Development of the Heart Failure Screening Tool (Heart-FaST) to measure barriers that impede engagement in self-care.
Screening for self-care capacity is advocated before applying educational strategies. No screening tool has been specifically developed to assess barriers that impede engagement in self-care in people with heart failure. Earlier conceptual work (InCOGNITO) identified NYHA class, mild cognitive impairment and depressive symptoms as barriers that impede engagement in HF self-care. Study aims were: 1) to develop the Heart Failure Screening Tool (Heart-FaST) as a means of assessing three critical barriers to self-care; 2) to assess the content validity of the Heart-FaST; and 3) to test the feasibility of implementing the Heart-FaST in clinical practice. The Heart-FaST was developed from barriers identified in previous research (InCOGNITO) and from expert panel consensus. Content validity was assessed by examining the proportion of experts who scored each item as relevant. The InCOGNITO study indicated that four cognitive tasks, seven emotional questions and NYHA functional class were significantly correlated with the self-care scales: maintenance, management and confidence. These factors were used to create the Heart-FaST items. Consensus on wording and items to be included in the Heart-FaST was reached after two rounds of panel discussion. All items had an item-level content validity index ≥ 0.78. High scores on each barrier (physical, cognitive and emotional functioning) suggest poor self-care and the need for more intensive disease management efforts. The Heart-FaST measures three critical barriers that impede engagement in self-care. In clinical practice this tool may assist in individually tailoring educational and support strategies to promote effective heart failure self-care.


Insight: An ontology-based integrated database and analysis platform for epilepsy self-management research.
We present Insight as an integrated database and analysis platform for epilepsy self-management research as part of the national Managing Epilepsy Well Network. Insight is the only available informatics platform for accessing and analyzing integrated data from multiple epilepsy self-management research studies with several new data management features and user-friendly functionalities. The features of Insight include, (1) use of Common Data Elements defined by members of the research community and an epilepsy domain ontology for data integration and querying, (2) visualization tools to support real time exploration of data distribution across research studies, and (3) an interactive visual query interface for provenance-enabled research cohort identification. The Insight platform contains data from five completed epilepsy self-management research studies covering various categories of data, including depression, quality of life, seizure frequency, and socioeconomic information. The data represents over 400 participants with 7552 data points. The Insight data exploration and cohort identification query interface has been developed using Ruby on Rails Web technology and open source Web Ontology Language Application Programming Interface to support ontology-based reasoning. We have developed an efficient ontology management module that automatically updates the ontology mappings each time a new version of the Epilepsy and Seizure Ontology is released. The Insight platform features a Role-based Access Control module to authenticate and effectively manage user access to different research studies. User access to Insight is managed by the Managing Epilepsy Well Network database steering committee consisting of representatives of all current collaborating centers of the Managing Epilepsy Well Network. New research studies are being continuously added to the Insight database and the size as well as the unique coverage of the dataset allows investigators to conduct aggregate data analysis that will inform the next generation of epilepsy self-management studies.


TRAM-34, a putatively selective blocker of intermediate-conductance, calcium-activated potassium channels, inhibits cytochrome P450 activity.
TRAM-34, a clotrimazole analog characterized as a potent and selective inhibitor of intermediate-conductance, calcium-activated K(+) (IKCa) channels, has been used extensively in vitro and in vivo to study the biological roles of these channels. The major advantage of TRAM-34 over clotrimazole is the reported lack of inhibition of the former drug on cytochrome P450 (CYP) activity. CYPs, a large family of heme-containing oxidases, play essential roles in endogenous signaling and metabolic pathways, as well as in xenobiotic metabolism. However, previously published work has only characterized the effects of TRAM-34 on a single CYP isoform. To test the hypothesis that TRAM-34 may inhibit some CYP isoforms, the effects of this compound were presently studied on the activities of four rat and five human CYP isoforms. TRAM-34 inhibited recombinant rat CYP2B1, CYP2C6 and CYP2C11 and human CYP2B6, CYP2C19 and CYP3A4 with IC50 values ranging from 0.9 µM to 12.6 µM, but had no inhibitory effects (up to 80 µM) on recombinant rat CYP1A2, human CYP1A2, or human CYP19A1. TRAM-34 also had both stimulatory and inhibitory effects on human CYP3A4 activity, depending on the substrate used. These results show that low micromolar concentrations of TRAM-34 can inhibit several rat and human CYP isoforms, and suggest caution in the use of high concentrations of this drug as a selective IKCa channel blocker. In addition, in vivo use of TRAM-34 could lead to CYP-related drug-drug interactions.


Clinical Evaluation of Lateral Pedicle Flap Stabilized with Cyanoacrylate Tissue Adhesive: A Randomized Controlled Clinical Trial.
Gingival recession is the most common mucogingival defect and is susceptible to tooth hypersensitivity, root caries, and esthetic problems if left untreated. A lateral pedicle flap is used to cover denuded roots that have adequate donor tissue laterally and adequate vestibular depth. A carefully planned surgery needs proper immobilization of the flap at the recipient site and this can be achieved by proper wound closure technique with appropriate material such as sutures or tissue adhesives. The aim of the present study is to evaluate the clinical outcomes of lateral pedicle flap stabilized with cyanoacrylate tissue adhesive and resorbable sutures. Twenty-two patients with Miller's class I and class II gingival recession were randomly divided into two groups: lateral pedicle flap stabilized with cyanoacrylate tissue adhesive (test) and lateral pedicle flap stabilized with resorbable sutures (control). Plaque index, gingival index, probing pocket depth, clinical attachment level, recession depth and width, height and thickness of keratinized gingiva were evaluated at baseline and 1st and 3rd month postoperatively. The percentage of root coverage was evaluated at the end of 3rd month postoperatively. Intergroup comparisons for the clinical attachment level, recession depth, recession width, thickness of keratinized gingiva, and height of keratinized gingiva were made by Mann-Whitney test by analyzing the difference of two time periods. Intragroup comparisons were made by the Kruskal-Wallis test. Mann-Whitney test was used to compare the difference between various time periods within the group for all the selected variables. The mean plaque index and gingival index at the 1st and 3rd month were found to be statistically significant and did not present any significant influence over other clinical parameters evaluated. A partial root coverage was observed in both the groups (71.97% for the test group and 61.36% for the control group). Cyanoacrylate tissue adhesive is clinically effective in the stabilization of the lateral pedicle flap and can be used as an alternative to resorbable sutures.


TREC-IN: gene knock-in genetic tool for genomes cloned in yeast.
With the development of several new technologies using synthetic biology, it is possible to engineer genetically intractable organisms including Mycoplasma mycoides subspecies capri (Mmc), by cloning the intact bacterial genome in yeast, using the host yeast's genetic tools to modify the cloned genome, and subsequently transplanting the modified genome into a recipient cell to obtain mutant cells encoded by the modified genome. The recently described tandem repeat coupled with endonuclease cleavage (TREC) method has been successfully used to generate seamless deletions and point mutations in the mycoplasma genome using the yeast DNA repair machinery. But, attempts to knock-in genes in some cases have encountered a high background of transformation due to maintenance of unwanted circularization of the transforming DNA, which contains possible autonomously replicating sequence (ARS) activity. To overcome this issue, we incorporated a split marker system into the TREC method, enabling seamless gene knock-in with high efficiency. The modified method is called TREC-assisted gene knock-in (TREC-IN). Since a gene to be knocked-in is delivered by a truncated non-functional marker, the background caused by an incomplete integration is essentially eliminated. In this paper, we demonstrate applications of the TREC-IN method in gene complementation and genome minimization studies in Mmc. In the first example, the Mmc dnaA gene was seamlessly replaced by an orthologous gene, which shares a high degree of identity at the nucleotide level with the original Mmc gene, with high efficiency and low background. In the minimization example, we replaced an essential gene back into the genome that was present in the middle of a cluster of non-essential genes, while deleting the non-essential gene cluster, again with low backgrounds of transformation and high efficiency. Although we have demonstrated the feasibility of TREC-IN in gene complementation and genome minimization studies in Mmc, the applicability of TREC-IN ranges widely. This method proves to be a valuable genetic tool that can be extended for genomic engineering in other genetically intractable organisms, where it may be implemented in elucidating specific metabolic pathways and in rationale vaccine design.


Differential Effects of HCN Channel Block on On and Off Pathways in the Retina as a Potential Cause for Medication-Induced Phosphene Perception.
Phosphene perception is a characteristic side effect of heart rate-reducing medication that acts on hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels. It is hypothesized that these phosphenes are caused by blocking HCN channels in photoreceptors and neurons of the retina, yet the underlying changes in visual signal processing in the retina caused by the HCN channel block are still unknown. We examined the effects of pharmacologic HCN channel block on the encoding of visual signals in retinal ganglion cells by recording ganglion cell spiking activity from isolated mouse retinas mounted on multielectrode arrays. Spontaneous activity and responses to various visual stimuli were measured before, during, and after administration of 3 μM ivabradine. Retinal ganglion cells generally showed slower response kinetics and reduced sensitivity to high temporal frequencies under ivabradine. Moreover, ivabradine differentially affected the sensitivity of On and Off ganglion cells. On cells showed reduced response gain, whereas Off cells experienced an increase in response threshold. In line with these differential effects, Off cells, in contrast to On cells, also showed reduced baseline activity during visual stimulation and reduced spontaneous activity. Furthermore, Off cells, but not On cells, showed increased burst-like spiking activity in the presence of ivabradine. Our data suggest that pharmacologic HCN channel block in the retina leads to a shift in the relative activity of the On and Off pathways of the retina. We hypothesize that this imbalance may underlie the medication-induced perception of phosphenes.


Future MS care: a consensus statement of the MS in the 21st Century Steering Group.
The "MS in the 21st Century" initiative was established with the purpose of (1) defining how multiple sclerosis (MS) treatment and standards of care should look in the 21st century; (2) developing a minimum standard of care across the world; and (3) motivating the broad MS community to align standards of care and challenge the current treatment paradigm. The aim was to develop a consensus statement to reach and influence the broader MS community. An expert steering group from Europe and Canada-consisting of neurologists, patient advocates, a pharmacoepidemiologist/pharmacoeconomist, and representatives from national MS centers-participated in a series of workshop-driven meetings between February 2011 and 2012. After three phases of discussions, the steering group identified that the overall vision for future care of MS should be full access to personalized treatment, with reimbursement, to achieve freedom from disease. They constructed seven overall principles that support this vision: personalized care, patient engagement, commitment to research, regulatory body education and reimbursement issues, new endpoints in clinical trials, more therapy options, and MS centers of excellence. This consensus statement outlines the key aspects of the seven principles that need to be addressed. The "MS in the 21st Century Steering Group" hopes that this consensus statement acts as a call to action for healthcare providers and decision-makers to address simultaneously the overarching principles that will guide patient management in order to improve outcomes for people with MS.


