analysis.
Studies of incarcerates with serious mental illnesses have found elevated rates of chronic medical conditions such as asthma and diabetes, and of infectious diseases such as tuberculosis compared with general population rates. This study explored the pattern of chronic medical conditions in a sample of adult detainees in psychiatric treatment in a large urban jail to develop a clinical profile encompassing the full range of medical conditions. A total of 431 male and female detainees were sampled with certainty from admissions to a residential psychiatric treatment program (overall recruitment rate = 67%). Interviews used the World Mental Health version of the Composite International Diagnostic Interview to assess psychiatric and substance use disorders per DSM-IV criteria and chronic medical conditions. Latent class analysis was conducted using 17 medical conditions as class indicators, yielding a 3-class model composed of: a latent class with a high to intermediate probability of multiple medical conditions (HMC; 12.5% of the sample); an intermediate class with a lower probability of having a smaller number of medical conditions (MMC; 43.2%); and a class with a low probability of any medical condition (44.3%). Those in the HMC class were more likely to report respiratory problems, severe headaches, musculoskeletal pain, hypertension, and arthritis, have greater functional impairment, and have a higher number of co-occurring psychiatric disorders. Being older (50+ years) and female were associated with higher odds of being in the HMC or MMC classes. The policy implications for providing medical care to incarcerates with complex mixtures of medical conditions and psychiatric disorders are considered.


Block-Matching Distortion Correction of Echo-Planar Images With Opposite Phase Encoding Directions.
By shortening the acquisition time of MRI, Echo Planar Imaging (EPI) enables the acquisition of a large number of images in a short time, compatible with clinical constraints as required for diffusion or functional MRI. However such images are subject to large, local distortions disrupting their correspondence with the underlying anatomy. The correction of those distortions is an open problem, especially in regions where large deformations occur. We propose a new block-matching registration method to perform EPI distortion correction based on the acquisition of two EPI with opposite phase encoding directions (PED). It relies on new transformations between blocks adapted to the EPI distortion model, and on an adapted optimization scheme to ensure an opposite symmetric transformation. We present qualitative and quantitative results of the block-matching correction using different metrics on a phantom dataset and on in-vivo data. We show the ability of the block-matching to robustly correct EPI distortion even in strongly affected areas.


"In a tree by the brook, there's a songbird who sings": Woodlands in an agricultural matrix maintain functionality of a wintering bird community.
The agricultural matrix has increasingly been recognized for its potential to supplement Protected Areas (PAs) in biodiversity conservation. This potential is highly contextual, depending on composition and spatial configuration of matrix elements and their mechanistic relationship with biological communities. We investigate the effects of local vegetation structure, and proximity to a PA on the site-use of different guilds in a wintering bird community within the PA, and in wooded land-use types in the surrounding matrix. We used occupancy models to estimate covariate-guild relationships and predict site-use. We also compared species richness (estimated through capture-recapture models) and species naïve site-use between the PA and the matrix to evaluate taxonomic changes. We found that tree cover did not limit the site-use of most guilds of the community, probably due to high canopy cover across all chosen sites. Exceptions to this were guilds comprising generalist species. Shrub cover and bamboo cover had important effects on some woodland-associated guilds, suggesting a change in limiting factors for site-use under adequate tree cover. Site-use across the matrix was high for all analyzed guilds. This was found to be due to three non-exclusive reasons: (i) presence of one or more ubiquitous species (found all across the landscape) within some guilds, (ii) redundancy of species within guilds that buffered against a decrease in site-use, and (iii) turnover in guild composition/abundances to more generalist species from PA to matrix. Estimated species richness was higher in the matrix (107± 11; mean ± SE) than in the PA (90± 7), which may have been in part due to the addition of generalist species in the matrix. Understanding factors that limit biological communities is crucial to better managing the ever-increasing matrix for biodiversity conservation. Our study provides insights into the effects of different components of vegetation structure on the bird community in wooded land-use types in the matrix. We highlight the value of woodlands surrounding PAs in maintaining multiple guilds, and hence, the functionality of a wintering bird community. However, we caution that the matrix may fall short in retaining some specialized species of the community.


