Meeting pragmatism halfway: making a pragmatic clinical trial protocol.
Pragmatic clinical trials (PCTs) are today an increasingly prominent means of measuring the 'effectiveness' of healthcare interventions in 'real world' clinical settings, in order to produce evidence on which to base regulatory and clinical decision-making. Although several sociological studies have shown persuasively how PCTs are co-constructed within particular healthcare systems in which they are based, they have tended to focus on relatively later stages in careers of trials. The paper contributes to literature by considering how the 'real world' of the UK National Health Service (NHS) is incorporated into the design of a research protocol. Drawing on a meeting held just prior to patient recruitment for a PCT in maternal health, the paper analyses a trial collective's efforts to purify the messy domain of NHS clinical care into the orderly confines of the protocol (Law 2004), which meant satisfying demands for both scientific and social robustness (c.f. Nowotny et al. 2001). The findings show how efforts to inscribe robustness into the PCT protocol were themselves mediated through epistemic and regulatory conventions surrounding protocols as devices in healthcare research. Finally it is argued that meetings constitute an important epistemic instrument through which to settle various emerging tensions in PCT protocol design.


Transgender populations and HIV: unique risks, challenges and opportunities.
Due to unique social, behavioural, structural and biological issues, transgender (TG) populations, especially TG women, are at high risk for HIV acquisition. This increased risk is multifactorial, due to differing psychosocial risk factors, poorer access to TG-specific healthcare, a higher likelihood of using exogenous hormones or fillers without direct medical supervision, interactions between hormonal therapy and antiretroviral therapy, and direct effects of hormonal therapy on HIV acquisition and immune control. Further research is needed to elucidate these mechanisms of risk and to help design interventions to reduce HIV risk among transgender populations.


Angiotensin inhibition potentiates the renal responses to neutral endopeptidase inhibition in dogs with congestive heart failure.
The renal natriuretic actions of endogenous atrial natriuretic factor are enhanced by neutral endopeptidase inhibition (NEP-I). Recognizing that activation of the renin-angiotensin-aldosterone system in congestive heart failure (CHF) antagonizes the renal actions of atrial natriuretic factor, we hypothesized that angiotensin II antagonism with converting enzyme inhibition would potentiate the renal actions of NEP-I in CHF. To test this hypothesis, the renal responses to a specific NEP-I (SQ 28,603) were assessed in dogs with eight days of experimental CHF produced by rapid ventricular pacing. The renal natriuretic responses to NEP-I in experimental CHF were significant. In the same model of CHF, chronic angiotensin antagonism with converting enzyme inhibition potentiated both renal hemodynamic and excretory responses to NEP-I. The potentiated renal hemodynamic response included significant increases in glomerular filtration rate and filtration fraction. In the CHF group with angiotensin antagonism, an intrarenal infusion of low-dose angiotensin abolished the potentiated renal responses to NEP-I, supporting the concept that intrarenal angiotensin antagonism, rather than improved systemic hemodynamics or potentiation of other peptide systems, mediated the enhanced renal responses to NEP-I in the presence of converting enzyme inhibition.


Addressee Identity and Morphosyntactic Processing in Basque Allocutive Agreement.
Information about interlocutor identity is pragmatic in nature and has traditionally been distinguished from explicitly coded linguistic information, including mophosyntax. Study of speaker identity in language processing has questioned this distinction, but addressee identity has been less considered. We used Basque to explore how addressee identity is processed during morphosyntactic analysis. In the familiar register hika, Basque has obligatory allocutive agreement, where verbal morphology represents the gender of a non-argument addressee. We manipulated the gender of the allocutive verb and the congruence of addressee gender in conversations between two interlocutors. Items with person agreement manipulations were included as a control comparison. Basque speakers familiar with hika completed speeded acceptability judgments and unspeeded, offline naturalness ratings for each conversation. Results showed a main effect of addressee identity congruence for naturalness ratings, but there was no main effect for addressee identity congruence for reaction times or accuracy in the acceptability judgment. Interactions and correlations with biographical data showed that the effect of congruence was modulated by the gender of the allocutive verb and that hika proficiency was related to participants' performance for the acceptability judgment. These results show an interaction between morphosyntactic and pragmatic information and are the first experimental data of allocutive processing. In comparison, clear effects were seen for the person agreement condition, indicating that person disagreement is more disruptive to processing than addressee identity incongruence. This study has implications for investigation of the role of extralinguistic information in morphosyntactic processing, and suggests that not all such information plays an equal role.


Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis.
The elimination of Mcl-1, an anti-apoptotic Bcl-2 family member, is an early and required step for DNA damage-induced apoptosis. The degradation of Mcl-1 can be blocked by proteasome inhibitors, suggesting a role for the ubiquitin proteasome pathway in apoptosis. Here, we demonstrate that Mcl-1 is ubiquinated at five lysines. Biochemical fractionation of cell extracts allowed us to identify a 482 kDa HECT-domain-containing ubiquitin ligase named Mule (Mcl-1 ubiquitin ligase E3) that is both required and sufficient for the polyubiquitination of Mcl-1. Mule also contains a region similar to the Bcl-2 homology region 3 (BH3) domain that allows Mule to specifically interact with Mcl-1. Elimination of Mule expression by RNA interference stabilizes Mcl-1 protein, resulting in an attenuation of the apoptosis induced by DNA-damage agents. Thus, Mule is a unique BH3-containing E3 ubiquitin ligase apical to Bcl-2 family proteins during DNA damage-induced apoptosis.


Structural features and the persistence of acquired proteins.
ORFan genes can constitute a large fraction of a bacterial genome, but due to their lack of homologs, their functions have remained largely unexplored. To determine if particular features of ORFan-encoded proteins promote their presence in a genome, we analyzed properties of ORFans that originated over a broad evolutionary timescale. We also compared ORFan genes to another class of acquired genes, heterogeneous occurrence in prokaryotes (HOPs), which have homologs in other bacteria. A total of 54 ORFan and HOP genes selected from different phylogenetic depths in the Escherichia coli lineage were cloned, expressed, purified, and subjected to circular dichroism (CD) spectroscopy. A majority of genes could be expressed, but only 18 yielded sufficient soluble protein for spectral analysis. Of these, half were significantly alpha-helical, three were predominantly beta-sheet, and six were of intermediate/indeterminate structure. Although a higher proportion of HOPs yielded soluble proteins with resolvable secondary structures, ORFans resembled HOPs with regard to most of the other features tested. Overall, we found that those ORFan and HOP genes that have persisted in the E. coli lineage were more likely to encode soluble and folded proteins, more likely to display environmental modulation of their gene expression, and by extrapolation, are more likely to be functional.


Dendritic arbor of neurons in the hypothalamic ventromedial nucleus in female prairie voles (Microtus ochrogaster).
Female mating behavior in rats is associated with hormone-induced changes in the dendritic arbor of neurons in the ventromedial nucleus of the hypothalamus (VMH), particularly the ventrolateral portion. Regulation of mating behavior in female prairie voles differs substantially from that in rats; therefore, we examined the dendritic morphology of VMH neurons in this species. Sexually naïve adult female prairie voles were housed with a male to activate the females' reproductive endocrine system. Following 48 h of cohabitation, females were tested for evidence of reproductive activation by assessing the level of male sexual interest, after which their brains were processed using Golgi impregnation, which allowed ventrolateral VMH neurons to be visualized and analyzed. Dendritic arborization in the female prairie vole VMH neurons was strikingly similar to that of female rats. The key difference was that in the prairie voles the long primary dendrites extended considerably further than those observed in rats. Although most female voles paired with males exhibited sexual activation, some females did not. These two groups displayed specific differences in their VMH dendrites. In particular, the long primary dendrites were longer in the reproductively active females compared with those in the non-activated females. Overall, dendrite lengths were positively correlated with plasma estradiol levels in females exposed to males, but not in unpaired females. Although causal relationships between the neuroendocrine events, dendrite length, and the outward, behavioral manifestation of reproductive activation cannot be determined from this study, these results suggest an association between ventrolateral VMH dendrite morphology and female mating behavior in prairie voles, akin to what has been observed in female rats.


Sense of coherence, social networks, and mental health among children with a cochlear implant.
The aim of this study was to explore the personal and social resources of children with a cochlear implant from a child's perspective. This descriptive cross-sectional study included 19 children with cochlear implants, aged 9-12 years. Data was collected, using the children's sense of coherence (CSOC) scale, the Network map, and the strengths and difficulties questionnaire (SDQ). The data was analyzed using descriptive and correlation statistics. Most children had a strong sense of coherence. School life was an important arena for their social network. The mental health was comparable to normal hearing children. Still, some of the children with implants had low SOC and poor mental health. High SOC and closeness of the social network, especially in school, were associated with good mental health. This study shows that Swedish school-aged children with cochlear implants as a group have access to personal and social resources as strong sense of coherence and social networks. Still, there are individual children with psychosocial problems who need support and treatment.


Is iron unique in promoting electrical conductivity in MOFs?
Identifying the metal ions that optimize charge transport and charge density in metal-organic frameworks is critical for systematic improvements in the electrical conductivity in these materials. In this work, we measure the electrical conductivity and activation energy for twenty different MOFs pertaining to four distinct structural families: M2(DOBDC)(DMF)2 (M = Mg2+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+); H4DOBDC = 2,5-dihydroxybenzene-1,4-dicarboxylic acid; DMF = N,N-dimethylformamide), M2(DSBDC)(DMF)2 (M = Mn2+, Fe2+; H4DSBDC = 2,5-disulfhydrylbenzene-1,4-dicarboxylic acid), M2Cl2(BTDD)(DMF)2 (M = Mn2+, Fe2+, Co2+, Ni2+; H2BTDD = bis(1H-1,2,3-triazolo[4,5-b],[4',5'-i]dibenzo[1,4]dioxin), and M(1,2,3-triazolate)2 (M = Mg2+, Mn2+, Fe2+, Co2+, Cu2+, Zn2+, Cd2+). This comprehensive study allows us to single-out iron as the metal ion that leads to the best electrical properties. The iron-based MOFs exhibit at least five orders of magnitude higher electrical conductivity and significantly smaller charge activation energies across all different MOF families studied here and stand out materials made from all other metal ions considered here. We attribute the unique electrical properties of iron-based MOFs to the high-energy valence electrons of Fe2+ and the Fe3+/2+ mixed valency. These results reveal that incorporating Fe2+ in the charge transport pathways of MOFs and introducing mixed valency are valuable strategies for improving electrical conductivity in this important class of porous materials.