A New Web-Based Big Data Analytics for Dynamic Public Opinion Mapping in Digital Networks on Contested Biotechnology Fields.
The expression "public opinion" has long been part of common parlance. However, its value as a scientific measure has been the topic of abundant academic debates over the past several decades. Such debates have produced more variety and contestations rather than consensus on the very definition of public opinion, let alone on how to measure it. This study reports on the usefulness of web-based big data digital network analytics in deciphering the distributed meanings and sense making related to controversial biotechnology applications. Using stem cell therapies as a case study, we argue that such digital network analysis can complement the traditional opinion polls while avoiding the sampling bias that is typical of opinion polls. Although the polls cannot account for the opinion dynamics, combining them with web-based big data analysis can shed light on three dimensions of public opinion essential for sense making: counts or volume of opinion data, content, and movement of opinions. This approach is particularly promising in the case of ongoing scientific controversies that increasingly overflow into the public sphere morphing into public political debates. In particular, our study focuses as a case study on public controversies over the clinical provision of stem cell therapies. Using web entities specifically addressing stem cell issues, including their dynamic aggregation, the internal architecture of the web corpus we report in this study brings the third dimension of public opinion (movement) into sharper focus. Notably, the corpus of stem cell networks through web connectivity presents hot spots of distributed meaning. Large-scale surveys conducted on these issues, such as the Eurobarometer of Biotechnology, reveal that European citizens only accept research on stem cells if they are highly regulated, while the stem cell digital network analysis presented in this study suggests that distributed meaning is promise centeredness. Although major scientific journals and companies tend to structure public opinion networks, our finding of promise centeredness as a key ingredient of distributed meaning and sense making is consistent with therapeutic tourism that remains as an important facet of the stem cell community despite the lack of material standards. This new approach to digital network analysis has crosscutting corollaries for rethinking the notion of public opinion, be it in electoral preferences or as we discuss in this study, for new ways to measure, monitor, and democratically govern emerging technologies.


Glycoprotein Profile Assessed by 1H-NMR as a Global Inflammation Marker in Patients with HIV Infection. A Prospective Study.
Plasma glycoproteins are a composite biomarker of inflammation and can be detected by 1H-NMR. The aim of this study was to prospectively appraise the clinical value of plasma glycoproteins assessed by 1H-NMR in people living with HIV (PLWH). A total of 221 patients with HIV infection were recruited and studied at baseline and at 48 and 144 weeks. Patients were distributed into two groups according to baseline CD4+ T-cell number below or above 200 cells/µL. Patients with fewer than 200 cells/µL were distributed into the responders and nonresponders according to antiretroviral therapy (ART) response at 144 weeks. Glycoprotein concentrations were determined by 1H-NMR arising from the protein bond N-acetylglucosamine and N-acetylgalactosamine signals (GlycA); and N-acetylneuraminic acid signal (GlycB) associated with the sugar-protein bond concentration and aggregation state (shapes (height/width)). Basal glycoprotein concentrations were higher in patients with < 200 CD4+ T-cell/μL (Glyc A: 1040(917.9-1199.1) vs. 950.4(845.5-1050.9), p < 0.001, and Glyc B: 521(440.3-610.3) vs. 468.6(417.9-507.0) μ mol/L, p < 0.001) being reduced by ART. The height/width (H/W) ratio was the parameter showing a better association with this clinical status. Baseline glycoproteins predict the condition of responder/nonresponder. In this study, 1H-NMR glycoproteins provide novel insights to assess inflammation status and have prognostic value in PLWH.


Increased BOLD sensitivity in the orbitofrontal cortex using slice-dependent echo times at 3 T.
Functional magnetic resonance imaging (fMRI) exploits the blood oxygenation level dependent (BOLD) effect to detect neuronal activation related to various experimental paradigms. Some of these, such as reversal learning, involve the orbitofrontal cortex and its interaction with other brain regions like the amygdala, striatum or dorsolateral prefrontal cortex. These paradigms are commonly investigated with event-related methods and gradient echo-planar imaging (EPI) with short echo time of 27 ms. However, susceptibility-induced signal losses and image distortions in the orbitofrontal cortex are still a problem for this optimized sequence as this brain region consists of several slices with different optimal echo times. An EPI sequence with slice-dependent echo times is suitable to maximize BOLD sensitivity in all slices and might thus improve signal detection in the orbitofrontal cortex. To test this hypothesis, we first optimized echo times via BOLD sensitivity simulation. Second, we measured 12 healthy volunteers using a standard EPI sequence with an echo time of 27 ms and a modified EPI sequence with echo times ranging from 22 ms to 47 ms. In the orbitofrontal cortex, the number of activated voxels increased from 87 ± 44 to 549 ± 83 and the maximal t-value increased from 4.4 ± 0.3 to 5.4 ± 0.3 when the modified EPI was used. We conclude that an EPI with slice-dependent echo times may be a valuable tool to mitigate susceptibility artifacts in event-related whole-brain fMRI studies with a focus on the orbitofrontal cortex.


A qualitative evidence synthesis on the management of male obesity.
To investigate what weight management interventions work for men, with which men, and under what circumstances. Realist synthesis of qualitative studies. Sensitive searches of 11 electronic databases from 1990 to 2012 supplemented by grey literature searches. Studies published between 1990 and 2012 reporting qualitative research with obese men, or obese men in contrast to obese women and lifestyle or drug weight management were included. The studies included men aged 16 years or over, with no upper age limit, with a mean or median body mass index of 30 kg/m(2) in all settings. 22 studies were identified, including 5 qualitative studies linked to randomised controlled trials of weight maintenance interventions and 8 qualitative studies linked to non-randomised intervention studies, and 9 relevant UK-based qualitative studies not linked to any intervention. Health concerns and the perception that certain programmes had 'worked' for other men were the key factors that motivated men to engage with weight management programmes. Barriers to engagement and adherence with programmes included: men not problematising their weight until labelled 'obese'; a lack of support for new food choices by friends and family, and reluctance to undertake extreme dieting. Retaining some autonomy over what is eaten; flexibility about treats and alcohol, and a focus on physical activity were attractive features of programmes. Group interventions, humour and social support facilitated attendance and adherence. Men were motivated to attend programmes in settings that were convenient, non-threatening and congruent with their masculine identities, but men were seldom involved in programme design. Men's perspectives and preferences within the wider context of family, work and pleasure should be sought when designing weight management services. Qualitative research is needed with men to inform all aspects of intervention design, including the setting, optimal recruitment processes and strategies to minimise attrition.


Self-Replicators Emerge from a Self-Organizing Prebiotic Computer World.
Amoeba, a computer platform inspired by the Tierra system, is designed to study the generation of self-replicating sequences of machine operations (opcodes) from a prebiotic world initially populated by randomly selected opcodes. Point mutations drive opcode sequences to become more fit as they compete for memory and CPU time. Significant features of the Amoeba system include the lack of artificial encapsulation (there is no write protection) and a computationally universal opcode basis set. Amoeba now includes two additional features: pattern-based addressing and injecting entropy into the system. It was previously thought such changes would make it highly unlikely that an ancestral replicator could emerge from a fortuitous combination of randomly selected opcodes. Instead, Amoeba shows a far richer emergence, exhibiting a self-organization phase followed by the emergence of self-replicators. First, the opcode basis set becomes biased. Second, short opcode building blocks are propagated throughout memory space. Finally, prebiotic building blocks can combine to form self-replicators. Self-organization is quantified by measuring the evolution of opcode frequencies, the size distribution of sequences, and the mutual information of opcode pairs.


Classification of bipolar disorder in psychiatric hospital. A prospective cohort study.
This study has explored the classification of bipolar disorder in psychiatric hospital. A review of the literature reveals that there is a need for studies using stringent methodological approaches. 480 first-time admitted patients to psychiatric hospital were found eligible and 271 of these gave written informed consent. The study sample was comprised of 250 patients (52%) with hospital diagnoses. For the study, expert diagnoses were given on the basis of a structured diagnostic interview (M.I.N.I.PLUS) and retrospective review of patient records. Agreement between the expert's and the clinicians' diagnoses was estimated using Cohen's kappa statistics. 76% of the primary diagnoses given by the expert were in the affective spectrum. Agreement concerning these disorders was moderate (kappa ranging from 0.41 to 0.47). Of 58 patients with bipolar disorder, only 17 received this diagnosis in the clinic. Almost all patients with a current manic episode were classified as currently manic by the clinicians. Forty percent diagnosed as bipolar by the expert, received a diagnosis of unipolar depression by the clinician. Fifteen patients (26%) were not given a diagnosis of affective disorder at all. Our results indicate a considerable misclassification of bipolar disorder in psychiatric hospital, mainly in patients currently depressed. The importance of correctly diagnosing bipolar disorder should be emphasized both for clinical, administrative and research purposes. The findings questions the validity of psychiatric case registers. There are potential benefits in structuring the diagnostic process better in the clinic.


The IFNL3/4 ΔG variant increases susceptibility to cytomegalovirus retinitis among HIV-infected patients.
Cytomegalovirus (CMV) retinitis is a major cause of visual impairment and blindness among patients with uncontrolled HIV infections. Whereas polymorphisms in interferon-lambda 3 (IFNL3, previously named IL28B) strongly influence the clinical course of hepatitis C, few studies examined the role of such polymorphisms in infections due to viruses other than hepatitis C virus. To analyze the association of newly identified IFNL3/4 variant rs368234815 with susceptibility to CMV-associated retinitis in a cohort of HIV-infected patients. This retrospective longitudinal study included 4884 white patients from the Swiss HIV Cohort Study, among whom 1134 were at risk to develop CMV retinitis (CD4 nadir < 00 /μl and positive CMV serology). The association of CMV-associated retinitis with rs368234815 was assessed by cumulative incidence curves and multivariate Cox regression models, using the estimated date of HIV infection as a starting point, with censoring at death and/or lost follow-up. A total of 40 individuals among 1134 patients at risk developed CMV retinitis. The minor allele of rs368234815 was associated with a higher risk of CMV retinitis (log-rank test P = 0.007, recessive mode of inheritance). The association was still significant in a multivariate Cox regression model (hazard ratio 2.31, 95% confidence interval 1.09-4.92, P = 0.03), after adjustment for CD4 nadir and slope, HAART and HIV-risk groups. We reported for the first time an association between an IFNL3/4 polymorphism and susceptibility to AIDS-related CMV retinitis. IFNL3/4 may influence immunity against viruses other than HCV.


