Elevated Expression of the NLRP3 Inflammasome and Its Correlation with Disease Activity in Adult-onset Still Disease.
The dysregulation of the NLRP3 (NLR containing a pyrin domain) inflammasome is involved in autoinflammatory diseases. Adult-onset Still disease (AOSD) is regarded as an autoinflammatory disease. However, the pathogenic involvement of NLRP3 inflammasome in AOSD remains unclear and NLRP3 activators in AOSD are currently unknown. The mRNA expression of NLRP3 inflammasome signaling in peripheral blood mononuclear cells (PBMC) from 34 patients with AOSD and 14 healthy subjects was determined using quantitative-PCR (qPCR). The changes in mRNA and protein levels of NLRP3 inflammasome signaling in PBMC treated with the potential activator [imiquimod (IMQ)] or inhibitor of NLRP3 were evaluated using qPCR and immunoblotting, respectively. The supernatant levels of interleukin (IL)-1β and IL-18 were determined by ELISA. Significantly higher mRNA levels of NLRP3 inflammasome signaling were observed in patients with AOSD compared with healthy controls. NLRP3 expressions were positively correlated with disease activity in patients with AOSD. IMQ (an effective Toll-like receptor 7 ligand; 10 µg/ml and 25 µg/ml) stimulation of PBMC from patients with AOSD induced dose-dependent increases of mRNA expression of NLRP3 (mean ± standard error of the mean, 2.06 ± 0.46 and 6.05 ± 1.84, respectively), caspase-1 (1.81 ± 0.23 and 4.25 ± 0.48), IL-1β (5.68 ± 1.51 and 12.13 ± 3.71), and IL-18 (2.32 ± 0.37 and 4.81 ± 0.51) compared with controls (all p < 0.005). IMQ stimulation of PBMC from patients similarly induced greater increases in protein expressions of NLRP3 inflammasome compared with controls. The protein expressions of NLRP3, IL-1β, and IL-18 on PBMC significantly decreased after treatment with NLRP3 inhibitor in patients with AOSD. Increased expression of NLRP3 inflammasome and its positive correlation with disease activity in AOSD suggest its involvement in disease pathogenesis. IMQ upregulated expressions of NLRP3 inflammasome signaling, and IMQ might be an activator of NLRP3 inflammasome in AOSD.


Deprescribing: is the law on your side?
Deprescribing can feel risky: prescribers need to consider the consequence of stopping a medication medicolegally, particularly where there may be a guideline or accepted practice that suggests its use. This review aims to provide reassurance and encouragement to safely deprescribe. Experience suggests that for many patients the prescribing of multiple medicines is the norm. In the right setting and at the right time, deprescribing provides a real opportunity to minimise side effects and unwanted interactions through patient-centred conversations. How does the prescriber stand if they stop a medication for which there is an evidence-based guideline to use it? This review explores the concepts of clinical negligence and informed patient consent in the context of deprescribing. Using examples from UK case law, the review discusses the legal tests which are applied to establish an action based on clinical negligence and lack of informed consent. It describes the recent changes in law which reinforce the importance of providing information focused on what is material to individual patients. The use of prescribing tools to support safe deprescribing and informed consent are also discussed. When deprescribing is undertaken in partnership with patients, supported by the knowledge, skills and experience of both patient and clinicians and the patient's values and preferences based on clinical skill, judgement and evidence-based medicine, law presents no barriers to deprescribing.


Hazard identification of cis/trans-zearalenone through the looking-glass.
Among the food-related health issues, the presence of contaminants has a prominent role, due to the wide range of exogenous compounds that can occur in food commodities and to their large differences in structure and biological activity. A comprehensive assessment of the related risk is thus actually demanding in terms of time and facilities involved. In this context, the use of computational strategies can be an effective choice for supporting the hazard identification procedure at the early stage. In this work, we focused on the food contaminant zearalenone by comparing the trans and cis isomers, respectively the well-known mycoestrogen and its still largely understudied isomer. We estimated the possible effects exerted by human metabolism on the xenoestrogenicity of cis-ZEN by using a validated in silico strategy based on docking simulations and rescoring procedures. Similarly, the exploitation of the most promising enzymatic detoxifying routes designed for trans-ZEN - which relies on the enzyme lactono hydrolase from Clonostachys rosea - has been assessed for the cis-isomer as well. Our results showed that both isomers can act as functional analogues with respect to xenoestrogenic activity, and several cis-ZEN metabolites with high biological potential have been identified. On the contrary, in spite of the high degree of structural analogy, the cis isomer showed a pattern of interaction with the degrading enzyme in stark contrast with that observed for trans-ZEN. For these reasons, the outcomes presented herein strongly support the inclusion of cis-ZEN in further studies of occurrence, metabolism and bioactivity assessment, and suggest the need for a dedicated handling for the cis isomer in risk assessment studies.


Heat-driven acoustic phonons in lamellar nanoplatelet assemblies.
Colloidal CdSe nanoplatelets, with the electronic structure of quantum wells, self-assemble into lamellar stacks due to large co-facial van der Waals attractions. These lamellar stacks are shown to display coherent acoustic phonons that are detected from oscillatory changes in the absorption spectrum observed in infrared pump, electronic probe measurements. Rather than direct electronic excitation of the nanocrystals using a femtosecond laser, impulsive transfer of heat from the organic ligand shell, excited at C-H stretching vibrational resonances, to the inorganic core of individual nanoplatelets occurs on a time-scale of <100 ps. This heat transfer drives in-phase longitudinal acoustic phonons of the nanoplatelet lamellae, which are accompanied by subtle deformations along the nanoplatelet short axes. The frequencies of the oscillations vary from 0.7 to 2 GHz (3-8 μeV and 0.5-1 ns oscillation period) depending on the thickness of the nanoplatelets-but not their lateral areas-and the temperature of the sample. Temperature-dependence of the acoustic phonon frequency conveys a substantial stiffening of the organic ligand bonds between nanoplatelets with reduced temperature. These results demonstrate a potential for acoustic modulation of the excitonic structure of nanocrystal assemblies in self-assembled anisotropic semiconductor systems at temperatures at or above 300 K.


Blood biomarkers as surrogate endpoints of treatment responses to aerobic exercise and cognitive training (ACT) in amnestic mild cognitive impairment: the blood biomarkers study protocol of a randomized controlled trial (the ACT Trial).
Alzheimer's disease (AD) is an epidemic with tremendous public health impacts because there are currently no disease-modifying therapeutics. Randomized controlled trials (RCTs) for prevention of AD dementia often use clinical endpoints that take years to manifest (e.g., cognition) or surrogate endpoints that are costly or invasive (e.g., magnetic resonance imaging [MRI]). Blood biomarkers represent a clinically applicable alternative surrogate endpoint for RCTs that would be both cost-effective and minimally invasive, but little is known about their value as surrogate endpoints for treatment responses in the prevention of AD dementia. The objective of this study is to investigate blood neuropathological, neurodegenerative, and neurotrophic biomarkers as surrogate endpoints for treatment responses to three interventions in older adults with amnestic mild cognitive impairment (aMCI, a prodromal stage of AD): aerobic exercise, cognitive training, and combined aerobic exercise and cognitive training (ACT). We chose these three sets of biomarkers for their unique mechanistic associations with AD pathology, neurodegeneration and neurogenesis. This study is built on the ACT Trial (1R01AG055469), a single-blinded, multi-site, 2 × 2 factorial phase II RCT that examines the synergistic effects of a 6-month ACT intervention on cognition and MRI biomarkers (AD-signature cortical thickness and hippocampal volume) (n = 128). In this ACT Trial blood biomarkers study, we will enroll 120 ACT Trial participants with aMCI and measure blood biomarkers at baseline and at 3, 6, 12, and 18 months. The goals are to (1) determine the effect of interventions on blood biomarkers over 6 months, (2) evaluate blood biomarkers as surrogate endpoints for predicting cognitive responses to interventions over 18 months, and (3, exploratory) examine blood biomarkers as surrogate endpoints for predicting brain MRI biomarker responses to interventions over 18 months. This study aims to identify new blood biomarkers that can track cognitive decline or AD-related brain atrophy among patients with aMCI subjected to a regimen of aerobic exercise and cognitive training. Findings from this study will drive the further use of blood biomarkers in developing effective prevention and treatment strategies for AD dementia. ClinicalTrials.gov, NCT03313895. Registered on 18 October 2017.


Early identification of reading disabilities within an RTI framework.
Early and accurate identification of children at risk for reading disabilities (RD) is critical for the prevention of RD within a response to intervention framework. In this study, we investigated the use of universal screening and progress monitoring for the early identification of RD in kindergarten children. A total of 366 children were administered a battery of screening measures at the beginning of kindergarten and progress-monitoring probes across the school year. A subset of children who showed initial risk for RD also received a 26-week Tier 2 intervention. Participants' achievement in word reading accuracy and/or fluency was assessed at the end of first grade. Results indicated that a screening battery containing measures of letter naming fluency, phonological awareness, rapid naming, or nonword repetition accurately identified good and poor readers at the end of first grade. Findings also showed that children's response to supplemental and/or classroom instruction measured in terms of growth in letter naming fluency added significantly to the prediction of reading outcomes.


Fabrication of an integrated optical filter using a large-core multimode waveguide vertically coupled to a single-mode waveguide.
We demonstrate the feasibility of the process for fabricating a single-mode waveguide and a large-core multimode waveguide aligned vertically on the same substrate. Using this process, we propose and demonstrate a filter that drops optical signal propagating in a single-mode waveguide to a multimode waveguide in the specific wavelength interval by a long-period grating. We use perfluorocyclobutane and benzocyclobutane for the cladding and core of the single-mode waveguide, respectively. The large core of the multimode waveguide is made of Norland Optical Adhesive 61. For the grating period of 315.9 um, the fabricated filter has the center wavelength of 1537.7 nm, at which the maximum attenuation is 17.8 dB.


