Transmembrane-4 superfamily proteins CD81 (TAPA-1), CD82, CD63, and CD53 specifically associated with integrin alpha 4 beta 1 (CD49d/CD29).
Anti-alpha 4 integrin mAb coprecipitated CD81 (TAPA-1), a 25-kDa cell surface protein, from various alpha 4 beta1 -positive hemopoietic cell lines, including Molt4, Jurkat, Ramos, and alpha 4-transfected K562 (KX4C4) cells. In reciprocal experiments, the integrin alpha 4 beta 1 (VLA4, CD49d/CD29) could be reprecipitated from CD81 immunoprecipitates. Anti-alpha 4 integrin mAb also coprecipitated CD81 from the alpha 4 beta 7-positive B cell line RPMI 8866. In contrast, no CD81 was identified in alpha 2 beta 1, alpha 5 beta 1, or alpha L beta 2 immunoprecipitates. Abs to other members of the transmembrane-4 superfamily, including CD53, CD63, and CD82, also coprecipitated alpha 4 beta 1. As shown by confocal microscopy, CD81 and CD82 colocalized with alpha 4 beta 1 in cell surface clusters. The cytoplasmic domain of the alpha 4 integrin was not necessary for alpha 4 beta 1/CD81 association, nor was the association influenced by divalent cations, EDTA, integrin-activating mAb, or alpha 4 subunit cleavage. Notably, two independent alpha 4 adhesion-deficient mutants (D346E and D408E) were deficient in their ability to associate with CD81. Thus, CD81 and other transmembrane-4 superfamily members may participate in functionally relevant interactions with alpha 4 beta 1 and other integrins.


Immunoglobulin E reactivity of recombinant allergen Tyr p 13 from Tyrophagus putrescentiae homologous to fatty acid binding protein.
The storage mite, Tyrophagus putrescentiae, is one of the important causes of allergic disorders. Fifteen allergenic components were demonstrated in storage mite by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting, but only the group 2 allergen Tyr p 2 has been cloned and characterized. In this study, we attempted to identify and characterize new allergens from T. putrescentiae, which is a dominant species of storage mite in Korea. Expressed sequence tags were analyzed to identify possible storage mite allergens, and the cDNA sequence encoding a protein homologous to fatty acid binding protein, a mite group 13 allergen, was identified and named Tyr p 13. Its deduced amino acid sequence showed 61.1 to 85.3% identity with other mite group 13 allergens. The recombinant protein was expressed in Escherichia coli using a pET 28b vector system, and its allergenicity was investigated by enzyme-linked immunosorbent assay (ELISA). The recombinant allergen was detected in 5 of 78 (6.4%) T. putrescentiae-positive sera tested, and it inhibited 61.9% of immunoglobulin E binding to crude extract at an inhibitor concentration of 10 mug/ml by inhibition ELISA using serum from the patient who showed the strongest reaction by ELISA. In this study, a novel allergen was identified in T. putrescentiae. This allergen could be helpful for more-detailed characterizations of storage mite allergy.


Association of Hg2+ with aqueous (C60)n aggregates facilitates increased bioavailability of Hg2+ in Zebrafish (Danio rerio).
Manufactured nanoparticles (NPs) can associate with toxicants in the aqueous phase and these associations can influence the environmental fate, transport, and bioavailability of these toxicants in organisms. Dissolved metals (e.g., Hg(2+)) can be toxic in aquatic organisms, and, if metals associate with NPs in the aqueous phase, changes in bioavailability and toxicology may result. Here we demonstrated that Hg(2+) (25 μg/L) can associate with aqueous (C60)n (termed nC60) and increase aggregate size and settlement of nC60 aggregates out of the water column over 24 h. The concentration of C60 was directly related to concentration of Hg for nC60 aggregates that settled to the bottom of the container. Bioavailability of Hg(2+) in larval zebrafish Danio rerio, evaluated by assessment of metallothionein gene (mt2) expression, was reduced in the water column when nC60was present. However, zebrafish residing at the container bottom and exposed to nC60 aggregates with associated Hg(2+) had elevated expression of mt2 when compared to fish exposed to 25 μg/L Hg(2+) preparations without nC60, which indicated nC60 led to a localized increase in Hg(2+) bioavailability. Results indicate that aqueous nC60 can sorb Hg(2+), transport Hg(2+) to substrate surface, and increase concentrations of bioavailable Hg(2+) in organisms located where settled nC60 aggregates accumulate.


Blinding trachoma in katsina state, Nigeria: population-based prevalence survey in ten local government areas.
To assess the prevalence of trachomatous inflammation follicular (TF) in children aged 1-9 years and trachomatous trichiasis (TT) in adults aged 15 years or more in Katsina State, Nigeria. Cross sectional population-based trachoma prevalence surveys were conducted using multistage cluster random sampling methodology and the WHO simplified grading system for trachoma in ten local government areas (LGAs). Individual and household risk factors were recorded using a standard questionnaire. A total of 11,407 children and 8,901 adults from 2,244 households were surveyed. Prevalence of TF in children aged 1-9 years ranged from 5.0 to 24.0%. Five LGAs exceeded the 10% threshold for intervention and a further three exceeded 10% in the 95% confidence limits. The prevalence of TT in adults aged 15 years or more ranged from 2.3 to 8.0%: all ten LGAs exceeded the 1% intervention threshold. Analysis of risk factors for active trachoma (TF and/or TI) in children showed the following significant independent associations: Presence of ocular discharge OR = 2.34 (95%CI 1.81-3.03); presence of nasal discharge OR = 1.44 (1.22-1.70); reported frequency of face washing once versus at least twice per day OR = 1.27 (1.02-1.58); disposal of trash inside the compound OR = 1.23 (1.02-1.48); and the absence of a household latrine OR = 1.43 (1.15-1.78). A trachoma control program is warranted in Katsina. Surgical interventions to correct TT are needed immediately in all LGAs surveyed and the full SAFE strategy is justified for five of the ten LGAs, and possibly for another three.


Effects of prolonged exposure to perchlorate on thyroid and reproductive function in zebrafish.
The objectives of this study were to determine the effects of prolonged exposure to perchlorate on (1) thyroid status and reproductive performance of adult zebrafish (Danio rerio) and (2) F1 embryo survival and early larval development. Using a static-renewal procedure, mixed sex populations of adult zebrafish were exposed to 0, 10, and 100 mg/l nominal concentrations of waterborne perchlorate for 10 weeks. Thyroid histology was qualitatively assessed, and females and males were separated and further exposed to their respective treatments for six additional weeks. Eight females in each tank replicate (n = 3) were paired weekly with four males from the same respective treatment, and packed-egg (spawn) volume (PEV) was measured each of the last five weeks. At least once during weeks 14-16 of exposure, other end points measured included fertilization rate, fertilized egg diameter, hatching rate, standard length, and craniofacial development of 4-day-postfertilization larvae and thyroid hormone content of 3.5-h embryos and of exposed mothers. At 10 weeks of exposure, perchlorate at both concentrations caused thyroidal hypertrophy and colloid depletion. A marked reduction in PEV was observed toward the end of the 6-week spawning period, but fertilization and embryo hatching rates were unaffected. Fertilized egg diameter and larval length were increased by parental exposure to perchlorate. Larval head depth was unaffected but the forward protrusion of the lower jaw-associated cartilage complexes, Meckel's and ceratohyal, was decreased. Exposure to both concentrations of perchlorate inhibited whole-body thyroxine content in mothers and embryos, but triiodothyronine content was unchanged. In conclusion, prolonged exposure of adult zebrafish to perchlorate not only disrupts their thyroid endocrine system but also impairs reproduction and influences early F1 development.


The autophagy sensor ITPR1 protects renal carcinoma cells from NK-mediated killing.
Clear cell renal cell carcinoma (ccRCC) is dominated by inactivating mutations in VHL (von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase), leading to constitutive activation of the hypoxia-inducible factors (HIFs) and induction of a hypoxia response transcription signature. Our study demonstrated that VHL mutation results in the acquisition of ccRCC resistance to NK-mediated lysis by a mechanism involving EPAS1/HIF-2α stabilization. More importantly we identified ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of EPAS1 and as a potent regulator of NK-mediated killing through the activation of autophagy in target cells by a signal derived from NK cells. Therefore, it is conceivable to consider EPAS1 or the autophagy sensor ITPR1 as a potential target in future therapeutic protocols that aim to improve NK cell responses in patients with RCC and other solid malignancies.


Staphylococcus petrasii diagnostics and its pathogenic potential enhanced by mobile genetic elements.
Staphylococcus petrasii is recently described coagulase negative staphylococcal species and an opportunistic human pathogen, still often misidentified in clinical specimens. Four subspecies are distinguished in S. petrasii by polyphasic taxonomical analyses, however a comparative study has still not been done on the majority of isolates and their genome properties have not yet been thoroughly analysed. Here, we describe the phenotypic and genotypic characteristics of 65 isolates and the results of de novo sequencing, whole genome assembly and annotation of draft genomes of five strains. The strains were identified by MALDI-TOF mass spectrometry to the species level and the majority of the strains were identified to the subspecies level by fingerprinting methods, (GTG)5 repetitive PCR and ribotyping. Macrorestriction profiling by pulsed-field gel electrophoresis was confirmed to be a suitable strain typing method. Comparative genomics revealed the presence of new mobile genetic elements carrying antimicrobial resistance factors such as staphylococcal cassette chromosome (SCC) mec, transposones, phage-inducible genomic islands, and plasmids. Their mosaic structure and similarity across coagulase-negative staphylococci and Staphylococcus aureus suggest the possible exchange of these elements. Numerous putative virulence factors such as adhesins, autolysins, exoenzymes, capsule formation genes, immunomodulators, the phage-associated sasX gene, and SCC-associated spermidine N-acetyltransferase gene, pseudouridine and sorbitol utilization operons might explain clinical manifestations of S. petrasii isolates. The increasing recovery of S. petrasii isolates from human clinical material, the multi-drug resistance including methicillin resistance of S. petrasii subsp. jettensis strains, and virulence factors homologous to other pathogenic staphylococci demonstrate the importance of the species in human disease.


