Modality-specific deterioration in naming verbs in nonfluent primary progressive aphasia.
A longitudinal study of oral and written naming and comprehension of nouns and verbs in an individual (M. M. L.) with nonfluent primary progressive aphasia (PPA) is reported. M. M. L. showed progressive deterioration of oral naming of verbs well before deterioration of written naming of verbs and before deterioration of oral or written naming of nouns. Her comprehension of both nouns and verbs remained intact, at least relative to oral naming of verbs. Her performance is compared to that of two other individuals with nonfluent PPA, who were tested at two time points. These patients showed similar patterns with respect to grammatical word class (verbs more impaired than nouns) and modality (spoken production more impaired than written production), but somewhat different courses of deterioration. The modality-specific nature of the observed verb production deficits rules out a semantic locus for the grammatical class effects. The results provide a new source of evidence for the hypothesis that there are distinct neural mechanisms for accessing lexical representations of nouns and verbs in language production.


De novo assembly and annotation of Hyalomma dromedarii tick (Acari: Ixodidae) sialotranscriptome with regard to gender differences in gene expression.
Hard ticks are hematophagous ectoparasites characterized by their long-term feeding. The saliva that they secrete during their blood meal is their crucial weapon against host-defense systems including hemostasis, inflammation and immunity. The anti-hemostatic, anti-inflammatory and immune-modulatory activities carried out by tick saliva molecules warrant their pharmacological investigation. The Hyalomma dromedarii Koch, 1844 tick is a common parasite of camels and probably the best adapted to deserts of all hard ticks. Like other hard ticks, the salivary glands of this tick may provide a rich source of many compounds whose biological activities interact directly with host system pathways. Female H. dromedarii ticks feed longer than males, thereby taking in more blood. To investigate the differences in feeding behavior as reflected in salivary compounds, we performed de novo assembly and annotation of H. dromedarii sialotranscriptome paying particular attention to variations in gender gene expression. The quality-filtered Illumina sequencing reads deriving from a cDNA library of salivary glands led to the assembly of 15,342 transcripts. We deduced that the secreted proteins included: metalloproteases, glycine-rich proteins, mucins, anticoagulants of the mandanin family and lipocalins, among others. Expression analysis revealed differences in the expression of transcripts between male and female H. dromedarii that might explain the blood-feeding strategies employed by both genders. The annotated sialome of H. dromedarii helps understand the interaction of tick-host molecules during blood-feeding and can lead to the discovery of new pharmacologically active proteins of ticks of the genus Hyalomma.


Short-term test-retest reliability of the ImPACT in healthy young athletes.
The present study examined the short-term test-retest reliability of the Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) variables with healthy 11- to 14-year-old athletes. 53 young athletes (Mage = 12.4 years, 9 female) were administered the ImPACT on two separate occasions two weeks apart. Participants were instructed to complete the Post-Concussion Symptom Scale (PCSS) and the baseline computerized neurocognitive test during both the baseline and retest phases. Intraclass correlation (ICC), standard error of measurement (SEM), and reliable change index (RCI) were used as reliability metrics. PCSS Total Symptoms and Visual-Motor Speed were the only scores to reach clinical reliability standards (i.e., R > 0.7). None of the scores exceeded RCI cut-offs. Results indicate that the composite scores of the ImPACT are differentially reliable in a preadolescent sample across a two-week retest period, with only motor processing speed and self-reported symptoms exceeding clinical reliability standards. The findings support the view that neurocognitive testing should not be the sole determining factor in concussion assessment. This study highlights the importance of continuing research with younger athletes to assess the reliability of neurocognitive measures in concussion management programs. Future research should focus on a larger, heterogeneous sample, including children with learning disabilities and ADHD.


Mechanics of composite hydrogels approaching phase separation.
For polymer-particle composites, limited thermodynamic compatibility of polymers and particles often leads to poor dispersal and agglomeration of the particles in the matrix, which negatively impacts the mechanics of composites. To study the impact of particle compatibility in polymer matrices on the mechanical properties of composites, we here study composite silica- protein based hydrogels. The polymer used is a previously studied telechelic protein-based polymer with end groups that form triple helices, and the particles are silica nanoparticles that only weakly associate with the polymer matrix. At 1mM protein polymer, up to 7% of silica nanoparticles can be embedded in the hydrogel. At higher concentrations the system phase separates. Oscillatory rheology shows that at high frequencies the particles strengthen the gels by acting as short-lived multivalent cross-links, while at low frequencies, the particles reduce the gel strength, presumably by sequestering part of the protein polymers in such a way that they can no longer contribute to the network strength. As is generally observed for polymer/particle composites, shear-induced polymer desorption from the particles leads to a viscous dissipation that strongly increases with increasing particle concentration. While linear rheological properties as function of particle concentration provide no signals for an approaching phase separation, this is very different for the non-linear rheology, especially fracture. Strain-at-break decreases rapidly with increasing particle concentration and vanishes as the phase boundary is approached, suggesting that the interfaces between regions of high and low particle densities in composites close to phase separation provide easy fracture planes.


The assessment of radiation exposures in Native American communities from nuclear weapons testing in Nevada.
Native Americans residing in a broad region downwind from the Nevada Test Site during the 1950s and 1960s received significant radiation exposures from nuclear weapons testing. Because of differences in diet, activities, and housing, their radiation exposures are only very imperfectly represented in the Department of Energy dose reconstructions. There are important missing pathways, including exposures to radioactive iodine from eating small game. The dose reconstruction model assumptions about cattle feeding practices across a year are unlikely to apply to the native communities as are other model assumptions about diet. Thus exposures from drinking milk and eating vegetables have not yet been properly estimated for these communities. Through consultations with members of the affected communities, these deficiencies could be corrected and the dose reconstruction extended to Native Americans. An illustration of the feasibility of extending the dose reconstruction is provided by a sample calculation to estimate radiation exposures to the thyroid from eating radio-iodine-contaminated rabbit thyroids after the Sedan test. The illustration is continued with a discussion of how the calculation results may be used to make estimates for other tests and other locations.


A common virulence region on plasmids from eleven serotypes of Salmonella.
Cured derivatives of Salmonella dublin and S. typhimurium showed reduced virulence following oral infection of mice (10(4)-10(5)-fold for S. dublin, 10(2)-fold for S. typhimurium). Large plasmids from S. dublin and S. typhimurium independently restored virulence to the cured S. dublin but truncated S. dublin plasmids with deletions in a previously identified virulence region did not. This common virulence region identified in plasmids from S. dublin and S. typhimurium was shown to be carried on plasmids from 11 other serotypes of Salmonella but was absent from 10 plasmid-containing serotypes. TnA and Tn10 were transduced from the virulence region of two TnA-insertion mutants of S. dublin and one Tn10-insertion mutant of S. typhimurium that showed diminished virulence to recipient wild-type strains of S. dublin, S. enteritidis and S. typhimurium. Each transductant showed a decrease in mouse virulence within the range 10(3)-10(5). It is therefore proposed that similar virulence determinants are expressed in different serotypes. It was also shown that integration that occurred during curing was Tn10 dependent.


LGBTQI+ Healthcare (in)Equalities in Portugal: What Can We Learn from Asexuality?
The main purpose of this article is to analyse how healthcare providers in Portugal perceive asexuality. To do so, the author makes use of qualitative data from both the CILIA LGBTQI+ Lives project and The Asexual Revolution doctoral research on asexuality in Portugal, namely, a focus group conducted with healthcare providers, drawing from their assessment of interview excerpts with people identifying as asexual. The data were explored according to thematic analysis and revealed three major tendencies: (1) old tropes at the doctor's office; (2) narratives of willingness to learn about the subject; and (3) constructive and encouraging views of asexuality. From this analysis, valuable lessons can be drawn concerning the respect for gender and sexual diversity. The author argues that both formal and informal learning play an important role in building cultural competence among healthcare providers. This could be achieved both by introducing sexual and gender diversity in curricula in HE and through media exposure on these subjects. Overall, it will lead to building knowledge and empathy about marginalised groups, and will help fight inequalities of LGBTQI+ people in healthcare. As such, LGTBQI+ activism that puts the topics of asexuality and LGBTQI+ in the media agenda, is a powerful strategy. Hence, because healthcare providers show willingness to learn, the media becomes a source for learning about asexual and LGTBQI+ experiences, which they can incorporate in their medical practice.


Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development.
Epidemiological and anatomical studies support the theory that disturbances of brain development may play a contributory role in the etiology of schizophrenia. Anatomical findings suggest that the normal pattern of neuronal migration during development of the cerebral cortex may be affected in the brains of schizophrenics, with the implication that cortical connectivity and associative function will be disrupted. In the present investigation in matched schizophrenic and control brains, we examined a particular population of neurons found in the prefrontal cortex and underlying white matter and characterized by histochemical staining for the enzyme nicotinamide-adenine dinucleotide phosphate-diaphorase. In normal brains, these neurons are found in highest numbers in the white matter immediately deep to layer VI of the cortex where they remain from the subplate, an early formed, but transitory structure that plays a key role in cortical development and connection formation. The dorsolateral prefrontal area of schizophrenics showed a significant decline in nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in the superficial white matter and in the overlying cortex but a significant increase in these neurons in white matter deeper than 3 mm from the cortex. These findings are consistent with a disturbance of the subplate during development in which the normal pattern of programmed cell death is compromised and accompanied by a defect in the normal orderly migration of neurons toward the cortical plate. These are likely to have serious consequences for the establishment of a normal pattern of cortical connections leading to a potential breakdown of frontal lobe function in schizophrenics.


