Projected costs associated with school-based screening to inform deployment of Dengvaxia: Vietnam as a case study.
After new analysis, Sanofi Pasteur now recommends their dengue vaccine (Dengvaxia) should only be given to individuals previously infected with dengue and the World Health Organization's recommendations regarding its use are currently being revised. As a result, the potential costs of performing large-scale individual dengue screening and/or dengue serosurveys have become an important consideration for decision making by policymakers in dengue-endemic areas. We used an ingredients-based approach to estimate the financial costs for conducting both a school-based dengue serosurvey and school-based individual dengue screening within a typical province in Vietnam, using an existing commercial indirect immunoglobulin G enzyme-linked immunosorbent assay kit. This costing is hypothetical and based on estimates regarding the resources that would be required to perform such activities. We estimated that performing a school-based individual screening of 9-year-olds would cost US$9.25 per child tested or US$197,827 in total for a typical province. We also estimated that a school-based serosurvey would cost US$10,074, assuming one class from each of the grades that include 8- to 11-year-olds are sampled at each of the 12 selected schools across the province. The study indicates that using this vaccine safely on a large-scale will incur noteworthy operational costs. It is crucial that these be considered in future cost-effectiveness analyses informing how and where the vaccine is deployed.


8-OH-DPAT-induced hyperphagia: its neural basis and possible therapeutic relevance.
The pharmacological and neurochemical bases of hyperphagia induced by the serotonin agonist 8-OH-DPAT were examined. In addition, the possible therapeutic potential of 8-OH-DPAT and related drugs in the treatment of anorexic pathology was assessed in an animal model of anorexia (as induced by acute immobilization stress). In normal rats 8-OH-DPAT elicited feeding after peripheral injection and after intracerebral application to the brainstem raphé nuclei. Feeding elicited by peripheral injection of the drug was attenuated by pretreatment with the serotonin synthesis inhibitor para-chlorophenylalanine. Following a hyperphagic dose of 8-OH-DPAT, brain serotonin metabolism was reduced, particularly in midbrain and pons-medulla. Our interpretation of these data is that 8-OH-DPAT elicits feeding via an agonist action on serotonin autoreceptors in the raphé nuclei. These receptors are probably of the 5-HT1A subtype as 8-OH-DPAT has a high affinity for this receptor and other putative 5-HT1A agonist (i.e. buspirone, TVX Q 7821) also elicit feeding. In contrast, putative 5-HT1B agonists (i.e. RU-24969 and quipazine) decrease feeding and cause anorexia. 8-OH-DPAT and other 5-HT1A agonists attenuated the anorexia and body weight loss caused by immobilization stress. Therefore, it seems possible that 5-HT1A agonists may be clinically useful in the treatment of anorexia.


Radical Coupling Reactions of Hydroxystilbene Glucosides and Coniferyl Alcohol: A Density Functional Theory Study.
The monolignols, p-coumaryl, coniferyl, and sinapyl alcohol, arise from the general phenylpropanoid biosynthetic pathway. Increasingly, however, authentic lignin monomers derived from outside this process are being identified and found to be fully incorporated into the lignin polymer. Among them, hydroxystilbene glucosides, which are produced through a hybrid process that combines the phenylpropanoid and acetate/malonate pathways, have been experimentally detected in the bark lignin of Norway spruce (Picea abies). Several interunit linkages have been identified and proposed to occur through homo-coupling of the hydroxystilbene glucosides and their cross-coupling with coniferyl alcohol. In the current work, the thermodynamics of these coupling modes and subsequent rearomatization reactions have been evaluated by the application of density functional theory (DFT) calculations. The objective of this paper is to determine favorable coupling and cross-coupling modes to help explain the experimental observations and attempt to predict other favorable pathways that might be further elucidated via in vitro polymerization aided by synthetic models and detailed structural studies.


Health Professions Education Scholarship Unit Leaders as Institutional Entrepreneurs.
Health professions education scholarship units (HPESUs) are organizational structures within which a group is substantively engaged in health professions education scholarship. Little research investigates the strategies employed by HPESU administrative leaders to secure and maintain HPESU success. Using institutional entrepreneurship as a theoretical lens, this study asks: Do HPESU administrative leaders act as institutional entrepreneurs (IEs)? This study recontextualizes two preexisting qualitative datasets that comprised interviews with leaders in health professions education in Canada (2011-2012) and Australia and New Zealand (2013-1014). Two researchers iteratively analyzed the data using the institutional entrepreneurship construct until consensus was achieved. A third investigator independently reviewed and contributed to the recontextualized analyses. A summary of the analyses was shared with all authors, and their feedback was incorporated into the final interpretations. HPESU leaders act as IEs in three ways. First, HPESU leaders construct arguments and position statements about how the HPESU resolves an institution's problem(s). This theorization discourse justifies the existence and support of the HPESU. Second, the leaders strategically cultivate relationships with the leader of the institution within which the HPESU sits, the leaders of large academic groups with which the HPESU partners, and the clinician educators who want careers in health professions education. Third, the leaders work to increase the local visibility of the HPESU. Practical insights into how institutional leaders interested in launching an HPESU can harness these findings are discussed.


Paracrine effects of embryo-derived FGF4 and BMP4 during pig trophoblast elongation.
The crosstalk between the epiblast and the trophoblast is critical in supporting the early stages of conceptus development. FGF4 and BMP4 are inductive signals that participate in the communication between the epiblast and the extraembryonic ectoderm (ExE) of the developing mouse embryo. Importantly, however, it is unknown whether a similar crosstalk operates in species that lack a discernible ExE and develop a mammotypical embryonic disc (ED). Here we investigated the crosstalk between the epiblast and the trophectoderm (TE) during pig embryo elongation. FGF4 ligand and FGFR2 were detected primarily on the plasma membrane of TE cells of peri-elongation embryos. The binding of this growth factor to its receptor triggered a signal transduction response evidenced by an increase in phosphorylated MAPK/ERK. Particular enrichment was detected in the periphery of the ED in early ovoid embryos, indicating that active FGF signalling was operating during this stage. Gene expression analysis shows that CDX2 and ELF5, two genes expressed in the mouse ExE, are only co-expressed in the Rauber's layer, but not in the pig mural TE. Interestingly, these genes were detected in the nascent mesoderm of early gastrulating embryos. Analysis of BMP4 expression by in situ hybridisation shows that this growth factor is produced by nascent mesoderm cells. A functional test in differentiating epiblast shows that CDX2 and ELF5 are activated in response to BMP4. Furthermore, the effects of BMP4 were also demonstrated in the neighbouring TE cells, as demonstrated by an increase in phosphorylated SMAD1/5/8. These results show that BMP4 produced in the extraembryonic mesoderm is directly influencing the SMAD response in the TE of elongating embryos. These results demonstrate that paracrine signals from the embryo, represented by FGF4 and BMP4, induce a response in the TE prior to the extensive elongation. The study also confirms that expression of CDX2 and ELF5 is not conserved in the mural TE, indicating that although the signals that coordinate conceptus growth are similar between rodents and pigs, the gene regulatory network of the trophoblast lineage is not conserved in these species.


The contribution of water contact behavior to the high Schistosoma mansoni Infection rates observed in the Senegal River Basin.
Schistosomiasis is one of the major parasitic diseases in the world in terms of people infected and those at risk. Infection occurs through contact with water contaminated with larval forms of the parasite, which are released by freshwater snails and then penetrate the skin of people. Schistosomiasis infection and human water contact are thus essentially linked, and more knowledge about their relationship will help us to develop appropriate control measures. So far, only few studies have related water contact patterns to infection levels. We have conducted detailed direct water contact observations in a village in Northern Senegal during the first years of a massive Schistosoma mansoni outbreak to determine the role of human water contact in the extent of the epidemic.We quantified water contact activities in terms of frequency and duration, and described how these vary with age and sex. Moreover, we assessed the relationship between water contact- and infection intensity patterns to further elucidate the contribution of exposure to the transmission of schistosomiasis. This resulted in over 120,000 recorded water contacts for 1651 subjects over 175 observation days. Bathing was the main activity, followed by household activities. Frequency and duration of water contact depended on age and sex rather than season. Water contacts peaked in adolescents, women spent almost twice as much time in the water as men, and water contacts were more intense in the afternoon than in the morning, with sex-specific intensity peaks. The average number of water contacts per person per day in this population was 0.42; the average time spent in the water per person per day was 4.3 minutes. The observed patterns of water contact behavior are not unusual and have been described before in various other settings in sub-Saharan Africa. Moreover, water contact levels were not exceptionally high and thus cannot explain the extremely high S. mansoni infection intensities as observed in Northern Senegal. Comparison with fecal egg counts in the respective age and sex groups further revealed that water contact levels did not unambiguously correspond with infection levels, indicating that factors other than exposure also play a role in determining intensity of infection.


Genetic and cellular evidence of decreased inflammation associated with reduced incidence of posttraumatic arthritis in MRL/MpJ mice.
To examine the relationship between inflammation and posttraumatic arthritis (PTA) in a murine intraarticular fracture model. Male C57BL/6 and MRL/MpJ "superhealer" mice received tibial plateau fractures using a previously established method. Mice were killed on day 0 (within 4 hours of fracture) and days 1, 3, 5, 7, 28, and 56 after fracture. Synovial tissue samples, obtained prior to fracture and on days 0, 1, 3, 5, and 7 after fracture, were examined by reverse transcription-polymerase chain reaction for gene expression of proinflammatory cytokines and chemokines. Synovial fluid and serum samples were collected to measure cytokine concentrations, using enzyme-linked immunosorbent assay. Whole joints were examined histologically for the extent of synovitis and cartilage degradation, and joint tissue samples from all time points were analyzed immunohistochemically to evaluate the distribution of interleukin-1 (IL-1). Compared to C57BL/6 mice, MRL/MpJ mice had less severe intraarticular and systemic inflammation following joint injury, as evidenced by lower gene expression of tumor necrosis factor α and IL-1β in the synovial tissue and lower protein levels of IL-1α and IL-1β in the synovial fluid, serum, and joint tissues. Furthermore, after joint injury, MRL/MpJ mice had lower gene expression of macrophage inflammatory proteins and macrophage-derived chemokine (CCL22) in the synovial tissue, and also had reduced acute and late-stage infiltration of synovial macrophages. C57BL/6 mice exhibited higher levels of inflammation than MRL/MpJ mice, indicating that MRL/MpJ mice are protected from PTA in this model. These data thus suggest an association between joint tissue inflammation and the development and progression of PTA in mice.


