Reaction of phenol with singlet oxygen.
Photo-degradation of organic pollutants plays an important role in their removal from the environment. This study provides an experimental and theoretical account of the reaction of singlet oxygen O2(1Δg) with the biodegradable-resistant species of phenol in an aqueous medium. The experiments combine customised LED-photoreactors, high-performance liquid chromatography (HPLC), and electron paramagnetic resonance (EPR) imaging, employing rose bengal as a sensitiser. Guided by density functional theory (DFT) calculations at the M062X level, we report the mechanism of the reaction and its kinetic model. Addition of O2(1Δg) to the phenol molecule branches into two competitive 1,4-cycloaddition and ortho ene-type routes, yielding 2,3-dioxabicyclo[2.2.2]octa-5,7-dien-1-ol (i.e., 1,4-endoperoxide 1-hydroxy-2,5-cyclohexadiene) and 2-hydroperoxycyclohexa-3,5-dien-1-one, respectively. Unimolecular rearrangements of the 1,4-endoperoxide proceed in a facile exothermic reaction to form the only experimentally detected product, para-benzoquinone. EPR revealed the nature of the oxidation intermediates and corroborated the appearance of O2(1Δg) as the only active radical participating in the photosensitised reaction. Additional experiments excluded the formation of hydroxyl (HO˙), hydroperoxyl (HO2˙), and phenoxy intermediates. We detected for the first time the para-semibenzoquinone anion (PSBQ), supporting the reaction pathway leading to the formation of para-benzoquinone. Our experiments and the water-solvation model result in the overall reaction rates of kr-solvation = 1.21 × 104 M-1 s-1 and kr = 1.14 × 104 M-1 s-1, respectively. These results have practical application to quantify the degradation of phenol in wastewater treatment.


School Start Times for Middle School and High School Students - United States, 2011-12 School Year.
Adolescents who do not get enough sleep are more likely to be overweight; not engage in daily physical activity; suffer from depressive symptoms; engage in unhealthy risk behaviors such as drinking, smoking tobacco, and using illicit drugs; and perform poorly in school. However, insufficient sleep is common among high school students, with less than one third of U.S. high school students sleeping at least 8 hours on school nights. In a policy statement published in 2014, the American Academy of Pediatrics (AAP) urged middle and high schools to modify start times as a means to enable students to get adequate sleep and improve their health, safety, academic performance, and quality of life. AAP recommended that "middle and high schools should aim for a starting time of no earlier than 8:30 a.m.". To assess state-specific distributions of public middle and high school start times and establish a pre-recommendation baseline, CDC and the U.S. Department of Education analyzed data from the 2011-12 Schools and Staffing Survey (SASS). Among an estimated 39,700 public middle, high, and combined schools* in the United States, the average start time was 8:03 a.m. Overall, only 17.7% of these public schools started school at 8:30 a.m. or later. The percentage of schools with 8:30 a.m. or later start times varied greatly by state, ranging from 0% in Hawaii, Mississippi, and Wyoming to more than three quarters of schools in Alaska (76.8%) and North Dakota (78.5%). A school system start time policy of 8:30 a.m. or later provides teenage students the opportunity to achieve the 8.5-9.5 hours of sleep recommended by AAP and the 8-10 hours recommended by the National Sleep Foundation.


The effects of joint aspiration and intra-articular corticosteroid injection on flexion reflex excitability, quadriceps strength and pain in individuals with knee synovitis: a prospective observational study.
Substantial weakness of the quadriceps muscles is typically observed in patients with arthritis. This is partly due to ongoing neural inhibition that prevents the quadriceps from being fully activated. Evidence from animal studies suggests enhanced flexion reflex excitability may contribute to this weakness. This prospective observational study examined the effects of joint aspiration and intra-articular corticosteroid injection on flexion reflex excitability, quadriceps muscle strength and knee pain in individuals with knee synovitis. Sixteen patients with chronic arthritis and clinically active synovitis of the knee participated in this study. Knee pain flexion reflex threshold, and quadriceps peak torque were measured at baseline, immediately after knee joint aspiration alone and 5 ± 2 and 15 ± 2 days after knee joint aspiration and the injection of 40 mg of methylprednisolone acetate. Compared to baseline, knee pain was significantly reduced 5 (p = 0.001) and 15 days (p = 0.009) post intervention. Flexion reflex threshold increased immediately after joint aspiration (p = 0.009) and 5 (p = 0.01) and 15 days (p = 0.002) post intervention. Quadriceps peak torque increased immediately after joint aspiration (p = 0.004) and 5 (p = 0.001) and 15 days (p <0.001) post intervention. The findings from this study suggest that altered sensory output from an inflamed joint may increase flexion reflex excitability in humans, as has previously been shown in animals. Joint aspiration and corticosteroid injection may be a clinically useful intervention to reverse quadriceps muscle weakness in individuals with knee synovitis.


Microscale fish bowls: a new class of latex particles with hollow interiors and engineered porous structures in their surfaces.
Microscale fish bowls, hollow particles with engineered holes in their surfaces, were prepared using two different methods. In the first method, commercial latex beads suspended in water were swollen with a good solvent of the polymer, followed by freezing with liquid nitrogen and evaporation of the solvent below 0 degrees C. While one big hole was generated when the amount of solvent used for the swelling was relatively low, small holes could be produced in the outer surface of each bowl by increasing the degree of swelling. The porosity and pore structure show a similar dependence on the degree of swelling for both amorphous and semicrystalline polymers even though they are supposed to exhibit different phase behaviors during the freezing and solvent evaporation processes. In the second method, a polymer emulsion in water was prepared and then frozen with liquid nitrogen, followed by solvent evaporation below 0 degrees C. The porosity and pore structure could be controlled by adjusting the concentration of the polymer solution used to prepare the emulsion. As for encapsulation, the bowl-shaped particles could be transformed back into solid beads via thermal annealing at a temperature near the glass transition temperature of the polymer or by adding a good solvent of the polymer to the colloidal suspension. In a proof-of-concept experiment, microscale fish bowls were fabricated from poly(caprolactone), quickly loaded with a fluorescent dye, and sealed through thermal annealing. The encapsulated dye could then be slowly released in a phosphate buffered saline, suggesting their potential use as a new class of microscale capsules for drug delivery.


Evolutionary persistence of phenotypic integration: influence of developmental and functional relationships on complex trait evolution.
Examination of historical persistence of integration patterns provides an important insight into understanding the origin and evolution of complex traits. Specifically, the distinct effects of developmental and functional integration on the evolution of complex traits are often overlooked. Because patterns of functional integration are commonly shaped by selection exerted by the external environment, whereas patterns of developmental integration can be determined by relatively environment-independent selection for developmental homeostasis, examination of historical persistence of morphological integration patterns among species should reveal the relative importance of current selection in the evolution of complex traits. We compared historical persistence of integration patterns produced by current developmental versus ecological requirements by examining the evolution of complex mandibular structures in nine species of soricid shrews. We found that, irrespective of phylogenetic relatedness of species, patterns of developmental and functional integration were highly concordant, suggesting that strong selection for developmental homeostasis favors concordant channeling of both internal and external variation. Overall, our results suggest that divergence in mandible shape among species closely follows variation in functional demands and ecological requirements regardless of phylogenetic relatedness among species.


Transcriptome analysis of highly purified mouse spermatogenic cell populations: gene expression signatures switch from meiotic-to postmeiotic-related processes at pachytene stage.
Spermatogenesis is a complex differentiation process that involves the successive and simultaneous execution of three different gene expression programs: mitotic proliferation of spermatogonia, meiosis, and spermiogenesis. Testicular cell heterogeneity has hindered its molecular analyses. Moreover, the characterization of short, poorly represented cell stages such as initial meiotic prophase ones (leptotene and zygotene) has remained elusive, despite their crucial importance for understanding the fundamentals of meiosis. We have developed a flow cytometry-based approach for obtaining highly pure stage-specific spermatogenic cell populations, including early meiotic prophase. Here we combined this methodology with next generation sequencing, which enabled the analysis of meiotic and postmeiotic gene expression signatures in mouse with unprecedented reliability. Interestingly, we found that a considerable number of genes involved in early as well as late meiotic processes are already on at early meiotic prophase, with a high proportion of them being expressed only for the short time lapse of lepto-zygotene stages. Besides, we observed a massive change in gene expression patterns during medium meiotic prophase (pachytene) when mostly genes related to spermiogenesis and sperm function are already turned on. This indicates that the transcriptional switch from meiosis to post-meiosis takes place very early, during meiotic prophase, thus disclosing a higher incidence of post-transcriptional regulation in spermatogenesis than previously reported. Moreover, we found that a good proportion of the differential gene expression in spermiogenesis corresponds to up-regulation of genes whose expression starts earlier, at pachytene stage; this includes transition protein-and protamine-coding genes, which have long been claimed to switch on during spermiogenesis. In addition, our results afford new insights concerning X chromosome meiotic inactivation and reactivation. This work provides for the first time an overview of the time course for the massive onset and turning off of the meiotic and spermiogenic genetic programs. Importantly, our data represent a highly reliable information set about gene expression in pure testicular cell populations including early meiotic prophase, for further data mining towards the elucidation of the molecular bases of male reproduction in mammals.


Brucella effectors NyxA and NyxB target SENP3 to modulate the subcellular localisation of nucleolar proteins.
The cell nucleus is a primary target for intracellular bacterial pathogens to counteract immune responses and hijack host signalling pathways to cause disease. Here we identify two Brucella abortus effectors, NyxA and NyxB, that interfere with host protease SENP3, and this facilitates intracellular replication of the pathogen. The translocated Nyx effectors directly interact with SENP3 via a defined acidic patch (identified from the crystal structure of NyxB), preventing nucleolar localisation of SENP3 at late stages of infection. By sequestering SENP3, the effectors promote cytoplasmic accumulation of nucleolar AAA-ATPase NVL and ribosomal protein L5 (RPL5) in effector-enriched structures in the vicinity of replicating bacteria. The shuttling of ribosomal biogenesis-associated nucleolar proteins is inhibited by SENP3 and requires the autophagy-initiation protein Beclin1 and the SUMO-E3 ligase PIAS3. Our results highlight a nucleomodulatory function of two Brucella effectors and reveal that SENP3 is a crucial regulator of the subcellular localisation of nucleolar proteins during Brucella infection, promoting intracellular replication of the pathogen.