Switching Transient Generation in Surface Interrogation Scanning Electrochemical Microscopy and Time-of-Flight Techniques.
In surface interrogation scanning electrochemical microscopy (SI-SECM), fine and accurate control of the delay time between substrate generation and tip interrogation (tdelay) is crucial because tdelay defines the decay time of the reactive intermediate. In previous applications of the SI-SECM, the resolution in the control of tdelay has been limited to several hundreds of milliseconds due to the slow switching of the bipotentiostat. In this work, we have improved the time resolution of tdelay control up to ca. 1 μs, enhancing the SI-SECM to be competitive in the time domain with the decay of many reactive intermediates. The rapid switching SI-SECM has been implemented in a substrate generation-tip collection time-of-flight (SG-TC TOF) experiment of a solution redox mediator, and the results obtained from the experiment exhibited good agreement with that obtained from digital simulation. The reaction rate constant of surface Co(IV) on oxygen-evolving catalyst film, which was inaccessible thus far due to the lack of tdelay control, has been measured by the rapid switching SI-SECM.


CHD7 targets active gene enhancer elements to modulate ES cell-specific gene expression.
CHD7 is one of nine members of the chromodomain helicase DNA-binding domain family of ATP-dependent chromatin remodeling enzymes found in mammalian cells. De novo mutation of CHD7 is a major cause of CHARGE syndrome, a genetic condition characterized by multiple congenital anomalies. To gain insights to the function of CHD7, we used the technique of chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-Seq) to map CHD7 sites in mouse ES cells. We identified 10,483 sites on chromatin bound by CHD7 at high confidence. Most of the CHD7 sites show features of gene enhancer elements. Specifically, CHD7 sites are predominantly located distal to transcription start sites, contain high levels of H3K4 mono-methylation, found within open chromatin that is hypersensitive to DNase I digestion, and correlate with ES cell-specific gene expression. Moreover, CHD7 co-localizes with P300, a known enhancer-binding protein and strong predictor of enhancer activity. Correlations with 18 other factors mapped by ChIP-seq in mouse ES cells indicate that CHD7 also co-localizes with ES cell master regulators OCT4, SOX2, and NANOG. Correlations between CHD7 sites and global gene expression profiles obtained from Chd7(+/+), Chd7(+/-), and Chd7(-/-) ES cells indicate that CHD7 functions at enhancers as a transcriptional rheostat to modulate, or fine-tune the expression levels of ES-specific genes. CHD7 can modulate genes in either the positive or negative direction, although negative regulation appears to be the more direct effect of CHD7 binding. These data indicate that enhancer-binding proteins can limit gene expression and are not necessarily co-activators. Although ES cells are not likely to be affected in CHARGE syndrome, we propose that enhancer-mediated gene dysregulation contributes to disease pathogenesis and that the critical CHD7 target genes may be subject to positive or negative regulation.


Organic foods contain higher levels of certain nutrients, lower levels of pesticides, and may provide health benefits for the consumer.
The multi-billion dollar organic food industry is fueled by consumer perception that organic food is healthier (greater nutritional value and fewer toxic chemicals). Studies of the nutrient content in organic foods vary in results due to differences in the ground cover and maturity of the organic farming operation. Nutrient content also varies from farmer to farmer and year to year. However, reviews of multiple studies show that organic varieties do provide significantly greater levels of vitamin C, iron, magnesium, and phosphorus than non-organic varieties of the same foods. While being higher in these nutrients, they are also significantly lower in nitrates and pesticide residues. In addition, with the exception of wheat, oats, and wine, organic foods typically provide greater levels of a number of important antioxidant phytochemicals (anthocyanins, flavonoids, and carotenoids). Although in vitro studies of organic fruits and vegetables consistently demonstrate that organic foods have greater antioxidant activity, are more potent suppressors of the mutagenic action of toxic compounds, and inhibit the proliferation of certain cancer cell lines, in vivo studies of antioxidant activity in humans have failed to demonstrate additional benefit. Clear health benefits from consuming organic dairy products have been demonstrated in regard to allergic dermatitis.