Effect of air quality alerts on human health: a regression discontinuity analysis in Toronto, Canada.
Ambient air pollution is a major health risk globally. To reduce adverse health effects on days when air pollution is high, government agencies worldwide have implemented air quality alert programmes. Despite their widespread use, little is known about whether these programmes produce any observable public-health benefits. We assessed the effectiveness of such programmes using a quasi-experimental approach. We assembled a population-based cohort comprising all individuals who resided in the city of Toronto (Ontario, Canada) from 2003 to 2012 (about 2·6 million people). We ascertained seven health outcomes known to be affected by short-term elevation of air pollution, using provincial health administrative databases. These health outcomes were cardiovascular-related mortality, respiratory-related mortality, and hospital admissions or emergency-department visits for acute myocardial infarction, heart failure, stroke, asthma, and chronic obstructive pulmonary disease (COPD). We applied a regression discontinuity design to assess the effectiveness of an intervention (ie, the air quality alert programme). To quantify the effect of the air quality alert programme, we estimated for each outcome both the absolute rate difference and the rate ratio attributable to programme eligibility (by intention-to-treat analysis) and the alerts themselves (by two-stage regression approach), respectively. Between Jan 1, 2003, and Dec 31, 2012, on average between three and 27 daily cardiovascular or respiratory events were reported in Toronto (depending on the outcome). Alert announcements reduced asthma-related emergency-department visits by 4·73 cases per 1 000 000 people per day (95% CI 0·55-9·38), or in relative terms by 25% (95% CI 1-47). Programme eligibility also led to 2·05 (95% CI 0·07-4·00) fewer daily emergency-department visits for asthma. We did not detect a significant reduction in any other health outcome as a result of alert announcements or programme eligibility. However, a non-significant trend was noted towards decreased asthma-related and COPD-related admissions. In this population-based cohort, the air quality alert programme was related to some reductions in respiratory morbidity, but not any other health outcome examined. This finding suggests that issuing air quality alerts alone has a limited effect on public health and that implementing enforced public actions to reduce air pollution on high pollution days could be warranted. Together with accumulating evidence of substantial burden from long-term air pollution exposure, this study underscores the need for further strengthening of global efforts that can lead to long-term improvement of overall air quality. Public Health Ontario, Canadian Institutes for Health Research.


Improving international research with clinical specimens: 5 achievable objectives.
Our increased interest in translational research has created a large demand for blood, tissue, and other clinical samples, which find use in a broad variety of research including genomics, proteomics, and metabolomics. Hundreds of millions of dollars have been invested internationally on the collection, storage, and distribution of samples. Nevertheless, many researchers complain in frustration about their inability to obtain relevant and/or useful samples for their research. Lack of access to samples, poor condition of samples, and unavailability of appropriate control samples have slowed our progress in the study of diseases and biomarkers. In this perspective, I focus on five major challenges that thwart clinical sample use for translational research and propose near term objectives to address them. They include: (1) defining our biobanking needs; (2) increasing the use of and access to standard operating procedures; (3) mapping interobserver differences for use in normalizing diagnoses; (4) identifying natural internal protein controls; and (5) redefining the clinical sample paradigm by building partnerships with the public. In each case, I believe that we have the tools at hand required to achieve the objective within 5 years. Potential paths to achieve these objectives are explored. However we solve these problems, the future of proteomics depends on access to high quality clinical samples, collected under standardized conditions, accurately annotated and shared under conditions that promote the research we need to do.


Developing a new research tool for use in free-ranging cetaceans: recovering cortisol from harbour porpoise skin.
We developed a chemical analytical procedure for sampling, extracting and determining epidermal skin cortisol concentrations (SCCs) in the harbour porpoise (Phocoena phocoena) using gas chromatography-tandem mass spectrometry. In brief, this involved a pressurized liquid extraction with a two-step solid-phase clean-up. A derivatization step was conducted prior to detection. To evaluate the new assay, cortisol was analysed in three different sample types obtained from four harbour porpoises: skin plates, dorsal fin skin plugs (with and without lidocaine) and epidermal scrapes. Skin cortisol concentrations could be measured using the new assay in the majority of the tested skin samples down to a minimal sample size of 49 mg dry weight (dw). Water content ranged from 10 to 46% in the plug samples, which had SCCs from 2.1 to 77.7 ng/g dw. Epidermal scrape samples had the highest water content (83-87%) and lower SCCs (0.6-15 ng/g dw), while the skin plates had intermediate water contents (60-66%) and SCCs of 2.6-13.0 ng/g dw. SCC was slightly higher in plugs with lidocaine than without (average values of 41 and 33 ng/g dw, respectively). Substantial within-individual variations in cortisol concentrations are also common in other matrices such as blood and hair. Some important factors behind this variation could be e.g. the animal's sex, age, body condition, reproductive stage, and the body region sampled, as well as season, moulting cycles and water temperature. Clearly, more research into SCCs is required. The findings described here represent the first critical steps towards using epidermal skin cell samples to assess chronic stress levels in cetaceans and the development of a widely applicable health-assessment tool in these species.


Autism-associated Nf1 deficiency disrupts corticocortical and corticostriatal functional connectivity in human and mouse.
Children with the autosomal dominant single gene disorder, neurofibromatosis type 1 (NF1), display multiple structural and functional changes in the central nervous system, resulting in neuropsychological cognitive abnormalities. Here we assessed the pathological functional organization that may underlie the behavioral impairments in NF1 using resting-state functional connectivity MRI. Coherent spontaneous fluctuations in the fMRI signal across the entire brain were used to interrogate the pattern of functional organization of corticocortical and corticostriatal networks in both NF1 pediatric patients and mice with a heterozygous mutation in the Nf1 gene (Nf1+/-). Children with NF1 demonstrated abnormal organization of cortical association networks and altered posterior-anterior functional connectivity in the default network. Examining the contribution of the striatum revealed that corticostriatal functional connectivity was altered. NF1 children demonstrated reduced functional connectivity between striatum and the frontoparietal network and increased striatal functional connectivity with the limbic network. Awake passive mouse functional connectivity MRI in Nf1+/- mice similarly revealed reduced posterior-anterior connectivity along the cingulate cortex as well as disrupted corticostriatal connectivity. The striatum of Nf1+/- mice showed increased functional connectivity to somatomotor and frontal cortices and decreased functional connectivity to the auditory cortex. Collectively, these results demonstrate similar alterations across species, suggesting that NF1 pathogenesis is linked to striatal dysfunction and disrupted corticocortical connectivity in the default network.


Membrane proteins: molecular dynamics simulations.
Molecular dynamics simulations of membrane proteins are making rapid progress, because of new high-resolution structures, advances in computer hardware and atomistic simulation algorithms, and the recent introduction of coarse-grained models for membranes and proteins. In addition to several large ion channel simulations, recent studies have explored how individual amino acids interact with the bilayer or snorkel/anchor to the headgroup region, and it has been possible to calculate water/membrane partition free energies. This has resulted in a view of bilayers as being adaptive rather than purely hydrophobic solvents, with important implications, for example, for interaction between lipids and arginines in the charged S4 helix of voltage-gated ion channels. However, several studies indicate that the typical current simulations fall short of exhaustive sampling, and that even simple protein-membrane interactions require at least ca. 1 micros to fully sample their dynamics. One new way this is being addressed is coarse-grained models that enable mesoscopic simulations on multi-micros scale. These have been used to model interactions, self-assembly and membrane perturbations induced by proteins. While they cannot replace all-atom simulations, they are a potentially useful technique for initial insertion, placement, and low-resolution refinement.


Fat-suppressed MR Imaging of the Spine for Metal Artifact Reduction at 3T: Comparison of STIR and Slice Encoding for Metal Artifact Correction Fat-suppressed T2-weighted Images.
To compare short tau inversion recovery (STIR) images with slice encoding for metal artifact correction (SEMAC)-corrected magnetic resonance imaging (MRI) of spectral presaturation with inversion recovery (SPIR) or inversion recovery (IR) at 3T in patients with metallic spinal instrumentation. Following institutional review board's approval, 71 vertebrae with interbody fixation in 26 patients who underwent transpedicular spondylodesis with spinal metallic prostheses were analyzed with SEMAC spinal MRI. All the fixated vertebrae were examined with STIR, and 41 vertebrae of 15 patients were scanned with SEMAC-SPIR T2-weighted MRI. The remaining 30 vertebrae of 11 patients were scanned with SEMAC-IR T2-weighted MRI. Two musculoskeletal radiologists compared the image sets and qualitatively analyzed the images with a five-point scale that included artifact reduction around the metallic implant and visualization of the rod and pedicle. Quantitative assessments were performed by calculating the signal intensity ratio of the fixated vertebra and non-metallic vertebra and by calculating the signal-to-noise ratios (SNRs) of the vertebrae. A paired t-test was used for the statistical analyses. The SEMAC-IR MRI had a significant decrease in the metallic artifact area (P < 0.05), while the SEMAC-SPIR MRI yielded significantly increased artifact areas (P < 0.05). However, the signal intensity ratios (i.e., metal-induced signal pile-up) were not significantly different (P > 0.05) between the STIR and SEMAC MRI. The SNR of the SEMAC MRI was significantly lower than the SNR of the STIR (P < 0.05). The metal artifact reduction scores were significantly higher in the SEMAC-SPIR MRI (P < 0.05). Despite the relatively larger artifact size and lower SNRs, the SEMAC-SPIR MRI was superior to the other types of fat-suppressed MRI of SEMAC-IR or T2-weighted STIR MRI. However, the drawbacks of high signal pile-up, large artifact size, and relatively low SNRs require further investigation to determine the best method for fat-suppressed MRI of metallic implants.