Endocrine disrupting potential of PAHs and their alkylated analogues associated with oil spills.
Polycyclic aromatic hydrocarbons (PAHs) and alkylated PAHs are known to be major toxic contaminants in spills of petroleum hydrocarbons (oil). Spilled oil undergoes weathering and over time, PAHs go through a series of compositional changes. PAHs can disrupt endocrine functions, and the type of functions affected and associated potencies vary with the type and alkylation status of PAH. In this study, the potential of five major PAHs of crude oil, i.e., naphthalene, fluorene, dibenzothiophene, phenanthrene, and chrysene, and their alkylated analogues (n = 25), to disrupt endocrine functions was evaluated by use of MVLN-luc and H295R cell lines. In the MVLN-luc bioassay, seven estrogen receptor (ER) agonists were detected among 30 tested PAHs. The greatest ER-mediated potency was observed for 1-methylchrysene (101.4%), followed by phenanthrene and its alkylated analogues (range of %-E2max from 1.6% to 47.3%). In the H295R bioassay, significantly greater syntheses of steroid hormones were observed for 20 PAHs. For major PAHs and their alkylated analogues, disruption of steroidogenesis appeared to be more significant than ER-mediated effects. The number and locations of alkyl-moieties alone could not explain differences in the types or the potencies of toxicities. This observation shows that disruption of endocrine functions by some constituents of oil spills could be underestimated if only parent compounds are considered in assessments of hazard and risk.


Effects of the olive oil phenol metabolite 3,4-DHPEA-EDAH2 on human erythrocyte oxidative damage.
Red blood cells (RBCs), as anucleated cells, have poor repair and biosynthetic mechanisms, suffering and accumulating oxidative lesions whenever oxidative stress develops. RBCs are particularly exposed to endogenous oxidative damage because of their specific role as oxygen carriers. However, as the most abundant blood cells, RBCs also play an important role in the oxidative status of the whole blood constituents. In previous studies by our group, the most important polyphenolic compounds found in virgin olive oil, 3,4-dihydroxyphenylethanol-elenolic acid (3,4-DHPEA-EA) and 3,4-dihydroxyphenylethanol-elenolic acid dialdehyde (3,4-DHPEA-EDA), were shown to significantly protect RBCs from oxidative damage initiated by AAPH and H2O2, with the most active compound being 3,4-DHPEA-EDA. However, the in vivo protective effects of these phenols are dependent on their bioavailability. It has been demonstrated that 3,4-DHPEA-EDA is absorbed by intestinal cells and is then metabolized, yielding a reduced metabolite, 3,4-DHPEA-EDAH2. In order to assess the importance of VOO phenolic compound metabolites for the overall in vivo protective activity, the capacity of this phase I metabolite to protect RBCs in the presence of the radical initiators AAPH or H2O2 was evaluated in the presence and absence of the naturally occurring antioxidant, ascorbic acid. The metabolite was shown to protect RBCs from haemolysis induced by both initiators, in a dose dependent way, after 2 h and 4 h of incubation. The protective effect was however lower than that of the parental compound. The analysis of the membrane proteins of erythrocytes showed that the metabolite can interact with these biological structures.


Tissue and imaging biomarkers for hypoxia predict poor outcome in endometrial cancer.
Hypoxia is frequent in solid tumors and linked to aggressive phenotypes and therapy resistance. We explored expression patterns of the proposed hypoxia marker HIF-1α in endometrial cancer (EC) and investigate whether preoperative functional imaging parameters are associated with tumor hypoxia. Expression of HIF-1α was explored both in the epithelial and the stromal tumor component. We found that low epithelial HIF-1α and high stromal HIF-1α expression were significantly associated with reduced disease specific survival in EC. Only stromal HIF-1α had independent prognostic value in Cox regression analysis. High stromal HIF-1α protein expression was rare in the premalignant lesions of complex atypical hyperplasia but increased significantly to invasive cancer. High stromal HIF-1α expression was correlated with overexpression of important genes downstream from HIF-1α, i.e. VEGFA and SLC2A1 (GLUT1). Detecting hypoxic tumors with preoperative functional imaging might have therapeutic benefits. We found that high stromal HIF-1α expression associated with high total lesion glycolysis (TLG) at PET/CT. High expression of a gene signature linked to hypoxia also correlated with low tumor blood flow at DCE-MRI and increased metabolism measured by FDG-PET. PI3K pathway inhibitors were identified as potential therapeutic compounds in patients with lesions overexpressing this gene signature. In conclusion, we show that high stromal HIF-1α expression predicts reduced survival in EC and is associated with increased tumor metabolism at FDG-PET/CT. Importantly; we demonstrate a correlation between tissue and imaging biomarkers reflecting hypoxia, and also possible treatment targets for selected patients.


Umbilical cord ghrelin concentrations in small- and appropriate-for-gestational age newborn infants: relationship to anthropometric markers.
Ghrelin is a newly discovered orexigenic peptide originating from the stomach. Circulating ghrelin levels reflect acute and chronic energy balance in humans. However, it is not known whether ghrelin also plays a role in energy homeostasis during fetal life. Forty-one small-for-gestational age (SGA) and 34 appropriate-for-gestational age (AGA) infants were studied in order to determine whether cord blood ghrelin concentrations were different in SGA infants compared with AGA infants and the relationship to anthropometric measurements at delivery. The cord blood ghrelin concentrations of SGA infants (means+/-S.E.M.; 15.20+/-3.08 ng/ml) were significantly greater than of AGA infants (2.19+/-0.24 ng/ml) (P<0.0001). They were negatively correlated with the infants' birth weights (r=-0.481, P<0.0001) and with body mass index values (r=-0.363, P<0.001). The higher ghrelin concentrations were found in female infants (20.42+/-4.55 ng/ml) than in males (7.05+/-2.27 ng/ml) in the SGA group (P=0.042). These data provide the first evidence that cord ghrelin levels of SGA infants are greater than those of AGA infants and it is suggested that ghrelin is also affected by nutritional status in the intrauterine period.


Targeting of motor proteins.
Microtubules are responsible for chromosome segregation and the movement and reorganization of membranous organelles. Many aspects of microtubule-based motility can be attributed to the action of motor proteins, producing force directed toward either end of microtubules. How these proteins are targeted to the appropriate organellar sites within the cell, however, has remained a mystery. Recent work has begun to define the targeting mechanism for two well-studied motor proteins, kinesin and cytoplasmic dynein.


Evaluation of hepatitis B virus in clinical trials of baricitinib in rheumatoid arthritis.
Reactivation of hepatitis B virus (HBV) replication is a well-recognised complication in patients receiving disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA). Limited data exist on HBV reactivation among patients with RA treated with janus kinase (JAK) inhibitors. The objective of the current study was to assess HBV reactivation in clinical trials of baricitinib, an oral selective JAK1 and JAK2 inhibitor in RA. Data were integrated from four completed Phase 3 trials and one ongoing long-term extension (data up to 1 April 2017) in patients naïve to DMARDs or who had inadequate response (IR) to DMARDs including methotrexate (MTX)-IR and/or other conventional synthetic DMARD (csDMARD)-IR, or tumour necrosis factor inhibitors-IR. Within the clinical programme, baricitinib-treated patients may have received concomitant csDMARDs including MTX, or previous treatment with active comparators including MTX or adalimumab + MTX. At screening, all patients were tested for HBV surface antigen (HBsAg), core antibody (HBcAb) and surface antibody (HBsAb). Patients were excluded if they had (1) HBsAg+, (2) HBcAb+/HBsAb- (in Japan, could enrol if HBV DNA-) or (3) HBsAb+ and HBV DNA+. HBV DNA monitoring, following randomisation in the originating Phase 3 studies, was performed in Japan for patients with HBcAb+ and/or HBsAb+ at screening, and was later instituted globally for HBcAb+ patients in accordance with evolving guidance for HBV monitoring and management with immunomodulatory therapy. In total, 2890 patients received at least one dose of baricitinib in Phase 3 (6993 patient-years exposure). Of 215 patients with baseline serology suggestive of prior HBV infection (HbcAb+) who received a post-baseline DNA test, 32 (14.9%) were HBV DNA+ at some point following treatment initiation; 8 of 215 patients (3.7%) had a single quantifiable result (≥29 IU/mL). Of these eight patients, four met the definition of reactivation of HBV (HBV DNA level ≥100 IU/mL); baricitinib was permanently discontinued in four patients, and temporarily interrupted in two patients. No patient developed clinical evidence of hepatitis and in five of eight patients, antiviral therapy was not used. HBV reactivation can occur among RA patients treated with DMARDs, including baricitinib, with prior HBV exposure. Our data suggest that such patients should be monitored for HBV DNA during treatment and might be treated safely with the use of antiviral therapy as needed. The risk of HBV reactivation in patients with HBsAg treated with baricitinib is unknown.


Neurologic evaluation of acute lacrimomimetic effect of cyclosporine in an experimental rabbit dry eye model.
To evaluate neurologically acute lacrimation caused by cyclosporine (CsA) eyedrops in rabbit. Normal adult male New Zealand White rabbits and those that underwent parasympathectomy each received a single instillation of 0.1% CsA or vehicle eyedrops. Schirmer tear test (STT) results, flow rate of lacrimal gland (LG) fluid from the excretory lacrimal duct of the main LG, and blink rate (over a 3-minute period) were measured before and after instillation of CsA or vehicle. Light microscopy was performed to examine the main LG in vitro. Protein release from LG fragments was assessed after incubation with CsA for 30 minutes. In normal rabbits, the STT value and the flow rate of LG fluid were significantly increased after treatment with CsA compared with vehicle (P < 0.05). In contrast, no changes were found in denervated eyes. The blink rate of CsA-treated eyes was significantly higher than that of vehicle-treated eyes in normal rabbits (P < 0.005), whereas that of denervated eyes decreased significantly after CsA instillation compared with before administration (P < 0.005). Light microscopy showed that the cytoplasm of acinar cells was packed with secretory granules in denervated LG tissue 7 days after parasympathectomy. The same finding was observed 3 hours after CsA instillation. CsA had no stimulatory effect on protein release by acinar cells in LG fragments at all concentrations tested. These results suggest that CsA has no direct effect on tear fluid secretion from the LG in an acute model. Instead, CsA increases reflex tear flow.


Sensorimotor training in a virtual reality environment: does it improve functional recovery poststroke?
To investigate the effectiveness of computerized virtual reality (VR) training of the hemiparetic hand of patients poststroke using a system that provides repetitive motor reeducation and skill reacquisition. Eight subjects in the chronic phase poststroke participated in a 3-week program using their hemiparetic hand in a series of interactive computer games for 13 days of training, weekend breaks, and pretests and posttests. Each subject trained for about 2 to 2.5 h per day. Outcome measures consisted of changes in the computerized measures of thumb and finger range of motion, thumb and finger velocity, fractionation (the ability to move fingers independently), thumb and finger strength, the Jebsen Test of Hand Function, and a Kinematic reach to grasp test. Subjects as a group improved in fractionation of the fingers, thumb and finger range of motion, and thumb and finger speed, retaining those gains at the 1-week retention test. Transfer of these improvements was demonstrated through changes in the Jebsen Test of Hand Function and a decrease after the therapy in the overall time from hand peak velocity to the moment when an object was lifted from the table. It is difficult in current service delivery models to provide the intensity of practice that appears to be needed to effect neural reorganization and functional changes poststroke. Computerized exercise systems may be a way to maximize both the patients' and the clinicians' time. The data in this study add support to the proposal to explore novel technologies for incorporation into current practice.


Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia.
Autosomal recessive hypercholesterolemia is a rare inherited disorder, characterized by extremely high total and low-density lipoprotein cholesterol levels, that has been previously linked to mutations in LDLRAP1. We identified a family with autosomal recessive hypercholesterolemia not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular pathogenesis of autosomal recessive hypercholesterolemia in this family. We used exome sequencing to assess all protein-coding regions of the genome in 3 family members and identified a homozygous exon 8 splice junction mutation (c.894G>A, also known as E8SJM) in LIPA that segregated with the diagnosis of hypercholesterolemia. Because homozygosity for mutations in LIPA is known to cause cholesterol ester storage disease, we performed directed follow-up phenotyping by noninvasively measuring hepatic cholesterol content. We observed abnormal hepatic accumulation of cholesterol in the homozygote individuals, supporting the diagnosis of cholesterol ester storage disease. Given previous suggestions of cardiovascular disease risk in heterozygous LIPA mutation carriers, we genotyped E8SJM in >27 000 individuals and found no association with plasma lipid levels or risk of myocardial infarction, confirming a true recessive mode of inheritance. By integrating observations from Mendelian and population genetics along with directed clinical phenotyping, we diagnosed clinically unapparent cholesterol ester storage disease in the affected individuals from this kindred and addressed an outstanding question about risk of cardiovascular disease in LIPA E8SJM heterozygous carriers.


Patient-Centered eHealth Interventions for Children, Adolescents, and Adults With Sickle Cell Disease: Systematic Review.
Sickle cell disease is an inherited blood disorder that affects over 100,000 Americans. Sickle cell disease-related complications lead to significant morbidity and early death. Evidence supporting the feasibility, acceptability, and efficacy of self-management electronic health (eHealth) interventions in chronic diseases is growing; however, the evidence is unclear in sickle cell disease. We systematically evaluated the most recent evidence in the literature to (1) review the different types of technological tools used for self-management of sickle cell disease, (2) discover and describe what self-management activities these tools were used for, and (3) assess the efficacy of these technologies in self-management. We reviewed literature published between 1995 and 2016 with no language limits. We searched MEDLINE, EMBASE, CINAHL, PsycINFO, and other sources. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two independent reviewers screened titles and abstracts, assessed full-text articles, and extracted data from articles that met inclusion criteria. Eligible studies were original research articles that included texting, mobile phone-based apps, or other eHealth interventions designed to improve self-management in pediatric and adult patients with sickle cell disease. Of 1680 citations, 16 articles met all predefined criteria with a total of 747 study participants. Interventions were text messaging (4/16, 25%), native mobile apps (3/16, 19%), Web-based apps (5/16, 31%), mobile directly observed therapy (2/16, 13%), internet-delivered cognitive behavioral therapy (2/16, 13%), electronic pill bottle (1/16, 6%), or interactive gamification (2/16, 13%). Interventions targeted monitoring or improvement of medication adherence (5/16, 31%); self-management, pain reporting, and symptom reporting (7/16, 44%); stress, coping, sleep, and daily activities reporting (4/16, 25%); cognitive training for memory (1/16, 6%); sickle cell disease and reproductive health knowledge (5/16, 31%); cognitive behavioral therapy (2/16, 13%); and guided relaxation interventions (1/16, 6%). Most studies (11/16, 69%) included older children or adolescents (mean or median age 10-17 years; 11/16, 69%) and 5 included young adults (≥18 years old) (5/16, 31%). Sample size ranged from 11 to 236, with a median of 21 per study: <20 in 6 (38%), ≥20 to <50 in 6 (38%), and >50 participants in 4 studies (25%). Most reported improvement in self-management-related outcomes (15/16, 94%), as well as high satisfaction and acceptability of different study interventions (10/16, 63%). Our systematic review identified eHealth interventions measuring a variety of outcomes, which showed improvement in multiple components of self-management of sickle cell disease. Despite the promising feasibility and acceptability of eHealth interventions in improving self-management of sickle cell disease, the evidence overall is modest. Future eHealth intervention studies are needed to evaluate their efficacy, effectiveness, and cost effectiveness in promoting self-management in patients with sickle cell disease using rigorous methods and theoretical frameworks with clearly defined clinical outcomes.


ERAP1 and ankylosing spondylitis.
The strong genetic association of ERAP1 (endoplasmic reticulum aminopeptidase 1) with ankylosing spondylitis (AS), which is restricted to HLA-B27 positive cases, has profound pathogenetic implications. ERAP1 is involved in trimming peptides to optimal length for binding to HLA class 1 molecules, thereby not only affecting the stability and processing of HLA-B27 but also influencing the peptide repertoire presented to the immune system. This could have secondary effects on specific adaptive or autoimmune responses in AS. However, it appears increasingly likely that the pathogenic effect of ERAP1 may be mediated through effects on innate immunity, such as altering the interaction between HLA-B27 and immune receptors such as the killer immunoglobulin-like receptors (KIR) found on a range of innate immune cells or via the endoplasmic reticulum unfolded protein response. ERAP1 variants associated with reduced endopeptidase activity appear to be protective against AS, raising the possibility that ERAP1 inhibition could represent a future treatment strategy.


Internal consistency, test-retest reliability and measurement error of the self-report version of the social skills rating system in a sample of Australian adolescents.
The social skills rating system (SSRS) is used to assess social skills and competence in children and adolescents. While its characteristics based on United States samples (US) are published, corresponding Australian figures are unavailable. Using a 4-week retest design, we examined the internal consistency, retest reliability and measurement error (ME) of the SSRS secondary student form (SSF) in a sample of Year 7 students (N = 187), from five randomly selected public schools in Perth, western Australia. Internal consistency (IC) of the total scale and most subscale scores (except empathy) on the frequency rating scale was adequate to permit independent use. On the importance rating scale, most IC estimates for girls fell below the benchmark. Test-retest estimates of the total scale and subscales were insufficient to permit reliable use. ME of the total scale score (frequency rating) for boys was equivalent to the US estimate, while that for girls was lower than the US error. ME of the total scale score (importance rating) was larger than the error using the frequency rating scale. The study finding supports the idea of using multiple informants (e.g. teacher and parent reports), not just student as recommended in the manual. Future research needs to substantiate the clinical meaningfulness of the MEs calculated in this study by corroborating them against the respective Minimum Clinically Important Difference (MCID).


Expression profiling of Dexamethasone-treated primary chondrocytes identifies targets of glucocorticoid signalling in endochondral bone development.
Glucocorticoids (GCs) are widely used anti-inflammatory drugs. While useful in clinical practice, patients taking GCs often suffer from skeletal side effects including growth retardation in children and adolescents, and decreased bone quality in adults. On a physiological level, GCs have been implicated in the regulation of chondrogenesis and osteoblast differentiation, as well as maintaining homeostasis in cartilage and bone. We identified the glucocorticoid receptor (GR) as a potential regulator of chondrocyte hypertrophy in a microarray screen of primary limb bud mesenchyme micromass cultures. Some targets of GC regulation in chondrogenesis are known, but the global effects of pharmacological GC doses on chondrocyte gene expression have not been comprehensively evaluated. This study systematically identifies a spectrum of GC target genes in embryonic growth plate chondrocytes treated with a synthetic GR agonist, dexamethasone (DEX), at 6 and 24 hrs. Conventional analysis of this data set and gene set enrichment analysis (GSEA) was performed. Transcripts associated with metabolism were enriched in the DEX condition along with extracellular matrix genes. In contrast, a subset of growth factors and cytokines were negatively correlated with DEX treatment. Comparing DEX-induced gene expression data to developmental changes in gene expression in micromass cultures revealed an additional layer of complexity in which DEX maintains the expression of certain chondrocyte marker genes while inhibiting factors that promote vascularization and ultimately ossification of the cartilaginous template. Together, these results provide insight into the mechanisms and major molecular classes functioning downstream of DEX in primary chondrocytes. In addition, comparison of our data with microarray studies of DEX treatment in other cell types demonstrated that the majority of DEX effects are tissue-specific. This study provides novel insights into the effects of pharmacological GC on chondrocyte gene transcription and establishes the foundation for subsequent functional studies.


Single-molecule methods in structural DNA nanotechnology.
Single molecules can now be visualised with unprecedented precision. As the resolution of single-molecule experiments improves, so too does the breadth, quantity and quality of information that can be extracted using these methodologies. In the field of DNA nanotechnology, we use programmable interactions between nucleic acids to generate complex, multidimensional structures. We can use single-molecule techniques - ranging from electron and fluorescence microscopies to electrical and force spectroscopies - to report on the structure, morphology, robustness, sample heterogeneity and other properties of these DNA nanoconstructs. In this Tutorial Review, we will detail how complementarity between static and dynamic single-molecule techniques can provide a unified image of DNA nanoarchitectures. The single-molecule methods that we discuss provide unprecedented insight into chemical and structural behaviour, yielding not just an average outcome but reporting on the distribution of values, ultimately showing how bulk properties arise from the collective behaviour of individual structures. As the fields of both DNA nanotechnology and single-molecule characterisation intertwine, a feedback loop is generated between disciplines, providing new opportunities for the development and operation of DNA-based materials as sensors, delivery vehicles, machinery and structural scaffolds.