Removal of contaminants from soils by electric fields.
Application of a direct-current electric field in soils that contain contaminated liquid is expected to produce an important in situ means of environmental restoration. The electric field induces a motion of the liquid and dissolved ions that transports the contaminant to wells for removal. Electrode chemistry plays an important role, and reagents can be introduced at the electrodes to enhance contaminant removal rates. Experiments and modeling demonstrate high degrees of contaminant removal, propagation of sharp acid and base wave fronts from the electrodes, and a "focusing" effect by which metals accumulate in regions of the soil.


Synergistic Antibacterial Effects of Chitosan-Caffeic Acid Conjugate against Antibiotic-Resistant Acne-Related Bacteria.
The object of this study was to discover an alternative therapeutic agent with fewer side effects against acne vulgaris, one of the most common skin diseases. Acne vulgaris is often associated with acne-related bacteria such as Propionibacteriumacnes, Staphylococcusepidermidis, Staphylococcusaureus, and Pseudomonasaeruginosa. Some of these bacteria exhibit a resistance against commercial antibiotics that have been used in the treatment of acne vulgaris (tetracycline, erythromycin, and lincomycin). In the current study, we tested in vitro antibacterial effect of chitosan-phytochemical conjugates on acne-related bacteria. Three chitosan-phytochemical conjugates used in this study exhibited stronger antibacterial activity than that of chitosan (unmodified control). Chitosan-caffeic acid conjugate (CCA) showed the highest antibacterial effect on acne-related bacteria along with minimum inhibitory concentration (MIC; 8 to 256 μg/mL). Additionally, the MIC values of antibiotics against antibiotic-resistant P. acnes and P.aeruginosa strains were dramatically reduced in combination with CCA, suggesting that CCA would restore the antibacterial activity of the antibiotics. The analysis of fractional inhibitory concentration (FIC) indices clearly revealed a synergistic antibacterial effect of CCA with antibiotics. Thus, the median sum of FIC (∑FIC) values against the antibiotic-resistant bacterial strains ranged from 0.375 to 0.533 in the combination mode of CCA and antibiotics. The results of the present study suggested a potential possibility of chitosan-phytochemical conjugates in the control of infections related to acne vulgaris.


Insular cortex abnormalities in psychotic major depression: relationship to gender and psychotic symptoms.
Recent data suggests that psychotic major depression (PMD) may be a discrete disorder distinguishable from nonpsychotic major depression (NPMD), and that patients with PMD may be more similar to individuals with schizophrenia than individuals with NPMD. The insula is a brain region in which morphometric changes have been associated with psychotic symptom severity in schizophrenia and affective psychosis. It was hypothesized that insular volumes would be reduced in PMD compared to NPMD and controls, and insular volumes would correlate with psychosis but not depression severity. Insular gray matter volumes were measured in PMD and NPMD patients and matched healthy controls using magnetic resonance images and manual morphometry. Clinical measures of illness severity were obtained to determine their relationship with insular volume. Posterior insular volumes were significantly reduced in PMD compared to HC. There were also significant group-by-gender interactions for total, anterior and posterior insular volumes. Using Pearson product-moment correlations, anterior insular volumes did not correlate with depression severity. Left anterior insular volume was significantly correlated with total and positive symptom psychosis severity in the PMD group. Atypical insular morphometry may be related to the inability to distinguish between internally and externally generated sensory inputs characteristic of psychosis.


New constructs and assessments for relapse and continued use potential in the ASAM Patient Placement Criteria.
One area of intensive study in recent years in addiction research is the characterization and prediction of relapse risk. Given the growing list of findings and assessment tools in this area, in preparation for the second edition, revised volume of the Patient Placement Criteria (PPC) of the American Society of Addiction Medicine (ASAM), a workgroup of the Coalition for National Criteria was assigned the task of creating a revised conceptual organization for Dimension 5: Relapse/Continued Use Potential. The workgroup conducted a review of the previous Dimension 5 constructs and criteria, including a decision analysis of the previous Dimension 5 decision rules. Following that analysis, field data from the ASAM Criteria Validity Study at Massachusetts General Hospital and Harvard Medical School were analyzed from a large cohort of public and indigent patients in eastern Massachusetts. After determining the concurrent validity of the Dimension 5 decision rules and their limitations, the decision rules were rewritten to gain improved validity. This exercise revealed techniques that can and should be used to improve the discrimination of levels of care among all Dimensions. Finally, the workgroup expanded and refined the constructs that should comprise a revised Dimension 5. This revised list of constructs is sequential and hierarchical. It offers face validity on several levels of current basic and clinical research knowledge: behavioral pharmacology, behavioral psychology, learning theory and psychopathology. While the Second Edition-Revised volume of the ASAM PPC (PPC-2R) does not go so far as to propose final decision rules for Dimension 5 based on these new constructs, it does recommend pilot adoption of several new assessment tools for this dimension and provides the framework incorporating those constructs and assessments in the next complete PPC edition.


The ecology and significance of below-ground bud banks in plants.
Below-ground bud banks have experienced much recent interest due to discoveries that they (1) account for the majority of seasonal population renewal in many communities, (2) are crucial to regeneration following disturbance, and (3) have important consequences for plant population dynamics and plant and ecosystem function across a number of habitats. This review presents an overview of the role of bud banks in plant population renewal, examines bud bank life history, summarizes bud bank traits and their potential ecological implications, synthesizes the response of bud banks to disturbance, and highlights gaps to guide future research. The characteristics and life history of buds, including their natality, dormancy, protection and longevity, provide a useful framework for advancing our understanding of bud banks. The fate of buds depends on their age, size, type, location, and biotic and abiotic factors that collectively regulate bud bank dynamics. A bud bank can provide a demographic storage effect stabilizing population dynamics, and also confer resistance to disturbance and invasion. Regeneration capacity following disturbance is determined by interactions among the rates of bud natality, depletion and dormancy (meristem limitation), and the resources available to support the regeneration process. The resulting response of plants and their bud banks to disturbances such as fire, herbivory and anthropogenic sources determines the community's regenerative capacity. Vegetation responses to environmental change may be mediated through changes in bud bank dynamics and phenology. Environmental change that depletes the bud bank or prohibits its formation likely results in a loss of vegetation resilience and plant species diversity. Standardization of bud sampling, examination of bud banks in more ecosystems and their response to environmental variation and disturbance regimes, employment of stage-structured bud bank modelling and evaluation of the cost of bud bank construction and maintenance will benefit this expanding field of research.


A Review on Treatment-Related Brain Changes in Aphasia.
Numerous studies have investigated brain changes associated with interventions targeting a range of language problems in patients with aphasia. We strive to integrate the results of these studies to examine (1) whether the focus of the intervention (i.e., phonology, semantics, orthography, syntax, or rhythmic-melodic) determines in which brain regions changes occur; and (2a) whether the most consistent changes occur within the language network or outside, and (2b) whether these are related to individual differences in language outcomes. The results of 32 studies with 204 unique patients were considered. Concerning (1), the location of treatment-related changes does not clearly depend on the type of language processing targeted. However, there is some support that rhythmic-melodic training has more impact on the right hemisphere than linguistic training. Concerning (2), we observed that language recovery is not only associated with changes in traditional language-related structures in the left hemisphere and homolog regions in the right hemisphere, but also with more medial and subcortical changes (e.g., precuneus and basal ganglia). Although it is difficult to draw strong conclusions, because there is a lack of systematic large-scale studies on this topic, this review highlights the need for an integrated approach to investigate how language interventions impact on the brain. Future studies need to focus on larger samples preserving subject-specific information (e.g., lesion effects) to cope with the inherent heterogeneity of stroke-induced aphasia. In addition, recovery-related changes in whole-brain connectivity patterns need more investigation to provide a comprehensive neural account of treatment-related brain plasticity and language recovery.


Reach and grasp by people with tetraplegia using a neurally controlled robotic arm.
Paralysis following spinal cord injury, brainstem stroke, amyotrophic lateral sclerosis and other disorders can disconnect the brain from the body, eliminating the ability to perform volitional movements. A neural interface system could restore mobility and independence for people with paralysis by translating neuronal activity directly into control signals for assistive devices. We have previously shown that people with long-standing tetraplegia can use a neural interface system to move and click a computer cursor and to control physical devices. Able-bodied monkeys have used a neural interface system to control a robotic arm, but it is unknown whether people with profound upper extremity paralysis or limb loss could use cortical neuronal ensemble signals to direct useful arm actions. Here we demonstrate the ability of two people with long-standing tetraplegia to use neural interface system-based control of a robotic arm to perform three-dimensional reach and grasp movements. Participants controlled the arm and hand over a broad space without explicit training, using signals decoded from a small, local population of motor cortex (MI) neurons recorded from a 96-channel microelectrode array. One of the study participants, implanted with the sensor 5 years earlier, also used a robotic arm to drink coffee from a bottle. Although robotic reach and grasp actions were not as fast or accurate as those of an able-bodied person, our results demonstrate the feasibility for people with tetraplegia, years after injury to the central nervous system, to recreate useful multidimensional control of complex devices directly from a small sample of neural signals.