Sulforaphane treatment of autism spectrum disorder (ASD).
Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medico-economic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled, double-blind, randomized trial, young men (aged 13-27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)--derived from broccoli sprout extracts--or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50-150 µmol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015-0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation.


Contribution of plus and minus end pathways to microtubule turnover.
Turnover is important for the maintenance and remodeling of the cytoskeleton during the processes of cell morphogenesis, mitosis and motility. Microtubule (MT) turnover is thought to occur by dynamic instability, growth and shortening at distal (plus) ends. Recent observation of MT release from the centrosome and depolymerization from proximal (minus) ends indicates the existence of a minus end pathway. To evaluate the relative contributions of plus and minus end pathways to turnover, we analyzed MT dynamics in a model system, the fish melanophore, a large non-motile cell with a regular radial array of long MTs. MT ends were tracked in digital fluorescence time-lapse sequences and life histories of individual MTs were analyzed using random walk theory generalized to the case of diffusion with drift. Analysis of plus end dynamics gave an apparent diffusion coefficient of D=7.5 microm2/minute. The random walk model predicts that the half-time for turnover driven solely by plus end dynamics will depend strongly on position in the cell. Based on the experimentally determined value of D, turnover of MTs near the center of a typical melanophore of radius 70 microm was calculated to require over 5 hours, a paradoxically long time. To examine MT behavior deep in the cytoplasm, we developed a novel, sequential subtraction mode of image analysis. This analysis revealed a subpopulation of MTs which shortened from their minus ends, presumably after constitutive release from the centrosome. Given the relative slowness of plus end dynamics to turn over the root of a long MT, the turnover of MTs near the cell center is determined primarily by the minus-end pathway. MTs released from the centrosome become replaced by newly nucleated ones. The relative contributions of plus and minus end pathways was estimated from the diffusion coefficient, D, for the plus end, the length distribution of MTs, t he frequency of free minus ends, and the rate of minus-end shortening. We conclude that, in large animal cells with a centrosomally focussed array of MTs, turnover occurs by a combination of plus and minus end pathways, the plus end dominating at the cell periphery and the minus end dominating near the cell center.


Sub-nanometre mapping of the aquaporin-water interface using multifrequency atomic force microscopy.
Aquaporins are integral membrane proteins that regulate the transport of water and small molecules in and out of the cell. In eye lens tissue, circulation of water, ions and metabolites is ensured by a microcirculation system in which aquaporin-0 (AQP0) plays a central role. AQP0 allows water to flow beyond the diffusion limit through lens membranes. AQP0 naturally arranges in a square lattice. The malfunction of AQP0 is related to numerous diseases such as cataracts. Despite considerable research into its structure, function and dynamics, the interface between the protein and the surrounding liquid and the effect of the lattice arrangement on the behaviour of water at the interface with the membrane are still not fully understood. Here we use a multifrequency atomic force microscopy (AFM) approach to map both the liquid at the interface with AQP0 and the protein itself with sub-nanometer resolution. Imaging using the fundamental eigenmode of the AFM cantilever probes mainly the interfacial water at the surface of the membrane. The results highlight a well-defined region that surrounds AQP0 tetramers and where water exhibits a higher affinity for the protein. Imaging in the second eigenmode is dominated by the mechanical response of the protein and provides sub-molecular details of the protein surface and the sub-surface structure. The relationship between modes and harmonics is also examined.


Back pain--a presentation of metastatic testicular germ cell tumours.
9 patients (21%) from a total of 42 young men with testicular germ cell malignancy had back pain as a major presenting symptom; 2 had back pain without unilateral testicular enlargement. Time to correct diagnosis from first visit to a doctor was significantly longer in those with back pain than in those with testicular symptoms. All patients with back pain had para-aortic node metastases. Young men with back pain should be examined for testicular disease and should also be asked about past testicular abnormalities.


Age of First Walking and Associations with Symptom Severity in Children with Suspected or Diagnosed Autism Spectrum Disorder.
Age of first walking (AOW) is reported to be later in autism spectrum disorder (ASD) compared with typical development. However, the relationship between AOW and variations in ASD symptoms across different neurodevelopmental disorders is largely unknown. This study investigated AOW and its association with autism symptom severity in a large sample of children (N = 490, 23% females) clinically evaluated for suspected ASD, differentiated into ASD (n = 376) and non-ASD (n = 114) diagnoses. Children with ASD achieved independent walking significantly later than children with non-ASD diagnoses. AOW was significantly associated with ASD symptom severity, and females had a non-significant later AOW. The current findings suggest that in cases with delayed AOW, ASD should be considered as an actual differential diagnosis, perhaps particularly in girls.


Actualizing Better Health And Health Care For Older Adults.
By 2030 more people in the United States will be older than age sixty-five than younger than age five. Our health care system is unprepared for the complexity of caring for a heterogenous population of older adults-a problem that has been magnified by the coronavirus disease 2019 (COVID-19) pandemic. Here, as part of the National Academy of Medicine's Vital Directions for Health and Health Care: Priorities for 2021 initiative, we identify six vital directions to improve the care and quality of life for all older Americans. The next administration must create an adequately prepared workforce; strengthen the role of public health; remediate disparities and inequities; develop, evaluate, and implement new approaches to care delivery; allocate resources to achieve patient-centered care and outcomes, including palliative and end-of-life care; and redesign the structure and financing of long-term services and supports. If these priorities are addressed proactively, an infrastructure can be created that promotes better health and equitable, goal-directed care that recognizes the preferences and needs of older adults.


Effects of Iscador preparations on the reactivity of mouse immune system.
Anticancer preparations made from plants have been an object of scientific interest for many years. It is worth noting that as many as 25% of cytostatics used in the anticancer chemotherapy are obtained from plants. One of the medical preparations which significantly influences cell metabolism is Iscador. Iscador preparations are used as complementary therapy in the conventional anticancer treatment. These are aqueous extracts of mistletoe (Viscum album L.). One repeatedly finds that mistletoe (Viscum album L.) extracts show immune-modulating effects. THE AIM at the present work was to study the influence of iscador Qu, M, P at a dose 5 mg/kg b.w., on the total protein concentration in blood serum and proportions of blood protein fractions determined by electrophoresis. Additionally leukocyte activity was estimated, which, served as indicators of the immune system reactivity in mice treated with anticancer preparations of vegetable origin. The experiment indicated statistically significant increase in albumin fraction level and lymphocyte count. Moreover, decrease of the total protein content, protein fractions globulins alpha2, beta, gamma and neutrophil, monocyte count in mouse serum was observed.


Down's syndrome: prevalence and ionising radiation in an area of north west England 1957-91.
To analyse the prevalence of Down's syndrome in a specific, geographical area and seek to explain variations with particular reference to ionising radiation. Cases were ascertained by one paediatrician as part of a prospective survey of major congenital malformations in children born to residents of an area of Lancashire between 1957 and 1991. Temporal changes in prevalence rates were detected by a grid search technique using Poisson log linear models. These models were also used to determine the association between prevalence and ionising radiation from atomic fall out. The Fylde district of Lancashire in the north west of England. There were 167 cases, including five stillbirths and eight terminations, among 124,015 total births in a population which increased from about 250,000 to over 300,000 during the study period. There was significant increase in the prevalence of all cases conceived in 1963 and 1964, and a lesser peak in 1958 which did not quite reach statistical significance. There was no evidence that the increased prevalence in 1963-64 was a result of changes in the maternal age distribution in the population. Babies of mothers aged 35 years and over accounted for more of the variation, especially in 1958 when their increase was significant. There was a highly significant association between prevalence and radiation from fallout produced by atmospheric testing of atomic weapons. The 1963-64 peak coincided with the maximum estimated radiation dose. The lesser peak in 1958 also coincided with increased exposure to radiation from fallout, possibly enhanced by ground deposits after a fire at the Windscale reactor in October 1957. This study provides further support for low dose ionising radiation as one aetiological factor in Down's syndrome.


Characterization of a BHK(TK-) cell clone resistant to postattachment entry by herpes simplex virus types 1 and 2.
BHK(TK-) cells selected for resistance to polyethylene glycol-mediated fusion give rise to clones that are resistant to herpes simplex virus (HSV) infection. We have characterized one such clone, designated 95-19, and found that it is resistant to entry of HSV type 1 (HSV-1), HSV-2, and the related alphaherpesvirus pseudorabies virus (PRV). Single-step growth experiments show no detectable replication of multiple strains of HSV-1 and HSV-2 on 95-19 cells. Three lines of evidence suggest that these cells are resistant to postattachment entry. (i) Measurements of binding of radiolabeled virus show that heparin-sensitive binding of HSV-1 and HSV-2 to 95-19 cells is identical to binding to BHK(TK-) cells, suggesting that the block to replication occurs after attachment to heparan sulfate proteoglycan. (ii) 95-19 cells exposed to HSV-1 or HSV-2 at high multiplicity show no detectable immediate-early (IE) mRNA expression. (iii) Exposure of attached virus and cells to polyethylene glycol results in partial recovery of both IE gene expression and virus yield in single-step growth. The degrees of recovery of single-step yield and IE gene expression are similar, suggesting that the only block to single-step replication is at the point of virus entry and that these cells are deficient in some cellular factor required for efficient postattachment entry of free virus. 95-19 cells are also highly resistant to entry by cell-to-cell spread, suggesting that the same cellular factor participates in both types of entry.