The latitudinal gradient in dispersal constraints: ecological specialisation drives diversification in tropical birds.
Physiological and behavioural constraints arising from ecological specialisation are proposed to limit gene flow and promote diversification in tropical lineages. In this study, we use phylogenetic analyses to test this idea in 739 Amazonian bird species. We show that patterns of species and subspecies richness are best predicted by a suite of avian specialisms common in tropical avifaunas but rare in the temperate zone. However, this only applied to niche traits associated with dispersal limitation rather than vagility. These findings are consistent with the view that diversity is promoted by more finely partitioned niches, although not simply by coevolutionary adaptation and niche packing as is often assumed. Instead, they suggest that diversification is driven by dispersal constraints, and that niches characterised by these constraints are biased towards tropical systems. We conclude that specialised tropical niches reduce the likelihood of dispersal across barriers, thereby increasing allopatric diversification and contributing to the latitudinal diversity gradient.


Amiloride inhibits the rise of urinary kallikrein excretion induced by frusemide administration in the rat.
The effect of amiloride administration on the urinary kallikrein response to the injection or continuous infusion of frusemide in normal Sprague-Dawley rats was investigated. Injections of frusemide induced repeatedly an increase in urinary kallikrein excretion. This effect was suppressed by amiloride. Amiloride also blocked the response to mannitol injection. A continuous infusion of frusemide lasting 100 min also induced an increase in urinary kallikrein excretion which persisted throughout the experiment. This response was completely blocked by the injection of amiloride. Urinary kallikrein excretion was directly and positively related to urine volume and urinary sodium excretion before and after amiloride injection. The regression lines had markedly decreased slopes after amiloride administration. The urinary kallikrein excretion was also positively related to the urine volume and urinary sodium excretion when frusemide was continuously infused. However, these relationships were abolished after amiloride injection. In both the injection and the infusion experiments, there was a direct relationship of urinary kallikrein excretion to urinary potassium excretion. Although this relationship persisted after amiloride injection, the regression line was shifted to the left. The suppression of the kallikrein stimulating effect of frusemide by the sodium channel blocker amiloride indicates that distal tubule sodium reabsorption is the triggering factor in urinary kallikrein excretion. The study suggests that the mechanism involved in the release of kallikrein by the distal tubular cells is linked to the renal mechanism affected by amiloride.


A Predictive Model for Acute Admission in Aged Population.
Acute hospital admission among the elderly population is very common and have a high impact on the health services and the community, as well as on the individuals. Several studies have focused on the possible risk factors, however, predicting who is at risk for acute hospitalization associated with disease and symptoms is still an open research question. In this study, we investigate the use of machine learning algorithms for predicting acute admission in older people based on admission data from individual citizens 70 years and older who were hospitalized in the acute medical unit of Svendborg Hospital in Denmark.


Hormonal Contraception and HIV/AIDS Transmission: Challenges for Zimbabwe's Reproductive Health Service Providers in Promoting Informed Contraception Choices.
None-barrier methods are the most predominant contraceptive methods of choice among Zimbabwean women, with the contraceptive pill being the most popular. The spread of HIV/AIDS is most prevalent in sub-Saharan African countries, Zimbabwe included. The prevalent mode of transmission is unprotected heterosexual sex. Although Zimbabwe boasts of a high literacy rate some women may still be vulnerable like in other parts of the world, as they may not understand the role of the Zimbabwe National Family Planning Council (ZNFPC) and other reproductive health service providers. This is because some women at risk may expose themselves to unprotected sex while they are on hormonal contraceptives. This paper seeks to infer into pros and cons of hormonal contraceptive use among Zimbabwean women. There is also need to discuss the effectiveness of providers (ZNFPC clinics and the Ministry of Health) in educating women about the risk of HIV transmission, which may be associated with some non-barrier methods of contraception. An understanding of women's attitudes towards the different forms of contraception is of paramount importance as is that of the factors that could contribute to women in different social settings resorting to uninformed contraceptive choices.


Impact of complete molecular response on survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.
The impact of achieving complete molecular response (CMR) in Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) remains undefined. We evaluated the impact of CMR on outcomes among 85 patients with Ph(+) ALL who received first-line hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine plus a tyrosine kinase inhibitor, had minimal residual disease (MRD) assessments for BCR-ABL1 by quantitative polymerase chain reaction at complete remission (CR) and at 3-month time points, and did not undergo allogeneic stem cell transplantation (SCT). MRD status at 3 months had better discrimination for overall survival (OS; P = .005) and relapse-free survival (RFS; P = .002) than did MRD status at CR (P = .11 and P = .04, respectively). At 3 months, achievement of CMR vs response less than CMR was associated with longer median OS (127 vs 38 months, respectively; P = .009) and RFS (126 vs 18 months, respectively; P = .007). By multivariate analysis, only CMR at 3 months was prognostic for OS (hazard ratio, 0.42; 95% confidence interval, 0.21-0.82; P = .01). Patients with Ph(+) ALL who achieve CMR at 3 months have superior survival compared with those with lesser molecular responses and have excellent long-term outcomes even without SCT.


Flatfoot diagnosis by a unique bimodal distribution of footprint index in children.
More than 1000 scientific papers have been devoted to flatfoot issue. However, a bimodal distribution of flatfoot indices in school-aged children has never been discovered. The purposes of this study were to establish a new classification of flatfoot by characteristic in frequency distribution of footprint index and to endue the classification with discrepancy in physical fitness. In a longitudinal survey of physical fitness and body structure, weight bearing footprints and 3 physical fitness related tests were measured in 1228 school-aged children. Frequency distribution of initial data was tested by Kolmogorov-Smirnov test for normality and a unique bimodal distribution of footprint index was identified. The frequency distribution of footprint index manifests two distinct modes, flatfoot and non-flatfoot, by deconvolution and bootstrapping procedures. A constant intersection value of 1.0 in Staheli's arch index and 0.6 in Chippaux-Smirak index could distinguish the two modes of children, and the value was constant in different age, sex, and weight status. The performance of the one leg balance was inferior in flatfoot girls (median, 4.0 seconds in flatfoot girls vs. 4.3 seconds in non-flatfoot girls, p = 0.04, 95% CI 0.404-0.484). The natural bimodality lends itself to a flatfoot classification. Bimodality suggests development of the child's foot arch would be a leap from one state to another, rather than a continuous growth as body height and weight. The underlying dynamics of the human foot arch and motor development will trigger research prospects.


Consequences of magnesium deficiency on the enhancement of stress reactions; preventive and therapeutic implications (a review).
Stress intensifies release of catecholamines and corticosteroids that increase survival of normal animals when their lives are threatened. When magnesium (Mg) deficiency exists, stress paradoxically increases risk of cardiovascular damage including hypertension, cerebrovascular and coronary constriction and occlusion, arrhythmias and sudden cardiac death (SCD). In affluent societies, severe dietary Mg deficiency is uncommon, but dietary imbalances such as high intakes of fat and/or calcium (Ca) can intensify Mg inadequacy, especially under conditions of stress. Adrenergic stimulation of lipolysis can intensify its deficiency by complexing Mg with liberated fatty acids (FA), A low Mg/Ca ratio increases release of catecholamines, which lowers tissue (i.e. myocardial) Mg levels. It also favors excess release or formation of factors (derived both from FA metabolism and the endothelium), that are vasoconstrictive and platelet aggregating; a high Ca/Mg ratio also directly favors blood coagulation, which is also favored by excess fat and its mobilization during adrenergic lipolysis. Auto-oxidation of catecholamines yields free radicals, which explains the enhancement of the protective effect of Mg by anti-oxidant nutrients against cardiac damage caused by beta-catecholamines. Thus, stress, whether physical (i.e. exertion, heat, cold, trauma--accidental or surgical, burns), or emotional (i.e. pain, anxiety, excitement or depression) and dyspnea as in asthma increases need for Mg. Genetic differences in Mg utilization may account for differences in vulnerability to Mg deficiency and differences in body responses to stress.


In Vitro Metabolism of Oprozomib, an Oral Proteasome Inhibitor: Role of Epoxide Hydrolases and Cytochrome P450s.
Oprozomib is an oral proteasome inhibitor currently under investigation in patients with hematologic malignancies or solid tumors. Oprozomib elicits potent pharmacological actions by forming a covalent bond with the active site N-terminal threonine of the 20S proteasome. Oprozomib has a short half-life across preclinical species and in patients due to systemic clearance via metabolism. Potential for drug-drug interactions (DDIs) could alter the exposure of this potent therapeutic; therefore, a thorough investigation of pathways responsible for metabolism is required. In the present study, the major drug-metabolizing enzyme responsible for oprozomib metabolism was identified in vitro. A diol of oprozomib was found to be the predominant metabolite in human hepatocytes, which formed via direct epoxide hydrolysis. Using recombinant epoxide hydrolases (EHs) and selective EH inhibitors in liver microsomes, microsomal EH (mEH) but not soluble EH (sEH) was found to be responsible for oprozomib diol formation. Coincubation with 2-nonylsulfanyl-propionamide, a selective mEH inhibitor, resulted in a significant decrease in oprozomib disappearance (>80%) with concurrent complete blockage of diol formation in human hepatocytes. On the contrary, a selective sEH inhibitor did not affect oprozomib metabolism. Pretreatment of hepatocytes with the pan-cytochrome P450 (P450) inhibitor 1-aminobenzotriazole resulted in a modest reduction (∼20%) of oprozomib metabolism. These findings indicated that mEH plays a predominant role in oprozomib metabolism. Further studies may be warranted to determine whether drugs that are mEH inhibitors cause clinically significant DDIs with oprozomib. On the other hand, pharmacokinetics of oprozomib is unlikely to be affected by coadministered P450 and sEH inhibitors and/or inducers.


Sources of Stress Among Midwest American Indian Adults with Type 2 Diabetes.
Despite alarming health disparities among American Indians (AIs) and acknowledgement that stressors negatively influence health, conceptualization of the full spectrum of stressors that impact Indigenous communities is underdeveloped. To address this gap, we analyze focus group transcripts of AI adults with type 2 diabetes from five tribal communities and classify stressors using an inductive/deductive analytical approach. A Continuum of American Indian Stressor Model was constructed from categorization of nineteen stressor categories within four domains. We further identified poverty, genocide, and colonization as fundamental causes of contemporary stress and health outcomes for AIs and conclude that stressors are generally experienced as chronic, regardless of the duration of the stressor. This work on AI-specific stressors informs future health research on the stress burden in AI communities and identifies target points for intervention and health promotion.


