Nutrient gradients in engineered cartilage: metabolic kinetics measurement and mass transfer modeling.
Since tissue-engineered cartilage is avascular, both nutrient supply and metabolic waste removal rely on diffusion. As a result, gradients of nutrients and wastes exist through the construct. Previous models usually calculate gradients of oxygen, glucose, and lactic acid separately, without taking into account the complex interdependence between concentrations of these substrates and rates of metabolism. In this study, these interactions were experimentally examined and incorporated into diffusion models. One-dimensional diffusion-reaction models were developed for three typical culture conditions, that is, static culture, perfusion culture, and suspended culture. The profiles of oxygen, glucose, lactic acid, and pH in the cultured constructs were calculated simultaneously using measured metabolic rates. The maximum construct size and cell density which could be supported before nutrients were depleted in the construct center was identified; a function predicting the relationship between construct dimension and the maximum viable cell density was developed. For constructs incubated under static culture the model demonstrated that the gradients which developed through the medium could not be neglected. Perfusion cultures could support a considerably higher cell density than static cultures, while for batch cultures in a rotating bioreactor, the volume of medium also influences the maximum cell density that could be supported. This study provides useful guidance for design of engineered cartilage constructs.


Persistence of strong electron coupling to a narrow boson spectrum in overdoped Bi2Sr2CaCu2O(8+delta) tunneling data.
A d-wave, Eliashberg analysis of break-junction and STM tunneling spectra on Bi2Sr2CaCu2O(8+delta) (Bi2212) reveals that the spectral dip feature is directly linked to strong electronic coupling to a narrow boson spectrum, evidenced by a large peak in alpha2F(omega). The tunneling dip feature remains robust in the overdoped regime of Bi2212 with bulk T(c) values of 56 K-62 K. This is contrary to recent optical conductivity measurements of the self-energy that suggest the narrow boson spectrum disappears in overdoped Bi2212 and therefore cannot be essential for the pairing mechanism. The discrepancy is resolved by considering the way each technique probes the electron self-energy, in particular, the unique sensitivity of tunneling to the off-diagonal or pairing part of the self-energy.


The embryonic development of the central American wandering spider Cupiennius salei.
The spider Cupiennius salei (Keyserling 1877) has become an important study organism in evolutionary and developmental biology. However, the available staging system for its embryonic development is difficult to apply to modern studies, with strong bias towards the earliest developmental stages. Furthermore, important embryonic events are poorly understood. We address these problems, providing a new description of the embryonic development of C. salei. The paper also discusses various observations that will improve our understanding of spider development. Conspicuous developmental events were used to define numbered stages 1 to 21. Stages 1 to 9 follow the existing staging system for the spider Achaearanea tepidariorum, and stages 10 to 21 provide a high-resolution description of later development. Live-embryo imaging shows cell movements during the earliest formation of embryonic tissue in C. salei. The imaging procedure also elucidates the encircling border between the cell-dense embryo hemisphere and the hemisphere with much lower cell density (a structure termed 'equator' in earlier studies). This border results from subsurface migration of primordial mesendodermal cells from their invagination site at the blastopore. Furthermore, our detailed successive sequence shows: 1) early differentiation of the precheliceral neuroectoderm; 2) the morphogenetic process of inversion and 3) initial invaginations of the opisthosomal epithelium for the respiratory system. Our improved staging system of development in C. salei development should be of considerable value to future comparative studies of animal development. A dense germ disc is not evident during development in C. salei, but we show that the gastrulation process is similar to that in spider species that do have a dense germ disc. In the opisthosoma, the order of appearance of precursor epithelial invaginations provides evidence for the non-homology of the tracheal and book lung respiratory systems.


NAB2-STAT6 fusion types account for clinicopathological variations in solitary fibrous tumors.
Solitary fibrous tumor (SFT) is characterized by the inv12(q13q13)-derived NAB2-STAT6 fusion, which exhibits variable breakpoints and drives STAT6 nuclear expression. The implications of NAB2-STAT6 fusion variants in pathological features and clinical behavior remain to be characterized in a large cohort of SFTs. We investigated the clinicopathological correlates of this genetic hallmark and analyzed STAT6 immunoexpression in 28 intrathoracic, 37 extrathoracic, and 23 meningeal SFTs. These 88 tumors were designated as histologically nonmalignant in 75 cases and malignant in 13, including 1 dedifferentiated SFT. Eighty cases had formalin-fixed and/or fresh samples to extract assessable RNAs for RT-PCR assay, which revealed NAB2-STAT6 fusion variants comprising 12 types of junction breakpoints in 73 fusion-positive cases, with 65 (89%) falling into 3 major types. The predominant NAB2ex4-STAT6ex2 (n=33) showed constant breakpoints at the ends of involved exons, whereas the NAB2ex6-STAT6ex16 (n=16) and NAB2ex6-STAT6ex17 (n=16) might exhibit variable breakpoints and incorporate NAB2 or STAT6 intronic sequence. Including 73 fusion-positive and 7 CD34-negative SFTs, STAT6 distinctively labeled 87 (99%) SFTs in nuclei, exhibited diffuse reactivity in 73, but did not decorate 98 mimics tested. In seven fusion-negative cases, 6 were STAT6-positive, suggesting rare fusion variants not covered by RT-PCR assay. Regardless of histological subtypes, intrathoracic SFTs affected older patients (P=0.035) and tended to be larger in size (P=0.073). Compared with other variants, NAB2ex4-STAT6ex2/4 fusions were significantly predominant in the SFTs characterised by intrathoracic location (P<0.001), older age (P=0.005), decreased mitoses (P=0.0028), and multifocal or diffuse STAT6 staining (P=0.013), but not found to correlate with disease-free survival. Conclusively, STAT6 nuclear expression was distinctive in the vast majority of SFTs, including all fusion-positive tumors, and exploitable as a robust diagnostics of CD34-negative cases. Despite the associations of NAB2-STAT6 fusion variants with several clincopathological factors, their prognostic relevance should be further validated in large-scale prospective studies of SFTs.


Human exposure to selamectin from dogs treated with revolution: methodological consideration for selamectin isolation.
This study was undertaken to determine selamectin residue in dog's blood and in gloves worn while petting dogs after Revolution application. Revolution contains the active ingredient selamectin (a semisynthetic avermectin), which controls endoparasites and ectoparasites, including adult fleas, flea eggs, ticks, heartworms, ear mites, and sarcoptic mange in dogs, for 30 days. Revolution was applied topically on a group of six adult house hold dogs (240 mg selamectin/dog). The gloves worn for 5 min while petting the dogs were collected in glass jars and the blood samples (5 mL/dog) were collected in EDTA tubes at 0 h, 24 h, and 72 h, and at 1, 2, 3, 4, and 5 weeks post-Revolution application for selamectin residue determination. At no time during the study did the dogs show any signs of toxicity, weight loss, or change in body temperature. Extracts of the blood and the gloves were analyzed for selamectin residue using RP-HPLC coupled with a UV detector (246 nm). Selamectin standard used for peak identification and quantitation was purified from Revolution. Selamectin residue was detected in the blood (10.26 +/- 1.06 ng/mL) only at 72 h post-Revolution application, probably due to its poor dermal absorption and rapid elimination from the circulation. In the glove extracts, the highest concentration of selamectin (518.90 +/- 66.80 ppm) was detected 24 h after Revolution application. Transferable residue of selamectin in gloves from dog's coat was detected at a lesser magnitude after 1 week of Revolution application, and that was followed by a further descending trend during the second, third, and fourth weeks. No selamectin residue was detected in the glove extracts after the fifth week. In spite of selamectin's binding to the sebaceous glands of the skin, gloves contained significant transferable residue. Thus, these findings suggest that repeated exposure to selamectin can pose potential health risks, especially to veterinarians, veterinary technologists, dog trainers/handlers, and pet owners.


Towards 'Engagement 2.0': Insights from a study of dynamic consent with biobank participants.
Web 2.0 technologies have enabled new methods of engagement, moving from static mono-directional sources of information to interactive user-led experiences. Use of Web 2.0 technologies for engagement is gaining momentum within the health sector however this is still in its infancy in biobanking research. This paper reports on findings from focus groups with biobank participants to gauge their views on a Web 2.0 dynamic consent interface. The findings from this study suggest that participants would welcome more interactive engagement with biobanks, and the opportunity to hear more about how their data and samples are being used in research. We propose that by adopting Web 2.0 tools for dynamic consent, we can move towards an 'Engagement 2.0' model whereby research participants have the opportunity for more interactive engagement with medical research, setting up a two-way communication channel between participants and researchers, for the benefit of both.


The relationship between childhood sexual abuse and sexual health practices of homeless adolescents.
This study explored the gender differences in sexual self-concept, personal resources for sexual health, safe sex behaviors, and risky sexual behaviors among homeless adolescents with and without histories of sexual abuse. Data for this secondary analysis were collected in 2003 to 2004 in the first phase of a larger repeated-measures sexual health intervention study; 371 homeless youth between 16 and 23 years of age (M = 19.26, SD = 1.83) were recruited from a street outreach center. The majority (64.6%) of participants were males. Self-report instruments were completed at the outreach center via audio computer-assisted self-interview (A-CASI) format. It was found that female participants were better off than males on numerous measures of sexual health behaviors and attitudes. Sexually abused participants had significantly less future time perspective (p = .05), fewer sexual self-care behaviors (p = .04), and less social support than nonabused participants (p = .01) and almost significantly more sexual risk-taking (p = .08). However, no significant differences were found between abused and nonabused participants on sexual self-concept, self-efficacy or intention to use condoms, safe sex behaviors, AIDS knowledge, assertive communication, or self-efficacy to perform testicular/ breast self-exams. Overall, participants who did not report a history of sexual abuse had significantly more sexual health resources and engaged in fewer sex-risk behaviors than those who reported having been abused. These differences have notable implications for screening adolescents for a history of sexual abuse. Adolescents who report sexual abuse should receive risk counseling and be screened regularly for the development of sexual risk behaviors.