A morphological approach to curvature-based evolution of curves and surfaces.
We introduce new results connecting differential and morphological operators that provide a formal and theoretically grounded approach for stable and fast contour evolution. Contour evolution algorithms have been extensively used for boundary detection and tracking in computer vision. The standard solution based on partial differential equations and level-sets requires the use of numerical methods of integration that are costly computationally and may have stability issues. We present a morphological approach to contour evolution based on a new curvature morphological operator valid for surfaces of any dimension. We approximate the numerical solution of the curve evolution PDE by the successive application of a set of morphological operators defined on a binary level-set and with equivalent infinitesimal behavior. These operators are very fast, do not suffer numerical stability issues, and do not degrade the level set function, so there is no need to reinitialize it. Moreover, their implementation is much easier since they do not require the use of sophisticated numerical algorithms. We validate the approach providing a morphological implementation of the geodesic active contours, the active contours without borders, and turbopixels. In the experiments conducted, the morphological implementations converge to solutions equivalent to those achieved by traditional numerical solutions, but with significant gains in simplicity, speed, and stability.


Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukemia.
The translocation t(8;21)(q22;q22) in acute myeloid leukemia (AML) results in the expression of the fusion protein RUNX1/MTG8, which in turn recruits histone deacetylases (HDAC) to silence RUNX1 target genes [e.g., interleukin-3 (IL-3)]. We previously reported that expression of the RUNX1/MTG8 target gene IL-3 is synergistically restored by the combination of inhibitors of HDACs (i.e., depsipeptide) and DNA methyltransferases (DNMT; i.e., decitabine) in RUNX1/MTG8-positive Kasumi-1 cells. Thus, we hypothesized that DNMT1 is also part of the transcriptional repressor complex recruited by RUNX1/MTG8. By a chromatin immunoprecipitation assay, we identified a RUNX1/MTG8-DNMT1 complex on the IL-3 promoter in Kasumi-1 cells and in primary RUNX1/MTG8-positive AML blasts. The physical association of RUNX1/MTG8 with DNMT1 was shown by coimmunoprecipitation experiments. Furthermore, RUNX1/MTG8 and DNMT1 were concurrently released from the IL-3 promoter by exposure to depsipeptide or stabilized on the promoter by decitabine treatment. Finally, we proved that RUNX1/MTG8 and DNMT1 were functionally interrelated by showing an enhanced repression of IL-3 after coexpression in 293T cells. These results suggest a novel mechanism for gene silencing mediated by RUNX1/MTG8 and support the combination of HDAC and DNMT inhibitors as a novel therapeutic approach for t(8;21) AML.


In situ TEM modification of individual silicon nanowires and their charge transport mechanisms.
Correlating the structure and composition of nanowires grown by the vapour-liquid-solid (VLS) mechanism with their electrical properties is essential for designing nanowire devices. In situ transmission electron microscopy (TEM) that can image while simultaneously measuring the current-voltage (I-V) characteristics of individual isolated nanowires is a unique tool for linking changes in structure with electronic transport. Here we grow and electrically connect silicon nanowires inside a TEM to perform in situ electrical measurements on individual nanowires both at high temperature and upon surface oxidation, as well as under ambient conditions. As-grown, the oxide-free nanowires have nonlinear I-V characteristics. We analyse the I-V measurements in terms of both bulk and injection limited transport models, finding Joule heating effects, bulk-limiting effects for thin nanowires and an injection-limiting effect for thick wires when high voltages are applied. When the nanowire surface is modified by in situ oxidation, drastic changes occur in the electronic properties. We investigate the relation between the observed geometry, changes in the surface structure and changes in electronic transport, obtaining information for individual nanowires that is inaccessible to other measuring techniques.


Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho-pulmonary disease.
Acetylcysteine and carbocysteine are the most commonly prescribed mucolytic drugs in many European countries. To our knowledge, no systematic review has been published on their efficacy and safety for acute upper and lower respiratory tract infections (ARTIs) in children without chronic broncho-pulmonary disease. The objective was to assess the efficacy and safety and to establish a benefit-risk ratio of acetylcysteine and carbocysteine as symptomatic treatments for ARTIs in children without chronic broncho-pulmonary disease. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, issue 4) which contains the Acute Respiratory Infections (ARI) Group's Specialized Register, MEDLINE (1966 to 2008), EMBASE (1980 to 2008); Micromedex (2008), Pascal (1987 to 2004), and Science Citation Index (1974 to 2008). To study efficacy, we used randomised controlled trials (RCTs) comparing the use of acetylcysteine or carbocysteine versus placebo either alone or as an add-on therapy.To study safety, we also used trials comparing the use of acetylcysteine or carbocysteine versus active treatment or no treatment and case reports. At least two review authors extracted data and assessed trial quality. We performed a subgroup analysis of children younger than two years of age. Six trials involving 497 participants were included to study efficacy. They showed some benefit from mucolytic agents, although differences were of little clinical relevance. No conclusion was drawn about the subgroup of infants younger than two years because the data were unavailable. Thirty-four studies including the previous six trials involving 2064 children were eligible to study safety. Overall safety was good but very few data were available to evaluate safety in infants younger than two years. However, 48 cases of paradoxically increased bronchorrhoea observed in infants were reported to the French pharmacovigilance system. The results of this review have to be interpreted with caution because it was based on a limited number of participants included in studies whose methodological quality is questionable. Acetylcysteine and carbocysteine seem to have a limited efficacy and appear to be safe in children older than two years. These results should take into consideration the fact that acetylcysteine and carbocysteine are prescribed for self-limiting diseases (for example, acute cough, bronchitis). Regarding children younger than two years, given concerns about safety, these drugs should only be used for ARTIs in the context of an RCT.


Increased fluid secretion after adenoviral-mediated transfer of the aquaporin-1 cDNA to irradiated rat salivary glands.
A replication-deficient, recombinant adenovirus encoding human aquaporin-1 (hAQP1), the archetypal water channel, was constructed. This virus, AdhAQP1, directed hAQP1 expression in several epithelial cell lines in vitro. In polarized MDCK cell monolayers, hAQP1 was localized in the apical and basolateral plasma membranes. Fluid movement across monolayers infected by AdhAQP1 in response to an osmotic gradient was approximately 4-fold that seen with uninfected monolayers or monolayers infected by a control virus. When AdhAQP1 was administered to rat submandibular glands by retrograde ductal instillation, significant hAQP1 expression was observed by Western blot analysis in crude plasma membranes and by immunohistochemical staining in both acinar and ductal cells. Three or four months after exposure to a single radiation dose (17.5 or 21 Gy, respectively), AdhAQP1 administration to rat submandibular glands led to a two- to threefold increase in salivary secretion compared with secretion from glands administered a control virus. These results suggest that hAQP1 gene transfer may have potential as an unique approach for the treatment of postradiation salivary hypofunction.


Molecular basis for the inactivation of Ca2+- and voltage-dependent BK channels in adrenal chromaffin cells and rat insulinoma tumor cells.
Large-conductance Ca2+- and voltage-dependent potassium (BK) channels exhibit functional diversity not explained by known splice variants of the single Slo alpha-subunit. Here we describe an accessory subunit (beta3) with homology to other beta-subunits of BK channels that confers inactivation when it is coexpressed with Slo. Message encoding the beta3 subunit is found in rat insulinoma tumor (RINm5f) cells and adrenal chromaffin cells, both of which express inactivating BK channels. Channels resulting from coexpression of Slo alpha and beta3 subunits exhibit properties characteristic of native inactivating BK channels. Inactivation involves multiple cytosolic, trypsin-sensitive domains. The time constant of inactivation reaches a limiting value approximately 25-30 msec at Ca2+ of 10 microM and positive activation potentials. Unlike Shaker N-terminal inactivation, but like native inactivating BK channels, a cytosolic channel blocker does not compete with the native inactivation process. Finally, the beta3 subunit confers a reduced sensitivity to charybdotoxin, as seen with native inactivating BK channels. Inactivation arises from the N terminal of the beta3 subunit. Removal of the beta3 N terminal (33 amino acids) abolishes inactivation, whereas the addition of the beta3 N terminal onto the beta1 subunit confers inactivation. The beta3 subunit shares with the beta1 subunit an ability to shift the range of voltages over which channels are activated at a given Ca2+. Thus, the beta-subunit family of BK channels regulates a number of critical aspects of BK channel phenotype, including inactivation and apparent Ca2+ sensitivity.


Aluminum in the diet and Alzheimer's disease: from current epidemiology to possible disease-modifying treatment.
In recent years, interest in the potential role of metals in the pathogenesis of Alzheimer's disease (AD) has grown considerably. In particular, aluminum (Al) neurotoxicity was suggested after its discovery in the senile plaques and neurofibrillary tangles that represent the principal neuropathological hallmarks of AD. Al is omnipresent in everyday life and can enter the human body from several sources, most notably from drinking water and food consumption. The evidence supporting association from ingestion of Al from drinking water is somewhat stronger than for its ingestion from food. However, other elements present in drinking water, such as fluoride, copper, zinc, or iron could also have an effect on cognitive impairment or modify any Al neurotoxicity. Some epidemiological studies, but not all, suggested that silica could be protective against Al damage, because it reduces oral absorption of Al and/or enhances Al excretion. Some epidemiological investigations suggested an association between chronic exposure to Al and risk of AD, although this relationship falls short of all the criteria generally attributed to causation. Future studies need to be more rigorous to truly test the validity of previous findings and in doing so attempt to identify dose-response relationships between Al and AD risk which may provide new routes to disease-modifying treatment of AD or possibly some lifestyle modification, to supplement existing symptomatic approaches.


A novel mutation in limb girdle muscular dystrophy.
We describe a patient with limb girdle muscular dystrophy with evidence of a D596N novel mutation of the LMNA gene. He presented with a dilated cardiomyopathy and heart failure. He successfully underwent a cardiac rehabilitation program without cardiovascular complications. Clinicians should suspect a variety of a wide array of diseases including laminopathy, dystrophinopathy, sarcoglynopathy and LGMD 2I. Further studies should focus on determining the specific mode of inheritance and genetic testing should be considered in these patients.