Potato sucrose transporter expression in minor veins indicates a role in phloem loading.
The major transport form of assimilates in most plants is sucrose. Translocation from the mesophyll into the phloem for long-distance transport is assumed to be carrier mediated in many species. A sucrose transporter cDNA was isolated from potato by complementation of a yeast strain that is unable to grow on sucrose because of the absence of an endogenous sucrose uptake system and the lack of a secreted invertase. The deduced amino acid sequence of the potato sucrose transporter gene StSUT1 is highly hydrophobic and is 68% identical to the spinach sucrose transporter SoSUT1 (pS21). In yeast, the sensitivity of sucrose transport to protonophores and to an increase in pH is consistent with an active proton cotransport mechanism. Substrate specificity and inhibition by protein modifiers are similar to results obtained for sucrose transport into protoplasts and plasma membrane vesicles and for the spinach transporter, with the exception of a reduction in maltose affinity. RNA gel blot analysis shows that the StSUT1 gene is highly expressed in mature leaves, whereas stem and sink tissues, such as developing leaves, show only low expression. RNA in situ hybridization studies show that the transporter gene is expressed specifically in the phloem. Both the properties and the expression pattern are consistent with a function of the sucrose transporter protein in phloem loading.


Salmonella enterica serovar Typhimurium interaction with dendritic cells: impact of the sifA gene.
Salmonella enterica serovar Typhimurium (S. Typhimurium) and several mutant derivatives were able to enter efficiently murine bone marrow-derived dendritic cells using mechanisms predominantly independent of the Salmonella pathogenicity island 1 type III secretion system. The levels of intracellular bacteria did not increase significantly over many hours after invasion. Using fluid endocytic tracers and other markers, S. Typhimurium-containing vacuoles (SCVs) were physically distinguishable from early endocytic compartments. Fifty to eighty per cent of SCVs harbouring wild-type S. Typhimurium or aroA, invH and ssaV mutant derivatives were associated with late endosome markers. In contrast, S. Typhimurium sifA was shown to escape the SCVs into the cytosol of infected dendritic cells. S. Typhimurium aroC sifA was more efficient than S. Typhimurium aroC in delivering a eukaryotic promoter-driven green fluorescent protein reporter gene for expression in dendritic cells. In contrast, S. Typhimurium aroC sifA did not detectably increase the efficiency of MHC class I presentation of the model antigen ovalbumin to T cells compared to a similar aroC derivative. Mice infected with the S. Typhimurium aroC sifA expressing ovalbumin did not develop detectably enhanced levels of cytotoxic T cell or interferon-gamma production compared to S. Typhimurium aroC derivatives.


Ultrasound acoustic startle response in scarab beetles.
We discovered an auditory sense in a night-flying scarab beetle, Euetheola humilis, the first scarab to be shown to hear airborne sounds. In the field, beetles were captured beneath speakers broadcasting ultrasound that simulated bat echolocation pulses. Apparently, the beetles took evasive action from a potential bat predator and flew into the traps. Using another behavioral assay in laboratory studies, the beetles were sensitive to frequencies ranging from 20 to 70 kHz at levels between 60 and 70 dB SPL. One component of the behavioral response, a head roll, was graded with stimulus intensity, and the number of potentials in electromyographic recordings from muscles involved in the roll increased as stimulus intensity increased. The response latency was about 40 ms at threshold, decreasing to about 30 ms at 20 dB above threshold. The beetle's short response latency is ideally suited for predator avoidance behavior and the frequency tuning of the response suggests that it could function in evasion from insectivorous bats. The beetle's acoustic sensitivity is remarkably similar to that of other night-flying insects showing ultrasound-induced startle and it should provide these scarab beetles with a similar advance warning of predation risk.


Exploiting Co Defects in CoFe-Layered Double Hydroxide (CoFe-LDH) Derivatives for Highly Efficient Photothermal Cancer Therapy.
Currently, two-dimensional materials are being actively pursued in catalysis and other fields due their abundance of defects, which results in enhanced performance relative to their bulk defect-free counterparts. To date, the exploitation of defects in two-dimensional materials to enhance photothermal therapies has received little attention, motivating a detailed investigation. Herein, we successfully fabricated a series of novel CoFe-based photothermal agents (CoFe-x) by heating CoFe-layered double hydroxide (CoFe-LDH) nanosheets at different temperatures (x) between 200-800 °C under a Ar atmosphere. The CoFe-x products differed in their particle size, cobalt defect concentration, and electronic structure, with the CoFe-500 product containing the highest concentration of Co2+ defects and most efficient photothermal performance under near-infrared (NIR, 808 nm) irradiation. Experiments and density functional theory (DFT) calculations revealed that Co2+ defects modify the electronic structure of CoFe-x, narrowing the band gap and thus increasing the nonradiative recombination rate, thereby improving the NIR-driven photothermal properties. In vitro and in vivo results demonstrated that CoFe-500 was an efficient agent for photothermal cancer treatment and also near-infrared (NIR) thermal imaging, magnetic resonance (MR) imaging, and photoacoustic (PA) imaging. This work provides valuable new insights about the role of defects in the rational design of nanoagents with optimized structures for improved cancer therapy.


Fatigue Induced Changes in Muscle Strength and Gait Following Two Different Intensity, Energy Expenditure Matched Runs.
To investigate changes in hip and knee strength, kinematics, and running variability following two energy expenditure matched training runs; a medium intensity continuous run (MICR) and a high intensity interval training session (HIIT). Twenty (10 Females, 10 Males) healthy master class runners were recruited. Each participant completed the HIIT consisting of six repetitions of 800 m with a 1:1 work: rest ratio. The MICR duration was set to match energy expenditure of the HIIT session. Hip and knee muscular strength were examined pre and post both HIIT and MICR. Kinematics and running variability for hip and knee, along with spatiotemporal parameters were assessed at start and end of each run-type. Changes in variables were examined using both 2 × 2 ANOVAs with repeated measures and on an individual level when the change in a variable exceeded the minimum detectable change (MDC). All strength measures exhibited significant reductions at the hip and knee (P < 0.05) with time for both run-types; 12% following HIIT, 10.6% post MICR. Hip frontal plane kinematics increased post run for both maximum angle (P < 0.001) and range of motion (P = 0.003). Runners exhibited increased running variability for nearly all variables, with the HIIT having a greater effect. Individual assessment revealed that not all runners were effected post run and that following HIIT more runners had reduced muscular strength, altered kinematics and increased running variability. Runners exhibited fatigue induced changes following typical training runs, which could potentially present risk of injury development. Group and individual assessment revealed different findings where the use of MDC is recommended over that of P-values.


Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis.
To estimate the regression, persistence, and progression of untreated cervical intraepithelial neoplasia grade 2 (CIN2) lesions managed conservatively as well as compliance with follow-up protocols. Systematic review and meta-analysis. Medline, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1 January 1973 to 20 August 2016. Studies reporting on outcomes of histologically confirmed CIN2 in non-pregnant women, managed conservatively for three or more months. Two reviewers extracted data and assessed risk of bias. Random effects model was used to calculate pooled proportions for each outcome, and heterogeneity was assessed using I2 statistics. Rates of regression, persistence, or progression of CIN2 and default rates at different follow-up time points (3, 6, 12, 24, 36, and 60 months). 36 studies that included 3160 women were identified (seven randomised trials, 16 prospective cohorts, and 13 retrospective cohorts; 50% of the studies were at low risk of bias). At 24 months, the pooled rates were 50% (11 studies, 819/1470 women, 95% confidence interval 43% to 57%; I2=77%) for regression, 32% (eight studies, 334/1257 women, 23% to 42%; I2=82%) for persistence, and 18% (nine studies, 282/1445 women, 11% to 27%; I2=90%) for progression. In a subgroup analysis including 1069 women aged less than 30 years, the rates were 60% (four studies, 638/1069 women, 57% to 63%; I2=0%), 23% (two studies, 226/938 women, 20% to 26%; I2=97%), and 11% (three studies, 163/1033 women, 5% to 19%; I2=67%), respectively. The rate of non-compliance (at six to 24 months of follow-up) in prospective studies was around 10%. Most CIN2 lesions, particularly in young women (<30 years), regress spontaneously. Active surveillance, rather than immediate intervention, is therefore justified, especially among young women who are likely to adhere to monitoring. PROSPERO 2014: CRD42014014406.


Adverse outcomes associated with media exposure to contradictory nutrition messages.
There is increasing concern that the media present conflicting health information on topics including cancer screening and nutrition. Although scholars have speculated that exposure to this information leads to increased public confusion, less trust in health recommendations, and less engagement in health behaviors, there is a lack of empirical research that directly addresses the role of media exposure to conflicting information. Using data from the Annenberg National Health Communication Survey, this study finds that exposure to conflicting information on the health benefits and risks of, for example, wine, fish, and coffee consumption is associated with confusion about what foods are best to eat and the belief that nutrition scientists keep changing their minds. There is evidence that these beliefs, in turn, may lead people to doubt nutrition and health recommendations more generally-including those that are not rife with contradictory information (e.g., fruit/vegetable consumption, exercise). The implications of these findings for healthy eating campaigns and interventions are discussed.


Update on the Regulation of HIPK1, HIPK2 and HIPK3 Protein Kinases by microRNAs.
The Homeodomain-Interacting Protein Kinases (HIPKs) HIPK1, HIPK2 and HIPK3 are Ser/Thr kinases which interact with homeobox proteins and other transcription factors, acting as transcriptional coactivators or corepressors. HIPKs contribute to regulate several biological processes, such as signal transduction, apoptosis, embryonic development, DNA-damage response, and cellular proliferation, in response to various extracellular stimuli. Recently it has emerged that, in addition to their role in cancer, fibrosis and diabetes, HIPKs may also be involved in other human diseases, including Amyotrophic Lateral Sclerosis (ALS), Rett syndrome, cerebellar diseases, and retinal vascular dysfunction. Here, we update our previous paper concerning the regulation of HIPK proteins expression by microRNAs (miRNAs), pointing out the most recent findings about new cellular mechanisms and diseases which are affected by the interplay between HIPKs and miRNAs. Recently, it has emerged that HIPKs and their related miRNAs are involved in diabetic nephropathy, gastric cancer chemoresistance, cervical cancer progression, and recombinant protein expression in cultured cells. Interestingly, circular RNAs (circRNAs) deriving from HIPK2 and HIPK3 loci also modulate cellular proliferation and viability by sponging several miRNAs, thus emerging as new putative therapeutic targets for diabetes-associated retinal vascular dysfunction, astrogliosis and cancer.