Conserved 33-kb haplotype in the MHC class III region regulates chronic arthritis.
Genome-wide association studies have revealed many genetic loci associated with complex autoimmune diseases. In rheumatoid arthritis (RA), the MHC gene HLA-DRB1 is the strongest candidate predicting disease development. It has been suggested that other immune-regulating genes in the MHC contribute to the disease risk, but this contribution has been difficult to show because of the strong linkage disequilibrium within the MHC. We isolated genomic regions in the form of congenic fragments in rats to test whether there are additional susceptibility loci in the MHC. By both congenic mapping in inbred strains and SNP typing in wild rats, we identified a conserved, 33-kb large haplotype Ltab-Ncr3 in the MHC-III region, which regulates the onset, severity, and chronicity of arthritis. The Ltab-Ncr3 haplotype consists of five polymorphic immunoregulatory genes: Lta (lymphotoxin-α), Tnf, Ltb (lymphotoxin-β), Lst1 (leukocyte-specific transcript 1), and Ncr3 (natural cytotoxicity-triggering receptor 3). Significant correlation in the expression of the Ltab-Ncr3 genes suggests that interaction of these genes may be important in keeping these genes clustered together as a conserved haplotype. We studied the arthritis association and the spliceo-transcriptome of four different Ltab-Ncr3 haplotypes and showed that higher Ltb and Ncr3 expression, lower Lst1 expression, and the expression of a shorter splice variant of Lst1 correlate with reduced arthritis severity in rats. Interestingly, patients with mild RA also showed higher NCR3 expression and lower LST1 expression than patients with severe RA. These data demonstrate the importance of a conserved haplotype in the regulation of complex diseases such as arthritis.


Comparing genetic ancestry and self-described race in african americans born in the United States and in Africa.
Genetic association studies can be used to identify factors that may contribute to disparities in disease evident across different racial and ethnic populations. However, such studies may not account for potential confounding if study populations are genetically heterogeneous. Racial and ethnic classifications have been used as proxies for genetic relatedness. We investigated genetic admixture and developed a questionnaire to explore variables used in constructing racial identity in two cohorts: 50 African Americans and 40 Nigerians. Genetic ancestry was determined by genotyping 107 ancestry informative markers. Ancestry estimates calculated with maximum likelihood estimation were compared with population stratification detected with principal components analysis. Ancestry was approximately 95% west African, 4% European, and 1% Native American in the Nigerian cohort and 83% west African, 15% European, and 2% Native American in the African American cohort. Therefore, self-identification as African American agreed well with inferred west African ancestry. However, the cohorts differed significantly in mean percentage west African and European ancestries (P < 0.0001) and in the variance for individual ancestry (P < or = 0.01). Among African Americans, no set of questionnaire items effectively estimated degree of west African ancestry, and self-report of a high degree of African ancestry in a three-generation family tree did not accurately predict degree of African ancestry. Our findings suggest that self-reported race and ancestry can predict ancestral clusters but do not reveal the extent of admixture. Genetic classifications of ancestry may provide a more objective and accurate method of defining homogenous populations for the investigation of specific population-disease associations.


Sub-1.5-cycle pulses from a single filament.
The temporal dynamics of ultrashort laser pulses undergoing filamentary propagation are investigated with a real-time stereographic above-threshold ionization (ATI) phasemeter. The experimental setup is capable of measuring the pulse duration as well as the carrier-envelope phase distribution of pulses originating from a femtosecond filament, which is either truncated in length or fully propagated. Truncation, by means of a semi-infinite gas cell, allows to elucidate the nonlinear evolution and temporal dynamics of ultrashort laser pulses as a function of the propagation length. We observe the formation of few-cycle pulses as well as temporal pulse splitting dynamics during the propagation of the pulse inside the filament. For the first time, we demonstrate the compression of 35 fs pulses down to a duration of sub-4 fs in a single femtosecond filament. This corresponds to sub-1.5 cycles of the electric field.


Clade diversification dynamics and the biotic and abiotic controls of speciation and extinction rates.
How ecological interactions, genetic processes, and environmental variability jointly shape the evolution of species diversity remains a challenging problem in biology. We developed an individual-based model of clade diversification to predict macroevolutionary dynamics when resource competition, genetic differentiation, and landscape fluctuations interact. Diversification begins with a phase of geographic adaptive radiation. Extinction rates rise sharply at the onset of the next phase. In this phase of niche self-structuring, speciation and extinction processes, albeit driven by biotic mechanisms (competition and hybridization), have essentially constant rates, determined primarily by the abiotic pace of landscape dynamics. The final phase of diversification begins when intense competition prevents dispersing individuals from establishing new populations. Species' ranges shrink, causing negative diversity-dependence of speciation rates. These results show how ecological and microevolutionary processes shape macroevolutionary dynamics and rates; they caution against the notion of ecological limits to diversity, and suggest new directions for the phylogenetic analysis of diversification.


Significance of 19-norandrosterone in athletes' urine samples.
Nandrolone and other 19-norsteroid potent anabolic steroids have been prohibited in sports for 30 years. The detection of the main urinary metabolite--19-norandrosterone--in amounts greater than 2 ng/ml constitutes an adverse analytical finding. The presence in nutritional sport supplements of steroids not listed on the label has undoubtedly resulted in positive tests, but inadvertent consumption of meat containing residues of hormonal treatment should not realistically cause apprehension. Although highly improbable, athletes should prudently avoid meals composed of pig offal in the hours preceding the test since the consumption of edible parts of a non-castrated pig, containing 19-nortestosterone, has been shown to results in the excretion of 19-norandrosterone in the following hours. Norsteroid metabolites are formed during pregnancy and excreted as minor metabolites of norethisterone, and minute amounts have been identified in some male and female samples when using more sensitive techniques of detection. Whereas exercise does not seem to be a significant factor in 19-norandrosterone excretion, some rare urine samples were found to be a suitable medium for in situ 19-demethylation of urinary metabolites.


Adult attention-deficit/hyperactivity disorder in major depressed and bipolar subjects: role of personality traits and clinical implications.
A significant comorbidity between attention-deficit/hyperactivity disorder (ADHD) and affective disorders has been consistently reported in adults. Less data regarding the role of personality traits and the influence of ADHD co-occurrence on clinical characteristics and outcome of mood disorders are currently available. One hundred and six remitted major depressed, 102 euthymic bipolar subjects, and 120 healthy controls, homogeneous with respect to demographic characteristics, were included in the study. ADHD diagnosis was based on DSM-IV-TR criteria. Childhood and adult ADHD features were measured with the Wender Utah Rating Scale, the Adult ADHD Self-rating Scale, and the Brown Attention-Deficit Disorder Scale. The Revised NEO Personality Inventory was also administered to the clinical groups, in order to investigate personality dimensions. The occurrence of adult ADHD in subjects with bipolar disorders (BD) or major depressive disorder (MDD) was 15.7 and 7.5 %, respectively, compared to 3.3 % in healthy controls (HC). Significant associations (p < .001) between personality traits (neuroticism, conscientiousness, and extraversion) and ADHD features were observed. Logistic regression analysis of all clinical subjects (n = 208) showed that those with lower levels of neuroticism (OR = 1.031; p = .025) had a lower frequency of ADHD comorbidity. The present study emphasizes the close relationship between affective disorders, especially BD, and ADHD in adults. Our findings support the need to assess subjects with mood disorders in the clinical setting for possible coexisting ADHD and to further investigate personality traits to better understand the etiology of affective disorders and ADHD co-occurrence.


Magnetization and magnetoresistance of common alloy wires used in cryogenic instrumentation.
We present magnetization and magnetoresistance data at liquid-helium and liquid-nitrogen temperatures for wire materials commonly used for instrumentation wiring of specimens, sensors, and heaters in cryogenic probes. The magnetic susceptibilities in Systeme International units at 4.2 K were found to be: Manganin 1.25x10(-2), Nichrome 5.6x10(-3), and phosphor bronze -3.3x10(-5), indicating that phosphor bronze is the most suitable for high-field applications. We also show the ferromagnetic hysteresis loop of Constantan wire at liquid-helium temperature. The magnetoresistance of these four wires was relatively small: the changes in resistance at 4 K due to a 10 T transverse magnetic field are -2.56% for Constantan, -2.83% for Manganin, +0.69% for Nichrome, and +4.5% for phosphor bronze, compared to about +188% for a typical copper wire under the same conditions.


The helical periodicity of DNA on the nucleosome.
The precise number of base pairs per turn of the DNA double helix in the nucleosome core particle has been the subject of controversy. In this paper the positions of nuclease cutting sites are analysed in three dimensions. Using this midpoint of the DNA on the nucleosome dyad as origin, the cutting site locations measured along a strand of DNA are mapped onto models of the nucleosome core containing DNA of different helical periodicities. It is found that a helical periodicity of 10.5 base pairs per turn leads to cutting site positions which are sterically inaccessible. In contrast, a periodicity of 10.0 base pairs per turn leads to cutting site positions which are not only sterically sound, but which fall into a pattern such as would be expected when the access of the nuclease to the DNA is restricted by the presence of the histone core on one side and of the adjacent superhelical turn of DNA on the other. As proposed earlier by us (1), a value for the helical periodicity close to 10 base pairs per turn on the nucleosome, taken together with a periodicity close to 10.5 for DNA in solution - a value now established - resolves the so-called linkage number paradox.


Molecular simulations of imidazolium-based tricyanomethanide ionic liquids using an optimized classical force field.
Imidazolium-based ionic liquids (ILs) incorporating the tricyanomethanide ([TCM(-)]) anion are studied using an optimized classical force field. These ILs are very promising candidates for use in a wide range of cutting-edge technologies and, to our knowledge, it is the first time that this IL family is subject to a molecular simulation study with the use of a classical atomistic force field. The [C4mim(+)][TCM(-)] ionic liquid at 298.15 K and at atmospheric pressure was used as the basis for force field optimization which primarily involved the determination of the Lennard-Jones parameters of [TCM(-)] and the implementation of three quantum mechanical schemes for the calculation of the partial charge distribution and the identification of the appropriate scaling factor for the reduction of the total ionic charge. The optimized force field was validated by performing simulations of the 1-alkyl-3-methylimidazolium tricyanomethanide ([Cnmim(+)][TCM(-)], n = 2, 4, 6, and 8) IL family at various temperatures. The results for density, self-diffusivity and viscosity are in very good agreement with the available experimental data for all ILs verifying that the force field reliably reproduces the behaviour of the imidazolium-based [TCM(-)] IL family in a wide temperature range. Furthermore, a detailed analysis of the microscopic structure and the complex dynamic behaviour of the ILs under study was performed.