'Participation': a systematic review of language, definitions, and constructs used in intervention research with children with disabilities.
Improving participation of children with disabilities is a priority; however, the participation construct lacks clarity. This systematic review investigated how researchers defined 'participation' and the language used in participation intervention research. Nine health and education databases were searched for intervention studies of children with disabilities that included a participation outcome. Quantitative data were extracted using a customized form, and participation text data were extracted verbatim. Themes were derived using a thematic coding approach. These participation themes were applied to the outcome measures used in the included studies to compare participation language with the methods used to quantify participation changes. Of the 2257 articles retrieved, 25 were included in this review. Five participation themes and nine subthemes were developed. Two themes, attendance and involvement, were directly related to the participation construct. Three additional themes described related concepts: preferences, activity competence, and sense of self. Attendance and involvement seem to describe the essence of the participation concept. The related themes may provide important avenues to enhance participation outcomes. This review highlighted the need for researchers to define the construct under investigation clearly and select measures carefully, as measurement choice is the mechanism through which the concept is operationalized in research.


Emotional intelligence increases over time: A longitudinal study of Australian pre-registration nursing students.
Emotional intelligence (EI) has been associated with positive outcomes for nursing students. Higher EI is associated with personal wellbeing and stress management, higher academic performance, stronger nursing leadership and practice performance, and greater patient safety. While there is an increasing body of evidence on nursing students' EI, there is minimal evidence on EI over time during pre-registration programs. To measure EI in pre-registration nursing students from program commencement to conclusion to ascertain EI over time and examine the relationship between EI and academic performance. Longitudinal repeated measures study between March 2010-February 2013 at a metropolitan university in Australia. 111 nursing students (74.8% female) contributed data on at least two occasions. Participants were enrolled in a pre-registration Master of Nursing degree. Half the cohort (55.0%) comprised Graduate Entry students who completed the course in two years full time. The other 45% were enrolled in an undergraduate degree in arts, science or health science, combined with the same pre-registration Master of Nursing Degree. These students completed their Combined Degree program in four years full time. Participants had a mean age of 24.7years (SD=7.36). EI was measured for commencing students (T1) using the Assessing Emotions Scale (AES), then a further three times: end of first year (T2; 9 months follow up); beginning of second year (12 months follow up; T3) and end of the program (T4; 24/36 months follow up). Students' EI was found to increase across the program; one subscale of EI (managing others' emotions) was related to higher academic performance; and there was a significant increase in the Utilising Emotions subscale scores over time. Pre-registration nurse education contributes to strengthening students' EI over time. Specific EI education scaffolded throughout programs is recommended in pre-registration curricula.


[Results or pelvi-perineal rehabilitation in patients with pelvic floor dyssynergia].
Pelvic floor dyssynergia (PPD) is a common cause of outlet obstruction constipation. Treatment for this condition is based on pelvi-perineal re-education (PPR). The aim of this study was to evaluate the results of PPR on patients with PPD METHODS: Patients with the diagnosis of PPD were included. The study was conducted between 2010 and 2011. PPR was performed by specialized kinesiologists. Prior and after treatment a constipation questionnaire was performed (KESS) (scale from 0 to 39 points, a higher score is associated with more symptom severity). KESS score before and after PPR were compared. Mann-Whitney-Wilcoxon rank sum test for paired samples was used for statistical analysis, p value <0,05 was considered as significant. Thirteen patients were included (11 women), mean age 44.3 years old (r: 18-76). Mean total KESS score prior and after PPR were 19.6 (SD: 5.8) and 12.6 (DS: 63), respectively (P=.002). Frequency of bowel movements, stool consistency, abdominal pain and abdominal bloating did not present statistically significant changes before and after treatment. Use of laxatives, enemas and/or digitations, as well as unsuccessful evacuation, feelings of incomplete evacuation improved significantly. Total evacuation time (before 1.53 vs after 1; P=.012) and difficult evacuation causing painful efforts (before 2.08 vs after 1.07; P=.001) also decreased significantly. PPR in patients with PPD, significantly improves the symptoms of obstructive constipation, mainly with respect to mechanical assistance and difficult evacuation.


DNA replication and damage checkpoints and meiotic cell cycle controls in the fission and budding yeasts.
The cell cycle checkpoint mechanisms ensure the order of cell cycle events to preserve genomic integrity. Among these, the DNA-replication and DNA-damage checkpoints prevent chromosome segregation when DNA replication is inhibited or DNA is damaged. Recent studies have identified an outline of the regulatory networks for both of these controls, which apparently operate in all eukaryotes. In addition, it appears that these checkpoints have two arrest points, one is just before entry into mitosis and the other is prior to chromosome separation. The former point requires the central cell-cycle regulator Cdc2 kinase, whereas the latter involves several key regulators and substrates of the ubiquitin ligase called the anaphase promoting complex. Linkages between these cell-cycle regulators and several key checkpoint proteins are beginning to emerge. Recent findings on post-translational modifications and protein-protein interactions of the checkpoint proteins provide new insights into the checkpoint responses, although the functional significance of these biochemical properties often remains unclear. We have reviewed the molecular mechanisms acting at the DNA-replication and DNA-damage checkpoints in the fission yeast Schizosaccharomyces pombe, and the modifications of these controls during the meiotic cell cycle. We have made comparisons with the controls in fission yeast and other organisms, mainly the distantly related budding yeast.


Hydroxyproline Metabolism and Oxalate Synthesis in Primary Hyperoxaluria.
Background Endogenous oxalate synthesis contributes to calcium oxalate stone disease and is markedly increased in the inherited primary hyperoxaluria (PH) disorders. The incomplete knowledge regarding oxalate synthesis complicates discovery of new treatments. Hydroxyproline (Hyp) metabolism results in the formation of oxalate and glycolate. However, the relative contribution of Hyp metabolism to endogenous oxalate and glycolate synthesis is not known.Methods To define this contribution, we performed primed, continuous, intravenous infusions of the stable isotope [15N,13C5]-Hyp in nine healthy subjects and 19 individuals with PH and quantified the levels of urinary 13C2-oxalate and 13C2-glycolate formed using ion chromatography coupled to mass detection.Results The total urinary oxalate-to-creatinine ratio during the infusion was 73.1, 70.8, 47.0, and 10.6 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3 and controls, respectively. Hyp metabolism accounted for 12.8, 32.9, and 14.8 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3, respectively, compared with 1.6 mg oxalate/g creatinine in controls. The contribution of Hyp to urinary oxalate was 15% in controls and 18%, 47%, and 33% in subjects with PH1, PH2, and PH3, respectively. The contribution of Hyp to urinary glycolate was 57% in controls, 30% in subjects with PH1, and <13% in subjects with PH2 or PH3.Conclusions Hyp metabolism differs among PH types and is a major source of oxalate synthesis in individuals with PH2 and PH3. In patients with PH1, who have the highest urinary excretion of oxalate, the major sources of oxalate remain to be identified.


Ether Anesthesia in the Austere Environment: An Exposure and Education.
Medical services in the austere and limited environment often require therapeutics and practices uncommon in modern times due to a lack of availability, affordability, or expertise in remote areas. In this setting, diethyl ether, or simply ether anesthesia, still serves a role today as an effective inhalation agent. An understanding of ether as an anesthetic not only illustrates the evolution in surgical anesthesia but also demonstrates ether's surviving function and durable use as a practical agent in developing nations. Although uncommon, it is not unseen, so a working knowledge should be understood if observation and advocacy for patients receiving this method of anesthesia are experienced.


Statistical evaluation of the feasibility of satellite-retrieved cloud parameters as indicators of PM2.5 levels.
The spatial and temporal characteristics of fine particulate matter (PM2.5, particulate matter <2.5 μm in aerodynamic diameter) are increasingly being studied from satellite aerosol remote sensing data. However, cloud cover severely limits the coverage of satellite-driven PM2.5 models, and little research has been conducted on the association between cloud properties and PM2.5 levels. In this study, we analyzed the relationships between ground PM2.5 concentrations and two satellite-retrieved cloud parameters using data from the Southeastern Aerosol Research and Characterization (SEARCH) Network during 2000-2010. We found that both satellite-retrieved cloud fraction (CF) and cloud optical thickness (COT) are negatively associated with PM2.5 levels. PM2.5 speciation and meteorological analysis suggested that the main reason for these negative relationships might be the decreased secondary particle generation. Stratified analyses by season, land use type, and site location showed that seasonal impacts on this relationship are significant. These associations do not vary substantially between urban and rural sites or inland and coastal sites. The statistically significant negative associations of PM2.5 mass concentrations with CF and COT suggest that satellite-retrieved cloud parameters have the potential to serve as predictors to fill the data gap left by satellite aerosol optical depth in satellite-driven PM2.5 models.


Accuracy of stated energy contents of restaurant foods.
National recommendations for the prevention and treatment of obesity emphasize reducing energy intake. Foods purchased in restaurants provide approximately 35% of the daily energy intake in US individuals but the accuracy of the energy contents listed for these foods is unknown. To examine the accuracy of stated energy contents of foods purchased in restaurants. A validated bomb calorimetry technique was used to measure dietary energy in food from 42 restaurants, comprising 269 total food items and 242 unique foods. The restaurants and foods were randomly selected from quick-serve and sit-down restaurants in Massachusetts, Arkansas, and Indiana between January and June 2010. The difference between restaurant-stated and laboratory-measured energy contents, which were corrected for standard metabolizable energy conversion factors. The absolute stated energy contents were not significantly different from the absolute measured energy contents overall (difference of 10 kcal/portion; 95% confidence interval [CI], -15 to 34 kcal/portion; P = .52); however, the stated energy contents of individual foods were variable relative to the measured energy contents. Of the 269 food items, 50 (19%) contained measured energy contents of at least 100 kcal/portion more than the stated energy contents. Of the 10% of foods with the highest excess energy in the initial sampling, 13 of 17 were available for a second sampling. In the first analysis, these foods contained average measured energy contents of 289 kcal/portion (95% CI, 186 to 392 kcal/portion) more than the stated energy contents; in the second analysis, these foods contained average measured energy contents of 258 kcal/portion (95% CI, 154 to 361 kcal/portion) more than the stated energy contents (P <.001 for each vs 0 kcal/portion difference). In addition, foods with lower stated energy contents contained higher measured energy contents than stated, while foods with higher stated energy contents contained lower measured energy contents (P <.001). Stated energy contents of restaurant foods were accurate overall. However, there was substantial inaccuracy for some individual foods, with understated energy contents for those with lower energy contents.