Host genetics and immune control of HIV-1 infection: fine mapping for the extended human MHC region in an African cohort.
Multiple major histocompatibility complex (MHC) loci encoding human leukocyte antigens (HLA) have allelic variants unequivocally associated with differential immune control of HIV-1 infection. Fine mapping based on single nucleotide polymorphisms (SNPs) in the extended MHC (xMHC) region is expected to reveal causal or novel factors and to justify a search for functional mechanisms. We have tested the utility of a custom fine-mapping platform (the ImmunoChip) for 172 HIV-1 seroconverters (SCs) and 449 seroprevalent individuals (SPs) from Lusaka, Zambia, with a focus on more than 6400 informative xMHC SNPs. When conditioned on HLA and nongenetic factors previously associated with HIV-1 viral load (VL) in the study cohort, penalized approaches (HyperLasso models) identified an intergenic SNP (rs3094626 between RPP21 and HLA-E) and an intronic SNP (rs3134931 in NOTCH4) as novel correlates of early set-point VL in SCs. The minor allele of rs2857114 (downstream from HLA-DOB) was an unfavorable factor in SPs. Joint models based on demographic features, HLA alleles and the newly identified SNP variants could explain 29% and 15% of VL variance in SCs and SPs, respectively. These findings and bioinformatics strongly suggest that both classic and nonclassic MHC genes deserve further investigation, especially in Africans with relatively short haplotype blocks.


Mapping urban physical distancing constraints, sub-Saharan Africa: a case study from Kenya.
With the onset of the coronavirus disease 2019 (COVID-19) pandemic, public health measures such as physical distancing were recommended to reduce transmission of the virus causing the disease. However, the same approach in all areas, regardless of context, may lead to measures being of limited effectiveness and having unforeseen negative consequences, such as loss of livelihoods and food insecurity. A prerequisite to planning and implementing effective, context-appropriate measures to slow community transmission is an understanding of any constraints, such as the locations where physical distancing would not be possible. Focusing on sub-Saharan Africa, we outline and discuss challenges that are faced by residents of urban informal settlements in the ongoing COVID-19 pandemic. We describe how new geospatial data sets can be integrated to provide more detailed information about local constraints on physical distancing and can inform planning of alternative ways to reduce transmission of COVID-19 between people. We include a case study for Nairobi County, Kenya, with mapped outputs which illustrate the intra-urban variation in the feasibility of physical distancing and the expected difficulty for residents of many informal settlement areas. Our examples demonstrate the potential of new geospatial data sets to provide insights and support to policy-making for public health measures, including COVID-19.


Oxidative Stress in Mesenchymal Stem Cell Senescence: Regulation by Coding and Noncoding RNAs.
Mesenchymal stem cells (MSCs), adult stem cells with the potential of differentiation into mesodermal lineages, play an important role in tissue homeostasis and regeneration. In different organs, a subpopulation of MSCs is located near the vasculature and possibly represents the original source of lineage-committed mesenchymal progenitors. Recent Advances: The plasticity and immune characteristics of MSCs render them a preferential tool for regenerative cell therapy. The culture expansion needed before MSC transplantation is associated with cellular senescence. Moreover, accelerated senescence of the total and perivascular MSC pool has been observed in humans and mouse models of premature aging disorders. MSC dysfunction is acknowledged as a culprit for the aging-associated degeneration of mesodermal tissues, but the underlying epigenetic pathways remain elusive. This article reviews current understanding of mechanisms impinging on MSC health, including oxidative stress, Nrf2-antioxidant responsive element activity, sirtuins, noncoding RNAs, and PKCs. We provide evidence that epigenetic profiling of MSCs is utilitarian to the prediction of therapeutic outcomes. In addition, strategies that target oxidative stress-associated mechanisms represent promising approaches to counteract the detrimental effect of age and senescence in MSCs.-Antioxid. Redox Signal. 29, 864-879.


MR elastography: Principles, guidelines, and terminology.
Magnetic resonance elastography (MRE) is a phase contrast-based MRI technique that can measure displacement due to propagating mechanical waves, from which material properties such as shear modulus can be calculated. Magnetic resonance elastography can be thought of as quantitative, noninvasive palpation. It is increasing in clinical importance, has become widespread in the diagnosis and staging of liver fibrosis, and additional clinical applications are being explored. However, publications have reported MRE results using many different parameters, acquisition techniques, processing methods, and varied nomenclature. The diversity of terminology can lead to confusion (particularly among clinicians) about the meaning of and interpretation of MRE results. This paper was written by the MRE Guidelines Committee, a group formalized at the first meeting of the ISMRM MRE Study Group, to clarify and move toward standardization of MRE nomenclature. The purpose of this paper is to (1) explain MRE terminology and concepts to those not familiar with them, (2) define "good practices" for practitioners of MRE, and (3) identify opportunities to standardize terminology, to avoid confusion.


Action of propranolol in the reaction of smooth musculature of tracheal rings induced with acetylcholine, histamine, serotonin (5-HT) and prostaglandin (PGF2-alfa) in vitro and in vivo.
Actions of acetylcholine (ACh), histamines, serotonins (5-HT) and prostaglandins (PGF2-alfa) in concentrations of 10(-4), 10(-3), 10(-2) and 10(-1) mol/dm(3) were analyzed in vitro conditions in isolated specimens of tracheas of 24 pigs, 7 guinea pigs, and dead persons for different reasons (8), in the presence and without presence of propranolol. Whilst, research regarding actions of aerosolized histamines (10 mg, 1%, 2 min), in the presence and without the presence of aerosolized propranolol (20 mg, 2%, 2 min) was done in vivo in 6 healthy persons. Study results show that propranolol does not emphasize contraction of the airways smooth musculature as induced by ACh, histamine, 5-HT and PGF2-alfa in vitro conditions (p>0,1). Also, in vivo we found a non-significance of tracheal smooth musculature constriction (p>0,1).


Speckle-tracking radial strain reveals left ventricular dyssynchrony in patients with permanent right ventricular pacing.
Speckle-tracking strain analysis was used to assess the effects of permanent right ventricular (RV) pacing on the heterogeneity in timing of regional wall strain and left ventricular (LV) dyssynchrony. Recent studies have shown detrimental effects of RV pacing, possibly related to the induction of LV dyssynchrony. Fifty-eight patients treated with His bundle ablation and pacemaker implantation were studied. To assess the effect of RV pacing on time-to-peak radial strain of different LV segments, we applied speckle-tracking analysis to standard LV short-axis images. In addition, New York Heart Association (NYHA) functional class, LV volumes, and systolic function were assessed at baseline and after long-term RV pacing. At baseline, similar time-to-peak strain for the 6 segments was observed (mean 371 +/- 114 ms). In contrast, after a mean of 3.8 +/- 2.0 years of RV pacing, there was a marked heterogeneity in time-to-peak strain of the 6 segments. In 33 patients (57%), LV dyssynchrony, represented by a time difference > or =130 ms between the time-to-peak strain of the (antero)septal and the posterolateral segments, was present. In these patients, a deterioration of LV systolic function and NYHA functional class was observed. In 11 patients, an "upgrade" of the conventional pacemaker to a biventricular pacemaker resulted in partial reversal of the detrimental effects of RV pacing. Speckle-tracking analysis revealed that permanent RV pacing induced heterogeneity in time-to-peak strain, resulting in LV dyssynchrony in 57% of patients, associated with deterioration of LV systolic function and NYHA functional class. Biventricular pacing may reverse these adverse effects of RV pacing.


Comparison of levetiracetam and oxcarbazepine monotherapy among Korean patients with newly diagnosed focal epilepsy: A long-term, randomized, open-label trial.
This open-label, multicenter, randomized phase IV trial (NCT01498822) of noninferiority design compared the long-term effectiveness, safety, and tolerability of levetiracetam (LEV) monotherapy with those of oxcarbazepine (OXC) monotherapy in adults with newly diagnosed focal epilepsy. Korean patients (16-80 years), with ≥2 unprovoked focal seizures in the year preceding the trial, who had not taken any antiepileptic drugs (AEDs) in the last 6 months, were randomized to receive LEV or OXC (1:1). Effectiveness, safety, and tolerability were assessed over a 50-week period. Treatment failure rates (per protocol set) were 15/118 (12.7%) in the LEV-treated group and 30/128 (23.4%) in the OXC-treated group, an absolute difference of -10.7% (95% confidence interval [CI] -20.2, -1.2). Because the upper 95% CI limit was less than the pre-specified noninferiority margin of 15%, LEV was considered noninferior to OXC. Twenty-four-week and 48-week seizure freedom rates were 53.8% and 34.7% for LEV vs. 58.5% and 40.9% for OXC. Both LEV and OXC were well tolerated, with 8.7% and 8.6% of patients reporting serious treatment-emergent adverse events, respectively. By comparing LEV with OXC, another newer AED, LEV can be considered a useful option as initial monotherapy for patients with newly diagnosed focal epilepsy.


Phase I study in melanoma patients of a vaccine with peptide-pulsed dendritic cells generated in vitro from CD34(+) hematopoietic progenitor cells.
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that can be used for vaccination purposes, to induce a specific T-cell response in vivo against melanoma-associated antigens. We have shown that the sequential use of early-acting hematopoietic growth factors, stem cell factor, IL-3 and IL-6, followed by differentiation with IL-4 and granulocyte-macrophage colony-stimulating factor allows the in vitro generation of large numbers of immature DCs from CD34(+) peripheral blood progenitor cells. Maturation to interdigitating DCs could specifically be induced within 24 hr by addition of TNF-alpha. Here, we report on a phase I clinical vaccination trial in melanoma patients using peptide-pulsed DCs. Fourteen HLA-A1(+) or HLA-A2(+) patients received at least 4 i.v. infusions of 5 x 10(6) to 5 x 10(7) DCs pulsed with a pool of peptides including either MAGE-1, MAGE-3 (HLA-A1) or Melan-A, gp100, tyrosinase (HLA-A2), depending on the HLA haplotype. A total of 83 vaccinations were performed. Clinical side effects were mild and consisted of low-grade fever (WHO grade I-II). Clinical and immunological responses consisted of anti-tumor responses in 2 patients, increased melanoma peptide-specific delayed-type hypersensitivity reactions in 4 patients, significant expansion of Melan-A- and gp100-specific cytotoxic T lymphocytes in the peripheral blood lymphocytes of 1 patient after vaccination and development of vitiligo in another HLA-A2(+) patient. Our data indicate that the vaccination of peptide-pulsed DCs is capable of inducing clinical and systemic tumor-specific immune responses without provoking major side effects.