MDB: the Metalloprotein Database and Browser at The Scripps Research Institute.
The Metalloprotein Database and Browser (MDB; http://metallo.scripps.edu) at The Scripps Research Institute is a web-accessible resource for metalloprotein research. It offers the scientific community quantitative information on geometrical parameters of metal-binding sites in protein structures available from the Protein Data Bank (PDB). The MDB also offers analytical tools for the examination of trends or patterns in the indexed metal-binding sites. A user can perform interactive searches, metal-site structure visualization (via a Java applet), and analysis of the quantitative data by accessing the MDB through a web browser without requiring an external application or platform-dependent plugin. The MDB also has a non-interactive interface with which other web sites and network-aware applications can seamlessly incorporate data or statistical analysis results from metal-binding sites. The information contained in the MDB is periodically updated with automated algorithms that find and index metal sites from new protein structures released by the PDB.


Smoking habits and alcohol use of patients with tuberculosis at Standerton Tuberculosis Specialised Hospital, Mpumalanga, South Africa.
A high prevalence of smoking and alcohol use has been reported in patients with tuberculosis (TB) by several researchers, even though these lifestyle habits have a negative impact on prognosis and treatment. To determine the smoking habits and alcohol use of patients with TB and TB/human immunodeficiency virus (HIV) co-infection, and how it is associated with gender, level of education and body mass index (BMI). The study was conducted at Standerton TB Specialised Hospital, Mpumalanga. A cross-sectional approach was applied. A structured interview was conducted by the researcher with each of the 100 hospitalised patients to obtain information about smoking habits, alcohol use and level of education. Weight and height were measured using standard techniques. Almost six out of 10 participants (58%) indicated that they were former (44%) or current (14%) smokers. Nearly half (49%) reported that they used alcohol, with 25% drinking alcohol more than three times per week. Significantly more women than men were non-smokers (60.0% vs. 30.0%) and more men drank alcohol three times or more per week than women (36.7% vs. 7.5%). Participants who indicated that they were either former or current smokers had significantly lower levels of education than participants who were non-smokers (95% confidence interval [CI] [-26.7%; -2.6%] and [-39.9%; -1.0%] respectively). A high percentage of patients with TB and TB/HIV co-infection previously or currently smoked and used alcohol. Smoking and alcohol use are likely to have a negative impact on nutritional status and may further affect the prognosis of patients with TB.


The utility of p53 immunostaining of transbronchial biopsy specimens of lung cancer: p53 overexpression predicts poor prognosis and chemoresistance in advanced non-small cell lung cancer.
There are few reports on the p53 status of small cell lung cancer (SCLC) and advanced non-SCLC (NSCLC) because surgically resected specimens are generally not available. Therefore, we evaluated p53 immunostaining in 175 transbronchial biopsy (TBB) specimens obtained from patients with all stages of lung cancer and retrospectively evaluated the relationship between p53 status and clinical parameters. All of the specimens were obtained prior to therapy. Formalin-fixed, paraffin-embedded TBB specimens were immunostained using an anti-p53 antibody (DO-1). p53 protein was detected in 55% (61 of 111) of NSCLCs and 58% (37 of 64) of SCLCs. The rate of positivity increased significantly with increasing stage (stages I and II, 45%; stage III, 54%; stage IV, 66%), but not with other clinical parameters. Ninety-five patients were evaluated for their response to chemotherapy. Positive staining for p53 correlated significantly with unresponsiveness to chemotherapy in NSCLC (response rate of 13 versus 60%; P = 0.006), but not in SCLC (80 versus 57%; P = 0.22). p53 positivity was a statistically significant negative prognostic factor for stage III and stage IV NSCLC (P = 0.02), but not for stage I and stage II NSCLC (P = 0.79). There was no survival difference relative to p53 status in SCLC (P = 0.35). These results indicate that p53 overexpression in TBB specimens predicts poor prognosis and chemoresistance in advanced stage NSCLC.


Muscle weakness in respiratory and peripheral skeletal muscles in a mouse model for nebulin-based nemaline myopathy.
Nemaline myopathy is among the most common non-dystrophic congenital myopathies, and is characterized by the presence of nemaline rods in skeletal muscles fibers, general muscle weakness, and hypotonia. Although respiratory failure is the main cause of death in nemaline myopathy, only little is known regarding the contractile strength of the diaphragm, the main muscle of inspiration. To investigate diaphragm contractility, in the present study we took advantage of a mouse model for nebulin-based nemaline myopathy that we recently developed. In this mouse model, exon 55 of Neb is deleted (NebΔExon55), a mutation frequently found in patients. Diaphragm contractility was determined in permeabilized muscle fibers and was compared to the contractility of permeabilized fibers from three peripheral skeletal muscles: soleus, extensor digitorum longus, and gastrocnemius. The force generating capacity of diaphragm muscle fibers of NebΔExon55 mice was reduced to 25% of wildtype levels, indicating severe contractile weakness. The contractile weakness of diaphragm fibers was more pronounced than that observed in soleus muscle, but not more pronounced than that observed in extensor digitorum longus and gastrocnemius muscles. The reduced muscle contractility was at least partly caused by changes in cross-bridge cycling kinetics which reduced the number of bound cross-bridges. The severe diaphragm weakness likely contributes to the development of respiratory failure in NebΔExon55 mice and might explain their early, postnatal death.


Adrenaline inhibits lipopolysaccharide-induced macrophage inflammatory protein-1 alpha in human monocytes: the role of beta-adrenergic receptors.
Macrophage inflammatory protein-1 alpha (MIP-1 alpha) has an important role in the development of inflammatory responses during infection by regulating leukocyte trafficking and function. Our study was conducted to investigate the effect of adrenaline on lipopolysaccharide (LPS)-induced MIP-1 alpha production by human peripheral blood monocytes and human monocytic THP-1 cells. Monocytes were incubated in vitro with LPS for 4 h at 37 degrees C in the presence and absence of adrenaline and/or specific alpha- and beta-adrenergic receptor antagonists and agonists. The effects of adrenaline on MIP-1 alpha synthesis were studied at the protein level by using enzyme-linked immunosorbent assays and at the messenger RNA level by using reverse transcriptase-polymerase chain reaction. Adrenaline inhibited LPS-induced MIP-1 alpha production in a dose-dependent manner. The suppressive effect could be completely prevented by propranolol, but not by phentolamine. The specific beta-adrenergic agonist isoproterenol produced the same inhibitory effect on LPS-induced MIP-1 alpha production, whereas the alpha-adrenergic agonist phenylephrine had a minimal effect. In addition, suppression of MIP-1 alpha production was associated with an increase of intracellular cyclic adenosine monophosphate (cAMP) by the cell membrane-permeable cAMP analog dibutyryl-cAMP. Furthermore, we found that adrenaline inhibited LPS-induced MIP-1 alpha messenger RNA expression. These findings suggest that adrenaline can modulate MIP-1 alpha production in inflammatory diseases and sepsis.


Leukocyte Telomere Length and Risks of Incident Coronary Heart Disease and Mortality in a Racially Diverse Population of Postmenopausal Women.
Telomeres are regions at the ends of chromosomes that maintain chromosomal structural integrity and genomic stability. In studies of mainly older, white populations, shorter leukocyte telomere length (LTL) is associated with cardiometabolic risk factors and increased risks of mortality and coronary heart disease (CHD). On average, African Americans (AfAm) have longer LTL than whites, but the LTL-CHD relationship in AfAm is unknown. We investigated the relationship of LTL with CHD and mortality among AfAm. Using a case-cohort design, 1525 postmenopausal women (667 AfAm and 858 whites) from the Women's Health Initiative had LTL measured in baseline blood samples by Southern blotting. CHD or mortality hazards ratios were estimated using race-stratified and risk factor-adjusted Cox proportional hazards models. There were 367 incident CHD (226 mortality) events in whites, whereas AfAm experienced 269 incident CHD (216 mortality) events during median follow-up of 13 years. Shorter LTL was associated with older age, current smoking, and white race/ethnicity. In whites, each 1 kilobase decrease in LTL was associated with 50% increased hazard of CHD, hazard ratio=1.50 (95% confidence interval, 1.08-2.10), P=0.017. There was no association between CHD and LTL in AfAm. White women with shorter LTL had higher risks of mortality. In contrast, shorter LTL was weakly associated with decreased mortality hazard in AfAm. As one of the largest prospective studies of LTL associations with incident CHD and mortality in a racially diverse sample, our study suggests differences in LTL associations with CHD and mortality between white and AfAm postmenopausal women.


Percutaneous Sampling of Local Biomolecule Gradients Across Coronary Artery Atherosclerotic Plaques.
A percutaneous catheter device, the Liquid Biopsy System, was developed to sample the unstirred boundary layer of blood upstream and downstream of intact and disrupted human coronary atherosclerotic plaques. Using multiplexed proximity extension assays, release of 20 biomolecules was simultaneously detected in samples taken across plaques before balloon angioplasty, including the soluble form of the endothelial lectin-like oxidized LDL receptor. Additional biomolecules, including matrix metalloproteinase-12, were released after plaque disruption with angioplasty. These experiments demonstrate the power of the Liquid Biopsy System to yield new scientific insights and its ultimate potential to generate new biomarkers and surrogate endpoints for clinical trials.


Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer.
We evaluated the addition of bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor, to platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients with chemotherapy-naïve (or with prior platinum as part of multimodal therapy completed ≥ 4 months earlier) recurrent or metastatic SCCHN were randomly assigned to receive a platinum-based chemotherapy doublet with or without bevacizumab 15 mg/kg given intravenously every 3 weeks until disease progression. Chemotherapy could be discontinued after six cycles if a maximum response was achieved. The study randomly assigned 403 patients. Median overall survival (OS) was 12.6 months with bevacizumab plus chemotherapy (BC) and 11.0 months with chemotherapy alone (hazard ratio, 0.87; 95% CI, 0.70 to 1.09; P = .22). At 2, 3, and 4 years, the OS rates were 25.2% v 18.1%, 16.4% v 10.0%, and 11.8% v 6.4% for BC versus chemotherapy, respectively. In an analysis of 365 eligible patients who started treatment, the hazard ratio was 0.82 (95% CI, 0.65 to 1.04; P = .10), with a median OS of 14.2 months on BC v 11.1 months on chemotherapy. Median progression-free survival with BC was 6.0 months v 4.3 months with chemotherapy (P = .0014). Overall response rates were 35.5% with BC and 24.5% with chemotherapy (P = .016). There was increased toxicity, including a higher rate of treatment-related grade 3 to 5 bleeding events (6.7% v 0.5%; P < .001) and treatment-related deaths (9.3% v 3.5%; P = .022) with BC versus chemotherapy. The addition of bevacizumab to chemotherapy did not improve OS but improved the response rate and progression-free survival with increased toxicities. These results encourage biomarker-driven studies of angiogenesis inhibitors with better toxicity profiles in select patients with SCCHN.