Acid:base and serum biochemistry changes in horses competing at a modified 1 Star 3-day-event.
We examined the effects of participation in each of 3 modifications of Day 2 of a 3-day-event on blood and serum variables indicative of hydration, acid:base status and electrolyte homeostasis of horses. Three groups of horses - 8 European (E) horses and 2 groups each of 9 North American horses performed identical Days 1 (dressage) and 3 (stadium jumping) of a 3-day-event. E horses and one group of the North American horses (TD) performed modifications of Day 2 of a 1 Star 3-day-event and the other group of North American horses (HT) performed a Horse Trial on Day 2. Jugular venous blood was collected from each horse on the morning of Day 2 before any warm-up activity, between 4 min 55 s and 5 min 15 s after Phase D and the following morning. Eight E horses, 5 TD horses and 8 HT horses completed the trials. There were few significant differences in acid:base or serum biochemistry variables detected among horses performing either 2 variations of the Speed and Endurance day of a 1 Star 3-day-event, or a conventional Horse Trial. Failure to detect differences among groups may have been related to the low statistical power associated with the small number of horses, especially in the TD group, variation in quality of horses among groups and the different times of the day at which the E horses competed. Differences detected among time points were usually common to all groups and demonstrated metabolic acidosis with a compensatory respiratory alkalosis, a reduction in total body water and cation content, and hypocalcaemia. Importantly, horses of all groups did not replenish cation, chloride, and calcium deficits after 14-18 h of recovery.


Factors Influencing Primary Care Providers' Unneeded Lumbar Spine MRI Orders for Acute, Uncomplicated Low-Back Pain: a Qualitative Study.
Clinical practice guidelines suggest that magnetic resonance imaging of the lumbar spine (LS-MRI) is unneeded during the first 6 weeks of acute, uncomplicated low-back pain. Unneeded LS-MRIs do not improve patient outcomes, lead to unnecessary surgeries and procedures, and cost the US healthcare system about $300 million dollars per year. However, why primary care providers (PCPs) order unneeded LS-MRI for acute, uncomplicated low-back pain is poorly understood. To characterize and explain the factors contributing to PCPs ordering unneeded LS-MRI for acute, uncomplicated low-back pain. Qualitative study using semi-structured interviews. Veterans Affairs PCPs identified from administrative data as having high or low rates of guideline-concordant LS-MRI ordering in 2016. Providers were interviewed about their use of LS-MRI for acute, uncomplicated low-back pain and factors contributing to their decision-making. Directed content analysis of transcripts was conducted to identify and compare environmental-, patient-, and provider-level factors contributing to unneeded LS-MRI. Fifty-five PCPs participated (8.6% response rate). Both low (n = 33) and high (n = 22) guideline-concordant providers reported that LS-MRIs were required for specialty care referrals, but they differed in how other environmental factors (stringency of radiology utilization review, management of patient travel burden, and time constraints) contributed to LS-MRI ordering patterns. Low- and high-guideline-concordant providers reported similar patient factors (beliefs in value of imaging and pressure on providers). However, provider groups differed in how provider-level factors (guideline familiarity and agreement, the extent to which they acquiesced to patients, and belief in the value of LS-MRI) contributed to LS-MRI ordering patterns. Results describe how diverse environmental, patient, and provider factors contribute to unneeded LS-MRI for acute, uncomplicated low-back pain. Prior research using a single intervention to reduce unneeded LS-MRI has been ineffective. Results suggest that multifaceted de-implementation strategies may be required to reduce unneeded LS-MRI.


Genome-Wide Sequence and Expression Analysis of the NAC Transcription Factor Family in Polyploid Wheat.
Many important genes in agriculture correspond to transcription factors (TFs) that regulate a wide range of pathways from flowering to responses to disease and abiotic stresses. In this study, we identified 5776 TFs in hexaploid wheat (Triticum aestivum) and classified them into gene families. We further investigated the NAC family exploring the phylogeny, C-terminal domain (CTD) conservation, and expression profiles across 308 RNA-seq samples. Phylogenetic trees of NAC domains indicated that wheat NACs divided into eight groups similar to rice (Oryza sativa) and barley (Hordeum vulgare). CTD motifs were frequently conserved between wheat, rice, and barley within phylogenetic groups; however, this conservation was not maintained across phylogenetic groups. Three homeologous copies were present for 58% of NACs, whereas evidence of single homeolog gene loss was found for 33% of NACs. We explored gene expression patterns across a wide range of developmental stages, tissues, and abiotic stresses. We found that more phylogenetically related NACs shared more similar expression patterns compared to more distant NACs. However, within each phylogenetic group there were clades with diverse expression profiles. We carried out a coexpression analysis on all wheat genes and identified 37 modules of coexpressed genes of which 23 contained NACs. Using gene ontology (GO) term enrichment, we obtained putative functions for NACs within coexpressed modules including responses to heat and abiotic stress and responses to water: these NACs may represent targets for breeding or biotechnological applications. This study provides a framework and data for hypothesis generation for future studies on NAC TFs in wheat.


Human tumor cells killed by anthracyclines induce a tumor-specific immune response.
Immunogenic cell death is characterized by the early surface exposure of chaperones including calreticulin and HSPs, which affect dendritic cell (DC) maturation and the uptake and presentation of tumor antigens. It has also been shown that it is characterized by the late release of high mobility group box 1 (HMGB1), which acts through Toll-like receptor 4 (TLR4) and augments the presentation of antigens from dying tumor cells to DCs. Most of the data on immunogenic tumor cell death were obtained using mouse models. In this study, we investigated the capacity of clinically used chemotherapeutics to induce immunogenic cell death in human tumor cell lines and primary tumor cells. We found that only anthracyclines induced a rapid translocation of calreticulin, HSP70, and HSP90 to the cell surface and the release of HMGB1 12 hours after the treatment. The interaction of immature DCs with immunogenic tumor cells led to an increased tumor cell uptake and induces moderate phenotypic maturation of DCs. Killed tumor cell-loaded DCs efficiently stimulated tumor-specific IFN-γ-producing T cells. DCs pulsed with killed immunogenic tumor cells also induced significantly lower numbers of regulatory T cells than those pulsed with nonimmunogenic tumor cells. These data indicate that human prostate cancer, ovarian cancer, and acute lymphoblastic leukemia cells share the key features of immunogenic cell death with mice tumor cells. These data also identify anthracyclines as anticancer drugs capable of inducing immunogenic cell death in sensitive human tumor cells.


Association of interruptions with an increased risk and severity of medication administration errors.
Interruptions have been implicated as a cause of clinical errors, yet, to our knowledge, no empirical studies of this relationship exist. We tested the hypothesis that interruptions during medication administration increase errors. We performed an observational study of nurses preparing and administering medications in 6 wards at 2 major teaching hospitals in Sydney, Australia. Procedural failures and interruptions were recorded during direct observation. Clinical errors were identified by comparing observational data with patients' medication charts. A volunteer sample of 98 nurses (representing a participation rate of 82%) were observed preparing and administering 4271 medications to 720 patients over 505 hours from September 2006 through March 2008. Associations between procedural failures (10 indicators; eg, aseptic technique) and clinical errors (12 indicators; eg, wrong dose) and interruptions, and between interruptions and potential severity of failures and errors, were the main outcome measures. Each interruption was associated with a 12.1% increase in procedural failures and a 12.7% increase in clinical errors. The association between interruptions and clinical errors was independent of hospital and nurse characteristics. Interruptions occurred in 53.1% of administrations (95% confidence interval [CI], 51.6%-54.6%). Of total drug administrations, 74.4% (n = 3177) had at least 1 procedural failure (95% CI, 73.1%-75.7%). Administrations with no interruptions (n = 2005) had a procedural failure rate of 69.6% (n = 1395; 95% CI, 67.6%-71.6%), which increased to 84.6% (n = 148; 95% CI, 79.2%-89.9%) with 3 interruptions. Overall, 25.0% (n = 1067; 95% CI, 23.7%-26.3%) of administrations had at least 1 clinical error. Those with no interruptions had a rate of 25.3% (n = 507; 95% CI, 23.4%-27.2%), whereas those with 3 interruptions had a rate of 38.9% (n = 68; 95% CI, 31.6%-46.1%). Nurse experience provided no protection against making a clinical error and was associated with higher procedural failure rates. Error severity increased with interruption frequency. Without interruption, the estimated risk of a major error was 2.3%; with 4 interruptions this risk doubled to 4.7% (95% CI, 2.9%-7.4%; P < .001). Among nurses at 2 hospitals, the occurrence and frequency of interruptions were significantly associated with the incidence of procedural failures and clinical errors.


Refined crystal structures of Escherichia coli and chicken liver dihydrofolate reductase containing bound trimethoprim.
Refined crystal structures are reported for complexes of Escherichia coli and chicken dihydrofolate reductase containing the antibiotic trimethoprim (TMP). Structural comparison of these two complexes reveals major geometrical differences in TMP binding that may be important in understanding the stereo-chemical basis of this inhibitor's selectivity for bacterial dihydrofolate reductases. For TMP bound to chicken dihydrofolate reductase we observe an altered binding geometry in which the 2,4-diaminopyrimidine occupies a position in closer proximity (by approximately 1 A) to helix alpha B compared to the pyrimidine position for TMP or methotrexate bound to E. coli dihydrofolate reductase. One important consequence of this deeper insertion of the pyrimidine into the active site of chicken dihydrofolate reductase is the loss of a potential hydrogen bond that would otherwise form between the carbonyl oxygen of Val-115 and the inhibitor's 4-amino group. In addition, for TMP bound to E. coli dihydrofolate reductase, the inhibitor's benzyl side chain is positioned low in the active-site pocket pointing down toward the nicotinamide-binding site, whereas, in chicken dihydrofolate reductase, the benzyl group is accommodated in a side channel running upward and away from the cofactor. As a result, the torsion angles about the C5-C7 and C7-C1' bonds for TMP bound to the bacterial reductase (177 degrees, 76 degrees) differ significantly from the corresponding angles for TMP bound to chicken dihydrofolate reductase (-85 degrees, 102 degrees). Finally, when TMP binds to the chicken holoenzyme, the Tyr-31 side chain undergoes a large conformational change (average movement is 5.4 A for all atoms beyond C beta), rotating down into a new position where it hydrogen bonds via an intervening water molecule to the backbone carbonyl oxygen of Trp-24.


