Cost of acute hospitalization and post-discharge follow-up care for meningococcal disease in the US.
The combined costs of acute hospitalization and post-discharge follow-up care in patients with meningococcal disease have not been widely documented. In this study, data were retrospectively analyzed from three large databases of hospital discharge records and commercial insurance claims in the US. Cases of meningococcal disease were defined as admissions with an ICD-9-CM diagnosis code in the range of 036.x. From the 2005 HCUP Nationwide Inpatient Sample, 349 (weighted N=1,710) meningococcal-related hospitalizations were identified with a mean facility cost (in 2009 dollars) of $19,526 per admission. Similar estimates ($18,119 and $20,066, respectively) were obtained from 268 admissions identified in the LifeLink (formerly PharMetrics) database during 1999-2007 and from 1,058 hospitalizations in the Perspective Comparative Database (PCD) during 2000-2007. Using insurance claims from LifeLink, we estimated that payers incur an additional $26,178 in non-facility (professional and other ancillary) costs during the course of a meningococcal admission, as well as $22,230 in additional medical and pharmacy expenses for post-discharge care during the ensuing year. The majority of follow-up costs ($14,637) were attributed to repeat hospitalizations. Mean length of stay for meningococcal disease was consistently estimated across databases at 8 to 9 days. Data from the PCD further suggested that meningococcal disease carries, on average, nearly 2 days of intensive care unit utilization. In conclusion, hospital admissions for meningococcal disease are costly to payers. These costs are heightened when non-facility services and post-discharge care are also considered. Awareness of the full cost burden of meningococcal disease is needed when evaluating vaccination programs targeting the disease.


Pathway-Wide Genetic Risks in Chlamydial Infections Overlap between Tissue Tropisms: A Genome-Wide Association Scan.
Chlamydia trachomatis is the most commonly diagnosed bacterial sexually transmitted infection and can lead to tubal factor infertility, a disease characterised by fibrosis of the fallopian tubes. Genetic polymorphisms in molecular pathways involving G protein-coupled receptor signalling, the Akt/PI3K cascade, the mitotic cell cycle, and immune response have been identified in association with the development of trachomatous scarring, an ocular form of chlamydia-related fibrotic pathology. In this case-control study, we performed genome-wide association and pathways-based analysis in a sample of 71 Dutch women who attended an STI clinic who were seropositive for Chlamydia trachomatis antibodies and 169 high-risk Dutch women who sought similar health services but who were seronegative. We identified two regions of within-gene SNP association with Chlamydia trachomatis serological response and found that GPCR signalling and cell cycle pathways were also associated with the trait. These pathway-level associations appear to be common to immunological sequelae of chlamydial infections in both ocular and urogenital tropisms. These pathways may be central mediators of human refractoriness to chlamydial diseases.


Serum Levels of Vitamin D, Retinol and Zinc in Relation to overweight among Toddlers: Findings from a National Study in Iran.
Some studies have examined the association between micronutrient deficiencies and overweight in children, but data in this regard are conflicting. This study was done to investigate the association between serum levels of vitamin D, A and zinc with overweight in a large sample of Iranian toddlers. A total of 4261 toddlers, aged 15-23 months, who had an Iranian birth certificate and attended primary health care, were included in the current cross-sectional study. Weight and height were measured by experts based on standard protocols and body mass index (BMI) was calculated. Based on WHO criteria, overweight was defined as BMI-z-score of ≥1SD. Serum levels of 25(OH)D3 , retinol and zinc were measured for each toddler. Binary logistic regression was applied to assess the association of 25(OH)D3 , retinol and zinc levels with overweight. Mean age of study participants was 19.2 ± 8.4 months. After controlling for potential confounders, children in the highest quartile of serum 25(OH)D3 levels had lower odds of overweight compared with those in the lowest quartile (OR: 0.79, 95% CI: 0.63-0.99). Furthermore, a marginally significant inverse association was found between serum levels of 25(OH)D3 and overweight among urban toddlers (OR: 0.75, 95%CI: 0.56-1.00). Such a relationship was not seen for rural children. No other significant association was seen between serum levels of retinol and zinc and overweight either before or after controlling for covariates. In conclusion, we found a significant inverse association between serum levels of vitamin D and overweight among toddlers. Further studies, particularly of prospective nature, are required to confirm our findings.


Simultaneous frequency and dissipation factor QCM measurements of biomolecular adsorption and cell adhesion.
We have measured the energy dissipation of the quartz crystal microbalance (QCM), operating in the liquid phase, when mono- or multi-layers of biomolecules and biofilms form on the QCM electrode (with a time resolution of ca. 1 s). Examples are taken from protein adsorption, lipid vesicle adsorption and cell adhesion studies. Our results show that even very thin (a few nm) biofilms dissipate a significant amount of energy owing to the QCM oscillation. Various mechanisms for this energy dissipation are discussed. Three main contributions to the measured increase in energy dissipation are considered. (i) A viscoelastic porous structure (the biofilm) that is strained during oscillation, (ii) trapped liquid that moves between or in and out of the pores due to the deformation of the film and (iii) the load from the bulk liquid which increases the strain of the film. These mechanisms are, in reality, not entirely separable, rather, they constitute an effective viscoelastic load. The biofilms can therefore not be considered rigidly coupled to the QCM oscillation. It is further shown theoretically that viscoelastic layers with thicknesses comparable to the biofilms studied in this work can induce energy dissipation of the same magnitude as the measured ones.


Chronic evaluation of a clinical system for deep brain stimulation and recording of neural network activity.
In conjunction with therapeutic stimulation, next-generation deep brain stimulation (DBS) devices may offer the ability to record and analyze neural signals, providing for unprecedented insight into DBS effects on neural networks. This work was conducted to evaluate an implantable, clinical-grade system that permits concurrent stimulation and recording using a large animal (ovine) model recently developed to study DBS for epilepsy. Following anesthesia and 1.5-tesla MRI acquisition, unilateral anterior thalamic and hippocampal DBS leads were implanted (n = 3) using a frameless stereotactic system. Chronic, awake recordings of evoked potentials (EPs) and local field potentials were collected with the implanted device and analyzed off-line. Hippocampal EPs were stable over long-term (>1 year) recording and consistent in morphology and latency with prior acute results. Thalamic and hippocampal DBS produced both excitatory and inhibitory network effects that were stimulation site and parameter dependent. Free roaming recordings illustrated periods of highly correlated activity between these two structures within the circuit of Papez. These results provide further insight into mechanisms of DBS therapy for epilepsy and an encouraging demonstration of the capabilities of this new technology, which in the future, may afford unique opportunities to study human brain function and neuromodulation mechanism of action.


Coping, Discrimination, and Physical Health Conditions Among Predominantly Poor, Urban African Americans: Implications for Community-Level Health Services.
African Americans and ethnic minorities experience racial discrimination in a variety of settings. Racial discrimination is a potent stressor that has been linked to psychosocial stress and poor physical health. To cope with discriminatory experiences and daily life event stressors, African Americans frequently use the concept of John Henryism (a high effort coping strategy with prolonged exposure to stress). This cross-sectional analysis explored the relationship between racism/discrimination, John Henryism, and health problems in a predominately African American sample. Data were collected through health care screenings for hypertension, diabetes, and obesity and a self-report survey to assess experiences of discrimination and use of John Henryism. Logistic and linear regression models were used to assess the relationship between the John Henryism score, racism/discrimination score, and health problems among 352 participants. John Henryism was associated with a decrease in systolic blood pressure (b = - 12.50, 95% CI = - 23.05, - 1.95) among men, after adjusting for experiences of racism/discrimination and demographic characteristics. Experiences of racism/discrimination were associated with an increase in systolic blood pressure (b = 11.23, 95% CI = 0.38, 22.09) among men, after adjusting for John Henryism and demographic characteristics. Among women, there was no association found between John Henryism and experiences of racism/discrimination with systolic blood pressure. No association was found between John Henryism and experiences of racism/discrimination with being overweight/obese in women nor men. The study found that John Henryism was positively associated with the health of men, while experiences of racism/discrimination were negatively associated with their health. Limitations of the study are discussed, and recommendations are made to guide future research exploring the concept of John Henryism as a relevant factor between stress, racial discrimination and poor health.


Diversifying bioenergy crops increases yield and yield stability by reducing weed abundance.
Relationships between species diversity, productivity, temporal stability of productivity, and plant invasion have been well documented in grasslands, and these relationships could translate to improved agricultural sustainability. However, few studies have explored these relationships in agricultural contexts where fertility and weeds are managed. Using 7 years of biomass yield and species composition data from 12 species mixture treatments varying in native species diversity, we found that species richness increased yield and interannual yield stability by reducing weed abundance. Stability was driven by yield as opposed to temporal variability of yield. Nitrogen fertilization increased yield but at the expense of yield stability. We show how relationships between diversity, species asynchrony, invasion, productivity, and stability observed in natural grasslands can extend into managed agricultural systems. Increasing bioenergy crop diversity can improve farmer economics via increased yield, reduced yield variability, and reduced inputs for weed control, thus promoting perennial vegetation on agricultural lands.


New amination strategies based on nitrogen-centered radical chemistry.
The interesting and diverse biological activities of nitrogen-containing compounds make the construction of the C-N bond of great importance. Despite the tremendous advances that have been made in this research field, C-N bond formation based on nitrogen-centered radicals remains a significant challenge due to the harsh conditions required for the generation of nitrogen-centered radicals and their propensity for hydrogen abstraction or engaging in other degradation pathways. In the past several years, novel methodologies for C-N bond constructions based on nitrogen centered-radical intermediates, coordinated with metal or generated in the presence of visible-light and a photocatalyst, have attracted considerable attention. This tutorial review will summarize the significant progress of these efficient and mild radical amination reactions, with an emphasis on approaches for the generation of nitrogen-centered radicals and their reaction patterns, related mechanisms and synthetic applications, as well as unmet challenges in this emerging and promising field.