The role of neurocognitive tests in the assessment of adult attention-deficit/hyperactivity disorder.
Despite widespread recognition that attention-deficit/hyperactivity disorder (ADHD) is a lifelong neurodevelopmental disorder, optimal methods of diagnosis among adults remain elusive. Substantial overlap between ADHD symptoms and cognitive symptoms of other mental health conditions, such as depression and anxiety, and concerns about validity in symptom reporting have made the use of neuropsychological tests in ADHD diagnostic assessment appealing. However, past work exploring the potential diagnostic utility of neuropsychological tests among adults has often relied on a relatively small subset of tests, has failed to include symptom and performance validity measures, and often does not include comparison groups of participants with commonly comorbid disorders, such as depression. The current study examined the utility of an extensive neuropsychological measure battery for diagnosing ADHD among adults. Two hundred forty-six participants (109 ADHD, 52 depressed, 85 nondisordered controls) completed a multistage screening and assessment process, which included a clinical interview, self, and informant report on behavior rating scales, performance and symptom validity measures, and an extensive neuropsychological testing battery. Results indicated that measures of working memory, sustained attention, response speed, and variability best discriminated ADHD and non-ADHD participants. While single test measures provided performed poorly in identifying ADHD participants, analyses revealed that a combined approach using self and informant symptom ratings, positive family history of ADHD, and a reaction time (RT) variability measure correctly classified 87% of cases. Findings suggest that neuropsychological test measures used in conjunction with other clinical assessments may enhance prediction of adult ADHD diagnoses. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Breeding for robustness: the role of cortisol.
Robustness in farm animals was defined by Knap as 'the ability to combine a high production potential with resilience to stressors, allowing for unproblematic expression of a high production potential in a wide variety of environmental conditions'. The importance of robustness-related traits in breeding objectives is progressively increasing towards the production of animals with a high production level in a wide range of climatic conditions and production systems, together with a high level of animal welfare. Current strategies to increase robustness include selection for 'functional traits', such as skeletal and cardiovascular integrity, disease resistance and mortality in various stages. It is also possible to use global evaluation of sensitivity to the environment (e.g. reaction norm analysis or canalization), but these techniques are difficult to implement in practice. The hypothalamic-pituitary-adrenocortical (HPA) axis is the most important stress-responsive neuroendocrine system. Cortisol (or corticosterone) released by the adrenal cortices exerts a large range of effects on metabolism, the immune system, inflammatory processes and brain function, for example. Large individual variations have been described in the HPA axis activity with important physiopathological consequences. In terms of animal production, higher cortisol levels have negative effects on growth rate and feed efficiency and increase the fat/lean ratio of carcasses. On the contrary, cortisol has positive effects on traits related to robustness and adaptation. For instance, newborn survival was shown to be directly related to plasma cortisol levels at birth, resistance to bacteria and parasites are increased in animals selected for a higher HPA axis response to stress, and tolerance to heat stress is better in those animals that are able to mount a strong stress response. Intense selection for lean tissue growth during the last decades has concomitantly reduced cortisol production, which may be responsible for the negative effects of selection on piglet survival. One strategy to improve robustness is to select animals with higher HPA axis activity. Several sources of genetic polymorphism have been described in the HPA axis. Hormone production by the adrenal cortices under stimulation by adrenocorticotropin hormone is a major source of individual differences. Several candidate genes have been identified by genomic studies and are currently under investigation. Bioavailability of hormones as well as receptor and post-receptor mechanisms are also subject to individual variation. Integration of these different sources of genetic variability will allow the development of a model for marker-assisted selection to improve animal robustness without negative side effects on production traits.


Development of a PROMIS item bank to measure pain interference.
This paper describes the psychometric properties of the PROMIS-pain interference (PROMIS-PI) bank. An initial candidate item pool (n=644) was developed and evaluated based on the review of existing instruments, interviews with patients, and consultation with pain experts. From this pool, a candidate item bank of 56 items was selected and responses to the items were collected from large community and clinical samples. A total of 14,848 participants responded to all or a subset of candidate items. The responses were calibrated using an item response theory (IRT) model. A final 41-item bank was evaluated with respect to IRT assumptions, model fit, differential item function (DIF), precision, and construct and concurrent validity. Items of the revised bank had good fit to the IRT model (CFI and NNFI/TLI ranged from 0.974 to 0.997), and the data were strongly unidimensional (e.g., ratio of first and second eigenvalue=35). Nine items exhibited statistically significant DIF. However, adjusting for DIF had little practical impact on score estimates and the items were retained without modifying scoring. Scores provided substantial information across levels of pain; for scores in the T-score range 50-80, the reliability was equivalent to 0.96-0.99. Patterns of correlations with other health outcomes supported the construct validity of the item bank. The scores discriminated among persons with different numbers of chronic conditions, disabling conditions, levels of self-reported health, and pain intensity (p<0.0001). The results indicated that the PROMIS-PI items constitute a psychometrically sound bank. Computerized adaptive testing and short forms are available.


c-Myc regulates cell proliferation during lens development.
Myc protooncogenes play important roles in the regulation of cell proliferation, growth, differentiation and survival during development. In various developing organs, c-myc has been shown to control the expression of cell cycle regulators and its misregulated expression is detected in many human tumors. Here, we show that c-myc gene (Myc) is highly expressed in developing mouse lens. Targeted deletion of c-myc gene from head surface ectoderm dramatically impaired ocular organogenesis, resulting in severe microphtalmia, defective anterior segment development, formation of a lens stalk and/or aphakia. In particular, lenses lacking c-myc presented thinner epithelial cell layer and growth impairment that was detectable soon after its inactivation. Defective development of c-myc-null lens was not caused by increased cell death of lens progenitor cells. Instead, c-myc loss reduced cell proliferation, what was associated with an ectopic expression of Prox1 and p27(Kip1) proteins within epithelial cells. Interestingly, a sharp decrease in the expression of the forkhead box transcription factor Foxe3 was also observed following c-myc inactivation. These data represent the first description of the physiological roles played by a Myc family member in mouse lens development. Our findings support the conclusion that c-myc regulates the proliferation of lens epithelial cells in vivo and may, directly or indirectly, modulate the expression of classical cell cycle regulators in developing mouse lens.


Risk adjusted therapy in chronic lymphocytic leukemia: a phase II cancer trials Ireland (CTRIAL-IE [ICORG 07-01]) study of fludarabine, cyclophosphamide, and rituximab therapy evaluating response adapted, abbreviated frontline therapy with FCR in non-del(17p) CLL.
Minimal residual disease negative complete response (MRD-negative CR) provides an early marker for time to treatment failure (TTF) in CLL treated with fludarabine, cyclophosphamide, and rituximab (FCR). MRD was assessed after four FCR cycles (FCR4); MRD-negative CR patients discontinued treatment. Fifty-two patients (35M; 17F) were enrolled. Eighteen (18/52; 34.6%) patients reached MRD-negative CR after FCR4 and 29/52 (55.8%) were MRD-negative CR at end of treatment (EOT). Median TTF was 71.1 months (95% CI 61.3-84.1 months), with median overall survival not reached. Mutated immunoglobulin heavy chain gene rearrangements (IGHV) were associated with early MRD-negative remissions, translating into prolonged TTF. Unmutated-IGHV, mutated-SF3B1 and mutated-NOTCH1 were associated with shortened TTF. No TTF difference was observed between patients in MRD-negative CR after four versus six cycles (82.2 versus 85.3 months, p = .6306). Abbreviated FCR therapy is effective for patients achieving early MRD-negative remissions. Interim MRD assessment assists in personalizing therapy and reducing chemotherapy-associated toxicity.


A novel Bayesian approach to accounting for uncertainty in fMRI-derived estimates of cerebral oxygen metabolism fluctuations.
Calibrated blood oxygenation level dependent (BOLD) imaging is a multimodal functional MRI technique designed to estimate changes in cerebral oxygen metabolism from measured changes in cerebral blood flow and the BOLD signal. This technique addresses fundamental ambiguities associated with quantitative BOLD signal analysis; however, its dependence on biophysical modeling creates uncertainty in the resulting oxygen metabolism estimates. In this work, we developed a Bayesian approach to estimating the oxygen metabolism response to a neural stimulus and used it to examine the uncertainty that arises in calibrated BOLD estimation due to the presence of unmeasured model parameters. We applied our approach to estimate the CMRO2 response to a visual task using the traditional hypercapnia calibration experiment as well as to estimate the metabolic response to both a visual task and hypercapnia using the measurement of baseline apparent R2' as a calibration technique. Further, in order to examine the effects of cerebral spinal fluid (CSF) signal contamination on the measurement of apparent R2', we examined the effects of measuring this parameter with and without CSF-nulling. We found that the two calibration techniques provided consistent estimates of the metabolic response on average, with a median R2'-based estimate of the metabolic response to CO2 of 1.4%, and R2'- and hypercapnia-calibrated estimates of the visual response of 27% and 24%, respectively. However, these estimates were sensitive to different sources of estimation uncertainty. The R2'-calibrated estimate was highly sensitive to CSF contamination and to uncertainty in unmeasured model parameters describing flow-volume coupling, capillary bed characteristics, and the iso-susceptibility saturation of blood. The hypercapnia-calibrated estimate was relatively insensitive to these parameters but highly sensitive to the assumed metabolic response to CO2.


Anatomical and physiological studies of bigheaded carps demonstrate that the epibranchial organ functions as a pharyngeal taste organ.
The epibranchial organ (EO) is an enigmatic tubular organ found in the pharyngeal cavity of many filter-feeding fishes. We investigated whether it might function as a taste organ that mediates aggregation and ingestion of planktonic food within the buccal cavity. The EO and associated structures of bighead and silver carps, two successful and invasive planktivorous fishes, were examined using histological and electrophysiological techniques. Both species possess finely structured gill rakers that extend directly via a series of protrusions into each of the four blind canals which are organized as the muscular EO, suggesting that the gill rakers and EO probably function in an integrated manner. Both the interior and exterior surfaces of the EOs of both species are covered with high densities of taste buds and solitary chemosensory cells (SCCs) as well as mucous cells. Conversely, taste buds are scarce in both the buccal cavities and external portions of the head and mouth of both species. Electrophysiological recordings from a caudal branch of the vagus nerve (cranial nerve X) found to innervate the EO showed it to be sensitive to chemicals found in a planktonic diet. l-Amino acids accounted for some, but not all of the neural activity. We conclude that taste buds and SCCs located on the EO and gill rakers probably serve to chemically detect food particles, which the EO then aggregates by mucus secretion before eventually expelling them onto the floor of the pharynx for ingestion. This specialized, pharyngeal chemosensory structure may explain the feeding success of these, and perhaps other planktivorous, filter-feeding fishes.