Medical causes of temporary or definitive leaves from a French counterterrorist unit pre-internship.
Each year, the French Special Weapons And Tactics team, Groupe d'Intervention de la Gendarmerie Nationale, recruits new members through a physically demanding 8-week selection process. The goal of this study is to estimate the incidence and the causes for temporary or final interruptions during this process for medical reasons. All of the candidates for the November 2015 selection process were included in this prospective study. The number and reasons for temporary or final interruptions were documented by military general practitioners. The applicants were 48 law enforcement professionals (2 women, mean age 29.4 years, range 22-35). In 14 cases, a temporary interruption was required and in five cases the selection process prematurely ended. Fifty-two per cent of the temporary interruptions were due to sprains, tendinopathies, fractures or muscle tears, 11% were due to burns, wounds or subcutaneous bruises, 16% were due to cranial trauma and 21% were due to medical causes. The high prevalence of minor traumatology that we observed is similar to the ones observed in other cohorts describing initial training for military personnel in the conventional forces. However, the presence of other pathologies in our study, such as cranial trauma or medical causes, is due to the specificity of this internship selection granting access to an elite unit.


The Formation of Microthrombi in Parenchymal Microvessels after Traumatic Brain Injury Is Independent of Coagulation Factor XI.
Microthrombus formation and bleeding worsen the outcome after traumatic brain injury (TBI). The aim of the current study was to characterize these processes in the brain parenchyma after experimental TBI and to determine the involvement of coagulation factor XI (FXI). C57BL/6 mice (n = 101) and FXI-deficient mice (n = 15) were subjected to controlled cortical impact (CCI). Wild-type mice received an inhibitory antibody against FXI (14E11) or control immunoglobulin G 24 h before or 30 or 120 min after CCI. Cerebral microcirculation was visualized in vivo by 2-photon microscopy 2-3 h post-trauma and histopathological outcome was assessed after 24 h. TBI induced hemorrhage and microthrombus formation in the brain parenchyma (p < 0.001). Inhibition of FXI activation or FXI deficiency did not reduce cerebral thrombogenesis, lesion volume, or hemispheric swelling. However, it also did not increase intracranial hemorrhage. Formation of microthrombosis in the brain parenchyma after TBI is independent of the intrinsic coagulation cascade since it was not reduced by inhibition of FXI. However, since targeting FXI has well-established antithrombotic effects in humans and experimental animals, inhibition of FXI could represent a reasonable strategy for the prevention of deep venous thrombosis in immobilized patients with TBI.


Altered brain-wide auditory networks in a zebrafish model of fragile X syndrome.
Loss or disrupted expression of the FMR1 gene causes fragile X syndrome (FXS), the most common monogenetic form of autism in humans. Although disruptions in sensory processing are core traits of FXS and autism, the neural underpinnings of these phenotypes are poorly understood. Using calcium imaging to record from the entire brain at cellular resolution, we investigated neuronal responses to visual and auditory stimuli in larval zebrafish, using fmr1 mutants to model FXS. The purpose of this study was to model the alterations of sensory networks, brain-wide and at cellular resolution, that underlie the sensory aspects of FXS and autism. Combining functional analyses with the neurons' anatomical positions, we found that fmr1-/- animals have normal responses to visual motion. However, there were several alterations in the auditory processing of fmr1-/- animals. Auditory responses were more plentiful in hindbrain structures and in the thalamus. The thalamus, torus semicircularis, and tegmentum had clusters of neurons that responded more strongly to auditory stimuli in fmr1-/- animals. Functional connectivity networks showed more inter-regional connectivity at lower sound intensities (a - 3 to - 6 dB shift) in fmr1-/- larvae compared to wild type. Finally, the decoding capacities of specific components of the ascending auditory pathway were altered: the octavolateralis nucleus within the hindbrain had significantly stronger decoding of auditory amplitude while the telencephalon had weaker decoding in fmr1-/- mutants. We demonstrated that fmr1-/- larvae are hypersensitive to sound, with a 3-6 dB shift in sensitivity, and identified four sub-cortical brain regions with more plentiful responses and/or greater response strengths to auditory stimuli. We also constructed an experimentally supported model of how auditory information may be processed brain-wide in fmr1-/- larvae. Our model suggests that the early ascending auditory pathway transmits more auditory information, with less filtering and modulation, in this model of FXS.


Blockade of IL-1R signaling diminishes Paneth cell depletion and Toxoplasma gondii induced ileitis in mice.
Interleukin 1 is a critical inflammatory mediator and involved in host defense to several pathogens. Oral T. gondii infection causes lethal ileitis in C57BL/6 (BL6) mice and serves to investigate the mechanisms of acute intestinal inflammation. Here we show that IL-1 is expressed upon oral T. gondii (76K strain) infection in the small intestine and mediates ileitis as IL-1R1 deficient mice have reduced neutrophil recruitment in the lamina propria, parasite invasion, inflammatory lesions and enhanced survival as compared to BL6 infected control mice. Protection in the absence of IL-1R1 signaling was associated with reduced IFN-γ expression and preserved Paneth cells, while these cells were eliminated in infected BL6 mice. Furthermore, blockade of IL-1 by IL-1β antibody attenuated inflammation in BL6 mice. In conclusion, IL-1 signaling contributes to the inflammatory response with increase IFN-γ expression and Paneth cell depletion upon oral T. gondii infection.


A vector-free microfluidic platform for intracellular delivery.
Intracellular delivery of macromolecules is a challenge in research and therapeutic applications. Existing vector-based and physical methods have limitations, including their reliance on exogenous materials or electrical fields, which can lead to toxicity or off-target effects. We describe a microfluidic approach to delivery in which cells are mechanically deformed as they pass through a constriction 30-80% smaller than the cell diameter. The resulting controlled application of compression and shear forces results in the formation of transient holes that enable the diffusion of material from the surrounding buffer into the cytosol. The method has demonstrated the ability to deliver a range of material, such as carbon nanotubes, proteins, and siRNA, to 11 cell types, including embryonic stem cells and immune cells. When used for the delivery of transcription factors, the microfluidic devices produced a 10-fold improvement in colony formation relative to electroporation and cell-penetrating peptides. Indeed, its ability to deliver structurally diverse materials and its applicability to difficult-to-transfect primary cells indicate that this method could potentially enable many research and clinical applications.


Search superiority in autism within, but not outside the crowding regime.
Visual cognition of observers with autism spectrum disorder (ASD) seems to show an unbalance between the complementary functions of integration and segregation. This study uses visual search and crowding paradigms to probe the relative ability of children with autism, compared to normal developments children, to extract individual targets from cluttered backgrounds both within and outside the crowding regime. The data show that standard search follows the same pattern in the ASD and control groups with a strong effect of the set size that is substantially weakened by cueing the target location with a synchronous spatial cue. On the other hand, the crowding effect of eight flankers surrounding a small peripheral target is virtually absent in the clinical sample, indicating a superior ability to segregate cluttered visual items. This data, along with evidence of an impairment to the neural system for binding contours in ASD, bring additional support to the general idea of a shift of the trade-off between integration and segregation toward the latter. More specifically, they show that when discriminability is balanced across conditions, an advantage in odd-man out tasks is evident in ASD observers only within the crowding regime, when binding mechanism might get compulsorily triggered in normal observers.


Knockdown of Sestrin2 Increases Lipopolysaccharide-Induced Oxidative Stress, Apoptosis, and Fibrotic Reactions in H9c2 Cells and Heart Tissues of Mice via an AMPK-Dependent Mechanism.
Sestrin2 (sesn2) is an endogenous antioxidant protein that has recently gained attention for its potential to treat various inflammatory diseases. However, the relationship of sesn2 with cardiomyopathy is still unclear. In H9c2 cells, sesn2 knockdown reduced the level of 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, downregulated antioxidant genes including catalase and superoxide dismutase (SOD2), and increased reactive oxygen species (ROS) production upon lipopolysaccharide (LPS) treatment. LPS-mediated cell death and the expression of matrix metalloproteinase (MMP) 2 and MMP9 were significantly increased by sesn2 knockdown. However, these increases were prevented by treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator. Consistent with the in vitro results, AMPK phosphorylation was decreased in heart tissue from sesn2 knockdown mice compared to heart tissue from control C57BL/6 mice, which was associated with decreased expression of antioxidant genes and increased LPS-mediated cell death signaling. Furthermore, the decrease in AMPK phosphorylation caused by sesn2 knockdown increased LPS-mediated expression of cardiac fibrotic factors, including collagen type I and type III, in addition to MMP2 and MMP9, in heart tissue from C57BL/6 mice. These results suggest that sesn2 is a novel potential therapeutic target for cardiomyopathy under inflammatory conditions.


Does the death of a child influence parental use of psychotropic medication? A follow-up register study from Finland.
Several studies have found that the loss of a child is associated with psychiatric health problems, yet few studies examined whether child loss influences psychotropic medication use. This study examined short- and long-term use of psychotropic medication, both before and after the death of a child, and its potential effect modifiers. A random sample of 205,456 parents, including 902 bereaved parents, were selected from a Finnish total population registry. The analyses were based on linear regressions using generalised estimation equations (GEE) and adjusted for sociodemographic factors. Annual psychotropic use was defined as having purchased prescribed psychotropic medication between 1996 and2012. Bereaved parents were followed for four years prior to and up to four years after the death of their child. An increase in the use of antidepressants and anxiolytics was found in parents following their loss. The highest percentage of use was found around one year after bereavement, followed by a steady decrease although this remained higher than the level of use among non-bereaved four years after the death. Between 20-25% of bereaved mothers and 10-15% of bereaved fathers used antidepressants or anxiolytics one year after bereavement while the corresponding number in non-bereaved was 5-10%. An increase in psychotropic medication was also found several years before the disease-related loss of a child. The use of psychotropic medication is markedly higher among parents after losing a child. Patterns of use leading up to and following the death of a child should be further examined in relation to clinical risk factors so as to identify at risk populations. Bereavement, child death, psychotropic medication, death, child, register, Finland.