Benefits and adverse effects of weight loss. Observations from the Framingham Study.
To identify the benefits and adverse effects of weight loss. Longitudinal, epidemiologic study in a defined population. Men and women (n = 2500) who were between 35 and 54 years old at baseline, followed for 20 years in Framingham, Massachusetts. Height, weight, lipid levels, blood pressure, smoking status, diet, physical activity, prevalent and incident cardiovascular disease, diabetes, other diseases, and mortality rate were assessed. Compared with those whose body mass index (BMI) or weight changed least, men and women who lost weight during a 10-year period were older, heavier, and had higher blood pressures and cholesterol levels initially but had the smallest gains in blood pressure and cholesterol levels. However, rates of cigarette smoking were higher, and rates of smoking cessation were lower. During 20 years of further follow-up, death rates were highest in those whose BMI decreased and in those with the highest BMI at study entry. Relative risks for death from cardiovascular disease, coronary heart disease, and all causes were significantly greater by 33% to 61% in men whose BMI decreased after adjusting for age and risk factors for cardiovascular disease. In women, weight loss and weight gain were associated with higher relative risks for cardiovascular disease and coronary heart disease, but only the 38% increase in total mortality rate among women who lost weight was statistically significant after adjusting for age. Weight loss was associated with improvements in blood pressure and cholesterol levels but also with continued cigarette smoking, prevalent and incident cardiovascular disease, diabetes mellitus, other diseases, and higher death rates. Leanness and maintenance of stable weight were beneficial to risk factors, and to the prevention of morbidity, and death.


The effect of hydroxyethyl starches (HES 130/0.42 and HES 200/0.5) on activated renal tubular epithelial cells.
Acute renal failure is a frequent complication of sepsis. Hydroxyethyl starch (HES) is widely used in the treatment of such patients. However, the effect of HES on renal function during sepsis remains controversial. We established an in vitro model of tumor necrosis factor-alpha (TNF-alpha)-stimulated human proximal tubular epithelial (HK-2) cells to assess the possible effects of HES 130/0.42 and HES 200/0.5 on these activated cells. HK-2 cells were stimulated with TNF-alpha in the presence or absence of HES 130/0.42 or 200/0.5. After 4, 10, and 18 h of incubation, monocyte chemoattractant protein-1 (MCP-1), a key chemoattractant for neutrophils and macrophages, was measured. In addition, viability and cytotoxicity assays were performed. MCP-1 expression was doubled upon TNF-alpha exposure. In the presence of 2% and 4% HES 200/0.5 in 98% (96%) medium over a stimulation time period of 10 h and 18 h, the MCP-1 concentration was decreased between 26% and 56% (P < 0.05). TNF-alpha stimulation resulted in a significant decrease of viability by 53%-63%, whereas viability decreased by only 32%-40% in coincubation with HES 130/0.42 (P < 0.005) and remained even less affected by TNF-alpha in the presence of HES 200/0.5 (P < 0.001). The TNF-alpha-induced cell death rate was attenuated in the presence of HES 200/0.5 (P < 0.05). This in vitro study shows that both HES products modulate cell injury upon inflammatory stimulation. The effect was more pronounced in the HES 200/0.5 group than for HES 130/0.42, suggesting a possible biological difference between the HES types.


Pulsed high-frequency electromagnetic field affects human sleep and sleep electroencephalogram.
To investigate whether the electromagnetic field (EMF) emitted by digital radiotelephone handsets affects the brain, healthy, young subjects were exposed during an entire night-time sleep episode to an intermittent radiation schedule (900 MHz; maximum specific absorption rate 1 W/kg) consisting of alternating 15-min on-15-min off intervals. Compared with a control night with sham exposure, the amount of waking after sleep onset was reduced from 18 to 12 min. Spectral power of the electroencephalogram in non-rapid eye movement sleep was increased. The maximum rise occurred in the 10-11 Hz and 13.5-14 Hz bands during the initial part of sleep and then subsided. The results demonstrate that pulsed high-frequency EMF in the range of radiotelephones may promote sleep and modify the sleep EEG.


Psychiatric interviewing techniques. III. Naturalistic study: eliciting feelings.
A naturalistic study was undertaken of 36 video and audio-taped interviews undertaken by 7 different psychiatric trainees. The interviews studied were those conducted in the ordinary course of clinic work for diagnostic and therapeutic planning purposes by trainees when first seeing the parent or parents of a child newly referred to a psychiatric clinic. It was found that a variety of rather different interview techniques seemed to facilitate emotional expression. These included a low level of interview talk with few interruptions, a high rate of open rather than closed questions, direct requests for feelings, interpretations and expressions of sympathy. The issue of how far these associations reflected causal influences is discussed.


Can adults adequately convert alpha-linolenic acid (18:3n-3) to eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3)?
A diet including 2-3 portions of fatty fish per week, which corresponds to the intake of 1.25 g EPA (20:5n-3) + DHA (22:6n-3) per day, has been officially recommended on the basis of epidemiological findings showing a beneficial role of these n-3 long-chain PUFA in the prevention of cardiovascular and inflammatory diseases. The parent fatty acid ALA (18:3n-3), found in vegetable oils such as flaxseed or rapeseed oil, is used by the human organism partly as a source of energy, partly as a precursor of the metabolites, but the degree of conversion appears to be unreliable and restricted. More specifically, most studies in humans have shown that whereas a certain, though restricted, conversion of high doses of ALA to EPA occurs, conversion to DHA is severely restricted. The use of ALA labelled with radioisotopes suggested that with a background diet high in saturated fat conversion to long-chain metabolites is approximately 6% for EPA and 3.8% for DHA. With a diet rich in n-6 PUFA, conversion is reduced by 40 to 50%. It is thus reasonable to observe an n-6/n-3 PUFA ratio not exceeding 4-6. Restricted conversion to DHA may be critical since evidence has been increasing that this long-chain metabolite has an autonomous function, e.g. in the brain, retina and spermatozoa where it is the most prominent fatty acid. In neonates deficiency is associated with visual impairment, abnormalities in the electroretinogram and delayed cognitive development. In adults the potential role of DHA in neurological function still needs to be investigated in depth. Regarding cardiovascular risk factors DHA has been shown to reduce triglyceride concentrations. These findings indicate that future attention will have to focus on the adequate provision of DHA which can reliably be achieved only with the supply of the preformed long-chain metabolite.


Revisiting the Fundamentals in the Design and Control of Nanoparticulate Colloids in the Frame of Soft Chemistry.
This review presents thoughts on some of the fundamental features of conceptual models applied in the design of fine particles in the frames of colloid and soft chemistry. A special emphasis is placed on the limitations of these models, an acknowledgment of which is vital in improving their intricacy and effectiveness in predicting the outcomes of the corresponding experimental settings. Thermodynamics of self-assembly phenomena illustrated on the examples of protein assembly and micellization is analyzed in relation to the previously elaborated thesis that each self-assembly in reality presents a co-assembly, since it implies a mutual reorganization of the assembling system and its immediate environment. Parameters used in the design of fine particles by precipitation are discussed while referring to solubility product, various measures of supersaturation levels, induction time, nucleation and crystal growth rates, interfacial energies, and the Ostwald-Lussac law of phases. Again, the main drawbacks and inadequacies of using the aforementioned parameters in tailoring the materials properties in a soft and colloidal chemical setting were particularly emphasized. The basic and practical limitations of zeta-potential analyses, routinely used to stabilize colloidal dispersions and initiate specific interactions between soft chemical entities, were also outlined. The final section of the paper reiterates the unavoidable presence of practical qualitative models in the design and control of nanoparticulate colloids, which is supported by the overwhelming complexity of quantitative relationships that govern the processes of their formation and assembly.


Identification of mip-like genes in the genus Legionella.
The mip gene of Legionella pneumophila serogroup 1 strain AA100 encodes a 24-kilodalton surface protein (Mip) and enhances the abilities of L. pneumophila to parasitize human macrophages and to cause pneumonia in experimental animals. To determine whether this virulence factor is conserved in the genus Legionella, a large panel of Legionella strains was examined by Southern hybridization and immunoblot analyses for the presence and expression of mip-related sequences. Strains representing all 14 serogroups of L. pneumophila contained a mip gene and expressed a 24-kilodalton Mip protein. Although the isolates of the 29 other Legionella species did not hybridize with mip DNA probes under high-stringency conditions, they did so at reduced stringency. In support of the notion that these strains possess mip-like genes, these species each expressed a protein (24 to 31 kilodaltons in size) that reacted with specific Mip antisera. Moreover, the cloned mip analog from Legionella micdadei encoded the cross-reactive protein. Thus, mip is conserved and specific to L. pneumophila, but mip-like genes are present throughout the genus, perhaps potentiating the intracellular infectivity of all Legionella species.


Maternal antibiotic use during pregnancy and childhood obesity at age 5 years.
The benefits of antibiotic treatment during pregnancy are immediate, but there may be long-term risks to the developing child. Prior studies show an association between early life antibiotics and obesity, but few have examined this risk during pregnancy. To evaluate the association of maternal antibiotic exposure during pregnancy on childhood BMI-z at 5 years, we conducted a retrospective cohort analysis. Using electronic health record data from seven health systems in PCORnet, a national distributed clinical research network, we included children with same-day height and weight measures who could be linked to mothers with vital measurements during pregnancy. The primary independent variable was maternal outpatient antibiotic prescriptions during pregnancy (any versus none). We examined dose response (number of antibiotic episodes), spectrum and class of antibiotics, and antibiotic episodes by trimester. The primary outcome was child age- and sex-specific BMI-z at age 5 years. The final sample was 53,320 mother-child pairs. During pregnancy, 29.9% of mothers received antibiotics. In adjusted models, maternal outpatient antibiotic prescriptions during pregnancy were not associated with child BMI-z at age 5 years (β = 0.00, 95% CI -0.03, 0.02). When evaluating timing during pregnancy, dose-response, spectrum and class of antibiotics, there were no associations of maternal antibiotics with child BMI-z at age 5 years. In this large observational cohort, provision of antibiotics during pregnancy was not associated with childhood BMI-z at 5 years.