Nutritional correlates of koala persistence in a low-density population.
It is widely postulated that nutritional factors drive bottom-up, resource-based patterns in herbivore ecology and distribution. There is, however, much controversy over the roles of different plant constituents and how these influence individual herbivores and herbivore populations. The density of koala (Phascolarctos cinereus) populations varies widely and many attribute population trends to variation in the nutritional quality of the eucalypt leaves of their diet, but there is little evidence to support this hypothesis. We used a nested design that involved sampling of trees at two spatial scales to investigate how leaf chemistry influences free-living koalas from a low-density population in south east New South Wales, Australia. Using koala faecal pellets as a proxy for koala visitation to trees, we found an interaction between toxins and nutrients in leaves at a small spatial scale, whereby koalas preferred trees with leaves of higher concentrations of available nitrogen but lower concentrations of sideroxylonals (secondary metabolites found exclusively in eucalypts) compared to neighbouring trees of the same species. We argue that taxonomic and phenotypic diversity is likely to be important when foraging in habitats of low nutritional quality in providing diet choice to tradeoff nutrients and toxins and minimise movement costs. Our findings suggest that immediate nutritional concerns are an important priority of folivores in low-quality habitats and imply that nutritional limitations play an important role in constraining folivore populations. We show that, with a careful experimental design, it is possible to make inferences about populations of herbivores that exist at extremely low densities and thus achieve a better understanding about how plant composition influences herbivore ecology and persistence.


Influence of uncertain electrical properties on the conditions for the onset of electroporation in an eukaryotic cell.
A detailed numerical investigation concerning the influence on the electrical response of an eukaryotic cell model due to the variations of the conductivity and permittivity of the plasma and nuclear membranes is carried out by means of a vertex analysis. The dynamics of three cell performances, the voltages across the external and the nuclear membrane, and the pores density are analyzed by adopting a novel FEM-based model coupled with the nonlinear equation describing the electroporation (EP) phenomenon. The variations of the electrical and morphological performances, when the cell is stressed by a nonideal step input, are studied in three interesting regimes, i.e., at the nominal threshold for the onset of EP, and when the applied stress is over or under the EP threshold. The performed numerical analysis puts in evidence that, around the nominal EP threshold, uncertainties may lead to an indeterminate state of the plasma membrane, whereas the other two regimes remain well definite.


Alternative tumour necrosis factor inhibitors (TNFi) or abatacept or rituximab following failure of initial TNFi in rheumatoid arthritis: the SWITCH RCT.
Rheumatoid arthritis (RA), the most common autoimmune disease in the UK, is a chronic systemic inflammatory arthritis that affects 0.8% of the UK population. To determine whether or not an alternative class of biologic disease-modifying antirheumatic drugs (bDMARDs) are comparable to rituximab in terms of efficacy and safety outcomes in patients with RA in whom initial tumour necrosis factor inhibitor (TNFi) bDMARD and methotrexate (MTX) therapy failed because of inefficacy. Multicentre, Phase III, open-label, parallel-group, three-arm, non-inferiority randomised controlled trial comparing the clinical and cost-effectiveness of alternative TNFi and abatacept with that of rituximab (and background MTX therapy). Eligible consenting patients were randomised in a 1 : 1 : 1 ratio using minimisation incorporating a random element. Minimisation factors were centre, disease duration, non-response category and seropositive/seronegative status. UK outpatient rheumatology departments. Patients aged ≥ 18 years who were diagnosed with RA and were receiving MTX, but had not responded to two or more conventional synthetic disease-modifying antirheumatic drug therapies and had shown an inadequate treatment response to a first TNFi. Alternative TNFi, abatacept or rituximab (and continued background MTX). The primary outcome was absolute reduction in the Disease Activity Score of 28 joints (DAS28) at 24 weeks post randomisation. Secondary outcome measures over 48 weeks were additional measures of disease activity, quality of life, cost-effectiveness, radiographic measures, safety and toxicity. Owing to third-party contractual issues, commissioning challenges delaying centre set-up and thus slower than expected recruitment, the funders terminated the trial early. Between July 2012 and December 2014, 149 patients in 35 centres were registered, of whom 122 were randomised to treatment (alternative TNFi, n = 41; abatacept, n = 41; rituximab, n = 40). The numbers, as specified, were analysed in each group [in line with the intention-to-treat (ITT) principle]. Comparing alternative TNFi with rituximab, the difference in mean reduction in DAS28 at 24 weeks post randomisation was 0.3 [95% confidence interval (CI) -0.45 to 1.05] in the ITT patient population and -0.58 (95% CI -1.72 to 0.55) in the per protocol (PP) population. Corresponding results for the abatacept and rituximab comparison were 0.04 (95% CI -0.72 to 0.79) in the ITT population and -0.15 (95% CI -1.27 to 0.98) in the PP population. General improvement in the Health Assessment Questionnaire Disability Index, Rheumatoid Arthritis Quality of Life and the patients' general health was apparent over time, with no notable differences between treatment groups. There was a marked initial improvement in the patients' global assessment of pain and arthritis at 12 weeks across all three treatment groups. Switching to alternative TNFi may be cost-effective compared with rituximab [incremental cost-effectiveness ratio (ICER) £5332.02 per quality-adjusted life-year gained]; however, switching to abatacept compared with switching to alternative TNFi is unlikely to be cost-effective (ICER £253,967.96), but there was substantial uncertainty in the decisions. The value of information analysis indicated that further research would be highly valuable to the NHS. Ten serious adverse events in nine patients were reported; none were suspected unexpected serious adverse reactions. Two patients died and 10 experienced toxicity. The results will add to the randomised evidence base and could be included in future meta-analyses. How to manage first-line TNFi treatment failures remains unresolved. Had the trial recruited to target, more credible evidence on whether or not either of the interventions were non-inferior to rituximab may have been provided, although this remains speculative. Current Controlled Trials ISRCTN89222125 and ClinicalTrials.gov NCT01295151. 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. 34. See the NIHR Journals Library website for further project information.


Lattice-Boltzmann method for the simulation of transport phenomena in charged colloids.
We present a simulation scheme based on the lattice-Boltzmann method to simulate the dynamics of charged colloids in an electrolyte. In our model we describe the electrostatics on the level of a Poisson-Boltzmann equation and the hydrodynamics of the fluid by the linearized Navier-Stokes equations. We verify our simulation scheme by means of a Chapman-Enskog expansion. Our method is applied to the calculation of the reduced sedimentation velocity U/U(0) for a cubic array of charged spheres in an electrolyte. We show that we recover the analytical solution first derived by Booth [F. Booth, J. Chem. Phys. 22, 1956 (1954)] for a weakly charged, isolated sphere in an unbounded electrolyte. The present method makes it possible to go beyond the Booth theory, and we discuss the dependence of the sedimentation velocity on the charge of the spheres. Finally we compare our results to experimental data.


Current Status of Loop-Mediated Isothermal Amplification Technologies for the Detection of Honey Bee Pathogens.
Approximately one-third of the typical human Western diet depends upon pollination for production, and honey bees (Apis mellifera) are the primary pollinators of numerous food crops, including fruits, nuts, vegetables, and oilseeds. Regional large scale losses of managed honey bee populations have increased significantly during the last decade. In particular, asymptomatic infection of honey bees with viruses and bacterial pathogens are quite common, and co-pathogenic interaction with other pathogens have led to more severe and frequent colony losses. Other multiple environmental stress factors, including agrochemical exposure, lack of quality forage, and reduced habitat, have all contributed to the considerable negative impact upon bee health. The ability to accurately diagnose diseases early could likely lead to better management and treatment strategies. While many molecular diagnostic tests such as real-time PCR and MALDI-TOF mass spectrometry have been developed to detect honey bee pathogens, they are not field-deployable and thus cannot support local apiary husbandry decision-making for disease control. Here we review the field-deployable technology termed loop-mediated isothermal amplification (LAMP) and its application to diagnose honey bee infections.


The effect of spatial-temporal audiovisual disparities on saccades in a complex scene.
In a previous study we quantified the effect of multisensory integration on the latency and accuracy of saccadic eye movements toward spatially aligned audiovisual (AV) stimuli within a rich AV-background (Corneil et al. in J Neurophysiol 88:438-454, 2002). In those experiments both stimulus modalities belonged to the same object, and subjects were instructed to foveate that source, irrespective of modality. Under natural conditions, however, subjects have no prior knowledge as to whether visual and auditory events originated from the same, or from different objects in space and time. In the present experiments we included these possibilities by introducing various spatial and temporal disparities between the visual and auditory events within the AV-background. Subjects had to orient fast and accurately to the visual target, thereby ignoring the auditory distractor. We show that this task belies a dichotomy, as it was quite difficult to produce fast responses (<250 ms) that were not aurally driven. Subjects therefore made many erroneous saccades. Interestingly, for the spatially aligned events the inability to ignore auditory stimuli produced shorter reaction times, but also more accurate responses than for the unisensory target conditions. These findings, which demonstrate effective multisensory integration, are similar to the previous study, and the same multisensory integration rules are applied (Corneil et al. in J Neurophysiol 88:438-454, 2002). In contrast, with increasing spatial disparity, integration gradually broke down, as the subjects' responses became bistable: saccades were directed either to the auditory (fast responses), or to the visual stimulus (late responses). Interestingly, also in this case responses were faster and more accurate than to the respective unisensory stimuli.