Functional analysis of a Wheat Homeodomain protein, TaR1, reveals that host chromatin remodelling influences the dynamics of the switch to necrotrophic growth in the phytopathogenic fungus Zymoseptoria tritici.
A distinguishing feature of Septoria leaf blotch disease in wheat is the long symptomless growth of the fungus amongst host cells followed by a rapid transition to necrotrophic growth resulting in disease lesions. Global reprogramming of host transcription marks this switch to necrotrophic growth. However no information exists on the components that bring about host transcriptional reprogramming. Gene-silencing, confocal-imaging and protein-protein interaction assays where employed to identify a plant homeodomain (PHD) protein, TaR1 in wheat that plays a critical role during the transition from symptomless to necrotrophic growth of Septoria. TaR1-silenced wheat show earlier symptom development upon Septoria infection but reduced fungal sporulation indicating that TaR1 is key for prolonging the symptomless phase and facilitating Septoria asexual reproduction. TaR1 is localized to the nucleus and binds to wheat Histone 3. Trimethylation of Histone 3 at lysine 4 (H3K4) and lysine 36 (H3K36) are found on open chromatin with actively transcribed genes, whereas methylation of H3K27 and H3K9 are associated with repressed loci. TaR1 specifically recognizes dimethylated and trimethylated H3K4 peptides suggesting that it regulates transcriptional activation at open chromatin. We conclude that TaR1 is an important component for the pathogen life cycle in wheat that promotes successful colonization by Septoria.


Association Between Cortical Bone Microstructure and Statin Use in Older Women.
Treatment with statins has been associated with increased bone mineral density, but whether this association depends on differences in cortical or trabecular volumetric bone microstructure is unknown. The aim of this study was to investigate if treatment with statins is associated with bone microstructure and geometry in older women. Older women were included in a population-based study of 3028 women (mean age ± SD, 77.8 ± 1.6 years) from the greater Gothenburg area in Sweden. Information regarding medical history, medication, and lifestyle factors was obtained from validated questionnaires. Bone geometry and microstructure were measured at the ultradistal and distal (14%) site of radius and tibia using high-resolution peripheral quantitative computed tomography. The 803 women in the cohort who used statins had higher body weight, worse physical function, and more frequent cardiovascular disease and diabetes than nonusers (P < 0.05). Statin users had lower cortical porosity (radius, 2.2 ± 1.9 vs 2.5 ± 2.0%; tibia, 5.2 ± 2.4 vs 5.4 ± 2.5; P = 0.01), higher cortical bone density (radius, 1008 ± 39.1 vs 1001 ± 38.4 mg/cm3; tibia, 919 ± 42.6 vs 914 ± 41.5; P < 0.01), and greater cortical area (radius, 60.5 ± 9.6 vs 58.6 ± 9.7 mm2; tibia, 150.0 ± 23.6 vs 146.7 ± 23.8; P < 0.01) than nonusers after adjustment for a large number of confounders, including age, weight, smoking, other medications, and prevalent diseases. Use of statins was associated with better cortical bone characteristics in older women.


Factors influencing the use of bed nets in Mbarara municipality of Uganda.
In order to identify independent predictors for bed net use, respondents from 643 households selected randomly from 21 clusters were interviewed in Mbarara municipality, Uganda. Respondents answered questions about demographic characteristics, social economic conditions, causes and transmission of malaria, beliefs about severity and complications of malaria, malaria morbidity and health care-seeking behavior, perceived control of malaria prevention, beliefs about utility of bed nets, perceived susceptibility to malaria, and whether they use bed nets or not. Univariate and multivariate logistic regression analyses were used to identify predictors for bed net use. Fifty-five percent (356 of 643) of the households had bed net users. The independent factors that favored bed net use were as follows: 1) age < 30 years, 2) ownership of a television, 3) having mosquito nets in ventilators of the house, 4) being a skilled worker or a professional, or owning a major business, 5) living in a permanent house, 6) believing that bed nets prevent malaria, 7) believing that bed nets are worth their cost, 8) not believing that convulsions cannot be cured by modern medicine, and 9) believing that bed nets are not expensive. The strongest predictors of bed net use are living in a permanent house and agreeing that bed nets are worth their cost, with adjusted odds ratios of 4.29 (95% confidence interval, 2.76-6.71) and 3.93 (95% confidence interval, 2.5-26.13), respectively. These data suggest that in order to increase the use of bed nets, the price of bed nets needs to be reduced and educational messages that stress the favorable use of bed nets need to be increased.


Temporal channels and disparity representations in stereoscopic depth perception.
Stereoscopic depth perception is supported by a combination of correlation-based and match-based representations of binocular disparity. It also relies on both transient and sustained temporal channels of the visual system. Previous studies suggest that the relative contribution of the correlation-based representation (over the match-based representation) and the transient channel (over the sustained channel) to depth perception increases with the disparity magnitude. The mechanisms of the correlation-based and match-based representations may receive preferential inputs from the transient and sustained channels, respectively. We examined near/far discrimination by observers using random-dot stereograms refreshed at various rates. The relative contribution of the two representations was inferred by changing the fraction of dots that were contrast reversed between the two eyes. Both representations contributed to depth discrimination over the tested range of refresh rates. As the rate increased, the correlation-based representation increased its contribution to near/far discrimination. Another experiment revealed that the match-based representation was constructed by exploiting the variability in correlation-based disparity signals. Thus, the relative weight of the transient over sustained channel differs between the two representations. The correlation-based representation dominates depth perception with dynamic inputs. The match-based representation, which may be a nonlinear refinement of the correlation-based representation, exerts more influence on depth perception with slower inputs.


Knee Extensor Power Relates to Mobility Performance in People With Knee Osteoarthritis: Cross-Sectional Analysis.
Quadriceps femoris muscle strengthening is a common rehabilitation exercise for knee osteoarthritis (OA). More information is needed to determine whether targeting muscle power is a useful adjunct to strengthening for people with knee OA. The purpose of this study was to identify the predictive ability of knee extensor strength and knee extensor power in the performance of physical tasks in adults with knee OA. This study used a cross-sectional design. Fifty-five participants with clinical knee OA were included (43 women; mean [SD] age=60.9 [6.9] years). Dependent variables were: timed stair ascent, timed stair descent, and the Six-Minute Walk Test (6MWT). Independent variables were: peak knee extensor strength and mean peak knee extensor power. Covariates were: age, body mass index, and self-efficacy. Multiple regression analyses were run for each dependent variable with just covariates, then a second model including strength, and then a third model including power. The R(2) values were compared between models. Power explained greater variance than strength in all models. Over and above the covariates, power explained an additional 6% of the variance in the 6MWT, increasing the R(2) value from .33 to .39; 8% in the stair ascent test, increasing the R(2) value from .52 to .60; and 3% in the stair descent test, increasing the R(2) value from .44 to .47. The sample demonstrated very good mobility and muscle function scores and may not be indicative of those with severe knee OA. In adults with knee OA, knee extensor power was a stronger determinant of walking and stair performance when compared with knee extensor strength. Clinicians should consider these results when advising patients on exercise to maintain or improve mobility.


Disease-Phenotype Deconvolution in Genetic Eye Diseases Using Online Mendelian Inheritance in Man.
Capturing organ-specific phenomes in genetic diseases is an uphill task for the eye as it comprises tissue types derived from all three germinal layers. We attempted to deconstruct genetic eye diseases (GEDs) into primary phenotypic features, to understand the complex genome-phenome relationship in GEDs. Using phenotype, molecular basis, and gene description features in OMIM as a primary resource, we analyzed gene-phenotype information. All ocular and systemic phenotypes were categorized and ranked based on occurrence. Clustering was performed on shared ocular features to identify genetic interactions and the largest cluster of each phenotype was used for functional analyses. We collected 527 GEDs associated with 440 unique protein-coding genes. We indexed 787 ocular and 3094 systemic features, for an average of 2.17 ocular and 8.14 systemic features, respectively, per disease unit. The most common ocular features included nystagmus, hypertelorism, and myopia, while neurological and skeletal are the most common systemic groups associated with GEDs. Functional analyses revealed pathways relevant to GEDs (e.g., extracellular matrix organization in ONH3 [glaucoma]) and protein metabolism in EOM35 (nystagmus) phenotype clusters. Our work imparts a structure in dissecting GEDs into unique phenotypes to study the relationship between genes and diseases involving the eye.


Continuing evolution in the approach to severe liver trauma.
Surgical and radiologic techniques from computed tomography (CT) scanning and embolization to temporary gauze packing and mesh hepatorrhaphy have been developed to make the management of severe liver injuries more effective. Surgical approaches for severe liver trauma have been oriented to two major consequences of these injuries: hemorrhage and infection. Early attempts at hemorrhagic control found benefit only in temporary intrahepatic gauze packing. The subsequent recognition of complications after liver injury blamed the practice of packing, which then remained unused for more than 30 years. Yet more aggressive attempts at controlling hemorrhage without temporary packing failed to improve results. Temporary perihepatic gauze packing therefore has been reintroduced, but this is probably an imperfect solution. Mesh hepatorrhaphy may control bleeding without many of the adverse effects of packing. Fourteen patients are reported with severe liver injuries who have undergone mesh hepatorrhaphy, bringing the current reported experience with mesh hepatorrhaphy to 24, with a combined mortality rate of 37.5%. Thus far, it appears that only juxtacaval injuries fail to have their hemorrhage controlled with mesh hepatorrhaphy, but many believe that these injuries may be controlled by perihepatic packing. Prophylactic drainage of severe liver injuries is a concept for which there is little evidence of benefit. Furthermore, recent radiologic developments appear capable of draining those collections that do occasionally develop in the postoperative period. The ultimate challenge of liver transplantation for trauma has been attempted, but the experience is thus far very limited.


