The Microbial Community of a Terrestrial Anoxic Inter-Tidal Zone: A Model for Laboratory-Based Studies of Potentially Habitable Ancient Lacustrine Systems on Mars.
Evidence indicates that Gale crater on Mars harboured a fluvio-lacustrine environment that was subjected to physio-chemical variations such as changes in redox conditions and evaporation with salinity changes, over time. Microbial communities from terrestrial environmental analogues sites are important for studying such potential habitability environments on early Mars, especially in laboratory-based simulation experiments. Traditionally, such studies have predominantly focused on microorganisms from extreme terrestrial environments. These are applicable to a range of Martian environments; however, they lack relevance to the lacustrine systems. In this study, we characterise an anoxic inter-tidal zone as a terrestrial analogue for the Gale crater lake system according to its chemical and physical properties, and its microbiological community. The sub-surface inter-tidal environment of the River Dee estuary, United Kingdom (53°21′15.40″ N, 3°10′24.95″ W) was selected and compared with available data from Early Hesperian-time Gale crater, and temperature, redox, and pH were similar. Compared to subsurface 'groundwater'-type fluids invoked for the Gale subsurface, salinity was higher at the River Dee site, which are more comparable to increases in salinity that likely occurred as the Gale crater lake evolved. Similarities in clay abundance indicated similar access to, specifically, the bio-essential elements Mg, Fe and K. The River Dee microbial community consisted of taxa that were known to have members that could utilise chemolithoautotrophic and chemoorganoheterotrophic metabolism and such a mixed metabolic capability would potentially have been feasible on Mars. Microorganisms isolated from the site were able to grow under environment conditions that, based on mineralogical data, were similar to that of the Gale crater's aqueous environment at Yellowknife Bay. Thus, the results from this study suggest that the microbial community from an anoxic inter-tidal zone is a plausible terrestrial analogue for studying habitability of fluvio-lacustrine systems on early Mars, using laboratory-based simulation experiments.


Decrease in musculoskeletal pain after 4 and 12 months of an aerobic exercise intervention: a worksite RCT among cleaners.
Prevalence of musculoskeletal pain is high in jobs with high physical work demands. An aerobic exercise intervention targeting cardiovascular health was evaluated for its long term side effects on musculoskeletal pain. The objective was to investigate if aerobic exercise affects level of musculoskeletal pain from baseline to 4- and 12-months follow-up. One-hundred-and-sixteen cleaners aged 18-65 years were cluster-randomized. The aerobic exercise group ( n = 57) received worksite aerobic exercise (30 min twice a week) and the reference group ( n = 59) lectures in health promotion. Strata were formed according to closest manager (total 11 strata); clusters were set within strata (total 40 clusters, 20 in each group). Musculoskeletal pain data from eight body regions was collected at baseline and after 4- and 12-months follow-up. The participants stated highest pain in the last month on a scale from 0, stating no pain, up to 10, stating worst possible pain. A repeated-measure 2 × 2 multi-adjusted mixed-models design was applied to compare the between-groups differences in an intention to treat analysis. Participants were entered as a random effect nested in clusters to account for the cluster-based randomization. Clinically significant reductions (>30%, f 2 > 0.25) in the aerobic exercise group, compared to the reference group, in pain intensity in neck, shoulders, arms/wrists were found at 12-months follow-up, and a tendency ( p = 0.07, f 2 = 0.18) to an increase for the knees. At 4-months follow-up the only significant between-group change was an increase in hip pain. This study indicates that aerobic exercise reduces musculoskeletal pain in the upper extremities, but as an unintended side effect may increase pain in the lower extremities. Aerobic exercise interventions among workers standing or walking in the majority of the working hours should tailor exercise to only maintain the positive effect on musculoskeletal pain.


Cancer incidence in an area of radioactive fallout downwind from the Nevada Test Site.
Exposures in southwestern Utah to radioactive fallout (1951 through 1962) from atmospheric nuclear detonations at the Nevada Test Site (NTS) were followed by smaller exposures (1962 through 1979) from venting of underground nuclear detonations. The cancer incidence in a 1951 cohort (4, 125) of Mormon families in southwestern Utah near the NTS was compared with that of all Utah Mormons (1967 through 1975). There were 109 more cases of cancer than expected (288[observed]/179[expected]). Leukemia was most prominent early (1958 through 1966), with 19 cases, five times more than expected (3.6). The excess of leukemia persisted into the later period (1972 through 1980), with 12 cases observed, 3.4 expected. There was an increase in lymphoma. Excess cases of thyroid cancer appeared early and a notable excess appeared later (14/1.7). An excess of breast cancer was noted later (27/14). There were more cancers of the gastrointestinal tract than expected. There was an excess of melanoma (12/4.5), bone cancer (8/0.7), and brain tumors (9/3.9). A subgroup with history of acute fallout effects had a higher cancer incidence. That these cases can be associated with radiation exposures is supported by a comparison between groups of the ratio of cancers of more radiosensitive organs with all other types of cancer.


Mapping of the IgE and IgG4 sequential epitopes of milk allergens with a peptide microarray-based immunoassay.
Peptide microarray analysis is a novel method that can provide useful information on the nature of specific allergies. We sought to determine the specificity and diversity of IgE and IgG4 antibodies binding to sequential epitopes of alpha(s1)-, alpha(s2)-, beta-, and kappa-caseins and beta-lactoglobulin by using a peptide microarray-based immunoassay. A microarray immunoassay was performed with sera from 31 children with IgE-mediated milk allergy (16 with positive oral milk challenge results [ie, the reactive group] and 15 with negative oral milk challenge results [ie, the tolerant group]). A library of peptides, consisting of 20 amino acids (AAs) overlapping by 17 (3-offset), corresponding to the primary sequences of alpha(s1)-, alpha(s2)-, beta-, and kappa-caseins and beta-lactoglobulin was printed on epoxy-coated slides. A region was defined as an epitope if it was statistically associated with reactive groups and recognized by at least 75% of reactive patients. By using this method, a total of 10 epitopes were identified: alpha(s1), AAs 28 to 50, 75% reactive and 26.7% tolerant; alpha(s2), AAs 1 to 20, 75% reactive and 13.3% tolerant; AAs 13 to 32, 75% reactive and 26.7% tolerant; AAs 67 to 86, 75% reactive and 33.3% tolerant; and AAs 181 to 207, 75% reactive and 20% tolerant; beta-casein, AAs 25 to 50, 75% reactive and 33.3% tolerant, AAs 52 to 74, 81.3% reactive and 26.7% tolerant; and AAs 154 to 173, 75% reactive and 33.3% tolerant; beta-lactoglobulin, AAs 58 to 77, 81.3% reactive and 40% tolerant; and kappa-casein, AAs 34 to 53, 87.5% reactive and 40% tolerant. Several regions have been defined as epitopes, which showed differential recognition patterns between reactive and tolerant patients. Further studies are needed to validate the utility of this assay in clinical practice.


Multiple regulatory elements for the glpA operon encoding anaerobic glycerol-3-phosphate dehydrogenase and the glpD operon encoding aerobic glycerol-3-phosphate dehydrogenase in Escherichia coli: further characterization of respiratory control.
In Escherichia coli, sn-glycerol-3-phosphate can be oxidized by two different flavo-dehydrogenases, an anaerobic enzyme encoded by the glpACB operon and an aerobic enzyme encoded by the glpD operon. These two operons belong to the glp regulon specifying the utilization of glycerol, sn-glycerol-3-phosphate, and glycerophosphodiesters. In glpR mutant cells grown under conditions of low catabolite repression, the glpA operon is best expressed anaerobically with fumarate as the exogenous electron acceptor, whereas the glpD operon is best expressed aerobically. Increased anaerobic expression of glpA is dependent on the fnr product, a pleiotropic activator of genes involved in anaerobic respiration. In this study we found that the expression of a glpA1(Oxr) (oxygen-resistant) mutant operon, selected for increased aerobic expression, became less dependent on the FNR protein but more dependent on the cyclic AMP-catabolite gene activator protein complex mediating catabolite repression. Despite the increased aerobic expression of glpA1(Oxr), a twofold aerobic repressibility persisted. Moreover, anaerobic repression by nitrate respiration remained normal. Thus, there seems to exist a redox control apart from the FNR-mediated one. We also showed that the anaerobic repression of the glpD operon was fully relieved by mutations in either arcA (encoding a presumptive DNA recognition protein) or arcB (encoding a presumptive redox sensor protein). The arc system is known to mediate pleiotropic control of genes of aerobic function.


Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant.
Numerous studies of circulating epithelial cells (CECs)have been described in cancer patients, and genetic abnormalities have been well documented. However, with one exception in colorectal cancer, there has been no report of matching the genetic abnormalities in the CECs with the primary tumor. The purpose of this investigation was to determine (a) whether CECs in patients including those with early tumors are aneusomic and (b) whether their aneusomic patterns match those from the primary tumor, indicating common clonality. Thirty-one cancer patients had CECs identified by immunofluorescence staining using a monoclonal anti-cytokeratin antibody. Their CECs were analyzed by enumerator DNA probes for chromosomes 1, 3, 4, 7, 8, 11, or 17 by dual or tricolor fluorescence in situ hybridization. Touch preparations of the primary tumor tissue were available from 17 of 31 patients and hybridized with the same set of probes used to genotype the CECs. The number of CECs from each patient ranged from 1-92 cells/cytospin. CECs showed abnormal copy numbers for at least one of the probes in 25 of 31 patients. Touch preparations from the primary tumors of 13 patients with aneusomic CECs were available. The pattern of aneusomy matched a clone in the primary tumor in 10 patients. We conclude that the vast majority of CECs in breast, kidney, prostate, and colon cancer patients are aneusomic and derived from the primary tumor.