Perforin binding to cells and lipid membranes determined by a simple competition assay.
Perforin-mediated lysis consists of at least three steps: perforin binding to the target cell, insertion into the plasma membrane, and polymerization to form pores. Perforin binding, the first step, is critical for pore formation. Accordingly, a competition assay was here established for detecting the perforin-binding activities of nucleated cells and lipid membrane vesicles such as cytoplasts or liposomes. The competition assay has certain advantages over the 51Cr release assay, since no isotope and less perforin are needed for the competition assay, and the perforin-binding activity of liposomes and proteolytic enzyme-treated and fixed nucleated cells can also be detected. The competition assay was used to study the mechanism of resistance of cytolytic T lymphocytes (CTL) to perforin-mediated lysis. The results from this assay indicate that perforin-binding activity is not a function of membrane rigidity, and that there is a direct correlation between the ability of cells to bind perforin and their susceptibility to lysis by perforin, i.e., resistant CTL and their corresponding cytoplasts bind perforin much less effectively than susceptible tumor cells and their cytoplasts. A model is proposed whereby a surface molecule or complex of molecules on CTL interferes with perforin-binding activity, thus protecting CTL from perforin-mediated lysis.


Carbene-functionalized single-walled carbon nanotubes and their electrical properties.
Pure metallic single-walled carbon nanotubes (m-SWCNTs) are very desirable for many electrode and interconnecting applications. However, the lack of reliable processing techniques to sort m-SWCNTs from the as-synthesized SWCNT samples is an obstacle to these applications. The effects of carbene-based covalent functionalization on the electrical properties of an isolated m-SWCNT, a semiconducting (s)-SWCNT, and a mixture network of both m- and s-SWCNTs are reported. For the first time, a semiconducting-to-metallic SWCNT transition upon dichlorocarbene functionalization is observed. Interestingly, the transition is reversible upon thermal annealing under ambient conditions. The electrical properties of m-SWCNTs remain largely unaffected whereas the on-state conductivity of s-SWCNTs is greatly reduced by this process, in agreement with the relevant theoretical predictions. These findings could pave the way for fabricating large-scale SWCNT-based interconnects and electrodes in full-carbon integrated circuits.


The Demographic and Neurocognitive Profile of Clients Diagnosed With Fetal Alcohol Spectrum Disorder in PATCHES Paediatrics Clinics Across Western Australia and the Northern Territory.
Fetal alcohol spectrum disorder (FASD) is a diagnosis relating to neurocognitive impairments associated with prenatal alcohol exposure. A key aspect of improving FASD diagnostic processes and management is understanding the demographic and neurocognitive profile of those living with FASD. The aim of this study was to describe the demographic and neurocognitive profile of the first 199 individuals diagnosed with FASD in PATCHES Paediatrics clinics. A retrospective cross-sectional descriptive study design was conducted with individuals diagnosed with FASD between 2013 and 2018 through a multidisciplinary team according to the Australian FASD Diagnostic Guidelines. Participants were primarily male 133 (66.8%) and Aboriginal Australian 147 (73.9%), aged 2 to 31 (mean 10.5), with 94 (47.3%) from remote or very remote parts of Western Australia. Participants came from low 119 (59.8%), medium 48 (24.1%), and high 32 (16.1%) socioeconomic (SE) backgrounds. Low SE background was found to be a predictor of number of sentinel facial features (Wald χ2 (1) = 4.03, p < 0.05). Most received a diagnosis of FASD with <3 sentinel features 165 (82.9%). Participants either had 6 or more 46 (23.1%), 5 44 (22.1%), 4 55 (27.6%), or 3 (27.1%) neurodevelopmental domains impaired. Executive functioning was the most commonly impaired neurodevelopmental domain 158 (79.4%), and 31 (61%) reported sleep disturbance. ADHD was the most observed comorbid condition (41.7%). This study improves our current understanding of neurocognitive and demographic profiles in individuals with FASD that have been clinically referred for diagnosis within Western Australia and the Northern Territory, and highlights the importance of prevention and early assessment/diagnosis as well as guidance regarding more targeted interventions. FASD affects individuals from all cultural and SE backgrounds. Individuals from middle to higher SE groups are at risk of FASD with prevention efforts needing to target these sectors of society. Suggestions for future research directions are also provided.


OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness.
Leber congenital amaurosis (LCA) encompasses a set of early-onset blinding diseases that are characterized by vision loss, involuntary eye movement, and nonrecordable electroretinogram (ERG). At least 19 genes are associated with LCA, which is typically recessive; however, mutations in homeodomain transcription factor CRX lead to an autosomal dominant form of LCA. The mechanism of CRX-associated LCA is not understood. Here, we identified a spontaneous mouse mutant with a frameshift mutation in Crx (CrxRip). We determined that CrxRip is a dominant mutation that results in congenital blindness with nonrecordable response by ERG and arrested photoreceptor differentiation with no associated degeneration. Expression of LCA-associated dominant CRX frameshift mutations in mouse retina mimicked the CrxRip phenotype, which was rescued by overexpression of WT CRX. Whole-transcriptome profiling using deep RNA sequencing revealed progressive and complete loss of rod differentiation factor NRL in CrxRip retinas. Expression of NRL partially restored rod development in CrxRip/+ mice. We show that the binding of homeobox transcription factor OTX2 at the Nrl promoter was obliterated in CrxRip mice and ectopic expression of OTX2 rescued the rod differentiation defect. Together, our data indicate that OTX2 maintains Nrl expression in developing rods to consolidate rod fate. Our studies provide insights into CRX mutation-associated congenital blindness and should assist in therapeutic design.


Peers at work: Evidence from the lab.
This paper reports the results of a lab experiment designed to study the role of observability for peer effects in the setting of a simple production task. In our experiment, participants in the role of workers engage in a team real-effort task. We vary whether they can observe, or be observed by, one of their co-workers. In contrast to earlier findings from the field, we find no evidence that low-productivity workers perform better when they are observed by high-productivity co-workers. Instead, our results imply that peer effects in our experiment are heterogeneous, with some workers reciprocating a high-productivity co-worker but others taking the opportunity to free ride.


Alternative induction of meiotic recombination from single-base lesions of DNA deaminases.
Meiotic recombination enhances genetic diversity as well as ensures proper segregation of homologous chromosomes, requiring Spo11-initiated double-strand breaks (DSBs). DNA deaminases act on regions of single-stranded DNA and deaminate cytosine to uracil (dU). In the immunoglobulin locus, this lesion will initiate point mutations, gene conversion, and DNA recombination. To begin to delineate the effect of induced base lesions on meiosis, we analyzed the effect of expressing DNA deaminases (activation-induced deaminase, AID, and APOBEC3C) in germ cells. We show that meiotic dU:dG lesions can partially rescue a spo11Delta phenotype in yeast and worm. In rec12 Schizosaccharomyces pombe, AID expression increased proper chromosome segregation, thereby enhancing spore viability, and induced low-frequency meiotic crossovers. Expression of AID in the germ cells of Caenorhabditis elegans spo-11 induced meiotic RAD-51 foci formation and chromosomal bivalency and segregation, as well as an increase in viability. RNAi experiments showed that this rescue was dependent on uracil DNA-glycosylase (Ung). Furthermore, unlike ionizing radiation-induced spo-11 rescue, AID expression did not induce large numbers of DSBs during the rescue. This suggests that the products of DNA deamination and base excision repair, such as uracil, an abasic site, or a single-stranded nick, are sufficient to initiate and alter meiotic recombination in uni- and multicellular organisms.


Effects of eye movement versus therapist instructions on the processing of distressing memories.
The effectiveness of components of eye movement desensitization and reprocessing (EMDR) was tested by randomly assigning 48 participants to either an eye movement or an eye stationary condition and to one of two types of therapist instructions (reliving or distancing). Participants were university students (mean age 23) who were asked to recall a personal distressing memory with measures of distress and vividness taken before and after treatment, and at follow-up. There was no significant effect of therapist's instruction on the outcome measures. There was a significant reduction in distress for eye movement at post-treatment and at follow-up but overall no significant reduction in vividness. Post hoc analysis revealed a significant reduction in vividness only for the eye movement and distancing instruction condition. The results were consistent with other evidence that the mechanism of change in EMDR is not the same as traditional exposure.


Hormone replacement therapy advertising: sense and nonsense on the web pages of the best-selling pharmaceuticals in Spain.
The balance of the benefits and risks of long term use of hormone replacement therapy (HRT) have been a matter of debate for decades. In Europe, HRT requires medical prescription and its advertising is only permitted when aimed at health professionals (direct to consumer advertising is allowed in some non European countries). The objective of this study is to analyse the appropriateness and quality of Internet advertising about HRT in Spain. A search was carried out on the Internet (January 2009) using the eight best-selling HRT drugs in Spain. The brand name of each drug was entered into Google's search engine. The web sites appearing on the first page of results and the corresponding companies were analysed using the European Code of Good Practice as the reference point. Five corporate web pages: none of them included bibliographic references or measures to ensure that the advertising was only accessible by health professionals. Regarding non-corporate web pages (n = 27): 41% did not include the company name or address, 44% made no distinction between patient and health professional information, 7% contained bibliographic references, 26% provided unspecific information for the use of HRT for osteoporosis and 19% included menstrual cycle regulation or boosting feminity as an indication. Two online pharmacies sold HRT drugs which could be bought online in Spain, did not include the name or contact details of the registered company, nor did they stipulate the need for a medical prescription or differentiate between patient and health professional information. Even though pharmaceutical companies have committed themselves to compliance with codes of good practice, deficiencies were observed regarding the identification, information and promotion of HRT medications on their web pages. Unaffected by legislation, non-corporate web pages are an ideal place for indirect HRT advertising, but they often contain misleading information. HRT can be bought online from Spain, without a medical consultation or prescription constituting a serious issue for public health. In our information society, it is the right and obligation of public health bodies to ensure that such information is not misleading.


Antioxidant activity of nanomaterials.
Nanomaterials represent one of the most promising frontiers in the research for improved antioxidants. Some nanomaterials, including organic (i.e. melanin, lignin) metal oxides (i.e. cerium oxide) or metal (i.e. gold, platinum) based nanoparticles, exhibit intrinsic redox activity that is often associated with radical trapping and/or with superoxide dismutase-like and catalase-like activities. Redox inactive nanomaterials can be transformed into antioxidants by grafting low molecular weight antioxidants on them. Herein, we propose a classification of nanoantioxidants based on their mechanism of action, and we review the chemical methods used to measure antioxidant activity by providing a rationale of the chemistry behind them.