IGF-I prevents glutamate-induced motor neuron programmed cell death.
Insulin-like growth factor I (IGF-I) is currently in clinical trials for treatment of amyotrophic lateral sclerosis (ALS), but little is known about how it promotes the survival of motor neurons. In the current study, we examined IGF-I-mediated neuroprotection in an in vitro model of ALS utilizing enriched cultures of embryonic rat spinal cord motor neurons. IGF-I binds to the IGF-I receptor (IGF-IR) in motor neurons and activates MAPK and the downstream effector of phosphatidylinositol 3-kinase (PI-3K) signaling, Akt. IGF-I:IGF-IR signaling involves phosphorylation of IRS-1 and Shc, but not IRS-2. Glutamate, which is elevated in the cerebrospinal fluid of ALS patients, induced DNA fragmentation and caspase-3 cleavage in the spinal cord motor neurons. These effects of glutamate were blocked by co-treatment with IGF-I. However, a delay of IGF-I treatment for as little as 30 min eliminated its neuroprotective effect. Finally, alone, neither the MAPK pathway inhibitor PD98059 nor the PI-3K inhibitor LY294002 blocked the neuroprotective effect of IGF-I, but both inhibitors together were effective in this regard. These results suggest that the dose and timing of IGF-I administration are critical for producing a neuroprotective effect, and also suggest that both the MAPK and PI-3K/Akt pathways can promote the survival of motor neurons. We discuss our results in terms of novel strategies for ALS therapy.


Risk factors, incidence and persistence of symptoms from the eyes among professional computer users.
Symptoms from the eyes are common among computer users. Knowledge is scarce about these problems, however. The aim was to study risk-factors, incidence and persistence of eye-symptoms among professionally active computer users. This was a questionnaire based prospective study where 1283 males and females from different professions and companies answered a baseline questionnaire about individual factors and working conditions, e.g. duration of daily computer work, comfort of screen work, psychosocial factors. Subjects were at baseline and 10 follow-ups asked about the number of days with eye-symptoms during the preceding month. The incidence-rate of symptoms persisting minimum three days was 0.38/person-year. A multivariate Hazard-ratio model showed significant associations with extended continuous computer work, tasks with high demands on eye-hand coordination, low level of control, visual discomfort, female sex and nicotine use. Eye-symptoms at baseline was a strong risk factor for new symptoms. The incidence of eye-symptoms among professional computer users is high and related to both individual and work-related factors. The organization of computer work should secure frequent breaks from near-work at the computer screen. The severity of vision-related problems could in field studies be quantified by asking for the persistence of symptoms.


Effects of Arm Cycling Exercise in Spinal Muscular Atrophy Type II Patients: A Pilot Study.
Exercise studies in neuromuscular diseases like spinal muscular atrophy (SMA), a devastating disease caused by survival of motor neuron 1 ( SMN1) gene mutations, are drawing attention due to its beneficial effects. In this study, we presented a constructed arm cycling exercise protocol and evaluated the benefits on SMA patients. Five SMA type II patients performed 12 weeks of supervised arm cycling exercise. The physical functions were evaluated together with the SMN2 copy numbers, SMN protein levels, insulin-like growth factor 1(IGF1) and binding protein 3 (IGFBP3) levels. The active cycling distance and duration of patients significantly improved. Significant changes could not have detected either SMN or IGF1 and IGFBP3 levels in response to exercise. The findings demonstrated that the patients tolerated the exercise protocol and gained a benefit from arm cycling but benefits could not be associated with SMN2 copy number, SMN protein level, IGF1, or IGFBP3 levels.


Proliferation of human colon cancer cells: role of epidermal growth factor and transforming growth factor alpha.
Human colon cancer cells produce and secrete a variety of polypeptide growth factors. The functional role of these growth factors, however, is poorly understood. Though the secretion of epidermal growth factor (EGF)-like activity and EGF-related molecules by human colon cancer cells in culture has been reported, it is not known whether colon cancer cells produce and secrete EGF, and the functional role of EGF in the growth control of these cells is also unknown. We have shown that EGF acts as a potent growth stimulator on the moderately differentiated Moser colon cancer cell line and as an inhibitor on the highly metastatic KM12SM cell line. In the present study, we show that EGF is produced by human colon cancer cells and characterize the levels of EGF mRNA expression and EGF protein secretion from 8 human colon cancer cell lines. The cell-surface EGF receptors on these cell lines were also characterized by radiolabeled ligand binding and Scatchard analyses. All the cell lines expressed EGF mRNA and secreted EGF. Both high- and low-affinity subtypes of EGF receptor were detected on 7 of the cell lines. These lines also secreted transforming growth factor (TGF)alpha. Some cell lines exhibited a proliferative response to treatment with either exogenous EGF or TGF alpha, while others did not respond to treatment with these growth factors. Antibody-blocking experiments, using anti-EGF or anti-EGF receptor antibody, suggested that these cell lines could be broadly classified into 2 groups in terms of their autocrine or paracrine growth regulation via the cell-surface EGF receptor: (1) cells that utilized EGF and/or TGF alpha; and (2) cells that did not utilize EGF or TGF alpha (via the cell-surface receptor), even though they secreted abundant amounts of these growth factors.


Half of obsessive-compulsive disorder cases misdiagnosed: vignette-based survey of primary care physicians.
Medical settings are the primary mode of care for mental health problems; physicians' abilities with regard to psychiatric diagnosis and treatment recommendations are therefore essential. While misdiagnosis can occur across all psychiatric conditions, the heterogeneous nature of obsessive-compulsive disorder (OCD) may make this condition at an elevated risk for misidentification. The study's aim was to assess primary care physicians' ability to identify OCD. The study was cross-sectional in design. An online, vignette-based survey was emailed to 1,172 physicians from 5 major medical hospitals in the Greater New York Area. The email included a link to the survey, which consisted of 1 of 8 randomized OCD vignettes; each vignette focused on one of the following common manifestations of OCD: obsessions regarding aggression, contamination, fear of saying things, homosexuality, pedophilia, religion, somatic concerns, or symmetry. Participants provided diagnostic impressions and treatment recommendations for the individual described in the vignette. Data collection took place from December 10, 2012, through January 18, 2013. Two hundred eight physicians completed the survey. The overall misidentification rate was 50.5%. Vignette type was the strongest predictor of a correct OCD response (Wald χ(2)7 = 40.58; P <.0001). Misidentification rates by vignette were homosexuality (84.6%), aggression (80.0%), saying certain things (73.9%), pedophilia (70.8%), somatic concerns (40.0%), religion (37.5%), contamination (32.3%), and symmetry (3.70%). Participants who misidentified the OCD vignette were less likely to recommend a first-line empirically supported treatment (cognitive-behavioral therapy [CBT] = 46.7%, selective serotonin reuptake inhibitor [SSRI] = 8.6%) compared to participants who correctly identified the OCD vignette (CBT = 66.0%, SSRI = 35.0%). Antipsychotic recommendation rates were elevated among incorrect versus correct responders (12.4% vs 1.9%). Elevated OCD misdiagnosis rates and the impact of incorrect diagnoses on treatment recommendations highlight the need for greater training regarding OCD symptomatology and empirically supported treatments.


Visualization of Bacterial Protein Complexes Labeled with Fluorescent Proteins and Nanobody Binders for STED Microscopy.
In situ visualization of molecular assemblies near their macromolecular scale is a powerful tool to investigate fundamental cellular processes. Super-resolution light microscopies (SRM) overcome the diffraction limit and allow researchers to investigate molecular arrangements at the nanoscale. However, in bacterial cells, visualization of these assemblies can be challenging because of their small size and the presence of the cell wall. Thus, although conceptually promising, successful application of SRM techniques requires careful optimization in labeling biochemistry, fluorescent dye choice, bacterial biology and microscopy to gain biological insights. Here, we apply Stimulated Emission Depletion (STED) microscopy to visualize cell division proteins in bacterial cells, specifically E. coli and B. subtilis. We applied nanobodies that specifically recognize fluorescent proteins, such as GFP, mCherry2 and PAmCherry, fused to targets for STED imaging and evaluated the effect of various organic fluorescent dyes on the performance of STED in bacterial cells. We expect this research to guide scientists for in situ macromolecular visualization using STED in bacterial systems.


Current State of Dendritic Cell-Based Immunotherapy: Opportunities for in vitro Antigen Loading of Different DC Subsets?
Dendritic cell (DC) based cancer immunotherapy aims at the activation of the immune system, and in particular tumor-specific cytotoxic T lymphocytes (CTLs) to eradicate the tumor. DCs represent a heterogeneous cell population, including conventional DCs (cDCs), consisting of cDC1s, cDC2s, plasmacytoid DCs (pDCs), and monocyte-derived DCs (moDCs). These DC subsets differ both in ontogeny and functional properties, such as the capacity to induce CD4+ and CD8+ T-cell activation. MoDCs are most frequently used for vaccination purposes, based on technical aspects such as availability and in vitro expansion. However, whether moDCs are superior over other DC subsets in inducing anti-tumor immune responses, is unknown, and likely depends on tumor type and composition of the tumor microenvironment. In this review, we discuss cellular aspects essential for DC vaccination efficacy, and the most recent findings on different DC subsets that could be used for DC-based cancer immunotherapy. This can prove valuable for the future design of more effective DC vaccines by choosing different DC subsets, and sheds light on the working mechanism of DC immunotherapy.