The generality of architectural isomerism in designer inclusion frameworks.
We describe herein new structural isomers of a lamellar host system based on organodisulfonate "pillars" that connect opposing hydrogen-bonded sheets, consisting of topologically complementary guanidinium (G) ions and sulfonate (S) groups, to generate inclusion cavities between the sheets. These new isomers-zigzag brick, double brick, V-brick, and crisscross bilayer-expand significantly on our earlier report of architectural isomerism displayed by the discrete bilayer and simple brick forms. We demonstrate here that the discrete bilayer-simple brick isomerism, which was limited to several host-guest combinations based on the G(2)(4,4'-biphenyldisulfonate) host and one pair of compounds based on the G(2)(2,6-naphthalenedisulfonate), can be generalized to other organodisulfonate pillars. Furthermore, in many cases the selectivity toward the different framework isomers reflects a rather systematic templating role of the guest molecules and host-guest recognition during assembly of the lattice. We also describe a convenient approach to identifying and classifying the innumerable possible host architectures based upon the pillar projection topologies for the GS sheets and the intersheet connectivities. The discovery of these new architectures reveals a structural versatility for this class of materials that exceeds initial expectations and observations. Each topology produces different connectivities between the sheets in the third dimension that endows each framework isomer with uniquely shaped and sized inclusion cavities, enabling this host system to conform readily to different guests. The unlimited number of architectures available, combined with the inherent conformational softness and structural tunability of these host lattices, suggests a near universality for the GS system with respect to guest inclusion.


Effect of early coronary artery reperfusion on infarct development in a model of low collateral flow.
To characterise collateral blood flow patterns after coronary artery occlusion in the rat and to determine whether tissue can be salvaged by reperfusion in this model, anaesthetised rats were subjected to 20, 30, 40, 60 min of coronary occlusion followed by 24 h of reperfusion or 24 h of permanent occlusion. Relative regional blood flow was measured by radioactive microspheres after 10 min of occlusion in rats undergoing 30 min of occlusion plus reperfusion and in those undergoing 24 h of permanent occlusion. The area at risk was determined by in vivo injection of fluorescent microspheres and necrosis delineated by in vitro tetrazolium staining. Tracings of heart slices were planimetered and the area of necrosis and transmural extent of the infarct measured. Blood flow in the area at risk during occlusion was similar in both the reperfused and permanent occlusion groups. In the 30 min group mean(SEM) subendocardial flow was reduced to 13(5)% of normal and subepicardial flow to 9(3)% and in the permanent occlusion group to 11(2)% and 8(3)% respectively. As delineated by fluorescent microspheres the area at risk was transmural in all rats; however, infarct size expressed as a percentage of the area at risk increased as the duration of occlusion increased. In rats reperfused up to 30 min after occlusion the area of necrosis as a percentage of the area at risk was significantly decreased compared with that in the permanent occlusion group (36.4(9.2)% in rats with 30 min occlusion plus 24 h reperfusion and 78.6(7.4)% in rats with permanent occlusion).(ABSTRACT TRUNCATED AT 250 WORDS)


Comparison of bisoprolol and verapamil in hypertension: influence on left ventricular mass and function--a pilot study.
The objective of this study was to test the influence of bisoprolol and verapamil on left ventricular filling in hypertensive patients in a 6 month randomized, double-blind trial in 54 hypertensive patients not previously treated with beta-blockers or calcium inhibitors. After administration of placebo for 14 days, an M echocardiogram of the left ventricle was recorded to determine left ventricular mass. Blood flow was evaluated by pulsed Doppler sonography. After randomization into two groups, one group received 10 mg of bisoprolol and the other 240 mg of verapamil LP in a single dose in the morning. After 2 months' treatment, the patients whose blood pressure was not well controlled were given a diuretic. Echo-Doppler was performed again by the same operator after 4-10 days on active treatment, after 6 months and after a subsequent 2 weeks of placebo for the patients treated with a single drug. The reduction in blood pressure was comparable in the two treated groups, but there was no significant decrease in left ventricular mass. Left ventricular filling was improved only in the patients receiving bisoprolol. The effect was observed immediately after the first administration and throughout the 6 months' treatment period declining slowly during the placebo wash-out. This effect appeared to be independent of any alteration in heart rate and was thought to be a specific action of this drug.


Drosophila brachyenteron regulates gene activity and morphogenesis in the gut.
Chromosomal region 68D/E is required for various aspects of Drosophila gut development; within this region maps the Brachyury homolog T-related gene (Trg), DNA of which rescues the hindgut defects of deficiency 68D/E. From a screen of 13,000 mutagenized chromosomes we identified six non-complementing alleles that are lethal over deficiencies of 68D/E and show a hindgut phenotype. These mutations constitute an allelic series and are all rescued to viability by a Trg transgene. We have named the mutant alleles and the genetic locus they define brachyenteron (byn); phenotypic characterization of the strongest alleles allows determination of the role of byn in embryogenesis. byn expression is activated by tailless, but byn does not regulate itself. byn expression in the hindgut and anal pad primordia is required for the regulation of genes encoding transcription factors (even-skipped, engrailed, caudal, AbdominalB and orthopedia) and cell signaling molecules (wingless and decapentaplegic). In byn mutant embryos, the defective program of gene activity in these primordia is followed by apoptosis (initiated by reaper expression and completed by macrophage engulfment), resulting in severely reduced hindgut and anal pads. Although byn is not expressed in the midgut or the Malpighian tubules, it is required for the formation of midgut constrictions and for the elongation of the Malpighian tubules.


Three-dimensional visual stimulator.
We describe a newly developed three-dimensional visual stimulator (TVS) that can change independently the directions, distances, sizes, luminance, and varieties of two sets of targets for both eyes. It consists of liquid crystal projectors (LCP's) that generate the flexible images of targets, Badal otometers that change target distances without changing the visual angles, and relay-lens systems that change target directions. A special control program is developed for real-time control of six motors and two LCP's in the TVS together with a three-dimensional optometer III that simultaneously measures eye movement, accommodation, pupil diameter, and head movement. The TVS measurement ranges are as follows: distance, 0 to -20 D; direction, ±16° horizontally and ±15° vertically; size, 0-2° visual angle; and luminance, 10(-2)-10(2) cd/m(2). The target images are refreshed at 60 Hz and speeds with which the target makes a smooth change (ramp stimuli) are as follows: distance, 5 D/s; direction, 30°/s, size, 10°/s. A simple application demonstrates the performance.


The ciliary rootlet maintains long-term stability of sensory cilia.
The striated ciliary rootlet is a prominent cytoskeleton originating from basal bodies of ciliated cells. Although a familiar structure in cell biology, its function has remained unresolved. In this study, we carried out targeted disruption in mice of the gene for rootletin, a component of the rootlet. In the mutant, ciliated cells are devoid of rootlets. Phototransduction and ciliary beating in sensory and motile cilia initially exhibit no apparent functional deficits. However, photoreceptors degenerate over time, and mutant lungs appear prone to pathological changes consistent with insufficient mucociliary clearance. Further analyses revealed a striking fragility at the ciliary base in photoreceptors lacking rootlets. In vitro assays suggest that the rootlet is among the least dynamic of all cytoskeletons and interacts with actin filaments. Thus, a primary function of the rootlet is to provide structural support for the cilium. Inasmuch as photoreceptors elaborate an exceptionally enlarged sensory cilium, they are especially dependent on the rootlet for structural integrity and long-term survival.


Cardiac abnormalities identified with echocardiography in anorexia nervosa: systematic review and meta-analysis.
Anorexia nervosa affects most organ systems, with 80% suffering from cardiovascular complications. To define echocardiographic abnormalities in anorexia nervosa through systematic review and meta-analysis. Two reviewers independently assessed eligibility of publications from Medline, EMBASE and Cochrane Database of Systematic Reviews registries. Studies were included if anorexia nervosa was the primary eating disorder and the main clinical association in described cardiac abnormalities. Data was extracted in duplicate and quality-assessed with a modified Newcastle-Ottawa scale. For continuous outcomes we calculated mean and standardised mean difference (SMD), and corresponding 95% confidence interval. For dichotomous outcomes we calculated proportion and corresponding 95% confidence interval. For qualitative data we summarised the studies. We identified 23 eligible studies totalling 960 patients, with a mean age of 17 years and mean body mass index of 15.2 kg/m2. Fourteen studies (469 participants) reported data suitable for meta-analysis. Cardiac abnormalities seen in anorexia nervosa compared with healthy controls were reduced left ventricular mass (SMD 1.82, 95% CI 1.32-2.31, P < 0.001), reduced cardiac output (SMD 1.92, 95% CI 1.38-2.45, P < 0.001), increased E/A ratio (SMD -1.10, 95% CI -1.67 to -0.54, P < 0.001), and increased incidence of pericardial effusions (25% of patients, P < 0.01, 95% CI 17-34%, I2 = 80%). Trends toward improvement were seen with weight restoration. Patients with anorexia nervosa have structural and functional cardiac changes, identifiable with echocardiography. Further work should determine whether echocardiography can help stratify severity and guide safe patient location, management and effectiveness of nutritional rehabilitation.


Role of CD4+ TH1- and TH2-cell-secreted cytokines in cryptosporidiosis.
Cryptosporidium parvum is now recognized as an important gastrointestinal pathogen around the world. Unfortunately, control measures for cryptosporidiosis are currently not well defined and very little is known about the immunological events relevant to the control of infection. Cytokine depletion experiments were conducted by injecting adult BALB/c mice with monoclonal antibodies directed to IL-2, IL-4, and IL-5, prior and during C. parvum infection. Faecal oocyst excretion and intestinal parasite number were monitored from day 4 to day 31 post-infection. Mice injected with monoclonal antibodies to IL-5 or IL-4/IL-5, but not IL-4 alone, harboured significantly higher numbers of both intestinal parasites and excreted oocysts. It is concluded that IL-5 complemented with IL-4 appears to be an important TH2-dependent mechanism for controlling cryptosporidiosis. Nevertheless, we suggest that cytokines secreted by both TH1 and TH2 cells may operate in concert in controlling cryptosporidiosis, triggering different functional mechanisms in a dynamic and simultaneous up- and down-regulatory fashion.