The association between moderate alcohol use and illness severity in bipolar disorder: a preliminary report.
To examine the association of alcohol consumption with symptoms, illness course, and health care utilization among non-alcoholic patients with bipolar disorder. Subjects were 148 patients with bipolar I or II disorder enrolled in a longitudinal study of cognitive-behavioral therapy versus psychoeducation. Subjects were 18 to 60 years old, in full or partial remission, and non-heavy drinkers with no history of substance use disorders. At least 4 weeks of consistent naturalistic treatment with mood stabilizer was required for enrollment. Measures included the Structured Clinical Interview for DSM-IV, the Hamilton Rating Scale for Depression, the Clinician-Administered Rating Scale for Mania, and the Khavari Alcohol Test. Data were gathered from July 2002 to December 2004. Mean weekly alcoholic beverage consumption was minimal among both men (3.8 standard drinks, SD = 8.9) and women (1.2 standard drinks, SD = 1.9). Nonetheless, total alcohol consumption among men was associated with lifetime manic episodes (F = 10.2, df = 1, p = .003) and emergency department visits (F = 4.3, df = 1, p = .046). Spirits consumption among men was strongly associated with lifetime manic episodes (F = 81.8, df = 1, p < .001) and emergency department visits (F = 14.0, df = 1, p < .001). Among women, the frequency of alcohol consumption was associated with lifetime episodes of depression (F = 15.5, df = 1, p < .001) and hypomania (F = 4.8, df = 1, p < .03). Wine consumption among women was associated with lifetime hypomanic episodes (F = 13.6, df = 1, p < .001) and current manic symptoms (F = 4.0, df = 1, p < .05). Despite low volumes of consumption, alcohol was associated with measures of illness severity in bipolar disorder among both men and women. The adverse effects of alcohol on bipolar disorder may occur over a range of consumption, rather than being confined to heavy drinkers.


Pesticide poisoning in non-fatal deliberate self-harm: A public health issue: Study from Sundarban delta, India.
Non-fatal deliberate self-harm (DSH), particularly with pesticides, is a major public health problem in many developing countries of the world. Agriculture is the primary occupation of most people living in the Sundarban region in West Bengal, India. Pesticides are extensively used in agriculture, and these agents are most frequently used in DSH. This study aimed to identify the nature of methods and agents used in non-fatal DSH attempts in the Sundarban area under South 24 Parganas district of West Bengal. Detailed demographic and clinical data on DSH cases of 13 Block Primary Health Centres' (BPHCs') admission registers were analyzed. One Focus Group Discussion (FGD) with the Panchayat Samiti of each block (totally 13 FDGs) was conducted to elicit the Samiti members' perception about the problem of pesticide-related DSH or suicide in the region. A total of 5,178 (1,887 male and 3,291 female) subjects were admitted at the BPHCs during the study period from 1999 to 2001. Organophosphorous pesticide poisoning was found to be the most common method (85.1%) in DSH. This emphasizes the importance of developing an urgent poisoning-prevention program with a special focus on improving clinical services, as well as initiating farmers' education programs focusing on safe pesticide practices at the primary-care level.


The prevalence of depression in general hospital inpatients: a systematic review and meta-analysis of interview-based studies.
Comorbid depression in the medically ill is clinically important. Admission to a general hospital offers an opportunity to identify and initiate treatment for depression. However, we first need to know how common depression is in general hospital inpatients. We aimed to address this question by systematically reviewing the relevant literature. We reviewed published prevalence studies in any language which had used diagnostic interviews of general hospital inpatients and met basic methodological quality criteria. We focussed on interview-based studies in order to estimate the proportion of patients with a diagnosis of depressive illness. Of 158 relevant articles, 65 (41%) describing 60 separate studies met our inclusion criteria. The 31 studies that focussed on general medical and surgical inpatients reported prevalence estimates ranging from 5% to 34%. There was substantial, highly statistically significant, heterogeneity between studies which was not materially explained by the covariates we were able to consider. The average of the reported prevalences was 12% (95% CI 10-15), with a 95% prediction interval of 4-32%. The remaining 29 studies, of a variety of specific clinical populations, are described. The available evidence suggests a likely prevalence high enough to make it worthwhile screening hospital inpatients for depression and initiating treatment where appropriate. Further, higher quality, research is needed to clarify the prevalence of depression in specific settings and to further explore the reasons for the observed heterogeneity in estimates.


Comparison of response patterns in different survey designs: a longitudinal panel with mixed-mode and online-only design.
Increasing availability of the Internet allows using only online data collection for more epidemiological studies. We compare response patterns in a population-based health survey using two survey designs: mixed-mode (choice between paper-and-pencil and online questionnaires) and online-only design (without choice). We used data from a longitudinal panel, the Hygiene and Behaviour Infectious Diseases Study (HaBIDS), conducted in 2014/2015 in four regions in Lower Saxony, Germany. Individuals were recruited using address-based probability sampling. In two regions, individuals could choose between paper-and-pencil and online questionnaires. In the other two regions, individuals were offered online-only participation. We compared sociodemographic characteristics of respondents who filled in all panel questionnaires between the mixed-mode group (n = 1110) and the online-only group (n = 482). Using 134 items, we performed multinomial logistic regression to compare responses between survey designs in terms of type (missing, "do not know" or valid response) and ordinal regression to compare responses in terms of content. We applied the false discovery rates (FDR) to control for multiple testing and investigated effects of adjusting for sociodemographic characteristic. For validation of the differential response patterns between mixed-mode and online-only, we compared the response patterns between paper and online mode among the respondents in the mixed-mode group in one region (n = 786). Respondents in the online-only group were older than those in the mixed-mode group, but both groups did not differ regarding sex or education. Type of response did not differ between the online-only and the mixed-mode group. Survey design was associated with different content of response in 18 of the 134 investigated items; which decreased to 11 after adjusting for sociodemographic variables. In the validation within the mixed-mode, only two of those were among the 11 significantly different items. The probability of observing by chance the same two or more significant differences in this setting was 22%. We found similar response patterns in both survey designs with only few items being answered differently, likely attributable to chance. Our study supports the equivalence of the compared survey designs and suggests that, in the studied setting, using online-only design does not cause strong distortion of the results.


A new protocol for removal of the endothelium from the perfused rat hind-limb preparation.
A new protocol has been developed for selective removal of the endothelium from the arteries of the perfused rat hind-limb preparation. The hind limb was perfused with oxygenated Krebs-Ringer bicarbonate solution with a combination of high flow and timed air bubbles (2 minutes at high flow followed by 5 minutes of air bubbles, followed by a further 2 minutes at high flow). Representative vessels at different diameters of the arterial tree--the femoral artery, the artery supplying the extensor hallucis proprius muscle, and the arteries, arterioles, and capillaries within the hallucis proprius muscle--were taken for examination by transmission and scanning electron microscopy. A graded degree of damage occurred along the length of the hind-limb vasculature, with endothelial cells having been completely removed from the femoral artery, removed from or severely damaged in the artery supplying the hallucis proprius muscle, and partially damaged in arteries within the hallucis proprius muscle. However, no damage occurred to the endothelial cells of the arterioles and capillaries within the hallucis proprius muscle. The integrity of the vascular bed after endothelial removal according to the above protocol was confirmed by the demonstration of no diminution, but in fact an increase, in contractile responses to bolus injections of alpha,beta-methylene ATP, resulting in a shift to the left of the dose-response curve. The viability was further confirmed by the fact that the conductance (flow/perfusion pressure) of the preparation during the periods of high flow was no different before and after removal of the endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)


Cone-beam imaging in dentistry.
Cone-beam imaging has gained broad acceptance in dentistry in the last 5 years. The purpose of this review is to describe the use in dentistry and consider issues requiring further development. Cone-beam machines emit an x-ray beam shaped liked a cone rather than a fan as in conventional computed tomography (CT) machines. After this beam passes through the patient the remnant beam is captured on an amorphous silicon flat panel or image intensifier/charge-coupled device (CCD) detector. The beam diameter ranges from 4 to 30 cm and exposes the head in one pass around the patient capturing from 160 to 599 basis images. These images are used to compute a volume from which planar or curved reconstructions can be extracted in any orientation. Voxels are isotropic and can be as small as 0.125 mm. 3-D images of bone or soft tissue surfaces can also be generated. In dentistry the most common indications for cone-beam imaging are assessment of the jaws for placement of dental implants, evaluation of the temporomandibular joints for osseous degenerative changes, examination of teeth and facial structures for orthodontic treatment planning, evaluation of the proximity of lower wisdom teeth to the mandibular nerve prior to extraction, and evaluation of teeth and bone for signs of infections, cysts, or tumors. Cone-beam images have largely replaced conventional tomography for these tasks. The effective dose from cone-beam imaging ranges from 6 to 477 microSv. The cost of the equipment is relatively low, about $150,000 to $300,000. Issues to be considered are the training of individuals making and interpreting cone-beam images, as well as means to further reduce patient exposure.


Pulmonary toxicity study in rats with three forms of ultrafine-TiO2 particles: differential responses related to surface properties.
Surface properties are critical to assess effects of ultrafine-TiO(2) particles. The aim of this study was to assess lung toxicity in rats of newly developed, well characterized, ultrafine-TiO(2) particles and compare them to TiO(2) samples in two different size ranges and surface modifications. Groups of rats were intratracheally instilled with doses of 1 or 5mg/kg of either two ultrafine rutile TiO(2) particles (uf-1 or uf-2); rutile R-100 fine-TiO(2) (F-1); 80/20 anatase/rutile P25 ultrafine-TiO(2) (uf-3); or alpha-quartz particles. Phosphate-buffered saline (PBS) solution instilled rats served as vehicle controls. Following exposures, the lungs of PBS and particle-exposed rats were evaluated for bronchoalveolar lavage (BAL) fluid inflammatory markers, cell proliferation, and by histopathology at post-instillation time points of 24h, 1 week, 1 and 3 months. The ranking of lung inflammation/cytotoxicity/cell proliferation and histopathological responses was quartz>uf-3>F-1=uf-1=uf-2. Exposures to quartz and to a lesser degree, uf-3 anatase/rutile TiO(2) particles produced pulmonary inflammation, cytotoxicity and adverse lung tissue effects. In contrast, exposures to F-1 fine-TiO(2) particles or to uf-1/uf-2 ultrafine-TiO(2) particle-types produced transient inflammation. We conclude that differences in responses to anatase/rutile uf-3 TiO(2) particles versus the rutile uf-1 and uf-2 TiO(2) particles could be related to crystal structure, inherent pH of the particles, or surface chemical reactivity. Thus, based on these results, inhaled rutile ultrafine-TiO(2) particles are expected to have a low risk potential for producing adverse pulmonary health effects. Finally, the results demonstrate that exposures to ultrafine-TiO(2) particle-types can produce differential pulmonary effects, based upon their composition, and crystal structure. Thus, the lung toxicity of anatase/rutile uf-3 should not be viewed as representative for all ultrafine-TiO(2) particle-types.