Coacervate whey protein improves inflammatory milieu in mice fed with high-fat diet.
Functional foods with bioactive properties may help in treat obesity, as they can lead to a decreased risks of inflammatory diseases. The aim of this study was to investigate the effects of chitosan coacervate whey protein on the proinflammatory processes in mice fed with high-fat diet. Mice were divided into two groups receiving either a normolipidic or high-fat diet; the animals in each of the two diet groups were given a diet supplement of either coacervate (gavage, 36 mg protein/kg of body weight) or tap water for four weeks [groups: normolipidic diet plus water (C); normolipidic diet and coacervate (CC); high-fat diet and water (H); and high-fat diet and coacervate (HC)]. The high-fat diet promoted inflammation, possibly by decreased adiponectin/sum of adipose tissues ratio and increased phosphorylation of NF-κB p50. In HC we observed a positive correlation between IL-10 and TNF-α in mesenteric adipose tissue, retroperitoneal adipose tissue and liver tissue. We also observed a positive correlation between lipopolisaccharide with IL-10 in the liver tissue. High-fat diet treatment promoted metabolic alterations and inflammation, and chitosan coacervate whey protein modulated inflammatory milieu.


Expectations and beliefs in science communication: Learning from three European gene therapy discussions of the early 1990s.
There is widespread agreement that the potential of gene therapy was oversold in the early 1990s. This study, however, comparing written material from the British, Danish and German gene therapy discourses of the period finds significant differences: Over-optimism was not equally strong everywhere; gene therapy was not universally hyped. Against that background, attention is directed towards another area of variation in the material: different basic assumptions about science and scientists. Exploring such culturally rooted assumptions and beliefs and their possible significance to science communication practices, it is argued that deep beliefs may constitute drivers of hype that are particularly difficult to deal with. To participants in science communication, the discouragement of hype, viewed as a practical-ethical challenge, can be seen as a learning exercise that includes critical attention to internalised beliefs.


Pediatric palliative care for youth with HIV/AIDS: systematic review of the literature.
Improvement in treatment has led to decreased death in youth with human immunodeficiency virus (HIV) in developed countries. Despite this, youth with HIV are still at risk for increased mortality and morbidity compared with their uninfected counterparts. In developing countries, high numbers of youth die from acquired immune deficiency syndrome (AIDS)-related illnesses due to lack of access to consistent antiretroviral treatment. As a result, pediatric palliative care is a relevant topic for those providing care to youth with HIV. A systematic review was conducted to gather information regarding the status of the literature related to pediatric palliative care and medical decision-making for youth with HIV. The relevant literature published between January 2002 and June 2012 was identified through searches conducted using PubMed, CINAHL, Scopus, and PSYCInfo databases and a series of key words. Articles were reviewed by thematic analysis using the pillars of palliative care set out by the National Consensus Project. Twenty-one articles were retained after review and are summarized by theme. In general, few empirically based studies evaluating palliative care and medical decision-making in youth with HIV were identified. Articles identified focused primarily on physical aspects of care, with less attention paid to psychological, social, ethical, and cultural aspects of care. We recommend that future research focuses on broadening the evaluation of pediatric palliative care among youth with HIV by directly evaluating the psychological, social, ethical, and cultural aspects of care and investigating the needs of all involved stakeholders.


Awake vs. anesthetized: layer-specific sensory processing in visual cortex and functional connectivity between cortical areas.
During general anesthesia, global brain activity and behavioral state are profoundly altered. Yet it remains mostly unknown how anesthetics alter sensory processing across cortical layers and modulate functional cortico-cortical connectivity. To address this gap in knowledge of the micro- and mesoscale effects of anesthetics on sensory processing in the cortical microcircuit, we recorded multiunit activity and local field potential in awake and anesthetized ferrets (Mustela putoris furo) during sensory stimulation. To understand how anesthetics alter sensory processing in a primary sensory area and the representation of sensory input in higher-order association areas, we studied the local sensory responses and long-range functional connectivity of primary visual cortex (V1) and prefrontal cortex (PFC). Isoflurane combined with xylazine provided general anesthesia for all anesthetized recordings. We found that anesthetics altered the duration of sensory-evoked responses, disrupted the response dynamics across cortical layers, suppressed both multimodal interactions in V1 and sensory responses in PFC, and reduced functional cortico-cortical connectivity between V1 and PFC. Together, the present findings demonstrate altered sensory responses and impaired functional network connectivity during anesthesia at the level of multiunit activity and local field potential across cortical layers.


Divergent age-dependent peripheral immune transcriptomic profile following traumatic brain injury.
The peripheral immune system is a major regulator of the pathophysiology associated with traumatic brain injury (TBI). While age-at-injury influences recovery from TBI, the differential effects on the peripheral immune response remain unknown. Here, we investigated the effects of TBI on gene expression changes in murine whole blood using RNAseq analysis, gene ontology and network topology-based key driver analysis. Genome-wide comparison of CCI-injured peripheral whole blood showed a significant increase in genes involved in proteolysis and oxidative-reduction processes in juvenile compared to adult. Conversely, a greater number of genes, involved in migration, cytokine-mediated signaling and adhesion, were found reduced in CCI-injured juvenile compared to CCI-injured adult immune cells. Key driver analysis also identified G-protein coupled and novel pattern recognition receptor (PRR), P2RY10, as a central regulator of these genes. Lastly, we found Dectin-1, a c-type lectin PRR to be reduced at the protein level in both naïve neutrophils and on infiltrating immune cells in the CCI-injured juvenile cortex. These findings demonstrate a distinct peripheral inflammatory profile in juvenile mice, which may impact the injury and repair response to brain trauma.


Stem-cell based organ-on-a-chip models for diabetes research.
Diabetes mellitus (DM) ranks among the severest global health concerns of the 21st century. It encompasses a group of chronic disorders characterized by a dysregulated glucose metabolism, which arises as a consequence of progressive autoimmune destruction of pancreatic beta-cells (type 1 DM), or as a result of beta-cell dysfunction combined with systemic insulin resistance (type 2 DM). Human cohort studies have provided evidence of genetic and environmental contributions to DM; yet, these studies are mostly restricted to investigating statistical correlations between DM and certain risk factors. Mechanistic studies, on the other hand, aimed at re-creating the clinical picture of human DM in animal models. A translation to human biology is, however, often inadequate owing to significant differences between animal and human physiology, including the species-specific glucose regulation. Thus, there is an urgent need for the development of advanced human in vitro models with the potential to identify novel treatment options for DM. This review provides an overview of the technological advances in research on DM-relevant stem cells and their integration into microphysiological environments as provided by the organ-on-a-chip technology.


Gastrointestinal symptoms and association with medication use patterns, adherence, treatment satisfaction, quality of life, and resource use in osteoporosis: baseline results of the MUSIC-OS study.
The Medication Use Patterns, Treatment Satisfaction, and Inadequate Control of Osteoporosis Study (MUSIC-OS) is a prospective, observational study of women with osteoporosis in Europe and Canada. At baseline, patients with gastrointestinal symptoms reported lower adherence to osteoporosis treatment, treatment satisfaction, and health-related quality of life, than those without gastrointestinal symptoms. The aim of the study was to examine gastrointestinal (GI) symptoms and the association between GI symptoms and treatment adherence, treatment satisfaction, and health-related quality of life (HRQoL) among osteoporotic women in Europe and Canada. Baseline results are reported here for a prospective study which enrolled postmenopausal, osteoporotic women who were initiating (new users) or continuing (experienced users) osteoporosis treatment at study entry (baseline). A patient survey was administered at baseline and included the occurrence of GI symptoms during 6-month pre-enrolment, treatment adherence (adherence evaluation of osteoporosis (ADEOS), score 0-22), treatment satisfaction (Osteoporosis Treatment Satisfaction Questionnaire for Medications (OPSAT-Q), score 0-100) and HRQoL (EuroQol-5 dimension (EQ-5D) utility, score 0-1; OPAQ-SV, score 0-100). The association between GI symptoms and ADEOS (experienced users), OPSAT-Q (experienced users), and HRQoL (new and experienced users) was assessed by general linear models adjusted for patient characteristics. A total of 2959 patients (2275 experienced and 684 new users) were included. Overall, 68.1% of patients experienced GI symptoms in the past 6 months. Compared with patients without GI symptoms, patients with GI symptoms had lower mean baseline scores on most measures. The mean adjusted differences were ADEOS, -0.43; OPSAT-Q, -5.68; EQ-5D, -0.04 (new users) and -0.06 (experienced users), all P < 0.01. GI symptoms were also associated with lower OPAQ-SV domain scores: physical function, -4.17 (experienced users); emotional status, -4.28 (new users) and -5.68 (experienced users); back pain, -5.82 (new users) and -11.33 (experienced users), all P < 0.01. Patients with GI symptoms have lower treatment adherence and treatment satisfaction and worse HRQoL than patients without GI symptoms.


Acute hepatic toxicity during cyclic chemotherapy in non Hodgkin's lymphoma.
Hepatic toxicity directly related to the drugs administered in cyclic chemotherapy (CT), although sometimes serious, does not limit the treatment of non-Hodgkin's lymphoma (NHL). Nevertheless, reports of reactivation of viral hepatitis in NHL patients with B virus (HBV) infection are becoming more frequent. The recent observation of two cases of severe liver toxicity directly correlated to CT and a case of fatal hepatic failure due to HBV replication prompted us to evaluate the hepatic toxicity of CT in 98 consecutive B-cell NHL patients treated with relatively homogeneous cyclic CT. Acute hepatic toxicity was retrospectively evaluated in 98 consecutive B-cell NHL patients who received induction CT. HBV and HCV markers were checked at presentation. All patients were tested for ALT and bilirubin before every CT course, while tests for HBV-DNA and/or for HCV-RNA were performed with PCR only when hepatitis occurred. At presentation 22 patients (22.4%) were positive for HBsAg, and 11 (15.9%) were positive for anti-HCV. Acute hepatitis developed in 12 (12.2%) NHL patients: 8 (out of 22) in HBsAg-positive and anti-HCV-negative patients, 3 (out of 76) in HBsAg-negative patients, and 1 (out of 11) in anti-HCV-positive patients. Hepatitis was attributed to reactivation of chronic B hepatitis in 3 patients and to drug toxicity in 3 others; hepatitis was undefined in 6 cases. Drug-related liver toxicity is not a rare occurrence in NHL patients. Reactivation of HBV replication is responsible for a relevant number of the hepatitis cases observed. We did not detect acute hepatitis due to the reactivation of HCV replication (in chronic C hepatitis carriers).