Chikungunya virus adaptation to a mosquito vector correlates with only few point mutations in the viral envelope glycoprotein.
Like most arthropod-borne viruses (arboviruses), chikungunya virus (CHIKV) is a RNA virus maintained in nature in an alternating cycle of replication between invertebrate and vertebrate hosts. It has been assumed that host alternation restricts arbovirus genome evolution and imposes fitness trade-offs. Despite their slower rates of evolution, arboviruses still have the capacity to produce variants capable to exploit new environments. To test whether the evolution of the newly emerged epidemic variant of CHIKV (E1-226V) is constrained by host alternation, the virus was alternately-passaged in hamster-derived BHK-21 cells and Aedes aegypti-derived Aag-2 cells. It was also serially-passaged in BHK-21 or Aag-2 cells to promote adaptation to one cell type and presumably, fitness cost in the bypassed cell type. After 30 passages, obtained CHIKV strains were genetically and phenotypically characterized using in vitro and in vivo systems. Serially- and alternately-passaged strains can be distinguished by amino-acid substitutions in the E2 glycoprotein, responsible for receptor binding. Two substitutions at positions E2-64 and E2-208 only lower the dissemination of the variant E1-226V in Ae. aegypti. These amino-acid changes in the E2 glycoprotein might affect viral infectivity by altering the interaction between CHIKV E1-226V and the cellular receptor on the midgut epithelial cells in Ae. aegypti but not in Aedesalbopictus.


Characterizing phosphorus speciation of Chesapeake Bay sediments using chemical extraction, 31P NMR, and X-ray absorption fine structure spectroscopy.
Nutrient contamination has been one of the lingering issues in the Chesapeake Bay because the bay restoration is complicated by temporally and seasonally variable nutrient sources and complex interaction between imported and regenerated nutrients. Differential reactivity of sedimentary phosphorus (P) pools in response to imposed biogeochemical conditions can record past sediment history and therefore a detailed sediment P speciation may provide information on P cycling particularly the stability of a P pool and the formation of one pool at the expense of another. This study examined sediment P speciation from three sites in the Chesapeake Bay: (i) a North site in the upstream bay, (ii) a middle site in the central bay dominated by seasonally hypoxic bottom water, and (iii) a South site at the bay-ocean boundary using a combination of sequential P extraction (SEDEX) and spectroscopic techniques, including (31)P NMR, P X-ray absorption near edge structure spectroscopy (XANES), and Fe extended X-ray absorption fine structure (EXAFS). Results from sequential P extraction reveal that sediment P is composed predominantly of ferric Fe-bound P and authigenic P, which was further confirmed by solid-state (31)P NMR, XANES, and EXAFS analyses. Additionally, solution (31)P NMR results show that the sediments from the middle site contain high amounts of organic P such as monoesters and diesters, compared to the other two sites, but that these compounds rapidly decrease with sediment depth indicating remineralized P could have precipitated as authigenic P. Fe EXAFS enabled to identify the changes in Fe mineral composition and P sinks in response to imposed redox condition in the middle site sediments. The presence of lepidocrocite, vermiculite, and Fe smectite in the middle site sediments indicates that some ferric Fe minerals can still be present along with pyrite and vivianite, and that ferric Fe-bound P pool can be a major P sink in anoxic sediments. These results provide improved insights into sediment P dynamics, particularly the rapid remineralization of organic P and the stability of Fe minerals and the ferric Fe-bound P pool in anoxic sediments in the Chesapeake Bay.


Assessment of genetically modified maize MZIR098 for food and feed uses, under Regulation (EC) No 1829/2003 (application EFSA-GMO-DE-2017-142).
Maize MZIR098 was developed to confer tolerance to glufosinate-ammonium-containing herbicides and resistance to certain coleopteran pests. The molecular characterisation data and bioinformatic analyses do not identify issues requiring food/feed safety assessment. None of the identified differences in the agronomic/phenotypic and compositional characteristics tested between maize MZIR098 and its conventional counterpart needs further assessment, except for neutral detergent fibre (NDF) in grains, which does not raise nutritional and safety concerns. The GMO Panel does not identify safety concerns regarding the toxicity and allergenicity of the eCry3.1Ab, mCry3A and PAT proteins as expressed in maize MZIR098, and finds no evidence that the genetic modification would change the overall allergenicity of maize MZIR098. In the context of this application, the consumption of food and feed from maize MZIR098 does not represent a nutritional concern in humans and animals. The GMO Panel concludes that maize MZIR098 is as safe as the conventional counterpart and non-GM maize reference varieties tested, and no post-market monitoring of food/feed is considered necessary. In the case of accidental release of viable maize MZIR098 grains into the environment, maize MZIR098 would not raise environmental safety concerns. The post-market environmental monitoring plan and reporting intervals are in line with the intended uses of maize MZIR098. In conclusion, the GMO Panel considers that maize MZIR098, as described in this application, is as safe as its conventional counterpart and the non-GM maize reference varieties tested with respect to potential effects on human and animal health and the environment.


APX3330 Promotes Neurorestorative Effects after Stroke in Type One Diabetic Rats.
APX3330 is a selective inhibitor of APE1/Ref-1 redox activity. In this study, we investigate the therapeutic effects and underlying mechanisms of APX3330 treatment in type one diabetes mellitus (T1DM) stroke rats. Adult male Wistar rats were induced with T1DM and subjected to transient middle cerebral artery occlusion (MCAo) and treated with either PBS or APX3330 (10mg/kg, oral gavage) starting at 24h after MCAo, and daily for 14 days. Rats were sacrificed at 14 days after MCAo and, blood brain barrier (BBB) permeability, ischemic lesion volume, immunohistochemistry, cell death assay, Western blot, real time PCR, and angiogenic ELISA array were performed. Compared to PBS treatment, APX3330 treatment of stroke in T1DM rats significantly improves neurological functional outcome, decreases lesion volume, and improves BBB integrity as well as decreases total vessel density and VEGF expression, while significantly increases arterial density in the ischemic border zone (IBZ). APX3330 significantly increases myelin density, oligodendrocyte number, oligodendrocyte progenitor cell number, synaptic protein expression, and induces M2 macrophage polarization in the IBZ of T1DM stroke rats. Compared to PBS treatment, APX3330 treatment significantly decreases plasminogen activator inhibitor type-1 (PAI-1), monocyte chemotactic protein-1 and matrix metalloproteinase 9 (MMP9) and receptor for advanced glycation endproducts expression in the ischemic brain of T1DM stroke rats. APX3330 treatment significantly decreases cell death and MMP9 and PAI-1 gene expression in cultured primary cortical neurons subjected to high glucose and oxygen glucose deprivation, compared to untreated control cells. APX3330 treatment increases M2 macrophage polarization and decreases inflammatory factor expression in the ischemic brain as well as promotes neuroprotective and neurorestorative effects after stroke in T1DM rats.


Thirteen-year follow-up of children and adolescents with chronic fatigue syndrome.
To describe the educational, social, and symptomatic outcome of children and adolescents with chronic fatigue syndrome 13 years after illness onset. Between January 1984 and December 1987, 46 children and adolescents developed an illness suggestive of chronic fatigue syndrome. Follow-up questionnaires were obtained from 35 participants an average of 13 years after illness onset. Data were obtained concerning subsequent medical diagnoses, amount of school missed, presence and severity of current symptoms, and subjective assessment of degree of illness resolution. Of the 35 participants, 24 were female (68.6%) and 11 were male (31.4%). Average age at illness onset was 12.1 years. Eight participants (22.9%) had an acute onset of symptoms, 27 (77.1%) had a gradual onset. No participant received an alternative medical diagnosis that could have explained the symptom complex between illness onset and follow-up. Thirteen participants (37.1%) considered themselves resolved of illness at follow-up; 15 participants (42.9%) considered themselves well but not resolved; 4 (11.4%) considered themselves chronically ill; and 3 (8.6%) considered themselves more ill than during the early years of illness. Correlation with the Medical Outcomes Study Short Form Health Survey was good for current level of symptoms and degree of recovery. Eight participants (22.9%) missed >2 years of school, and 5 of these were still ill at follow-up. Amount of school missed correlated with both illness severity at follow-up and perceived social impact of the illness. These data demonstrate the presence of an illness consistent with the current definition of chronic fatigue syndrome. Eighty percent of children and adolescents affected had a satisfactory outcome from their fatiguing illness, although the majority of these participants had mild to moderate persisting symptoms. Twenty percent of participants remain ill with significant symptoms and activity limitation 13 years after illness onset. Chronic fatigue syndrome in children and adolescents may result in persistent somatic symptoms and disability in a minority of those affected.


Manganese superoxide dismutase deficiency exacerbates the mitochondrial ROS production and oxidative damage in Chagas disease.
In this study, we have investigated the effects of manganese superoxide dismutase (SOD2 or MnSOD) deficiency on mitochondrial function and oxidative stress during Chagas disease. For this, C57BL/6 wild type (WT) and MnSOD+/- mice were infected with Trypanosoma cruzi (Tc), and evaluated at 150 days' post-infection that corresponded to chronic disease phase. Genetic deletion of SOD2 decreased the expression and activity of MnSOD, but it had no effect on the expression of other members of the SOD family. The myocardial expression and activity of MnSOD were significantly decreased in chronically infected WT mice, and it was further worsened in MnSOD+/- mice. Chronic T. cruzi infection led to a decline in mitochondrial complex I and complex II driven, ADP-coupled respiration and ATP synthesis in the myocardium of WT mice. The baseline oxidative phosphorylation (OXPHOS) capacity in MnSOD+/- mice was decreased, and it had an additive effect on mitochondrial dysregulation of ATP synthesis capacity in chagasic myocardium. Further, MnSOD deficiency exacerbated the mitochondrial rate of reactive oxygen species (ROS) production and myocardial oxidative stress (H2O2, protein carbonyls, malondialdehyde, and 4-hydroxynonenal) in Chagas disease. Peripheral and myocardial parasite burden and inflammatory response (myeloperoxidase, IL-6, lactate dehydrogenase, inflammatory infiltrate) were increased in all chagasic WT and MnSOD+/- mice. We conclude that MnSOD deficiency exacerbates the loss in mitochondrial function and OXPHOS capacity and enhances the myocardial oxidative damage in chagasic cardiomyopathy. Mitochondria targeted, small molecule mitigators of MnSOD deficiency will offer potential benefits in averting the mitochondrial dysfunction and chronic oxidative stress in Chagas disease.