Complex PTSD and phased treatment in refugees: a debate piece.
Asylum seekers and refugees have been claimed to be at increased risk of developing complex posttraumatic stress disorder (complex PTSD). Consequently, it has been recommended that refugees be treated with present-centred or phased treatment rather than stand-alone trauma-focused treatment. This recommendation has contributed to a clinical practice of delaying or waiving trauma-focused treatment in refugees with PTSD. The aim of this debate piece is to defend two theses: (1) that complex trauma leads to complex PTSD in a minority of refugees only and (2) that trauma-focused treatment should be offered to all refugees who seek treatment for PTSD. The first thesis is defended by comparing data on the prevalence of complex PTSD in refugees to those in other trauma-exposed populations, using studies derived from a systematic review. The second thesis is defended using conclusions of systematic reviews and a meta-analysis of the efficacy of psychotherapeutic treatment in refugees. Research shows that refugees are more likely to meet a regular PTSD diagnosis or no diagnosis than a complex PTSD diagnosis and that prevalence of complex PTSD in refugees is relatively low compared to that in survivors of childhood trauma. Effect sizes for trauma-focused treatment in refugees, especially narrative exposure therapy (NET) and culturally adapted cognitive-behaviour therapy (CA-CBT), have consistently been found to be high. Complex PTSD in refugees should not be assumed to be present on the basis of complex traumatic experiences but should be carefully diagnosed using a validated interview. In line with treatment guidelines for PTSD, a course of trauma-focused treatment should be offered to all refugees seeking treatment for PTSD, including asylum seekers.


Region-specific Wnt signaling responses promote gastric polyp formation in familial adenomatous polyposis patients.
Germline APC mutation in familial adenomatous polyposis (FAP) patients promotes gastrointestinal polyposis, including the formation of frequent gastric fundic gland polyps (FGPs). In this study, we investigated how dysregulated Wnt signaling promotes FGPs and why they localize to the corpus region of the stomach. We developed a biobank of FGP and surrounding non-polyp corpus biopsies and organoids from FAP patients for comparative studies. Polyp biopsies and polyp-derived organoids exhibited enhanced Wnt target gene expression. Polyp-derived organoids with intrinsically upregulated Wnt signaling showed poor tolerance to further induction, suggesting that high Wnt restricts growth. Targeted genomic sequencing revealed that most gastric polyps did not arise via APC loss-of-heterozygosity. Studies in genetic mouse models demonstrated that heterozygous Apc loss increased epithelial cell proliferation in the corpus but not the antrum, while homozygous Apc loss was not maintained in the corpus yet induced hyperproliferation in antrum. Our findings suggest that heterozygous APC mutation in FAP patients may be sufficient to drive polyp formation in the corpus region while subsequent loss-of-heterozygosity to further enhance Wnt signaling is not tolerated. This finding contextualizes the abundant yet benign nature of gastric polyps in FAP patient corpus compared to the rare, yet adenomatous polyps in the antrum.


Anthropogenic-induced acceleration of elemental burial rates in blue carbon repositories of the Arabian Gulf.
Along the past century, the Arabian Gulf has experienced a continuous and fast coastal development leading to increase the human pressures on the marine environment. The present study attempts to describe the historical changes of trace elements in the sediments of vegetated coastal habitats in the western Arabian Gulf. 210Pb-dated sediment cores collected from seagrass, mangrove and saltmarsh habitats were analyzed to evaluate historical variations in concentrations and burial rates of 20 trace elements (Al, As, Ba, Ca, Co, Cr, Cu, Fe, Hg, K, Mg, Mn, Na, Ni, P, Pb, S, Sr, V and Zn). The highest correlations (Spearman correlation coefficients ≥0.51) were found between crustal elements (Al, Fe, Co, Cr, K, Na, Mg, Mn, Ni, V, and P), suggesting a common crustal source in the Gulf. The increased concentrations of these crustal elements in modern marine sediments of the Arabian Gulf seem to be linked to increased mineral dust deposition in the area. Over the last century, both elemental concentrations and burial rates increased by factors of 1-9 and 1-15, respectively, with a remarkably fast increase occurring in the past six decades (~1960 - early 2000). This is most likely due to an increase in anthropogenic pressures along the Gulf coast. Our study demonstrates that sediments in vegetated coastal habitats provide long-term archives of trace elements concentrations and burial rates reflecting human activities in the Arabian Gulf.


Ontogenetic variation in the chemical defenses of cane toads (Bufo marinus): toxin profiles and effects on predators.
We conducted a quantitative and qualitative chemical analysis of cane toad bufadienolides--the cardioactive steroids that are believed to be the principal cane toad toxins. We found complex shifts in toxin composition through toad ontogeny: (1) eggs contain at least 28 dominant bufadienolides, 17 of which are not detected in any other ontogenetic stage; (2) tadpoles present a simpler chemical profile with two to eight dominant bufadienolides; and (3) toxin diversity decreases during tadpole life but increases again after metamorphosis (larger metamorph/juvenile toads display five major bufadienolides). Total bufadienolide concentrations are highest in eggs (2.64 +/- 0.56 micromol/mg), decreasing during tadpole life stages (0.084 +/- 0.060 micromol/mg) before rising again after metamorphosis (2.35 +/- 0.45 micromol/mg). These variations in total bufadienolide levels correlate with toxicity to Australian frog species. For example, consumption of cane toad eggs killed tadpoles of two Australian frog species (Limnodynastes convexiusculus and Litoria rothii), whereas no tadpoles died after consuming late-stage cane toad tadpoles or small metamorphs. The high toxicity of toad eggs reflects components in the egg itself, not the surrounding jelly coat. Our results suggest a dramatic ontogenetic shift in the danger that toads pose to native predators, reflecting rapid changes in the types and amounts of toxins during toad development.


Osr2, a new mouse gene related to Drosophila odd-skipped, exhibits dynamic expression patterns during craniofacial, limb, and kidney development.
We have isolated a new mouse gene, odd-skipped related 2 (Osr2), that encodes a zinc finger containing protein related to Drosophila Odd-skipped. The putative OSR2 protein shares 65% amino acid sequence identity overall and 98% sequence identity in the zinc finger region, respectively, with the previously reported Osr1 gene product. During mouse embryonic development, Osr2 expression is first detected at E9.25, specifically in the mesonephric vesicles. By E10.0, Osr2 expression is also observed in the rostro-lateral mandibular mesenchyme immediately adjacent to the maxillary processes. In the developing limb buds, Osr2 is expressed in a unique mesenchymal domain and the onset of Osr2 expression follows a distinct dorsal to ventral developmental time sequence beginning in the forelimb and then in the hindlimb. Osr2 exhibits a dynamic expression pattern during craniofacial development, in the mandibular and maxillary processes as well as the developing palate. Osr2 is also expressed at sites of epithelial-mesenchymal interactions during tooth and kidney development.


Plasma elimination and urinary excretion of methapyrilene in the rat.
The metabolism and elimination of methapyrilene (2-[(2-dimethylaminoethyl)-2-thenylamino]pyridine) were characterized after the iv administration of 0.7 mg/kg or 3.5 mg/kg methapyrilene HCl plus [14C]methapyrilene HCl to adult male Fischer-344 rats. Approximately 40% and 35% of the administered dose was excreted in the urine in the first 24 hr in the low and high dose groups, respectively, as determined by liquid scintillation spectrophotometry. Fecal excretion accounted for 38% and 44% of the administered dose in the first 24 hr in the low and high dose groups, respectively, as confirmed via combustion analysis. The 24-hr urinary metabolic products consisted of one major and five minor radiolabeled compounds. The major metabolite was isolated with reversed-phase HPLC and identified as methapyrilene N-oxide. This was accomplished by comparison of the chromatographic and mass spectral characteristics of this metabolite with that of authentic methapyrilene N-oxide. Methapyrilene and mono-N-desmethyl methapyrilene also were identified after isolation with reversed-phase HPLC and comparison of their mass spectral and/or chromatographic properties with those of authentic compounds. The plasma metabolic profile was essentially the same as the urinary profile. The elimination of methapyrilene from plasma occurred through a first-order process. The terminal plasma elimination t1/2 of methapyrilene did not increase with increasing doses (2.75 hr, 0.7 mg/kg; 2.81 hr, 3.5 mg/kg); thus, methapyrilene does not exhibit dose-dependent elimination over this 5-fold dose range.


A novel explanation for the enhanced colloidal stability of silver nanoparticles in the presence of an oppositely charged surfactant.
The structural behavior in aqueous mixtures of negatively charged silver nanoparticles (Ag NPs) together with the cationic surfactants cetyltrimethylammonium bromide (CTAB) and dodecyltrimethylammonium chloride (DTAC), respectively, has been investigated using SANS and SAXS. From our SANS data analysis we are able to conclude that the surfactants self-assemble into micellar clusters surrounding the Ag NPs. We are able to quantify our results by means of fitting experimental SANS data with a model based on cluster formation of micelles with very good agreement. Based on our experimental results, we propose a novel mechanism for the stabilization of negatively charged Ag NPs in a solution of positively charged surfactants in which cluster formation of micelles in the vicinity of the particles prevents the particles from aggregating. Complementary SAXS and DLS measurements further support this novel way of explaining stabilization of small hydrophilic nanoparticles in surfactant-containing solutions.