Spatiotemporal and molecular epidemiology of cutaneous leishmaniasis in Libya.
Cutaneous leishmaniasis (CL) is a major public health problem in Libya. In this paper, we describe the eco-epidemiological parameters of CL during the armed conflict period from January 2011 till December 2012. Current spatiotemporal distributions of CL cases were explored and projected to the future using a correlative modelling approach. In addition the present results were compared with our previous data obtained for the time period 1995-2008. We investigated 312 CL patients who presented to the Dermatology Department at the Tripoli Central Hospital and came from 81 endemic areas distributed in 10 districts. The patients presented with typical localized lesions which appeared commonly on the face, arms and legs. Molecular identification of parasites by a PCR-RFLP approach targeting the ITS1 region of the rDNA was successful for 81 patients with two causative species identified: L. major and L. tropica comprised 59 (72.8%) and 22 (27.2%) cases, respectively. Around 77.3% of L. tropica CL and 57.7% of L. major CL caused single lesions. Five CL patients among our data set were seropositive for HIV. L. tropica was found mainly in three districts, Murqub (27.3%), Jabal al Gharbi (27.3%) and Misrata (13.7%) while L. major was found in two districts, in Jabal al Gharbi (61%) and Jafara (20.3%). Seasonal occurrence of CL cases showed that most cases (74.2%) admitted to the hospital between November and March, L. major cases from November till January (69.4%), and L. tropica cases mainly in January and February (41%). Two risk factors were identified for the two species; the presence of previously infected household members, and the presence of rodents and sandflies in patient's neighborhoods. Spatiotemporal projections using correlative distribution models based on current case data and climatic conditions showed that coastal regions have a higher level of risk due to more favourable conditions for the transmitting vectors. Future projection of CL until 2060 showed a trend of increasing incidence of CL in the north-western part of Libya, a spread along the coastal region and a possible emergence of new endemics in the north-eastern districts of Libya. These results should be considered for control programs to prevent the emergence of new endemic areas taking also into consideration changes in socio-economical factors such as migration, conflicts, urbanization, land use and access to health care.


Substrate evaluation for a microbeam endstation using unstained cell imaging.
A cellular imaging system, optimized for unstained cells seeded onto a thin substrate, is under development. This system will be a component of the endstation for the microbeam cell-irradiation facility at the University of Surrey. Previous irradiation experiments at the Gray Cancer Institute (GCI) have used Mylar film to support the cells [Folkard, M., Prise, K., Schettino, G., Shao, C., Gilchrist, S., Vojnovic, B., 2005. New insights into the cellular response to radiation using microbeams. Nucl. Instrum. Methods B 231, 189-194]. Although suitable for fluorescence microscopy, the Mylar often creates excessive optical noise when used with non-fluorescent microscopy. A variety of substrates are being investigated to provide appropriate optical clarity, cell adhesion, and radiation attenuation. This paper reports on our investigations to date.


Taxonomic revision of freshwater foraminifera with the description of two new agglutinated species and genera.
Most foraminifera inhabit marine habitats, but some species of monothalamids have been described from freshwater environments, mainly from Swiss water bodies over 100 years ago. Recent environmental DNA surveys revealed the presence of four major phylogenetic clades of freshwater foraminifera. However, until now only one of them (clade 2) has been associated to a morphologically described taxon-the family Reticulomyxidae. Here, we present morphological and molecular data for the genera representing the three remaining clades. We describe two new agglutinated freshwater genera from China and the Netherlands, Lacogromia and Limnogromia, which represent clades 3 and 4, respectively. We also report the first ribosomal DNA sequences of the genus Lieberkuehnia, which place this genus within clade 1. Our study provides the first morphotaxonomic documentation of molecular clades of freshwater foraminifera, showing that the environmental DNA sequences correspond to the agglutinated monothalamous species, morphologically similar to those described 100 years ago.


Pathological determinants of the transition to clinical dementia in Alzheimer's disease.
The authors developed multivariate models to examine the association between Clinical Dementia Rating (CDR) scale scores and the spatial distribution of paired helical filament tau (PHF-tau) pathology. Severity of tauopathy was examined in 14 cortical regions of interest (ROIs). Classification trees were used to test the independent hierarchical contributions of each ROI to dementia. Multiple-regression and cluster analyses were performed to determine the relative contributions of select ROIs to dementia. Dementia (CDR > or = 1) was modeled as a dichotomous variable. Autopsy material was obtained from 124 demented and nondemented elderly patients. All ROIs except the hippocampus made significant contributions to dementia. However, they were not independent. In multivariate models, only a single step (Step 7 in a hierarchical progression), which contained four ROIs, contributed significantly to dementia. A classification tree resulted in a single decision split, suggesting that only Step 7 ROIs need be considered. A total of 89.4% of the cases were correctly classified (p < .0001). Twelve discrepant cases all had superimposed vasculopathy that might also have affected the function of Step 7 ROIs. The transition to clinical dementia was associated with the presence of tauopathy in A9/10, A22, A23, and A39. Animal studies suggest that these represent a single distributed cortical network focusing on prefrontal regions that provide "executive control" over complex goal-directed behaviors. A22, A23, and A39 provide major afferents to other frontal systems and have previously been implicated in very early clinical Alzheimer's disease.


A Genome-Wide Association Study Reveals a Rich Genetic Architecture of Flour Color-Related Traits in Bread Wheat.
Flour color-related traits, including brightness (L*), redness (a*), yellowness (b*) and yellow pigment content (YPC), are very important for end-use quality of wheat. Uncovering the genetic architecture of these traits is necessary for improving wheat quality by marker-assisted selection (MAS). In the present study, a genome-wide association study (GWAS) was performed on a collection of 166 bread wheat cultivars to better understand the genetic architecture of flour color-related traits using the wheat 90 and 660 K SNP arrays, and 10 allele-specific markers for known genes influencing these traits. Fifteen, 28, 25, and 32 marker-trait associations (MTAs) for L*, a*, b*, and YPC, respectively, were detected, explaining 6.5-20.9% phenotypic variation. Seventy-eight loci were consistent across all four environments. Compared with previous studies, Psy-A1, Psy-B1, Pinb-D1, and the 1B•1R translocation controlling flour color-related traits were confirmed, and four loci were novel. Two and 11 loci explained much more phenotypic variation of a* and YPC than phytoene synthase 1 gene (Psy1), respectively. Sixteen candidate genes were predicted based on biochemical information and bioinformatics analyses, mainly related to carotenoid biosynthesis and degradation, terpenoid backbone biosynthesis and glycolysis/gluconeogenesis. The results largely enrich our knowledge of the genetic basis of flour color-related traits in bread wheat and provide valuable markers for wheat quality improvement. The study also indicated that GWAS was a powerful strategy for dissecting flour color-related traits and identifying candidate genes based on diverse genotypes and high-throughput SNP arrays.


Compared with intensity-modulated radiotherapy, image-guided radiotherapy reduces severity of acute radiation-induced skin toxicity during radiotherapy in patients with breast cancer.
Radiotherapy (RT) is an effective treatment for breast cancer. The side effects of breast irradiation, including skin toxicity in the irradiation field, cause considerable discomfort. This study compared the severity of skin toxicity caused by image-guided RT (IGRT) and intensity-modulated RT (IMRT) combined with an electronic portal imaging device (EPID) in breast cancer. This study retrospectively analyzed 458 patients with breast cancer who had received RT. The patients were divided into two groups: 302 and 156 patients in the IMRT and IGRT groups. In the IGRT group, 8 and 148 patients had received helical tomotherapy irradiation and IMRT with cone-beam computed tomography. Simple and multiple logistic regression analyses were used to estimate the relationship between RT technique and the severity of radiation skin toxicity. In our study, 284, 97, and 6 patients exhibited grades I, II, and III radiation dermatitis (RD). Moreover, 75 patients in the IMRT group (24.80%) and 22 patients in the IGRT group (14.10%) exhibited grade II RD. All patients with grade III RD were in the IMRT group (2.00%). No patient exhibited grade IV RD. The patients in the IGRT group exhibited less severity of RD than in the IMRT group. The severity of acute RD due to IGRT is significantly lower than that due to IMRT with EPID.


Patients and their family members prioritize post-transplant survival over waitlist survival when considering donor hearts for transplantation.
Heart transplant providers often focus on post-transplant outcomes when making donor decisions, potentially at the expense of higher waitlist mortality. This study aimed to assess public opinion regarding the selection of donor hearts and the balance between pre- and post-transplant risk. The authors generated a survey to investigate public opinion regarding donor acceptance. The survey was shared freely online across social media platforms in April-May 2019. A total of 718 individuals responded to the survey, with an equal distribution between patients and family members. Respondents consistently favored post-transplant outcomes over waitlist outcomes. About 83.9% of respondents favored a hospital with longer waitlist times, worse waitlist outcomes, but excellent post-transplant survival over a hospital with short waitlist times, a high waitlist survival, and inferior post-transplant survival. This preference was no different between pediatric and adult populations (P = .7), patient and family members (P = .935), or those with a pre- vs post-transplant perspective (P = .985). Patients and their family members consistently favor improved post-transplant survival over waitlist survival when considering the risks of accepting a donor organ. These findings suggest that current practice patterns of donor selection align with the opinions of patients and family members with heart failure or who have undergone heart transplantation.


Fish consumption and risk of depression: a meta-analysis.
The association between fish consumption and risk of depression is controversial. We performed a meta-analysis to evaluate the association. A literature search was performed in PubMed, EMBASE and Web of Science database for all relevant studies up to March 2015. We pooled the relative risks (RRs) with 95% CIs from individual studies with random effects model, and conducted meta-regression to explore potential sources of heterogeneity. Publication bias was estimated by Egger's test and the funnel plot. A total of 26 studies involving 150,278 participants were included in the present meta-analysis. The pooled RR of depression for the highest versus lowest consumption of fish was 0.83 (95% CI 0.74 to 0.93). The findings remained significant in the cohort studies (RR=0.84, 95% CI 0.75 to 0.94, n=10) as well as in the cross-sectional studies (RR=0.82, 95% CI 0.68 to 1.00, n=16). When men and women were analysed separately, a significant inverse association was also observed. There was no evidence of publication bias. This meta-analysis indicates that high-fish consumption can reduce the risk of depression.