Exosome-like vesicles in Apis mellifera bee pollen, honey and royal jelly contribute to their antibacterial and pro-regenerative activity.
Microvesicles are key players in cellular communication. As glandular secretions present a rich source of active exosomes, we hypothesized that exosome-like vesicles are present in Apis mellifera hypopharyngeal gland secretomal products (honey, royal jelly and bee pollen), and participate in their known antibacterial and pro-regenerative effects. We developed an isolation protocol based on serial centrifugation and ultracentrifugation steps and demonstrated the presence of protein-containing exosome-like vesicles in all three bee-derived products. Assessing their antibacterial properties, we found that exosome-like vesicles had bacteriostatic, bactericidal and biofilm-inhibiting effects on Staphylococcus aureus Furthermore, we demonstrated that mesenchymal stem cells (MSCs) internalize bee-derived exosome-like vesicles and that these vesicles influence the migration potential of the MSCs. In an in vitro wound-healing assay, honey and royal jelly exosome-like vesicles increased migration of human MSCs, demonstrating their inter-kingdom activity. In summary, we have discovered exosome-like vesicles as a new, active compound in bee pollen, honey and royal jelly.


Flow-based evaluation of cerebral revascularization using near-infrared indocyanine green videoangiography.
Indocyanine green (ICG) videoangiography has been established as a noninvasive technique to gauge the patency of a bypass graft; however, intraoperative graft patency may not always correlate with graft flow. Altered flow through the bypass graft may directly cause delayed graft occlusion. Here, the authors report on 3 types of flow that were observed through cerebral revascularization procedures. Between February 2009 and September 2013, 48 bypass procedures were performed. Excluded from analysis were those cases in which ICG videoangiography was not performed during surgery (whether it was not available or there was a technical issue with the microscope or the quality of ICG angiography) and/or in which angiography or CT angiography was not done within 24-72 hours after surgery. After anastomosis, bypass patency was assessed first using a noninvasive technique and then with ICG videoangiography, and flow through the graft was characterized. Patients who received a vein or radial artery graft were also evaluated with intraoperative angiography. Thirty-three patients eligible for analysis were retrospectively analyzed. The patients had undergone extracranial-intracranial (EC-IC) or IC-IC bypass for ischemic stroke (13 patients), moyamoya disease (10 patients), and complex aneurysms (10 patients; 6 giant or large aneurysms, 2 carotid blister-like aneurysms, and 2 dissecting posterior inferior cerebellar artery [PICA] aneurysms). Thirty-six bypasses were performed including 26 superficial temporal artery (STA)-middle cerebral artery (MCA) bypasses (2 bilateral and 1 double-barrel), 6 EC-IC vein grafts, 1 EC-IC radial artery graft, 1 PICA-PICA bypass, 1 MCA-posterior cerebral artery bypass, and 1 occipital artery-PICA bypass. Robust anterograde flow (Type I) was noted in 31 grafts (86%). Delayed but patent graft enhancement and anterograde flow (Type II) was observed in 4 cases (11%); 1 of these cases with an EC-IC vein graft degraded gradually to very delayed flow with no continuity to the bypass site (Type III). Additionally, 1 STA-MCA bypass graft revealed no convincing flow (Type III). The 5 patients with Type II or III grafts were evaluated with a flow probe and reexploration of the bypass site, and in all cases the reason the graft became occluded was believed to be recipient-vessel competitive flow. In no case was there evidence of stenosis or a technical issue at the site of the anastomosis. Three patients with Type II and the 1 patient with Type III flow (11% of procedures) did not have a patent bypass on postoperative imaging. Indocyanine green videoangiography is reliable for evaluating flow through the EC-IC or IC-IC bypass. The type of flow observed through the graft has a direct relationship with postoperative imaging findings. Despite the possibility of competitive flow, Type III and some Type II flows through the graft indicate the need for graft evaluation and anastomosis exploration.


Child psychiatry: A scientometric analysis 1980-2016.
Background: The field of child and adolescent psychiatry lags behind adult psychiatry significantly. In recent years, it has witnessed a significant increase in the publication of journals and articles. This study provides a detailed bibliometric analysis of articles published from 1980 to 2016, in the top seven journals of child and adolescent psychiatry. Methods: Using the Web of Science core collection, we selected 9,719 research papers published in seven psychiatric journals from 1980 to 2016. We utilized the Web of Science Analytics tool and Network Analysis Interface for Literature Studies (NAILS) Project scripts to delineate the general trends of publication in these journals. Then, co-citation analysis and hierarchical cluster analysis was performed using CiteSpace to map important papers, landmark theories and foci of research in child and adolescent psychiatry. Results: The field of child and adolescent psychiatry has experienced an increasing trend in research, which was reflected in the results of this study. Hierarchical cluster analysis revealed that the research foci in psychiatry were primarily studies related to the design of psychometric instruments, checklists, taxonomy, attention deficit hyperactivity disorder (ADHD), depression, PTSD, social phobia, and psychopharmacology. Moreover, several landmark studies, including the validation of a child behavior checklist, Ainsworth's empirical evidence of Bowlby's attachment theory, and adult outcomes of childhood dysregulation were published. This study also reports rapid expansion and innovation in research areas in the field of child and adolescent psychiatry from 1980-2016. Conclusions: Rapid expansion and innovation in research areas in the field of child and adolescent psychiatry has been observed, from 1980 to 2016.


Gap between contact and content in maternal and newborn care: An analysis of data from 20 countries in sub-Saharan Africa.
Over the last decade, coverage of maternal and newborn health indicators used for global monitoring and reporting have increased substantially but reductions in maternal and neonatal mortality have remained slow. This has led to an increased recognition and concern that these standard globally agreed upon measures of antenatal care (ANC), skilled birth attendance (SBA) and postnatal care (PNC) only capture the level of contacts with the health system and provide little indication of actual content of services received by mothers and their newborns. Over this period, large household surveys have captured measures of maternal and newborn care mainly through questions assessing contacts during the antenatal, delivery and postnatal periods along with some measures of content of care. This study aims to describe the gap between contact and content -as a proxy for quality- of maternal and newborn health services by assessing level of co-coverage of ANC and PNC interventions. We used Demographic and Health Surveys (DHS) data from 20 countries between 2010 and 2015. We analysed the proportion of women with at least 1 and 4+ antenatal care visit, who received 8 interventions. We also assessed the percentage of newborns delivered with a skilled birth attendant who received 7 interventions. We ran random effect logistic regression to assess factors associated with receiving all interventions during the antenatal and postnatal period. While on average 51% of women in the analysis received four ANC visits with at least one visit from a skilled health provider, only 5% of them received all 8 ANC interventions. Similarly, during the postnatal period though two-thirds (65%) of births were attended by a skilled birth attendant, only 3% of newborns received all 7 PNC interventions. The odds of receiving all ANC and PNC interventions were higher for women with higher education and higher wealth status. The gap between coverage and content as a proxy of quality of antenatal and postnatal care is excessively large in all countries. In order to accelerate maternal and newborn survival and achieve Sustainable Development Goals, increased efforts are needed to improve both the coverage and quality of maternal and newborn health interventions.


Microdissection-based genotyping assists discrimination of reactive gliosis from glioma.
We used molecular anatomic pathology to determine the mutational status (loss of heterozygosity [LOH]) to make the distinction between reactive gliosis and glial neoplasia. LOH has been shown to be absent in reactive states and present in neoplastic cellular proliferations. Three groups of patient specimens were analyzed: group 1, reactive gliosis (n = 15); group 2, gliomas of varying histologic type and grade (n = 54); group 3, diagnostically challenging reactive gliosis vs glioma (n = 16). No group 1 cases (0/15 [0%]) showed allelic loss, whereas all high-grade glial neoplasms, a subset of group 2 (35/35 [100%]) manifested at least 1 allelic loss alteration, with most cases (33/35 [94%]) displaying 2 or more such changes. During a look forward at the group 3 patients, clinical history clarified the problematic diagnosis in a subset of 11 patients: 8 (73%) of 11 clinical outcomes were predicted correctly by our analysis. The molecular anatomic pathology approach outlined herein is designed for minute, formalin-fixed, paraffin-embedded specimens, which are encountered in everyday surgical pathology practice. Molecular anatomic pathology opens the possibilities of molecular analysis to everyday pathology practice.


Giant viruses coexisted with the cellular ancestors and represent a distinct supergroup along with superkingdoms Archaea, Bacteria and Eukarya.
The discovery of giant viruses with genome and physical size comparable to cellular organisms, remnants of protein translation machinery and virus-specific parasites (virophages) have raised intriguing questions about their origin. Evidence advocates for their inclusion into global phylogenomic studies and their consideration as a distinct and ancient form of life. Here we reconstruct phylogenies describing the evolution of proteomes and protein domain structures of cellular organisms and double-stranded DNA viruses with medium-to-very-large proteomes (giant viruses). Trees of proteomes define viruses as a 'fourth supergroup' along with superkingdoms Archaea, Bacteria, and Eukarya. Trees of domains indicate they have evolved via massive and primordial reductive evolutionary processes. The distribution of domain structures suggests giant viruses harbor a significant number of protein domains including those with no cellular representation. The genomic and structural diversity embedded in the viral proteomes is comparable to the cellular proteomes of organisms with parasitic lifestyles. Since viral domains are widespread among cellular species, we propose that viruses mediate gene transfer between cells and crucially enhance biodiversity. Results call for a change in the way viruses are perceived. They likely represent a distinct form of life that either predated or coexisted with the last universal common ancestor (LUCA) and constitute a very crucial part of our planet's biosphere.