Toll-like receptor mRNA expression is selectively increased in the colonic mucosa of two animal models relevant to irritable bowel syndrome.
Irritable bowel syndrome (IBS) is largely viewed as a stress-related disorder caused by aberrant brain-gut-immune communication and altered gastrointestinal (GI) homeostasis. Accumulating evidence demonstrates that stress modulates innate immune responses; however, very little is known on the immunological effects of stress on the GI tract. Toll-like receptors (TLRs) are critical pattern recognition molecules of the innate immune system. Activation of TLRs by bacterial and viral molecules leads to activation of NF-kB and an increase in inflammatory cytokine expression. It was our hypothesis that innate immune receptor expression may be changed in the gastrointestinal tract of animals with stress-induced IBS-like symptoms. In this study, our objective was to evaluate the TLR expression profile in the colonic mucosa of two rat strains that display colonic visceral hypersensitivity; the stress-sensitive Wistar-Kyoto (WKY) rat and the maternally separated (MS) rat. Quantitative PCR of TLR2-10 mRNA in both the proximal and distal colonic mucosae was carried out in adulthood. Significant increases are seen in the mRNA levels of TLR3, 4 & 5 in both the distal and proximal colonic mucosa of MS rats compared with controls. No significant differences were noted for TLR 2, 7, 9 & 10 while TLR 6 could not be detected in any samples in both rat strains. The WKY strain have increased levels of mRNA expression of TLR3, 4, 5, 7, 8, 9 & 10 in both the distal and proximal colonic mucosa compared to the control Sprague-Dawley strain. No significant differences in expression were found for TLR2 while as before TLR6 could not be detected in all samples in both strains. These data suggest that both early life stress (MS) and a genetic predisposition (WKY) to stress affect the expression of key sentinels of the innate immune system which may have direct relevance for the molecular pathophysiology of IBS.


High-throughput cervical cancer screening using intracellular human papillomavirus E6 and E7 mRNA quantification by flow cytometry.
The Papanicolaou (Pap) test, based solely on the morphologic examination of exfoliated cells from the cervix, has reduced deaths due to cervical cancer by 74% in the United States during the past 40 years. During that time, the molecular mechanisms of cervical cancer have largely been elucidated. Taken together, these observations have identified a need for a high-throughput cervical cancer screening assay. We report the development of a high-throughput assay consisting of simultaneous immunophenotyping and ultrasensitive in situ hybridization for human papillomavirus (HPV) E6 and E7 messenger RNA (mRNA). This assay can be performed in less than 3 hours directly from liquid-based cervical cytology specimens. Overall, HPV fluorescence in situ hybridization (FISH) for E6 and E7 mRNA demonstrated 83.3% sensitivity and 91.3% specificity for high-grade squamous intraepithelial lesions compared with the Pap test in 231 liquid-based cytology samples from 2 cohorts. In a subset of these samples, HPV FISH demonstrated higher sensitivity and specificity than Hybrid Capture (Digene, Gaithersburg, MD) for high-risk genotypes.


Erosion of organic carbon in the Arctic as a geological carbon dioxide sink.
Soils of the northern high latitudes store carbon over millennial timescales (thousands of years) and contain approximately double the carbon stock of the atmosphere. Warming and associated permafrost thaw can expose soil organic carbon and result in mineralization and carbon dioxide (CO2) release. However, some of this soil organic carbon may be eroded and transferred to rivers. If it escapes degradation during river transport and is buried in marine sediments, then it can contribute to a longer-term (more than ten thousand years), geological CO2 sink. Despite this recognition, the erosional flux and fate of particulate organic carbon (POC) in large rivers at high latitudes remains poorly constrained. Here, we quantify the source of POC in the Mackenzie River, the main sediment supplier to the Arctic Ocean, and assess its flux and fate. We combine measurements of radiocarbon, stable carbon isotopes and element ratios to correct for rock-derived POC. Our samples reveal that the eroded biospheric POC has resided in the basin for millennia, with a mean radiocarbon age of 5,800 ± 800 years, much older than the POC in large tropical rivers. From the measured biospheric POC content and variability in annual sediment yield, we calculate a biospheric POC flux of 2.2(+1.3)(-0.9) teragrams of carbon per year from the Mackenzie River, which is three times the CO2 drawdown by silicate weathering in this basin. Offshore, we find evidence for efficient terrestrial organic carbon burial over the Holocene period, suggesting that erosion of organic carbon-rich, high-latitude soils may result in an important geological CO2 sink.


Severity of virilization of external genitalia in Japanese patients with salt-wasting 21-hydroxylase deficiency.
Females with salt-wasting (SW) 21-hydroxylase deficiency (21OHD) may present with mild external genitalia virilization, despite complete or almost complete enzyme inactivation. We therefore analyzed genotype/phenotype correlation in 13 Japanese female patients with SW 21OHD. Criteria for classification into the SW phenotype included history of a salt-losing crisis with documented hyponatremia, hyperkalemia, and markedly elevated plasma renin activity. Urologists and pediatricians determined the Prader genital stage and classified the location of the vaginal entrance into the common urogenital sinus as low, moderate, or high. CYP21A2 gene, coding for 21-hydroxylase, was analyzed with Southern blotting and direct sequencing. Genotypes were categorized into four mutation groups, based on the degree of enzymatic activity (N, complete enzyme inactivation; groups A, < 2%, B, 3-7%, and C > 30%). Basal androgen levels were available from only six out of thirteen patients, so we could not relate androgen levels with the severity of external genitalia virilization. We compared the degree of external genitalia virilization with genotype. The severity of external genitalia virilization varied from Prader stage 1 to 4. One patient who presented with Prader 1 had a genotype consistent with Group B. In addition, discordance between Prader classification and the location of the vaginal entrance was noted; one patient classified as Prader 4 showed low vaginal entrance, while another patient classified as Prader 3 showed high vaginal entrance. The degree of the impairment of 21-hydroxylase activity does not correlate with the severity of virilization of the external genitalia in female patients with the SW type of 21OHD.


Objective measures of binaural masking level differences and comodulation masking release based on late auditory evoked potentials.
The audibility of important sounds is often hampered due to the presence of other masking sounds. The present study investigates if a correlate of the audibility of a tone masked by noise is found in late auditory evoked potentials measured from human listeners. The audibility of the target sound at a fixed physical intensity is varied by introducing auditory cues of (i) interaural target signal phase disparity and (ii) coherent masker level fluctuations in different frequency regions. In agreement with previous studies, psychoacoustical experiments showed that both stimulus manipulations result in a masking release (i: binaural masking level difference; ii: comodulation masking release) compared to a condition where those cues are not present. Late auditory evoked potentials (N1, P2) were recorded for the stimuli at a constant masker level, but different signal levels within the same set of listeners who participated in the psychoacoustical experiment. The data indicate differences in N1 and P2 between stimuli with and without interaural phase disparities. However, differences for stimuli with and without coherent masker modulation were only found for P2, i.e., only P2 is sensitive to the increase in audibility, irrespective of the cue that caused the masking release. The amplitude of P2 is consistent with the psychoacoustical finding of an addition of the masking releases when both cues are present. Even though it cannot be concluded where along the auditory pathway the audibility is represented, the P2 component of auditory evoked potentials is a candidate for an objective measure of audibility in the human auditory system.


Surveillance of waterborne disease in European member states: a qualitative study.
We sought to explore perceived strengths and weaknesses of surveillance systems for the detection of drinking-water-related illness in Europe based on the experience of individuals utilising such systems. We designed and conducted a qualitative semi-structured interview study with thematic analysis. Interviews took place in six European countries with seven experts in epidemiology, water and public health. Interviewees remarked upon variation between and within countries in laboratory and sampling protocols and reporting practice; these were felt to influence timeliness and sensitivity of laboratory- and clinician-report-based surveillance. Electronic reporting, reminders to report and direct report relay to national level were considered strengths of report-based surveillance. A need was expressed for more detailed case demographic information to facilitate outbreak detection. Existing infrastructure permitting, prescriptions data, anti-diarrhoeal pharmaceutical sales, absenteeism and consultations were cited as useful outbreak indicators. Information regarding consumer water quality complaints was highlighted as a potentially useful data source. Collaboration with water companies (concerning water distribution and incidents), and constructing and maintaining relationships with local and external data providers were cited as requisites of effective surveillance. Inter- and intra-organisational collaboration and information integration are likely to improve surveillance, leading to more astute estimates of the waterborne disease burden.


Characterization of the hrpZ gene from Pseudomonas syringae pv. maculicola M2.
Pseudomonas syringae pv. maculicola is a natural pathogen of members of the Brassicaceae plant family. Using a transposon-based mutagenesis strategy in Pseudomonas syringaepv. maculicola M2 (PsmM2), we conducted a genetic screen to identify mutants that were capable of growing in M9 medium supplemented with a crude extract from the leaves of Arabidopsis thaliana. A mutant containing a transposon insertion in the hrpZ gene (PsmMut8) was unable to infect adult plants from Arabidopsis thaliana or Brassica oleracea, suggesting a loss of pathogenicity. The promotorless cat reporter present in the gene trap was expressed if PsmMut8 was grown in minimal medium (M9) supplemented with the leaf extract but not if grown in normal rich medium (KB). We conducted phylogenetic analysis using hrpAZB genes, showing the classical 5-clade distribution, and nucleotide diversity analysis, showing the putative position for selective pressure in this operon. Our results indicate that the hrpAZB operon from Pseudomonas syringaepv. maculicola M2 is necessary for its pathogenicity and that its diversity would be under host-mediated diversifying selection.