Aquatic productivity and the evolution of diadromous fish migration.
Diadromous migration, in which some fish species migrate from freshwater and feed in the ocean (anadromous species) and others migrate from the ocean and feed in freshwater (catadromous), has long been perplexing. However, when the distribution of diadromous species is examined with respect to global patterns in aquatic productivity, this apparent paradox is resolved. The contrasting directions of migration can largely be explained by the relative availability of food resources in ocean and freshwater habitats. Oceans are more productive than freshwaters in temperate latitudes, and anadromous species predominate. In contrast, catadromous species generally occur in tropical latitudes where freshwater productivity exceeds that of the ocean.


Rhythmic Chanting and Mystical States across Traditions.
Chanting is a form of rhythmic, repetitive vocalization practiced in a wide range of cultures. It is used in spiritual practice to strengthen community, heal illness, and overcome psychological and emotional difficulties. In many traditions, chanting is used to induce mystical states, an altered state of consciousness characterised by a profound sense of peace. Despite the global prevalence of chanting, its psychological effects are poorly understood. This investigation examined the psychological and contextual factors associated with mystical states during chanting. Data were analyzed from 464 participants across 33 countries who regularly engaged in chanting. Results showed that 60% of participants experienced mystical states during chanting. Absorption, altruism, and religiosity were higher among people who reported mystical states while chanting compared to those who did not report mystical states. There was no difference in mystical experience scores between vocal, silent, group or individual chanting and no difference in the prevalence of mystical states across chanting traditions. However, an analysis of subscales suggested that mystical experiences were especially characterised by positive mood and feelings of ineffability. The research sheds new light on factors that impact upon chanting experiences. A framework for understanding mystical states during chanting is proposed.


Hydrogen inhalation ameliorates ventilator-induced lung injury.
Mechanical ventilation (MV) can provoke oxidative stress and an inflammatory response, and subsequently cause ventilator-induced lung injury (VILI), a major cause of mortality and morbidity of patients in the intensive care unit. Inhaled hydrogen can act as an antioxidant and may be useful as a novel therapeutic gas. We hypothesized that, owing to its antioxidant and anti-inflammatory properties, inhaled hydrogen therapy could ameliorate VILI. VILI was generated in male C57BL6 mice by performing a tracheostomy and placing the mice on a mechanical ventilator (tidal volume of 30 ml/kg without positive end-expiratory pressure, FiO(2) 0.21). The mice were randomly assigned to treatment groups and subjected to VILI with delivery of either 2% nitrogen or 2% hydrogen in air. Sham animals were given same gas treatments for two hours (n = 8 for each group). The effects of VILI induced by less invasive and longer exposure to MV (tidal volume of 10 ml/kg, 5 hours, FiO(2) 0.21) were also investigated (n = 6 for each group). Lung injury score, wet/dry ratio, arterial oxygen tension, oxidative injury, and expression of pro-inflammatory mediators and apoptotic genes were assessed at the endpoint of two hours using the high-tidal volume protocol. Gas exchange and apoptosis were assessed at the endpoint of five hours using the low-tidal volume protocol. Ventilation (30 ml/kg) with 2% nitrogen in air for 2 hours resulted in deterioration of lung function, increased lung edema, and infiltration of inflammatory cells. In contrast, ventilation with 2% hydrogen in air significantly ameliorated these acute lung injuries. Hydrogen treatment significantly inhibited upregulation of the mRNAs for pro-inflammatory mediators and induced antiapoptotic genes. In the lungs treated with hydrogen, there was less malondialdehyde compared with lungs treated with nitrogen. Similarly, longer exposure to mechanical ventilation within lower tidal volume (10 mg/kg, five hours) caused lung injury including bronchial epithelial apoptosis. Hydrogen improved gas exchange and reduced VILI-induced apoptosis. Inhaled hydrogen gas effectively reduced VILI-associated inflammatory responses, at both a local and systemic level, via its antioxidant, anti-inflammatory and antiapoptotic effects.


The safe insertion of peripheral intravenous catheters: a mixed methods descriptive study of the availability of the equipment needed.
Intravenous cannulation is undertaken in a high proportion of hospitalised patients. Much international attention has been given to the use of care bundles to reduce the incidence of infection in these patients. However, less attention has been given to the systems required to ensure availability of the equipment needed to support these care bundles. Our objectives were to assess how reliably the equipment recommended for a peripheral intravenous care bundle was available for use, and to explore factors which contributed to its non-availability. We studied 350 peripheral cannula insertions in three NHS hospital organisations across the UK. Staff inserting cannulae were asked to report details of all equipment problems. Key staff were then interviewed to identify the causes of problems with equipment availability, using semi-structured qualitative interviews and a standard coding frame. 47 equipment problems were recorded during 46 of 350 cannulations, corresponding to a reliability of 87%, or 94% if problems with sharps disposal were excluded. Overall reliability was similar in all three organisations, but the types of problem varied. Interviews revealed a variety of causes including issues associated with purchasing policies, storage facilities, and lack of teamwork and communication in relation to reordering. The many human factors related to the supply chain were highlighted. Often staff had adopted work-arounds to deal with these problems. Overall, 87% of cannulations had the correct and functional equipment available. Different problems were identified in different organisations, suggesting that each had resolved some issues. Supply chain management principles may be useful to support best practice in care bundle delivery.


Astrocytes: New Targets for the Treatment of Neurodegenerative Diseases.
The causes of neurodegenerative disorders are multiple, and for most of them a mechanistic understanding is still lacking. However, neurodegenerative diseases such as Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD) all share common features that include elevated oxidative stress levels and impaired energy metabolism in the nervous system. Most of the current treatments are only successful at alleviating some of the pathological symptoms, but fail at preventing neurodegeneration. There is therefore an urgent need for innovative and more efficient treatments for neurodegenerative disorders. We review here the central role played by astrocytes in the regulation of brain homeostasis, protection and function by supporting neuronal health and activity. In particular, astrocytes are key partners of neuronal metabolism, notably through activation of the astrocyteneuron lactate shuttle (ANLS). They also control the levels of extracellular glutamate, production of antioxidant molecules, disposal of neuronal waste products, storage of energy in the form of glycogen, and expression of neurotrophic factors. These mechanisms, which are key for brain activity and cognition, also largely contribute to neuronal degeneration in pathological situations. Thus, as astrocytes appear to play a key role in the etiology of neurodegenerative disorders, a growing interest has arisen for astrocytemediated pathways as targets for drugs that aim at treating the root causes of the pathology. We present here the most recent and promising astrocyte-based therapeutic approaches - from fundamental discoveries to clinical trials - that intent to sustain neuronal health and function in neurodegenerative disorders.


NKX3.1 homeodomain protein binds to topoisomerase I and enhances its activity.
The prostate-specific homeodomain protein NKX3.1 is a tumor suppressor that is commonly down-regulated in human prostate cancer. Using an NKX3.1 affinity column, we isolated topoisomerase I (Topo I) from a PC-3 prostate cancer cell extract. Topo I is a class 1B DNA-resolving enzyme that is ubiquitously expressed in higher organisms and many prokaryotes. NKX3.1 interacts with Topo I to enhance formation of the Topo I-DNA complex and to increase Topo I cleavage of DNA. The two proteins interacted in affinity pull-down experiments in the presence of either DNase or RNase. The NKX3.1 homeodomain was essential, but not sufficient, for the interaction with Topo I. NKX3.1 binding to Topo I occurred independently of the Topo I NH2-terminal domain. The binding of equimolar amounts of Topo I to NKX3.1 caused displacement of NKX3.1 from its cognate DNA recognition sequence. Topo I activity in prostates of Nkx3.1+/- and Nkx3.1-/- mice was reduced compared with wild-type mice, whereas Topo I activity in livers, where no NKX3.1 is expressed, was independent of Nkx3.1 genotype. Endogenous Topo I and NKX3.1 could be coimmunoprecipitated from LNCaP cells, where NKX3.1 and Topo I were found to colocalize in the nucleus and comigrate within the nucleus in response to either gamma-irradiation or mitomycin C exposure, two DNA-damaging agents. This is the first report that a homeodomain protein can modify the activity of Topo I and may have implications for organ-specific DNA replication, transcription, or DNA repair.


Laparoscopy in the management of pediatric intraabdominal tumors.
Unresectable intraabdominal tumors pose a challenge to the pediatric oncology team. Tumor tissue is needed for diagnostic and prognostic analyses. Laparotomy is quite invasive and computerized tomography-guided needle biopsies, though less invasive, may not procure enough tissue for a complete analysis. This study aimed to evaluate our experience with laparoscopy in managing these tumors. Nine children underwent laparoscopy: 6 for primary tumor biopsy, 2 for tumor resection, and 1 for tumor dissection followed by laparotomy for tumor resection. The study included 7 females and 2 males with a median age of 5 years (range, 3 to 15 years). Three patients had neuroblastoma, 2 had mature ovarian teratomas, 2 had rhabdomyosarcoma, 1 had erythrophagocytic histiocytosis, and 1 had T-cell hepatosplenic lymphoma. In each case, adequate tissue was procured for diagnostic and prognostic analyses. No perioperative complications occurred. Both patients with ovarian teratomas are well. Four patients continue to receive anti-cancer therapy. The patient with erythrophagocytic histiocytosis underwent a cord-blood stem cell transplant. One patient with neuroblastoma was lost to follow-up, and 1 patient with rhabdomyosarcoma died of progressive disease. Laparoscopy is a valuable technique in the management of pediatric intraabdominal tumors. It allows for tumor biopsy under direct vision, and adequate tissue is procured for all analyses. Moreover, it allows the surgeon to dissect the tumor and determine resectability.


Advance decisions and the Mental Capacity Act.
This article considers the requirements set out in the Mental Capacity Act 2005 for valid advance decisions. The Act recognizes that an adult with capacity may refuse treatment, including life-sustaining treatment, in advance of losing capacity. If that advance decision is valid and applicable, it will bind health-care professionals, taking effect as if the patient had contemporaneously refused the treatment. However, in cases where the advance decision does not relate to treatment for a progressive disease, it will be extremely difficult for the patient to meet the dual specificity requirement - specifying the treatment to be refused and the circumstances in which that refusal should operate. Moreover, while a patient may explicitly revoke an advance decision while she retains the capacity to do so, the continuing validity of an advance decision may be called into question by the patient implicitly revoking her advance refusal or by a change of circumstance. This article concludes that the key to enabling patients to exercise precedent autonomy will be full and frank discussion of the scope and intentions underlying advance decisions between patients and their health-care professionals.