Expectations of food satiation and satiety reviewed with special focus on food properties.
Expectations of satiation are beliefs about the extent to which food is expected to deliver fullness and expectation of satiety relates to the extent to which food is expected to give respite from hunger and to inhibit further eating. In recent years they have increasingly been investigated because of the interest in how they can modulate energy intake. The present paper reviews the body of research into concepts underlying these expectations, measurement methods and the factors influencing their perception, with special focus on the sensory features and composition of foods. Food science and technology can provide tools and knowledge to aid in designing food with enhanced expectations of satiation and satiety.


Angiokeratoma corporis diffusum with glycopeptiduria due to deficient lysosomal alpha-N-acetylgalactosaminidase activity. Clinical, morphologic, and biochemical studies.
Angiokeratoma corporis diffusum is a prominent cutaneous feature of certain lysosomal storage diseases. In this article, the clinical, morphologic, and biochemical features of a new, adult-onset lysosomal disease with angiokeratoma are described. A 46-year-old Japanese woman had diffuse angiokeratoma, mild intellectual impairment, and peripheral neuroaxonal degeneration. The angiokeratoma first appeared on her lower torso when she was 28 years old, and then it became diffusely distributed. Histopathologically, the telangiectasia had localized hyperkeratosis; ultrastructural examination revealed clear cytoplasmic vacuoles in all dermal cells, particularly in vascular and lymphatic endothelial cells and in eccrine sweat gland cells. The lysosomal pathologic features and increased urinary excretion of O-linked glycopeptides suggested the deficiency of a specific glycosidase. Enzyme analyses revealed less than 2% of normal alpha-N-acetylgalactosaminidase activity and the absence of immunodetectable enzyme protein. Her two unaffected children had half-normal alpha-N-acetylgalactosaminidase levels, consistent with the autosomal recessive inheritance of the enzymatic defect. Since this enzyme deficiency was previously identified in patients with an infantile form of inherited neuroaxonal dystrophy, the occurrence of the enzymopathy in the 46-year-old proband described herein represents an adult-onset form of alpha-N-acetylgalactosaminidase deficiency. This newly recognized entity should be considered in the differential diagnosis of angiokeratoma corporis diffusum.


SU-E-T-263: Luminescent Dosimetry to Measure the Out-Of-Field Low and High LET Dose Components in High Energy Photon and Proton Therapy Beams.
Luminescent dosimetry using thermoluminescent detectors (TLDs) and optically stimulated luminescent detectors (OSLDs) were used in mixed radiation fields containing both low LET (photons and protons) and high LET (neutrons)components to obtain their out-of-field absorbed dose, dose equivalent and quality factor. LiF Thermoluminescent Detectors (TLDs) 600 and 700 chips with dimensions 0.31×0.31×0.038 cm3 were used in a 25.4 cm diameter Bonner sphere centered 42 cm from the isocenter of a 15×x15 cm2 field to measure the secondary doses for 10, 15 and 18 MV photons and a 200 MeV proton therapy beam. From the sensitivity difference to LET radiation between the210 and 280 C peaks in the glow curve, the areas under the peaks were used to obtain the absorbed dose, dose equivalent and QF of the secondary radiation. The OSLD detector measured the low LET dose component to compare with the TLD dose measurement. The neutron calibration of the TLDs was obtained from an Am-Be source at the Argonne National Laboratory. The photon and proton TLD and OSLD calibrations were obtained in 6 MV and 200 MeV beams, respectively. From the two-peak analysis of the TLDs in the Bonner sphere the ratios of the neutron dose to photon dose were 0.001, 0.014 and 0.17 for 10, 15 and 18 MV, respectively. The low LET OSLD measurements agreed within 10% of the TLD results. From the dose equivalent measurements the QFs (+/-14%) obtained were 4.5, 3.9 and 4.0 for these beam energies. For the 200 MeV proton beam the ratio of neutron to proton dose was 0.28 with a measured QF of 13. Luminescent detectors in a Bonner Sphere provide measurements of the secondary photon, proton and neutron doses and provide an estimate of the neutron QF.


A pedometer-based walking intervention in 45- to 75-year-olds, with and without practice nurse support: the PACE-UP three-arm cluster RCT.
Guidelines recommend walking to increase moderate to vigorous physical activity (MVPA) for health benefits. To assess the effectiveness, cost-effectiveness and acceptability of a pedometer-based walking intervention in inactive adults, delivered postally or through dedicated practice nurse physical activity (PA) consultations. Parallel three-arm trial, cluster randomised by household. Seven London-based general practices. A total of 11,015 people without PA contraindications, aged 45-75 years, randomly selected from practices, were invited. A total of 6399 people were non-responders, and 548 people self-reporting achieving PA guidelines were excluded. A total of 1023 people from 922 households were randomised to usual care (n = 338), postal intervention (n = 339) or nurse support (n = 346). The recruitment rate was 10% (1023/10,467). A total of 956 participants (93%) provided outcome data. Intervention groups received pedometers, 12-week walking programmes advising participants to gradually add '3000 steps in 30 minutes' most days weekly and PA diaries. The nurse group was offered three dedicated PA consultations. The primary and main secondary outcomes were changes from baseline to 12 months in average daily step counts and time in MVPA (in ≥ 10-minute bouts), respectively, from 7-day accelerometry. Individual resource-use data informed the within-trial economic evaluation and the Markov model for simulating long-term cost-effectiveness. Qualitative evaluations assessed nurse and participant views. A 3-year follow-up was conducted. Baseline average daily step count was 7479 [standard deviation (SD) 2671], average minutes per week in MVPA bouts was 94 minutes (SD 102 minutes) for those randomised. PA increased significantly at 12 months in both intervention groups compared with the control group, with no difference between interventions; additional steps per day were 642 steps [95% confidence interval (CI) 329 to 955 steps] for the postal group and 677 steps (95% CI 365 to 989 steps) for nurse support, and additional MVPA in bouts (minutes per week) was 33 minutes per week (95% CI 17 to 49 minutes per week) for the postal group and 35 minutes per week (95% CI 19 to 51 minutes per week) for nurse support. Intervention groups showed no increase in adverse events. Incremental cost per step was 19p and £3.61 per minute in a ≥ 10-minute MVPA bout for nurse support, whereas the postal group took more steps and cost less than the control group. The postal group had a 50% chance of being cost-effective at a £20,000 per quality-adjusted life-year (QALY) threshold within 1 year and had both lower costs [-£11M (95% CI -£12M to -£10M) per 100,000 population] and more QALYs [759 QALYs gained (95% CI 400 to 1247 QALYs)] than the nurse support and control groups in the long term. Participants and nurses found the interventions acceptable and enjoyable. Three-year follow-up data showed persistent intervention effects (nurse support plus postal vs. control) on steps per day [648 steps (95% CI 272 to 1024 steps)] and MVPA bouts [26 minutes per week (95% CI 8 to 44 minutes per week)]. The 10% recruitment level, with lower levels in Asian and socioeconomically deprived participants, limits the generalisability of the findings. Assessors were unmasked to the group. A primary care pedometer-based walking intervention in 45- to 75-year-olds increased 12-month step counts by around one-tenth, and time in MVPA bouts by around one-third, with similar effects for the nurse support and postal groups, and persistent 3-year effects. The postal intervention provides cost-effective, long-term quality-of-life benefits. A primary care pedometer intervention delivered by post could help address the public health physical inactivity challenge. Exploring different recruitment strategies to increase uptake. Integrating the Pedometer And Consultation Evaluation-UP (PACE-UP) trial with evolving PA monitoring technologies. Current Controlled Trials ISRCTN98538934. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 37. See the NIHR Journals Library website for further project information.


Maintaining quality of life at the end of life.
Despite the successful growth of the hospice movement during the past 30 years in the United States, almost 85% of Americans continue to die in hospitals or nursing homes. While the benefits of palliative care principles are well established, palliative care interventions remain underused in clinical practice in the settings in which most Americans die. Our premise is that physicians as a group perpetuate end-of-life suffering rather than ease the transition from life to death. We also believe that maintaining quality of life (QOL) at the end of life requires a multidimensional approach orchestrated by physicians drawing on the full range of available physical, psychological, social, and spiritual interventions. This article defines the meaning of QOL at the end of life and then examines the ramifications of failing to attend to QOL concerns in dying patients. It reviews strategies that physicians can use to advance palliative care approaches, thereby reducing terminally ill patients' suffering in the institutions in which most die.


Management of Αcute Non-Variceal Upper Gastrointestinal Bleeding: Drugs, Endoscopic Hemostasis, or Both?
Acute upper gastrointestinal bleeding remains one of the most frequent and emergent conditions in everyday clinical practice and a challenge for doctors. Peptic ulcer is responsible for more than half of acute upper gastrointestinal bleeding and is the most frequent cause of serious non-variceal bleeding. Despite progress in diagnosis and management in these patients, the recurrence of bleeding remains an important problem. Several drugs and endoscopic techniques, alone or in combination, have been evaluated in many studies and there is presently enough experience in terms of their efficacy. Endoscopic hemostasis is more effective than any other therapeutic intervention in the treatment of patients with non-variceal upper gastrointestinal bleeding. In patients with high risk of rebleeding spots, the combination of endoscopic hemostasis with high dose proton pump inhibitors is the most effective strategy to reduce bleeding recurrences and the need for surgery.