Agreement between ELISA and plaque reduction neutralisation assay in Detection of respiratory syncytial virus specific antibodies in a birth Cohort from Kilifi, coastal Kenya.
Background: Severe disease associated with respiratory syncytial virus (RSV) infection occurs predominantly among infants under 6 months of age. Vaccines for prevention are in clinical development. Assessment of the vaccine effectiveness in large epidemiological studies requires serological assays which are rapid, economical and standardised between laboratories. The objective of this study was to assess the agreement between two enzyme linked immunosorbent assays (ELISA) and the plaque reduction neutralisation test (PRNT) in quantifying RSV specific antibodies. Methods: Archived sera from 99 participants of the Kilifi Birth Cohort (KBC) study (conducted 2002-2007) were screened for RSV antibodies using 3 methods: ELISA using crude RSV lysate as antigen, a commercial RSV immunoglobulin G (IgG) ELISA kit from IBL International GmbH, and PRNT. Pearson correlation, Bland-Altman plots and regression methods were used in analysis. Results: There was high positive correlation between the IBL RSV IgG ELISA and PRNT antibodies (Pearson r=0.75), and moderate positive correlation between the crude RSV lysate IgG ELISA and PRNT antibodies (r= 0.61). Crude RSV lysate IgG ELISA showed a wider 95% limit of agreement (-1.866, 6.157) with PRNT compared to the IBL RSV IgG ELISA (1.392, 7.595). Mean PRNT titres were estimated within a width of 4.8 log 2PRNT and 5.6 log 2PRNT at 95% prediction interval by IBL RSV IgG and crude RSV lysate IgG ELISA, respectively. Conclusion: Although, the IBL RSV IgG ELISA is observed to provide a reasonable correlate for PRNT assay in detecting RSV specific antibodies, it does not provide an accurate prediction for neutralizing antibody levels. An RSV neutralising antibody level is likely to fall within 2.4 fold higher and 2.4 fold lower than the true value if IBL RSV IgG ELISA is used to replace PRNT assay. The utility of an ELISA assay in vaccine studies should be assessed independent of the PRNT method.


Adoption, Sustainability, and Dissemination of Chronic Disease Prevention Policies in Community-Based Organizations.
Introduction. Despite increasing interest in structural (policy, systems, and environmental) changes to improve health, little attention has focused on the adoption, implementation, sustainability, and potential for dissemination of these changes among local community-based organizations. Method. A mixed methods approach was used for this process evaluation. Representatives of nine community-based organizations were surveyed using closed-ended questions and in-depth qualitative interviews to describe 32 policy changes. Diffusion of Innovation theory was used to inform the development of survey questions and the interview guide. Results. Policies adopted by local community-based organizations concerned types of food/beverages provided to staff/clients, methods to encourage physical activity, breastfeeding support, and tobacco control. The majority of the policies were either fully (66%) or partially (31%) implemented 1 year after their initial adoption. In general, participants somewhat/strongly agreed that policies had characteristics that predict sustainability/diffusion (relative advantage, compatibility, complexity, trialability, observability). In-depth interview responses described a generally smooth process for policy adoption and high levels of optimism for continued sustainability but revealed few efforts to disseminate the policies beyond the original organization. Conclusions. Structural changes in community-based organizations are a valuable tool for encouraging healthy changes in communities and have great potential to be adopted, sustained, and diffused.


Child neglect and its relation to emotional and behavioral problems: A cross-sectional study of primary school-aged children in Tanzania.
Child maltreatment is known to engender negative emotional and behavioral consequences. Although neglect is the most frequent form of maltreatment, it has thus far only received little attention, especially when looking at low-resource countries. The current study investigated possible associations between neglect and internalizing and externalizing problems. As neglect and abuse often co-occur, the latter was controlled for. In total, 409 Tanzanian primary school students (52% boys, M = 10.5 years, range = 6-15) participated in the cross-sectional study. Structured clinical interviews were conducted assessing maltreatment, internalizing problems, and externalizing problems. Overall, 31% (n = 128) of the children reported at least one type of physical neglect and 31% (n = 127) of emotional neglect. Using structural equation modeling, we found a significant association between neglect and internalizing (β = 0.59, p < .01) and externalizing problems (β = 0.35, p < .05). However, these associations could only be detected in younger children (ages 6-9), whereas in older children (ages 10-15), mental health problems were significantly related to violence and abuse. Our findings suggest that the current age may influence the association between maltreatment type and the development of internalizing and/or externalizing problems.


High-performance sodium-ion batteries and sodium-ion pseudocapacitors based on MoS(2) /graphene composites.
Sodium-ion energy storage, including sodium-ion batteries (NIBs) and electrochemical capacitive storage (NICs), is considered as a promising alternative to lithium-ion energy storage. It is an intriguing prospect, especially for large-scale applications, owing to its low cost and abundance. MoS2 sodiation/desodiation with Na ions is based on the conversion reaction, which is not only able to deliver higher capacity than the intercalation reaction, but can also be applied in capacitive storage owing to its typically sloping charge/discharge curves. Here, NIBs and NICs based on a graphene composite (MoS2 /G) were constructed. The enlarged d-spacing, a contribution of the graphene matrix, and the unique properties of the MoS2 /G substantially optimize Na storage behavior, by accommodating large volume changes and facilitating fast ion diffusion. MoS2 /G exhibits a stable capacity of approximately 350 mAh g(-1) over 200 cycles at 0.25 C in half cells, and delivers a capacitance of 50 F g(-1) over 2000 cycles at 1.5 C in pseudocapacitors with a wide voltage window of 0.1-2.5 V.


EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.
The ataxias are a challenging group of neurological diseases due the aetiological heterogeneity and the complexity of the genetic subtypes. This guideline focuses on the heredodegenerative ataxias. The aim is to provide a peer-reviewed evidence-based guideline for clinical neurologists and other specialist physicians responsible for the care of patients with ataxia. This guideline is based on systematic evaluations of the relevant literature and on three consensus meetings of the task force. If acquired causes are ruled out, and if the disease course is rather slowly progressive, a (heredo)degenerative disease is likely. A positive family history gives much guidance. In the case of a dominant family history, first line genetic screening is recommended for spinocerebellar ataxia (SCA) 1, 2, 3, 6, 7 and 17 (level B), and in Asian patients also for dentatorubral-pallidoluysian atrophy (DRPLA). In the case of recessive disease, a stepwise diagnostic work-up is recommended, including both biochemical markers and targeted genetic testing, particularly aimed at Friedreich's ataxia, ataxia telangiectasia, ataxia due to vitamin E deficiency, polymerase gamma gene (POLG gene, various mutations), autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and ataxia with oculomotor apraxia (AOA) types 1 and 2. If family history is negative, we still advise to screen for the more common dominant and recessive ataxias. In addition, if onset is below 45 years we recommend the full work-up for recessive ataxias; if onset is above 45 years we recommend to screen for fragile X mental retardation 1 FMR1 premutations (good practice points). In sporadic cases with an onset after 30 years, a diagnosis of multiple system atrophy should be considered (good practice point). In particular the genetic work-up will change over the upcoming years due to the diagnostic utility of new techniques such as gene panel diagnostics based on next generation sequencing for routine work-up, or even whole exome and genome sequencing for selected cases. Some of the rare recessive ataxias are treatable, but for most of the heredodegenerative ataxias treatment is purely symptomatic. Idebenone is not effective in Friedreich's ataxia (level A). Riluzole (level B) and amantadine (level C) might provide symptomatic relief, irrespective of exact etiology. Also, varenicline for SCA3 patients (level B) can be considered. There is level Class II evidence to recommend physiotherapy, and Class III data to support occupational therapy.


Magnetization transfer ratio measures in normal-appearing white matter show periventricular gradient abnormalities in multiple sclerosis.
In multiple sclerosis, there is increasing evidence that demyelination, and neuronal damage occurs preferentially in cortical grey matter next to the outer surface of the brain. It has been suggested that this may be due to the effects of pathology outside the brain parenchyma, in particular meningeal inflammation or through cerebrospinal fluid mediated factors. White matter lesions are often located adjacent to the ventricles of the brain, suggesting the possibility of a similar outside-in pathogenesis, but an investigation of the relationship of periventricular normal-appearing white matter abnormalities with distance from the ventricles has not previously been undertaken. The present study investigates this relationship in vivo using quantitative magnetic resonance imaging and compares the abnormalities between secondary progressive and relapsing remitting multiple sclerosis. Forty-three patients with relapsing remitting and 28 with secondary progressive multiple sclerosis, and 38 healthy control subjects were included in this study. T1-weighted volumetric, magnetization transfer and proton density/T2-weighted scans were acquired for all subjects. From the magnetization transfer data, magnetization transfer ratio maps were prepared. White matter tissue masks were derived from SPM8 segmentations of the T1-weighted images. Normal-appearing white matter masks were generated by subtracting white matter lesions identified on the proton density/T2 scan, and a two-voxel perilesional ring, from the SPM8 derived white matter masks. White matter was divided in concentric bands, each ∼1-mm thick, radiating from the ventricles toward the cortex. The first periventricular band was excluded from analysis to mitigate partial volume effects, and normal-appearing white matter and lesion magnetization transfer ratio values were then computed for the 10 bands nearest to the ventricles. Compared with controls, magnetization transfer ratio in the normal-appearing white matter bands was significantly lower in patients with multiple sclerosis. In controls, magnetization transfer ratio was highest in the band adjacent to the ventricles and declined with increasing distance from the ventricles. In the multiple sclerosis groups, relative to controls, reductions in magnetization transfer ratio were greater in the secondary progressive multiple sclerosis compared with relapsing remitting multiple sclerosis group, and these reductions were greatest next to the ventricles and became smaller with distance from them. White matter lesion magnetization transfer ratio reductions were also more apparent adjacent to the ventricle and decreased with distance from the ventricles in both the relapsing remitting and secondary progressive multiple sclerosis groups. These findings suggest that in people with multiple sclerosis, and more so in secondary progressive than relapsing remitting multiple sclerosis, tissue structural abnormalities in normal-appearing white matter and white matter lesions are greatest near the ventricles. This would be consistent with a cerebrospinal fluid or ependymal mediated pathogenesis.