Pulmonary rehabilitation for chronic obstructive pulmonary disease.
Widespread application of pulmonary rehabilitation (also known as respiratory rehabilitation) in chronic obstructive pulmonary disease (COPD) should be preceded by demonstrable improvements in function (health-related quality of life, functional and maximal exercise capacity) attributable to the programmes. This review updates the review reported in 2006. To compare the effects of pulmonary rehabilitation versus usual care on health-related quality of life and functional and maximal exercise capacity in persons with COPD. We identified additional randomised controlled trials (RCTs) from the Cochrane Airways Group Specialised Register. Searches were current as of March 2014. We selected RCTs of pulmonary rehabilitation in patients with COPD in which health-related quality of life (HRQoL) and/or functional (FEC) or maximal (MEC) exercise capacity were measured. We defined 'pulmonary rehabilitation' as exercise training for at least four weeks with or without education and/or psychological support. We defined 'usual care' as conventional care in which the control group was not given education or any form of additional intervention. We considered participants in the following situations to be in receipt of usual care: only verbal advice was given without additional education; and medication was altered or optimised to what was considered best practice at the start of the trial for all participants. We calculated mean differences (MDs) using a random-effects model. We requested missing data from the authors of the primary study. We used standard methods as recommended by The Cochrane Collaboration. Along with the 31 RCTs included in the previous version (2006), we included 34 additional RCTs in this update, resulting in a total of 65 RCTs involving 3822 participants for inclusion in the meta-analysis.We noted no significant demographic differences at baseline between members of the intervention group and those who received usual care. For the pulmonary rehabilitation group, the mean forced expiratory volume at one second (FEV1) was 39.2% predicted, and for the usual care group 36.4%; mean age was 62.4 years and 62.5 years, respectively. The gender mix in both groups was around two males for each female. A total of 41 of the pulmonary rehabilitation programmes were hospital based (inpatient or outpatient), 23 were community based (at community centres or in individual homes) and one study had both a hospital component and a community component. Most programmes were of 12 weeks' or eight weeks' duration with an overall range of four weeks to 52 weeks.The nature of the intervention made it impossible for investigators to blind participants or those delivering the programme. In addition, it was unclear from most early studies whether allocation concealment was undertaken; along with the high attrition rates reported by several studies, this impacted the overall risk of bias.We found statistically significant improvement for all included outcomes. In four important domains of quality of life (QoL) (Chronic Respiratory Questionnaire (CRQ) scores for dyspnoea, fatigue, emotional function and mastery), the effect was larger than the minimal clinically important difference (MCID) of 0.5 units (dyspnoea: MD 0.79, 95% confidence interval (CI) 0.56 to 1.03; N = 1283; studies = 19; moderate-quality evidence; fatigue: MD 0.68, 95% CI 0.45 to 0.92; N = 1291; studies = 19; low-quality evidence; emotional function: MD 0.56, 95% CI 0.34 to 0.78; N = 1291; studies = 19; mastery: MD 0.71, 95% CI 0.47 to 0.95; N = 1212; studies = 19; low-quality evidence). Statistically significant improvements were noted in all domains of the St. George's Respiratory Questionnaire (SGRQ), and improvement in total score was better than 4 units (MD -6.89, 95% CI -9.26 to -4.52; N = 1146; studies = 19; low-quality evidence). Sensitivity analysis using the trials at lower risk of bias yielded a similar estimate of the treatment effect (MD -5.15, 95% CI -7.95 to -2.36; N = 572; studies = 7).Both functional exercise and maximal exercise showed statistically significant improvement. Researchers reported an increase in maximal exercise capacity (mean Wmax (W)) in participants allocated to pulmonary rehabilitation compared with usual care (MD 6.77, 95% CI 1.89 to 11.65; N = 779; studies = 16). The common effect size exceeded the MCID (4 watts) proposed by Puhan 2011(b). In relation to functional exercise capacity, the six-minute walk distance mean treatment effect was greater than the threshold of clinical significance (MD 43.93, 95% CI 32.64 to 55.21; participants = 1879; studies = 38).The subgroup analysis, which compared hospital-based programmes versus community-based programmes, provided evidence of a significant difference in treatment effect between subgroups for all domains of the CRQ, with higher mean values, on average, in the hospital-based pulmonary rehabilitation group than in the community-based group. The SGRQ did not reveal this difference. Subgroup analysis performed to look at the complexity of the pulmonary rehabilitation programme provided no evidence of a significant difference in treatment effect between subgroups that received exercise only and those that received exercise combined with more complex interventions. However, both subgroup analyses could be confounded and should be interpreted with caution. Pulmonary rehabilitation relieves dyspnoea and fatigue, improves emotional function and enhances the sense of control that individuals have over their condition. These improvements are moderately large and clinically significant. Rehabilitation serves as an important component of the management of COPD and is beneficial in improving health-related quality of life and exercise capacity. It is our opinion that additional RCTs comparing pulmonary rehabilitation and conventional care in COPD are not warranted. Future research studies should focus on identifying which components of pulmonary rehabilitation are essential, its ideal length and location, the degree of supervision and intensity of training required and how long treatment effects persist. This endeavour is important in the light of the new subgroup analysis, which showed a difference in treatment effect on the CRQ between hospital-based and community-based programmes but no difference between exercise only and more complex pulmonary rehabilitation programmes.