Dyspnoea assessed by visual analogue scale in patients with chronic obstructive lung disease during progressive and high intensity exercise.
A study was carried out to determine whether rating of dyspnoea by means of a visual analogue scale during a progressive exercise test is affected by the subject's awareness of the progressive nature of the protocol. Nineteen patients with chronic obstructive lung disease (FEV1 mean (SE) 1.06 (0.07) 1) were studied. A preliminary incremental test was carried out with a work rate increasing by 10 watts every minute until the subject could no longer exercise, to determine the maximum work load (Wmax) and to anchor the upper end of the visual analogue scale. This was followed by two exercise tests performed one day apart in randomised sequence, with two different protocols. One was a 12 minute protocol that included two sudden bursts of three minute high intensity exercise, up to the subject's Wmax, each preceded by three minutes of low level exercise. The other test was a conventional three minute incremental test lasting 12 minutes. On both study days the only information given to the subject about the temporal profile of load was that a change would be made every three minutes. The relation between dyspnoea, as assessed by the visual analogue scale, and ventilation, measured during high intensity or progressive exercise, was studied. The mean (SE) rates of increase of dyspnoea with increasing ventilation (% of line length 1(-1) min) obtained by linear regression analysis were similar for the two tests (2.86 (0.20) for progressive exercise and 2.87 (0.25) for high intensity exercise); it was 2.59 (0.25) for the initial burst of high intensity exercise when the data on this were analysed separately. In six subjects with stable disease studied again two months later the reproducibility of the rating of dyspnoea was reasonably good for both protocols. The results suggest that in most patients with chronic obstructive lung disease the assessment of exercise induced dyspnoea by means of a visual analogue scale during a progressive exercise test is not affected by the subject's awareness of the progressive increase in work intensity.


Pulsed digital holography for high-speed contouring that uses a two-wavelength method.
A two-wavelength method for a fast shape measurement by use of a pulsed ruby laser is presented. The wavelength change is produced by alteration of the distance between the plates of the laser's output etalon. One plate of the etalon is mounted on a vibrating piezoelectric element; this allows a fast wavelength change. Two holograms at different wavelengths are recorded in a few microseconds by use of a CCD. The holograms are reconstructed digitally, and the wave-front phase is calculated. The shape is obtained by subtraction of the phases of the wave fronts recorded at different wavelengths. Environmental disturbances at low frequencies, such as air turbulence, vibrations, and object drift, have no influence on the measurement. Experimental results are presented.


Cr-Cr Quintuple Bonds: Ligand Topology and Interplay Between Metal-Metal and Metal-Ligand Bonding.
Chromium-chromium quintuple bonds seem to be approaching the lower limit for their bond distances, and this computational density functional theory study tries to explore the geometrical and electronic factors that determine that distance and to find ways to fine-tune it via the ligand choice. While for monodentate ligands the Cr-Cr distance is predicted to shorten as the Cr-Cr-L bond angle increases, with bridging bidentate ligands the trend is the opposite, since those ligands with a larger number of spacers between the donor atoms favor larger bond angles and longer bond distances. Compared to Cr-Cr quadruple bonds, the quintuple bonding in Cr2L2 compounds (with L a bridging bidentate N-donor ligand) involves a sophisticated mechanism that comprises a positive pyramidality effect for the σ and one π bond, but a negative effect for one of the δ bonds. Moreover, the shorter Cr-Cr distances produce a mismatch of the bridging ligand lone pairs and the metal acceptor orbitals, which results in a negative correlation of the Cr-Cr and Cr-N bond distances in both experimental and calculated structures.


Cigarillos Compromise the Mucosal Barrier and Protein Expression in Airway Epithelia.
Smoking remains a leading cause of preventable morbidity and mortality worldwide. Despite a downward trend in cigarette use, less-regulated tobacco products, such as cigarillos, which are often flavored to appeal to specific demographics, such as younger people, are becoming increasingly popular. Cigar/cigarillo smoking has been considered a safer alternative to cigarettes; however, the health risks associated with cigar in comparison with cigarette smoking are not well understood. To address this knowledge gap, we characterized the effects of multiple brands of cigarillos on the airway epithelium using ex vivo and in vivo models. To analyze these effects, we assessed the cellular viability and integrity of smoke-exposed primary airway cell cultures. We also investigated the protein compositions of apical secretions from cigarillo-exposed airway epithelial cultures and BAL fluid of cigarillo-exposed mice through label-free quantitative proteomics and determined the chemical composition of smoke collected from the investigated cigarillo products. We found that cigarillo smoke exerts similar or greater effects than cigarette smoke in terms of reduced cell viability; altered protein levels, including those of innate immune proteins; induced oxidative-stress markers; and greater nicotine delivery to cells. The analysis of the chemical composition of the investigated cigarillo products revealed differences that might be linked to the differential effects of these products on cell viability and protein abundance profiles, which have been associated with a range of health risks in the context of airway biology. These findings contradict the assumption that cigarillos might be safer and less harmful than cigarettes. Instead, our results indicate that cigarillo smoke is associated with equal or greater health risks and the same or increased airway toxicity compared with cigarette smoke.


Hospital certification for optimizing cardiovascular disease and stroke quality of care and outcomes.
Cardiovascular disease and stroke remain leading causes of mortality, disability, and rising healthcare expenditures in the United States. Although a number of organizations provide hospital accreditation, recognition, and certification programs, existing programs do not address cardiovascular disease and stroke care in a comprehensive way. Current evidence suggests mixed findings for correlation between accreditation, recognition, and certification programs and hospitals' actual quality of care and outcomes. This advisory discusses potential opportunities to develop and enhance hospital certification programs for cardiovascular disease and stroke. The American Heart Association/American Stroke Association is uniquely positioned as a patient-centered, respected, transparent healthcare organization to help drive improvements in care and outcomes for patients hospitalized with cardiovascular disease and stroke. As a part of its commitment to promoting high-quality, evidence-based care for cardiovascular and stroke patients, it is recommended that the American Heart Association/American Stroke Association explore hospital certification programs to develop truly meaningful programs to facilitate improvements in and recognition for cardiovascular disease and stroke quality of care and outcomes. Future strategies should standardize objective, unbiased assessments of hospital structural, process, and outcome performance while allowing flexibility as technology and methodology advances occur.


Xenopus laevis transgenesis by sperm nuclear injection.
The stable integration of transgenes into embryos of the frog Xenopus laevis is achieved using the procedure described here. Linear DNA containing the transgene is incorporated randomly into sperm nuclei that have had their membranes disrupted with detergent treatment. Microinjection of these nuclei into unfertilized eggs produces viable embryos that can be screened for activity of the transgene. The proportion of embryos that harbor the transgene varies from 10 to 40% of the total number of surviving embryos. Multiple copies of the transgene can integrate as a concatemer into the sperm genome, and more than one site of DNA integration might occur within resulting animals. Germ cell transmission of the transgene is routine and the procedure is well suited to the production of transgenic reporter frog lines. One day should be allocated for the preparation of the sperm nuclei, which are stored as aliquots for future use. The transgenesis reaction and egg injection take one morning.


The Utility of Digital Rectal Examination in Estimating Prostate Volume in a Rural Hospital Setting.
To determine the correlation between prostate volume estimated by digital rectal examination (DRE) and that estimated by abdominal ultrasound in the same patients. Men who presented to our urology outpatient clinic with lower urinary tract symptoms were recruited in this study. We estimated the prostate size by digital rectal examination using the sliding scale as a guide and subsequently measured the prostate volume by transabdominal ultrasound. A total of 100 patients completed this study. The mean age was 65.6 ± 9.84 years. The Kappa's reliability test comparing the prostate size estimated by DRE and the prostate size measured by transabdominal ultrasound was 0.579832, the Kappa's standard error was 0.097768 and Kappa's t value was 5.93. The Kappa's reliability test fell into good agreement range (0.4-0.75). This is further validated by the Pearson's correlation test ascertaining correlation between Ultrasound and DRE and generated a correlation coefficient(®) of 0.59 (P = 0.00). This implies a high positive correlation between ultrasound estimated prostate volume and that estimated by DRE that is statistically significant (P < 0.01). Estimation of prostate volume by digital rectal examination is reliable. This is very important in an environment where esoteric laboratory facilities are not readily available, and the clinician has to depend mainly on his clinical acumen.


Protective effects of selenium on fluoride induced alterations in certain enzymes in brain of mice.
This study reports the protective effects of selenium on fluoride induced alterations in the activities of pro-oxidative (xanthine oxidase (XOD), lipid peroxidation (LPO) free radical scavenging, [catalase, superoxide dismutase (SOD), glutathione-s-transferase (GST), glutathione peroxidase (GPX), glutathione reductase (GR), glutathione) and metabolic (glucose-6-phosphate dehydrogenase, alanine amino transferase (ALAT), aspartate aminotransferase (AAT), creatine phosphokinase (CPK), acid phosphatase (AP), alkaline phosphatase (ALP)] enzymes along with fluoride and selenium levels in brain of mice. Animals were divided into control, NaF treated group (20 mg kg(-1) body wt.(-1) intraperitonial) and Selenium+NaF treated group (sodium selenite, 5 microg of selenium/0.2 ml distilled water kg(-1) body wt.(-1) day) and were maintained for 14 days on respective treatments. The decreased bodyweight (-11.35%) as well as organosomatic index (-15.1%) of brain in NaF group were recovered in treatment of selenium along with NaF. The increased accumulation of fluoride (32.1%) in brain observed in NaF treated group compared to control was diminished in selenium+NaF treated group. Selenium levels (3.03%) increased in selenium+NaF treated group in compared to decrement in NaF treatment. The SOD (-16.6%), Catalase (-21.5%), GST(-13.72%), GPX (-19.16%), GR (-44.97%) activities and Glutathione (-23%) content in NaF treated group were decreased significantly compared to controls, which were significantly (p < 0.01) recovered in selenium+NaF group. Increased XOD (10.85%) and LPO (8.61%) levels observed in brain of NaF treated mice were reversed with selenium treatment. Glucose-6-phosphate dehydrogenase (-46.98%), ALAT (-10.44%), AAT (-10.21%), CPK (-27.98%) were decreased and alkaline phosphatase (10.6%), acid phosphatase (24.09%) increased in brain of mice after administration of NaF. All metabolic enzymes were significantly (p < 0.01) reversed after administration of selenium to the NaF treated group. Thus, the adverse effects of NaF on oxidative and metabolic enzymes of brain were reversible with ameliorative action of selenium supplementation. As evident in this study the antioxidative nature of selenium coupled with its reversal effect on metabolic enzymes in brain of mice treated with fluoride suggests its use as antidote agent against fluorosis.