Guidelines for Cervical Cancer Screening in Immunosuppressed Women Without HIV Infection.
The risk of cervical cancer (CC) among women immunosuppressed for a variety of reasons is well documented in the literature. Although there is improved organ function, quality of life and life expectancy gained through use of immunosuppressant therapy, there may be increased long-term risk of cervical neoplasia and cancer and the need for more intense screening, surveillance, and management. Although guidance for CC screening among HIV-infected women (see Table 1) has been supported by evidence from retrospective and prospective studies, recommendations for CC screening among non-HIV immunosuppressed women remains limited because quality evidence is lacking. Moreover, CC screening guidelines for HIV-infected women have changed because better treatments evolved and resulted in longer life expectancy.The objective of this report was to summarize current knowledge of CC, squamous intraepithelial lesions, and human papillomavirus (HPV) infection in non-HIV immunocompromised women to determine best practices for CC surveillance in this population and provide recommendations for screening. We evaluated those with solid organ transplant, hematopoietic stem cell transplant, and a number of autoimmune diseases.A panel of health care professionals involved in CC research and care was assembled to review and discuss existing literature on the subject and come to conclusions about screening based on available evidence and expert opinion. Literature searches were performed using key words such as CC, cervical dysplasia/squamous intraepithelial lesion, HPV, and type of immunosuppression resulting in an initial group of 346 articles. Additional publications were identified from review of citations in these articles. All generated abstracts were reviewed to identify relevant articles. Articles published within 10 years were considered priority for review. Reviews of the literature were summarized with relevant statistical comparisons. Recommendations for screening generated from each group were largely based on expert opinion. Adherence to screening, health benefits and risks, and available clinical expertise were all considered in formulating the recommendations to the degree that information was available. Solid Organ Transplant: Evidence specific for renal, heart/lung, liver, and pancreas transplants show a consistent increase in risk of cervical neoplasia and invasive CC, demonstrating the importance of long-term surveillance and treatment. Reports demonstrate continued risk long after transplantation, emphasizing the need for screening throughout a woman's lifetime.Hematopoietic Stem Cell Transplant: Although there is some evidence for an increase in CC in large cohort studies of these patients, conflicting results may reflect that many patients did not survive long enough to evaluate the incidence of slow-growing or delayed-onset cancers. Furthermore, history of cervical screening or previous hysterectomy was not included in registry study analysis, possibly leading to underestimation of CC incidence rates.Genital or chronic graft versus host disease is associated with an increase in high-grade cervical neoplasia and posttransplant HPV positivity.Inflammatory Bowel Disease: There is no strong evidence to support that inflammatory bowel disease alone increases cervical neoplasia or cancer risk. In contrast, immunosuppressant therapy does seem to increase the risk, although results of observational studies are conflicting regarding which type of immunosuppressant medication increases risk. Moreover, misclassification of cases may underestimate CC risk in this population. Recently published preventive care guidelines for women with inflammatory bowel disease taking immunosuppressive therapy recommend a need for continued long-term CC screening.Systemic Lupus Erythematosus and Rheumatoid Arthritis: The risk of cervical high-grade neoplasia and cancer was higher among women with systemic lupus erythematosus than those with rheumatoid arthritis (RA), although studies were limited by size, inclusion of women with low-grade neoplasia in main outcomes, and variability of disease severity or exposure to immunosuppressants. In studies designed to look specifically at immunosuppressant use, however, there did seem to be an increase in risk, identified mostly in women with RA. Although the strength of the evidence is limited, the increase in risk is consistent across studies.Type 1 DM: There is a paucity of evidence-based reports associating type 1 DM with an increased risk of cervical neoplasia and cancer. The panel proposed that CC screening guidelines for non-HIV immunocompromised women follow either the (1) guidelines for the general population or (2) current center for disease control guidelines for HIV-infected women. The following are the summaries for each group reviewed, and more details are noted in accompanying table:Solid Organ Transplant: The transplant population reflects a greater risk of CC than the general population and guidelines for HIV-infected women are a reasonable approach for screening and surveillance.Hematopoietic Stem Cell Transplant: These women have a greater risk of CC than the general population and guidelines for HIV-infected women are a reasonable approach for screening. A new diagnosis of genital or chronic graft versus host disease in a woman post-stem cell transplant results in a greater risk of CC than in the general population and should result in more intensive screening and surveillance.Inflammatory Bowel Disease: Women with inflammatory bowel disease being treated with immunosuppressive drugs are at greater risk of cervical neoplasia and cancer than the general population and guidelines for HIV-infected women are a reasonable approach for screening and surveillance. Those women with inflammatory bowel disease not on immunosuppressive therapy are not at an increased risk and should follow screening guidelines for the general population.Systemic Lupus Erythematosus and Rheumatoid Arthritis: All women with systemic lupus erythematosus, whether on immunosuppressant therapy or not and those women with RA on immunosuppressant therapy have a greater risk of cervical neoplasia and cancer than the general population and should follow CC screening guidelines for HIV-infected women. Women with RA not on immunosuppressant therapy should follow CC screening guidelines for the general population.Type 1 Diabetes Mellitus: Because of a lack of evidence of increased risk of cervical neoplasia and cancer among women with type 1 DM, these women should follow the screening guidelines for the general population.


Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease.
Genome-wide association studies have identified a number of susceptibility loci in sporadic Parkinson's disease (PD). Recent larger studies and meta-analyses have greatly expanded the list of proposed association signals. We performed a case-control replication study in a Scandinavian population, analyzing samples from 1345 unrelated PD patients and 1225 control subjects collected by collaborating centers in Norway and Sweden. Single-nucleotide polymorphisms representing 18 loci previously reported at genome-wide significance levels were genotyped, as well as 4 near-significant, suggestive, loci. We replicated 11 association signals at p < 0.05 (SNCA, STK39, MAPT, GPNMB, CCDC62/HIP1R, SYT11, GAK, STX1B, MCCC1/LAMP3, ACMSD, and FGF20). The more recently nominated susceptibility loci were well represented among our positive findings, including 3 which have not previously been validated in independent studies. Conversely, some of the more well-established loci failed to replicate. While future meta-analyses should corroborate disease associations further on the level of common markers, efforts to pinpoint functional variants and understand the biological implications of each risk locus in PD are also warranted.


GP attitudes to early diagnosis of dementia: evidence of improvement.
This paper offers a comparative analysis of GPs attitudes towards early diagnosis of dementia in 1997 and 2001. It draws on data from two studies conducted in the same area using the same research instrument. Overall, findings reveal a significantly greater commitment to early diagnosis at Time 2 than at Time 1. More GPs hold positive attitudes and consider early diagnosis to facilitate a number of practical and therapeutic benefits for users and carers. Further, fewer GPs regard early diagnosis as having negative consequences. Findings also support existing evidence about attitudes being underpinned by drivers and barriers. Those GPs who are committed regard it as an opportunity to offer preventive treatment and plan for the future; barriers include limited treatment options. Primary reasons for the attitudinal shift are greater accessibility of psychiatric colleagues, additional investment in support services, and enhanced policy and clinical emphasis on the value of early diagnosis.


Beta blocker specificity: a building block toward personalized medicine.
Drugs known as beta blockers, which antagonize the beta-adrenergic receptor (beta-AR), are an important component of the treatment regimen for chronic heart failure (HF). However, a significant body of evidence indicates that genetic heterogeneity at the level of the beta(1)-AR may be a factor in explaining the variable responses of HF patients to beta blockade. In this issue of the JCI, Rochais et al. describe how a single amino acid change in beta(1)-AR alters its structural conformation and improves its functional response to carvedilol, a beta blocker currently used in the treatment of HF (see the related article beginning on page 229). This may explain why some HF patients have better responses not only to carvedilol but to certain other beta blockers as well. The data greatly enhance our mechanistic understanding of myocardial adrenergic signaling and support the development of "tailored" or "personalized" medicine, in which specific therapies could be prescribed based on a patient's genotype.


Intergenic Splicing between Four Adjacent UGT Genes (2B15, 2B29P2, 2B17, 2B29P1) Gives Rise to Variant UGT Proteins That Inhibit Glucuronidation via Protein-Protein Interactions.
Recent studies have investigated alternative splicing profiles of UDP-glucuronosyltransferase (UGT) genes and identified over 130 different alternatively spliced UGT transcripts. Although UGT genes are highly clustered, the formation of chimeric transcripts by intergenic splicing between two or more UGT genes has not yet been reported. This study identified 12 chimeric transcripts (chimeras A-L) containing exons from two or three genes of the four neighboring UGT genes (UGT2B15, UGT2B29P2, UGT2B17, and UGT2B29P1) in human liver and prostate cancer cells. These chimeras typically contain the first five exons of UGT2B15 or UGT2B17 (exons 1-5) spliced to a terminal exon (exon 6) from a downstream UGT gene. Hence they encode truncated UGTs with novel C-terminal peptides. Functional assays of representative chimeric UGT proteins (termed chimeric UGT2B15 and chimeric UGT2B17) showed that they are inactive and can repress the activity of wild-type UGTs. Coimmunoprecipitation assays demonstrated heterotypic interactions between chimeric UGT2B15 (or chimeric UGT2B17) and the UGT2B7 protein. Thus oligomerization of the chimeric UGTs with wild-type UGTs may explain their inhibitory activity. Studies in breast and prostate cancer cells showed that both wild-type and chimeric UGT2B15 and UGT2B17 transcripts are regulated in a similar way at the transcriptional level by sex hormones through their canonical promoters but are differentially regulated at the post-transcriptional level by micro-RNA 376c via their unique 3'-untranslated regions. In conclusion, the formation of chimeric transcripts by intergenic splicing among UGT genes represents a novel mechanism contributing to the diversity of the human UGT transcriptome and proteome. The differential post-transcriptional regulation of wild-type and variant transcripts by micro-RNAs may contribute to their deregulated expression in cancer.