Rapid quantitative detection of chytridiomycosis (Batrachochytrium dendrobatidis) in amphibian samples using real-time Taqman PCR assay.
Batrachochytrium dendrobatidis is a major pathogen of frogs worldwide, associated with declines in amphibian populations. Diagnosis of chytridiomycosis to date has largely relied upon histological and immunohistochemical examination of toe clips. This technique is invasive and insensitive particularly at early stages of infection when treatment may be possible. We have developed a real-time PCR Taqman assay that can accurately detect and quantify one zoospore in a diagnostic sample. This assay will assist the early detection of B. dendrobatidis in both captive and wild populations, with a high degree of sensitivity and specificity, thus facilitating treatment and protection of endangered populations, monitoring of pristine environments and preventing further global spread via amphibian trade.


Sleep is essential to health: an American Academy of Sleep Medicine position statement.
Sleep is a biological necessity, and insufficient sleep and untreated sleep disorders are detrimental for health, well-being, and public safety. Healthy People 2030 includes several sleep-related objectives with the goal to improve health, productivity, well-being, quality of life, and safety by helping people get enough sleep. In addition to adequate sleep duration, healthy sleep requires good quality, appropriate timing, regularity, and the absence of sleep disorders. It is the position of the American Academy of Sleep Medicine (AASM) that sleep is essential to health. There is a significant need for greater emphasis on sleep health in education, clinical practice, inpatient and long-term care, public health promotion, and the workplace. More sleep and circadian research is needed to further elucidate the importance of sleep for public health and the contributions of insufficient sleep to health disparities. Ramar K, Malhotra RK, Carden KA, et al. Sleep is essential to health: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2021;17(10):2115-2119.


Par3/Bazooka and phosphoinositides regulate actin protrusion formation during Drosophila dorsal closure and wound healing.
Effective wound closure mechanisms are essential for maintenance of epithelial structure and function. The repair of wounded epithelia is primarily driven by the cells bordering the wound, which become motile after wounding, forming dynamic actin protrusions along the wound edge. The molecular mechanisms that trigger wound edge cells to become motile following tissue damage are not well understood. Using wound healing and dorsal closure in Drosophila, we identify a direct molecular link between changes in cell-cell adhesion at epithelial edges and induction of actin protrusion formation. We find that the scaffolding protein Par3/Bazooka and the lipid phosphatase Pten are specifically lost from cell-cell junctions at epithelial edges. This results in a localized accumulation of phosphatidylinositol 3,4,5-trisphosphate (PIP3), which promotes the formation of actin protrusions along the epithelial edge. Depleting PIP3 results in defective epithelial closure during both dorsal closure and wound healing. These data reveal a novel mechanism that directly couples loss of epithelial integrity to activation of epithelial closure.


Development and initial psychometric evaluation of the hospitalization-related stressors questionnaire for elderly patients.
Various factors threaten the health and recovery of hospitalized elderly, including stressors in medical service centers. Therefore, the aim of the present study was to develop and preliminary validate a measurement tool to assess hospitalization-related stressors (HRS) among the elderly. This methodological research was conducted in 2015. The study was performed in two main phases. In the first phase, which was to develop the questionnaire, the data were collected through literature review, interview with few elderly patients, and calculating content validity index with the participation of 16 experts. The second phase included preliminary validation of the questionnaire in which a convenient sample of 200 hospitalized elderly patients recruited from 4 educational medical centers of the Isfahan University of Medical Sciences were studied. Principal component analysis method was used to identify the factorial structure of the questionnaire. In order to evaluate validity, Cronbach's alpha coefficient was calculated. After evaluating the results and relocating and merging some of the items, a version of 26 items in 7 categories was prepared with acceptable internal consistency (Cronbach's alpha coefficient from 0.67 to 0.78 for the components and 0.83 for the tool). In this study, we were able to identify a set of important components and indicators of HRS in elderly; so it can be used as a useful instrument. Future studies are recommended in order to develop and validate this tool in other communities.


Obesity, endothelial function and inflammation: the effects of weight loss after bariatric surgery.
Obesity is associated with a high risk for atherosclerotic cardiovascular disease. There is a causal association between obesity, inflammation, insulin resistance (IR) and endothelial dysfunction. The aim of this study was to evaluate changes in IR, proinflammatory state and markers of endothelial dysfunction in morbidly obese patients after weight loss following bariatric surgery. In this study, we measured the levels of soluble intracellular adhesion molecule-1 (sICAM1), plasminogen activator inhibitor 1 (PAI-1), high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6) in 79 morbidly obese patients at baseline and 3, 6 and 12 months after gastric bypass. Also, we evaluated changes in IR. Twelve months after surgery, there was a significant decrease in plasma levels of sICAM1 (p < 0.001), PAI-1 (p < 0.05), hs-CRP (p < 0.001), IL-6 (p < 0.001) and homeostasis model assessment (HOMA) (p < 0.001) and a significant increase of McAuley index (McAuley) (p < 0.001). Baseline levels of hs-PCR were positively correlated with sICAM-1 (r = 0.450, p < 0.01) and IL-6 (r = 0.451, p < 0.01). Significant correlations were also found between the decrease of PAI-1 and the decrease of hs-PCR (r = 0.425, p < 0.01) and tryglicerides (r = 0.351, p < 0.01). In patients with morbid obesity, substantial surgically induced weight loss is followed by a significant improvement in the endothelial function, inflammatory state and insulin sensitivity, that may reduce their cardiovascular risk. A relationship exists between improved inflammatory profile and endothelial function.


Aptima Trichomonas vaginalis assay elucidates significant underdiagnosis of trichomoniasis among women in Brazil according to an observational study.
Trichomonas vaginalis (TV) infection is the most common non-viral STI globally and can result in adverse pregnancy outcomes and exacerbated HIV acquisition/transmission. Nucleic acid amplification tests (NAATs) are the most sensitive diagnostic tests, with high specificity, but TV NAATs are rarely used in Brazil. We investigated the TV prevalence and compared the performance of the US Food and Drug Association-cleared Aptima TV assay with microscopy (wet mount and Gram-stained) and culture for TV detection in women in Pelotas, Brazil in an observational study. From August 2015 to December 2016, 499 consecutive asymptomatic and symptomatic sexually active women attending a Gynaecology and Obstetrics Outpatient Clinic were enrolled. Vaginal fluid and swab specimens were collected and wet mount microscopy, Gram-stained microscopy, culture and the Aptima TV assay performed. The median age of enrolled women was 36.5 years (range: 15-77). The majority were white, had a steady sexual partner and low levels of education. The TV detection rate was 4.2%, 2.4%, 1.2% and 0% using the Aptima TV assay, culture, wet mount microscopy and Gram-stained microscopy, respectively. The sensitivity of culture and wet mount microscopy was only 57.1% (95% CI 36.5 to 75.5) and 28.6% (95% CI 13.8 to 50.0), respectively. A 4.2% positivity rate of T. vaginalis was found among women in Pelotas, Brazil and the routine diagnostic test (wet mount microscopy) and culture had low sensitivities. More sensitive diagnostic tests (NAATs) and enhanced testing of symptomatic and asymptomatic at-risk women are crucial to mitigate the transmission of TV infection, TV-associated sequelae and enhanced HIV acquisition and transmission.


From local structure to nanosecond recrystallization dynamics in AgInSbTe phase-change materials.
Phase-change optical memories are based on the astonishingly rapid nanosecond-scale crystallization of nanosized amorphous 'marks' in a polycrystalline layer. Models of crystallization exist for the commercially used phase-change alloy Ge(2)Sb(2)Te(5) (GST), but not for the equally important class of Sb-Te-based alloys. We have combined X-ray diffraction, extended X-ray absorption fine structure and hard X-ray photoelectron spectroscopy experiments with density functional simulations to determine the crystalline and amorphous structures of Ag(3.5)In(3.8)Sb(75.0)Te(17.7) (AIST) and how they differ from GST. The structure of amorphous (a-) AIST shows a range of atomic ring sizes, whereas a-GST shows mainly small rings and cavities. The local environment of Sb in both forms of AIST is a distorted 3+3 octahedron. These structures suggest a bond-interchange model, where a sequence of small displacements of Sb atoms accompanied by interchanges of short and long bonds is the origin of the rapid crystallization of a-AIST. It differs profoundly from crystallization in a-GST.


First evaluation of legacy persistent organic pollutant contamination status of stranded Yangtze finless porpoises along the Yangtze River Basin, China.
Yangtze finless porpoises (Neophocaena asiaeorientalis asiaeorientalis), inhabiting the Yangtze River, are an endangered species in China. They are threatened by various kinds of pollutants, among which persistent organic pollutants (POPs) are of special concern due to their toxicities, high persistency and bioaccumulation potential. To better understand the POP contamination status of Yangtze finless porpoises, an investigation of stranded porpoises along the Yangtze River and adjacent two major lakes in the Yangtze River basin was conducted; the concentrations of four groups of legacy POPs, i.e., hexachlorocyclohexanes (HCHs), dichlorodiphenyltrichloroethanes (DDTs), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyl (PCBs), were determined in the blubber samples. The mean concentrations of ΣHCHs (the sum of all congeners/isomers), ΣDDTs, ΣPBDEs and ΣPCBs, were 1670 ± 4210, 28,800 ± 52,300, 141 ± 174, and 1020 ± 1070 ng/g lipid weight, respectively; the high DDTs/PCBs ratio reflected a strong influence of agricultural pollution in the Yangtze River basin, and the high α/γ ratio of HCH isomers indicated the usage of lindane in the corresponding areas; the predominance of low-brominated congeners of PBDEs may be related to congruent patterns in the related environmental matrices. A hazard quotient risk assessment revealed that DDTs could pose a relatively high risk to Yangtze finless porpoises compared with the risks posed by the other POPs.


AGGRESCAN: a server for the prediction and evaluation of "hot spots" of aggregation in polypeptides.
Protein aggregation correlates with the development of several debilitating human disorders of growing incidence, such as Alzheimer's and Parkinson's diseases. On the biotechnological side, protein production is often hampered by the accumulation of recombinant proteins into aggregates. Thus, the development of methods to anticipate the aggregation properties of polypeptides is receiving increasing attention. AGGRESCAN is a web-based software for the prediction of aggregation-prone segments in protein sequences, the analysis of the effect of mutations on protein aggregation propensities and the comparison of the aggregation properties of different proteins or protein sets. AGGRESCAN is based on an aggregation-propensity scale for natural amino acids derived from in vivo experiments and on the assumption that short and specific sequence stretches modulate protein aggregation. The algorithm is shown to identify a series of protein fragments involved in the aggregation of disease-related proteins and to predict the effect of genetic mutations on their deposition propensities. It also provides new insights into the differential aggregation properties displayed by globular proteins, natively unfolded polypeptides, amyloidogenic proteins and proteins found in bacterial inclusion bodies. By identifying aggregation-prone segments in proteins, AGGRESCAN http://bioinf.uab.es/aggrescan/ shall facilitate (i) the identification of possible therapeutic targets for anti-depositional strategies in conformational diseases and (ii) the anticipation of aggregation phenomena during storage or recombinant production of bioactive polypeptides or polypeptide sets.