Characterization of silver nanoparticle products using asymmetric flow field flow fractionation with a multidetector approach--a comparison to transmission electron microscopy and batch dynamic light scattering.
Due to the already prevalent and increasing use of silver-nanoparticle (Ag-NP) products and the raised concerns in particular for the aquatic environment, analytical techniques for the characterization of such products are of need. However, because Ag-NP products are of different compositions and polydispersities, analysis especially of the size distribution is challenging. In this work, an asymmetric flow field flow fractionation (A4F) multidetector system (UV/vis, light scattering, inductively coupled plasma mass spectrometry - ICPMS), in combination with a method to distinguish and quantify the particle and dissolved Ag fractions (ICPMS after ultracentrifugation), for the characterization of Ag-NP products with different degrees of polydispersities is presented. For validation and to outline benefits and limitations, results obtained from batch dynamic light scattering (batch-DLS) and transmission electron microscopy (TEM) were compared. With the developed method a comprehensive understanding in terms of dissolved Ag and Ag-NP concentration as well as an element selective, mass- and number particle size distribution (PSD) was obtained. In relation to batch-DLS, the reliability of the data was improved significantly. In comparison to TEM, faster measurement times and the ability to determine the samples directly in dispersions are clearly advantageous. The proposed setup shows potential for a rapid- and reliable characterization method of virtually any polydisperse metallic NP dispersion, many of them available on the market already.


Adipokines and the role of visceral adipose tissue in inflammatory bowel disease.
Recently, adipocytes have been recognized as actively participating in local and systemic immune responses via the secretion of peptides detectable in relevant levels in the systemic circulation, the so-called "adipo(cyto)kines". Multiple studies appearing within the last 10-15 years have focused on the possible impact of adipose tissue depots on inflammatory bowel disease (IBD). Consequently, various hypotheses regarding the role of different adipokines in inflammatory diseases in general and in intestinal inflammatory processes in particular have been developed and have been further refined in recent years. After a focused summary of the data reported concerning the impact of visceral adipose tissue on IBD, such as Crohn's disease and ulcerative colitis, our review focuses on recent developments indicating that adipocytes as part of the innate immune system actively participate in antimicrobial host defenses in the context of intestinal bacterial translocation, which are of utmost importance for the homeostasis of the whole organism. Modulators of adipose tissue function and regulators of adipokine secretion, as well as modifiers of adipocytic pattern recognition molecules, might represent future potential drug targets in IBD.


Comparison of Preterm and Term Wharton's Jelly-Derived Mesenchymal Stem Cell Properties in Different Oxygen Tensions.
Mesenchymal stem cells (MSCs) have shown promise as therapeutic agents in treating morbidities associated with premature birth. MSCs derived from the human umbilical cord are easy to isolate and have low immunogenicity and a robust ability to secrete paracrine factors. To date, there are no studies evaluating preterm versus term umbilical cord tissue-derived MSCs. Therefore, our aim was twofold: (1) to compare stem cell properties in preterm versus term MSCs and (2) to examine the impact of oxygen tension on stem cell behavior. Umbilical cord tissue was obtained from 5 preterm and 5 term neonates. The cells were isolated and characterized as MSCs in accordance with the International Society for Cellular Therapy. We exposed MSCs to different oxygen tensions to examine the impact of environmental factors on cell performance. We studied the following stem cell properties: (i) motility, (ii) proliferation, (iii) senescence, (iv) cell viability, (v) colony-forming unit efficiency, and (vi) inflammatory cytokine expression. Under normoxia (21% O2), cells from preterm and term infants had similar properties. Under hypoxic conditions (1% O2), term MSCs had better cell proliferation; however, cells exposed to hyperoxia (90% O2) had the slowest motility and lowest cell viability (p < 0.05). There was no difference in the expression of senescence or cytokine expression between the groups. The term cells demonstrated more colony-forming efficiency than the preterm cells. In sum, our preliminary findings suggest that MSCs derived from term and preterm umbilical cords have similar characteristics, offering the potential of future autologous/allogeneic MSC transplants in neonates.


A randomized, controlled pilot study of a home-based exercise program for individuals with mild and moderate stroke.
Many stroke survivors have minimal to moderate neurological deficits but are physically deconditioned and have a high prevalence of cardiovascular problems; all of these are potentially modifiable with exercise. The purposes of this randomized, controlled pilot study were (1) to develop a home-based balance, strength, and endurance program; (2) to evaluate the ability to recruit and retain stroke subjects; and (3) to assess the effects of the interventions used. Twenty minimally and moderately impaired stroke patients who had completed inpatient rehabilitation and who were 30 to 90 days after stroke onset were randomized to a control group or to an experimental group that received a therapist-supervised, 8-week, 3-times-per-week, home-based exercise program. The control group received usual care as prescribed by the patients' physicians. Baseline and postintervention assessments included the Fugl-Meyer Motor Assessment, the Barthel Index of Activities of Daily Living (ADL), the Lawton Scale of Instrumental ADL, and the Medical Outcomes Study-36 Health Status Measurement. Functional assessments of balance and gait included a 10-m walk, 6-Minute Walk, and the Berg Balance Scale. Upper extremity function was evaluated by the Jebsen Test of Hand Function. Of 22 patients who met study criteria, 20 completed the study and 2 refused to participate. The experimental group tended to improve more than the control group in motor function (Fugl-Meyer Upper Extremity: mean change in score, 8. 4 versus 2.2; Fugl-Meyer Lower Extremity: 4.7 versus -0.9; gait velocity: median change, 0.25 versus .09 m/s; 6-Minute Walk: 195 versus 114 ft; Berg Balance Score: 7.8 versus 5; and Medical Outcomes Study-36 Health Status Measurement of Physical Function: 15. 5 versus 9). There were no trends in differences in change scores by the Jebsen Test of Hand Function, Barthel Index, and Lawton Instrumental ADL Scale. This study demonstrated that a randomized, controlled clinical trial of a poststroke exercise program is feasible. Measures of neurological impairments and lower extremity function showed the most benefit. Effects of the intervention on upper extremity dexterity and functional health status were equivocal. The lasting effects of the intervention were not assessed.


Actuated plasmonic nanohole arrays for sensing and optical spectroscopy applications.
Herein, we report a new approach to rapidly actuate the plasmonic characteristics of thin gold films perforated with nanohole arrays that are coupled with arrays of gold nanoparticles. The near-field interaction between the localized and propagating surface plasmon modes supported by the structure was actively modulated by changing the distance between the nanoholes and nanoparticles and varying the refractive index symmetry of the structure. This approach was applied by using a thin responsive hydrogel cushion, which swelled and collapsed by a temperature stimulus. The detailed experimental study of the changes and interplay of localized and propagating surface plasmons was complemented by numerical simulations. We demonstrate that the interrogation and excitation of the optical resonance to these modes allow the label-free SPR observation of the binding of biomolecules, and is applicable for in situ SERS studies of low molecular weight molecules attached in the gap between the nanoholes and nanoparticles.


Prevention and treatment of senile osteoporosis and hip fractures.
Osteoporosis is a major health issue worldwide, with significant economic consequences and adverse impacts on the quality of life. Hip fractures are the most devastating complication of osteoporosis, are likely to increase exponentially with an increasingly aged population, are associated with high recurrence rate, and lead to significant morbidity and mortality. This review discusses the prevalence and impact of hip fractures, the assessment of fracture risk, fall prevention, and treatment of osteoporosis with emphasis on evidence for hip fracture reduction among the various agents currently available. The aim is to provide recommendations to optimize hip fracture prevention and treatment. Ample evidence exists in the literature of many other risk factors independent from bone mineral density that increase fracture risk. These clinical risk factors have been validated in large cohorts and are incorporated into clinical tools that are invaluable in treatment decisions. In addition, strategies to prevent or reduce falls are integral to comprehensive osteoporosis management. Vitamin D combined with calcium has a role in primary prevention. Alendronate, residronate, strontium and zoledronic acid have proven efficacy in primary and secondary hip fracture prevention. An aggressive approach to investigate, assess and manage an individual's fracture risk and fall risk is paramount to reduce the high morbidity and mortality associated with hip fractures. The choice of therapy should be determined by the patient's calculated fracture risk and efficacy of the potential treatment, including long term compliance associated with the agent of choice.


Expression of gangliosides in neuronal development of P19 embryonal carcinoma stem cells.
Gangliosides are constituents of the cell membrane and are known to have important functions in neuronal differentiation. We employed an embryonal carcinoma stem cell line P19 as an in vitro model to investigate the expression of gangliosides during neuronal development. After treatment with retinoic acid, these cells differentiate synchronously into neuron-like cells by a series of well-defined events of development. We examined several aspects of ganglioside metabolism, including the changes of ganglioside pattern, the activities and gene expression of several enzymes at different stages of differentiation, and the distribution of gangliosides in differentiating neurons. Undifferentiated P19 cells express mainly GM3 and GD3. After P19 cells were committed to differentiation, the synthesis of complex gangliosides was elevated more than 20-fold, coinciding with the stage of neurite outgrowth. During the maturation of differentiated cells, the expression of c-series gangliosides was downregulated concomitantly with upregulation of the expression of a- and b-series gangliosides. We also examined the distribution of gangliosides in differentiating neurons by confocal and transmission electron microscopy after cholera toxin B subunit and sialidase treatment. Confocal microscopic studies showed that gangliosides were distributed on the growth cones and exhibited a punctate localization on neurites and soma. Electron microscopic studies indicated that they also are enriched on the plasma membranes of neurites and the filopodia as well as on the lamellipodia of growth cones during the early stage of neurite outgrowth. Our data demonstrate that the expression of gangliosides in P19 cells during RA-induced neuronal differentiation resembles that of the in vivo development of the vertebrate brain, and hence validates it as an in vitro model for investigating the function of gangliosides in neuronal development.