Do not feed the wildlife: associations between garbage use, aggression, and disease in banded mongooses (Mungos mungo).
Urbanization and other human modifications of the landscape may indirectly affect disease dynamics by altering host behavior in ways that influence pathogen transmission. Few opportunities arise to investigate behaviorally mediated effects of human habitat modification in natural host-pathogen systems, but we provide a potential example of this phenomenon in banded mongooses (Mungos mungo), a social mammal. Our banded mongoose study population in Botswana is endemically infected with a novel Mycobacterium tuberculosis complex pathogen, M. mungi, that primarily invades the mongoose host through the nasal planum and breaks in the skin. In this system, several study troops have access to human garbage sites and other modified landscapes for foraging. Banded mongooses in our study site (N = 4 troops, ~130 individuals) had significantly higher within-troop aggression levels when foraging in garbage compared to other foraging habitats. Second, monthly rates of aggression were a significant predictor of monthly number of injuries in troops. Finally, injured individuals had a 75% incidence of clinical tuberculosis (TB) compared to a 0% incidence in visibly uninjured mongooses during the study period. Our data suggest that mongoose troops that forage in garbage may be at greater risk of acquiring TB by incurring injuries that may allow for pathogen invasion. Our study suggests the need to consider the indirect effects of garbage on behavior and wildlife health when developing waste management approaches in human-modified areas.


Renal and neuronal abnormalities in mice lacking GDNF.
Glial cell-line derived neurotrophic factor (GDNF) is a potent survival factor for embryonic midbrain dopaminergic, spinal motor, cranial sensory, sympathetic, and hindbrain noradrenergic neurons, and is available to these cells in vivo. It is therefore considered a physiological trophic factor and a potential therapeutic agent for Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Here we show that at postnatal day 0 (P0), GDNF-deficient mice have deficits in dorsal root ganglion, sympathetic and nodose neurons, but not in hindbrain noradrenergic or midbrain dopaminergic neurons. These mice completely lack the enteric nervous system (ENS), ureters and kidneys. Thus GDNF is important for the development and/or survival of enteric, sympathetic and sensory neurons and the renal system, but is not essential for catecholaminergic neurons in the central nervous system (CNS).


Bicarbonate Modulates Photoreceptor Guanylate Cyclase (ROS-GC) Catalytic Activity.
By generating the second messenger cGMP in retinal rods and cones, ROS-GC plays a central role in visual transduction. Guanylate cyclase-activating proteins (GCAPs) link cGMP synthesis to the light-induced fall in [Ca(2+)]i to help set absolute sensitivity and assure prompt recovery of the response to light. The present report discloses a surprising feature of this system: ROS-GC is a sensor of bicarbonate. Recombinant ROS-GCs synthesized cGMP from GTP at faster rates in the presence of bicarbonate with an ED50 of 27 mM for ROS-GC1 and 39 mM for ROS-GC2. The effect required neither Ca(2+) nor use of the GCAPs domains; however, stimulation of ROS-GC1 was more powerful in the presence of GCAP1 or GCAP2 at low [Ca(2+)]. When applied to retinal photoreceptors, bicarbonate enhanced the circulating current, decreased sensitivity to flashes, and accelerated flash response kinetics. Bicarbonate was effective when applied either to the outer or inner segment of red-sensitive cones. In contrast, bicarbonate exerted an effect when applied to the inner segment of rods but had little efficacy when applied to the outer segment. The findings define a new regulatory mechanism of the ROS-GC system that affects visual transduction and is likely to affect the course of retinal diseases caused by cGMP toxicity.


Whole genome sequencing of metastatic colorectal cancer reveals prior treatment effects and specific metastasis features.
In contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data of metastases of 429 CRC patients participating in the pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups characterized by signatures known from primary CRC, signatures associated with received prior treatments, and metastasis-specific signatures. Compared to primary CRC, we identify additional putative (non-coding) driver genes and increased frequencies in driver gene mutations. In addition, we identify specific genes preferentially affected by microsatellite instability. CRC-specific 1kb-10Mb deletions, enriched for common fragile sites, and LINC00672 mutations are associated with response to treatment in general, whereas FBXW7 mutations predict poor response specifically to EGFR-targeted treatment. In conclusion, the genomic landscape of mCRC shows defined changes compared to primary CRC, is affected by prior treatments and contains features with potential clinical relevance.


Measurement Repeatability of 18F-FDG PET/CT Versus 18F-FDG PET/MRI in Solid Tumors of the Pelvis.
Knowledge of the within-subject variability of 18F-FDG PET/MRI measurements is necessary for proper interpretation of quantitative PET or MRI metrics in the context of therapeutic efficacy assessments with integrated PET/MRI scanners. The goal of this study was to determine the test-retest repeatability of these metrics on PET/MRI, with comparison to similar metrics acquired by PET/CT. Methods: This prospective study enrolled subjects with pathology-proven pelvic malignancies. Baseline imaging consisted of PET/CT immediately followed by PET/MRI, using a single 370-MBq 18F-FDG dose. Repeat imaging was performed within 7 d using an identical imaging protocol, with no oncologic therapy between sessions. PET imaging on both scanners consisted of a list-mode acquisition at a single pelvic station. The MRI consisted of 2-point Dixon imaging for attenuation correction, standard sequences for anatomic correlation, and diffusion-weighted imaging. PET data were statically reconstructed using various frame durations and minimizing uptake time differences between sessions. SUV metrics were extracted for both PET/CT and PET/MRI in each imaging session. Apparent diffusion coefficient (ADC) metrics were extracted for both PET/MRI sessions. Results: The study cohort consisted of 14 subjects (13 female, 1 male) with various pelvic cancers (11 cervical, 2 rectal, 1 endometrial). For SUVmax, the within-subject coefficient of variation (wCV) appeared higher for PET/CT (8.5%-12.8%) than PET/MRI (6.6%-8.7%) across all PET reconstructions, though with no significant repeatability differences (all P values ≥ 0.08) between modalities. For lean body mass-adjusted SUVpeak, the wCVs appeared similar for PET/CT (9.9%-11.5%) and PET/MRI (9.2%-11.3%) across all PET reconstructions, again with no significant repeatability differences (all P values ≥ 0.14) between modalities. For PET/MRI, the wCV for ADCmedian of 3.5% appeared lower than the wCVs for SUVmax (6.6%-8.7%) and SULpeak (9.2%-11.3%), though without significant repeatability differences (all P values ≥ 0.23). Conclusion: For solid tumors of the pelvis, the repeatability of the evaluated SUV and ADC metrics on 18F-FDG PET/MRI is both acceptably high and similar to previously published values for 18F-FDG PET/CT and MRI, supporting the use of 18F-FDG PET/MRI for quantitative oncologic treatment response assessments.


Interaction of rat alveolar macrophages with dental composite dust.
Dental composites have become the standard filling material to restore teeth, but during the placement of these restorations, high amounts of respirable composite dust (<5 μm) including many nano-sized particles may be released in the breathing zone of the patient and dental operator. Here we tested the respirable fraction of several composite particles for their cytotoxic effect using an alveolar macrophage model system. METHODS: Composite dust was generated following a clinical protocol, and the dust particles were collected under sterile circumstances. Dust was dispersed in fluid, and 5-μm-filtered to enrich the respirable fractions. Quartz DQ12 and corundum were used as positive and negative control, respectively. Four concentrations (22.5 μg/ml, 45 μg/ml, 90 μg/ml and 180 μg/ml) were applied to NR8383 alveolar macrophages. Light and electron microscopy were used for subcellular localization of particles. Culture supernatants were tested for release of lactate dehydrogenase, glucuronidase, TNF-α, and H2O2. Characterization of the suspended particles revealed numerous nano-sized particles but also many high volume particles, most of which could be removed by filtering. Even at the highest concentration (180 μg/ml), cells completely cleared settled particles from the bottom of the culture vessel. Accordingly, a mixture of nano- and micron-scaled particles was observed inside cells where they were confined to phagolysosomes. The filtered particle fractions elicited largely uniform dose-dependent responses, which were elevated compared to the control only at the highest concentration, which equaled a mean cellular dose of 120 pg/cell. A low inflammatory potential was identified due to dose-dependent release of H2O2 and TNF-α. However, compared to the positive control, the released levels of H2O2 and TNF-α were still moderate, but their release profiles depended on the type of composite. Alveolar macrophages are able to phagocytize respirable composite dust particle inclusive nanoparticles. Since NR8383 cells tolerate a comparatively high cell burden (60 pg/cell) of each of the five materials with minimal signs of cytotoxicity or inflammation, the toxic potential of respirable composite dust seems to be low. These results are reassuring for dental personnel, but more research is needed to characterize the actual exposure and uptake especially of the pure nano fraction.


Transcriptomic profiling of purified patient-derived dopamine neurons identifies convergent perturbations and therapeutics for Parkinson's disease.
While induced pluripotent stem cell (iPSC) technologies enable the study of inaccessible patient cell types, cellular heterogeneity can confound the comparison of gene expression profiles between iPSC-derived cell lines. Here, we purified iPSC-derived human dopaminergic neurons (DaNs) using the intracellular marker, tyrosine hydroxylase. Once purified, the transcriptomic profiles of iPSC-derived DaNs appear remarkably similar to profiles obtained from mature post-mortem DaNs. Comparison of the profiles of purified iPSC-derived DaNs derived from Parkinson's disease (PD) patients carrying LRRK2 G2019S variants to controls identified significant functional convergence amongst differentially-expressed (DE) genes. The PD LRRK2-G2019S associated profile was positively matched with expression changes induced by the Parkinsonian neurotoxin rotenone and opposed by those induced by clioquinol, a compound with demonstrated therapeutic efficacy in multiple PD models. No functional convergence amongst DE genes was observed following a similar comparison using non-purified iPSC-derived DaN-containing populations, with cellular heterogeneity appearing a greater confound than genotypic background.