Connections of Grasping and Horizontal Hand Movements with Articulation in Czech Speakers.
We have recently shown in Finnish speakers that articulation of certain vowels and consonants has a systematic influence on simultaneous grasp actions as well as on forward and backward hand movements. Here we studied whether these effects generalize to another language, namely Czech. We reasoned that if the results generalized to another language environment, it would suggest that the effects arise through other processes than language-dependent semantic associations. Rather, the effects would be likely to arise through language-independent interactions between processes that plan articulatory gestures and hand movements. Participants were presented with visual stimuli specifying articulations to be uttered (e.g., A or I), and they were required to produce a manual response concurrently with the articulation. In Experiment 1 they responded with a precision or a power grip, whereas in Experiment 2 they responded with a forward or a backward hand movement. The grip congruency effect was fully replicated: the consonant [k] and the vowel [α] were associated with power grip responses, while the consonant [t] and the vowel [i] were associated with precision grip responses. The forward/backward congruency effect was replicated with vowels [α], [o], which were associated with backward movement and with [i], which was associated with forward movement, but not with consonants [k] and [t]. These findings suggest that the congruency effects mostly reflect interaction between processes that plan articulatory gestures and hand movements with an exception that the forward/backward congruency effect might only work with vowel articulation.


Screening foster children for mental disorders: properties of the strengths and difficulties questionnaire.
High prevalence of mental disorders among foster children highlight the need to examine the mental health of children placed out of home. We examined the properties of the Strengths and Difficulties Questionnaire (SDQ) in screening school-aged foster children for mental disorders. Foster parents and teachers of 279 foster children completed the SDQ and the diagnostic interview Developmental and Well-Being Assessment (DAWBA). Using the diagnoses derived from the DAWBA as the standard, we examined the performance of the SDQ scales as dimensional measures of mental health problems using receiver operating characteristic (ROC) analyses. Recommended cut-off scores were derived from ROC coordinates. The SDQ predictive algorithms were also examined. ROC analyses supported the screening properties of the SDQ Total difficulties and Impact scores (AUC = 0.80-0.83). Logistic regression analyses showed that the prevalence of mental disorders increased linearly with higher SDQ Total difficulties scores (X2 = 121.47, df = 13, p<.001) and Impact scores (X2 = 69.93, df = 6, p<.001). Our results indicated that there is an additive value of combining the scores from the Total difficulties and Impact scales, where scores above cut-off on any of the two scales predicted disorders with high sensitivity (89.1%), but moderate specificity (62.1%). Scores above cut-off on both scales yielded somewhat lower sensitivity (73.4%), but higher specificity (81.1%). The SDQ multi-informant algorithm showed low discriminative ability for the main diagnostic categories, with an exception being the SDQ Conduct subscale, which accurately predicted the absence of behavioural disorders (LHR- = 0.00). The results support the use of the SDQ Total difficulties and Impact scales when screening foster children for mental health problems. Cut-off values for both scales are suggested. The SDQ multi-informant algorithms are not recommended for mental health screening of foster children in Norway.


Treatment of a GIST patient with modified dose of sunitinib by measurement of plasma drug concentrations.
In this study we report the pharmacokinetics and severe adverse effects of sunitinib in a woman with a gastrointestinal stromal tumor (GIST). A 60-year-old woman with small intestinal GIST developed severe thrombocytopenia (1.7×10(4)/μl) following 1 week of treatment with sunitinib at 50 mg/day. Although the dose of sunitinib was reduced to 25 mg/day, platelet levels remained low. On day 7, the trough concentration of sunitinib plus SU12662 was 46.1 ng/ml and the area under the curve (AUC) was 1,393.0 ng·h/l. The dose was again reduced to 12.5 mg/day. However, the day after resumption of treatment, the patient developed symptoms of left heart failure due to myocardosis caused by sunitinib. Sunitinib has been reported to inhibit platelet-derived growth factor receptor (PDGFR) phosphorylation at concentrations over the range of 50-100 ng/ml (sunitinib plus SU12662) in vivo. In this case, the plasma concentration was sufficient to inhibit PDGFR at 25 or 50 mg/day. However, thrombocytopenia appeared at both dosages. Although the results in this case did not suggest a correlation between thrombocytopenia and plasma concentration, the degree of thrombocytopenia was decreased by reduction of the dose. In conclusion, the findings reported here indicate that the plasma concentration of sunitinib plus SU12662 is an important indicator to reduce adverse effects.


When are psychotherapy and pharmacotherapy combinations the treatment of choice for major depressive disorder?
Treating major depressive disorder with the combination of psychotherapy and pharmacotherapy is highly valued by both psychiatrists and their patients. However, results of most systematic research studies suggest that this approach may be overvalued: evidence of additive benefits (in relation to the respective component therapies, alone) is meager. In this paper it is argued that the advantage of combined treatment may be limited to treatment of patients with more complex depressive disorders, including characteristics such as comorbidity, chronicity, treatment resistance, episodicity, and severity. Said another way, milder acute depressions, especially initial or sporadic episodes, probably do not warrant the routine use of psychotherapy and pharmacotherapy. By focusing attention on the patient subgroups most likely to show a true additive response to combined treatment, it may be possible to obtain maximum benefits from dwindling resources.


Flagellar pocket restructuring through the Leishmania life cycle involves a discrete flagellum attachment zone.
Leishmania promastigote parasites have a flagellum, which protrudes from the flagellar pocket at the cell anterior, yet, surprisingly, have homologs of many flagellum attachment zone (FAZ) proteins--proteins used in the related Trypanosoma species to laterally attach the flagellum to the cell body from the flagellar pocket to the cell posterior. Here, we use seven Leishmania mexicana cell lines that expressed eYFP fusions of FAZ protein homologs to show that the Leishmania flagellar pocket includes a FAZ structure. Electron tomography revealed a precisely defined 3D organisation for both the flagellar pocket and FAZ, with striking similarities to those of Trypanosoma brucei. Expression of two T. brucei FAZ proteins in L. mexicana showed that T. brucei FAZ proteins can assemble into the Leishmania FAZ structure. Leishmania therefore have a previously unrecognised FAZ structure, which we show undergoes major structural reorganisation in the transition from the promastigote (sandfly vector) to amastigote (in mammalian macrophages). Morphogenesis of the Leishmania flagellar pocket, a structure important for pathogenicity, is therefore intimately associated with a FAZ; a finding with implications for understanding shape changes involving component modules during evolution.


Free radical scavenging and antimicrobial properties of extracts of wild mushrooms.
Antioxidant and antimicrobial potentials of extracts obtained from four wild mushrooms, Termitomyces clypeatus (TCE), Termitomyces robustus (TRE), Lentinus subnudus (LSE) and Lenzites species (LZE) collected in Nigeria were investigated. LSE and LZE displayed good scavenging activity against 2, 2-Diphenyl-1-Picrylhydrazyl (DPPH) and ferrous ion radicals at concentration of 2 mg/mL. However, TRE and TCE exhibited better superoxide anion scavenging effect at 2 mg/mL. All extracts (TCE, TRE, LSE and LZE) had comparable scavenging effect on hydroxyl radicals as butylated Hydroxytoluene (BHT) used as control. Moreover, extracts from the wild mushrooms were able to inhibit the growth of all indicator organisms at concentrations between 12.5 mg/mL to 100 mg/mL. LSE and LZE, however, showed better antimicrobial effect on the indicator organisms. The results suggest that extracts obtained from the four wild mushrooms may serve as sources of new bioactive compounds with effective antioxidant and antimicrobial activity.


Cell-type specific four-component hydrogel.
In the field of regenerative medicine we aim to develop implant matrices for specific tissue needs. By combining two per se, cell-permissive gel systems with enzymatic crosslinkers (gelatin/transglutaminase and fibrinogen/thrombin) to generate a blend (technical term: quattroGel), an unexpected cell-selectivity evolved. QuattroGels were porous and formed cavities in the cell diameter range, possessed gelation kinetics in the minute range, viscoelastic properties and a mechanical strength appropriate for general cell adhesion, and restricted diffusion. Cell proliferation of endothelial cells, chondrocytes and fibroblasts was essentially unaffected. In contrast, on quattroGels neither endothelial cells formed vascular tubes nor did primary neurons extend neurites in significant amounts. Only chondrocytes differentiated properly as judged by collagen isoform expression. The biophysical quattroGel characteristics appeared to leave distinct cell processes such as mitosis unaffected and favored differentiation of sessile cells, but hampered differentiation of migratory cells. This cell-type selectivity is of interest e.g. during articular cartilage or invertebral disc repair, where pathological innervation and angiogenesis represent adverse events in tissue engineering.


Single-shot readout of multiple nuclear spin qubits in diamond under ambient conditions.
We use the electronic spin of a single nitrogen-vacancy defect in diamond to observe the real-time evolution of neighboring single nuclear spins under ambient conditions. Using a diamond sample with a natural abundance of (13)C isotopes, we first demonstrate high fidelity initialization and single-shot readout of an individual (13)C nuclear spin. By including the intrinsic (14)N nuclear spin of the nitrogen-vacancy defect in the quantum register, we then report the simultaneous observation of quantum jumps linked to both nuclear spin species, providing an efficient initialization of the two qubits. These results open up new avenues for diamond-based quantum information processing including active feedback in quantum error correction protocols and tests of quantum correlations with solid-state single spins at room temperature.


Brain responses associated with consciousness of breathlessness (air hunger).
Little is known about the physiological mechanisms subserving the experience of air hunger and the affective control of breathing in humans. Acute hunger for air after inhalation of CO(2) was studied in nine healthy volunteers with positron emission tomography. Subjective breathlessness was manipulated while end-tidal CO(2-) was held constant. Subjects experienced a significantly greater sense of air hunger breathing through a face mask than through a mouthpiece. The statistical contrast between the two conditions delineated a distributed network of primarily limbic/paralimbic brain regions, including multiple foci in dorsal anterior and middle cingulate gyrus, insula/claustrum, amygdala/periamygdala, lingual and middle temporal gyrus, hypothalamus, pulvinar, and midbrain. This pattern of activations was confirmed by a correlational analysis with breathlessness ratings. The commonality of regions of mesencephalon, diencephalon and limbic/paralimbic areas involved in primal emotions engendered by the basic vegetative systems including hunger for air, thirst, hunger, pain, micturition, and sleep, is discussed with particular reference to the cingulate gyrus. A theory that the phylogenetic origin of consciousness came from primal emotions engendered by immediate threat to the existence of the organism is discussed along with an alternative hypothesis by Edelman that primary awareness emerged with processes of ongoing perceptual categorization giving rise to a scene [Edelman, G. M. (1992) Bright Air, Brilliant Fire (Penguin, London)].