Target Tracking While Jamming by Airborne Radar for Low Probability of Detection.
Although radiation power minimization is the most important method for an advanced stealth aircraft to achieve the low probability of detection (LPD) performance against the opposite passive detection system (PDS), it is not always effective when the performance of PDS is advanced. In a target tracking scenario, an interference tactic is proposed in this paper to keep the airborne radar in an LPD state. Firstly, this paper introduces the minimization radiation power design of airborne radar based on the distance between the radar and the target, and introduces the minimization radiation power design of the airborne jammer based on the predicted detection probability of the opposite PDS. Then, after consulting the most commonly used constant false alarm rate (CFAR) technologies in passive detection systems, including the cell average CFAR, the greatest of CFAR, the smallest of CFAR and the ordered statistic CFAR, this paper analyzes their relationships and points out the way of interference. Finally, based on the constraints, not only including the predicted detection probabilities of airborne radar and opposite PDS, respectively, but also including the time synchronization which is necessary to avoid the leaked interference power generated by airborne jammer jamming the airborne radar echoes from the target, this paper establishes a math model to minimize the total interference power of airborne jammer without interfering target tracking. Simulation results show that the proposed model is effective.


Are physical activity interventions equally effective in adolescents of low and high socio-economic status (SES): results from the European Teenage project.
The aim was to study whether physical activity (PA) interventions in European teenagers are equally effective in adolescents of low versus high socio-economic status (SES). Based on a systematic review (Project TEENAGE), three school-based studies for secondary analyses were selected. SES stratified analyses were run in: (i) a Belgian multi-component intervention, (ii) a French multi-component intervention and (iii) a Belgian computer-tailored education trial. Results of the secondary analyses showed that no overall significant differences between low and high SES groups were found, but some interesting specific effects were revealed. Results from the first study showed an increase in objective PA in the low SES group (P = 0.015) compared with no significant effects in the high SES group. In the second study, larger effects were found in adolescents of high SES (increase of 11 min day(-1) P < 0.001), compared with adolescents of lower SES (increase of 7 min day(-1), P = 0.02) at the longer term. The third study showed a positive effect on school-related PA in adolescents of high SES (P < 0.05) and on leisure time transportation in adolescents of low SES (P < 0.05). To conclude, we were not able to show a significant widening or narrowing of inequalities in European adolescents.


Age- and sex-related reference ranges of alanine aminotransferase levels in children: European paediatric HCV network.
Serum alanine aminotransferase (ALT) levels are commonly used to indicate liver damage. Although elevated levels indicate possible liver injury, abnormalities, or disease, some patients with "normal" ALT levels have minimal to mild liver disease. Recently, ALT reference ranges for adults were queried and revised ranges proposed with lower upper limits of normality. The appropriateness of current paediatric ALT reference ranges is unclear. Hepatitis C virus (HCV)-uninfected children from the European Paediatric HCV Network represent a large population of healthy children born to HCV-infected mothers, with ALT observations collected prospectively from birth. Linear regression identified factors associated with ALT levels while accounting for within-child repeated measurements. ALT centiles stratified by sex were calculated using maximum penalized likelihood methods and LMS software. A total of 1293 HCV-uninfected children had 5011 ALT measurements during follow-up. ALT levels significantly decreased with increasing age, whilst ALT levels were significantly lower in girls than boys. Reference cutoffs representing the 95th centiles before 18 months of age were 60 U/L for boys and 55 U/L for girls, decreasing to 40 U/L for boys and 35 U/L for girls after 18 months of age. These reference ranges represent a unique investigation of ALT levels in a healthy child population. We show lower and more detailed age-related cutoffs of normality than available. Additionally, we demonstrate a significant effect of sex on ALT reference ranges, which has not previously been described in children younger than 5 years of age.


Characteristics and outcome of false cardiac arrests in hospital.
Not all hospitalised patients with symptoms of a presumed or threatened cardiac arrest, for whom the rescue team is alerted, eventually suffer a cardiac arrest. This article aims to describe the characteristics and outcome of "false cardiac arrests". All patients hospitalised at Sahlgrenska University Hospital for whom the rescue team was alerted between 1 November 1994 and 15 October 2002 were included. In all, there were 1538 calls for the rescue team, of which 70% were caused by cardiac arrest, 9% by respiratory arrest and 21% by "other causes". Survival to discharge was 36% among patients with cardiac arrest, 64% among patients with respiratory arrest and 77% among patients with "other reasons for calling" (p<0.0001 for trend). Among survivors, a cerebral performance categories (CPC) score of 1 at hospital discharge was found in 83% of those with a cardiac arrest, 59% with respiratory arrest and 82% with other reasons for calling (NS for trend). Among patients at a Swedish university hospital for whom the rescue team was alerted, about one-third have a "false cardiac arrest". These patients had a survival rate which was about twice that of patients with a "true cardiac arrest". However, among survivors, cerebral function at discharge was similar, regardless of "false" or "true" cardiac arrest.


Comment on "Promising blood-derived biomarkers for estimation of the postmortem interval" by I. Costa, F. Carvalho, T. Magalhães, P. G. de Pinho, R. Silvestre & R. J. Dinis-Oliveira. (Toxicol. Res., 2015, 4, 1443-1452).
Recently, Costa et al. published an article about promising biomarkers for estimating the postmortem interval. Instead of postmortem blood, antemortem blood was putrefied in vitro by exposing the blood to a temperature gradient. However, in this way several other influencing factors were excluded, hence, the accuracy of the proposed model is doubtful. Therefore, the aim of this comment is to discuss the methodology, results and shortcomings of the study of Costa et al.


Prostate cancer cell telomere length variability and stromal cell telomere length as prognostic markers for metastasis and death.
Current prognostic indicators are imperfect predictors of outcome in men with clinically localized prostate cancer. Thus, tissue-based markers are urgently needed to improve treatment and surveillance decision-making. Given that shortened telomeres enhance chromosomal instability and such instability is a hallmark of metastatic lesions, we hypothesized that alterations in telomere length in the primary cancer would predict risk of progression to metastasis and prostate cancer death. To test this hypothesis, we conducted a prospective cohort study of 596 surgically treated men who participated in the ongoing Health Professionals Follow-up Study. Men who had the combination of more variable telomere length among prostate cancer cells (cell-to-cell) and shorter telomere length in prostate cancer-associated stromal (CAS) cells were substantially more likely to progress to metastasis or die of their prostate cancer. These findings point to the translational potential of this telomere biomarker for prognostication and risk stratification for individualized therapeutic and surveillance strategies. In this prospective study, the combination of more variable telomere length among cancer cells and shorter telomere length in CAS cells was strongly associated with progression to metastasis and prostate cancer death, pointing to the translational potential for prognostication and risk stratifi cation for individualized therapeutic and surveillance strategies.


The role of arthrodesis of the wrist in spastic disorders.
We investigated the functional and radiographic outcome of wrist arthrodesis in 11 adults with spastic wrist deformities, carried out by one surgeon between 2003 and 2012. The underlying cause of spasticity was a cerebrovascular insult in five, traumatic brain injury in four, and cerebral palsy in two patients. A dorsal plate and local bone graft was used in all patients. The mean radiographic flexion deformity significantly improved from 67° pre-operatively to 4° of dorsal angulation post-operatively. Thumb-in-palm deformity was more pronounced in three patients after the operation. The functional House score improved in all patients an average of two levels (range 1-3).


Multilevel modeling of county-level excessive alcohol use, rurality, and COVID-19 case fatality rates in the US.
Reports of disparities in COVID-19 mortality rates are emerging in the public health literature as the pandemic continues to unfold. Alcohol misuse varies across the US and is related to poorer health and comorbidities that likely affect the severity of COVID-19 infection. High levels of pre-pandemic alcohol misuse in some counties may have set the stage for worse COVID-19 outcomes. Furthermore, this relationship may depend on how rural a county is, as access to healthcare in rural communities has lagged behind more urban areas. The objective of this study was to test for associations between county-level COVID-19 mortality, pre-pandemic county-level excessive drinking, and county rurality. We used national COVID-19 data from the New York Times to calculate county-level case fatality rates (n = 3,039 counties and county equivalents; October 1 -December 31, 2020) and other external county-level data sources for indicators of rurality and health. We used beta regression to model case fatality rates, adjusted for several county-level population characteristics. We included a multilevel component to our model and defined state as a random intercept. Our focal predictor was a single variable representing nine possible combinations of low/mid/high alcohol misuse and low/mid/high rurality. The median county-level COVID-19 case fatality rate was 1.57%. Compared to counties with low alcohol misuse and low rurality (referent), counties with high levels of alcohol and mid (β = -0.17, p = 0.008) or high levels of rurality (β = -0.24, p<0.001) demonstrated significantly lower case fatality rates. Our findings highlight the intersecting roles of county-level alcohol consumption, rurality, and COVID-19 mortality.


Tuning the absorption, charge transport properties, and solar cell efficiency with the number of thienyl rings in platinum-containing poly(aryleneethynylene)s.
The synthesis, characterization, and photophysics of a series of solution-processable and strongly visible-light absorbing platinum(II) polyynes containing bithiazole-oligo(thienyl) rings were presented. Tuning the polymer solar cell efficiency, as well as optical and charge transport properties, in soluble, low-band gap PtII-based conjugated poly(heteroaryleneethynylene)s using the number of oligothienyl rings is described. These materials are highly soluble in polar organic solvents due to the presence of solubilizing bithiazole moieties and show strong absorptions in the solar spectra, rendering them excellent candidates for bulk heterojunction polymer solar cells. Their photovoltaic responses and power conversion efficiencies (PCEs) depend to a large extent on the number of thienyl rings along the main chain, and some of them can be used to fabricate highly efficient solar cells with PCEs of up to 2.7% and a peak external quantum efficiency to 83% under AM1.5 simulated solar illumination, which is comparable to that of poly(3-hexylthiophene)-based devices fabricated without additional processing (annealing or TiO(x) layer). The influence of the number of thienyl rings and the metal group on the performance parameters and optimization of solar cell efficiency was evaluated and discussed in detail. At the same blend ratio of 1:4, the light-harvesting ability and PCE increase sharply as the thienyl chain length increases. The present work provides an attractive approach to developing conjugated metallopolymers offering broad solar absorptions and tunable solar cell efficiency and demonstrates the potential of metalated conjugated polymers for efficient power generation.