Sexual relationship power and depression among HIV-infected women in Rural Uganda.
Depression is associated with increased HIV transmission risk, increased morbidity, and higher risk of HIV-related death among HIV-infected women. Low sexual relationship power also contributes to HIV risk, but there is limited understanding of how it relates to mental health among HIV-infected women. Participants were 270 HIV-infected women from the Uganda AIDS Rural Treatment Outcomes study, a prospective cohort of individuals initiating antiretroviral therapy (ART) in Mbarara, Uganda. Our primary predictor was baseline sexual relationship power as measured by the Sexual Relationship Power Scale (SRPS). The primary outcome was depression severity, measured with the Hopkins Symptom Checklist (HSCL), and a secondary outcome was a functional scale for mental health status (MHS). Adjusted models controlled for socio-demographic factors, CD4 count, alcohol and tobacco use, baseline WHO stage 4 disease, social support, and duration of ART. The mean HSCL score was 1.34 and 23.7% of participants had HSCL scores consistent with probable depression (HSCL>1.75). Compared to participants with low SRPS scores, individuals with both moderate (coefficient b = -0.21; 95%CI, -0.36 to -0.07) and high power (b = -0.21; 95%CI, -0.36 to -0.06) reported decreased depressive symptomology. High SRPS scores halved the likelihood of women meeting criteria for probable depression (adjusted odds ratio = 0.44; 95%CI, 0.20 to 0.93). In lagged models, low SRPS predicted subsequent depression severity, but depression did not predict subsequent changes in SPRS. Results were similar for MHS, with lagged models showing SRPS predicts subsequent mental health, but not visa versa. Both Decision-Making Dominance and Relationship Control subscales of SRPS were associated with depression symptom severity. HIV-infected women with high sexual relationship power had lower depression and higher mental health status than women with low power. Interventions to improve equity in decision-making and control within dyadic partnerships are critical to prevent HIV transmission and to optimize mental health of HIV-infected women.


Ocular pigmentation in white and Siamese cats.
Ocular pigmentation in white cats with blue and yellow eyes and in Siamese cats was examined ophthalmoscopically and histologically. Yellow-eyed white cats had entirely normal ocular pigmentation. Blue eyes of white cats had normal pigmentation of the iridial and retinal pigment epithelia but no stromal pigmentation of the iris or choroid. This deficit is apparently due to the absence of stromal pigment cells, certainly in the iris. As a general rule, the blue eye of white cats had no tapetum. Siamese cats had reduced pigmentation of the iridial and retinal pigment epithelia and no stromal pigmentation of the iris or choroid. The lack of pigmentation is apparently due to the inability of stromal pigment cells to produce pigment, certainly in the iris. We conclude that the abnormality of visual pathways previously described in the Siamese cat is not due simply to a deficiency of pigment of cells of neural crest origin.


Expression of a novel member of the TGF-beta superfamily, growth/differentiation factor-15/macrophage-inhibiting cytokine-1 (GDF-15/MIC-1) in adult rat tissues.
We have cloned a novel member of the transforming growth factor-beta (TGF-beta) superfamily from a human placental cDNA library. The sequence is identical to five very recently published sequences, of which only one (macrophage inhibitory cytokine-1, MIC-1) has been characterized in terms of function. In light of the present data demonstrating the wide distribution of the mRNA and putative multifunctionality, we propose to name this molecule growth/differentiation factor-15/MIC-1 (GDF-15/MIC-1). The deduced amino acid sequence reveals typical features of a secreted molecule. The epithelium of the choroid plexus is the only site in the adult brain expressing detectable levels of GDF-15/MIC-1 mRNA. Many epithelia of non-neural tissues including those of the prostate and intestinal mucosa, bronchi and bronchioli, secretory tubuli of the submandibular gland, and lactating mammary gland are prominent sites of GDF-15/MIC-1 synthesis. GDF-15/MIC-1 is also strongly expressed by macrophages in the adrenal gland. Thus, GDF-15/MIC-1, like many other members of the TGF-beta superfamily, is widely distributed in adult tissues, being most strongly expressed in epithelial cells and macrophages.


Modified Frailty Index and Body Mass Index as Predictors of Adverse Surgical Outcomes in Degenerative Spinal Disease.
To reveal the potential relationships and interactive effects between frailty and body weight and adverse surgical outcomes for degenerative spinal disease. Patients who underwent open surgery for degenerative spinal disease in our hospital were included. Data on the patients and disease variables was obtained. The primary independent variables included body mass index (BMI) and modified Frailty Index (mFI). The primary outcome was the Clavien-Dindo complications classification. After univariate analyses, multinomial and ordinal regression analyses were applied with the Clavien-Dindo complications grade as the dependent variable and the potential risk factors for complications as independent variables, respectively, to determine the potential interactive relationship between the two primary risk factors and their impact on postoperative complications grading. A total of 1970 patients were included in the study. The results showed that "underweight" could significantly increase the odds ratios of "prefrail" and "frail" at the same time; however, "obese" could only increase the odds ratio of "frail". The "underweight", "obese", "prefrail" and "frail" subgroups could significantly increase the grading of postoperative complications, respectively. If mFI and BMI were combined as an interactive variable, the results showed that in the "underweight" and "normal weight" subgroups, both "prefrail" and "frail" could significantly increase the grading of postoperative complications; however, in the "overweight" and "obese" subgroups, only the "overweight/frail", "obese/non-frail" and "obese/frail" subgroups displayed significantly increased grading of postoperative complications. The present results serve to stratify susceptible patients with easily identified risk factors preoperatively.


Pharmacological Induction of RAS-GTP Confers RAF Inhibitor Sensitivity in KRAS Mutant Tumors.
Targeting KRAS mutant tumors through inhibition of individual downstream pathways has had limited clinical success. Here we report that RAF inhibitors exhibit little efficacy in KRAS mutant tumors. In combination drug screens, MEK and PI3K inhibitors synergized with pan-RAF inhibitors through an RAS-GTP-dependent mechanism. Broad cell line profiling with RAF/MEK inhibitor combinations revealed synergistic efficacy in KRAS mutant and wild-type tumors, with KRASG13D mutants exhibiting greater synergy versus KRASG12 mutant tumors. Mechanistic studies demonstrate that MEK inhibition induced RAS-GTP levels, RAF dimerization and RAF kinase activity resulting in MEK phosphorylation in synergistic tumor lines regardless of KRAS status. Taken together, our studies uncover a strategy to rewire KRAS mutant tumors to confer sensitivity to RAF kinase inhibition.


Progestin-only contraceptives: effects on weight.
Progestin-only contraceptives (POCs) are appropriate for many women who cannot or should not take estrogen. Many POCs are long-acting, cost-effective methods of preventing pregnancy. However, concern about weight gain can deter the initiation of contraceptives and cause early discontinuation among users. The primary objective was to evaluate the association between progestin-only contraceptive use and changes in body weight. Through May 2013, we searched MEDLINE, CENTRAL, POPLINE, LILACS, ClinicalTrials.gov, and ICTRP. The 2010 search also included EMBASE. For the initial review, we contacted investigators to identify other trials. All comparative studies were eligible that examined a POC versus another contraceptive method or no contraceptive. The primary outcome was mean change in body weight or mean change in body composition. We also considered the dichotomous outcome of loss or gain of a specified amount of weight. Two authors extracted the data. We computed the mean difference (MD) with 95% confidence interval (CI) for continuous variables. For dichotomous outcomes, the Mantel-Haenszel odds ratio (OR) with 95% CI was calculated. We found 16 studies; one examined progestin-only pills, one studied the levonorgestrel-releasing intrauterine system (LNG-IUS), four examined an implant, and 10 focused on depot medroxyprogesterone acetate (DMPA). Outcomes examined were changes in body weight only (14 studies), changes in both body weight and body composition (1 study), and changes in body composition only (1 study). We did not conduct meta-analysis due to the various contraceptive methods and weight change measures.Comparison groups did not differ significantly for weight change in 12 studies. However, three studies showed weight change differences for POC users compared to women not using a hormonal method. In one study, weight gain (kg) was greater for the DMPA group than the group using a non-hormonal IUD in years one through three [(MD 2.28; 95% CI 1.79 to 2.77), (MD 2.71, 95% CI 2.12 to 3.30), and (MD 3.17; 95% CI 2.51 to 3.83), respectively]. The differences were notable within the normal weight and overweight subgroups. Two implant studies also showed differences in weight change. The implant group (six-capsule) had greater weight gain (kg) compared to the group using a non-hormonal IUD in both studies [(MD 0.47 (95% CI 0.29 to 0.65); (MD 1.10; 95% CI 0.36 to 1.84)]. In one of those studies, the implant group also had greater weight gain than a group using a barrier method or no contraceptive (MD 0.74; 95% CI 0.52 to 0.96).The two studies that assessed body composition change showed differences between POC users and women not using a hormonal method. Adolescents using DMPA had a greater increase in body fat (%) compared to a group not using a hormonal method (MD 11.00; 95% CI 2.64 to 19.36). The DMPA group also had a greater decrease in lean body mass (%) (MD -4.00; 95% CI -6.93 to -1.07). The other study reported differences between an LNG-IUS group and a non-hormonal IUD group in percent change in body fat mass (2.5% versus -1.3%, respectively; reported P value = 0.029) and percent change in lean body mass (-1.4% versus 1.0%, respectively; reported P value = 0.027). The overall quality of evidence was moderate to low, given that the studies were evenly divided across the evidence quality groups (high, moderate, low, or very low quality). We found limited evidence of weight gain when using POCs. Mean gain was less than 2 kg for most studies up to 12 months. Weight change for the POC group generally did not differ significantly from that of the comparison group using another contraceptive. Two studies that assessed body composition showed that POC users had greater increases in body fat and decreases in lean body mass compared to users of non-hormonal methods. Appropriate counseling about typical weight gain may help reduce discontinuation of contraceptives due to perceptions of weight gain.