Endothelial renin-angiotensin pathway. Adrenergic regulation of angiotensin secretion.
Cultured bovine aortic endothelial cells (BAECs) express the complete renin-angiotensin system and secrete angiotensins. In this study, we examined the adrenergic influence on the secretion of angiotensins from BAECs. Angiotensins were determined by high-performance liquid chromatography and radioimmunoassay. At basal state, BAECs contain angiotensin I, angiotensin II, and angiotensin III at concentrations of 2.5 +/- 1.3, 4.8 +/- 2.3, and 3.4 +/- 1.5 pg/10(6) cells, respectively. Angiotensin I, angiotensin II, and angiotensin III concentrations in the culture medium were 8.3 +/- 4.4, 9.4 +/- 3.5, and 9.9 +/- 3.3 pg/10(6) cells, respectively. Isoproterenol (0.1-10 microM) increases secretion of angiotensins I, II, and III in a dose-dependent manner. Increase in angiotensin secretion induced by isoproterenol (10 microM) can be inhibited by beta 2-adrenoceptor antagonist ICI 118,551 (1 microM), but not by beta 1-adrenoceptor antagonist atenolol (1 microM). Forskolin (1-1,000 microM) mimics the isoproterenol-induced response. In contrast, alpha-adrenergic agonist phenylephrine (1-100 microM) inhibits the secretion. Pretreatment of BAECs with captopril (1 microM) inhibits the accumulation of angiotensin II and angiotensin III in the culture medium, but not angiotensin I. These findings suggest that BAEC production and/or secretion of angiotensins is regulated by adrenergic mechanisms.


Androgen deprivation therapy and radiation for prostate cancer-cognitive impairment, sleep, symptom burden: a prospective study.
This paper (1) sought to compare sleep, mood and physical symptom profiles of men with prostate cancer (PCa) who experienced subjective and objective cancer-related cognitive impairment (CRCI) during the first year of treatment and (2) examine if fluctuations in mood and physical symptoms are associated with change in subjective or objective CRCI. This prospective observational cohort study examined 24 new patients with PCa receiving androgen deprivation therapy (ADT) and radiation therapy (RT) during the first 12 months of treatment. Participants completed subjective and objective assessments of cognition, sleep continuity and self-report measures of insomnia, fatigue, depression and anxiety. Independent sample t-tests, correlations and hierarchical regressions were used to compare groups, explore associations, and assess change over time. Effects are reported as corrected Cohen's d (dc). Men with objective CRCI reported worse subjective time asleep (dc=0.47) and more depression (dc=0.55). Men with subjective CRCI reported worse insomnia (dc=0.99), hot flashes (dc=0.76), sleep quality (dc=0.54), subjective total sleep time (dc=0.41), wake after sleep onset (dc=0.71), sleep efficiency (dc=0.49), fatigue (dc=0.67) and objectively estimated sleep latency (dc=0.72) than men without subjective CRCI. Declines in perceived cognition was associated with higher anxiety (p=0.05), fatigue (p≤0.01) and symptoms of insomnia (p=0.01). Finally, subjective time awake during the night (p=0.03) and fatigue (p=0.02) were associated with subjective cognitive decline, controlling for objective change. Subjective concerns of CRCI appear more critical to patient experience than objective measurements in men with PCa who have received RT and ADT. Interventions to improve sleep may result in an improved perception of cognition.


Combined 1,25-Dihydroxy-vitamin D and Resveratrol: A Novel Therapeutic Approach to Ameliorate Ischemia Reperfusion-Induced Myocardial Injury.
The aim of this study was to assess the effect of combined 1,25-dihydroxyvitamin D (1,25 D) and resveratrol on cardiac arrhythmias, infarct size, and transcription of catalase, thioredoxin-1 and B-cell lymphoma 2 (Bcl-2), following myocardial ischemia-reperfusion (IR) in male rats. Ligation of coronary artery was performed in rats (n = 6 per group) without any treatment (IR group), pretreated with 0.1 μg/kg/day of 1,25 D (1,25 D + IR), 1 mg/kg/day of resveratrol (Res + IR) or a combination (1,25 D + Res + IR) for 14 days. Arrhythmias were analyzed according to the Lambeth conventions, and infarct size was measured by 2,3,5-triphenyl-2H-tetrazolium chloride staining. Expression of prosurvival genes was evaluated by real-time polymerase chain reaction. In the 1,25 D + Res + IR group the mean infarct size was 17.6 ± 3.5 %, which was significantly less than that in the IR, 1,25 D + IR, and Res + IR groups (p < 0.001). Although the single therapy of either 1,25 D or resveratrol did not change the incidence of arrhythmias significantly, a reduction in the number of ventricular ectopic beats was noted in group 1,25 D + Res + IR (179.19 ± 58.87, p < 0.001 vs IR; p < 0.05 vs Res + IR; p < 0.01 vs Vit D + IR). Combination of 1,25 D and resveratrol increased transcription of catalase by 119 ± 37 % (p < 0.001 vs IR, p < 0.01 vs Res + IR, p < 0.001 vs 1,25 D + IR). Our study showed that combination of a non-hypotensive dose of 1,25 D and resveratrol can be a novel and effective strategy for protecting against ischemia.


Plasma vitamin C modifies the association between hypertension and risk of stroke.
There are no prospective studies to determine whether plasma vitamin C modifies the risk of stroke among hypertensive and overweight individuals. We sought to examine whether plasma vitamin C modifies the association between overweight and hypertension and the risk of stroke in middle-aged men from eastern Finland. We conducted a 10.4-year prospective population-based cohort study of 2419 randomly selected middle-aged men (42 to 60 years) with no history of stroke at baseline examination. A total of 120 men developed a stroke, of which 96 were ischemic and 24 hemorrhagic strokes. Men with the lowest levels of plasma vitamin C (<28.4 micromol/L, lowest quarter) had a 2.4-fold (95% CI, 1.4 to 4.3; P=0.002) risk of any stroke compared with men with highest levels of plasma vitamin C (>64.96 micromol/L, highest quarter) after adjustment for age and examination months. An additional adjustment for body mass index, systolic blood pressure, smoking, alcohol consumption, serum total cholesterol, diabetes, and exercise-induced myocardial ischemia attenuated the association marginally (relative risk, 2.1; 95% CI, 1.2 to 3.8; P=0.01). Adjustment for prevalent coronary heart disease and atrial fibrillation did not attenuate the association any further. Furthermore, hypertensive men with the lowest vitamin C levels (<28.4 micromol/L) had a 2.6-fold risk (95% CI, 1.52 to 4.48; P<0.001), and overweight men (> or =25 kg/m2) with low plasma vitamin C had a 2.7-fold risk (95% CI, 1.48 to 4.90; P=0.001) for any stroke after adjustment for age, examination months, and other risk factors. Low plasma vitamin C was associated with increased risk of stroke, especially among hypertensive and overweight men.


Covalent organic frameworks for membrane separation.
Covalent organic frameworks (COFs), which are constructed from organic linkers, are a new class of crystalline porous materials comprising periodically extended and covalently bound network structures. The intrinsic structures and the tailorable organic linkers endow COFs with a low density, large surface area, tunable pore size and structure, and facilely-tailored functionality, attracting increasing interests in different fields including membrane separations. Exciting research activities ranging from fabrication strategies to separation applications of COF-based membranes have appeared. This review analyzes the synthesis and applications of diverse continuous/discontinuous COF membranes, such as COF-based mixed matrix membranes (MMMs), COF-based thin film nanocomposite (TFN) membranes, and free-standing COF films. Special attention was given to pore size, stability, hydrophilicity/hydrophobicity and surface charge of COFs in view of determining proper COFs for membrane fabrication, along with the approaches to fabricate COF-based membranes, such as blending, in situ growth, layer-by-layer stacking and interfacial polymerization (IP). Moreover, applications of COF-based membranes in gas separation, water treatment (deaslination and dye removal), organic solvent nanofiltration (OSN), pervaporation and fuel cell are disscussed. Finally, we illustrate the advantages and disadvantages of COF-based membranes through a comparison with MOF-based membranes, and the remaining challenges and future opportunities in this field.


Fasting and cancer treatment in humans: A case series report.
Short-term fasting (48 hours) was shown to be effective in protecting normal cells and mice but not cancer cells against high dose chemotherapy, termed Differential Stress Resistance (DSR), but the feasibility and effect of fasting in cancer patients undergoing chemotherapy is unknown. Here we describe 10 cases in which patients diagnosed with a variety of malignancies had voluntarily fasted prior to (48-140 hours) and/or following (5-56 hours) chemotherapy. None of these patients, who received an average of 4 cycles of various chemotherapy drugs in combination with fasting, reported significant side effects caused by the fasting itself other than hunger and lightheadedness. Chemotherapy associated toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI). The six patients who underwent chemotherapy with or without fasting reported a reduction in fatigue, weakness, and gastrointestinal side effects while fasting. In those patients whose cancer progression could be assessed, fasting did not prevent the chemotherapy-induced reduction of tumor volume or tumor markers. Although the 10 cases presented here suggest that fasting in combination with chemotherapy is feasible, safe, and has the potential to ameliorate side effects caused by chemotherapies, they are not meant to establish practice guidelines for patients undergoing chemotherapy. Only controlled-randomized clinical trials will determine the effect of fasting on clinical outcomes including quality of life and therapeutic index.