Credibility of In Silico Trial Technologies-A Theoretical Framing.
Different research communities have developed various approaches to assess the credibility of predictive models. Each approach usually works well for a specific type of model, and under some epistemic conditions that are normally satisfied within that specific research domain. Some regulatory agencies recently started to consider evidences of safety and efficacy on new medical products obtained using computer modelling and simulation (which is referred to as In Silico Trials); this has raised the attention in the computational medicine research community on the regulatory science aspects of this emerging discipline. But this poses a foundational problem: in the domain of biomedical research the use of computer modelling is relatively recent, without a widely accepted epistemic framing for model credibility. Also, because of the inherent complexity of living organisms, biomedical modellers tend to use a variety of modelling methods, sometimes mixing them in the solution of a single problem. In such context merely adopting credibility approaches developed within other research communities might not be appropriate. In this paper we propose a theoretical framing for assessing the credibility of a predictive models for In Silico Trials, which accounts for the epistemic specificity of this research field and is general enough to be used for different type of models.


Biliary reconstruction in pediatric live donor liver transplantation: duct-to-duct or Roux-en-Y hepaticojejunostomy.
Duct-to-duct biliary reconstruction (DD) is currently a standard procedure in adult live donor liver transplantation (LDLT). Its pediatric feasibility, however, has rarely been reported. The goal of this study is to assess the incidence and treatment of biliary complication after pediatric LDLT with DD or Roux-en-Y hepaticojejunostomy (RY). Sixty children received LDLT between November 2005 and June 2008, and their database was reviewed. Biliary reconstruction was achieved with DD in 14 patients and with RY in 46 patients with mean follow-up period of 26.0 and 22.3 months, respectively. The incidence of biliary leakage in the DD and RY groups was 7.1% and 8.7%, respectively, and that of stricture was 28.6% and 10.9%, respectively; but the differences were not statistically significant. Biliary stricture in the DD group tended to require revision surgery with RY and longer treatment with percutaneous transhepatic cholangiodrainage compared with that in the RY group. Theoretical advantages of DD over RY were not confirmed in this study. Duct-to-duct biliary reconstruction tended to encounter more biliary complications, especially stricture, with more difficulty in treating it than RY. Roux-en-Y hepaticojejunostomy seems preferable to DD in the setting of pediatric LDLT, but DD must be considered when making new Roux-en-Y limb seems impossible or troublesome owing to abdominal dense adhesion or short bowel syndrome.


Transcriptional inhibition of type I collagen gene expression in scleroderma fibroblasts by the antineoplastic drug ecteinascidin 743.
We previously showed that COL1A1 expression is up-regulated at the transcriptional level in systemic sclerosis (SSc) fibroblasts and that the CCAAT-binding factor (CBF) is involved in this increased expression. Ecteinascidin 743 (ET-743) is a chemotherapeutic agent that binds with sequence specificity to the minor groove of DNA and inhibits CBF-mediated transcriptional activation of numerous genes. Therefore, we examined the effects of ET-743 on the increased COL1A1 expression in SSc fibroblasts. The drug caused a potent and dose-dependent inhibition of type I collagen biosynthesis, which reached 70-90% at 700 pM without affecting cell viability. The same drug concentration caused 60-80% reduction in COL1A1 mRNA levels. The stability of the corresponding transcripts was not affected. In vitro nuclear transcription assays demonstrated a 54% down-regulation of COL1A1 transcription. Transient transfections with COL1A1 promoter constructs containing the specific CBF binding sequence into SSc cells previously treated with 700 pM ET-743 failed to show an effect on COL1A1 promoter activity. Furthermore, ET-743 did not affect the binding of CBF or Sp1 transcription factors to their cognate COL1A1 elements. However, treatment with 700 pM ET-743 of stably transfected NIH 3T3 cells expressing a human type II procollagen gene under the control of the human COL1A1 promoter caused a greater than 50% reduction in the production of type II procollagen and a similar decrease in the corresponding type II procollagen transcripts. These results indicate that ET-743 is a potent inhibitor of COL1A1 transcription. However, this effect cannot be explained by a direct effect on CBF binding to the COL1A1 promoter. Although the exact mechanisms responsible for the transcriptional inhibition of COL1A1 by ET-743 are not apparent, our observations suggest that the drug may be an effective agent to decrease collagen overproduction in SSc and other fibrotic diseases.


Tonal interface to MacroMolecules (TIMMol): A textual and tonal tool for molecular visualization.
We developed the three-dimensional visualization software, Tonal Interface to MacroMolecules or TIMMol, for studying atomic coordinates of protein structures. Key features include audio tones indicating x, y, z location, identification of the cursor location in one-dimensional and three-dimensional space, textual output that can be easily linked to speech or Braille output, and the ability to scroll along the main chain backbone of a protein structure. This program was initially designed for visually impaired users, and it already has shown its effectiveness in helping a blind researcher study X-ray crystal structure data. Subsequently, TIMMol has been enhanced with a graphical display to act as a bridge to ease communication between sighted and visually impaired users as well as to serve users with spatial visualization difficulties. We performed a pilot study to assess the efficacy of the program in conveying three-dimensional information about proteins with and without graphical output to a general scientific audience. Attitudes regarding using TIMMol were assessed using Rasmol, a common visualization package, for comparison. With the use of text and tones exclusively, a majority of users were able to identify specific secondary structure elements, three-dimensional relationships among atoms, and atoms coordinating a ligand. In addition, a majority of users saw benefits in using TIMMol and would recommend it to those having difficulty with standard tools.


Generative-Discriminative Complementary Learning.
The majority of state-of-the-art deep learning methods are discriminative approaches, which model the conditional distribution of labels given inputs features. The success of such approaches heavily depends on high-quality labeled instances, which are not easy to obtain, especially as the number of candidate classes increases. In this paper, we study the complementary learning problem. Unlike ordinary labels, complementary labels are easy to obtain because an annotator only needs to provide a yes/no answer to a randomly chosen candidate class for each instance. We propose a generative-discriminative complementary learning method that estimates the ordinary labels by modeling both the conditional (discriminative) and instance (generative) distributions. Our method, we call Complementary Conditional GAN (CCGAN), improves the accuracy of predicting ordinary labels and is able to generate high-quality instances in spite of weak supervision. In addition to the extensive empirical studies, we also theoretically show that our model can retrieve the true conditional distribution from the complementarily-labeled data.


Prospective Evaluation of Semiquantitative Strain Ratio and Quantitative 2D Ultrasound Shear Wave Elastography (SWE) in Association with TIRADS Classification for Thyroid Nodule Characterization.
To evaluate the diagnostic performance of strain ratio elastography (SRE) and shear wave elastography (SWE) alone and in combination with Thyroid Imaging Reporting and Data System (TIRADS) classification parameters to improve differentiation between benign and malignant thyroid nodules. In this prospective study benign (n = 191) and malignant (n = 52) thyroid nodules were examined with high-resolution ultrasound (US) features using the TIRADS lexicon and SRE semiquantitative and SWE quantitative findings using histology or cytology as the gold standard with a 12-month follow-up. Sensitivity (Se), specificity (Sp) and the area under the ROC curve (AUROC) were used to evaluate the diagnostic performance of each feature and combinations of the methods. TIRADS score showed a sensitivity of 59.6 %, a specificity of 83.8 % with an AUROC of 0.717, a PPV of 50.0 % and an NPV of 88.4 %. SRE yielded the highest performance with a sensitivity of 82.7 %, a specificity of 92.7 % with AUROC of 0.877, a PPV 75.4 % and an NPV of 95.2 %. SWE (kPa) had a sensitivity and specificity of 67.3 % and 82.7 %, respectively, with an AUROC of 0.750, a PPV of 51.5 % and an NPV of 90.3 %. Differences were significant for SRE only but not for SWE. Ultrasound elastography may improve thyroid nodule discrimination. In particular, SRE has a better performance than TIRADS classification, while their combination improves sensitivity.


Dichotic Listening Deficit Associated With Solvent Exposure.
A significant left ear deficit can be observed in solvent-exposed individuals using the dichotic digit test. Solvents are ubiquitous in global industrial processes. Due to their lipophilic nature, solvents can adversely affect large white matter tracks such as the corpus callosum. Previous investigations reveal that long-term workplace exposure to solvents is also deleterious to various auditory processes. Investigations in exposed populations suggest a decreased performance for dichotic listening. In this present study, we examined the lateralization of a dichotic digit test score for 49 solvent-exposed individuals along with 49 age- and sex-matched controls. We evaluated group differences between test scores and the right ear advantage using a laterality index (LI). Individual ear results suggest that long-term workplace solvent exposure is associated with a significantly lower dichotic listening score for the left ear. A binaural compound score analysis using a laterality index supports this left-ear deficit. These results provide an insight on the effects of solvent exposure on dichotic listening abilities. Further research should investigate the importance of using dichotic listening tasks to screen for solvent-induced auditory dysfunction in exposed individuals.


Local contractions regulate E-cadherin rigidity sensing.
E-cadherin is a major cell-cell adhesion molecule involved in mechanotransduction at cell-cell contacts in tissues. Because epithelial cells respond to rigidity and tension in tissue through E-cadherin, there must be active processes that test and respond to the mechanical properties of these adhesive contacts. Using submicrometer, E-cadherin-coated polydimethylsiloxane pillars, we find that cells generate local contractions between E-cadherin adhesions and pull to a constant distance for a constant duration, irrespective of pillar rigidity. These cadherin contractions require nonmuscle myosin IIB, tropomyosin 2.1, α-catenin, and binding of vinculin to α-catenin. Cells spread to different areas on soft and rigid surfaces with contractions, but spread equally on soft and rigid without. We further observe that cadherin contractions enable cells to test myosin IIA-mediated tension of neighboring cells and sort out myosin IIA-depleted cells. Thus, we suggest that epithelial cells test and respond to the mechanical characteristics of neighboring cells through cadherin contractions.


The epidemiology of norovirus gastroenteritis in China: disease burden and distribution of genotypes.
With the improvements of sanitation and nationwide safe water supply the occurrence of bacterial diarrhea declined remarkably, while viruses became the leading causes of acute gastroenteritis (AGE). Of these viruses, noroviruses (NoVs) are responsible for a considerable burden of gastroenteritis, especially in children < 2 years and elderly ⩾ 65 years. NoVs circulating in the Chinese population are antigenically highly diverse with the genotype GII.4 being the dominant strain followed by GII.3. Given the widespread contamination in environmental sources, and highly infectious nature of NoVs, vaccination would be the desirable strategy for the control of NoV infections. However, a better understanding of acquired immunity after infection, and a reliable immunological surrogate marker are urgently needed, since two vaccine candidates based on virus-like particles (VLPs) are currently moving into clinical evaluations in China.