Decreased expression of GRAF1/OPHN-1-L in the X-linked alpha thalassemia mental retardation syndrome.
ATRX is a severe X-linked disorder characterized by mental retardation, facial dysmorphism, urogenital abnormalities and alpha-thalassemia. The disease is caused by mutations in ATRX gene, which encodes a protein belonging to the SWI/SNF DNA helicase family, a group of proteins involved in the regulation of gene transcription at the chromatin level. In order to identify specific genes involved in the pathogenesis of the disease, we compared, by cDNA microarray, the expression levels of approximately 8500 transcripts between ATRX and normal males of comparable age. cDNA microarray was performed using total RNA from peripheral blood mononuclear cells of ATRX and normal males. Microarray results were validated by quantitative real-time polymerase chain reaction. cDNA microarray analysis showed that 35 genes had a lower expression (30-35% of controls) while 25 transcripts had a two-fold higher expression in comparison to controls. In the microarray results the probe for oligophrenin-1, a gene known for its involvement in mental retardation, showed a decreased hybridization signal. However, such gene was poorly expressed in blood mononuclear cells and its decrease was not confirmed in the quantitative real-time RT-PCR assay. On the other hand, the expression of an homologous gene, the GTPase regulator associated with the focal adhesion kinase 1/Oligophrenin-1-like (GRAF1/OPHN-1-L), was relatively high in blood mononuclear cells and significantly decreased in ATRX patients. The analysis of the expression pattern of the GRAF1/OPHN-1-L gene in human tissues and organs revealed the predominant brain expression of a novel splicing isoform, called variant-3. Our data support the hypothesis of a primary role for altered gene expression in ATRX syndrome and suggest that the GRAF1/OPHN-1-L gene might be involved in the pathogenesis of the mental retardation. Moreover a novel alternative splicing transcript of such gene, predominantly expressed in brain tissues, was identified.


A review of fetal volumetry: the need for standardization and definitions in measurement methodology.
Volume charts of fetal organs and structures vary considerably among studies. This review identified 42 studies reporting normal volumes, namely for fetal brain (n = 3), cerebellum (n = 4), liver (n = 6), femur (n = 2), lungs (n = 15), kidneys (n = 3) and first-trimester embryo (n = 9). The differences among median volumes were expressed both in percentage form and as standard deviation scores. Wide discrepancies in reported normal volumes make it extremely difficult to diagnose pathological organ growth reliably. Given its magnitude, this variation is likely to be due to inconsistencies in volumetric methodology, rather than population differences. Complicating factors include the absence of clearly defined anatomical landmarks for measurement; inadequate assessment and reporting of method repeatability; the inherent difficulty in validating fetal measurements in vivo against a reference standard; and a multitude of mutually incompatible three-dimensional (3D) imaging formats and software measuring tools. An attempt to standardize these factors would improve intra- and inter-researcher agreement concerning reported volumetric measures, would allow generalization of reference data across different populations and different ultrasound systems, and would allow quality assurance in 3D fetal biometry. Failure to ensure a quality control process may hamper the wide use of 3D ultrasound.


An overlapping pattern of cerebral cortical thinning is associated with both positive symptoms and aggression in schizophrenia via the ENIGMA consortium.
Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample. To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls. The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression. These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.


Scale distortion from pressure baselines as a source of inaccuracy in triple-isotope measurements.
Isotope ratio measurements have become extremely precise in recent years, with many approaching parts-per-million (ppm) levels of precision. However, seemingly innocuous errors in signal baselines, which exist only when gas enters the instrument, might lead to significant errors. These "pressure-baseline" (PBL) offsets may have a variety of origins, such as incoherent scattering of the analyte, isobaric interferences, or electron ablation from the walls of the flight tube. They are probably present in all but ultra-high-resolution instruments, but their importance for high-precision measurements has not been investigated. We derive the governing equations for the PBL effect. We compare the oxygen triple-isotope composition of gases on three different mass spectrometers before and after applying a correction for PBLs to determine their effects. We also compare the composition of atmospheric O2 with that of several standard minerals (San-Carlos Olivine and UWG-2) on two high-precision mass spectrometers and compare those results with the differences reported in the literature. We find that PBLs lead to stretching or compression of isotopic variations. The scale distortion is non-mass-dependent, affecting the accuracy of triple-isotope covariations. The governing equations suggest that linear stretching corrections using traditional isotopic delta values (e.g., δ18 O) are rigorous for PBL-induced errors in pure gases. When the reference and sample gases are not comparable in composition or purity, however, a different correction scheme may be required. These non-mass-dependent errors are systematic and may have influenced previous measurements of triple-isotope covariations in natural materials. Accurate measurements of isotopic variations are essential to biogeochemistry and for testing theoretical models of isotope effects. PBLs are probably ubiquitous, contributing to the interlaboratory disagreements in triple-isotope compositions of materials differing greatly in δ18 O values. Moreover, they may lead to inaccurate determination of triple-isotope compositions and fractionation factors, which has implications for isotopic studies in hydrology and biogeochemistry.


CC3/TIP30 affects DNA damage repair.
The pro-apoptotic protein CC3/TIP30 has an unusual cellular function as an inhibitor of nucleocytoplasmic transport. This function is likely to be activated under conditions of stress. A number of studies support the notion that CC3 acts as a tumor and metastasis suppressor in various types of cancer. The yeast homolog of CC3 is likely to be involved in responses to DNA damage. Here we examined the potential role of CC3 in regulation of cellular responses to genotoxic stress. We found that forced expression of CC3 in CC3-negative cells strongly delays the repair of UV-induced DNA damage. Exogenously introduced CC3 negatively affects expression levels of DDB2/XPE and p21CIP1, and inhibits induction of c-FOS after UV exposure. In addition, exogenous CC3 prevents the nuclear accumulation of P21CIP in response to UV. These changes in the levels/localization of relevant proteins resulting from the enforced expression of CC3 are likely to contribute to the observed delay in DNA damage repair. Silencing of CC3 in CC3-positive cells has a modest delaying effect on repair of the UV induced damage, but has a much more significant negative affect on the translesion DNA synthesis after UV exposure. This could be related to the higher expression levels and increased nuclear localization of p21CIP1 in cells where expression of CC3 is silenced. Expression of CC3 also inhibits repair of oxidative DNA damage and leads to a decrease in levels of nucleoredoxin, that could contribute to the reduced viability of CC3 expressing cells after oxidative insult. Manipulation of the cellular levels of CC3 alters expression levels and/or subcellular localization of proteins that exhibit nucleocytoplasmic shuttling. This results in altered responses to genotoxic stress and adversely affects DNA damage repair by affecting the recruitment of adequate amounts of required proteins to proper cellular compartments. Excess of cellular CC3 has a significant negative effect on DNA repair after UV and oxidant exposure, while silencing of endogenous CC3 slightly delays repair of UV-induced damage.


A machine-learning approach for extending classical wildlife resource selection analyses.
Resource selection functions (RSFs) are tremendously valuable for ecologists and resource managers because they quantify spatial patterns in resource utilization by wildlife, thereby facilitating identification of critical habitat areas and characterizing specific habitat features that are selected or avoided. RSFs discriminate between known-use resource units (e.g., telemetry locations) and available (or randomly selected) resource units based on an array of environmental features, and in their standard form are performed using logistic regression. As generalized linear models, standard RSFs have some notable limitations, such as difficulties in accommodating nonlinear (e.g., humped or threshold) relationships and complex interactions. Increasingly, ecologists are using flexible machine-learning methods (e.g., random forests, neural networks) to overcome these limitations. Herein, we investigate the seasonal resource selection patterns of mule deer (Odocoileus hemionus) by comparing a logistic regression framework with random forest (RF), a popular machine-learning algorithm. Random forest (RF) models detected nonlinear relationships (e.g., optimal ranges for slope and elevation) and complex interactions which would have been very challenging to discover and characterize using standard model-based approaches. Compared with standard RSF models, RF models exhibited improved predictive skill, provided novel insights about resource selection patterns of mule deer, and, when projected across a relevant geographic space, manifested notable differences in predicted habitat suitability. We recommend that wildlife researchers harness the strengths of machine-learning tools like RF in addition to "classical" tools (e.g., mixed-effects logistic regression) for evaluating resource selection, especially in cases where extensive telemetry data sets are available.


[Transfusion practices in brazilian Intensive Care Units (pelo FUNDO-AMIB)].
Anemia of critical illness is a multifactorial condition caused by blood loss, frequent phlebotomies and inadequate production of red blood cells (RBC). Controversy surrounds the most appropriate hemoglobin concentration "trigger" for transfusion of RBC. We aimed to evaluate transfusion practices in Brazilian ICUs. A prospective study throughout a 2-week period in 19 Brazilian ICUs. Hemoglobin (Hb) level, transfusion rate, organ dysfunction assessment and 28-day mortality were evaluated. Primary indication for transfusion and pretransfusion hemoglobin level were collected for each transfusion. Two hundred thirty-one patients with an ICU length of stay longer than 48h were included. An Hb level lower than 10 g/dL was found in 33% on admission in the ICU. A total of 348 RBC units were transfused in 86 patients (36.5%). The mean pretransfusion hemoglobin level was 7.7 ± 1.1 g/dL. Transfused-patients had significantly higher SOFA score (7.9 ± 4.6 vs 5.6 ± 3.8, p < 0.05, respectively), days on mechanical ventilation (10.7 ± 8.2 vs 7.2 ± 6.4, p < 0.05) and days on vasoactive drugs (6.7 ± 6.4 vs 4.2 ± 4.0, p < 0.05) than non-transfused patients despite similar APACHE II scores (15.2 ± 8.1 vs 14.2 ± 8.1, NS). Transfused patients had higher mortality rate (43.5%) than non-transfused patients (36.3%) (RR 0.60-1.15, NS). Only one patient (0.28%) had febrile non-hemolytic transfusion and urticarial reactions. Anemia is common in critically ill patients.It seems from the present study that transfusion practices in Brazil have had a more restrictive approach with a lower limit "transfusion trigger".


Regional and neuronal reductions of polyadenylated messenger RNA in Alzheimer's disease.
Messenger RNA (mRNA) is the key intermediate in the gene expression pathway. The amount of mRNA in Alzheimer's disease (AD) brains has been determined using in situ hybridization histochemistry (ISHH) to detect the poly(A) tails of polyadenylated mRNA (poly(A) + mRNA). On a regional basis, AD cases had significantly less poly(A) + mRNA than controls in hippocampus (field CA3) and cerebellum (granule cell layer). Analysis of constituent pyramidal neurons showed mean reductions per cell within AD hippocampus (field CA3) and temporal cortex, but not in visual cortex. Similar changes were seen in a small group of non-AD dementias. The finding of reduced poly(A) + mRNA content is another indication of the altered brain gene expression occurring in AD. It is proposed that measurement of poly(A) + mRNA may be valuable in identifying functionally impaired neuronal populations. The methodology also provides a means by which changes in the quantitative distribution of individual mRNAs can be determined relative to that of poly(A) + mRNA as a whole.