Cytoreduction (Peritonectomy Procedures) Combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Advanced Ovarian Cancer: Retrospective Italian Multicenter Observational Study of 511 Cases.
The aim of this study was to help with the process of selecting patients with advanced ovarian cancer to undergo cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) by analyzing outcome data at distinct clinical time points reflecting the natural history of the disease. In a retrospective Italian multicenter study investigating patients with advanced ovarian cancer who underwent CRS plus HIPEC between 1998 and 2014, we analyzed data for consecutive patients at eight treatment time points: primary debulking surgery (PDS); interval debulking surgery after partial response, after no response, and after a pathologic complete response to neoadjuvant chemotherapy; first recurrence with a progression-free interval >12, <12 months, or >12 months in patients who underwent further chemotherapy before CRS and HIPEC; and patients who underwent two or more CRS procedures and chemotherapy lines before CRS and HIPEC. The 511 enrolled patients underwent 3373 procedures; 72.6% achieved complete cytoreduction, with an overall major morbidity of 17.4%. At a median follow-up of 53.8 months, overall survival (OS) was 54.2 months (95% confidence interval [CI] 44-58.4) and progression-free (PFS) survival was 16.6 months (95% CI 14.7-19.1). Outcome analysis in patients in whom CRS plus HIPEC was used for primary advanced cancer or recurrent ovarian cancer showed significant differences in OS and PFS according to the time points analyzed. Multivariate analysis identified completeness of CRS, Peritoneal Cancer Index, and the times when patients underwent CRS plus HIPEC as independent prognostic factors. This selective information on survival should help in interpreting the findings from ongoing randomized studies focusing on CRS plus HIPEC in patients with advanced ovarian cancer.


Inline extracorporeal photopheresis: evaluation of cell collection efficiency.
Extracorporeal photopheresis (ECP) therapy has proved to be an effective and safe treatment for graft-versus-host-disease (GvHD), an important complication after hematopoietic stem cell transplantation. In 2016, we acquired Therakos CellEx, a dedicated inline ECP device to accomplish a significant increase in ECP activity. In literature, we found few data reporting CellEx performance evaluated in terms of collection efficiency to qualify the device. Hence, we decided to collect and analyze our data in order to build a reference in terms of expected results of the procedure. Here we report our data of ECP performed using CellEx in a 12-month period focusing on collection efficiency assessment, as well as procedural and apheretic product characteristics. We collected data of patients undergoing ECP from April 2018 to March 2019 using CellEx in order to evaluate collection efficiency. Between April 2018 and March 2019 we treated 28 adult patients affected by GvHD performing 319 ECP using CellEx. CellEx mononuclear cell product was characterized by high mononuclear cell percentage and low percentage of granulocytes, resulting particularly suitable for ECP treatments. Median collection efficiency for total nucleated cells and for mononuclear cells was 31.2% and 62.3%, respectively. Collection efficiency of CellEx was comparable to that usually obtained by cell separators designed for cell collection and was comparable to that of offline systems. Our results provide a detailed performance evaluation for inline ECP system users.


Evidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials.
Evidence on preventing Alzheimer's disease (AD) is challenging to interpret due to varying study designs with heterogeneous endpoints and credibility. We completed a systematic review and meta-analysis of current evidence with prospective designs to propose evidence-based suggestions on AD prevention. Electronic databases and relevant websites were searched from inception to 1 March 2019. Both observational prospective studies (OPSs) and randomised controlled trials (RCTs) were included. The multivariable-adjusted effect estimates were pooled by random-effects models, with credibility assessment according to its risk of bias, inconsistency and imprecision. Levels of evidence and classes of suggestions were summarised. A total of 44 676 reports were identified, and 243 OPSs and 153 RCTs were eligible for analysis after exclusion based on pre-decided criteria, from which 104 modifiable factors and 11 interventions were included in the meta-analyses. Twenty-one suggestions are proposed based on the consolidated evidence, with Class I suggestions targeting 19 factors: 10 with Level A strong evidence (education, cognitive activity, high body mass index in latelife, hyperhomocysteinaemia, depression, stress, diabetes, head trauma, hypertension in midlife and orthostatic hypotension) and 9 with Level B weaker evidence (obesity in midlife, weight loss in late life, physical exercise, smoking, sleep, cerebrovascular disease, frailty, atrial fibrillation and vitamin C). In contrast, two interventions are not recommended: oestrogen replacement therapy (Level A2) and acetylcholinesterase inhibitors (Level B). Evidence-based suggestions are proposed, offering clinicians and stakeholders current guidance for the prevention of AD.


Image authentication using distributed source coding.
We present a novel approach using distributed source coding for image authentication. The key idea is to provide a Slepian-Wolf encoded quantized image projection as authentication data. This version can be correctly decoded with the help of an authentic image as side information. Distributed source coding provides the desired robustness against legitimate variations while detecting illegitimate modification. The decoder incorporating expectation maximization algorithms can authenticate images which have undergone contrast, brightness, and affine warping adjustments. Our authentication system also offers tampering localization by using the sum-product algorithm.


Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism.
Interleukin-10 (IL-10) is a recently described pleiotropic cytokine secreted mainly by type 2 helper T cells. Previous studies have shown that IL-10 suppresses cytokine expression by natural killer (NK) and type 1 T cells, thus down-regulating cell-mediated immunity and stimulating humoral responses. We here report that injected IL-10 protein is an efficient inhibitor of tumor metastasis in experimental (B16-F10) and spontaneous (M27 and Lox human melanoma) metastasis models in vivo at doses that do not have toxic effects on normal or cancer cells. Histological characterization after IL-10 treatment confirmed the absence of CD8+ and CD4+ T cells and macrophages at the sites of tumor growth, but abundant NK cells were localized at these sites. This unexpected finding was confirmed by showing that IL-10 inhibits most B16-F10 and Lox metastases in mice deficient in T or B cells (SCID and nu/nu mice), but not in those deficient in NK cells (beige mice or NK cell-depleted mice). However, IL-10 downregulation of pro-inflammatory cytokine production and/or recruitment of additional effector cells may also be involved in the anti-tumor effect at higher local concentrations of IL-10, since transfected B16 tumor cells expressing high amounts of IL-10 were rejected by normal, nu/nu, or SCID mice at the primary tumor stage, and there was still a 33% inhibition of tumor metastasis in beige mice.


Validation of H2O continuum absorption models in the wave number range 180-600 cm(-1) with atmospheric emitted spectral radiance measured at the Antarctica Dome-C site.
This work presents the results concerning the analysis of a set of atmospheric emitted (down welling) spectral radiance observations in the spectral range 180 to 1100 cm(-1) acquired at the Dome-C site in Antarctica during an extensive field campaign in 2011-2012. The work has been mainly focused on retrieving and validating the coefficients of the foreign contribution to the water vapour continuum absorption, within a spectral range overlapping the water vapour rotational band. Retrievals have been performed by using a simultaneous physical retrieval procedure for atmospheric and spectroscopic parameters. Both day (summer) and night (winter) spectra have been used in our analysis. This new set of observations in the far infrared range has allowed us to extend validation and verification of state-of-art water vapour continuum absorption models down to 180 cm(-1). Results show that discrepancies between measurements and models are less than 10% in the interval 350-590 cm(-1), while they are slightly larger at wave numbers below 350 cm(-1). On overall, our study shows a good consistency between observations and state-of-art models and provides evidence toward needing to adjust absorptive line strengths. Finally, it has been found that there is a good agreement between the coefficients retrieved using either summer or winter spectra, which are acquired in far different meteorological conditions.


Presymptomatic cortical thinning in familial Alzheimer disease: A longitudinal MRI study.
To identify a cortical signature pattern of cortical thinning in familial Alzheimer disease (FAD) and assess its utility in detecting and tracking presymptomatic neurodegeneration. We recruited 43 FAD mutation carriers-36 PSEN1, 7 APP (20 symptomatic, 23 presymptomatic)-and 42 healthy controls to a longitudinal clinical and MRI study. T1-weighted MRI scans were acquired at baseline in all participants; 55 individuals (33 mutation carriers; 22 controls) had multiple (mean 2.9) follow-up scans approximately annually. Cortical thickness was measured using FreeSurfer. A cortical thinning signature was identified from symptomatic FAD participants. We then examined cortical thickness changes in this signature region in presymptomatic carriers and assessed associations with cognitive performance. The cortical signature included 6 regions: entorhinal cortex, inferior parietal cortex, precuneus, superior parietal cortex, superior frontal cortex, and supramarginal gyrus. There were significant differences in mean cortical signature thickness between mutation carriers and controls 3 years before predicted symptom onset. The earliest significant difference in a single region, detectable 4 years preonset, was in the precuneus. Rate of change in cortical thickness became significantly different in the cortical signature at 5 years before predicted onset, and in the precuneus at 8 years preonset. Baseline mean signature thickness predicted rate of subsequent thinning and correlated with presymptomatic cognitive change. The FAD cortical signature appears to be similar to that described for sporadic AD. All component regions showed significant presymptomatic thinning. A composite signature may provide more robust results than a single region and have utility as an outcome measure in presymptomatic trials.


Evidence of positive selection for a glycogen synthase (GYS1) mutation in domestic horse populations.
A dominantly inherited gain-of-function mutation in the glycogen synthase (GYS1) gene, resulting in excess skeletal muscle glycogen, has been identified in more than 30 horse breeds. This mutation is associated with the disease Equine Polysaccharide Storage Myopathy Type 1, yet persists at high frequency in some breeds. Under historical conditions of daily work and limited feed, excess muscle glycogen may have been advantageous, driving the increase in frequency of this allele. Fine-scale DNA sequencing in 80 horses and genotype assays in 279 horses revealed a paucity of haplotypes carrying the mutant allele when compared with the wild-type allele. Additionally, we found increased linkage disequilibrium, measured by relative extended haplotype homozygosity, in haplotypes carrying the mutation compared with haplotypes carrying the wild-type allele. Coalescent simulations of Belgian horse populations demonstrated that the high frequency and extended haplotype associated with the GYS1 mutation were unlikely to have arisen under neutrality or due to population demography. In contrast, in Quarter Horses, elevated relative extended haplotype homozygosity was associated with multiple haplotypes and may be the result of recent population expansion or a popular sire effect. These data suggest that the GYS1 mutation underwent historical selection in the Belgian, but not in the Quarter Horse.