Learning at any rate: action-effect learning for stimulus-based actions.
Recent studies reported converging evidence for action-effect associations if participants adopted an intention-based action control mode in free choice conditions, whereas no evidence for action-effect associations was found when participants adopted a stimulus-based mode in forced choice conditions. However, it is not yet clear whether action control modes moderate acquisition or usage of action-effect associations. In the present experiment, two groups of participants underwent an acquisition phase consisting of either free or forced choice key presses that produced irrelevant, but contingent effect tones. In a subsequent test phase, participants freely chose the key to press after former effect tones were presented. A reliable consistency effect resulted for both the groups, i.e. participants preferred the key that produced the irrelevant tone in the preceding acquisition phase. In combination with prior findings, this consistency effect suggests that usage, but not acquisition of action-effect associations depends on an intention-based action control mode.


The economic burden of TB diagnosis and treatment in South Africa.
Social protection against the cost of illness is a central policy objective of Universal Health Coverage and the post-2015 Global strategy for Tuberculosis (TB). Understanding the economic burden associated with TB illness and care is key to identifying appropriate interventions towards achieving this target. The aims of this study were to identify points in patient pathways from start of TB symptoms to treatment completion where interventions could be targeted to reduce the economic impact on patients and households, and to identify those most vulnerable to these costs. Two cohorts of patients accessing TB services from ten clinics in four provinces in South Africa were surveyed between July 2012 and June 2013. One cohort of 351 people with suspected TB were interviewed at the point of receiving a TB diagnostic and followed up six months later. Another cohort of 168 patients on TB treatment, at the same ten facilities, was interviewed at two-months and five-months on treatment. Patients were asked about their health-seeking behaviour, associated costs, income loss, and coping strategies used. Patients incurred the greatest share of TB episode costs (41%) prior to starting treatment, with the largest portion of these costs being due to income loss. Poorer patients incurred higher direct costs during treatment than those who were less poor but only 5% of those interviewed were accessing cash-transfers during treatment. Indirect costs accounted for 52% of total episode cost. Despite free TB diagnosis and care in South Africa, patients incur substantial direct and indirect costs particularly prior to starting treatment. The poorest group of patients were incurring higher costs, with fewer resources to pay for it. Both the direct and indirect cost of illness should be taken into account when setting levels of financial protection and social support, to prevent TB illness from pushing the poor further into poverty.


Endotoxin shock in antibody-deficient mice: unraveling the role of natural antibody and complement in the clearance of lipopolysaccharide.
While the significance of natural Ab is not entirely clear, one proposed role is clearance of bacterial Ags. To determine whether natural Ab was involved in clearance of endotoxin, we have examined novel strains of mice with either a total or selective deficiency in Ig. Recombinase-activating gene-2 (RAG-2(-/-))-deficient mice, which have no serum Ig due to arrested development of B cells at the pro-B stage, demonstrate increased sensitivity to endotoxin that correlates with an impaired clearance. When RAG-2(-/-) mice are reconstituted with pooled sera from normal mice, both survival and clearance of circulating endotoxin are enhanced. To further define the nature of the protective Ab, Bruton's tyrosine kinase (Btk)-deficient mice were characterized in the high dose LPS model. Like RAG-2(-/-) mice, they are highly sensitive to endotoxin and have an impaired clearance of LPS. Reconstitution of Btk(-/-) mice, which have reduced levels of IgG3 and IgM, with purified normal mouse IgM dramatically enhances their ability to clear endotoxin compared with mock (saline)-reconstituted littermates. The cellular source of natural anti-LPS IgM was identified as the peritoneal-residing B-1 cell by enzyme-linked immunospot (ELISPOT) assay. Taken together, these studies demonstrate the important role of natural Ab and complement in the clearance of pathogenic substances from the circulation.


Benchmarking Spike-Based Visual Recognition: A Dataset and Evaluation.
Today, increasing attention is being paid to research into spike-based neural computation both to gain a better understanding of the brain and to explore biologically-inspired computation. Within this field, the primate visual pathway and its hierarchical organization have been extensively studied. Spiking Neural Networks (SNNs), inspired by the understanding of observed biological structure and function, have been successfully applied to visual recognition and classification tasks. In addition, implementations on neuromorphic hardware have enabled large-scale networks to run in (or even faster than) real time, making spike-based neural vision processing accessible on mobile robots. Neuromorphic sensors such as silicon retinas are able to feed such mobile systems with real-time visual stimuli. A new set of vision benchmarks for spike-based neural processing are now needed to measure progress quantitatively within this rapidly advancing field. We propose that a large dataset of spike-based visual stimuli is needed to provide meaningful comparisons between different systems, and a corresponding evaluation methodology is also required to measure the performance of SNN models and their hardware implementations. In this paper we first propose an initial NE (Neuromorphic Engineering) dataset based on standard computer vision benchmarksand that uses digits from the MNIST database. This dataset is compatible with the state of current research on spike-based image recognition. The corresponding spike trains are produced using a range of techniques: rate-based Poisson spike generation, rank order encoding, and recorded output from a silicon retina with both flashing and oscillating input stimuli. In addition, a complementary evaluation methodology is presented to assess both model-level and hardware-level performance. Finally, we demonstrate the use of the dataset and the evaluation methodology using two SNN models to validate the performance of the models and their hardware implementations. With this dataset we hope to (1) promote meaningful comparison between algorithms in the field of neural computation, (2) allow comparison with conventional image recognition methods, (3) provide an assessment of the state of the art in spike-based visual recognition, and (4) help researchers identify future directions and advance the field.


A test of the Whitaker scoring system for estimating age from the bones of the foot.
Within the literature pertaining to skeletal age estimation, there is a paucity of statistically validated methods of age estimation from the foot. Given the prevalence of recovery of pedal elements in isolation, it is critical that methods exist to facilitate the estimation of age from this anatomical region and that those methods be tested to ensure they are reliable, repeatable and statistically robust. A study was carried out to determine the validity of using the Whitaker method of age estimation from the bones of the foot as a tool in forensic age estimation within a modern Scottish population. Two-hundred and sixty radiographs from individuals aged between birth and 18 years were assessed according to the Whitaker method; the results were compared with chronological age. The results of this study suggest that the method of Whitaker et al. is highly unlikely to estimate the age of females below 16 years of age or males below 18 years of age correctly. When the methodology was altered to correspond with best practice principles of age estimation, the estimated age ranges were found to be too wide to be of practical value in forensic age estimation. The results of this study therefore suggest that the Whitaker method for estimating age from the bones of the foot should not be used in forensic age assessment.


Survival trends in European cancer patients diagnosed from 1988 to 1999.
We analysed data from 49 cancer registries in 18 European countries over the period 1988-1999 to delineate time trends in cancer survival. Survival increased in Europe over the study period for all cancer sites that were considered. There were major survival increases in 5 year age-adjusted relative survival for prostate (from 58% to 79%), colon and rectum (from 48% to 54% men and women), and breast (from 74% to 83%). Improvements were also significant for stomach (from 22% to 24%), male larynx (from 62% to 64%), skin melanoma (from 78% to 83%), Hodgkin disease (from 77% to 83%), non-Hodgkin lymphoma (from 49% to 56%), leukaemias (from 37% to 42%), and for all cancers combined (from 34% to 39% in men, and from 52% to 59% in women). Survival did not change significantly for female larynx, lung, cervix or ovary. The largest increases in survival typically occurred in countries with the lowest survival, and contributed to the overall reduction of survival disparities across Europe over the study period. Differences in the extent of PSA testing and mammographic screening, and increasing use of colonoscopy and faecal blood testing together with improving cancer care are probably the major underlying reasons for the improvements in survival for cancers of prostate, breast, colon and rectum. The marked survival improvements in countries with poor survival may indicate that these countries have made efforts to adopt the new diagnostic procedures and the standardised therapeutic protocols in use in more affluent countries.


Quality of Life Among Primary Family Caregivers of Patients with Heart Failure in Southwest China.
The aim of this study was to investigate the quality of life (QOL) and to identify the factors (characteristics of patients and caregivers, caregiver burden, self-efficacy, and social support) related to QOL among family caregivers of patients with heart failure (HF) in Southwest China. The study had a cross-sectional descriptive design. Patients and their family caregiver dyads (N = 251) in three hospitals in Chengdu were recruited from April 2013 to September 2014. Data were collected by in-person interviews. Multivariate analyses were used to identify the factors associated with physical and mental QOL of caregivers. The median scores of physical and mental QOL were 70 and 60, respectively. Multivariate analysis demonstrated that higher New York Heart Association (NYHA) classification, more caregiving hours per day, more readmissions in the last 6 months, higher caregiver burden, and lower social support were associated with poorer physical and mental QOL. Lower self-efficacy was also associated with poorer physical QOL. The variances of physical (73%) and mental (70%) QOL of caregivers were explained by these identified significant factors. The caregivers of patients with HF in Southwest China had perceived reduced QOL and experienced more seriously impaired mental health than physical health. Early assessments, strategies, and policy supports developed particularly for caregivers in undeveloped areas are necessary to identify caregivers who are at a high risk of reduced QOL and to improve their well-being.


Establishment and characterization of human embryonic stem cell lines, Turkey perspectives.
Human embryonic stem cells (hESC), which are derived from the inner cell mass (ICM) of blastocyst stage embryos, are of great importance because of their unpredictable two unique features: their differentiation ability into all types of cells derived from three germ layers and their potentially unlimited capacity of self renewing with stable karyotype. These distinguished properties make hESC very promising cell source for regenerative medicine, tissue replacement therapies, and drug screening studies as well as genomics. However, due to the several technical problems, such as risk of teratoma formation, immune response, and unknown genetic pathways for lineage specific differentiation, and ethical drawbacks of their using in clinical treatments, hESC researches are still waiting to advance beyond to animal trials and drug studies. During the last decade, more than 300 new hESC lines have been derived and published by researchers worldwide. However, despite their similar well-known unique properties, recent studies reported that hESC lines have very individual properties and are differed from each other with regards to their differentiation ability and gene expression profiles. Therefore, all hESC lines should be characterized in detail and then registered in a stem cell bank for generating global database. In this report, the characteristic of hESC lines, which were established in Istanbul Memorial Hospital between 2003 and 2005, and derivation methods were described in detail to inform researchers and to facilitate new prospective cooperative studies.