Long-term experience with diaphragm pacing for traumatic spinal cord injury: Early implantation should be considered.
Cervical spinal cord injury can result in catastrophic respiratory failure requiring mechanical ventilation with high morbidity, mortality, and cost. Diaphragm pacing was developed to replace/decrease mechanical ventilation. We report the largest long-term results in traumatic cervical spinal cord injury. In this retrospective review of prospective institutional review board protocols, all patients underwent laparoscopic diaphragm mapping and implantation of electrodes for diaphragm strengthening and ventilator weaning. From 2000 to 2017, 92 patients out of 486 diaphragm pacing implants met the criteria. The age at time of injury ranged from birth to 74 years (average: 27 years). Time on mechanical ventilation was an average of 47.5 months (range, 6 days to 25 years, median = 1.58 years). Eighty-eight percent of patients achieved the minimum of 4 hours of pacing. Fifty-six patients (60.8%) used diaphragm pacing 24 hours a day. Five patients had full recovery of breathing with subsequent diaphragm pacing removal. Median survival was 22.2 years (95% confidence interval: 14.0-not reached) with only 31 deaths. Subgroup analysis revealed that earlier diaphragm pacing implantation leads to greater 24-hour use of diaphragm pacing and no need for any mechanical ventilation. Diaphragm pacing can successfully decrease the need for mechanical ventilation in traumatic cervical spinal cord injury. Earlier implantation should be considered.


The aryl hydrocarbon receptor nuclear transporter is modulated by the SUMO-1 conjugation system.
The aryl hydrocarbon receptor nuclear transporter (ARNT) is a member of the basic helix-loop-helix/PAS (Per-ARNT-Sim) family of transcription factors, which are important for cell regulation in response to environmental conditions. ARNT is an indispensable partner of the aryl hydrocarbon receptor (AHR) or hypoxia-inducible factor-1alpha. This protein is also able to form homodimers such as ARNT/ARNT. However, the molecular mechanism that regulates the transcriptional activity of ARNT remains to be elucidated. Here, we report that ARNT is modified by SUMO-1 chiefly at Lys(245) within the PAS domain of this protein, both in vivo and in vitro. Substitution of the target lysine with alanine enhanced the transcriptional potential of ARNT per se. Furthermore, green fluorescent protein-fused ARNT tended to form nuclear foci in approximately 20% of the transfected cells, and the foci partly colocalized with PML nuclear bodies. PML, one of the well known substrates for sumoylation, was found to augment the transcriptional activities of ARNT. ARNT bound AHR or PML, whereas the sumoylated form of ARNT associated with AHR, but not with PML, resulting in a reduced effect of PML on transactivation by ARNT. Our data suggest that the sumoylation of ARNT modulates its transcriptional role through affecting the ability of ARNT to interact with cooperative molecules such as PML. This exemplifies a crucial role of protein sumoylation in modulating protein-protein interactions.


B-lymphocyte typing (HLA-DR, MT, MB) interlaboratory reproducibility.
Frozen lymphocytes from six persons were shipped, in three batches, from one location to 11 other participating laboratories for B-lymphocyte typing. The cells were received by the participating laboratories in a frozen state with one exception. Four of the 12 (including the host laboratory) used two-color fluorescence method, seven used nylon wool to isolate B-lymphocytes followed by cytotoxicity testing using trypan blue, and one laboratory used goat anti-human F(ab')2 to isolate B-lymphocytes for two cells and two-color fluorescence method for the other four cells. Reference antigen assignments of the various cells were essentially the consensus of the various laboratories and major departures from those assignments were considered errors. Twelve typing errors were seen in a total of 67 typings (for HLA-DR), i.e., an error rate of 17.9%. Four of the errors might have been due to the poor state of cells resulting from the participating laboratory storing the cells for over four weeks before testing. Six of the 12 laboratories were in agreement for all six cells and made no errors. Typing for MT antigens did not appear to be particularly reliable, but there was a good interlaboratory correlation for MB antigen assignments. The exercise has established the feasibility of conducting a cell exchange for B-lymphocyte typing over a fairly wide geographic area, and has shown that the overall error rate for HLA-DR antigen assignments is about three times the rate of HLA-AB typing.


Diversity as Opportunity: Insights from 600 Million Years of AHR Evolution.
The aryl hydrocarbon receptor (AHR) was for many years of interest only to pharmacologists and toxicologists. However, this protein has fundamental roles in biology that are being revealed through studies in diverse animal species. The AHR is an ancient protein. AHR homologs exist in most major groups of modern bilaterian animals, including deuterostomes (chordates, hemichordates, echinoderms) and the two major clades of protostome invertebrates [ecdysozoans (e.g. arthropods and nematodes) and lophotrochozoans (e.g. molluscs and annelids)]. AHR homologs also have been identified in cnidarians such as the sea anemone Nematostella and in the genome of Trichoplax, a placozoan. Bilaterians, cnidarians, and placozoans form the clade Eumetazoa, whose last common ancestor lived approximately 600 million years ago (MYA). The presence of AHR homologs in modern representatives of all these groups indicates that the original eumetazoan animal possessed an AHR homolog. Studies in invertebrates and vertebrates reveal parallel functions of AHR in the development and function of sensory neural systems, suggesting that these may be ancestral roles. Vertebrate animals are characterized by the expansion and diversification of AHRs, via gene and genome duplications, from the ancestral protoAHR into at least five classes of AHR-like proteins: AHR, AHR1, AHR2, AHR3, and AHRR. The evolution of multiple AHRs in vertebrates coincided with the acquisition of high-affinity binding of halogenated and polynuclear aromatic hydrocarbons and the emergence of adaptive functions involving regulation of xenobiotic-metabolizing enzymes and roles in adaptive immunity. The existence of multiple AHRs may have facilitated subfunction partitioning and specialization of specific AHR types in some taxa. Additional research in diverse model and non-model species will continue to enrich our understanding of AHR and its pleiotropic roles in biology and toxicology.


2016 Consensus statement on return to sport from the First World Congress in Sports Physical Therapy, Bern.
Deciding when to return to sport after injury is complex and multifactorial-an exercise in risk management. Return to sport decisions are made every day by clinicians, athletes and coaches, ideally in a collaborative way. The purpose of this consensus statement was to present and synthesise current evidence to make recommendations for return to sport decision-making, clinical practice and future research directions related to returning athletes to sport. A half day meeting was held in Bern, Switzerland, after the First World Congress in Sports Physical Therapy. 17 expert clinicians participated. 4 main sections were initially agreed upon, then participants elected to join 1 of the 4 groups-each group focused on 1 section of the consensus statement. Participants in each group discussed and summarised the key issues for their section before the 17-member group met again for discussion to reach consensus on the content of the 4 sections. Return to sport is not a decision taken in isolation at the end of the recovery and rehabilitation process. Instead, return to sport should be viewed as a continuum, paralleled with recovery and rehabilitation. Biopsychosocial models may help the clinician make sense of individual factors that may influence the athlete's return to sport, and the Strategic Assessment of Risk and Risk Tolerance framework may help decision-makers synthesise information to make an optimal return to sport decision. Research evidence to support return to sport decisions in clinical practice is scarce. Future research should focus on a standardised approach to defining, measuring and reporting return to sport outcomes, and identifying valuable prognostic factors for returning to sport.


Akt-mediated phosphorylation of CDK2 regulates its dual role in cell cycle progression and apoptosis.
Here, we show that CDK2, an S-phase cyclin-dependent kinase, is a novel target for Akt during cell cycle progression and apoptosis. Akt phosphorylates CDK2 at threonine 39 residue both in vitro and in vivo. Although CDK2 threonine 39 phosphorylation mediated by Akt enhances cyclin-A binding, it is dispensable for its basal binding and the kinase activity. In addition, for the first time, we report a transient nucleo-cytoplasmic shuttling of Akt during specific stages of the cell cycle, in particular during the late S and G2 phases. The Akt that is re-localized to the nucleus phosphorylates CDK2 and causes the temporary cytoplasmic localization of the CDK2-cyclin-A complex. The CDK2 cytoplasmic redistribution is required for cell progression from S to G2-M phase, because the CDK2 T39A mutant, which lacks the phosphorylation site and is defective in cytoplasmic localization, severely affects cell cycle progression at the transition from S to G2-M. Interestingly, we also show that the Akt/CDK2 pathway is constitutively activated by some anticancer drugs, such as methotrexate and docetaxel, and under these conditions it promotes, rather than represses, cell death. Thus, the constitutive activation of the Akt/CDK2 pathway and changed subcellular localization promotes apoptosis. By contrast, the transient, physiological Akt/CDK2 activation is necessary for cell cycle progression.


Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies.
Monitoring of minimal residual disease (MRD) has become routine clinical practice in frontline treatment of virtually all childhood acute lymphoblastic leukemia (ALL) and in many adult ALL patients. MRD diagnostics has proven to be the strongest prognostic factor, allowing for risk group assignment into different treatment arms, ranging from significant treatment reduction to mild or strong intensification. Also in relapsed ALL patients and patients undergoing stem cell transplantation, MRD diagnostics is guiding treatment decisions. This is also why the efficacy of innovative drugs, such as antibodies and small molecules, are currently being evaluated with MRD diagnostics within clinical trials. In fact, MRD measurements might well be used as a surrogate end point, thereby significantly shortening the follow-up. The MRD techniques need to be sensitive (≤10(-4)), broadly applicable, accurate, reliable, fast, and affordable. Thus far, flow cytometry and polymerase chain reaction (PCR) analysis of rearranged immunoglobulin and T-cell receptor genes (allele-specific oligonucleotide [ASO]-PCR) are claimed to meet these criteria, but classical flow cytometry does not reach a solid 10(-4), whereas classical ASO-PCR is time-consuming and labor intensive. Therefore, 2 high-throughput technologies are being explored, ie, high-throughput sequencing and next-generation (multidimensional) flow cytometry, both evaluating millions of sequences or cells, respectively. Each of them has specific advantages and disadvantages.