Cell division in Apicomplexan parasites is organized by a homolog of the striated rootlet fiber of algal flagella.
Apicomplexa are intracellular parasites that cause important human diseases including malaria and toxoplasmosis. During host cell infection new parasites are formed through a budding process that parcels out nuclei and organelles into multiple daughters. Budding is remarkably flexible in output and can produce two to thousands of progeny cells. How genomes and daughters are counted and coordinated is unknown. Apicomplexa evolved from single celled flagellated algae, but with the exception of the gametes, lack flagella. Here we demonstrate that a structure that in the algal ancestor served as the rootlet of the flagellar basal bodies is required for parasite cell division. Parasite striated fiber assemblins (SFA) polymerize into a dynamic fiber that emerges from the centrosomes immediately after their duplication. The fiber grows in a polarized fashion and daughter cells form at its distal tip. As the daughter cell is further elaborated it remains physically tethered at its apical end, the conoid and polar ring. Genetic experiments in Toxoplasma gondii demonstrate two essential components of the fiber, TgSFA2 and 3. In the absence of either of these proteins cytokinesis is blocked at its earliest point, the initiation of the daughter microtubule organizing center (MTOC). Mitosis remains unimpeded and mutant cells accumulate numerous nuclei but fail to form daughter cells. The SFA fiber provides a robust spatial and temporal organizer of parasite cell division, a process that appears hard-wired to the centrosome by multiple tethers. Our findings have broader evolutionary implications. We propose that Apicomplexa abandoned flagella for most stages yet retained the organizing principle of the flagellar MTOC. Instead of ensuring appropriate numbers of flagella, the system now positions the apical invasion complexes. This suggests that elements of the invasion apparatus may be derived from flagella or flagellum associated structures.


Antimicrobial peptides extend lifespan in Drosophila.
Antimicrobial peptides (AMPs) are important defense molecules of the innate immune system. High levels of AMPs are induced in response to infections to fight pathogens, whereas moderate levels induced by metabolic stress are thought to shape commensal microbial communities at barrier tissues. We expressed single AMPs in adult flies either ubiquitously or in the gut by using the inducible GeneSwitch system to tightly regulate AMP expression. We found that activation of single AMPs, including Drosocin, resulted in a significant extension of Drosophila lifespan. These animals showed reduced activity of immune pathways over lifetime, less intestinal regenerative processes, reduced stress response and a delayed loss of gut barrier integrity. Furthermore, intestinal Drosocin induction protected the animals against infections with the natural Drosophila pathogen Pseudomonas entomophila, whereas a germ-reduced environment prevented the lifespan extending effect of Drosocin. Our study provides new insights into the crosstalk of innate immunity, intestinal homeostasis and ageing.


Dopamine-rich grafts alleviate deficits in contralateral response space induced by extensive dopamine depletion in rats.
Unilateral infusion of 6-hydroxydopamine into the nigro-striatal pathway in the rat is the most common dopamine lesion model of Parkinson's disease. In the present study, we explore the impact of near complete unilateral loss of dopamine along the nigro-striatal pathway and subsequent cell replacement therapy in a choice reaction time task in rats, with assessment of spatial responding towards either side of the body (ipsilateral or contralateral to the lesion) on alternate days. Results indicated a stable contralateral deficit in response accuracy, reaction times and motor function for 50 consecutive days of testing, with no signs of recovery or compensation. All lesioned rats developed a near-hole bias and displayed prolonged movement and reaction times when responses had to be directed towards a distal response location on the side of the body contralateral to the lesion, as well as a smaller ipsilateral impairment in response accuracy and movement times. Grafts of dopamine-rich tissue into the denervated striatum improved some, but not all, of the deficits induced by the lesion. Specifically, grafted rats performed at a similar level to control animals when assessed on the ipsilateral side, they demonstrated a partial restitution of their ability to respond to far contralateral stimuli, and they exhibited a marked reduction in the time to complete all lateralised responses on both sides. The present characterisation of the task and the effects of cell replacement via primary fetal mesencephalic tissue demonstrate restorative properties in alleviating the marked spatial response bias induced by unilateral loss of dopamine.


Type II Medial Meniscus Root Repair With Peripheral Release for Addressing Meniscal Extrusion.
Medial meniscal root tears are often disabling injuries that can occur in isolation during low-velocity, deep knee flexion maneuvers in middle-aged patients. The most common meniscal root tear pattern is a radial tear near the root attachment (type II). Root tears are often associated with meniscal extrusion, identified on magnetic resonance imaging. Relocation of the meniscal root to its anatomic center is a reported current difficulty faced by surgeons during surgical repair. However, this can be achieved via sufficient peripheral release of the posteromedial capsular attachment of the medial meniscus. The purpose of this Technical Note is to describe the authors' current surgical technique for medial meniscus root repair with a peripheral release for addressing meniscal extrusion. Classifications: level I (knee); level II (meniscus).


Traceability of solar UV measurements using the Qasume reference spectroradiometer.
One major objective of the European Joint Research Project "Traceability for surface spectral solar ultraviolet (UV) radiation" was to reduce the uncertainty of spectral UV measurements. The measurement instrument used for this work was the portable UV European reference spectroradiometer Qasume. The calibration uncertainty of this instrument was decreased and validated by a comparison of direct calibrations against a primary standard for spectral irradiance, a high temperature blackbody radiator, and against a reference detector using a spectrally tunable laser as a monochromatic source. The spectral irradiance responsivity of the reference detector is traceable to the primary standard of optical power, realized through a cryogenic radiometer, and to the SI unit of meter. The measuring technique was improved by the construction of a new reference spectroradiometer, QasumeII. An improved input optics removes the dependences of the measured solar irradiance on the angle of incident for solar zenith angle smaller than 75 deg. Moreover, a hybrid photon detection system enables continuous tracking of the instrument's responsivity changes. For both spectroradiometer systems an uncertainty budget was calculated. The improvements have reduced the measurement uncertainties of solar spectral UV irradiance measurements from 4.8% in 2005 to 2.0% (k=2) in the spectral region above 310 nm. The largest sources of uncertainty were the absolute spectral irradiance responsivity calibration, the angular response uncertainty, and the instrument stability using the hybrid detector, which were reduced from 3.6% to 1.1%, from 1.2% to 0.6%, and from 0.65% to 0.4%, with respect to the situation prior to the project. The new instrument was validated during a four month intercomparison relative to the Qasume reference. The mean ratio of the solar irradiance scans between the two reference spectroradiometers has an offset of +0.7% and a standard deviation of ±1.5% for a wavelength greater than 305 nm, which is well within the combined uncertainty of 3.7% calculated from the uncertainties of the two systems.


New candidate biomarkers in the female genital tract to evaluate microbicide toxicity.
Vaginal microbicides hold great promise for the prevention of viral diseases like HIV, but the failure of several microbicide candidates in clinical trials has raised important questions regarding the parameters to be evaluated to determine in vivo efficacy in humans. Clinical trials of the candidate microbicides nonoxynol-9 (N9) and cellulose sulfate revealed an increase in HIV infection, vaginal inflammation, and recruitment of HIV susceptible lymphocytes, highlighting the need to identify biomarkers that can accurately predict microbicide toxicity early in preclinical development and in human trials. We used quantitative proteomics and RT-PCR approaches in mice and rabbits to identify protein changes in vaginal fluid and tissue in response to treatment with N9 or benzalkonium chloride (BZK). We compared changes generated with N9 and BZK treatment to the changes generated in response to tenofovir gel, a candidate microbicide that holds promise as a safe and effective microbicide. Both compounds down regulated mucin 5 subtype B, and peptidoglycan recognition protein 1 in vaginal tissue; however, mucosal brush samples also showed upregulation of plasma proteins fibrinogen, plasminogen, apolipoprotein A-1, and apolipoprotein C-1, which may be a response to the erosive nature of N9 and BZK. Additional proteins down-regulated in vaginal tissue by N9 or BZK treatment include CD166 antigen, olfactomedin-4, and anterior gradient protein 2 homolog. We also observed increases in the expression of C-C chemokines CCL3, CCL5, and CCL7 in response to treatment. There was concordance in expression level changes for several of these proteins using both the mouse and rabbit models. Using a human vaginal epithelial cell line, the expression of mucin 5 subtype B and olfactomedin-4 were down-regulated in response to N9, suggesting these markers could apply to humans. These data identifies new proteins that after further validation could become part of a panel of biomarkers to effectively evaluate microbicide toxicity.


S 38093, a histamine H3 antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice.
Strategies designed to increase adult hippocampal neurogenesis (AHN) may have therapeutic potential for reversing memory impairments. H3 receptor antagonists/inverse agonists also may be useful for treating cognitive deficits. However, it remains unclear whether these ligands have effects on AHN. The present study aimed to investigate the effects of a 28-day treatment with S 38093, a novel brain-penetrant antagonist/inverse agonist of H3 receptors, on AHN (proliferation, maturation and survival) in 3-month-old and in aged 16-month-old mice. In addition, the effects of S 38093 treatment on 7-month-old APPSWE Tg2576 transgenic mice, a model of Alzheimer's disease, were also assessed. In all tested models, chronic treatment with S 38093 stimulated all steps of AHN. In aged animals, S 38093 induced a reversal of age-dependent effects on hippocampal brain-derived neurotrophic factor (BDNF) BDNF-IX, BDNF-IV and BDNF-I transcripts and increased vascular endothelial growth factor (VEGF) expression. Finally, the effects of chronic administration of S 38093 were assessed on a neurogenesis-dependent "context discrimination (CS) test" in aged mice. While ageing altered mouse CS, chronic S 38093 treatment significantly improved CS. Taken together, these results provide evidence that chronic S 38093 treatment increases adult hippocampal neurogenesis and may provide an innovative strategy to improve age-associated cognitive deficits.


High-resolution quantitative sodium imaging at 9.4 Tesla.
Investigation of the feasibility to perform high-resolution quantitative sodium imaging at 9.4 Tesla (T). A proton patch antenna was combined with a sodium birdcage coil to provide a proton signal without compromising the efficiency of the X-nucleus coil. Sodium density weighted images with a nominal resolution of 1 × 1 × 5 mm(3) were acquired within 30 min with an ultrashort echo time sequence. The methods used for signal calibration as well as for B0, B1, and off-resonance correction were verified on a phantom and five healthy volunteers. An actual voxel volume of roughly 40 μL could be achieved at 9.4T, while maintaining an acceptable signal-to-noise ratio (8 for brain tissue and 35 for cerebrospinal fluid). The measured mean sodium concentrations for gray and white matter were 36 ± 2 and 31 ± 1 mmol/L of wet tissue, which are comparable to values previously reported in the literature. The reduction of partial volume effects is essential for accurate measurement of the sodium concentration in the human brain. Ultrahigh field imaging is a viable tool to achieve this goal due to its increased sensitivity.