Assortative mating for psychiatric disorders and psychological traits.
This article reviews the literature on assortative mating for psychological traits and psychiatric illness. Assortative mating appears to exist for personality traits, but to a lesser degree than that observed for physical traits, sociodemographic traits, intelligence, and attitudes and values. Concordance between spouses for psychiatric illness has also been consistently reported in numerous studies. This article examines alternative explanations for such observed concordance and discusses the effects of assortative mating on population genetics and the social environment.


College students on the autism spectrum: prevalence and associated problems.
As more young people are identified with autism spectrum diagnoses without co-occurring intellectual disability (i.e. high-functioning autism spectrum disorder; HFASD), it is imperative that we begin to study the needs of this population. We sought to gain a preliminary estimate of the scope of the problem and to examine psychiatric risks associated HFASD symptoms in university students. In a large sample (n = 667), we examined prevalence of ASD in students at a single university both diagnostically and dimensionally, and surveyed students on other behavioral and psychiatric problems. Dependent upon the ascertainment method, between .7 per cent and 1.9 per cent of college students could meet criteria for HFASD. Of special interest, none of the students who were found to meet diagnostic criteria (n = 5) formally for HFASD in this study had been previously diagnosed. From a dimensional perspective, those students scoring above the clinical threshold for symptoms of autism (n = 13) self-reported more problems with social anxiety than a matched comparison group of students with lower autism severity scores. In addition, symptoms of HFASD were significantly correlated with symptoms of social anxiety, as well as depression and aggression. Findings demonstrate the importance of screening for autism-related impairment among university students.


RNA sequencing by primer extension.
Direct sequencing of RNA by primer extension is a fast and accurate method that is useful in a variety of situations. It is a valuable technique for determining the faithfulness of in vitro processing reactions, such as splicing or RNA editing. It is often used as an alternative to reverse transcription PCR (RT-PCR) followed by cloning and DNA sequencing. In the primer extension reaction, a radiolabeled probe (almost always a 5'-end-labeled DNA oligonucleotide) is annealed to the target RNA of interest. After hybridization, cDNA synthesis by reverse transcription proceeds from the 3' end of the primer in the presence of chain-terminating dideoxynucleotide triphosphates. The cDNA products are fractionated on denaturing polyacrylamide gels and analyzed by phosphorimaging or autoradiography.


[Study of viremia in experimental neuroviral infections].
Study of viremia in susceptible experimental animals showed all the blood fractions to take part in the infectious process both in acute diseases and in the chronic course of infections caused by various neuroviruses. Thus in animals infected with human acute encephalomyelitis, tick-borne encephalitis, lymphocytic choriomeningitis viruses viremia was observed throughout the entire short period of infection terminating fatally, as a rule. In such cases viremia was of a mixed character, the viruses being found in all blood fractions. The intensity of viremia and the degree of involvement of plasm and blood cell elements into the infectious process may depend upon the animal species, virus strains, form of the disease (acute, chronic). In chronic encephalomyelitis in rats and guinea pigs infected with human acute encephalomyelitis virus viremia are observed for two years (the observation period). In chronic encephalomyelitis blood cells were more actively involved in the infectious process. Virus was found in leukocytes and erythrocytes more frequently than in plasm, though the total amount of virus in the blood was much lower than that in the acute form of this disease. Sequential multiple passages of AEM virus from the blood to the brain in experiments with some strains resulted in intensive viremia thereby demonstrating the possibility of AEM adaptation to the blood tissue.


Generation of three-dimensional integral images from a holographic pattern of 3-D objects.
We present a novel approach for generating three-dimensional (3-D) integral images from a fringe pattern of 3-D objects. A recorded hologram of 3-D objects is segmented into a number of subholograms. Then, different views of 3-D objects are reconstructed from them because each subhologram has its own perspective of 3-D objects in the recording process. These locally reconstructed images can be rearranged as the same subimage array of the conventional integral-imaging system and transformed into virtually picked-up elemental images of 3-D objects. From this newly generated elemental image array, 3-D images could easily be reconstructed by using a white light. Experiments with a 3-D test object have been performed and the results have been presented.


Two-dimensional segmentation for analyzing Hi-C data.
The spatial conformation of the chromosome has a deep influence on gene regulation and expression. Hi-C technology allows the evaluation of the spatial proximity between any pair of loci along the genome. It results in a data matrix where blocks corresponding to (self-)interacting regions appear. The delimitation of such blocks is critical to better understand the spatial organization of the chromatin. From a computational point of view, it results in a 2D segmentation problem. We focus on the detection of cis-interacting regions, which appear to be prominent in observed data. We define a block-wise segmentation model for the detection of such regions. We prove that the maximization of the likelihood with respect to the block boundaries can be rephrased in terms of a 1D segmentation problem, for which the standard dynamic programming applies. The performance of the proposed methods is assessed by a simulation study on both synthetic and resampled data. A comparative study on public data shows good concordance with biologically confirmed regions. The HiCseg R package is available from the Comprehensive R Archive Network and from the Web page of the corresponding author.


Emergence of Antibiotic Resistance-Associated Clones Among Escherichia coli Recovered From Newborns With Early-Onset Sepsis and Meningitis in the United States, 2008-2009.
Escherichia coli associated with early-onset sepsis (EOS) have historically been antibiotic-susceptible and K1-encapsulated. In the era of emerging antibiotic resistance, however, the clonal makeup of E coli associated with EOS has not been well characterized. Escherichia coli isolates were collected from 28 cases of EOS and early-onset meningitis (EOM) from April 2008 through December 2009, during a parent study conducted at National Institute of Child Health and Human Development Neonatal Research Network centers from February 2006 through December 2009. Clinical and microbiologic data were collected for the parent study. We applied polymerase chain reaction- and sequence-based molecular techniques to determine clonal, virulence-associated and antibiotic resistance-associated traits of the E coli isolates. Among 28 E coli strains, phylogroup B2 strains predominated (68%), of which more than half were K1-encapsulated (53%). Phylogroup D strains were prominent as well (18%), but none were K1-encapsulated. Across the strain collection, the rate of ampicillin resistance was high (78%). The sole strain resistant to either extended-spectrum cephalosporins or fluoroquinolones represented ST131 H30-Rx, the multidrug-resistant subclone that has emerged worldwide in the last decade. This strain encoded extended-spectrum β-lactamase CTX-M-15 and carried an IncF plasmid of type F2:A1:B-. In this collection of EOS/EOM-associated E coli isolates, we observed a high rate of ampicillin resistance, a low rate of fluoroquinolone resistance, and no aminoglycoside resistance, with resistance to third-generation cephalosporins appearing in only a single strain, from the worldwide emerging ST131 clone. Ongoing surveillance of antibiotic resistance among EOS isolates is warranted, to ensure that standard empiric regimens remain effective.


Calcium Sensitization Mechanisms in Gastrointestinal Smooth Muscles.
An increase in intracellular Ca(2+) is the primary trigger of contraction of gastrointestinal (GI) smooth muscles. However, increasing the Ca(2+) sensitivity of the myofilaments by elevating myosin light chain phosphorylation also plays an essential role. Inhibiting myosin light chain phosphatase activity with protein kinase C-potentiated phosphatase inhibitor protein-17 kDa (CPI-17) and myosin phosphatase targeting subunit 1 (MYPT1) phosphorylation is considered to be the primary mechanism underlying myofilament Ca(2+) sensitization. The relative importance of Ca(2+) sensitization mechanisms to the diverse patterns of GI motility is likely related to the varied functional roles of GI smooth muscles. Increases in CPI-17 and MYPT1 phosphorylation in response to agonist stimulation regulate myosin light chain phosphatase activity in phasic, tonic, and sphincteric GI smooth muscles. Recent evidence suggests that MYPT1 phosphorylation may also contribute to force generation by reorganization of the actin cytoskeleton. The mechanisms responsible for maintaining constitutive CPI-17 and MYPT1 phosphorylation in GI smooth muscles are still largely unknown. The characteristics of the cell-types comprising the neuroeffector junction lead to fundamental differences between the effects of exogenous agonists and endogenous neurotransmitters on Ca(2+) sensitization mechanisms. The contribution of various cell-types within the tunica muscularis to the motor responses of GI organs to neurotransmission must be considered when determining the mechanisms by which Ca(2+) sensitization pathways are activated. The signaling pathways regulating Ca(2+) sensitization may provide novel therapeutic strategies for controlling GI motility. This article will provide an overview of the current understanding of the biochemical basis for the regulation of Ca(2+) sensitization, while also discussing the functional importance to different smooth muscles of the GI tract.


Engineering tailored nanoparticles with microbes: quo vadis?
In the quest for less toxic and cleaner methods of nanomaterials production, recent developments in the biosynthesis of nanoparticles have underscored the important role of microorganisms. Their intrinsic ability to withstand variable extremes of temperature, pressure, and pH coupled with the minimal downstream processing requirements provide an attractive route for diverse applications. Yet, controlling the dispersity and facile tuning of the morphology of the nanoparticles of desired chemical compositions remains an ongoing challenge. In this Focus Review, we critically review the advances in nanoparticle synthesis using microbes, ranging from bacteria and fungi to viruses, and discuss new insights into the cellular mechanisms of such formation that may, in the near future, allow complete control over particle morphology and functionalization. In addition to serving as paradigms for cost-effective, biocompatible, and eco-friendly synthesis, microbes hold the promise for a unique template for synthesis of tailored nanoparticles targeted at therapeutic and diagnostic platform technologies.