Optimized kinoform structures for highly efficient fan-out elements.
We discuss the realization of highly efficient fan-out elements. Laser-beam writing lithography is available now for fabricating smooth surface relief microstructures. We develop several methods for optimizing microstructure profiles. Only a small number of parameters in the object plane are necessary for determining the kinoform. This simplifies the calculation of M x N arrays also for large M and N. Experimental results for a 9-beam fan-out element are presented.


Frequency and clinical predictors of adverse reactions to chiropractic care in the UCLA neck pain study.
Randomized clinical trial. To document the types and frequencies of adverse reactions associated with the most common chiropractic treatments for neck pain, and to identify possible clinical predictors of adverse reactions to chiropractic treatment. Chiropractic care is frequently sought by patients for relief from neck pain; however, adverse reactions related to its primary modes of treatment have not been well examined. A total of 336 patients with neck pain presenting to 4 southern California health care clinics were randomized in a balanced 2 x 2 x 2 factorial design to manipulation with or without heat, and with or without electrical muscle stimulation (EMS); and mobilization with or without heat and with or without EMS. Discomfort or unpleasant reactions from chiropractic care were self-assessed at 2 weeks after the randomization/baseline visit. Of the 280 participants (83%) who responded, 85 (30.4%) had 212 adverse symptoms as a result of chiropractic care. Increased neck pain or stiffness was the most common symptom, reported by 25% of the participants. Less common were headache and radiating pain. Patients randomized to manipulation were more likely than those randomized to mobilization to have an adverse symptom occurring within 24 hours of treatment (adjusted odds ratio [OR] = 1.44, 95% confidence interval [CI] = 0.83, 2.49). Heat and EMS were only weakly associated with adverse symptoms (heat: OR = 0.94, 95% CI = 0.54, 1.62; EMS: OR = 1.09, 95% CI = 0.63, 1.89). Moderate-to-severe neck disability at baseline was strongly associated with adverse neurologic symptoms (OR = 5.70, 95% CI = 1.49, 21.80). Our results suggest that adverse reactions to chiropractic care for neck pain are common and that despite somewhat imprecise estimation, adverse reactions appear more likely to follow cervical spine manipulation than mobilization. Given the possible higher risk of adverse reactions and lack of demonstrated effectiveness of manipulation over mobilization, chiropractors should consider a conservative approach for applying manipulation to their patients, especially those with severe neck pain.


The impact of DNA methylation on the cancer proteome.
Aberrant DNA methylation disrupts normal gene expression in cancer and broadly contributes to oncogenesis. We previously developed MethylMix, a model-based algorithmic approach to identify epigenetically regulated driver genes. MethylMix identifies genes where methylation likely executes a functional role by using transcriptomic data to select only methylation events that can be linked to changes in gene expression. However, given that proteins more closely link genotype to phenotype recent high-throughput proteomic data provides an opportunity to more accurately identify functionally relevant abnormal methylation events. Here we present a MethylMix analysis that refines nominations for epigenetic driver genes by leveraging quantitative high-throughput proteomic data to select only genes where DNA methylation is predictive of protein abundance. Applying our algorithm across three cancer cohorts we find that using protein abundance data narrows candidate nominations, where the effect of DNA methylation is often buffered at the protein level. Next, we find that MethylMix genes predictive of protein abundance are enriched for biological processes involved in cancer including functions involved in epithelial and mesenchymal transition. Moreover, our results are also enriched for tumor markers which are predictive of clinical features like tumor stage and we find clustering using MethylMix genes predictive of protein abundance captures cancer subtypes.


Value and limitation of in vitro bioassays to support the application of the threshold of toxicological concern to prioritise unidentified chemicals in food contact materials.
Some of the chemicals in materials used for packaging food may leak into the food, resulting in human exposure. These include so-called Non-intentionally Added Substances (NIAS), many of them being unidentified and toxicologically uncharacterized. This raises the question of how to address their safety. An approach consisting of identification and toxicologically testing all of them appears neither feasible nor necessary. Instead, it has been proposed to use the threshold of toxicological concern (TTC) Cramer class III to prioritise unknown NIAS on which further safety investigations should focus. Use of the Cramer class III TTC for this purpose would be appropriate if amongst others sufficient evidence were available that the unknown chemicals were not acetylcholinesterase inhibitors or direct DNA-reactive mutagens. While knowledge of the material and analytical chemistry may efficiently address the first concern, the second could not be addressed in this way. An alternative would be use of a bioassay capable of detecting DNA-reactive mutagens at very low levels. No fully satisfactory bioassay was identified. The Ames test appeared the most suitable since it specifically detects DNA-reactive mutagens and the limit of biological detection of highly potent genotoxic carcinogens is low. It is proposed that for a specific migrate, the evidence for absence of mutagenicity based on the Ames test, together with analytical chemistry and information on packaging manufacture could allow application of the Cramer class III TTC to prioritise unknown NIAS. Recommendations, as well as research proposals, have been developed on sample preparation and bioassay improvement with the ultimate aim of improving limits of biological detection of mutagens. Although research is still necessary, the proposed approach should bring significant benefits over the current practices used for safety evaluation of food contact materials.


Effect of endotoxemia on intestinal villus microcirculation in rats.
Intestinal mucosal hypoperfusion with subsequent ischemia during endotoxemia might cause a breakdown of the gut barrier with translocation of bacteria and their toxins into the systemic circulation, thus maintaining a "gut-derived" septic state. The aim of this study was to investigate the influence of endotoxin on the microcirculation of intestinal villi, which represent the most vulnerable part of the mucosa. The changes in blood flow and in the diameters of the central villus arterioles located in the distal ileum were monitored in control rats without lipopolysaccharide (LPS) exposure (n=7), and in rats receiving 1.5 mg/kg b.w. LPS (n=7) or 15 mg/kg b.w. LPS (n=7) over 60 min. The blood flow and the arteriolar diameters were determined using in vivo videomicroscopy at baseline, and 60 min and 120 min later. In control animals, no change in blood flow and arteriolar diameters were observed during the entire experiment. Administration of 1.5 mg/kg b.w. LPS reduced the blood flow to 69.5 +/- 9.0% of the baseline value at the end of the study period. This decrease in blood flow was associated with a decrease in the villus arteriolar diameters by 17.4 +/- 2.5% from the baseline values. In animals exposed to 15 mg/kg b.w. LPS, the decrease in villus blood flow at 60 min was 64.8 +/- 10.9% of baseline, and at 120 min 66.9 +/- 12.6% of baseline. The diameters of the villus arterioles were reduced by 11.5 +/- 2.4% and 15.1 +/- 1.7%, respectively. In the control group and in the 1.5-mg/kg LPS group, the mean arterial blood pressure did not change during the entire study period. In the 15-mg/kg LPS group, the mean arterial pressure tended to decrease after 60 min. These data suggest a reduction of villus blood flow due to vasoconstriction in the central villus arterioles during normotensive endotoxmia, which might represent the mechanism for the mucosal ischemia observed in critically ill patients.


How to maintain the maximal level of blinding in randomisation for a placebo-controlled drug trial.
We illustrate the approach of randomising treatments and compare it with the traditional approach of randomising patients, using a case study drawn from the authors' experience in clinical trials. The setting is a double-blind parallel two-arm randomised controlled trial (RCT), but the method in this paper can be extended to single-blind, cross-over, or multi-arm RCTs. We propose the concept of two different levels of blinding: full blinding and partial blinding. We subsequently show how to maintain the maximal level of blinding. Using an example, we show that a pharmacist can be fully blinded if the investigational medical products (IMPs) that they prescribe (instead of patients) are randomised, and they can be partially blinded if they need to dispense replacement (i.e., surplus) IMPs. A small number of surplus IMPs is commonly required in a clinical trial to replace lost or damaged IMPs. We note that the concept of full blinding and partial blinding is different from double-blind trial, and the level of blinding is relevant in both single-blind and double-blind trials. A trial statistician needs to work closely with all parties in the design of the randomisation, including the pharmacist, the trial manager, and the manufacturer. We detail what should and should not be shown in the various documents that the trial statistician need to provide to the pharmacist and to the manufacturer. We provide template tables for these documents.


The private funding of public research. New directions in the administration of occupational and environmental health research.
Dr. Cullen: The experience with the new research models, starting with the prototypic experience of the rubber industry studies of the 1970s and expanding to diverse sectors of American industry in the 1980s, has yielded some important lessons for the future. In closing this symposium I shall try to summarize these briefly. Certain strengths of the evolving process seem common to each of the models. Alone and collectively, the new research arrangements have quite apparently served to increase substantially the pool of funds available to the academic sector for the study of occupational health and safety problems. As a consequence, a larger pool of investigators has participated in the research process, greatly strengthening the future academic capability and experience of our fragilely supported teaching centers. Combined with the involvement of the academic centers in the review process, there has been an undeniable broadening and deepening of the nation's research output and long-term capability in occupational health. On the side of the private sector, the new relationships have led to marked progress in the knowledge base about health and safety problems, with a heavily directed focus on those of greatest relevance to the industries involved. The credibility of the knowledge acquired has been enhanced, an important achievement in a society in which perception of truth is often as important as the truth itself! Because of the requirements of the process for broad involvement by the organizations which undertake these activities, health and safety have achieved far greater visibility and attention by corporate and union leaders who may have previously had no involvement in issues of health and safety.(ABSTRACT TRUNCATED AT 250 WORDS)


[Results of percutaneous cryoablation for malignant lung tumors compared with radiotherapy].
Radiotherapy has been regularly applied mainly for inoperable patients with non- small cell lung cancer, and various clinical trials have been performed. On the other hand, we have applied percutaneous cryoablation for lung tumors (PCLT) since 2002. In this paper, we describe our experience of PCLT compared to the results of radiation treatment. Three-year local progression-free rates with stereotactic body radiotherapy were 79-92% in stage I A and 30-79% in stage I B. Those with proton radiotherapy were 82-89% in stage I A and 49-62% in stage I B. CTCAE grade ≥3 complications occurred in 3-28% cases, such as radiation pneumonitis. As for PCLT, 1-, 2- and 3-year local progression-free rates were 80.4%, 69.0% and 67.7%, respectively. Pneumothorax, pleural effusion, and hemoptysis occurred after 61.7%, 70.5%, and 36.8% sessions, respectively. Of all cases with pneumothorax, 17.6% required chest tube insertion and 1.7% required pleurodesis. Delayed and recurrent pneumothorax occurred in 7.8% each. CTCAE grade ≥3 complications occurred in 1.5% cases. The biggest advantage of PCLT compared with radiotherapy is the possibility to treat local recurrence at the same site as treated before. In addition, no radiation pneumonitis occurs in PCLT. Moreover, less space or budget is needed when PCLT is newly introduced in a hospital. Although high reliable clinical data is not achieved yet, PCLT is one of the promising methods in local treatment.