From gene to therapy in spinal and bulbar muscular atrophy: Are we there yet?
Abnormal polyglutamine expansions in the androgen receptor (AR) cause a muscular condition, known as Kennedy's disease or spinal and bulbar muscular atrophy (SBMA). The disease is transmitted in an X-linked fashion and is clinically characterized by weakness, atrophy and fasciculations of the limb and bulbar muscles as a result of a toxic gain-of-function of the mutant protein. Notably, affected males also show signs of androgen insensitivity, such as gynaecomastia and reduced fertility. The characterization of the natural history of the disease, the increasing understanding of the mechanism of pathogenesis and the elucidation of the functions of normal and mutant AR have offered a momentum for developing a rational therapeutic strategy for this disease. In this special issue on androgens and AR functions, we will review the molecular, biochemical, and cellular mechanisms underlying the pathogenesis of SBMA. We will discuss recent advances on therapeutic approaches and opportunities for this yet incurable disease, ranging from androgen deprivation, to gene silencing, to an expanding repertoire of peripheral targets, including muscle. With the advancement of these strategies into the clinic, it can be reasonably anticipated that the landscape of treatment options for SBMA and other neuromuscular conditions will change rapidly in the near future.


The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro.
Banisteriopsis caapi is the basic ingredient of ayahuasca, a psychotropic plant tea used in the Amazon for ritual and medicinal purposes, and by interested individuals worldwide. Animal studies and recent clinical research suggests that B. caapi preparations show antidepressant activity, a therapeutic effect that has been linked to hippocampal neurogenesis. Here we report that harmine, tetrahydroharmine and harmaline, the three main alkaloids present in B. caapi, and the harmine metabolite harmol, stimulate adult neurogenesis in vitro. In neurospheres prepared from progenitor cells obtained from the subventricular and the subgranular zones of adult mice brains, all compounds stimulated neural stem cell proliferation, migration, and differentiation into adult neurons. These findings suggest that modulation of brain plasticity could be a major contribution to the antidepressant effects of ayahuasca. They also expand the potential application of B. caapi alkaloids to other brain disorders that may benefit from stimulation of endogenous neural precursor niches.


The journal impact factor: too much of an impact?
The journal impact factor is often used to judge the scientific quality of individual research articles and individual journals. Despite numerous reviews in the literature criticising such use, in some countries the impact factor has become an outcome measure for grant applications, job applications, promotions and bonuses. The aim of this review is to highlight the major issues involved with using the journal impact factor as a measure of research quality. A literature review of articles on journal impact factors, science citation index, and bibliometric methods was undertaken to identify relevant articles. The journal impact factor is a quantitative measure based on the ratio between yearly citations in a particular journal to total citations in that journal in the previous 2 years. Its use as a criterion for measuring the quality of research is biased. The major sources of bias include database problems from the Institute for Scientific Information and research field effects. The journal impact factor, originally designed for purposes other than the individual evaluation of research quality, is a useful tool provided its interpretation is not extrapolated beyond its limits of validity. Research quality cannot be measured solely using the journal impact factor. The journal impact factor should be used with caution, and should not be the dominant or only factor determining research quality.


Emerging clinical role of ranolazine in the management of angina.
Chronic stable angina is an exceedingly prevalent condition with tremendous clinical, social, and financial implications. Traditional medical therapy for angina consists of beta-blockers, calcium channel blockers, and nitrates. These agents decrease myocardial oxygen demand and ischemia by reducing heart rate, lowering blood pressure, and/or optimizing ventricular loading characteristics. Unique in its mechanism of action, ranolazine is the first new antianginal agent approved for use in the US for chronic angina in over 25 years. By inhibiting the late inward sodium current (I(Na)), ranolazine prevents pathologic intracellular calcium accumulation that leads to ischemia, myocardial dysfunction, and electrical instability. Ranolazine has been proven in multiple clinical trials to reduce the symptoms of angina safely and effectively and to improve exercise tolerance in patients with symptomatic coronary heart disease. These benefits occur without reduction in heart rate and blood pressure or increased mortality. Although ranolazine prolongs the QT(c), experimental data indicate that ranolazine may actually be antiarrhythmic. In a large acute coronary syndrome clinical trial, ranolazine reduced the incidence of supraventricular tachycardia, ventricular tachycardia, new-onset atrial fibrillation, and bradycardic events. Additional benefits of ranolazine under investigation include reductions in glycosylated hemoglobin levels and improved left ventricular function. Ranolazine is a proven antianginal medication in patients with symptomatic coronary heart disease, and should be considered as an initial antianginal agent for those with hypotension or bradycardia.


Bacterial genomics.
During the last decade, great advances have been made in the study of bacterial genomes which is perhaps better described by the term bacterial genomics. The application of powerful techniques, such as pulsed-field gel electrophoresis of macro-restriction fragments of genomic DNA, has freed the characterisation of the chromosomes of many bacteria from the constraints imposed by classical genetic analysis. It is now possible to analyse the genome of virtually every microorganism by direct molecular methods and to construct detailed physical and gene maps. In this review, the various practical approaches are compared and contrasted, and some of the emerging themes of bacterial genomics, such as the size, shape, number and organisation of chromosomes are discussed.


Androgens Are Differentially Associated with Ovarian Cancer Subtypes in the Ovarian Cancer Cohort Consortium.
Invasive epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The etiology of EOC remains elusive; however, experimental and epidemiologic data suggest a role for hormone-related exposures in ovarian carcinogenesis and risk factor differences by histologic phenotypes and developmental pathways. Research on prediagnosis androgen concentrations and EOC risk has yielded inconclusive results, and analyses incorporating EOC subtypes are sparse. We conducted a pooled analysis of 7 nested case-control studies in the Ovarian Cancer Cohort Consortium to investigate the association between pre-diagnosis circulating androgens [testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS)], sex hormone binding globulin (SHBG), and EOC risk by tumor characteristics (i.e., histology, grade, and stage). The final study population included 1,331 EOC cases and 3,017 matched controls. Multivariable conditional logistic regression was used to assess risk associations in pooled individual data. Testosterone was positively associated with EOC risk (all subtypes combined, ORlog2 = 1.12; 95% confidence interval 1.02-1.24); other endogenous androgens and SHBG were not associated with overall risk. Higher concentrations of testosterone and androstenedione associated with an increased risk in endometrioid and mucinous tumors [e.g., testosterone, endometrioid tumors, ORlog2 = 1.40 (1.03-1.91)], but not serous or clear cell. An inverse association was observed between androstenedione and high grade serous tumors [ORlog2 = 0.76 (0.60-0.96)]. Our analyses provide further evidence for a role of hormone-related pathways in EOC risk, with differences in associations between androgens and histologic subtypes of EOC. Cancer Res; 77(14); 3951-60. ©2017 AACR.


Eating Problems in Men and Women with an Autism Spectrum Disorder.
The presence of eating problems was assessed in 53 males and 36 females with an autism spectrum disorder (ASD), with and without housing and residential support. The results were compared to a neurotypical group of 30 men and 38 women. The results indicate that men and especially women with ASD experience various eating problems. Women with ASD also recognized symptoms of an eating disorder. Hence, it is important to be aware of eating problems and symptoms of an eating disorder in adults with ASD, to ensure they receive the care they need.


Single-cell RNA-seq reveals dynamic, random monoallelic gene expression in mammalian cells.
Expression from both alleles is generally observed in analyses of diploid cell populations, but studies addressing allelic expression patterns genome-wide in single cells are lacking. Here, we present global analyses of allelic expression across individual cells of mouse preimplantation embryos of mixed background (CAST/EiJ × C57BL/6J). We discovered abundant (12 to 24%) monoallelic expression of autosomal genes and that expression of the two alleles occurs independently. The monoallelic expression appeared random and dynamic because there was considerable variation among closely related embryonic cells. Similar patterns of monoallelic expression were observed in mature cells. Our allelic expression analysis also demonstrates the de novo inactivation of the paternal X chromosome. We conclude that independent and stochastic allelic transcription generates abundant random monoallelic expression in the mammalian cell.


Thrombin induces epithelial-mesenchymal transition via PAR-1, PKC, and ERK1/2 pathways in A549 cells.
Thrombin activates protease-activated receptor (PAR)-1 and induces a myofibroblast phenotype in normal lung fibroblasts. The origins of myofibroblasts are resident fibroblasts, fibrocytes, and epithelial-mesenchymal transition (EMT). We investigated the effects of thrombin, an important mediator of interstitial lung fibrosis, on EMT in A549 human alveolar epithelial cells. We show that thrombin induced EMT and collagen I secretion through the activation of PAR-1, and PKC and ERK1/2 phosphorylation in A549 cells. These effects were largely prevented by a specific PAR-1 antagonist, short interfering RNA (siRNA) directed against PAR-1, or specific PKCα/β, δ, and ε inhibitors. These data indicated that interaction with thrombin and alveolar epithelial cells might directly contribute to the pathogenesis of pulmonary fibrosis through EMT. Targeting PAR-1 on the pulmonary epithelium or specific inhibitors to PKCα/β, δ, and ε might stop the fibrotic processes in human idiopathic pulmonary fibrosis by preventing thrombin-induced EMT.