To What Extent Local Forest Soil Pollen Can Assist Restoration in Subtropical China?
Long-term ecological data play a vital role in ecological conservation and restoration, however, using information from local forest soil pollen data to assist restoration remains a challenge. This study analyzed two data sets, including 1) surface soil pollen (0-5 cm) and current vegetation data from four near-natural communities and four plantations, and 2) fossil pollen from soil profiles (0-80 cm) from a regional climax community and a degraded land. The pollen representativeness and similarity indexes were calculated. The results showed a low similarity between soil pollen and current vegetation (about 20%) thus forest soil pollen data should be used with caution when defining reference ecosystems. Pollen from Gironniera and Rutaceae which were abundant in broadleaved forest, were also detected in the 40-80 cm layer of a soil profile from the degraded land, which indicates its restoration possibility. Our study considered that the early restoration stage of the study area may benefit from using plant taxa of Pinus, Poaceae, Lonicera, Casuarina, Trema and Quercus. As Pinus, Castanopsis, Gironniera, Rutaceae, Helicia, Randia, Poaceae, Dicranopteris and Pteris always existed during succession, for regional forest restoration under global climate change, the roles of such "stable species" should be considered.


CEDNIK syndrome results from loss-of-function mutations in SNAP29.
CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis and keratoderma) syndrome is a rare genodermatosis which was shown 5 years ago in one family to be associated with a loss-of-function mutation in SNAP29, encoding a member of the SNARE family of proteins. Decrease in SNAP29 expression was found to result in abnormal lamellar granule maturation leading to aberrant epidermal differentiation and ichthyosis. To delineate the molecular consequences of disease-causing mutations in SNAP29. We used direct sequencing, in vitro mutagenesis and three-dimensional organotypic cell cultures. We identified a novel homozygous insertion in SNAP29 (c.486insA) in two sibs presenting with ichthyosis and dysgenesis of the corpus callosum. In vitro transfection experiments indicated that this mutation results in SNAP29 loss-of-function. Further substantiating this notion, we could replicate histological features typical for CEDNIK syndrome in three-dimensional primary human keratinocyte organotypic cell cultures downregulated for SNAP29. The identification of a second mutation in SNAP29 in the present study definitely establishes a causal relationship between defective function of SNAP29 and the pleiotropic manifestations of CEDNIK syndrome. Our present and previous data position SNAP29 as an essential component of the epidermal differentiation machinery.


Treatment patterns and outcomes of Stage IIIB/IIIC melanoma in France, Germany and the UK: A retrospective and prospective observational study (MELABIS).
Real-world data on treatment patterns/outcomes in patients with advanced melanoma, while scarce, are useful for health technology assessments that govern patient access in many countries. We collected retrospective data on treatment patterns among patients in France, Germany and the UK with Stage IIIB/IIIC melanoma with macroscopic lymph node involvement, whose primary melanoma and regional lymph node metastases had been completely resected. Patients ≥18 years were diagnosed between 1 January 2009 and 31 December 2011. Data were obtained from patients' medical records and a patient survey. Forty-nine centres provided data on 558 patients: 53.6% had Stage IIIB disease; 58.2% were of working age (<65 years), 22.5% reported a change in employment status due to melanoma, 8% were on long-term sick leave; and 35.1% were deceased over the study period. Overall median distant metastases-free survival was 23.4 months and median disease-free survival was 13.3 months. Hospitalisation frequency increased during distant metastatic/terminal disease phases. Adjuvant therapy was received by 7.0% (14/199) of patients in France, 2.6% (5/195) in the UK, and 33.5% (55/164) in Germany. Low-dose interferon was used more frequently than other regimens. High-dose interferon was associated with discontinuation in 28.6% and dose delay/reduction in 33.3% of patients. Rapid disease progression combined with increased use of healthcare resources in later phases of disease result in a high burden-of-illness for patients and healthcare providers. The use of adjuvant interferon therapy varies considerably in this population in the countries studied, highlighting the need for improved treatments for melanoma.


Enhancement in sample collection for the detection of MDMA using a novel planar SPME (PSPME) device coupled to ion mobility spectrometry (IMS).
Trace detection of illicit drugs challenges the scientific community to develop improved sensitivity and selectivity in sampling and detection techniques. Ion mobility spectrometry (IMS) is one of the prominent trace detectors for illicit drugs and explosives, mostly due to its portability, high sensitivity and fast analysis. Current sampling methods for IMS rely on wiping suspected surfaces or withdrawing air through filters to collect particulates. These methods depend greatly on the particulates being bound onto surfaces or having sufficient vapour pressure to be airborne. Many of these compounds are not readily available in the headspace due to their low vapour pressure. This research presents a novel SPME device for enhanced air sampling and shows the use of optimized IMS by genetic algorithms to target volatile markers and/or odour signatures of illicit substances. The sampling method was based on unique static samplers, planar substrates coated with sol-gel polydimethyl siloxane (PDMS) nanoparticles, also known as planar solid-phase microextraction (PSPME). Due to its surface chemistry, high surface area and capacity, PSPME provides significant increases in sensitivity over conventional fibre SPME. The results show a 50-400 times increase in the detection capacity for piperonal, the odour signature of 3,4-methylenedioxymethamphetamine (MDMA). The PSPME-IMS technique was able to detect 600 ng of piperonal in a 30 s extraction from a quart-sized can containing 5 MDMA tablets, while detection using fibre SPME-IMS was not attainable. In a blind study of six cases suspected to contain varying amounts of MDMA in the tablets, PSPME-IMS successfully detected five positive cases and also produced no false positives or false negatives. One positive case had minimal amounts of MDMA resulting in a false negative response for fibre SPME-IMS.


Ocean convection linked to the recent ice edge retreat along east Greenland.
Warm subtropical-origin Atlantic water flows northward across the Greenland-Scotland Ridge into the Nordic Seas, where it relinquishes heat to the atmosphere and gradually transforms into dense Atlantic-origin water. Returning southward along east Greenland, this water mass is situated beneath a layer of cold, fresh surface water and sea ice. Here we show, using measurements from autonomous ocean gliders, that the Atlantic-origin water was re-ventilated while transiting the western Iceland Sea during winter. This re-ventilation is a recent phenomenon made possible by the retreat of the ice edge toward Greenland. The fresh surface layer that characterises this region in summer is diverted onto the Greenland shelf by enhanced onshore Ekman transport induced by stronger northerly winds in fall and winter. Severe heat loss from the ocean offshore of the ice edge subsequently triggers convection, which further transforms the Atlantic-origin water. This re-ventilation is a counterintuitive occurrence in a warming climate, and highlights the difficulties inherent in predicting the behaviour of the complex coupled climate system.


Low density lipoprotein subfractions and [Ca2+]i in vascular smooth muscle cells.
Several studies have established that plasma low density lipoprotein (LDL) consists of various discrete subfractions. Using a variety of techniques (analytical ultracentrifugation, equilibrium density gradient ultracentrifugation, and gradient gel electrophoresis), LDL has been fractionated into a maximum of seven subclasses that differ in particle size, density, and physiochemical composition. Recently, a predominance of smaller denser LDL particles has been associated with an increased risk of coronary artery disease. However, other lipoprotein changes, such as elevated triglycerides and lower HDL cholesterol levels, have been shown in patients with a predominance of the smaller denser LDL subfractions. Thus, it is unclear whether the enhanced atherogenic potential is induced by the LDL subfraction pattern per se or by concomitant lipoprotein changes. Because intracellular free Ca2+ is an important second messenger involved in atherogenesis and regulation of vascular tone, we studied the influence of three LDL subfractions (very light [LDL1], 1.030 to 1.033 g/mL; light [LDL2], 1.033 to 1.040 g/mL; and dense [LDL3], 1.040 to 1.045 g/mL) on [Ca2+]i in vascular smooth muscle cells (VSMCs) cultured from rat aorta. LDL subfractions were isolated by density gradient ultracentrifugation from human EDTA-plasma (n = 15). [Ca2+]i was measured by fura 2 fluorescence. Basal [Ca2+]i was 77 +/- 6 nmol/L. Stimulation of VSMCs with dense LDL3 caused a significantly (P < .05) more pronounced increase (+71 +/- 13 nmol/L) compared with LDL1 (+38 +/- 8 nmol/L) and LDL2 (+36 +/- 9 nmol/L). To further investigate the mechanisms leading to the stimulation of [Ca2+]i by LDL subfractions, we incubated VSMCs with the Ca2+ antagonists nifedipine, diltiazem, and verapamil in concentrations up to 10 mumol/L.(ABSTRACT TRUNCATED AT 250 WORDS)


Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain.
RNA splicing is a key mechanism linking genetic variation with psychiatric disorders. Splicing profiles are particularly diverse in brain and difficult to accurately identify and quantify. We developed a new approach to address this challenge, combining long-range PCR and nanopore sequencing with a novel bioinformatics pipeline. We identify the full-length coding transcripts of CACNA1C in human brain. CACNA1C is a psychiatric risk gene that encodes the voltage-gated calcium channel CaV1.2. We show that CACNA1C's transcript profile is substantially more complex than appreciated, identifying 38 novel exons and 241 novel transcripts. Importantly, many of the novel variants are abundant, and predicted to encode channels with altered function. The splicing profile varies between brain regions, especially in cerebellum. We demonstrate that human transcript diversity (and thereby protein isoform diversity) remains under-characterised, and provide a feasible and cost-effective methodology to address this. A detailed understanding of isoform diversity will be essential for the translation of psychiatric genomic findings into pathophysiological insights and novel psychopharmacological targets.