Predicting treatment benefit in multiple myeloma through simulation of alternative treatment effects.
Many cancer treatments are associated with serious side effects, while they often only benefit a subset of the patients. Therefore, there is an urgent clinical need for tools that can aid in selecting the right treatment at diagnosis. Here we introduce simulated treatment learning (STL), which enables prediction of a patient's treatment benefit. STL uses the idea that patients who received different treatments, but have similar genetic tumor profiles, can be used to model their response to the alternative treatment. We apply STL to two multiple myeloma gene expression datasets, containing different treatments (bortezomib and lenalidomide). We find that STL can predict treatment benefit for both; a twofold progression free survival (PFS) benefit is observed for bortezomib for 19.8% and a threefold PFS benefit for lenalidomide for 31.1% of the patients. This demonstrates that STL can derive clinically actionable gene expression signatures that enable a more personalized approach to treatment.


Modification of xenogeneic graft materials for improved release of P-15 peptides in a calvarium defect model.
Particulate bone augmentation is an established clinical alternative to regenerate bone. However, in regions of poor bone quality or previously infected sites, the clinical outcomes are more inconsistent. For that purpose, peptides have been added to particulate materials in an attempt to render them with antibacterial properties or to improve their osseoconductivity. For instance, competence-stimulating peptide (CSP) has been studied to decrease the division rate of Streptococcus mutans. Also, the addition of a specific short amino acid sequence peptide derived from type I collagen (P-15) to the bone substitutes has been introduced in an attempt to increase its osseoconductivity. The present study hypothesized that xenogeneic graft materials with and without CSP would present improved host-to-biomaterial response when used in combination with P-15. Particulate graft materials with and without P-15, OsteoGraf with CSP and OsteoGraf, were implanted in an 8-mm rabbit calvarial defect for 4 weeks, and thereafter, histological and histomorphometrical evaluation was performed. The results showed that both OsteoGraf and CSP groups with the addition of P-15 induced bone growth towards the center of the defect. Furthermore, the addition of CSP to Osteograf showed a tendency to increase its osteoconductivity when combined with P-15. The results of the current study suggested that P-15 had some impact on osteogenesis; however, the effect differed between different bone substitute materials. Further investigation is necessary to clarify its effectiveness when used in combination with bone substitutes.


The novel reversible fatty acid amide hydrolase inhibitor ST4070 increases endocannabinoid brain levels and counteracts neuropathic pain in different animal models.
The effect of the enol carbamate 1-biphenyl-4-ylethenyl piperidine-1-carboxylate (ST4070), a novel reversible inhibitor of fatty acid amide hydrolase (FAAH), was investigated for acute pain sensitivity and neuropathic pain in rats and mice. Brain enzymatic activity of FAAH and the endogenous levels of its substrates, anandamide (AEA; N-arachidonoylethanolamine), 2-arachidonoylglycerol (2-AG), and N-palmitoylethanolamine (PEA), were measured in control and ST4070-treated mice. ST4070 (10, 30, and 100 mg/kg) was orally administered to assess mechanical nociceptive thresholds and allodynia by using the Randall-Selitto and von Frey tests, respectively. Neuropathy was induced in rats by either the chemotherapeutic agent vincristine or streptozotocin-induced diabetes, whereas the chronic constriction injury (CCI) model was chosen to evaluate neuropathy in mice. ST4070 produced a significant increase of nociceptive threshold in rats and counteracted the decrease of nociceptive threshold in the three distinct models of neuropathic pain. In diabetic mice, ST4070 inhibited FAAH activity and increased the brain levels of AEA and PEA, without affecting that of 2-AG. The administration of ST4070 generated long-lasting pain relief compared with pregabalin and the FAAH inhibitors 1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL135) and cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-ylester (URB597) in CCI neuropathic mice. The antiallodynic effects of ST4070 were prevented by pretreatment with cannabinoid type 1 and cannabinoid type 2 receptor antagonists and by the selective peroxisome proliferator-activated receptor α antagonist [(2S)-2-[[(1Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl]amino]-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-carbamic acid ethyl ester (GW6471). The administration of ST4070 generated long-lasting neuropathic pain relief compared with pregabalin and the FAAH inhibitors OL135 and URB597. Taken together, the reversible FAAH inhibitor ST4070 seems to be a promising novel therapeutic agent for the management of neuropathic pain.


A Radiographic comparison of mandibular bone quality in pre- and post-menopausal women in Indian population.
The main objective of the study is to assess mandibular bone changes in pre and postmenopausal women with chronic generalized periodontitis using different radiomorphometric indices, mandibular cortical index (MCI), mental index (MI), and panoramic mandibular index (PMI) in Indian population. Panoramic radiographs of 60 patients visiting the Department of Periodontology were taken and divided in two groups - pre and post-menopausal. Detailed medical and menopausal history was recorded for each patient. All the radiographs were assessed for PMI, MI and MCI and presence of periodontitis. The destructive periodontitis was assessed as distance from the cementoenamel junction to the alveolar crest greater than 2mm. Student-t test was applied to compare mean values of MI and PMI. Intra and inter group comparison of MCI were made using chi-square test. Correlation of age and MI and PMI was found by Pearson's correlation coefficient. MCI, PMI and MI were related to the menopausal status. Patients with C3 category were seen only in post-menopausal group after 54 years of age. Higher mean values for both MI (p<0.05) and PMI (p<0.05) were observed in pre-menopausal group with statistically significant differences. MI showed negative correlation with age in both the groups; however PMI was positively correlated with age. Radiomorphometric indices could be used by general dentists after a little training to detect post-menopausal women at higher risk of osteoporosis.


Selenium Levels in Serum, Red Blood Cells, and Cerebrospinal Fluid of Alzheimer's Disease Patients: A Report from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL).
Selenium (Se) protects cells against oxidative stress damage through a range of bioactive selenoproteins. Increased oxidative stress is a prominent feature of Alzheimer's disease (AD), and previous studies have shown that Se deficiency is associated with age-related cognitive decline. In this study, we assessed Se status in different biofluids from a subgroup of participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. As Se in humans can either be an active component of selenoproteins or inactive via non-specific incorporation into other proteins, we used both size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) and tandem mass spectrometry to characterize selenoproteins in serum. We observed no differences in total Se concentration in serum or cerebrospinal fluid of AD subjects compared to mildly cognitively impairment patients and healthy controls. However, Se levels in erythrocytes were decreased in AD compared to controls. SEC-ICP-MS analysis revealed a dominant Se-containing fraction. This fraction was subjected to standard protein purification and a bottom-up proteomics approach to confirm that the abundant Se in the fraction was due, in part, to selenoprotein P. The lack of change in the Se level is at odds with our previous observations in a Brazilian population deficient in Se, and we attribute this to the Australian cohort being Se-replete.


Extrasynaptic exocytosis and its mechanisms: a source of molecules mediating volume transmission in the nervous system.
We review the evidence of exocytosis from extrasynaptic sites in the soma, dendrites, and axonal varicosities of central and peripheral neurons of vertebrates and invertebrates, with emphasis on somatic exocytosis, and how it contributes to signaling in the nervous system. The finding of secretory vesicles in extrasynaptic sites of neurons, the presence of signaling molecules (namely transmitters or peptides) in the extracellular space outside synaptic clefts, and the mismatch between exocytosis sites and the location of receptors for these molecules in neurons and glial cells, have long suggested that in addition to synaptic communication, transmitters are released, and act extrasynaptically. The catalog of these molecules includes low molecular weight transmitters such as monoamines, acetylcholine, glutamate, gama-aminobutiric acid (GABA), adenosine-5-triphosphate (ATP), and a list of peptides including substance P, brain-derived neurotrophic factor (BDNF), and oxytocin. By comparing the mechanisms of extrasynaptic exocytosis of different signaling molecules by various neuron types we show that it is a widespread mechanism for communication in the nervous system that uses certain common mechanisms, which are different from those of synaptic exocytosis but similar to those of exocytosis from excitable endocrine cells. Somatic exocytosis has been measured directly in different neuron types. It starts after high-frequency electrical activity or long experimental depolarizations and may continue for several minutes after the end of stimulation. Activation of L-type calcium channels, calcium release from intracellular stores and vesicle transport towards the plasma membrane couple excitation and exocytosis from small clear or large dense core vesicles in release sites lacking postsynaptic counterparts. The presence of synaptic and extrasynaptic exocytosis endows individual neurons with a wide variety of time- and space-dependent communication possibilities. Extrasynaptic exocytosis may be the major source of signaling molecules producing volume transmission and by doing so may be part of a long duration signaling mode in the nervous system.


Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications.
Persistent oxidative stress is one of the major causes of most lifestyle-related diseases, cancer and the aging process. Acute oxidative stress directly causes serious damage to tissues. Despite the clinical importance of oxidative damage, antioxidants have been of limited therapeutic success. We have proposed that molecular hydrogen (H(2)) has potential as a "novel" antioxidant in preventive and therapeutic applications [Ohsawa et al., Nat Med. 2007: 13; 688-94]. H(2) has a number of advantages as a potential antioxidant: H(2) rapidly diffuses into tissues and cells, and it is mild enough neither to disturb metabolic redox reactions nor to affect reactive oxygen species (ROS) that function in cell signaling, thereby, there should be little adverse effects of consuming H(2). There are several methods to ingest or consume H(2), including inhaling hydrogen gas, drinking H(2)-dissolved water (hydrogen water), taking a hydrogen bath, injecting H(2)- dissolved saline (hydrogen saline), dropping hydrogen saline onto the eye, and increasing the production of intestinal H(2) by bacteria. Since the publication of the first H(2) paper in Nature Medicine in 2007, the biological effects of H(2) have been confirmed by the publication of more than 38 diseases, physiological states and clinical tests in leading biological/medical journals, and several groups have started clinical examinations. Moreover, H(2) shows not only effects against oxidative stress, but also various anti-inflammatory and antiallergic effects. H(2) regulates various gene expressions and protein-phosphorylations, though the molecular mechanisms underlying the marked effects of very small amounts of H(2) remain elusive.