Curcumin inhibits prosurvival pathways in chronic lymphocytic leukemia B cells and may overcome their stromal protection in combination with EGCG.
Chronic lymphocytic leukemia (CLL) is incurable with current chemotherapy treatments. Curcumin (diferuloylmethane), an active ingredient in the spice turmeric, inhibits tumor metastasis, invasion, and angiogenesis in tumor cell lines. We evaluated the effects of curcumin on the viability of primary CLL B cells and its ability to overcome stromal mediated protection. The in vitro effect of curcumin on primary CLL B cells was evaluated using fluorescence activated cell sorter analysis and Western blotting. For some experiments, CLL B cells were cocultured with human stromal cells to evaluate the effects of curcumin on leukemia cells cultured in their microenvironment. Finally, the effect of curcumin in combination with the green tea extract epigallocatechin-3 gallate (EGCG) was evaluated. Curcumin induced apoptosis in CLL B cells in a dose-dependent (5-20 micromol/L) manner and inhibited constitutively active prosurvival pathways, including signal transducers and activators of transcription 3 (STAT3), AKT, and nuclear factor kappaB. Moreover, curcumin suppressed expression of the anti-apoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP), and up-regulated the pro-apoptotic protein BIM. Coculture of CLL B cells with stromal cells resulted in elevated levels of STAT3, increased expression of Mcl-1 and XIAP, and decreased sensitivity to curcumin. When curcumin was administered simultaneously with EGCG, antagonism was observed for most patient samples. In contrast, sequential administration of these agents led to substantial increases in CLL B-cell death and could overcome stromal protection. Curcumin treatment was able to overcome stromal protection of CLL B cells on in vitro testing and to synergize with EGCG when administered in a sequential fashion. Additional evaluation of curcumin as a potential therapeutic agent for treatment of CLL seems warranted.


Fish mercury concentration in the Alto Pantanal, Brazil: influence of season and water parameters.
The tropical flood plain Pantanal is one of the world's largest wetlands and a wildlife sanctuary. Mercury (Hg) emissions from some upstream gold mining areas and recent findings of high natural Hg levels in tropical oxisols motivated studies on the Hg cycle in the Pantanal. A survey was made on total Hg in the most consumed piscivorous fish species from rivers and floodplain lakes in the north (Cáceres and Barão de Melgaço) and in the south part of Alto Pantanal (around the confluence of the Cuiabá and Paraguai rivers). Samples were collected in both the rainy and dry seasons (March and August 1998) and included piranha (Serrasalmus spp.), and catfish (Pseudoplatystoma coruscans, pintado, and Pseudoplatystoma fasciatum, cachara or surubim). There was only a small spatial variation in Hg concentration of the 185 analyzed fish samples from the 200 x 200 km large investigation area, and 90% contained total Hg concentration below the safety limit for regular fish consumption (500 ng g(-1)). Concentration above this limit was found in both Pseudoplatystoma and Serrasalmus samples from the Baia Siá Mariana, the only acid soft-water lake included in this study, during both the rainy and dry seasons. Concentration above this limit was also found in fish outside Baia Siá Mariana during the dry season, especially in Rio Cuiabá in the region of Barão de Melgaço. The seasonal effect may be connected with decreasing water volumes and changing habitat during the dry season. The results indicate that fertile women should restrict their consumption of piscivorous fishes from the Rio Cuiabá basin during the dry season. Measures should be implanted to avoid a further deterioration of fish Hg levels.


A randomized trial of peppermint gel, lanolin ointment, and placebo gel to prevent nipple crack in primiparous breastfeeding women.
Sore nipples are common during lactation and remain the major reason for failing to establish successful breastfeeding. To formulate a peppermint gel and to evaluate its effect on the prevention of nipple crack associated with breast-feeding, a randomized double-blinded clinical trial comparing the above formulation with modified lanolin and a neutral ointment was carried out. Two hundred and sixteen primiparous participants were assigned randomly to three groups. Each group applied only one of the above three preparations on both breasts for 14 days. Each group consisted of 72 primiparous mothers and was seen for a maximum of four follow-up visits within 14 days and a final visit at week 6. The rate of nipple and areola crack and pain was evaluated. The study groups were comparable in mean age and route of delivery. Nipple crack were less in mothers who received peppermint gel than in those who received lanolin ointment or placebo (chi(2)=16.8, df=6, P=0.01). Relative risk of nipple crack in the lanolin group (RR: 2.41, 95%CI: 1.20-3.01) was higher than in the peppermint group (RR: 1.85, 95%CI: 1.64-3.10). Prophylactic peppermint gel in breastfeeding lactating women is associated with fewer nipple cracks and is more effective than lanolin and placebo. It could be recommended for preventing of nipple crack along with teaching better breastfeeding technique at the initiation of breastfeeding.


Effects of Maternal Deprivation and Complex Housing on Rat Social Behavior in Adolescence and Adulthood.
Early life context and stressful experiences are known to increase the risk of developing psychiatric disorders later in life, including disorders with deficits in the social domain. Our study aimed to investigate the influence of early life environment on social behavior in a well-controlled animal model. To this end we tested the effects of maternal deprivation (MD) on rat social play behavior in adolescence and social interaction in adulthood. Additionally, we provided a stimulating environment during adolescence (complex housing) as a potential intervention to diminish the effects of early life stress. Male and female Wistar rats were deprived from their mother for 24 h on postnatal day 3 (PND 3) or were left undisturbed. Complex housing started 5 days after weaning and consisted of housing 10 same-sex conspecifics in large, two-floor MarlauTM cages until the end of the study. Social play behavior in adolescence was tested under different conditions (3 h vs. 24 h social isolation prior to testing). Maternally deprived males - but not females - showed a longer latency to play and a decreased total amount of social play behavior, after a 24 h isolation period. In adulthood, social discrimination was impaired in deprived male and female rats in the three-chamber social approach task. Complex housing did not moderate the effects of MD, but in itself induced a strong behavioral phenotype. Both complex housed males and females hardly displayed any play behavior after a 3 h isolation period. However, after 24 h of isolation, these animals showed shorter latencies to engage in social play behavior. Only complex housed males truly showed more social play behavior here, while showing less social interest in adulthood. We conclude that MD has mild negative effects on social behavior in adolescence and adulthood, which are not counteracted by complex housing. Complex housing induces a specific phenotype associated with rapid habituation; a lack of social play after short isolation periods, while increasing play behavior after a prolonged period of isolation in adolescence, and less social interest, paired with intact social discrimination in adulthood. In both early life settings, males seem to be more influenced by the early life environment compared to females.


Alice in Wonderland syndrome: A systematic review.
To summarize the literature on Alice in Wonderland syndrome (AIWS), a disorder characterized by distortions of visual perception, the body schema, and the experience of time. On the basis of 169 published case descriptions, the etiology of AIWS is divided into 8 main groups, with neurologic disorders affecting mostly adults and elderly patients and encephalitides affecting mostly patients aged ≤18 years. Symptoms of AIWS are also experienced in the general population, with up to 30% of adolescents reporting nonclinical symptoms. In clinical cases of AIWS, auxiliary investigations (including blood tests, EEG, and brain MRI) are strongly advised. Treatment should be directed at the suspected underlying condition, although reassurance that the symptoms themselves are not harmful seems to suffice in about 50% of the cases. International classifications such as the DSM and ICD should consider placing the syndrome on their research agenda.


Mapping epigenetic mutations in fission yeast using whole-genome next-generation sequencing.
Fission yeast is an important model for epigenetic studies due to the ease with which genetic mutants can be isolated. However, it can be difficult to complement epigenetic phenotypes with genomic libraries in order to identify the genes responsible. This is because epigenetic phenotypes are typically unstable, and can prohibit complementation if silencing cannot be reestablished. Here we have resequenced the fission yeast genome following mutagenesis to readily identify a novel mutant involved in heterochromatic silencing. Candidate genes were identified as functional single base changes linked to the mutation, which were then reconstituted in a wild-type strain to recapitulate the mutant phenotype. By this procedure we identified a weak allele of ubc4, which encodes an essential E2 ubiquitin ligase, as responsible for the swi*603 mutant phenotype. In combination with a large collection of mutants and suppressor plasmids, next-generation genomic resequencing promises to dramatically enhance the power of yeast genetics, permitting the isolation of subtle alleles of essential genes, alleles with quantitative effects, and enhancers and suppressors of heterochromatic silencing.


Biomarkers of disease activity in multiple sclerosis.
As therapeutic options for multiple sclerosis widen, validated biomarkers of clinical disease activity are urgently needed. Reliable biomarkers would assist in choosing initial therapy, monitoring response to therapy, detecting subclinical disease activity, predicting and possibly preventing therapeutic failure, and hopefully improving both short (relapses) and long-term (disability) outcomes. The presence of oligoclonal bands in the cerebrospinal fluid is a well-validated biomarker that is useful in initial diagnosis. Neutralizing antibodies to interferon-beta are also useful in identifying treatment failure and possibly guiding changes in therapy. The discovery of antibodies to aquaporin-4 in patients with neuromyelitis optica delineates patients with a fundamentally different underlying pathophysiology and clinical course who may require alternate therapeutic approaches. While numerous other candidate biomarkers in serum and cerebrospinal fluid have been described, none so far have the validated reliability necessary for widespread clinical use. The availability of multiple genetic and protein microarray technology may assist in identifying more reliable candidate biomarkers or patterns of multiple biomarkers and improve specificity. The heterogeneity of multiple sclerosis may necessitate individualized biomarkers and therapeutic decisions within distinct subsets of patients.