Dramatic Reduction in 30-Day Readmissions Through High-Risk Screening and Two-Phase Interdisciplinary Care.
Thirty-day readmissions are common, serious, and costly. Most important, often they are preventable. The purpose of this quality improvement study was to evaluate an interdisciplinary, two-phase intervention to reduce 30-day readmissions among high-risk medical patients. One or two high-risk patients were selected each weekday by a hospitalist using literature-based, locally tested criteria that included common medical illnesses, active psychiatric illness, and recent or recurrent hospital admissions. Patients admitted to 1 of 5 medical hospitalist teams were selected to receive the intervention; patients admitted to the 4 remaining teams were used for comparison. The two-phase care coordination intervention consisted of a daily interdisciplinary team meeting for the selected high-risk patients and postdischarge interventions that included outpatient care coordination until the patients' first follow-up appointment. The care plan addressed medical/geriatric assessment, social stability, medication reconciliation, nutritional needs, care coordination including future appointments/testing, and community services. Eighty-five patients in the intervention group were compared with 84 patients from the comparison group using propensity score matching. Patient characteristics were similar at baseline. The intervention group demonstrated a reduction in 30-day readmissions by 52% (11 vs 23, P = 0.019). Length of stay was reduced: 5.5 days compared with 7.2 days (P = 0.258). This intervention produced a significant reduction in 30-day readmissions for high-risk patients and a trend for shorter lengths of stay compared with similarly matched patients. Future research trials are needed to verify these results.


Theory of passive permeability through lipid bilayers.
Recently measured water permeability through bilayers of different lipids is most strongly correlated with the area per lipid A rather than with other structural quantities such as the thickness. This paper presents a simple three-layer theory that incorporates the area dependence in a physically realistic way and also includes the thickness as a secondary modulating parameter. The theory also includes the well-known strong correlation of permeability upon the partition coefficients of general solutes in hydrocarbon environments (Overton's rule). Two mathematical treatments of the theory are given; one model uses discrete chemical kinetics and one model uses the Nernst-Planck continuum equation. The theory is fit to the recent experiments on water permeability in the accompanying paper.


PERINEAL REPAIR AFTER ABDOMINOPERINEAL EXCISION WITH RECTUS ABDOMINIS MYOCUTANEOUS FLAP.
Myocutaneous flap of the rectus abdominis filling the perineal defect after APR.. Abdominoperineal excision of the rectum (APR) remains the only potential curative treatment for very low rectal adenocarcinoma and squamous cell carcinoma of the anus. Yet, it implies a significant perineal exenteration and has set the attention on the perineal reconstruction. To present technique used in one case of APR for anal cancer, with resection of the vaginal posterior wall with large perineal defect which has called for the necessity of a flap for reconstruction. To cover the large perineal defect and reconstruct the posterior vaginal wall was perform a standardized and reproducible surgical technique using oblique rectus abdominis myocutaneous (ORAM) flap. The overlying skin of this flap is thick and well vascularized by both superficial branches and perforators of the superior epigastric artery and the deep inferior epigastric artery which serves as the vascular pedicle for the ORAM flap. This procedure was applied in a 65-year-old woman with recurrent squamous cell carcinoma of the anus infiltrating the posterior wall of the vagina. Was performed an APR with en-bloc resection of the vaginal posterior wall in order to achieve tumor-free margins. Postoperative course was uneventful and she was discharged home at postoperative day 9. Final pathological report confirmed the oncological adequacy of the procedure (R0) and showed a rypT4N0 lesion. Flap reconstruction is an effective way to cover the perineal wound reducing both perineal complication rate and wound healing delay. The ORAM is particularly interesting for female whose tumors require resection and subsequent reconstruction of the posterior wall of the vagina.


An intramolecular disulfide bridge as a catalytic switch for serotonin N-acetyltransferase.
Serotonin N-acetyltransferase (EC. 126.96.36.199) (AA-NAT) is a melatonin rhythm-generating enzyme in pineal glands. To establish a melatonin rhythm, AA-NAT activity is precisely regulated through several signaling pathways. Here we show novel regulation of AA-NAT activity, in which an intramolecular disulfide bond may function as a switch for the catalysis. Recombinant AA-NAT activity was irreversibly inhibited by N-ethylmaleimide (NEM) in an acetyl-CoA-protected manner. Oxidized glutathione or dissolved oxygen reversibly inhibited AA-NAT in an acetyl-CoA-protected manner. To identify the cysteine residues responsible for the inhibition, AA-NAT was first oxidized with dissolved oxygen, treated with NEM, reduced with dithiothreitol, and then labeled with [(14)C]NEM. Cys(61) and Cys(177) were specifically labeled in an acetyl-CoA-protected manner. The AA-NAT with the Cys(61) to Ala and Cys(177) to Ala double substitutions (C61A/C177A-AA-NAT) was fully active but did not exhibit sensitivity to either oxidation or NEM, whereas the AA-NATs with only the single substitutions retained about 40% of these sensitivities. An intramolecular disulfide bond between Cys(61) and Cys(177) formed upon oxidation and cleaved upon reduction was identified. Furthermore, C61A/C177A-AA-NAT expressed in COS7 cells was relatively insensitive to H(2)O(2)-evoked oxidative stress, whereas wild-type AA-NAT was strongly inhibited under the same conditions. These results indicate that the formation and cleavage of the disulfide bond between Cys(61) and Cys(177) produce the active and inactive states of AA-NAT. It is possible that intracellular redox conditions regulate AA-NAT activity through switching via an intramolecular disulfide bridge.


Explanations and information-giving: clinician strategies used in talking to parents of preterm infants.
The study is part of a larger research programme on neonatal brain imaging in the trial element of which parents were randomised to receive prognostic information based upon either magnetic resonance imaging (MRI) or ultrasound findings (ePrime study). The aim of this study was to investigate the strategies used by clinicians in communicating with parents following imaging at term age of the brain of preterm infants born before 33 weeks gestation, focusing on explanations and information-giving about prognosis Audio recordings of discussions between parents and clinicians were made following MRI and ultrasound assessment. Parents were given the scan result and the baby's predicted prognosis. A framework was developed based on preliminary analysis of the recordings and findings of other studies of information-giving in healthcare. Communication of scan results by the clinicians was further explored in qualitative analysis with 36 recordings using NVivo 10 and the specifically developed framework. Emerging themes and associated sub-themes were identified. The ways in which clinicians gave information and helped parents to understand were identified. Within the over-arching theme of clinician strategies a wide range of approaches were used to facilitate parental understanding. These included orienting, checking on previously acquired information, using analogies, explaining terminology, pacing the information, confirming understanding, inviting clarification, answering parents' questions and recapping at intervals. Ultimately four key themes were identified: 'Framing the information-giving', 'What we are looking at', 'Presenting the numbers and explaining the risk' and 'Appreciating the position of parents'. The interviews represent a multifaceted situation in which there is a tension between the need to explain and inform and the inherent complexity of neurological development, potential problems following preterm birth and the technology used to investigate and monitor these.


Determinants of haemoglobin level in steady-state homozygous sickle cell disease.
High total haemoglobin levels in homozygous sickle cell (SS) disease are a risk factor for painful crises, avascular necrosis of the femoral head, proliferative sickle retinopathy, and the acute chest syndrome. Since lowering the haemoglobin level may ameliorate these features, understanding the determinants of total haemoglobin may be of practical importance. A range of possible determinants including red cell characteristics, reticulocytes, serum iron, transferrin saturation, serum ferritin, alpha thalassaemia status, red cell mass and plasma volume, oxygen affinity, red cell survival, transferrin receptor and erythropoietin levels have been measured in 62 patients selected to provide a range of total haemoglobin and fetal haemoglobin levels. There were weak negative associations of haemoglobin with mean cell volume and mean cell haemoglobin concentration, strong negative associations with proportional reticulocyte counts, oxygen affinity, plasma volume, serum transferrin receptors, and erythropoietin levels and strong positive associations with red cell mass. Weighted analysis suggested that the statistically independent determinants of haemoglobin level were alpha thalassaemia, sex, red cell mass/body weight, plasma volume/body weight, fetal haemoglobin, and red cell count. The apparent contributions of red cell survival, P50, reticulocyte count, serum transferrin receptor and erythropoietin levels were explained by the effects of these other variables. The independent determinants as a group explained 91% of the variation in haemoglobin level.


Tea in chemoprevention of cancer.
This review summarizes available information on epidemiological and experimental data showing an association of tea consumption with cancer prevention. Studies showing cancer risk associated with tea consumption are also summarized. Tea is grown in about 30 countries and, next to water, is the most widely consumed beverage in the world. Experimental studies demonstrating the chemopreventive effects of tea have been conducted principally with green tea; limited studies have also assessed the usefulness of black tea. Majority of these studies have been carried out in skin tumor model system where consumption through drinking water of water extracts of tea or a polyphenolic fraction isolated from tea has been shown to afford protection against chemical carcinogen- or ultraviolet radiation-induced skin tumorigenesis. Tea consumption has also been shown to afford protection against chemical carcinogen-induced lung, forestomach, esophagus, duodenum, pancreas, liver, breast and colon carcinogenesis in specific bioassay models. Evidence has also accumulated showing that tea polyphenols prevent tumor promoter- and ultraviolet B-induced inflammatory responses in murine skin. The species and strains of animals, dose, route, frequency and duration of carcinogen administration, as well as types, route of administration and duration of tea or its polyphenolic component(s) treatment are described in detail. A brief description regarding mechanism(s) responsible for the broad chemopreventive effects of tea is provided. Epidemiologic studies, though inconclusive, in general suggest a possible preventive effect of tea consumption on human cancer. On the basis of available information, epidemiologic and experimental studies are ongoing to draw the possible relationship between tea consumption and cancer causation and prevention. Appropriate strategies for future clinical chemoprevention trials to translate animal data to human cancer risk are warranted.