Evaluation of a virtual-reality-based simulator using passive haptic feedback for knee arthroscopy.
The aim of this work is to determine face validity and construct validity of a new virtual-reality-based simulator for diagnostic and therapeutic knee arthroscopy. The study tests a novel arthroscopic simulator based on passive haptics. Sixty-eight participants were grouped into novices, intermediates, and experts. All participants completed two exercises. In order to establish face validity, all participants filled out a questionnaire concerning different aspects of simulator realism, training capacity, and different statements using a seven-point Likert scale (range 1-7). Construct validity was tested by comparing various simulator metric values between novices and experts. Face validity could be established: overall realism was rated with a mean value of 5.5 points. Global training capacity scored a mean value of 5.9. Participants considered the simulator as useful for procedural training of diagnostic and therapeutic arthroscopy. In the foreign body removal exercise, experts were overall significantly faster in the whole procedure (6 min 24 s vs. 8 min 24 s, p < 0.001), took less time to complete the diagnostic tour (2 min 49 s vs. 3 min 32 s, p = 0.027), and had a shorter camera path length (186 vs. 246 cm, p = 0.006). The simulator achieved high scores in terms of realism. It was regarded as a useful training tool, which is also capable of differentiating between varying levels of arthroscopic experience. Nevertheless, further improvements of the simulator especially in the field of therapeutic arthroscopy are desirable. In general, the findings support that virtual-reality-based simulation using passive haptics has the potential to complement conventional training of knee arthroscopy skills. II.


The Association Between Technology Use and Health Status in a Chronic Obstructive Pulmonary Disease Cohort: Multi-Method Study.
Telemedicine and electronic health (eHealth) interventions have been proposed to improve management of chronic obstructive pulmonary disease (COPD) for patients between traditional clinic and hospital visits to reduce complications. However, the effectiveness of such interventions may depend on patients' comfort with technology. The aim was to describe the relationship between patient demographics and COPD disease severity and the use of communication-related technology. We administered a structured survey about the use of communication technologies to a cohort of persons in the COPDGene study at one midwestern hospital in the United States. Survey results were combined with clinical and demographic data previously collected as part of the cohort study. A subsample of patients also completed eHealth simulation tasks. We used logistic or linear regression to determine the relationship between patient demographics and COPD disease severity and reported use of communication-related technology and the results from our simulated eHealth-related tasks. A total of 686 patients completed the survey and 100 participated in the eHealth simulation. Overall, those who reported using communication technology were younger (P=.005) and had higher incomes (P=.03). Men appeared less likely to engage in text messaging (P<.001) than women. Patients who spent more time on tasks in the eHealth simulation had greater odds of a COPD Assessment Test score >10 (P=.02) and walked shorter distances in their 6-minute walk tests (P=.003) than those who took less time. Older patients, patients with lower incomes, and less healthy patients were less likely to report using communication technology, and they did not perform as well on our simulated eHealth tasks. Thus, eHealth-based interventions may not be as effective in these populations, and additional training in communication technology may be needed.


Travel-associated antimicrobial drug-resistant nontyphoidal Salmonellae, 2004-2009.
To evaluate trends in and risk factors for acquisition of antimicrobial-drug resistant nontyphoidal Salmonella infections, we searched Oregon surveillance data for 2004-2009 for all culture-confirmed cases of salmonellosis. We defined clinically important resistance (CIR) as decreased susceptibility to ampicillin, ceftriaxone, ciprofloxacin, gentamicin, or trimethoprim/sulfamethoxazole. Of 2,153 cases, 2,127 (99%) nontyphoidal Salmonella isolates were obtained from a specific source (e.g., feces, urine, blood, or other normally sterile tissue) and had been tested for drug susceptibility. Among these, 347 (16%) isolates had CIR. The odds of acquiring CIR infection significantly increased each year. Hospitalization was more likely for patients with than without CIR infections. Among patients with isolates that had been tested, we analyzed data from 1,813 (84%) who were interviewed. Travel to eastern or Southeast Asia was associated with increased CIR. Isolates associated with outbreaks were less likely to have CIR. Future surveillance activities should evaluate resistance with respect to international travel.


Functional, Structural and Biochemical Features of Plant Serinyl-Glutathione Transferases.
Glutathione transferases (GSTs) belong to a ubiquitous multigenic family of enzymes involved in diverse biological processes including xenobiotic detoxification and secondary metabolism. A canonical GST is formed by two domains, the N-terminal one adopting a thioredoxin (TRX) fold and the C-terminal one an all-helical structure. The most recent genomic and phylogenetic analysis based on this domain organization allowed the classification of the GST family into 14 classes in terrestrial plants. These GSTs are further distinguished based on the presence of the ancestral cysteine (Cys-GSTs) present in TRX family proteins or on its substitution by a serine (Ser-GSTs). Cys-GSTs catalyze the reduction of dehydroascorbate and deglutathionylation reactions whereas Ser-GSTs catalyze glutathione conjugation reactions and eventually have peroxidase activity, both activities being important for stress tolerance or herbicide detoxification. Through non-catalytic, so-called ligandin properties, numerous plant GSTs also participate in the binding and transport of small heterocyclic ligands such as flavonoids including anthocyanins, and polyphenols. So far, this function has likely been underestimated compared to the other documented roles of GSTs. In this review, we compiled data concerning the known enzymatic and structural properties as well as the biochemical and physiological functions associated to plant GSTs having a conserved serine in their active site.


Molecular medicine of microRNAs: structure, function and implications for diabetes.
MicroRNAs (miRNAs) are a family of endogenous small noncoding RNA molecules, of 19-28 nucleotides in length. In humans, up to 3% of all genes are estimated to encode these evolutionarily conserved sequences. miRNAs are thought to control expression of thousands of target mRNAs. Mammalian miRNAs generally negatively regulate gene expression by repressing translation, possibly through effects on mRNA stability and compartmentalisation, and/or the translation process itself. An extensive range of in silico and experimental techniques have been applied to our understanding of the occurrence and functional relevance of such sequences, and antisense technologies have been successfully used to control miRNA expression in vitro and in vivo. Interestingly, miRNAs have been identified in both normal and pathological conditions, including differentiation and development, metabolism, proliferation, cell death, viral infection and cancer. Of specific relevance and excitement to the area of diabetes research, miRNA regulation has been implicated in insulin secretion from pancreatic beta-cells, diabetic heart conditions and nephropathy. Further analyses of miRNAs in vitro and in vivo will, undoubtedly, enable us determine their potential to be exploited as therapeutic targets in diabetes.


Sudden and unexpected deaths in an adult population, Cape Town, South Africa, 2001-2005.
According to the regulations of the National Health Act, all 'sudden and unexpected' deaths in South Africa should be referred to Forensic Pathology Services (FPS) for further investigation. We aimed to determine the final outcomes of forensic postmortem examinations in 'sudden and unexpected' adult deaths referred to Tygerberg FPS between 2001 and 2005. The study was a retrospective descriptive study. Demographic and autopsy data from adult cases of 'sudden and unexpected deaths' referred to Tygerberg FPS were collected and analysed. Results. Some 816 adult cases of 'sudden' deaths were studied. The presumed manner of death was natural in 645 (79.0%) cases, unnatural in 99 (12.2%), and undetermined in 72 (8.8%). Diseases of the cardiovascular, respiratory and central nervous systems accounted for the majority of natural deaths. Infectious diseases accounted for most deaths in the youngest age group studied (18 - 29 years); however, ischaemic heart disease was the most prevalent cause of death in the total study population. This study highlighted the lack of useful pre-autopsy information and therefore the performance of 'unnecessary' medicolegal autopsies in a resource-limited country. Clinicians could ease the burden by giving useful information when referring cases to FPS. Feedback should be given to family members, especially where the cause of death may have an impact on surviving family members.


Do attitudes and beliefs influence work loss due to low back trouble?
Recent evidence indicates that the influence of psychosocial factors on low back disability is as great as, if not greater than, ergonomic aspects; negative attitudes and beliefs are likely to be related to absenteeism. To measure workers attitudes and beliefs about low-back trouble, pain, work and activity five questionnaires were used. Two new instruments (Back Beliefs Questionnaire and Psychosocial Aspects of Work questionnaire) were developed and tested. The attitudes and beliefs were measured among workers in a biscuit manufacturing factory, and the responses related to absenteeism. Workers who had taken in excess of one week's absence due to low-back trouble had significantly more negative attitudes and beliefs when compared with workers who had taken shorter absence (or indeed those reporting no history of back trouble). A subset of the psychosocial parameters accounted for 32% of the variance in absence. Interventions designed to reduce negative attitudes and promote positive beliefs may help to reduce detrimental, inappropriate longer-term absenteeism due to low-back trouble.


Chemical-vapor deposited ultra-fast diamond detectors for temporal measurements of ion bunches.
This article reports on the development of thin diamond detectors and their characterization for their application in temporal profile measurements of subnanosecond ion bunches. Two types of diamonds were used: a 20 μm thin polycrystalline chemical vapor deposited (CVD) diamond and a membrane with a thickness of (5 ± 1) μm etched out of a single crystal (sc) CVD diamond. The combination of a small detector electrode and an impedance matched signal outlet leads to excellent time response properties with a signal pulse resolution (FWHM) of τ = (113 ± 11) ps. Such a fast diamond detector is a perfect device for the time of flight measurements of MeV ions with bunch durations in the subnanosecond regime. The scCVD diamond membrane detector was successfully implemented within the framework of the laser ion generation handling and transport project, in which ion beams are accelerated via a laser-driven source and shaped with conventional accelerator technology. The detector was used to measure subnanosecond proton bunches with an intensity of 108 protons per bunch.


Does literacy improve finance?
When economists ask questions about basic financial principles, most ordinary people answer incorrectly. Economic experts call this condition "financial illiteracy," which suggests that poor financial outcomes are due to a personal deficit of reading-related skills. The analogy to reading is compelling because it suggests that we can teach our way out of population-wide financial failure. In this comment, we explain why the idea of literacy appeals to policy makers in the advanced industrial nations. But we also show that the narrow skill set laid out by economists does not satisfy the politically inclusive definition of literacy that literacy studies fought for. We identify several channels through which people engage with ideas about finance and demonstrate that not all forms of literacy will lead people to the educational content prescribed by academic economists. We argue that truly financial literate people can defy the demands of financial theory and financial institutions.