Roles of bioactive sphingolipid metabolites in ovarian cancer cell biomechanics.
Bioactive sphingolipid metabolites have emerged as important lipid second messengers in the regulation of cell growth, death, motility and many other events. These processes are important in cancer development and progression; thus, sphingolipid metabolites have been implicated in both cancer development and cancer prevention. Despite recent considerable progress in understanding the multi-faceted functions of these bioactive metabolites, little is known about their influence on the biomechanical property of cells. The biomechanical properties of cancer cells change during progression with aggressive and invasive cells being softer compared to their benign counterparts. In this paper, we investigated the effects of exogenous sphingolipid metabolites on the Young's modulus and cytoskeletal organization of cells representing aggressive ovarian cancer. Our findings demonstrate that the elasticity of aggressive ovarian cancer cells decreased ∼15% after treatment with ceramide and sphingosine-1-phosphate. In contrast, sphingosine treatment caused a ∼30% increase in the average elasticity which was associated with a more defined actin cytoskeleton organization. This indicates that sphingolipid metabolites differentially modulate the biomechanic properties of cancer cells which may have a critical impact on cancer cell survival and progression, and the use of sphingolipid metabolites as chemopreventive or chemo-therapeutic agents.


Compartmentalisation and localisation of the translation initiation factor (eIF) 4F complex in normally growing fibroblasts.
Previous observations of association of mRNAs and ribosomes with subcellular structures highlight the importance of localised translation. However, little is known regarding associations between eukaryotic translation initiation factors and cellular structures within the cytoplasm of normally growing cells. We have used detergent-based cellular fractionation coupled with immunofluorescence microscopy to investigate the subcellular localisation in NIH3T3 fibroblasts of the initiation factors involved in recruitment of mRNA for translation, focussing on eIF4E, the mRNA cap-binding protein, the scaffold protein eIF4GI and poly(A) binding protein (PABP). We find that these proteins exist mainly in a soluble cytosolic pool, with only a subfraction tightly associated with cellular structures. However, this "associated" fraction was enriched in active "eIF4F" complexes (eIF4E.eIF4G.eIF4A.PABP). Immunofluorescence analysis reveals both a diffuse and a perinuclear distribution of eIF4G, with the perinuclear staining pattern similar to that of the endoplasmic reticulum. eIF4E also shows both a diffuse staining pattern and a tighter perinuclear stain, partly coincident with vimentin intermediate filaments. All three proteins localise to the lamellipodia of migrating cells in close proximity to ribosomes, microtubules, microfilaments and focal adhesions, with eIF4G and eIF4E at the periphery showing a similar staining pattern to the focal adhesion protein vinculin.


Pathways to inflated responsibility beliefs in adolescent obsessive-compulsive disorder: a preliminary investigation.
An inflated sense of responsibility is characteristic of obsessive-compulsive disorder (OCD). No previous studies have investigated its origins. Five potential pathways to inflated responsibility beliefs have been proposed; these are tested in this study. A novel measure, the Origins Questionnaire for Adolescents (OQA), was developed to assess experiences on these five pathways. Reliability of the OQA was investigated. The experiences on the five pathways to inflated responsibility beliefs of 16 adolescents with a history of OCD were compared to 16 adolescents with no history of OCD. Parents also reported on adolescents' experiences on the five pathways. Test-retest reliability was high. The internal consistency of the subscales was only partly satisfactory. The groups differed on one pathway; the clinical group reported a higher sense of responsibility for significant incidents with a negative outcome prior to onset of OCD. An inflated sense of responsibility, in combination with the occurrence of specific incidents, might act as a vulnerability factor for development of OCD. Future research should consider how to measure the subtle effects of experiences of responsibility over the course of development.


Defects in thalamocortical axon pathfinding correlate with altered cell domains in Mash-1-deficient mice.
We have analyzed the pathfinding of thalamocortical axons (TCAs) from dorsal thalamus to neocortex in relation to specific cell domains in the forebrain of wild-type and Mash-1-deficient mice. In wild-type mice, we identified four cell domains that constitute the proximal part of the TCA pathway. These domains are distinguished by patterns of gene expression and by the presence of neurons retrogradely labeled from dorsal thalamus. Since the cells that form these domains are generated in forebrain proliferative zones that express high levels of Mash-1, we studied Mash-1 mutant mice to assess the potential roles of these domains in TCA pathfinding. In null mutants, each of the domains is altered: the two Pax-6 domains, one in ventral thalamus and one in hypothalamus, are expanded in size; a complementary RPTP(delta) domain in ventral thalamus is correspondingly reduced and the normally graded expression of RPTP(delta) in that domain is no longer apparent. In ventral telencephalon, a domain characterized in the wild type by Netrin-1 and Nkx-2.1 expression and by retrogradely labeled neurons is absent in the mutant. Defects in TCA pathfinding are localized to the borders of each of these altered domains. Many TCAs fail to enter the expanded, ventral thalamic Pax-6 domain that constitutes the most proximal part of the TCA pathway, and form a dense whorl at the border between dorsal and ventral thalamus. A proportion of TCAs do extend further distally into ventral thalamus, but many of these stall at an aberrant, abrupt border of high RPTP(delta) expression. A small proportion of TCAs extend around the RPTP(delta) domain and reach the ventral thalamic-hypothalamic border, but few of these axons turn at that border to extend into the ventral telencephalon. These findings demonstrate that Mash-1 is required for the normal development of cell domains that in turn are required for normal TCA pathfinding. In addition, these findings support the hypothesis that ventral telencephalic neurons and their axons guide TCAs through ventral thalamus and into ventral telencephalon.


The hydatidiform mole.
The hydatidiform mole (HM) is a placental pathology of androgenetic origin. Placental villi have an abnormal hyperproliferation event and hydropic degeneration. Three situations can be envisaged at its origin: 1. The destruction/expulsion of the female pronucleus at the time of fertilization by 1 or 2 spermatozoa with the former being followed by an endoreplication of the male pronucleus leading to a complete hydatidiform mole (CHM) 2. A triploid zygote (fertilization by 2 spermatozoa) leading to a partial hydatidiform mole (PHM) but can also lead to haploid and diploid clones. The diploid clone may produce a normal fetus while the haploid clone after endoreplication generates a CHM 3. A nutritional defect during the differentiation of the oocytes or the deterioration of the limited oxygen pressure during the first trimester of gestation may lead to the formation of a HM. In countries with poor medical health care system, moles (mainly the CHM) can become invasive or, in rare cases, lead to gestational choriocarcinomas.


Gaussian beam photothermal single particle microscopy.
We explore the intuitive lensing picture of laser-heated nanoparticles occurring in single particle photothermal (PT) microscopy. The effective focal length of the thermal lens (TL) is derived from a ray-optics treatment and used to transform the probing focused Gaussian beam with ABCD Gaussian matrix optics. The relative PT signal is obtained from the relative beam-waist change far from the TL. The analytical expression is semiquantitative, capable of describing the entire phenomenology of single particle PT microscopy, and shows that the signal is the product of the point-spread functions of the involved lasers times a linear function of the axial coordinate. The presented particularly simple and intuitive Gaussian beam lensing picture compares favorably to the experimental results for 60 nm gold nanoparticles and provides the prescription for optimum setup calibration.


Cacodemonomania.
The experience of having had intercourse with the devil has in the past been regarded as evidence that the individual is a witch. Those investigating cases of witchcraft were advised to seek the judgment of doctors, and the verdict of physicians became a test for the presence or absence of witchcraft. The woman described in this case study might well have suffered the death penalty in former times. She is unusual because of her belief that she had had intercourse with the Devil, and because the belief was shared by her religious minister. The patient also presents a diagnostic problem.


Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states.
Familial multiple endocrine neoplasia type 1 (FMEN1) is an autosomal dominant trait characterized by tumors of the parathyroids, gastro-intestinal endocrine tissue, anterior pituitary and other tissues. We recently cloned the MEN1 gene and confirmed its identity by finding mutations in FMEN1. We have now extended our mutation analysis to 34 more unrelated FMEN1 probands and to two related states, sporadic MEN1 and familial hyperparathyroidism. There was a high prevalence of heterozygous germline MEN1 mutations in sporadic MEN1 (8/11 cases) and in FMEN1 (47/50 probands). One case of sporadic MEN1 was proven to be a new MEN1 mutation. Eight different mutations were observed more than once in FMEN1. Forty different mutations (32 FMEN1 and eight sporadic MEN1) were distributed across the MEN1 gene. Most predicted loss of function of the encoded menin protein, supporting the prediction that MEN1 is a tumor suppressor gene. No MEN1 germline mutation was found in five probands with familial hyperparathyroidism, suggesting that familial hyperparathyroidism often is caused by mutation in another gene or gene(s).


Exposure to hycanthone alters chromatin structure around specific gene functions and specific repeats in Schistosoma mansoni.
Schistosoma mansoni is a parasitic plathyhelminth responsible for intestinal schistosomiasis (or bilharzia), a disease affecting 67 million people worldwide and causing an important economic burden. The schistosomicides hycanthone, and its later proxy oxamniquine, were widely used for treatments in endemic areas during the twentieth century. Recently, the mechanism of action, as well as the genetic origin of a stably and Mendelian inherited resistance for both drugs was elucidated in two strains. However, several observations suggested early on that alternative mechanisms might exist, by which resistance could be induced for these two drugs in sensitive lines of schistosomes. This induced resistance appeared rapidly, within the first generation, but was metastable (not stably inherited). Epigenetic inheritance could explain such a phenomenon and we therefore re-analyzed the historical data with our current knowledge of epigenetics. In addition, we performed new experiments such as ChIP-seq on hycanthone treated worms. We found distinct chromatin structure changes between sensitive worms and induced resistant worms from the same strain. No specific pathway was discovered, but genes in which chromatin structure modifications were observed are mostly associated with transport and catabolism, which makes sense in the context of the elimination of the drug. Specific differences were observed in the repetitive compartment of the genome. We finally describe what types of experiments are needed to understand the complexity of heritability that can be based on genetic and/or epigenetic mechanisms for drug resistance in schistosomes.