Molecular dynamics simulations of membrane proteins.
Membrane protein structures are underrepresented in the Protein Data Bank (PDB) due to difficulties associated with expression and crystallization. As such, it is one area where computational studies, particularly Molecular Dynamics (MD) simulations, can provide useful additional information. Recently, there has been substantial progress in the simulation of lipid bilayers and membrane proteins embedded within them. Initial efforts at simulating membrane proteins embedded within a lipid bilayer were relatively slow and interactive processes, but recent advances now mean that the setup and running of membrane protein simulations is somewhat more straightforward, though not without its problems. In this chapter, we outline practical methods for setting up and running MD simulations of a membrane protein embedded within a lipid bilayer and discuss methodologies that are likely to contribute future improvements.


INVISIBLE WOMEN IRELAND AND THE FIGHT TO ACCESS SAFE AND LEGAL ABORTION.
The Irish legal framework regulating abortion represents one of the most restrictive ones worldwide. It allows for abortion only when medical practitioners assess a risk of lfe of the pregnant woman, therefore excluding the vast majority of women from legality, and not allowing them to have control over their own bodies. The only option in order to have a lawfid termination is travelling abroad. Against such background, this article holds that the Irish legislation on abortion creates three levels of 'invisible women'. Firstly, the constitutional equation between the pregnant womans life and the foetus'one downgrades the first to be the biological support of the second, not seeing her as a subject. Secondly, the option of travelling further 'invisibilizes', both geographically and politically, the wills and choices of the majority of women. Thirdly, the women who cannot afford the journey are completely neglected, forced to act clandestinely and criminalised.


Anthropometric and anaerobic fitness profile of elite and non-elite female soccer players.
The main aim of the current study was to compare the anthropometrical and fitness profile of female soccer players by level and by playing positions. The second purpose was to explore correlations between kicking speed on the one hand and anthropometric features and explosive strength on the other. Female soccer players (N.=190) were tested divided in two groups: elite group (N.=100) and non-elite group (N.=90). Body mass, height, leg length, body composition, counter movement jump, drop jump and kicking speed with both legs were measured. After controlling for experience with multivariate analysis of covariance (MANCOVA), body mass, body fat and muscle mass differed significantly by level. MANCOVA also revealed that all the anthropometrical variables differed by playing position. However, MANCOVA did not show significant differences by level of play, neither for explosive strength nor for kicking speed but revealed significant differences among playing positions. There were significant positive correlations between body mass, height, leg length, muscle mass, counter movement jump height, drop jump height and experience on the one hand and kicking speed with dominant and non-dominant leg on the other for the elite and non-elite players. Elite players differ from their non-elite counterparts in terms of anthropometrical features, while explosive strength and kicking speed are not sensitive enough to distinguish between levels. On the other hand, the findings indicate few positional variations, and only goalkeepers, tend to have a specific anthropometric and fitness profile. Anthropometric variables, explosive strength and experience have an influence on kicking speed.


Immunologic recognition of influenza virus-infected cells. II. Expression of influenza A matrix protein on the infected cell surface and its role in recognition by cross-reactive cytotoxic T cells.
Two distinct subpopulations of cytotoxic T cells are generated in the primary or secondary response of mice to type A influenza viruses. One subpopulation is specific for the immunizing virus strain. The other subpopulation shows a high degree of cross-reactivity for heterologous type A virus of a different subtype. This report examines the possibility that distinct influenza virus antigens, expressed on the surface of the infected cell, are recognized by the different subpopulations of influenza-specific cytotoxic T cells. Data are presented which demonstrate that influenza A matrix protein, an internal virion antigen, is detectable on the surface of target cells infected with influenza A viruses of different subtypes. Since this viral antigen is type specific, i.e., serologically cross-reactive among all type A influenza viruses, it could serve as the target for cross-reactive cytotoxic T cells. To further examine the specificity of the two cytotoxic T-cell subpopulations, experiments were carried out by using the inhibitor of glycoprotein synthesis - 2-Deoxy-D-Glucose 2-DG. These experiments examine first the effect of 2-DG on the expression of influenza matrix protein and viral glycoprotein on the infected cell surface and second, the susceptibility of 2-DG-treated target cells to lysis by cytotoxic T cells. 2-DG inhibits the expression of the viral hemagglutinin glycoprotein on the cell surface but does not inhibit the expression of the nonglycosylated matrix protein. Furthermore, inhibition of glycoprotein synthesis in infected target cells abrogates the reactivity of infected target cells to lysis by virus strain-specific but not cross- reactive cytotoxic T cells. These findings suggest that the influenza glycoproteins (hemagglutinin and/or neuraminidase) and the nonglycosylated matrix protein are the targets for the virus strain- specific and cross-reactive cytotoxic T cells, respectively. These results are discussed in the light of available information on influenza virus structure and the biology of influenza infection and in terms of current models for cytotoxic T-cell recognition of virus-infected cells.


Modeling bi-modality improves characterization of cell cycle on gene expression in single cells.
Advances in high-throughput, single cell gene expression are allowing interrogation of cell heterogeneity. However, there is concern that the cell cycle phase of a cell might bias characterizations of gene expression at the single-cell level. We assess the effect of cell cycle phase on gene expression in single cells by measuring 333 genes in 930 cells across three phases and three cell lines. We determine each cell's phase non-invasively without chemical arrest and use it as a covariate in tests of differential expression. We observe bi-modal gene expression, a previously-described phenomenon, wherein the expression of otherwise abundant genes is either strongly positive, or undetectable within individual cells. This bi-modality is likely both biologically and technically driven. Irrespective of its source, we show that it should be modeled to draw accurate inferences from single cell expression experiments. To this end, we propose a semi-continuous modeling framework based on the generalized linear model, and use it to characterize genes with consistent cell cycle effects across three cell lines. Our new computational framework improves the detection of previously characterized cell-cycle genes compared to approaches that do not account for the bi-modality of single-cell data. We use our semi-continuous modelling framework to estimate single cell gene co-expression networks. These networks suggest that in addition to having phase-dependent shifts in expression (when averaged over many cells), some, but not all, canonical cell cycle genes tend to be co-expressed in groups in single cells. We estimate the amount of single cell expression variability attributable to the cell cycle. We find that the cell cycle explains only 5%-17% of expression variability, suggesting that the cell cycle will not tend to be a large nuisance factor in analysis of the single cell transcriptome.


Effects of Black Hoof Medicinal Mushroom, Phellinus linteus (Agaricomycetes), Polysaccharide Extract in Streptozotocin-Induced Diabetic Rats.
In this article we report the healing effects of a Phellinus linteus fruiting body hot water extract (PLE) in streptozotocin (STZ)-induced diabetic rats. PLE was given before and after STZ. The preprotective, protective, and postprotective effects of PLE on STZ-induced oxidative stress were studied using biochemical (caspase 3 activity, cytosolic-to-lysosomal ratio of cathepsin B and L, DNA fragmentation levels), ordinary histological and immuno-histochemical investigation parameters. Following oral administration of PLE after STZ application, the serum glucose concentration significantly decreased up to 41.13% compared with the control group (P < 0.05). The hypoglycemic potential of the PLE was further supported by an increase of insulin secretion in the islets of Langerhans. In addition, the number of cells in Langerhans islets increased by 45.89% when PLE was given after STZ application. On the other hand, the use of PLE before oxidative stress could not prevent the onset of diabetes. This is, to our knowledge, the first study of the effect of application time of orally administered Ph. Linteus hot water extract on STZ-induced diabetes.


Enhanced resting-state connectivity of amygdala in the immediate aftermath of acute psychological stress.
Recent neuroimaging studies investigating responses to stressful stimuli may importantly further our understanding of psychological trauma etiology. However, theory posits that sustained activation of these stress circuits after the stressful event may play an equally important role in the development of stress-related psychopathology. Importantly, such post-stress network changes remain poorly characterized. The amygdala with its connections is crucially positioned in the central stress circuitry that mediates the initial stress response. Hence, we investigated post-stress amygdala-centered connectivity patterns in order to characterize the aftermath of acute, experimentally-induced stress in healthy humans. We recorded resting-state functional MRI in 26 female participants following a period of moderate psychological stress induced by means of aversive (vs. emotionally neutral) movie watching with a self-referencing instruction. Next, we implemented a seedregion analysis calculating the voxel-wise correlation with the anatomically extracted time-series of the amygdala. Various stress measures confirmed successful stress induction. Moreover, we demonstrated enhanced functional coupling of the amygdala with dorsal anterior cingulate cortex, anterior insula, and a dorso-rostral pontine region, which appears to overlap with the anatomical location of the locus coeruleus (LC), when contrasting the stress with the control group. Thus, we show that the aftermath of acute stress is qualified by prolonged activation in an amygdala-connectivity network. This pattern of co-activation may indicate an extended state of hypervigilance that promotes sustained salience and mnemonic processing after stress. Characterization of the post-stress brain state may provide initial insight into the early phases of psychological trauma formation.


Relations between Continuous Performance Test performance measures and ADHD behaviors.
The Conners' Continuous Performance Test (CPT) is a neuropsychological task that has repeatedly been shown to differentiate ADHD from normal groups. Several variables may be derived from the Conners' CPT including errors of omission and commission, mean hit reaction time(RT), mean hit RT standard error, d', and beta. What each CPT parameter actually assesses has largely been based upon clinical assumptions and the face validity of each measure (e.g., omission errors measure inattention, commission errors measure impulsivity). This study attempts to examine relations between various CPT variables and phenotypic behaviors so as to better understand the various CPT variables. An epidemiological sample of 817 children was administered the Conners' CPT. Diagnostic interviews were conducted with parents to determine ADHD symptom profiles for all children. Children diagnosed with ADHD had more variable RTs, made more errors of commission and omission, and demonstrated poorer perceptual sensitivity than nondiagnosed children. Regarding specific symptoms, generalized estimating equations (GEE) and ANCOVAs were conducted to determine specific relationships between the 18 DSM-IV ADHD symptoms and 6 CPT parameters. CPT performance measures demonstrated significant relationships to ADHD symptoms but did not demonstrate symptom domain specificity according to a priori assumptions. Overall performance on the two signal detection measures, d' and beta, was highly related to all ADHD symptoms across symptom domains. Further, increased variability in RTs over time was related to most ADHD symptoms. Finally, it appears that at least 1 CPT variable, mean hit RT, is minimally related to ADHD symptoms as a whole, but does demonstrate some specificity in its link with symptoms of hyperactivity.