Quantitative autoradiography of central beta adrenoceptor subtypes: comparison of the effects of chronic treatment with desipramine or centrally administered l-isoproterenol.
This study compares the regulation of the subtypes of central beta adrenoceptors produced by treatment of rats with desipramine (10 mg/kg i.p. twice daily for 10 days) to that caused by central infusion of l-isoproterenol (5 micrograms/hr for 7 days). Beta adrenoceptors were measured by quantitative autoradiography of the binding of [125I]iodopindolol ([125I]IPIN) to coronal sections of rat brain as well as the binding of this radioligand to homogenates of certain areas of brain. Administration of desipramine caused significant reductions in the total specific binding of [125I]IPIN in many areas of the brain, including regions of the amygdala, cerebral cortex, hippocampus, hypothalamus and thalamus. This reduction in the total specific binding of [125I]IPIN was primarily the result of a reduction in its binding to beta-1 adrenoceptors in most brain regions. With the exception of the paraventricular nuclei of the thalamus, no desipramine-induced change in the binding of [125I]IPIN to beta-2 adrenoceptors was observed in any region of the brain. Treatment of rats with desipramine did not alter the binding of [125I]IPIN to the caudate putamen, globus pallidus or the cerebellum. Intracerebroventricular fusion of the nonselective beta adrenoceptor agonist, isoproterenol, reduced the maximum binding site density of the binding of [125I]IPIN to homogenates of cerebellum and hypothalamus, but not to homogenates of cerebral cortex. Autoradiography of the binding of [125I]IPIN to brain sections from rats treated with isoproterenol revealed reductions in many subcortical areas and the cerebellum. In contrast to the effects produced by treatment with desipramine, reductions in the binding of [125I]IPIN after infusions of isoproterenol were a result of a decrease in the binding of [125I]IPIN to beta-2 adrenoceptors in most brain regions. Infusion of isoproterenol reduced the binding of [125I]IPIN to beta-2 adrenoceptors in 10 areas of brain in which the binding of the ligand to beta-1 adrenoceptors was not affected significantly. Inasmuch as there is a selective regulation of beta-1 adrenoceptors by the norepinephrine uptake blocker, desipramine, it may be inferred that these receptors are under the influence of endogenous norepinephrine. By contrast, the density of central beta-2 adrenoceptors are regulated more easily by an exogenous beta adrenoceptor agonist, even one like isoproterenol which is a full agonist at both beta-1 and beta-2 adrenoceptors.


The role of protonation states in ligand-receptor recognition and binding.
In this review we discuss the role of protonation states in receptor-ligand interactions, providing experimental evidences and computational predictions that complex formation may involve titratable groups with unusual pKa's and that protonation states frequently change from unbound to bound states. These protonation changes result in proton uptake/release, which in turn causes the pH-dependence of the binding. Indeed, experimental data strongly suggest that almost any binding is pH-dependent and to be correctly modeled, the protonation states must be properly assigned prior to and after the binding. One may accurately predict the protonation states when provided with the structures of the unbound proteins and their complex; however, the modeling becomes much more complicated if the bound state has to be predicted in a docking protocol or if the structures of either bound or unbound receptor-ligand are not available. The major challenges that arise in these situations are the coupling between binding and protonation states, and the conformational changes induced by the binding and ionization states of titratable groups. In addition, any assessment of the protonation state, either before or after binding, must refer to the pH of binding, which is frequently unknown. Thus, even if the pKa's of ionizable groups can be correctly assigned for both unbound and bound state, without knowing the experimental pH one cannot assign the corresponding protonation states, and consequently one cannot calculate the resulting proton uptake/release. It is pointed out, that while experimental pH may not be the physiological pH and binding may involve proton uptake/release, there is a tendency that the native receptor-ligand complexes have evolved toward specific either subcellular or tissue characteristic pH at which the proton uptake/release is either minimal or absent.


Ultralow friction of ink-jet printed graphene flakes.
We report the frictional response of few-layer graphene (FLG) flakes obtained by the liquid phase exfoliation (LPE) of pristine graphite. To this end, we inkjet print FLG on bare and hexamethyldisilazane-terminated SiO2 substrates, producing micrometric patterns with nanoscopic roughness that are investigated by atomic force microscopy. Normal force spectroscopy and atomically-resolved morphologies indicate reduced surface contamination by solvents after a vacuum annealing process. Notably, the printed FLG flakes show ultralow friction comparable to that of micromechanically exfoliated graphene flakes. Lubricity is retained on flakes with a lateral size of a few tens of nanometres, and with a thickness as small as ∼2 nm, confirming the high crystalline quality and low defects density in the FLG basal plane. Surface exposed step edges exhibit the highest friction values, representing the preferential sites for the origin of the secondary dissipative processes related to edge straining, wear or lateral displacement of the flakes. Our work demonstrates that LPE enables fundamental studies on graphene friction to the single-flake level. The capability to deliver ultralow-friction-graphene over technologically relevant substrates, using a scalable production route and a high-throughput, large-area printing technique, may also open up new opportunities in the lubrication of micro- and nano-electromechanical systems.


The efficacy of DNA vaccination is enhanced in mice by targeting the encoded protein to dendritic cells.
DNA vaccines promote an immune response by providing antigen-encoding DNA to the recipient, but the efficacy of such vaccines needs improving. Many approaches have considerable potential but currently induce relatively weak immune responses despite multiple high doses of DNA vaccine. Here, we asked whether targeting vaccine antigens to DCs would increase the immunity and protection that result from DNA vaccines. To determine this, we generated a DNA vaccine encoding a fusion protein comprised of the vaccine antigen and a single-chain Fv antibody (scFv) specific for the DC-restricted antigen-uptake receptor DEC205. Following vaccination of mice, the vaccine antigen was expressed selectively by DCs, which were required for the increased efficacy of MHC class I and MHC class II antigen presentation relative to a control scFv DNA vaccine. In addition, a DNA vaccine encoding an HIV gag p41-scFv DEC205 fusion protein induced 10-fold higher antibody levels and increased numbers of IFN-gamma-producing CD4+ and CD8+ T cells. After a single i.m. injection of the DNA vaccine encoding an HIV gag p41-scFv DEC205 fusion protein, mice were protected from an airway challenge with a recombinant vaccinia virus expressing the HIV gag p41, even with 1% of the dose of nontargeted DNA vaccine. The efficacy of DNA vaccines therefore may be enhanced by inclusion of sequences such as single-chain antibodies to target the antigen to DCs.


Prevalence of diabetes in Mexican Americans, Cubans, and Puerto Ricans from the Hispanic Health and Nutrition Examination Survey, 1982-1984.
The purpose of this study was to estimate the prevalence of diagnosed and undiagnosed diabetes among Mexican Americans, Cubans, and Puerto Ricans in the United States and compare these estimates to data from prior surveys for U.S. non-Hispanic whites and blacks. Data for this study are from the Hispanic Health and Nutrition Examination Survey, a multipurpose cross-sectional survey of three U.S. Hispanic populations conducted in 1982-1984. The interviewed sample of people aged 20-74 yr included 3935 Mexican Americans in the southwest, 1134 Cubans in Florida, and 1519 Puerto Ricans in the New York City area. The diabetes component consisted of interview questions on diabetes diagnosis and treatment and an oral glucose tolerance test administered to a subsample. The prevalence of diabetes was two to three times greater for Mexican Americans and Puerto Ricans than for non-Hispanic whites surveyed in 1976-1980. In Cubans, the prevalence was similar to that for non-Hispanic whites. In men and women 45-74 yr of age, the prevalence of diabetes was extremely high for both Mexican Americans (23.9%) and Puerto Ricans (26.1%) compared with Cubans (15.8%) or non-Hispanic whites (12%). The total prevalence of diabetes was not significantly different for Mexican Americans and Puerto Ricans but was significantly lower for Cubans. The relatively lower prevalence of diabetes among Cubans and the high prevalence in both Mexican Americans and Puerto Ricans may be related to socioeconomic, genetic, behavioral, or environmental factors.


The Combination of Particle Irradiation With the Hedgehog Inhibitor GANT61 Differently Modulates the Radiosensitivity and Migration of Cancer Cells Compared to X-Ray Irradiation.
Due to the advantages of charged particles compared to conventional radiotherapy, a vast increase is noted in the use of particle therapy in the clinic. These advantages include an improved dose deposition and increased biological effectiveness. Metastasis is still an important cause of mortality in cancer patients and evidence has shown that conventional radiotherapy can increase the formation of metastasizing cells. An important pathway involved in the process of metastasis is the Hedgehog (Hh) signaling pathway. Recent studies have demonstrated that activation of the Hh pathway, in response to X-rays, can lead to radioresistance and increased migratory, and invasive capabilities of cancer cells. Here, we investigated the effect of X-rays, protons, and carbon ions on cell survival, migration, and Hh pathway gene expression in prostate cancer (PC3) and medulloblastoma (DAOY) cell lines. In addition, the potential modulation of cell survival and migration by the Hh pathway inhibitor GANT61 was investigated. We found that in both cell lines, carbon ions were more effective in decreasing cell survival and migration as well as inducing more significant alterations in the Hh pathway genes compared to X-rays or protons. In addition, we show here for the first time that the Hh inhibitor GANT61 is able to sensitize DAOY medulloblastoma cells to particle radiation (proton and carbon ion) but not to conventional X-rays. This important finding demonstrates that the results of combination treatment strategies with X-ray radiotherapy cannot be automatically extrapolated to particle therapy and should be investigated separately. In conclusion, combining GANT61 with particle radiation could offer a benefit for specific cancer types with regard to cancer cell survival.