A mathematical model of idiopathic intracranial hypertension incorporating increased arterial inflow and variable venous outflow collapsibility.
A collapsible segment in the venous outflow has been noted in many patients with idiopathic intracranial hypertension (IIH). Mathematical modeling has shown that these collapsible segments can account for the elevated cerebrospinal fluid (CSF) pressures associated with IIH. However, the model required an elevated outflow resistance of up to 10 times normal to predict the CSF pressures actually found clinically. Measurement of blood flow in patients with IIH has shown that inflow rates vary, with higher rates noted in patients with lesser outflow stenoses. The aim of this work was to extend a simple model of cerebral hydrodynamics to accommodate a collapsible sinus and elevations in cerebral blood flow in accordance with in vivo measurements. Forty patients with IIH underwent MR imaging in which the degree of stenosis on MR venography was compared with the total blood inflow by using MR flow quantification. The relative outflow resistance in IIH was estimated using the CSF opening pressure. The patients were compared with 14 age-matched control individuals. Patients were divided into 3 groups based on MR venography appearances (minimal stenosis, stenosis of 40-70% and > 70% stenosis). In vivo measurements suggested a relative resistance elevation of 2.5 times normal, 4.2 times normal, and 4.8 times normal in the 3 groups, respectively. There was an increased inflow of 1.56 times normal, 1.28 times normal, and 1.19 times normal in these groups. The model correctly predicted the CSF pressures noted in vivo, suggesting that high arterial inflow is required for patients with low-grade stenoses to be symptomatic.


Multiple sclerosis: risk factors and their interactions.
Multiple sclerosis (MS) is a highly debilitating immune mediated disorder of the central nervous system and represents a substantial burden to the developed world. Despite the recent advances in MS research, which risk factors are implicated and how they contribute to MS pathogenesis is largely unknown. However, in line with older studies investigating the genetic and geographical epidemiology of this complex disease, more recent studies have highlighted how MS arises from a combination of genetic susceptibility and environmental exposures acting from gestation to early adulthood. Vitamin D deficiency, season of birth, Epstein Barr virus infection, and smoking behaviour are strongly implicated and able to influence genetic predisposition to MS. Furthermore, these factors appear to act synergistically and the risk of MS in individuals exposed to more than one factor combines multiplicatively. Current evidence suggests that a large part of MS could be prevented and understanding how and when during life risk factors act will ultimately aid the development of prevention strategies.


Amontonian friction induced by flexible surface features on microstructured silicon.
Friction between nonadhering sliding surfaces are normally described by Amontons' law, which states that there exists a linear relationship between the friction force and the normal applied load and that the friction force is independent of the macroscopic contact area between the surfaces and the sliding velocity. In this study we have measured friction as a function of applied load between a spherical silica particle and a microstructured silicon surface consisting of arrays of vertical microneedles, and we have challenged Amontons' law by changing the size of the silica particle and the sliding velocity. First, when looking at the friction as a function of time for a given applied load, the friction force was observed to oscillate with a period related to the spacing between the microneedles when using a small silica particle, whereas the friction force exhibited a more random variation when a larger silica particle was used. The oscillation in the friction force is a direct evidence for bending and release of individual microneedles and the observation illustrates that the energy dissipating mechanism becomes hidden in the friction data when the dimensions of the sliding body becomes much larger than the length scale of the surface features causing the friction. Second, when looking at the average friction force as a function of applied load we find, in accordance with Amontons' law, a linear relationship between the friction force and the applied load and the friction force is independent of both the size of the sliding silica particle and of the sliding velocity. One exception from this, however, was observed when sliding a small silica particle at low velocity, where a deviation from Amontons' law was noticed. The deviation from Amontons' law is suggested to be attributed to a change in the energy dissipating mechanism giving rise to the friction force. In light of that it is suggested that Amontons' law only is valid as long as the main energy dissipating mechanism does not change with the applied load. To get a better understanding of the general validity of Amontons' law, our results were evaluated against different microscopic models.


Event-related potentials in the retina and optic tectum of fish.
1. Compound field potentials were recorded with up to 18 microelectrodes in comb, brush, or spear arrays on and in the optic tectum and with suction electrodes from the distal stump of the cut optic nerve and from the optic nerve head in the opened eye in elasmobranchs and teleosts. Diffuse light flashes of different durations and submaximal intensities were delivered in trains with regular or irregular interstimulus intervals (ISI). 2. Event-related potentials (ERPs) are visible in single trials and begin at 50-200 ms after an "oddball" flash, especially one that is slightly weaker, briefer, or delayed by as little as 6% of ISI, compared with the more frequent stimulus. ERPs to the opposite condition are not of the same form or size. 3. One or more stimuli were omitted from a train or the train terminated after various conditioning times. Deflections occur beyond the expected visual-evoked potentials (VEPs) to the last flash and are called omitted-stimulus potentials (OSPs). They occur on schedule--approximately 100 ms after the next flash would be due--almost independent of intensity, duration, or conditioning time. They are considered to be ERPs without any necessary implication or denial of a temporally specific expectation. 4. Three components of OSP occur alone or in combination: an initial fast peak, a slow wave, and an oscillatory spindle up to ls or more in duration. This resembles the OFF response to steady light. 5. All these components are already present in the retina with optic nerve cut. 6. The same mean ISI with a high proportion of jitter gives OSPs with only slightly longer latencies and smaller amplitudes; the OSP acts as though the retina makes an integrated prediction of ISI, intensity, and duration. 7. During a conditioning train the equilibrium between excitation and inhibition after each flash changes according to frequency, intensity, duration, and conditioning time; the VEP reflects this in a shape unique to the ISI; inhibition increases rapidly after each flash and then decays slowly according to the recent mean ISI. This allows rebound disinhibition after missing, weak, or delayed flashes (OSP or ERP) or causes an altered VEP after a longer or stronger oddball. 8. It seems unlikely that the OSP or oddball ERP in fish tectum is equivalent to mammalian ERPs under the same regime or signals higher cognitive events, because they are already present in the retina, require flash frequencies greater than 1 Hz, and grow with frequency up to and beyond flicker fusion.(ABSTRACT TRUNCATED AT 400 WORDS)


Chromium (VI)-induced transformation is enhanced by Zn deficiency in BALB/c 3T3 cells.
Hexavalent chromium [Cr(VI)] is a carcinogenic heavy metal that is reduced to intermediate oxidation states, such as Cr(V) and Cr(IV), in the process of forming stable Cr(III) forms; it is these intermediate forms that are thought to be responsible for much of the DNA damage and mutations that are induced by Cr(VI). Metallothionein (MT), a heavy metal-binding protein, is induced by zinc and other heavy metals and protects cells from the toxic effects of these metals by sequestering them. MT cannot bind Cr, but by scavenging reactive oxygen species through its cysteine residues, it may act as a protective factor against Cr(VI)-induced DNA lesions by reducing Cr(VI) directly to Cr(III), thereby avoiding the creation of the toxic intermediates. Here, we showed that Zn deficiency decreased MT expression in BALB/3T3 clone A31-1-1 cells and caused them to become highly susceptible to Cr(VI)-induced transformation. To obtain Zn-deficient cultures, cells were cultured in medium supplemented with 10% Chelex(®)-100 chelating resin-treated FBS. The increase in susceptibility to transformation was abolished by culturing the cells with supplemental Zn (50 µM). Previously, we reported that Cr(VI) inhibits MT transcription by preventing the zinc-dependent formation of a complex of metal response element-binding transcription factor-1 (MTF-1) and the co-activator p300. Our results suggest that the carcinogenicity of Cr(VI) is enhanced by MTF-1 dysfunction.


Structure-function relationships of the plant cuticle and cuticular waxes - a smart material?
The cuticle is the main interface between plants and their environment. It covers the epidermis of all aerial primary parts of plant organs as a continuous extracellular matrix. This hydrophobic natural composite consists mainly of the biopolymer, cutin, and cuticular lipids collectively called waxes, with a high degree of variability in composition and structure. The cuticle and cuticular waxes exhibit a multitude of functions that enable plant life in many different terrestrial habitats and play important roles in interfacial interactions. This review highlights structure-function relationships that are the subjects of current research activities. The surface waxes often form complex crystalline microstructures that originate from self-assembly processes. The concepts and results of the analysis of model structures and the influence of template effects are critically discussed. Recent investigations of surface waxes by electron and X-ray diffraction revealed that these could be assigned to three crystal symmetry classes, while the background layer is not amorphous, but has an orthorhombic order. In addition, advantages of the characterisation of formation of model wax types on a molecular scale are presented. Epicuticular wax crystals may cause extreme water repellency and, in addition, a striking self-cleaning property. The principles of wetting and up-to-date concepts of the transfer of plant surface properties to biomimetic technical applications are reviewed. Finally, biomechanical studies have demonstrated that the cuticle is a mechanically important structure, whose properties are dynamically modified by the plant in response to internal and external stimuli. Thus, the cuticle combines many aspects attributed to smart materials.


The role of carbonic anhydrase 9 in regulating extracellular and intracellular ph in three-dimensional tumor cell growths.
We have studied the role of carbonic anhydrase 9 (CA9), a cancer-associated extracellular isoform of the enzyme carbonic anhydrase in multicellular spheroid growths (radius of approximately 300 microm) of human colon carcinoma HCT116 cells. Spheroids were transfected with CA9 (or empty vector) and imaged confocally (using fluorescent dyes) for both intracellular pH (pH(i)) and pH in the restricted extracellular spaces (pH(e)). With no CA9 expression, spheroids developed very low pH(i) (approximately 6.3) and reduced pH(e) (approximately 6.9) at their core, associated with a diminishing gradient of acidity extending out to the periphery. With CA9 expression, core intracellular acidity was less prominent (pH(i) = approximately 6.6), whereas extracellular acidity was enhanced (pH(e) = approximately 6.6), so that radial pH(i) gradients were smaller and radial pH(e) gradients were larger. These effects were reversed by eliminating CA9 activity with membrane-impermeant CA inhibitors. The observation that CA9 activity reversibly reduces pH(e) indicates the enzyme is facilitating CO(2) excretion from cells (by converting vented CO(2) to extracellular H(+)), rather than facilitating membrane H(+) transport (such as H(+) associated with metabolically generated lactic acid). This latter process requires titration of exported H(+) ions with extracellular HCO(3)(-), which would reduce rather than increase extracellular acidity. In a multicellular structure, the net effect of CA9 on pH(e) will depend on the cellular CO(2)/lactic acid emission ratio (set by local oxygenation and membrane HCO(3)(-) uptake). Our results suggest that CO(2)-producing tumors may express CA9 to facilitate CO(2) excretion, thus raising pH(i) and reducing pH(e), which promotes tumor proliferation and survival. The results suggest a possible basis for attenuating tumor development through inhibiting CA9 activity.