Efficient infection of cells in culture by type O foot-and-mouth disease virus requires binding to cell surface heparan sulfate.
Foot-and-mouth disease virus (FMDV) enters cells by attaching to cellular receptor molecules of the integrin family, one of which has been identified as the RGD-binding integrin alpha(v)beta3. Here we report that, in addition to an integrin binding site, type O strains of FMDV share with natural ligands of alpha(v)beta3 (i.e., vitronectin and fibronectin) a specific affinity for heparin and that binding to the cellular form of this sulfated glycan, heparan sulfate, is required for efficient infection of cells in culture. Binding of the virus to paraformaldehyde-fixed cells was powerfully inhibited by agents such as heparin, that compete with heparan sulfate or by agents that compete for heparan sulfate (platelet factor 4) or that inactivate it (heparinase). Neither chondroitin sulfate, a structurally related component of the extracellular matrix, nor dextran sulfate appreciably inhibited binding. The functional importance of heparan sulfate binding was demonstrated by the facts that (i) infection of live cells by FMDV could also be blocked specifically by heparin, albeit at a much higher concentration of inhibitor; (ii) pretreatment of cells with heparinase reduced the number of plaques formed compared with that for untreated cells; and (iii) mutant cell lines deficient in heparan sulfate expression were unable to support plaque formation by FMDV, even though they remained equally susceptible to another picornavirus, bovine enterovirus. The results show that entry of type O FMDV into cells is a complex process and suggest that the initial contact with the cell surface is made through heparan sulfate.


Molecular mechanisms of hexavalent chromium-induced apoptosis in human bronchoalveolar cells.
Hexavalent chromium (Cr[VI]) is classified by the International Agency for Research on Cancer as a group I carcinogen. Although the U.S. Occupational Safety and Health Administration was obliged to reduce the permissible exposure limit (PEL), it was reported that U.S. workers continue to be exposed to dangerously high Cr(VI) levels. In this study, we examined the role of p53 and target genes in a bronchoalveolar carcinoma isogenic cell line system and in primary human bronchial epithelial cells. p53-Negative parental H358 cell line, the same line in which the wild-type p53 expression vector (pC53-SN3) was introduced, and cells obtained from biopsies of human bronchus were exposed to chromate. Induction of DNA strand breaks were evaluated by alkaline elution assay, and apoptosis was analyzed by gel ladder, annexin V-PI staining, and ELISA, whereas p53 and target genes were evaluated by Western blots. Although Cr(VI) induced DNA strand breaks in both H358 cell clones, apoptosis was present only in the p53-transfected cells (H358p53(+/+)). In these cells, Cr(VI)-induced apoptosis is mediated by p53 upregulation of p53-upregulated modulator of apoptosis (PUMA), BAX translocation to mitochondria, cytochrome c release, and caspase-3 activation. In primary human bronchial epithelial cells expressing functional p53, Cr(VI) induced expression of PUMA and Noxa, which promote apoptosis through BAX. This result establishes p53 as the "necessary" player in Cr(VI)-induced apoptosis. To the best of our knowledge, this is the first report indicating strict correlation of Cr(VI) apoptosis to PUMA induction on primary human bronchoalveolar cells in short-term cultures.


Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK.
First identified as histone-modifying proteins, lysine acetyltransferases (KATs) and deacetylases (KDACs) antagonize each other through modification of the side chains of lysine residues in histone proteins. Acetylation of many non-histone proteins involved in chromatin, metabolism or cytoskeleton regulation were further identified in eukaryotic organisms, but the corresponding enzymes and substrate-specific functions of the modifications are unclear. Moreover, mechanisms underlying functional specificity of individual KDACs remain enigmatic, and the substrate spectra of each KDAC lack comprehensive definition. Here we dissect the functional specificity of 12 critical human KDACs using a genome-wide synthetic lethality screen in cultured human cells. The genetic interaction profiles revealed enzyme-substrate relationships between individual KDACs and many important substrates governing a wide array of biological processes including metabolism, development and cell cycle progression. We further confirmed that acetylation and deacetylation of the catalytic subunit of the adenosine monophosphate-activated protein kinase (AMPK), a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 and p300. Deacetylation of AMPK enhances physical interaction with the upstream kinase LKB1, leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. These findings provide new insights into previously underappreciated metabolic regulatory roles of HDAC1 in coordinating nutrient availability and cellular responses upstream of AMPK, and demonstrate the importance of high-throughput genetic interaction profiling to elucidate functional specificity and critical substrates of individual human KDACs potentially valuable for therapeutic applications.


Tractography-Driven Groupwise Multi-scale Parcellation of the Cortex.
The analysis of the connectome of the human brain provides key insight into the brain's organisation and function, and its evolution in disease or ageing. Parcellation of the cortical surface into distinct regions in terms of structural connectivity is an essential step that can enable such analysis. The estimation of a stable connectome across a population of healthy subjects requires the estimation of a groupwise parcellation that can capture the variability of the connectome across the population. This problem has solely been addressed in the literature via averaging of connectivity profiles or finding correspondences between individual parcellations a posteriori. In this paper, we propose a groupwise parcellation method of the cortex based on diffusion MR images (dMRI). We borrow ideas from the area of cosegmentation in computer vision and directly estimate a consistent parcellation across different subjects and scales through a spectral clustering approach. The parcellation is driven by the tractography connectivity profiles, and information between subjects and across scales. Promising qualitative and quantitative results on a sizeable data-set demonstrate the strong potential of the method.


Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set.
Epithelial neuroendocrine tumors (NETs) have been the subject of much debate regarding their optimal classification. Although multiple systems of nomenclature, grading, and staging have been proposed, none has achieved universal acceptance. To help define the underlying common features of these classification systems and to identify the minimal pathology data that should be reported to ensure consistent clinical management and reproducibility of data from therapeutic trials, a multidisciplinary team of physicians interested in NETs was assembled. At a group meeting, the participants discussed a series of "yes" or "no" questions related to the pathology of NETs and the minimal data to be included in the reports. After discussion, anonymous votes were taken, using the Delphic principle that 80% agreement on a vote of either yes or no would define a consensus. Questions that failed to achieve a consensus were rephrased once or twice and discussed, and additional votes were taken. Of 108 questions, 91 were answerable either yes or no by more than 80% of the participants. There was agreement about the importance of proliferation rate for tumor grading, the landmarks to use for staging, the prognostic factors assessable by routine histology that should be reported, the potential for tumors to progress biologically with metastasis, and the current status of advanced immunohistochemical and molecular testing for treatment-related biomarkers. The lack of utility of a variety of immunohistochemical stains and pathologic findings was also agreed upon. A consensus could not be reached for the remaining 17 questions, which included both minor points related to extent of disease assessment and some major areas such as terminology, routine immunohistochemical staining for general neuroendocrine markers, use of Ki67 staining to assess proliferation, and the relationship of tumor grade to degree of differentiation. On the basis of the results of the Delphic voting, a minimum pathology data set was developed. Although there remains disagreement among experts about the specific classification system that should be used, there is agreement about the fundamental pathology data that should be reported. Examination of the areas of disagreement reveals significant opportunities for collaborative study to resolve unanswered questions.


Comparison studies of tacrine and bis7-tacrine on the suppression of scopolamine-induced behavioral changes and inhibition of acetylcholinesterase in mice.
Effects of the cholinesterase inhibitors tacrine and bis(7)- tacrine (0.25-20 micromol/kg, s.c.) on locomotor activity and passive-avoidance response were investigated in mice treated with scopolamine (SCP, 1 or 5 micromol/kg, i.p.), using an open-field test and step-through task with a 24-hour retention interval. Drugs were given 30 min prior to the first session. During the acquisition session, SCP treatment increased the locomotor activity (10-16%). Tacrine, but not bis(7)-tacrine, cotreatment significantly reduced the locomotor activity by 23 or 27%, when compared with the SCP-treated control mice. In the step-through task, tacrine or bis(7)-tacrine coadministration dose-dependently attenuated the increase in the number of footshocks (by 50 or 58%) in SCP-treated mice. The lowest dose of tacrine and bis(7)-tacrine for prolonging the retention latency (up to 500%) in SCP-treated mice was 5 and 1 micromol/kg, respectively. Tacrine and bis(7)-tacrine inhibited brain acetylcholinesterase (AChE) activity 15 min (but not 30 min) after the drug administration in mice. At the same dose of 20 micromol/kg, the bis(7)-tacrine-induced AChE inhibition in serum was 14-fold higher than that of tacrine. The results indicated that bis(7)-tacrine was less potent than tacrine in causing motor dysfunction. However, bis(7)-tacrine was more potent than tacrine in the cognitive enhancement of SCP-induced memory loss and in AChE inhibition.


Primary adult liver transplantation under tacrolimus: more than 90 months actual follow-up survival and adverse events.
The introduction of tacrolimus has shown decreased rates of acute and steroid-resistant rejection after liver transplantation (LTx). The aim of the present study is to examine the long-term efficacy and safety of tacrolimus in primary liver transplant recipients. The first 121 consecutive adults (aged >16 years) who underwent primary LTx at a single center from August 1989 to February 1990 were followed up until August 1997. The mean follow-up was 93.2 +/- 1.2 months (range, 90.5 to 96.5 months). Patient survival, graft survival, rate of rejection, and adverse events were examined. The actual 7-year patient survival rate was 67.8%, and the graft survival rate was 63.6%. Infections, recurrence of disease, de novo malignancies, and cardiovascular events constituted the main causes of graft loss and death in the long term. Graft loss related to acute or chronic rejection was rare. The rate of acute rejection beyond 2 years was approximately 3% per year, and most rejections were steroid responsive. Approximately 70% of the patients received only tacrolimus after 1 year. Four patients developed end-stage renal disease, and 2 patients underwent kidney transplantation. Hyperkalemia and hypertension were observed in one third of the patients. New-onset insulin-dependent diabetes mellitus was observed in 9% and 13% of the patients at the 1-year and 7-year follow-up, respectively. Seven patients developed de novo malignancies, including two skin malignancies. Six patients developed posttransplantation lymphoproliferative disorder during the entire follow-up period. Actual patient and graft survival at 7 years was excellent, and few adverse events developed after the first year. Graft loss from acute or chronic rejection was rare under tacrolimus, and approximately 70% of the patients were steroid free on tacrolimus monotherapy after the first year after LTx.