A step toward the wet surface chemistry of glycine and alanine on Cu{110}: destabilization and decomposition in the presence of near-ambient water vapor.
The coadsorption of water with organic molecules under near-ambient pressure and temperature conditions opens up new reaction pathways on model catalyst surfaces that are not accessible in conventional ultrahigh-vacuum surface-science experiments. The surface chemistry of glycine and alanine at the water-exposed Cu{110} interface was studied in situ using ambient-pressure photoemission and X-ray absorption spectroscopy techniques. At water pressures above 10(-5) Torr a significant pressure-dependent decrease in the temperature for dissociative desorption was observed for both amino acids, accompanied by the appearance of a new CN intermediate, which is not observed for lower pressures. The most likely reaction mechanisms involve dehydrogenation induced by O and/or OH surface species resulting from the dissociative adsorption of water. The linear relationship between the inverse decomposition temperature and the logarithm of water pressure enables determination of the activation energy for the surface reaction, between 213 and 232 kJ/mol, and a prediction of the decomposition temperature at the solid-liquid interface by extrapolating toward the equilibrium vapor pressure. Such experiments near the equilibrium vapor pressure provide important information about elementary surface processes at the solid-liquid interface, which can be retrieved neither under ultrahigh vacuum conditions nor from interfaces immersed in a solution.


Referral to medical outpatients department at teaching hospitals in Birmingham and Amsterdam.
A method of comparing the referral of patients by general practitioners to medical outpatients departments at teaching hospitals in Amsterdam and Birmingham was devised. This was applied to 89 referral letters to medical specialists at the Free University Medical School Policlinic in Amsterdam and to 88 referral letters to clinics at Birmingham University Medical School, UK. The standards of referral were lower in the Netherlands than in Britain, and this may be related to differences in the health care systems, in the culture, or in the organisation of general practice. The delay between the general practitioner's referral and the consultation to the outpatient department was four times greater in Britain than in the Netherlands.


A Secured and Intelligent Communication Scheme for IIoT-enabled Pervasive Edge Computing.
Industrial Internet of Things (IIoT) ensures reliable and efficient data exchanges among the industrial processes using Artificial Intelligence (AI) within the cyber-physical systems. In the IIoT ecosystem, devices of industrial applications communicate with each other with little human intervention. They need to act intelligently to safeguard the data confidentiality and devices' authenticity. The ability to gather, process, and store real-time data depends on the quality of data, network connectivity, and processing capabilities of these devices. Pervasive Edge Computing (PEC) is gaining popularity nowadays due to the resource limitations imposed on the sensor-embedded IIoT devices. PEC processes the gathered data at the network edge to reduce the response time for these devices. However, PEC faces numerous research challenges in terms of secured communication, network connectivity, and resource utilization of the edge servers. To address these challenges, we propose a secured and intelligent communication scheme for PEC in an IIoT-enabled infrastructure. In the proposed scheme, forged identities of adversaries, i.e., Sybil devices, are detected by IIoT devices and shared with edge servers to prevent upstream transmission of their malicious data. Upon Sybil attack detection, each edge server executes a parallel Artificial Bee Colony (pABC) algorithm to perform optimal network configuration of IIoT devices. Each edge server performs the job migration to their neighboring servers for load balancing and better network performance, based on their processing and storage capabilities. The experimental results justify the efficiency of our proposed scheme in terms of Sybil attack detection, the convergence curves of our pABC algorithm, delay, throughput, and control overhead of data communication using PEC for IIoT.


Metabolism and disposition of [14C]dibromoacetonitrile in rats and mice following oral and intravenous administration.
1. Tissue distribution, metabolism, and disposition of oral (0.2-20 mg/kg) and intravenous (0.2 mg/kg) doses of [2-(14)C]dibromoacetonitrile (DBAN) were investigated in male rats and mice. 2. [(14)C]DBAN reacts rapidly with rat blood in vitro and binds covalently. Prior depletion of glutathione (GSH) markedly diminished loss of DBAN. Chemical reaction with GSH readily yielded glutathionylacetonitrile. 3. About 90% of the radioactivity from orally administered doses of [(14)C]DBAN was absorbed. After intravenous administration, 10% and 20% of the radioactivity was recovered in mouse and rat tissues, respectively, at 72 h. After oral dosing, three to four times less radioactivity was recovered, but radioactivity in stomach was mostly covalently bound. 4. Excretion of radioactivity into urine exceeded that in feces; 9-15% was exhaled as labeled carbon dioxide and 1-3% as volatiles in 72 h. 5. The major urinary metabolites were identified by liquid chromatography-mass spectrometry, and included acetonitrile mercaptoacetate (mouse), acetonitrile mercapturate, and cysteinylacetonitrile. 6.The primary mode of DBAN metabolism is via reaction with GSH, and covalent binding may be due to reaction with tissue sulphydryls.


Mechanism of superoxide dismutase-like activity of Fe(II) and Fe(III) complexes of tetrakis-N,N,N',N'(2-pyridylmethyl)ethylenediamine.
The superoxide dismutase (SOD) activity of iron(II) tetrakis-N,N,N',N'(2-pyridylmethyl)ethylenediamine complex (Fe-TPEN) was reexamined using a pulse radiolysis method. In our previous study (J. Biol. Chem., 264, 9243-9249 (1989)), we reported that this complex has a potent SOD activity in a cyt. c (cytochrome c)-based system (IC50 = 0.8 microM) and protects E. coli cells against paraquat toxicity. The present pulse radiolysis experiment revealed that Fe(II)TPEN reacts stoichiometrically with superoxide to form Fe(III)TPEN with a second-order rate constant of 3.9 x 10(6) M-1 S-1 at pH 7.1, but superoxide did not reduce Fe(III)TPEN to Fe(II)TPEN. The reaction of Fe(III)TPEN and superoxide was biphasic. In the fast reaction, an adduct (Fe(III)TPEN-superoxide complex) was formed at the second-order rate constant of 8.5 x 10(5) M-1 S-1 at pH 7.4. In the slow one, the adduct reacted with another molecule of the adduct, regenerating Fe(III)TPEN. In the cyt. c method with catalase, this Fe(III)TPEN-superoxide complex showed cyt. c oxidation activity, which had led to overestimation of its SOD activity. Based on the titration data, the main species of complex in aqueous media at neutral pH was indicated to be Fe(III)TPEN(OH-). A spectral change after the reduction with hydrated electron indicates that the OH- ion coordinates directly to Fe(III) by displacing one of the pyridine rings. The X-ray analysis of [Fe(II)TPEN]SO4 supported this structure. From the above results we propose a novel reaction mechanism of FeTPEN and superoxide which resembles a proton catalyzed dismuting process, involving Fe(III)TPEN-superoxide complex.


Safety and feasibility of the NanoKnife system for irreversible electroporation ablative treatment of canine spontaneous intracranial gliomas.
Irreversible electroporation (IRE) is a novel nonthermal ablation technique that has been used for the treatment of solid cancers. However, it has not been evaluated for use in brain tumors. Here, the authors report on the safety and feasibility of using the NanoKnife IRE system for the treatment of spontaneous intracranial gliomas in dogs. Client-owned dogs with a telencephalic glioma shown on MRI were eligible. Dog-specific treatment plans were generated by using MRI-based tissue segmentation, volumetric meshing, and finite element modeling. After biopsy confirmation of glioma, IRE treatment was delivered stereotactically with the NanoKnife system using pulse parameters and electrode configurations derived from therapeutic plans. The primary end point was an evaluation of safety over the 14 days immediately after treatment. Follow-up was continued for 12 months or until death with serial physical, neurological, laboratory, and MRI examinations. Seven dogs with glioma were treated. The mean age of the dogs was 9.3 ± 1.6 years, and the mean pretreatment tumor volume was 1.9 ± 1.4 cm(3). The median preoperative Karnofsky Performance Scale score was 70 (range 30-75). Severe posttreatment toxicity was observed in 2 of the 7 dogs; one developed fatal (Grade 5) aspiration pneumonia, and the other developed treatment-associated cerebral edema, which resulted in transient neurological deterioration. Results of posttreatment diagnostic imaging, tumor biopsies, and neurological examinations indicated that tumor ablation was achieved without significant direct neurotoxicity in 6 of the 7 dogs. The median 14-day post-IRE Karnofsky Performance Scale score of the 6 dogs that survived to discharge was 80 (range 60-90), and this score was improved over the pretreatment value in every case. Objective tumor responses were seen in 4 (80%) of 5 dogs with quantifiable target lesions. The median survival was 119 days (range 1 to > 940 days). With the incorporation of additional therapeutic planning procedures, the NanoKnife system is a novel technology capable of controlled IRE ablation of telencephalic gliomas.


Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons.
The primary cytotoxic mechanism of camptothecin has been proposed to involve an interaction between the replication machinery and the camptothecin-mediated topoisomerase I-DNA cleavable complex (Y. H. Hsiang, M.G. Lihou, and L.F. Liu, Cancer Res., 49:5077-5082, 1989). In the present study, we show that killing of V79 cells by the topoisomerase II poisons 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and etoposide may involve ongoing RNA synthesis in addition to ongoing DNA synthesis. V79 cells synchronized by mitotic shake-off were treated with topoisomerase poisons in the presence of inhibitors of nucleic acid synthesis. S-Phase V79 cells were more sensitive to the topoisomerase I poison camptothecin and the topoisomerase II poison m-AMSA than G1-phase cells. The greater sensitivity of S-phase cells to killing by m-AMSA and camptothecin was abolished during cotreatment, but not posttreatment, with aphidicolin, suggesting that ongoing DNA synthesis in involved in cell killing by both topoisomerase I and II poisons. Cotreatment with transcription inhibitors, such as 5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole or cordycepin, partially protected cells from the cytotoxic effects of m-AMSA but had no effect on camptothecin-mediated cytotoxicity. These results suggest that ongoing RNA transcription may be involved in cell killing by topoisomerase II poisons but not topoisomerase I poisons. Cotreatment with camptothecin reduced m-AMSA-mediated cytotoxicity in G1-phase V79 cells, suggesting a possible antagonism between topoisomerase I and II poisons. This antagonistic effect between topoisomerase I and II poisons could be explained by the strong inhibitory effect of camptothecin on RNA transcription.