Effect of different bariatric operations on food tolerance and quality of eating.
Many bariatric operations are associated with reduced food tolerance and frequent vomiting, which may cause nutritional deficiencies and influence quality of life. However, the impact of different bariatric procedures on quality of eating and food tolerance has not yet been studied enough. Two hundred and eighteen participants filled a quality of eating questionnaire, at three different time periods after bariatric operation: short-term (3-6 months, n = 63), medium-term (6-12 months, n = 69) and long-term follow-up (over 12 months, n = 86). The participants underwent the following procedures: 99 patients have had Roux-en-Y gastric bypass (RYGB), 49 laparoscopic gastric banding (LAGB), 56 sleeve gastrectomy (SG), and 14 biliopancreatic diversion with duodenal switch (BPD-DS). At short-term period score achieved for all section of the questionnaire was similar for all operations. The total score of the questionnaire at the medium-term group was 20.27 ± 3.57, 14.47 ± 5.92, 22.27 ± 4.66, and 20.91 ± 3.26 (p < 0.001) and the total score for the long-term group of was 21.56 ± 5.16, 15.5 ± 3.75, 20.45 ± 4.9, and 24.2 ± 2.16 (p < 0.001) for RYGB, LAGB, SG, and BPD-DS, respectively. In a linear regression model we found that LAGB patients had a significantly lower total score compared to all other procedures (p < 0.001). Every 1% of %EWL was associated with a total score decrease in 0.045 points (p = 0.009). Impaired quality of eating and food intolerance is common following many types of bariatric procedures. However, the difficulties diminish as time passes after operation and can be affected by the type of procedure. Patients undergoing LAGB have significantly greater limitations and difficulties to ingest variety of foods.


Study of cell differentiation by phylogenetic analysis using histone modification data.
In cell differentiation, a cell of a less specialized type becomes one of a more specialized type, even though all cells have the same genome. Transcription factors and epigenetic marks like histone modifications can play a significant role in the differentiation process. In this paper, we present a simple analysis of cell types and differentiation paths using phylogenetic inference based on ChIP-Seq histone modification data. We precisely defined the notion of cell-type trees and provided a procedure of building such trees. We propose new data representation techniques and distance measures for ChIP-Seq data and use these together with standard phylogenetic inference methods to build biologically meaningful cell-type trees that indicate how diverse types of cells are related. We demonstrate our approach on various kinds of histone modifications for various cell types, also using the datasets to explore various issues surrounding replicate data, variability between cells of the same type, and robustness. We use the results to get some interesting biological findings like important patterns of histone modification changes during cell differentiation process. We introduced and studied the novel problem of inferring cell type trees from histone modification data. The promising results we obtain point the way to a new approach to the study of cell differentiation. We also discuss how cell-type trees can be used to study the evolution of cell types.


Palladium-Catalyzed [3 + 2]-C-C/N-C Bond-Forming Annulation.
The synthesis of bi- and tricyclic structures incorporating pyrrolidone rings is disclosed, starting from resonance-stabilized acetamides and cyclic α,β-unsaturated-γ-oxycarbonyl derivatives. This process involves an intermolecular Tsuji-Trost allylation/intramolecular nitrogen 1,4-addition sequence. Crucial for the success of this bis-nucleophile/bis-electrophile [3 + 2] annulation is its well-defined step chronology in combination with the total chemoselectivity of the former step. When the newly formed annulation product carries a properly located o-haloaryl moiety at the nitrogen substituent, a further intramolecular keto α-arylation can join the cascade, thereby forming two new cycles and three new bonds in the same synthetic operation.


Integrating targeted gene expression and a skin model system to identify functional inhibitors of the UV activated p38 MAP kinase.
The stress-activated p38α MAP Kinase is an integral and critical component of the UV-induced inflammatory response. Despite the advances in recent years in the development of p38 kinase inhibitors, validation of these compounds in the diseased models remains limited. Based on the pharmacological profile of p38α inhibitor lead compound, SB203580, we synthesized a series of pyrrole-derivatives. Using UV-irradiated human skin punch-biopsies and cell cultures, we identified and validated the inhibitory activity of the derivatives by quantitatively measuring their effect on the expression of p38α target genes using real-time PCR. This approach not only identified pyrrole-2 as a unique derivative of this series that specifically inhibited the UV-activated p38α kinase, but also documented the skin permeation, bioavailability and reversible properties of this derivative in a 3D structure. The successful skin permeation of pyrrole-2 and its impact on AREG, COX-2 and MMP-9 gene expression demonstrates its potential use in modulating inflammatory processes in the skin. This study underscored the importance of using adapted biological models to identify accurate bioactive compounds.


How did the mental health symptoms of children and adolescents change over early lockdown during the COVID-19 pandemic in the UK?
The COVID-19 pandemic has caused extensive disruption to the lives of children and young people. Understanding the psychological effects on children and young people, in the context of known risk factors is crucial to mitigate the effects of the pandemic. This study set out to explore how mental health symptoms in children and adolescents changed over a month of full lockdown in the United Kingdom in response to the pandemic. UK-based parents and carers (n = 2673) of school-aged children and young people aged between 4 and 16 years completed an online survey about their child's mental health at two time points between March and May 2020, during early lockdown. The survey examined changes in emotional symptoms, conduct problems and hyperactivity/inattention. The findings highlighted particular deteriorations in mental health symptoms among preadolescent children, which translated to a 10% increase in those meeting possible/probable caseness criteria for emotional symptoms, a 20% increase in hyperactivity/inattention, and a 35% increase in conduct problems. In contrast, changes among adolescents were smaller (4% and 8% increase for hyperactivity/inattention and conduct problems, respectively) with a small reduction in emotional symptoms (reflecting a 3% reduction in caseness). Overall, there were few differences in change in symptoms or caseness over time according to demographic characteristics, but children and young people in low income households and those with special educational needs and/or neurodevelopmental disorders exhibited elevated symptoms (and caseness) at both time points. The findings highlight important areas of concern in terms of the potential impact of the first national lockdown on children and young people's adjustment. Developing an understanding of who has been most severely affected by the pandemic, and in what ways, is crucial in order to target effective support where it is most needed.


Effectiveness of residential wood-burning regulation on decreasing particulate matter levels and hospitalizations in the San Joaquin Valley Air Basin.
We examined the impact of Rule 4901, aimed at reducing residential wood burning, on particulate matter levels and hospitalizations in the San Joaquin Valley Air Basin (SJVAB). Using general linear mixed models and generalized estimating equation models, we compared levels of particulate matter and of hospital admissions (age groups = 45-64 and ≥ 65 years) in the SJVAB for cardiovascular disease (CVD), ischemic heart disease (IHD), and chronic obstructive pulmonary disease during the burn seasons before (2000-2003) and after (2003-2006) implementation. After implementation, we observed reductions of 12%, 11%, and 15% in particulate matter 2.5 micrometers in diameter or smaller (PM2.5), and 8%, 7%, and 11% in coarse particles, in the entire SJVAB and in rural and urban regions of the air basin, respectively. Among those aged 65 years and older, Rule 4901 was estimated to prevent 7%, 8%, and 5% of CVD cases, and 16%, 17%, and 13% of IHD cases, in the entire SJVAB and in rural and urban regions, respectively. The study suggests that Rule 4901 is effective at reducing wintertime ambient PM2.5 levels and decreasing hospital admissions for heart disease among people aged 65 years and older.


Far-field polarization characterization of the fundamental modes of a strip silicon waveguide.
The fundamental quasi-TE and quasi-TM modes of a sub-wavelength strip silicon waveguide are not purely TE or TM as the plane waves in free space. We investigate theoretically and experimentally the far-field polarization compositions of the two waveguide modes after they emanate from the waveguide facet. The measured polarization extinction ratios (PERs) of 31 dB for the quasi-TM mode and 26 dB for quasi-TE mode using free-space polarizers are consistent with our numerical analysis. Moreover, our far-field simulations show that the free-space measurement of PERs is influenced, and in many cases limited, by the sizes of various apertures in the experimental setup. This suggests a potential trade-off between achievable PERs and overall power detection/collection efficiency.


Evaluating natural infrastructure for flood management within the watersheds of selected global cities.
Cities are dependent on their upstream watersheds for storage and gradual release of water into river systems. These watersheds act as important flood mitigation infrastructure, providing an essential ecosystem service. In this paper we use metrics from the WaterWorld model to examine the flood management-relevant natural infrastructure of the upstream watersheds of selected global cities. These metrics enable the characterisation of different types, magnitudes and geographical distributions of potential natural flood storage. The storages are categorised as either green (forest canopy, wetland and soil) or blue (water body and floodplain) storages and the proportion of green to blue indicates how different city upstream basin contexts provide different types and levels of storage which may buffer flood risk. We apply the WaterWorld method for examining flood risk as the ratio of accumulated modelled annual runoff volume to accumulated available green and blue water storage capacity. The aim of these metrics is to highlight areas where there is more runoff than storage capacity and thus where the maintenance or restoration of further natural infrastructure (such as canopy cover, wetlands and soil) could aid in storing more water and thus better alleviate flood risks. Such information is needed by urban planners, city authorities and governments to help prepare cities for climate change impacts.