Treatment strategies and outcome of surgery for synchronous colorectal liver metastases.
To report survival following different operative strategies and perioperative chemotherapy in patients with synchronous colorectal liver metastases in a tertiary academic referral centre. We performed a retrospective analysis, based on a prospective database, of patients who presented with synchronous colorectal liver metastases. Follow-up data were obtained from medical records, letters or telephone contacts. The main endpoint was overall survival. An additional event of interest was postoperative mortality according to treatment strategy. Predefined variables were analysed to identify associated risk factors. Overall, 109 patients undergoing liver resection for synchronous colorectal liver metastases between 2000 and 2010 were identified. The majority of patients had resection of the primary tumour first (n = 82), the classic approach; notably fewer were treated according to a combined (n = 20) or a reverse "liver first" strategy (n = 7). Most patients (92%) received preoperative, interval and/or postoperative chemotherapy. Median overall survival of the entire population was 33.6 months (interquartile range [IQR] 11-92.7 months). Patients undergoing classic surgery had a median overall survival of 40.3 months (IQR 14.9-96.6 months). The 3-year survival rates of the three patient groups were 53% in the classic, 47% in the combined and 58% in the reverse group. The lowest rate of 180-day mortality (9%) was after the classic surgical approach. On a multivariate Cox proportional hazards regression analysis, patient age >60 years (hazard ratio [HR] 2.1, 95% confidence interval [CI] 1.1-3.9; p = 0.018), R2-status (HR 2.08, 95% CI 1.03-4.2; p = 0.040), and >4 liver metastases (HR 2.4, 95% CI 1.2-4.6; p = 0.011) were associated significantly with worse overall survival. In patients undergoing surgical resection for synchronous colorectal liver metastases, promising survival rates could be achieved, irrespective of the chosen surgical strategy. The presence of five or more liver metastases, patient age over 60 years and R2-status were found to be adverse risk factors.


Isoetes pedersenii, a new species from Southern South America.
The name Isoetes pedersenii H.P. Fuchs (Lycophyta), a species known only from the Mburucuyá National Park, Corrientes, Argentina, is validated. Observations were carried out on herbarium material with stereoscopic, light and scanning electron microscopes. The species is described and typified. A diagnosis and discussion about its distribution and its relationship with the morphology of other species of Isoetes are provided.


The Role of Carrageenan and Carboxymethylcellulose in the Development of Intestinal Inflammation.
Although the exact pathophysiology remains unknown, the development of inflammatory bowel disease (IBD) is influenced by the interplay between genetics, the immune system, and environmental factors such as diet. The commonly used food additives, carrageenan and carboxymethylcellulose (CMC), are used to develop intestinal inflammation in animal models. These food additives are excluded from current dietary approaches to induce disease remission in Crohn's disease such as exclusive enteral nutrition (EEN) using a polymeric formula. By reviewing the existing scientific literature, this review aims to discuss the role that carrageenan and CMC may play in the development of IBD. Animal studies consistently report that carrageenan and CMC induce histopathological features that are typical of IBD while altering the microbiome, disrupting the intestinal epithelial barrier, inhibiting proteins that provide protection against microorganisms, and stimulating the elaboration of pro-inflammatory cytokines. Similar trials directly assessing the influence of carrageenan and CMC in humans are of course unethical to conduct, but recent studies of human epithelial cells and the human microbiome support the findings from animal studies. Carrageenan and CMC may trigger or magnify an inflammatory response in the human intestine but are unlikely to be identified as the sole environmental factor involved in the development of IBD or in disease recurrence after treatment. However, the widespread use of carrageenan and CMC in foods consumed by the pediatric population in a "Western" diet is on the rise alongside a corresponding increase in IBD incidence, and questions are being raised about the safety of frequent usage of these food additives. Therefore, further research is warranted to elucidate the role of carrageenan and CMC in intestinal inflammation, which may help identify novel nutritional strategies that hinder the development of the disease or prevent disease relapse post-EEN treatment.


Mercury biomagnification in the aquaculture pond ecosystem in the Pearl River Delta.
This is the first study to investigate the rate of mercury (Hg) biomagnification in the aquaculture pond ecosystem of the Pearl River Delta (PRD), China, by analyzing total mercury (THg) and methyl mercury (MeHg) concentrations in various species of fish at different trophic levels (TLs). Species representing a gradient of trophic positions in the aquaculture pond food chains were chosen for analyzing THg and MeHg concentrations. In this study, there were two kinds of the aquaculture pond food chains: (1) omnivorous (fish feeds, zooplankton, grass carp [Ctenopharyngodon idellus], and bighead carp [Aristichthys nobilis]) and (2) predatory (zooplankton, mud carp [Cirrhina molitorella], and mandarin fish [Siniperca kneri]). Bighead carp and mandarin fish had the highest MeHg and THg concentrations, i.e., an order of magnitude higher than other species, in their respective food chains. More than 90% of the THg concentrations detected in bighead carp, mandarin fish, and mud carp were in the methylated form. In this study, %MeHg increased with TLs and MeHg concentrations, reflecting that MeHg is the dominant chemical species of Hg accumulated in higher concentrations in biota, especially biota associated with higher TLs in the food chains. The trophic magnification factors were 2.32 and 2.60 for MeHg and 1.94 and 2.03 for THg in omnivorous and predatory food chains, respectively, in PRD. Hg concentrations in fish tissue correlated to Hg levels in the ambient environment, and sediment seemed to be the major source for Hg accumulated in fish. In addition, feeding habit also affected Hg accumulation in different fish species. Four significant linear relationships were obtained between log-THg and δ(15)N and between log-MeHg and δ(15)N. The slope of the regression equations, as biomagnification power, was smaller in magnitude compared with those reported for temperate and arctic marine and freshwater ecosystems, indicating that THg and MeHg biomagnifications were lower in this PRD subtropical aquaculture pond ecosystem. This was probably due to low Hg bioavailability at lower TLs as well as individual feeding behavior of fish.


Recent developments in the treatment of anxiety disorders in children and adolescents.
Anxiety disorders are among the most common emotional difficulties experienced by children and young people. They cause significant disturbance to the lives of young people and their families and present a risk for lifelong psychological disturbance. Effective psychological (ie, cognitive-behaviour therapy (CBT)) and pharmacological interventions (eg, selective serotonin reuptake inhibitors (SSRIs)) have been established. However, the risk of adverse effects and unknown long-term effects of using SSRIs has led to recommendations that CBT is delivered as a first-line intervention. Recent innovations have included the development of low-intensity CBT programmes, delivered briefly via parents or online. These hold promise to increase access to psychological therapies for children and young people with these common and severe difficulties.


RBC micromotors carrying multiple cargos towards potential theranostic applications.
Red blood cell (RBC)-based micromotors containing both therapeutic and diagnostic modalities are described as a means for potential theranostic applications. In this natural RBC-based multicargo-loaded micromotor system, quantum dots (QDs), anti-cancer drug doxorubicin (DOX), and magnetic nanoparticles (MNPs), were co-encapsulated into RBC micromotors. The fluorescent emission of both QDs and DOX provides direct visualization of their loading inside the RBC motors at two distinct wavelengths. The presence of MNPs within the RBCs allows for efficient magnetic guidance under ultrasound propulsion along with providing the potential for magnetic resonance imaging. The simultaneous encapsulation of the imaging nanoparticles and therapeutic payloads within the same RBC micromotor has a minimal effect upon its propulsion behavior. The ability of the RBC micromotors to transport imaging and therapeutic agents at high speed and spatial precision through a complex microchannel network is also demonstrated. Such ability to load and transport diagnostic imaging agents and therapeutic drugs within a single cell-based motor, in addition to a lower toxicity observed once the drug is encapsulated within the multicargo RBC motor, opens the door to the development of theranostic micromotors that may simultaneously treat and monitor diseases.


Vaccine safety and efficacy evaluation of a recombinant bovine respiratory syncytial virus (BRSV) with deletion of the SH gene and subunit vaccines based on recombinant human RSV proteins: N-nanorings, P and M2-1, in calves with maternal antibodies.
The development of safe and effective vaccines against both bovine and human respiratory syncytial viruses (BRSV, HRSV) to be used in the presence of RSV-specific maternally-derived antibodies (MDA) remains a high priority in human and veterinary medicine. Herein, we present safety and efficacy results from a virulent BRSV challenge of calves with MDA, which were immunized with one of three vaccine candidates that allow serological differentiation of infected from vaccinated animals (DIVA): an SH gene-deleted recombinant BRSV (ΔSHrBRSV), and two subunit (SU) formulations based on HRSV-P, -M2-1, and -N recombinant proteins displaying BRSV-F and -G epitopes, adjuvanted by either oil emulsion (Montanide ISA71VG, SUMont) or immunostimulating complex matrices (AbISCO-300, SUAbis). Whereas all control animals developed severe respiratory disease and shed high levels of virus following BRSV challenge, ΔSHrBRSV-immunized calves demonstrated almost complete clinical and virological protection five weeks after a single intranasal vaccination. Although mucosal vaccination with ΔSHrBRSV failed to induce a detectable immunological response, there was a rapid and strong anamnestic mucosal BRSV-specific IgA, virus neutralizing antibody and local T cell response following challenge with virulent BRSV. Calves immunized twice intramuscularly, three weeks apart with SUMont were also well protected two weeks after boost. The protection was not as pronounced as that in ΔSHrBRSV-immunized animals, but superior to those immunized twice subcutaneously three weeks apart with SUAbis. Antibody responses induced by the subunit vaccines were non-neutralizing and not directed against BRSV F or G proteins. When formulated as SUMont but not as SUAbis, the HRSV N, P and M2-1 proteins induced strong systemic cross-protective cell-mediated immune responses detectable already after priming. ΔSHrBRSV and SUMont are two promising DIVA-compatible vaccines, apparently inducing protection by different immune responses that were influenced by vaccine-composition, immunization route and regimen.


Evaluation of mechanistic and statistical methods in forecasting influenza-like illness.
A variety of mechanistic and statistical methods to forecast seasonal influenza have been proposed and are in use; however, the effects of various data issues and design choices (statistical versus mechanistic methods, for example) on the accuracy of these approaches have not been thoroughly assessed. Here, we compare the accuracy of three forecasting approaches-a mechanistic method, a weighted average of two statistical methods and a super-ensemble of eight statistical and mechanistic models-in predicting seven outbreak characteristics of seasonal influenza during the 2016-2017 season at the national and 10 regional levels in the USA. For each of these approaches, we report the effects of real time under- and over-reporting in surveillance systems, use of non-surveillance proxies of influenza activity and manual override of model predictions on forecast quality. Our results suggest that a meta-ensemble of statistical and mechanistic methods has better overall accuracy than the individual methods. Supplementing surveillance data with proxy estimates generally improves the quality of forecasts and transient reporting errors degrade the performance of all three approaches considerably. The improvement in quality from ad hoc and post-forecast changes suggests that domain experts continue to possess information that is not being sufficiently captured by current forecasting approaches.