Whole-body and site-specific bone remodelling in patients with previous femoral fractures: relationships between reduced physical activity, reduced bone mass and increased bone resorption.
1. A new tracer method is described for the non-invasive measurement of bone formation in the proximal femur. The method is based on our previously described whole-body method using 85Sr as the tracer (Reeve, J., Hesp, R. & Wootton, R. Calcif. Tissue Res. 1976; 22, 191-206). It allows correction to be made for long-term exchange processes within the skeleton. 2. The method has been applied in a study of regional and whole-body bone formation in 12 rehabilitated patients who had previously suffered a fracture of the proximal femur. Twelve healthy control subjects were studied, who were selected for their good health and continued physical activity. The aim was to explore the relationship between bone formation and physical activity. 3. Bone formation was similar in the two groups, both regionally and in the whole body. Based on analyses of four cadaver specimens, bone formation in the proximal femur was about one and two-thirds times that in the whole skeleton when related to mass of calcium in the region of interest. 4. Whole-body bone resorption, estimated from five measurements per subject of hydroxyproline excretion in relation to creatinine excretion, was significantly higher in the fracture patients (P < 0.01, Wilcoxon's test). 5. Estimates of current physical activity (and immediate pre-fracture physical activity) were made with a newly devised questionnaire. Historical levels of physical activity (at ages 15-45 years) were determined with Astrom's questionnaire. No bone formation index correlated with any index of physical activity. Urinary hydroxyproline excretion correlated inversely both with current physical activity and historical physical activity (for both regression coefficients P < 0.01). 6. The results are discussed in the light of our current understanding of the control of bone remodelling by the discrete basic multicellular units of bone. The opportunity to study regional bone resorption by the additional use of serial dual X-ray absorptiometry of the same region will in future allow the direct monitoring of the effects of therapeutic interventions which have been designed to prevent contralateral hip fracture.


Antibody repertoire development in fetal and neonatal piglets. XVII. IgG subclass transcription revisited with emphasis on new IgG3.
Fetal piglets offer an in vivo model for determining whether Ag-independent IgG subclass transcription proceeds in a manner that differs from subclass transcription in pigs exposed to environmental Ags and TLR ligands. Our data from approximately 12,000 Cgamma clones from > 60 piglets provide the first report on the relative usage of all known porcine Cgamma genes in fetal and young pigs. Studies revealed that among the six Cgamma genes, allelic variants of IgG1 comprised 50-80% of the repertoire, and IgG2 alleles comprised < 10% in nearly all tissues. However, relative transcription of allelic variants of IgG1 randomly deviate from the 1:1 ratio expected in heterozygotes. Most surprising was the finding that IgG3 accounted for half of all Cgamma transcripts in the ileal Peyer's patches (IPPs) and mesenteric lymph nodes but on average only approximately 5% of the clones from the thymus, tonsil, spleen, peripheral blood, and bone marrow of newborns. Lymphoid tissues from late term fetuses revealed a similar expression pattern. Except for IgG3 in the IPPs and mesenteric lymph nodes, no stochastic pattern of Cgamma expression during development was seen in animals from mid-gestation through 5 mo. The age and tissue dependence of IgG3 transcription paralleled the developmental persistence of the IPP, and its near disappearance corresponds to the diversification of the preimmune VDJ repertoire in young piglets. We hypothesize that long-hinged porcine IgG3 may be important in preadaptive responses to T cell-independent Ags similar to those described for its murine namesake.


Effects of internet use on health and depression: a longitudinal study.
The rapid expansion of the Internet has increased the ease with which the public can obtain medical information. Most research on the utility of the Internet for health purposes has evaluated the quality of the information itself or examined its impact on clinical populations. Little is known about the consequences of its use by the general population. Is use of the Internet by the general population for health purposes associated with a subsequent change in psychological well-being and health? Are the effects different for healthy versus ill individuals? Does the impact of using the Internet for health purposes differ from the impact of other types of Internet use? Data come from a national US panel survey of 740 individuals conducted from 2000 to 2002. Across three surveys, respondents described their use of the Internet for different purposes, indicated whether they had any of 13 serious illnesses (or were taking care of someone with a serious illness), and reported their depression. In the initial and final surveys they also reported on their physical health. Lagged dependent variable regression analysis was used to predict changes in depression and general health reported on a later survey from frequency of different types of Internet use at an earlier period, holding constant prior depression and general health, respectively. Statistical interactions tested whether uses of the Internet predicted depression and general health differently for people who initially differed on their general health, chronic illness, and caregiver status. Health-related Internet use was associated with small but reliable increases in depression (ie, increasing use of the Internet for health purposes from 3 to 5 days per week to once a day was associated with .11 standard deviations more symptoms of depression, P = .002). In contrast, using the Internet for communication with friends and family was associated with small but reliable decreases in depression (ie, increasing use of the Internet for communication with friends and family purposes from 3 to 5 days per week to once a day was associated with .07 standard deviations fewer symptoms of depression, P = .007). There were no significant effects of respondents' initial health status (P = .234) or role as a caregiver (P = .911) on the association between health-related Internet use and depression. Neither type of use was associated with changes in general health (P = .705 for social uses and P = .494 for health uses). Using the Internet for health purposes was associated with increased depression. The increase may be due to increased rumination, unnecessary alarm, or over-attention to health problems. Additionally, those with unmeasured problems or those more prone to health anxiety may self-select online health resources. In contrast, using the Internet to communicate with friends and family was associated with declines in depression. This finding is comparable to other studies showing that social support is beneficial for well-being and lends support to the idea that the Internet is a way to strengthen and maintain social ties.


Review: Fluid biomarkers in the human prion diseases.
The human prion diseases are a diverse set of often rapidly progressive neurodegenerative conditions associated with abnormal forms of the prion protein. We review work to establish diagnostic biomarkers and assays that might fill other important roles, particularly those that could assist the planning and interpretation of clinical trials. The field now benefits from highly sensitive and specific diagnostic biomarkers using cerebrospinal fluid: detecting by-products of rapid neurodegeneration or specific functional properties of abnormal prion protein, with the second generation real time quaking induced conversion (RT-QuIC) assay being particularly promising. Blood has been a more challenging analyte, but has now also yielded valuable biomarkers. Blood-based assays have been developed with the potential to screen for variant Creutzfeldt-Jakob disease, although it remains uncertain whether these will ever be used in practice. The very rapid neurodegeneration of prion disease results in strong signals from surrogate protein markers in the blood that reflect neuronal, axonal, synaptic or glial pathology in the brain: notably the tau and neurofilament light chain proteins. We discuss early evidence that such tests, applied alongside robust diagnostic biomarkers, may have potential to add value as clinical trial outcome measures, predictors of future disease course (including for asymptomatic individuals at high risk of prion disease), and as rapidly accessible and sensitive markers to aid early diagnosis.


A clear urban-rural gradient of allergic rhinitis in a population-based study in Northern Europe.
The protective effect of farm upbringing on allergic rhinitis is well known, but how upbringing in other environments influences the development of allergic rhinitis is scarcely investigated. The aim of this study was to investigate the association between place of upbringing and pet keeping in childhood and allergic rhinitis and nasal symptoms in adulthood. The population-based Respiratory Health in Northern Europe study includes subjects from Denmark, Norway, Sweden, Iceland, and Estonia born in 1945-1973. This paper analyses 13,376 participants of the third study wave. Six categories of place of upbringing were defined: farm with livestock, farm without livestock, village in rural area, small town, city suburb, and inner city. Pets in the home at birth and during childhood were recorded. Data were analysed using adjusted logistic regression models. Livestock farm upbringing predicted less adult allergic rhinitis [odds ratio (OR) 0.68, 0.54-0.85] and nasal symptoms (OR 0.82, 0.68-0.99) than city upbringing, and an urban-rural gradient with decreasing risk per level of urbanisation was observed (OR 0.92, 0.88-0.94). Pets in the home at birth (OR 0.78, 0.68-0.88) and during childhood (OR 0.83, 0.74-0.93) were associated with less subsequent allergic rhinitis. Pet keeping did not explain the protective effect of place of upbringing. Risk of allergic rhinitis and nasal symptoms in adulthood was inversely associated with the level of urbanisation during upbringing. Pets at birth decreased the risk further, but did not explain the urban-rural gradient. Persistent beneficial effects of microbial diversity in early life might be an explanation for the findings.


Teaching and assessing professionalism in medical learners and practicing physicians.
Professionalism is a core competency of physicians. Clinical knowledge and skills (and their maintenance and improvement), good communication skills, and sound understanding of ethics constitute the foundation of professionalism. Rising from this foundation are behaviors and attributes of professionalism: accountability, altruism, excellence, and humanism, the capstone of which is professionalism. Patients, medical societies, and accrediting organizations expect physicians to be professional. Furthermore, professionalism is associated with better clinical outcomes. Hence, medical learners and practicing physicians should be taught and assessed for professionalism. A number of methods can be used to teach professionalism (e.g. didactic lectures, web-based modules, role modeling, reflection, interactive methods, etc.). Because of the nature of professionalism, no single tool for assessing it among medical learners and practicing physicians exists. Instead, multiple assessment tools must be used (e.g. multi-source feedback using 360-degree reviews, patient feedback, critical incident reports, etc.). Data should be gathered continuously throughout an individual's career. For the individual learner or practicing physician, data generated by these tools can be used to create a "professionalism portfolio," the totality of which represents a picture of the individual's professionalism. This portfolio in turn can be used for formative and summative feedback. Data from professionalism assessments can also be used for developing professionalism curricula and generating research hypotheses. Health care leaders should support teaching and assessing professionalism at all levels of learning and practice and promote learning environments and institutional cultures that are consistent with professionalism precepts.


Multifocal ERG responses in infants.
To assess function of the central retina in 10-week-old infants, multifocal electroretinograms (mfERGs) were recorded. mfERG responses represent postreceptor retinal activity. In infants (n = 23) and adults (n = 10), mfERG responses to both unscaled and scaled 61 hexagon arrays were recorded. Amplitude and implicit time of negative (N(1), N(2)) and positive (P(1)) peaks of the first-order kernel were examined. The response from the entire area stimulated and responses to concentric rings were analyzed separately. The overall averaged response of the first slice of the second-order kernel was also evaluated. Results from infants and adults were compared. Amplitudes of the infants' responses (N(1), P(1), N(2)) were significantly smaller and implicit times were significantly longer than those of adults. In infants, amplitude and implicit time varied little with eccentricity. In adults, amplitude decreased with eccentricity, whereas implicit time varied little. In infants, the second-order kernel was relatively more attenuated than the first-order kernel. The infants' mfERG responses indicated immaturities of processing in the central retina. Infant-adult differences in the distribution of cones and bipolar cells may account for the results.