Short-term clarithromycin administration impairs clearance and enhances pharmacodynamic effects of trazodone but not of zolpidem.
The kinetic and dynamic interactions of 5 mg zolpidem and 50 mg trazodone with 500 mg clarithromycin (4 doses given over 32 h) were investigated in a 5-way double crossover study with 10 healthy volunteers. The five treatment conditions were: placebo + placebo; zolpidem + placebo; zolpidem + clarithromycin; trazodone + placebo; and trazodone + clarithromycin. Coadministration of clarithromycin increased trazodone area under the curve, prolonged elimination half-life, increased peak plasma concentration (C(max)), and reduced oral clearance. In contrast, clarithromycin had no significant effect on any kinetic parameter for zolpidem. Clarithromycin did not potentiate sedation caused by zolpidem. However, clarithromycin coadministered with trazodone significantly increased self- and observer-rated sedation and ratings of feeling "spacey." Thus, short-term clarithromycin coadministration significantly impairs trazodone clearance, elevates plasma concentrations, and enhances sedative effects. However, clarithromycin has no significant kinetic or dynamic interaction with zolpidem.


Sequential therapy compared with combination therapy in multiple myeloma.
A timed sequential chemotherapeutic regimen for multiple myeloma was desinged, based on plasma cell kinetics. A randomized study comparing this regimen with the combination of intermittent melphalan and prednisone was started after an adequate pilot study. Studies with tritiated thymidine labeling and mitotic indexes were performed on patients treated with sequential therapy. Of 13 patients treated with the combination therapy, the responses were as follows: two, objective improvement; nine, subjective improvement; and two, no responses. Of nine patients treated with sequential therapy, the responses in six patients who could have evaluations were as follows: one, objective improvement; two, subjective improvement; one, no response; one, with progressive disease; and one, cardiac death. The two studies showed differences in pertubation of cell kinetics of myeloma that may be related to exponential growth and immunoblobulin types.


Electroencephalographic sleep of adolescents with major depression and normal controls.
Forty-nine, mostly outpatient (86%), nonbipolar adolescents, aged Tanner stage III to 18 years, with a current diagnosis of major depressive disorder and 40 adolescents without current presence or history of psychiatric disorder were studied polysomnographically for three consecutive nights. Sleep latency was significantly longer in the depressive groups. The nonendogenous depressive patients exhibited significantly more awake time and lower sleep efficiency during the sleep period. No significant group differences were found for first rapid eye movement (REM) period latency, REM density, or any other REM sleep measures. Age correlated significantly with REM latency and delta sleep time, especially among depressive patients. No significant correlations between sleep measures and severity of illness were found. It appears that the classic REM sleep findings associated with the adult depressive syndrome are not present among depressive adolescents, indicating a later ontogeny for these abnormalities.


EEG Neurofeedback therapy: Can it attenuate brain changes in TBI?
Electroencephalogram Neurofeedback therapy (EEG-NFT) has several potential beneficial effects in terms of improving cognition and electrophysiological regulation among patients with brain injury. However, in vivo structural and functional changes remain less explored. The aim of the present study is to explore EEG-NFT induced in vivo changes in traumatic brain injury (TBI) patients. Two patients with mean age of 15 years with moderate head injury who had more than seven post concussion symptoms and poor cognitive performances (<5 percentile) were subjected to 20 sessions of EEG-NFT. The neuropsychological test scores, post concussion symptoms and MRI scan of the brain were recorded pre-post to EEG-NFT. During EEG-NFT the cognitive scores and concussion symptoms improved significantly (p < 0.05). The EEG-NFT has shown significant increase in cortical grey matter (GM) volumes (p < 0.0001) and fractional anisotropy (FA) of cortical white matter (WM) tracts (p < 0.0001, voxel max 60 and above). There was a significant decrease in global, local efficiency, cost and clustering coefficient of functional connectivity (Wilcoxon Sign Rank Test p < 0.05). Interestingly there was a significant increase in thalamo-cortical connection (increase FA value) after EEG-NFT. The EEG-NFT therapy has shown significant changes in structural and functional connectivity among young moderately injured TBI patients.


Clinical and Histologic Liver Improvement in Siblings With Lysosomal Acid Lipase Deficiency After Enzyme Replacement.
To assess the effect of long-term (104 weeks) treatment with recombinant sebelipase alpha (rhSA) on serum lipid and hepatic transaminase levels, and liver histopathology in 4 siblings diagnosed with lysosomal acid lipase deficiency (LAL-D). Four male siblings from the same nonconsanguineous parents were diagnosed with the late-onset phenotype of LAL-D in 2015. Liver specimens were obtained by biopsy at baseline and after 104 weeks of enzyme replacement with rhSA (1 mg/kg, IV, every 2 weeks). Hepatic transaminase, lipid and lipoprotein levels were assessed at baseline and sequentially every 16 weeks for 104 weeks. Hepatic steatosis was evaluated from hematoxylin and eosin-stained specimens, and fibrosis was evaluated (Metavir-scoring system) from trichrome-stained specimens obtained at baseline and following 104 weeks of treatment with rhSA. All 4 siblings had improvement in their serum lipid and hepatic transaminase levels after treatment with rhSA. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels decreased from baseline by an average of 47% and 56%, respectively. The fasting triglyceride and low-density lipoprotein cholesterol (LDL-C) levels decreased from baseline by an average of 43% and 60%, respectively. Hepatic steatosis decreased from baseline grade 3 to posttreatment grade 1. Hepatic fibrosis did not advance following 104 weeks of treatment with rhSA and regressed in 1 sibling. Treatment with rhSA for 104 weeks in 4 siblings with LAL-D demonstrated improvement in their hepatic transaminase and serum lipid levels, accompanied by reduction of hepatic steatosis and no progression of fibrosis.


Exploring the future of land use and food security: A new set of global scenarios.
Facing a growing and more affluent world population, changing climate and finite natural resources, world food systems will have to change in the future. The aim of the Agrimonde-Terra foresight study was to build global scenarios linking land use and food security, with special attention paid to overlooked aspects such as nutrition and health, in order to help explore the possible future of the global food system. In this article, we seek to highlight how the resulting set of scenarios contributes to the debate on land use and food security and enlarges the range of possible futures for the global food system. We highlight four main contributions. Combining a scenario building method based on morphological analysis and quantitative simulations with a tractable and simple biomass balance model, the proposed approach improves transparency and coherence between scenario narratives and quantitative assessment. Agrimonde-Terra's scenarios comprise a wide range of alternative diets, with contrasting underlying nutritional and health issues, which accompany contrasting urbanization and rural transformation processes, both dimensions that are lacking in other sets of global scenarios. Agrimonde-Terra's scenarios share some similarities with existing sets of global scenarios, notably the SSPs, but are usually less optimistic regarding agricultural land expansion up to 2050. Results suggest that changing global diets toward healthier patterns could also help to limit the expansion in agricultural land area. Agrimonde-Terra's scenarios enlarge the scope of possible futures by proposing two pathways that are uncommon in other sets of global scenarios. The first proposes to explore possible reconnection of the food industry and regional production within supranational regional blocs. The second means that we should consider that a 'perfect storm', induced by climate change and an ecological crisis combined with social and economic crises, is still possible. Both scenarios should be part of the debate as the current context of the COVID-19 pandemic shows.


Living Shorelines: Coastal Resilience with a Blue Carbon Benefit.
Living shorelines are a type of estuarine shoreline erosion control that incorporates native vegetation and preserves native habitats. Because they provide the ecosystem services associated with natural coastal wetlands while also increasing shoreline resilience, living shorelines are part of the natural and hybrid infrastructure approach to coastal resiliency. Marshes created as living shorelines are typically narrow (< 30 m) fringing marshes with sandy substrates that are well flushed by tides. These characteristics distinguish living shorelines from the larger meadow marshes in which most of the current knowledge about created marshes was developed. The value of living shorelines for providing both erosion control and habitat for estuarine organisms has been documented but their capacity for carbon sequestration has not. We measured carbon sequestration rates in living shorelines and sandy transplanted Spartina alterniflora marshes in the Newport River Estuary, North Carolina. The marshes sampled here range in age from 12 to 38 years and represent a continuum of soil development. Carbon sequestration rates ranged from 58 to 283 g C m-2 yr-1 and decreased with marsh age. The pattern of lower sequestration rates in older marshes is hypothesized to be the result of a relative enrichment of labile organic matter in younger sites and illustrates the importance of choosing mature marshes for determination of long-term carbon sequestration potential. The data presented here are within the range of published carbon sequestration rates for S. alterniflora marshes and suggest that wide-scale use of the living shoreline approach to shoreline management may come with a substantial carbon benefit.


Millipede taxonomy after 250 years: classification and taxonomic practices in a mega-diverse yet understudied arthropod group.
The arthropod class Diplopoda is a mega-diverse group comprising >12,000 described millipede species. The history of taxonomic research within the group is tumultuous and, consequently, has yielded a questionable higher-level classification. Few higher-taxa are defined using synapomorphies, and the practice of single taxon descriptions lacking a revisionary framework has produced many monotypic taxa. Additionally, taxonomic and geographic biases render global species diversity estimations unreliable. We test whether the ordinal taxa of the Diplopoda are consistent with regards to underlying taxonomic diversity, attempt to provide estimates for global species diversity, and examine millipede taxonomic effort at a global geographic scale. A taxonomic distinctness metric was employed to assess uniformity of millipede ordinal taxa. We found that ordinal-level taxa are not uniform and are likely overinflated with higher-taxa when compared to related groups. Several methods of estimating global species richness were employed (Bayesian, variation in taxonomic productivity, extrapolation from nearly fully described taxa). Two of the three methods provided estimates ranging from 13,413-16,760 species. Variations in geographic diversity show biases to North America and Europe and a paucity of works on tropical taxa. Before taxa can be used in an extensible way, they must be definable with respect to the diversity they contain and the diagnostic characters used to delineate them. The higher classification for millipedes is shown to be problematic from a number of perspectives. Namely, the ordinal taxa are not uniform in their underlying diversity, and millipedes appear to have a disproportionate number of higher-taxa. Species diversity estimates are unreliable due to inconsistent taxonomic effort at temporal, geographic, and phylogenetic scales. Lack of knowledge concerning many millipede groups compounds these issues. Diplopods are likely not unique in this regard as these issues may persist in many other diverse yet poorly studied groups.


Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
VTE is a serious, but decreasing complication following major orthopedic surgery. This guideline focuses on optimal prophylaxis to reduce postoperative pulmonary embolism and DVT. The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. In patients undergoing major orthopedic surgery, we recommend the use of one of the following rather than no antithrombotic prophylaxis: low-molecular-weight heparin; fondaparinux; dabigatran, apixaban, rivaroxaban (total hip arthroplasty or total knee arthroplasty but not hip fracture surgery); low-dose unfractionated heparin; adjusted-dose vitamin K antagonist; aspirin (all Grade 1B); or an intermittent pneumatic compression device (IPCD) (Grade 1C) for a minimum of 10 to 14 days. We suggest the use of low-molecular-weight heparin in preference to the other agents we have recommended as alternatives (Grade 2C/2B), and in patients receiving pharmacologic prophylaxis, we suggest adding an IPCD during the hospital stay (Grade 2C). We suggest extending thromboprophylaxis for up to 35 days (Grade 2B). In patients at increased bleeding risk, we suggest an IPCD or no prophylaxis (Grade 2C). In patients who decline injections, we recommend using apixaban or dabigatran (all Grade 1B). We suggest against using inferior vena cava filter placement for primary prevention in patients with contraindications to both pharmacologic and mechanical thromboprophylaxis (Grade 2C). We recommend against Doppler (or duplex) ultrasonography screening before hospital discharge (Grade 1B). For patients with isolated lower-extremity injuries requiring leg immobilization, we suggest no thromboprophylaxis (Grade 2B). For patients undergoing knee arthroscopy without a history of VTE, we suggest no thromboprophylaxis (Grade 2B). Optimal strategies for thromboprophylaxis after major orthopedic surgery include pharmacologic and mechanical approaches.


Soil microbes regulate ecosystem productivity and maintain species diversity.
One of the major goals in ecology is to determine the mechanisms that drive the asymptotic increase in ecosystem productivity with plant species diversity. Niche complementarity, the current paradigm for the asymptotic diversity-productivity pattern, posits that the addition of species to a community increases productivity because each species specializes on different resources and thus can more thoroughly utilize the available resources. At higher diversity the increase in productivity decreases because resources become limiting, resulting in the classic asymptotic diversity-productivity pattern. An alternative but less tested explanation is that density-dependent disease from species-specific soil microbes drive the diversity-productivity relationship by increasing disease and thus decreasing productivity at low diversity. At higher diversity, productivity asymptotes because disease decreases with increasing diversity until it reaches a uniformly low level. Using a series of field experiments, we found that the classic asymptotic diversity-productivity pattern existed only when soil microbes were present. Soil microbes created the well-known pattern by depressing plant growth at low productivity though negative density dependent disease. In contrast, niche complementarity played only a weak role in explaining the diversity-productivity relationship because productivity remained high at low abundance in the absence of soil microbes. Based on our findings, the ongoing loss of species in natural ecosystems will likely increase per capita plant disease and lower ecosystem productivity. Furthermore, recent evidence suggests that negative density dependent disease maintains plant species diversity, and thus this single mechanism appears to link diversity maintenance to the diversity-productivity curve--two important ecological processes.


Genomic imprinting and cancer.
Genomic imprinting is the phenomenon by which individual alleles of certain genes are expressed differentially according to their parent of origin. The alleles appear to be differentially marked during gametogenesis or during the early part of development. This mark is heritable but reversible from generation to generation, implying a stable epigenetic modification. Approximately 25 imprinted genes have been identified to date, and dysregulation of a number of these has been implicated in tumour development. The normal physiological role of many imprinted genes is in the control of cell proliferation and fetal growth, indicating potential mechanisms of action in tumour formation. Both dominant and recessive modes of action have been postulated for the role of imprinted genes in neoplasia, as a result of effective gene dosage alterations by epigenetic modification of the normal pattern of allele specific transcription. The aim of this review is to assess the importance of imprinted genes in generating tumours and to discuss the implications for novel mechanisms of transforming mutation.


Features of oligodontia in three generations.
Congenitally missing teeth of three generations of a family and the spousal influence on the oligodontia of the third generation is investigated. For clarification, a review of commonly used terms is included in the paper. Although there are a number of factors affecting the failure to develop permanent tooth buds, most researchers believe that an autosomal dominant trait is responsible for the oligodontia in this family. Many syndromes are associated with oligodontia, but none seem to be prevalent in the direct descendants of the first generation. A member of the second generation married a person with Witkop's (tooth-and-nail) syndrome. Subsequently, their child exhibits the same manifestations. A feature noted in this three generation pedigree is missing permanent first molars. This is considered rare, especially when few abnormal ectodermal findings are reported. Additional findings include an increased number of missing teeth, decreased tooth size and a prominent maxillary labial frenum. The dental treatment for patients affected will likely involve a multidisciplinary approach. The treatment is particularly important since the lack of a full complement of teeth impacts the emotional and physical well-being of the individual. Children who are missing permanent teeth should be screened for other ectodermal abnormalities to rule out syndromes associated with congenitally missing teeth. Oligodontia is predicted to affect fifty percent of the fourth generation. It may vary in penetrance and expression.


LinkRbrain: multi-scale data integrator of the brain.
LinkRbrain is an open-access web platform for multi-scale data integration and visualization of human brain data. This platform integrates anatomical, functional, and genetic knowledge produced by the scientific community. The linkRbrain platform has two major components: (1) a data aggregation component that integrates multiple open databases into a single platform with a unified representation; and (2) a website that provides fast multi-scale integration and visualization of these data and makes the results immediately available. LinkRbrain allows users to visualize functional networks or/and genetic expression over a standard brain template (MNI152). Interrelationships between these components based on topographical overlap are displayed using relational graphs. Moreover, linkRbrain enables comparison of new experimental results with previous published works. Previous tools and studies illustrate the opportunities of data mining across multiple tiers of neuroscience and genetic information. However, a global systematic approach is still missing to gather cognitive, topographical, and genetic knowledge in a common framework in order to facilitate their visualization, comparison, and integration. LinkRbrain is an efficient open-access tool that affords an integrative understanding of human brain function.


Regulation of calcium metabolism in streptozotocin-induced diabetes.
Sixty-nine-day-old female Wistar rats that had been made diabetic 9 days earlier by an intraperitoneal injection of streptozotocin were studied by a combination radioisotope and balance technique that evaluates calcium absorption, excretion, and bone calcium deposition and resorption rates. Streptozotocin-induced diabetes was associated with a marked drop in calcium absorption and a threefold rise in urinary calcium excretion, changes that greatly exceeded the expected effects from the hyperphagia and increased calcium intake of the experimental animals. Bone calcium deposition was halved in the diabetic rats, with bone resorption unchanged and equal to the deposition rate. As a result, the bone and body calcium balances were zero in the experimental animals. To maintain plasma calcium near normal under these circumstances, the diabetic animals turned over their skeletal calcium in relationship to the central pool much more rapidly than the controls. Although the skeleton in the normal animals serves as both storehouse and regulator of the plasma calcium, in short-term streptozotocin-induced diabetes there is no calcium storage in bone, with the skeleton only playing the role of regulator of calcium homeostasis.


Treatment of Periprosthetic Knee Infection With a Two-stage Protocol Using Static Spacers.
Two-stage exchange arthroplasty is a standard approach for treating total knee arthroplasty periprosthetic joint infection in the United States, but whether this should be performed with a static antibiotic spacer or an articulating one that allows range of motion before reimplantation remains controversial. It is unclear if the advantages of articulating spacers (easier surgical exposure during reimplantation and improved postoperative flexion) outweigh the disadvantages of increased cost and complexity in the setting of similar rates of infection eradication. The purposes of this study were (1) to determine the ultimate range of motion; and (2) to determine the proportion of patients who remained free of infection at a minimum 2 years after treatment with static antibiotic spacers as part of a two-stage revision TKA for the treatment of periprosthetic joint infection. Between 1999 and 2011, we treated 121 patients with chronically infected TKAs, of whom three had medical comorbidities precluding a two-stage exchange, four had died before 2-year followup for reasons other than the surgical intervention, and seven were lost to followup. The remaining 107 patients (109 knees; 53 men and 54 women) were treated using a two-stage approach with static spacers and are evaluated here at a mean of 3.7 years (range, 2.0-9.8 years); no patients were treated with articulating spacers during this study period. Twenty-five percent (27 of 109) of the organisms isolated the first-stage procedure were resistant to methicillin and/or vancomycin. Median age at the time of reimplantation was 67 years (range, 42-89 years). Range of motion was measured by an independent physical therapist with a standard goniometer. Knee Society knee and function scores were calculated before the first stage and at the 2-year mark. Because many of these patients were treated before consensus definitions of infection were established, we made the diagnosis of infection (and established that a patient was believed to be free of infection) using the approaches prevalent at that time, which generally included presence of a sinus tract communicating directly with the implant, two positive tissue cultures, or a combination of cultures, fluid analysis, and serology. Postoperatively, 67 knees had full extension and no patients had a flexion contracture > 10°. Median flexion was 100° (range, 60°-139°). Thirty-nine knees had postoperative flexion > 120°. Ninety-four percent of patients were clinically free of infection at last followup. Our two-stage exchange protocol with static spacers yielded comparable flexion and infection eradication when compared with other recent studies that have used articulating spacers. The large proportion of resistant organisms is alarming. Future multicenter studies should compare static with articulating spacers and should evaluate both cost and efficacy, because our study suggests that adequate range of motion can be achieved without the added cost of the articulating spacer. Level IV, therapeutic study.