Frequency of indeterminate colitis in children and adults with IBD - a metaanalysis.
Indeterminate colitis (IC) remains an enigmatic inflammatory bowel disease (IBD) phenotype. It is currently not clear whether it constitutes merely a problem of terminology, classification, or possibly an early stage of IBD distinct from Crohn's disease (CD) and ulcerative colitis (UC). We analysed epidemiological data of studies comparing IC, UC and CD. We selected 14 studies investigating paediatric patients (10 prospective and 4 retrospective) and 18 studies investigating adult IBD patients (11 prospective and 7 retrospective) for this analysis. Compared to adults (n=15,776) the frequency of IC is higher in children (n=6262) (children 12.7% versus adults 6.0%, p<0.0001). This difference between children and adults has been detected irrespective whether prospective or retrospective studies were selected. In both, children and adults IC was more frequent in prospective studies compared to retrospective studies (children p=0.0004; adults p=0.0024). IC has been detected in a substantial proportion of paediatric patients with IBD. IC is more frequently found in children compared to adults. Further studies are required to clarify whether IC represents an IBD phenotype associated with childhood disease onset or whether the high IC frequency is due to difficulties in establishing a UC or CD diagnosis.


Sampling Migrants from their Social Networks: The Demography and Social Organization of Chinese Migrants in Dar es Salaam, Tanzania.
The streams of Chinese migration to Africa are growing in tandem with rising Chinese investments and trade flows in and to the African continent. In spite of the high profile of this phenomenon in the media, there are few rich and broad descriptions of Chinese communities in Africa. Reasons for this include the rarity of official statistics on foreign-born populations in African censuses, the absence of predefined sampling frames required to draw representative samples with conventional survey methods and difficulties to reach certain segments of this population. Here, we use a novel network-based approach, Network Sampling with Memory, which overcomes the challenges of sampling 'hidden' populations in the absence of a sampling frame, to recruit a sample of recent Chinese immigrants in Dar es Salaam, Tanzania and collect information on the demographic characteristics, migration histories and social ties of members of this sample. These data reveal a heterogeneous Chinese community composed of "state-led" migrants who come to Africa to work on projects undertaken by large Chinese state-owned enterprises and "independent" migrants who come on their own accord to engage in various types of business ventures. They offer a rich description of the demographic profile and social organization of this community, highlight key differences between the two categories of migrants and map the structure of the social ties linking them. We highlight needs for future research on inter-group differences in individual motivations for migration, economic activities, migration outcomes, expectations about future residence in Africa, social integration and relations with local communities.


Do SmartSite antireflux valves limit the flow rate of 0.9% normal saline through intravenous cannulas?
The aim of the study was to determine whether the placement of a SmartSite antireflux valve between a bag of fluid with line giving set and an intravenous cannula decreases the flow rate. Fluid flow rates were compared in paired experiments with and without an antireflux valve using a pressure infuser or allowing fluid to flow by gravity only for four different sizes of intravenous cannulas (20-14 G). Antireflux valves significantly decreased the fluid flow rates for all cannula sizes, irrespective of whether a pressure infuser was used. The decrease in the flow rate was most marked for larger cannulas [gravity only: 14 G: 52% (95% confidence interval (CI): 37-68), 16 G: 39% (95% CI: 34-43); pressure bag: 14 G: 74% (95% CI: 70-78), 16 G: 56% (95% CI: 54-57); all P<0.001]. Where maximum fluid flow rates are desirable, clinicians should consider not using an antireflux valve.


Biosynthesis of the biomarker okenone: χ-ring formation.
Purple sulfur bacteria (PSB) mainly occur in anoxic aquatic and benthic environments, where they play important roles in cycling carbon and sulfur. Many PSB characteristically produce the unique keto-carotenoid, okenone, which is important not only for its light absorption and photoprotection properties but also because of its diagenesis product, okenane, which is a biomarker for ancient sediments derived from anoxic environments. The specific methylation pattern of the χ-ring of okenane is unlikely to be formed by diagenetic processes and should therefore reflect an enzymatic activity from okenone biosynthesis. This study describes two enzymes that produce the χ-ring of okenone, the only structural element of okenone preserved in okenane. Genes encoding enzymes of carotenogenesis were identified in the draft genome sequence of an okenone-producing PSB, Thiodictyon sp. strain CAD16. Two divergently transcribed genes encoded a CrtY-type lycopene cyclase and a CrtU/CruE-type γ-carotene desaturase/methyltransferase. Expression of crtY in Escherichia coli showed that this gene encoded a lycopene cyclase that produced γ-carotene as the only product. Although the sequence of the γ-carotene desaturase/methyltransferase was more similar to CrtU sequences of green sulfur bacteria than to CruE sequences of cyanobacteria, expression of the crtU gene in Chlorobaculum tepidum showed that the enzyme produced carotenoids with χ-rings rather than φ-rings. Phylogenetic analysis of the carotene desaturase/methyltransferases revealed that enzymes capable of converting β-rings to χ-rings have independently evolved at least two times. These results indicate that it probably will not be possible to deduce the activity of carotene desaturase/methyltransferases solely from sequence data.


Mind-body therapies for the management of pain.
This paper reviews the evidence for mind-body therapies (eg, relaxation, meditation, imagery, cognitive-behavioral therapy) in the treatment of pain-related medical conditions and suggests directions for future research in these areas. Based on evidence from randomized controlled trials and in many cases, systematic reviews of the literature, the following recommendations can be made: 1) multi-component mind-body approaches that include some combination of stress management, coping skills training, cognitive restructuring and relaxation therapy may be an appropriate adjunctive treatment for chronic low back pain; 2) multimodal mind-body approaches such as cognitive-behavioral therapy, particularly when combined with an educational/informational component, can be an effective adjunct in the management of rheumatoid and osteoarthritis; 3) relaxation and thermal biofeedback may be considered as a treatment for recurrent migraine while relaxation and muscle biofeedback can be an effective adjunct or stand alone therapy for recurrent tension headache; 4) an array of mind-body therapies (eg, imagery, hypnosis, relaxation) when employed pre-surgically, can improve recovery time and reduce pain following surgical procedures; 5) mind-body approaches may be considered as adjunctive therapies to help ameliorate pain during invasive medical procedures.


Differences in sleep disturbance parameters between oncology outpatients and their family caregivers.
This study compared the occurrence rates for and severity ratings of sleep disturbance in patient-family caregiver (FC) dyads. In total, 102 dyads were recruited from two radiation therapy (RT) departments. Patients and their FCs completed the Pittsburgh Sleep Quality Index (PSQI) and the General Sleep Disturbance Scale (GSDS) and wore wrist actigraphs to obtain subjective and objective measures of the occurrence and severity of sleep disturbance at the initiation of RT. Match paired t tests were used to evaluate for dyadic differences. No differences were found in the occurrence of clinically significant levels of sleep disturbance between patients and their FCs that ranged between 40% and 50% using subjective and objective measures. Few differences were found in the severity of any of the sleep-wake parameters between patients and FCs using both the subjective and objective measures of sleep disturbance. The findings from this study suggest that patients with cancer and their FCs experience similar levels of sleep disturbance and that both groups could benefit from interventions that aim to promote restful sleep. In addition to routine and systematic assessment of sleep disturbance by oncology clinicians, interventions are needed that take into account the specific needs of the patient and the FC as well as the potential for partners' sleep patterns to influence one another.


Home monitoring with IT-supported specialist management versus home monitoring alone in patients with heart failure: Design and baseline results of the SUPPORT-HF 2 randomized trial.
SUPPORT-HF 2 tests the hypothesis that home monitoring with information technology-supported specialist management is more effective in optimizing medical therapy than is home monitoring alone for patients with heart failure. The study was designed as a 2-armed partially blinded parallel randomized controlled trial. Seven sites in the United Kingdom (UK) recruited a total of 202 adults with heart failure at high risk of adverse outcomes and with potential to benefit from remote management (mean age 73 years, 28% female, median left ventricular ejection fraction 37%). Both arms are given a home monitoring and communication kit (Internet-enabled tablet computer, Bluetooth-enabled blood pressure and heart rate monitor, and weighing scale). For each participant, an individualized plan for treatment of heart failure and major comorbidities is developed before randomization. Participants randomized to intervention receive regular feedback to support self-management, and their physicians receive advice on blood investigations and pharmacological treatment from a central specialist heart failure team. Participants in the control arm use the same monitoring system but with no central medical management support. The primary outcome is the use of recommended medical therapy, defined as treatment consistent with the guidelines for management of patients with chronic heart failure, and will be measured as a composite opportunity score. The trial data collection ended in October 2017, and results will be reported in 2019. ISRCTN86212709. Preliminary experience suggests that central provision of tailored specialist management using commercially available low-cost monitoring and computing devices, enhanced by customized applications, is feasible.


Multimodality imaging in takotsubo syndrome: a joint consensus document of the European Association of Cardiovascular Imaging (EACVI) and the Japanese Society of Echocardiography (JSE).
Takotsubo syndrome (TTS) is a complex and still poorly recognized heart disease with a wide spectrum of possible clinical presentations. Despite its reversibility, it is associated with serious adverse in-hospital events and high complication rates during follow-up. Multimodality imaging is helpful for establishing the diagnosis, guiding therapy, and stratifying prognosis of TTS patients in both the acute and post-acute phase. Echocardiography plays a key role, particularly in the acute care setting, allowing for the assessment of left ventricular (LV) systolic and diastolic function and the identification of the typical apical-midventricular ballooning pattern, as well as the circumferential pattern of wall motion abnormalities. It is also useful in the early detection of complications (i.e. LV outflow tract obstruction, mitral regurgitation, right ventricular involvement, LV thrombi, and pericardial effusion) and monitoring of systolic function recovery. Left ventriculography allows the evaluation of LV function and morphology, identifying the typical TTS patterns when echocardiography is not available or wall motion abnormalities cannot be properly assessed with ultrasound. Cardiac magnetic resonance provides a more comprehensive depiction of cardiac morphology and function and tissue characterization and offers additional value to other imaging modalities for differential diagnosis (myocardial infarction and myocarditis). Coronary computed tomography angiography has a substantial role in the diagnostic workup of patients with acute chest pain and a doubtful TTS diagnosis to rule out other medical conditions. It can be considered as a non-invasive appropriate alternative to coronary angiography in several clinical scenarios. Although the role of nuclear imaging in TTS has not yet been well established, the combination of perfusion and metabolic imaging may provide useful information on myocardial function in both the acute and post-acute phase.