Schnyder corneal dystrophy-associated UBIAD1 inhibits ER-associated degradation of HMG CoA reductase in mice.
Autosomal-dominant Schnyder corneal dystrophy (SCD) is characterized by corneal opacification owing to overaccumulation of cholesterol. SCD is caused by mutations in UBIAD1, which utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize vitamin K2. Using cultured cells, we previously showed that sterols trigger binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase (HMGCR), thereby inhibiting its endoplasmic reticulum (ER)-associated degradation (ERAD) (Schumacher et al. 2015). GGpp triggers release of UBIAD1 from HMGCR, allowing maximal ERAD and ER-to-Golgi transport of UBIAD1. SCD-associated UBIAD1 resists GGpp-induced release and is sequestered in ER to inhibit ERAD. We now report knockin mice expressing SCD-associated UBIAD1 accumulate HMGCR in several tissues resulting from ER sequestration of mutant UBIAD1 and inhibition of HMGCR ERAD. Corneas from aged knockin mice exhibit signs of opacification and sterol overaccumulation. These results establish the physiological significance of UBIAD1 in cholesterol homeostasis and indicate inhibition of HMGCR ERAD contributes to SCD pathogenesis.


Clinical significance of the V-shaped space in the subluxed shoulder of hemiplegics.
Recently, it has been proposed that shoulder subluxation in hemiplegia is accompanied by 1) the appearance of a V-shaped articular configuration occurring between the humeral head and glenoid fossa and 2) the presence of chronic pain. The main purpose of this study was to investigate the validity of these statements. We evaluated 40 hemiplegic subjects over 3 months. Radiographs of the affected and nonaffected shoulders were taken at both a frontal plane (0 degree) and a 45 degree incidence. From these patients, subluxed (n = 19) and nonsubluxed (n = 21) groups were formed. Pain was evaluated using the Present Pain Intensity index of the McGill Pain Questionnaire. On these x-ray films, measurements were taken of the V-shaped space, abduction of the arm, and rotation of the scapula. The statistical analysis (analysis of variance for repeated measures) contrasted the results obtained from the nonaffected side with those from the affected side over the 3 months studied. At the 45 degree angle, which better exposes the articular configuration of the shoulder, the difference in the V angle between the affected and nonaffected shoulders was significant for the subluxed group (p less than 0.01), indicating that such a V-shaped space can be identified. The measures taken also indicate that a downward subluxation of the humeral head occurs relative to the scapula without any systematic abduction of the humerus or downward rotation of the scapula. None of the results obtained from the frontal plane x-ray films was significant. Finally, no significant relation was found between subluxation and shoulder pain.


Erythrocyte sodium and potassium in patients with hypokalaemia.
1. The erythrocyte content of sodium and of potassium were measured in 231 unselected patients with hypokalaemia, and together with net ouabain-sensitive sodium efflux in patients with severe hypokalaemia, before (20 patients) and during potassium repletion (14 patients). 2. The erythrocytes of the patients with hypokalaemia compared with control subjects had on average an increase in sodium content, a decrease in potassium content and a reduction in the rate constant of ouabain-sensitive sodium efflux. All three changes had a similar curvilinear relation to the concentration of potassium in plasma with relatively little change in the measured variable unless the plasma potassium was very low. 3. There was a similar curvilinear relation between the final sodium and potassium content of normal erythrocytes and the potassium concentration of the medium in which they were incubated for 48 h in vitro. 4. These results suggest that the changes in the sodium and potassium content of erythrocytes in hypokalaemia are due to a direct inhibiting effect of the hypokalaemia on the activity of the sodium pump. 5. In many patients with hypokalaemia of moderate degree the increase in erythrocyte sodium content was less than expected from the effect in vitro of a low extracellular potassium concentration. This finding suggests that a compensatory change, presumably an increase in the number of sodium pumps, is a common event even in moderate hypokalaemia.


Management of herpes zoster (shingles) during pregnancy.
An infection with the varicella-zoster virus (VZV) causes both varicella and herpes zoster (HZ). Although rare, the development of HZ does occur during pregnancy. Maternal HZ does not result in increased foetal mortality, and the passage of VZV to the foetus rarely occurs. However, HZ does increase maternal morbidity. Upon infection with HZ, patients typically present with a viral prodrome preceding the appearance of the characteristic zoster rash. HZ is usually diagnosed clinically by the zoster rash, but can also be confirmed by a polymerase chain reaction and an enzyme-linked immunosorbent assay. Pregnant women with an uncomplicated HZ should be treated with oral acyclovir. The major complications of HZ are subacute herpetic neuralgia and post-herpetic neuralgia. Other complications include zoster ophthalmicus, disseminated HZ and secondary bacterial infections. Regarding prophylaxis, the varicella and the zoster vaccines are not recommended for pregnant women, and it is important to advise non-immune pregnant women to avoid an exposure to VZV. Although HZ infection has a minimal effect on the foetus, maternal HZ and its complications cause a significant burden. It is important to focus care on the mother with appropriate treatment and management of complications as they develop.


Vagus nerve stimulation produces immediate dose-dependent anxiolytic effect in rats.
Chronic vagus nerve stimulation (VNS) attenuates anxiety in rats and humans. However, it is unclear whether VNS can promote acute anxiolytic effects. Here we examined short-term anxiolytic effects of VNS using single or multiple trains in rats submitted to a battery of tests. Three groups of rats were implanted with VNS cuffs and tested for anxiety using the elevated plus maze (EPM), novelty suppressed feeding (NSF), and acoustic startle response (ASR), after receiving either one or five VNS trains (0.4 mA/30 Hz/30‑sec), or sham stimulation. Both single and multiple VNS trains reduced state anxiety as measured using the EPM, but only multiple trains reduced anxiety in the EPM and NSF. VNS did not decrease arousal as measured using the ASR. The anxiolytic effects of VNS may be differently influenced by test order or prior-exposure to stress. VNS did not affect startle responses in naïve rats but the present findings do not determine whether VNS would affect startle responses that are potentiated by fear or anxiety. A single VNS train can produce an anxiolytic-like effect in the EPM minutes later, an effect that is not observed in the NSF. Delivering 5 VNS trains restores the immediate effects across tests of anxiety, indicating that more trains produce a more robust anxiolytic effect. The lack of effects on ASR suggests that VNS affects state anxiety but not baseline arousal in naïve rats. We suggest that the anxiolytic effect of VNS can increase tolerability and reduce dropout in exposure-based therapies.


First Reported Cases of Biomechanically Adaptive Bone Modeling in Non-Avian Dinosaurs.
Predator confrontation or predator evasion frequently produces bone fractures in potential prey in the wild. Although there are reports of healed bone injuries and pathologies in non-avian dinosaurs, no previously published instances of biomechanically adaptive bone modeling exist. Two tibiae from an ontogenetic sample of fifty specimens of the herbivorous dinosaur Maiasaura peeblesorum (Ornithopoda: Hadrosaurinae) exhibit exostoses. We show that these outgrowths are cases of biomechanically adaptive periosteal bone modeling resulting from overstrain on the tibia after a fibula fracture. Histological and biomechanical results are congruent with predictions derived from this hypothesis. Histologically, the outgrowths are constituted by radial fibrolamellar periosteal bone tissue formed at very high growth rates, as expected in a process of rapid strain equilibration response. These outgrowths show greater compactness at the periphery, where tensile and compressive biomechanical constraints are higher. Moreover, these outgrowths increase the maximum bending strength in the direction of the stresses derived from locomotion. They are located on the antero-lateral side of the tibia, as expected in a presumably bipedal one year old individual, and in the posterior position of the tibia, as expected in a presumably quadrupedal individual at least four years of age. These results reinforce myological evidence suggesting that Maiasaura underwent an ontogenetic shift from the primitive ornithischian bipedal condition when young to a derived quadrupedal posture when older.


Associations With Definitive Outcomes and Clinical Benefit of Cancer Drugs at the Time of Marketing Approval and in the Postmarketing Period.
Most anticancer drugs are approved by regulatory agencies based on surrogate measures. This article explores the variables associated with overall survival (OS), quality of life (QoL), and substantial clinical benefit among anticancer drugs at the time of approval and in the postmarketing period. Anticancer drugs approved by the FDA between January 2006 and December 2015 and with postmarketing follow-up until April 2019 were identified. We evaluated trial-level data supporting approval and any updated OS and/or QoL data. We applied the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the ASCO Value Framework (ASCO-VF) to initial and follow-up studies. We found that 58 drugs were approved for 96 indications based on 96 trials. At registration, approval was based on improved OS in 39 trials (41%) and improved QoL in 16 of 45 indications (36%). Postmarketing data showed an improvement in OS for 28 of 59 trials (47%) and in QoL for 22 of 48 indications (46%). At the time of approval, 25 of 94 (27%) and 26 of 80 scorable trials (33%) met substantial benefit thresholds using the ESMO-MCBS and ASCO-VF, respectively. In the postmarketing period, 37 of 69 (54%) and 35 of 65 (54%) trials met the substantial benefit thresholds. Drugs with companion diagnostics and immune checkpoint inhibitors were associated significantly with substantial clinical benefit. Compared with the time of approval, more anticancer drugs showed improved OS and QoL and met the ESMO-MCBS or ASCO-VF thresholds for substantial benefit over the course of postmarketing time. However, only approximately half of the trials met the threshold for substantial benefit. Companion diagnostic drugs and immunotherapy seemed to be associated with greater clinical benefit.