The incidence of and risk factors for venous thromboembolism (VTE) and bleeding among 1514 patients undergoing hematopoietic stem cell transplantation: implications for VTE prevention.
Venous thromboembolism (VTE) is increasingly diagnosed among individuals with hematologic malignancies. However, the risk of VTE among patients undergoing hematopoietic stem cell transplantation (HSCT) is unclear. We examined the incidence and risk factors for VTE and bleeding among 1514 patients undergoing in-patient HSCT. No protocolized VTE prophylaxis was used. By HSCT day 180, 75 symptomatic VTE occurred in 70 patients (4.6%; 95% confidence interval [CI], 3.6%-5.8%). Fifty-five (3.6%) were catheter-associated, 11 (0.7%) were non-catheter-associated deep venous thromboses, and 9 (0.6%) were pulmonary emboli. Thirty-four percent of VTE occurred at a platelet count less than 50 x10(9)/L; 13% occurred at a platelet count less than 20 x10(9)/L. In multivariate analysis, VTE was associated with prior VTE (odds ratio [OR], 2.9; 95% CI, 1.3-6.6) and with graft-versus-host disease (GVHD; OR, 2.4; 95% CI, 1.4-4.0). Clinically significant bleeding occurred in 230 patients (15.2%; 95% CI, 13.4%-17.1%); 55 patients (3.6%; 95% CI, 2.7%-4.7%) had fatal bleeding. Bleeding was associated with anticoagulation (OR, 3.1; 95% CI, 1.8-5.5), GVHD (OR, 2.4; 95% CI, 1.8-3.3), and veno-occlusive disease (OR, 2.2; 95% CI, 1.4-3.6). In HSCT patients, VTE is primarily catheter-related and 3-fold less common than clinically significant bleeding. These findings warrant consideration when selecting VTE prophylaxis in HSCT patients.


The gibbon's Achilles tendon revisited: consequences for the evolution of the great apes?
The well-developed Achilles tendon in humans is generally interpreted as an adaptation for mechanical energy storage and reuse during cyclic locomotion. All other extant great apes have a short tendon and long-fibred triceps surae, which is thought to be beneficial for locomotion in a complex arboreal habitat as this morphology enables a large range of motion. Surprisingly, highly arboreal gibbons show a more human-like triceps surae with a long Achilles tendon. Evidence for a spring-like function similar to humans is not conclusive. We revisit and integrate our anatomical and biomechanical data to calculate the energy that can be recovered from the recoiling Achilles tendon during ankle plantar flexion in bipedal gibbons. Only 7.5% of the required external positive work in a stride can come from tendon recoil, yet it is delivered at an instant when the whole-body energy level drops. Consequently, an additional similar amount of mechanical energy must simultaneously dissipate elsewhere in the system. Altogether, this challenges the concept of an energy-saving function in the gibbon's Achilles tendon. Cercopithecids, sister group of the apes, also have a human-like triceps surae. Therefore, a well-developed Achilles tendon, present in the last common 'Cercopithecoidea-Hominoidea' ancestor, seems plausible. If so, the gibbon's anatomy represents an evolutionary relict (no harm-no benefit), and the large Achilles tendon is not the premised key adaptation in humans (although the spring-like function may have further improved during evolution). Moreover, the triceps surae anatomy of extant non-human great apes must be a convergence, related to muscle control and range of motion. This perspective accords with the suggestions put forward in the literature that the last common hominoid ancestor was not necessarily great ape-like, but might have been more similar to the small-bodied catarrhines.


Characterization of Sodium and Potassium Nitrate Contaminated Polyaniline-Poly (Ethylene Oxide) Composites Synthesized via Facile Solution Casting Technique.
Fabrication of composites by developing simple techniques can be an effective way to modify some properties of individual materials. The present study relates to facile synthesis of sodium nitrate (NaNO3) and potassium nitrate (KNO3) contaminated polyaniline (PANI) and poly (ethylene oxide) (PEO) composites without using any additives, plasticizers, or fibers. The physic-chemical and rheological properties of synthesized composites were analyzed. The composites showed enhancement in both storage and loss modules in comparison with the polymer matrices. The dynamic viscosity of the synthesized materials has inverse relation with that of temperature and shear stress. Rheological analysis reveals a continuous drop off in viscosity by increasing shear stress. The flow behavior was affected little by temperature. However, the overall results showed a shear thinning effect suggesting that polymer composites show non-Newtonian behavior. The addition of NaNO3 and KNO3 had a profound effect on shear viscosity of the materials, although the overall shear thinning behavior prevails. The PANI-PEO composite follows, as the first approximation models, both Bingham and modified Bingham models, while the salt contaminated system follows only the Bingham model. Both show shear stress values. The greater values of storage (G') and loss (G″) modulus of composites than PANI-PEO blend suggests excellent elasticity, better stiffness, and good mechanical strength of the composites. Furthermore, the composites were more thermally stable than pure polymers.


Dietary glycemic load and glycemic index and risk of cerebrovascular disease in the EPICOR cohort.
Studies on the association of stroke risk to dietary glycemic index (GI) and glycemic load (GL) have produced contrasting results. To investigate the relation of dietary GI and GL to stroke risk in the large EPIC-Italy cohort (EPICOR) recruited from widely dispersed geographic areas of Italy. We studied 44099 participants (13,646 men and 30,453 women) who completed a dietary questionnaire. Multivariable Cox modeling estimated adjusted hazard ratios (HRs) of stroke with 95% confidence intervals (95%CI). Over 11 years of follow-up, 355 stroke cases (195 ischemic and 83 hemorrhagic) were identified. Increasing carbohydrate intake was associated with increasing stroke risk (HR = 2.01, 95%CI = 1.04-3.86 highest vs. lowest quintile; p for trend 0.025). Increasing carbohydrate intake from high-GI foods was also significantly associated with increasing stroke risk (HR 1.87, 95%CI = 1.16-3.02 highest vs. lowest, p trend 0.008), while increasing carbohydrate intake from low-GI foods was not. Increasing GL was associated with significantly increasing stroke risk (HR 2.21, 95%CI = 1.16-4.20, highest vs. lowest; p trend 0.015). Dietary carbohydrate from high GI foods was associated with increased both ischemic stroke risk (highest vs. lowest HR 1.92, 95%CI = 1.01-3.66) and hemorrhagic stroke risk (highest vs. lowest HR 3.14, 95%CI = 1.09-9.04). GL was associated with increased both ischemic and hemorrhagic stroke risk (HR 1.44, 95%CI = 1.09-1.92 and HR 1.56, 95%CI = 1.01-2.41 respectively, continuous variable). In this Italian cohort, high dietary GL and carbohydrate from high GI foods consumption increase overall risk of stroke.


Occurrence of epileptiform discharges and sleep during EEG recordings in children after melatonin intake versus sleep-deprivation.
To determine if melatonin is equally efficient as partial sleep deprivation in inducing sleep without interfering with epileptiform discharges in EEG recordings in children 1-16 years old. We retrospectively analysed 129 EEGs recorded after melatonin intake and 113 EEGs recorded after partial sleep deprivation. Comparisons were made concerning occurrence of epileptiform discharges, the number of children who fell asleep and the technical quality of EEG recordings. Comparison between different age groups was also made. No significant differences were found regarding occurrence of epileptiform discharges (33% after melatonin intake, 36% after sleep deprivation), or proportion of unsuccessful EEGs (8% and 10%, respectively). Melatonin and sleep deprivation were equally efficient in inducing sleep (70% in both groups). Significantly more children aged 1-4 years obtained sleep after melatonin intake in comparison to sleep deprivation (82% vs. 58%, p⩽0.01), and in comparison to older children with melatonin induced sleep (58-67%, p⩽0.05). Sleep deprived children 9-12 years old had higher percentage of epileptiform discharges (62%, p⩽0.05) compared to younger sleep deprived children. Melatonin is equally efficient as partial sleep deprivation to induce sleep and does not affect the occurrence of epileptiform discharges in the EEG recording. Sleep deprivation could still be preferable in older children as melatonin probably has less sleep inducing effect. Melatonin induced sleep have advantages, especially in younger children as they fall asleep easier than after sleep deprivation. The procedure is easier for the parents than keeping a young child awake for half the night.


Teaching communication skills to clinical students.
Seven years' experience in teaching communication skills to first year clinical students at St Mary's Hospital School of Medicine is described. The first component consists of a day during the introductory clinical course; this is divided into a lecture and small seminar groups and involves behavioural scientists and clinicians from many departments. The second component uses simulated patients and video feedback and takes place in small groups later in the year. Participation of the students through active critical discussion, role play, and interactive video feedback are important aspects in the success of the course. The methods have been refined through evaluation by students and tutors. This article aims to allow others, already running or considering such a course, to develop effective courses within the practical constraints of their own institutions.


Service delivery and community: social capital, service systems integration, and outcomes among homeless persons with severe mental illness.
This study evaluated the influence of features of community social environment and service system integration on service use, housing, and clinical outcomes among homeless people with serious mental illness. A one-year observational outcome study was conducted of homeless people with serious mental illness at 18 sites. Measures of community social environment (e.g., social capital) were based on local surveys and voting records. Housing affordability was assessed with housing survey data. Service system integration was assessed through interviews with key informants at each site to document interorganizational transactions. Standardized clinical measures were used to assess clinical and housing outcomes in face-to-face interviews. Structural equation modeling was used to determine the relationship between (1) characteristics of the social environment (social capital, housing affordability); (2) the level of integration of the service system for persons who are homeless in each community; (3) access to and use of services by individual clients; and (4) successful exit from homelessness or clinical improvement. Social capital was associated with greater service systems integration, which was associated in turn with greater access to assistance from a public housing agency and to a greater probability of exiting from homelessness at 12 months. Housing affordability also predicted exit from homelessness. Neither environmental factors nor systems integration predicted outcomes for psychiatric problems, substance abuse, employment, physical health, or income support. Community social capital and service system integration are related through a series of direct and indirect pathways with better housing outcomes but not with superior clinical outcomes for homeless people with mental illness. Implications for designing improved service systems are discussed.