A randomised controlled trial and cost-effectiveness evaluation of "booster" interventions to sustain increases in physical activity in middle-aged adults in deprived urban neighbourhoods.
Systematic reviews have identified a range of brief interventions which increase physical activity in previously sedentary people. There is an absence of evidence about whether follow up beyond three months can maintain long term physical activity. This study assesses whether it is worth providing motivational interviews, three months after giving initial advice, to those who have become more active. Study candidates (n = 1500) will initially be given an interactive DVD and receive two telephone follow ups at monthly intervals checking on receipt and use of the DVD. Only those that have increased their physical activity after three months (n = 600) will be randomised into the study. These participants will receive either a "mini booster" (n = 200), "full booster" (n = 200) or no booster (n = 200). The "mini booster" consists of two telephone calls one month apart to discuss physical activity and maintenance strategies. The "full booster" consists of a face-to-face meeting with the facilitator at the same intervals. The purpose of these booster sessions is to help the individual maintain their increase in physical activity. Differences in physical activity, quality of life and costs associated with the booster interventions, will be measured three and nine months from randomisation. The research will be conducted in 20 of the most deprived neighbourhoods in Sheffield, which have large, ethnically diverse populations, high levels of economic deprivation, low levels of physical activity, poorer health and shorter life expectancy. Participants will be recruited through general practices and community groups, as well as by postal invitation, to ensure the participation of minority ethnic groups and those with lower levels of literacy. Sheffield City Council and Primary Care Trust fund a range of facilities and activities to promote physical activity and variations in access to these between neighbourhoods will make it possible to examine whether the effectiveness of the intervention is modified by access to community facilities. A one-year integrated feasibility study will confirm that recruitment targets are achievable based on a 10% sample. The choice of study population, study interventions, brief intervention preceding the study, and outcome measure are discussed. Current Controlled Trials: ISRCTN56495859; ClinicalTrials.gov: NCT00836459.


myc family DNA amplification in 107 tumors and tumor cell lines from patients with small cell lung cancer treated with different combination chemotherapy regimens.
We studied 107 specimens (38 tumors and 69 tumor cell lines) from 90 patients with small cell lung cancer to determine the characteristics and clinical situations of patients from whom tumor cell lines could be established and the myc family DNA copy number. The proportion of extensive stage small cell lung cancer patients from whom a tumor cell line could be established prior to the initiation of therapy increased during the 10 years of the study (P less than 0.001). Amplification of one of the myc family genes occurred in 3 of 40 (8%) of the untreated patient specimens compared to 19 of 67 (28%) of the treated patient specimens (P = 0.01). The myc family DNA amplification occurred in 17 of 54 (31%) of the specimens from patients treated with cyclophosphamide-based combinations and 2 of 13 (15%) of the specimens from patients treated with etoposide/cisplatin (P = 0.25). Both tumors and tumor cell lines were obtained from 17 patients with small cell lung cancer and the myc family DNA copy number was similar in 16 of the 17 patients. We conclude that: (a) myc family DNA amplification occurs more commonly in specimens from treated than untreated patients (b) there are no prominent differences in the frequency of amplification following treatment with different chemotherapy regimens; and (c) myc family DNA amplification is similar in tumors and tumor cell lines from the same patients.


HOLE: a program for the analysis of the pore dimensions of ion channel structural models.
A method (HOLE) that allows the analysis of the dimensions of the pore running through a structural model of an ion channel is presented. The algorithm uses a Monte Carlo simulated annealing procedure to find the best route for a sphere with variable radius to squeeze through the channel. Results can be displayed in a graphical fashion or visualized with most common molecular graphical packages. Advances include a method to analyze the anisotropy within a pore. The method can also be used to predict the conductance of channels using a simple empirically corrected ohmic model. As an example the program is applied to the cholera toxin B-subunit pentamer. The compatibility of the crystal structure and conductance data is established.


A decision tree to determine fitness to drive in epilepsy: Results of a pilot in two Australian states.
Certification by treating physicians of fitness to drive in people with epilepsy creates a conflict of interest that may result in unsafe decisions, damage the doctor-patient relationship, expose the physician to legal liability and prevent optimal treatment. Ideally, the treating physician should provide objective clinical information to the driver licensing authority (DLA), which then determines fitness or otherwise. However, DLAs in Australia do not employ medical staff and the national standards are complex. Fitness is determined by the treating physician, according to published national standards. The purpose of this study was to determine the feasibility of using a decision tree to determine fitness, according to the Australian standards. A decision tree was constructed to use clinical data to determine whether a patient met the national standard to drive a private motorcar, failed to meet it or required further assessment. A form was designed to collect the necessary clinical data from the treating physician. A computerized version of the decision tree was then used in a pilot in two Australian states in parallel with the existing certification system. Four hundred thirty-nine drivers with declared epilepsy and their treating physicians were invited to participate when their annual driver licence review was due. Two hundred fifty-three (58%) forms were returned. All patients were considered fit to drive by their physician. Seventy-six percent had not had a seizure for over two years. In 88.1%, there was agreement between the decision tree and treating physician, with 3.6% identified by the decision tree as requiring review. Although considered fit by their physician, 6.3% did not meet the national standard to drive. The decision tree model is a practical alternative to fitness certification by treating physicians. This Australian pilot can serve as a model for applying objective standards to driving assessments in other jurisdictions, using local driving standards. It has the potential to improve road safety by avoiding the negative effects of certification by treating physicians and can cope with complex standards. It is now in use in two states of Australia.


CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity.
Aberrant activation of the canonical WNT/beta-catenin pathway occurs in almost all colorectal cancers and contributes to their growth, invasion and survival. Although dysregulated beta-catenin activity drives colon tumorigenesis, further genetic perturbations are required to elaborate full malignant transformation. To identify genes that both modulate beta-catenin activity and are essential for colon cancer cell proliferation, we conducted two loss-of-function screens in human colon cancer cells and compared genes identified in these screens with an analysis of copy number alterations in colon cancer specimens. One of these genes, CDK8, which encodes a member of the mediator complex, is located at 13q12.13, a region of recurrent copy number gain in a substantial fraction of colon cancers. Here we show that the suppression of CDK8 expression inhibits proliferation in colon cancer cells characterized by high levels of CDK8 and beta-catenin hyperactivity. CDK8 kinase activity was necessary for beta-catenin-driven transformation and for expression of several beta-catenin transcriptional targets. Together these observations suggest that therapeutic interventions targeting CDK8 may confer a clinical benefit in beta-catenin-driven malignancies.


FLOW-INDUCED MORPHOLOGICAL VARIATIONS AFFECT DIFFUSION BOUNDARY-LAYER THICKNESS OF MACROCYSTIS PYRIFERA (HETEROKONTOPHYTA, LAMINARIALES)(1).
In slow mainstream flows (<4-6 cm · s(-1) ), the transport of dissolved nutrients to seaweed blade surfaces is reduced due to the formation of thicker diffusion boundary layers (DBLs). The blade morphology of Macrocystis pyrifera (L.) C. Agardh varies with the hydrodynamic environment in which it grows; wave-exposed blades are narrow and thick with small surface corrugations (1 mm tall), whereas wave-sheltered blades are wider and thinner with large (2-5 cm) edge undulations. Within the surface corrugations of wave-exposed blades, the DBL thickness, measured using an O2 micro-optode, ranged from 0.67 to 0.80 mm and did not vary with mainstream velocities between 0.8 and 4.5 cm · s(-1) . At the corrugation apex, DBL thickness decreased with increasing seawater velocity, from 0.4 mm at 0.8 cm · s(-1) to being undetectable at 4.5 cm · s(-1) . Results show how the wave-exposed blades trap fluid within the corrugations at their surface. For wave-sheltered blades at 0.8 cm · s(-1) , a DBL thickness of 0.73 ± 0.31 mm within the edge undulation was 10-fold greater than at the undulation apex, while at 2.1 cm · s(-1) , DBL thicknesses were similar at <0.07 mm. Relative turbulence intensity was measured using an acoustic Doppler velocimeter (ADV), and overall, there was little evidence to support our hypothesis that the edge undulations of wave-sheltered blades increased turbulence intensity compared to wave-exposed blades. We discuss the positive and negative effects of thick DBLs at seaweed surfaces.


IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice.
A hallmark of SLE is the production of high-titer, high-affinity, isotype-switched IgG autoantibodies directed against nucleic acid-associated antigens. Several studies have established a role for both type I IFN (IFN-I) and the activation of TLRs by nucleic acid-associated autoantigens in the pathogenesis of this disease. Here, we demonstrate that 2 IFN-I signaling molecules, IFN regulatory factor 9 (IRF9) and STAT1, were required for the production of IgG autoantibodies in the pristane-induced mouse model of SLE. In addition, levels of IgM autoantibodies were increased in pristane-treated Irf9 -/- mice, suggesting that IRF9 plays a role in isotype switching in response to self antigens. Upregulation of TLR7 by IFN-alpha was greatly reduced in Irf9 -/- and Stat1 -/- B cells. Irf9 -/- B cells were incapable of being activated through TLR7, and Stat1 -/- B cells were impaired in activation through both TLR7 and TLR9. These data may reveal a novel role for IFN-I signaling molecules in both TLR-specific B cell responses and production of IgG autoantibodies directed against nucleic acid-associated autoantigens. Our results suggest that IFN-I is upstream of TLR signaling in the activation of autoreactive B cells in SLE.


Allergic bronchopulmonary aspergillosis in patient with cystic fibrosis - a case report.
Asthma with allergic bronchopulmonary aspergillosis (ABPA), a hypersensitivity disease of the lungs due to an immune response to Aspergillus fumigattus (Af) antigens, is rarely seen in children, other than complicating cystic fibrosis. We present the case of a 14 - year- old female teenager with cystic fibrosis (CF), admitted in our hospital with respiratory failure and persistent cyanosis. Chest X-ray showed perihilar and upper lobes pulmonary infiltrates. Her airway cultures were positive for methicillin resistant staphilococcus aureus (MRSA) and non-mucoid Pseudomonas aeruginosa. She was prescribed intravenous antibiotherapy with ceftazidime and vancomycine (to which MRSA and Pseudomonas aeruginosa were susceptible). Pulmonary function testing (PFT) revealed severe obstructive lung disease. After ten days of intravenous antibiotics and first five days of corticosteroid, the patient's FEV1 was 68% of predicted. Total serum IgE and IgE antibodies to Aspergillus fumigatus were elevated. These results raised the possibility of allergic bronchopulmonary aspergillosis (ABPA). The possibility of ABPA should be considered in all pulmonary exacerbation and in order to determine if ABPA is developing or if an exacerbation is occurring, a serial monitoring of IgE levels should be performed.