Interaction of the prion protein fragment PrP 185-206 with biological membranes: effect on membrane permeability.
Amyloids are proteinaceous aggregates related to the so-called conformational diseases, such as Alzheimer's and prion diseases. The cytotoxicity of amyloids may be related to the interaction of the amiloidogenic peptides or proteins with the cell membrane. In order to gain information on the physico-chemical effects of amyloids on membranes, we have studied the interaction of the human prion amyloidogenic fragment PrP 185-206 with negatively charged model membranes. The results show that the peptide causes the destabilization of the membrane, making it permeable to potassium ions and to charged organic compounds. This effect correlates with the interaction of the peptide with the membrane, causing a variation in the magnitude of the electrostatic surface and dipole membrane potentials. This effect on the electrostatic properties of the membranes may help explaining the observed permeability: a neutralization of the surface negative charge and a decrease of the inside-positive dipole potential would facilitate the translocation of positive ions. The structural analysis of the peptide in the presence of model membranes reveals that it adopts a predominantly unordered structure without any signs of amyloid formation. The results may be relevant in relation to the recently described cell toxic capacity of the peptide.


Formation of tethered bilayer lipid membranes probed by various surface sensitive techniques.
Tethered bilayer lipid membranes are promising biomimetic architectures. Their formation has been investigated using four different surface sensitive techniques, including optical, acoustic, and electrical methods. The lipid bilayers are built in a two-step procedure; the proximal layer is formed by self-assembly and is then completed to a bilayer by fusion with small vesicles. The different technical approaches revealed specific aspects of the layer formation processes, namely, first a fast adsorption process followed by a longer rearrangement period. Similar phenomena have been observed for the vesicle fusion process. The results allow for a more controlled assembly protocol for the preparation of highly insulating lipid membranes.


The management of chronic external otitis.
Longstanding diffuse otitis externa can lead to irreversible skin changes, canal stenosis, and deafness. Although usually responsive to aggressive medical management, some cases prove refractory. Surgery consisting of a canalplasty and meatoplasty is recommended in these rare instances. The senior author's management of this disease is outlined in detail. Three refractory cases are described, of which two required and responded to surgery with satisfactory hearing and healing. The so-called "malignant external otitis" variety has been excluded from this report.


Quantification of topically delivered 5-aminolevulinic acid by lontophoresis across ex vivo human stratum corneum.
Iontophoretic transport of the prodrug 5-aminolevulinic acid (ALA), which is used for photodynamic therapy (PDT), across human stratum corneum (SC) was studied quantitatively in vitro. The experiments were carried out in a three-compartment iontophoresis cell consisting of two electrode chambers equipped with Ag-AgCl electrodes, each separated from a central acceptor chamber by a sheet of SC, supported by a dialysis membrane, to mimic the side-by-side configuration normally used in vivo. Acceptor fluid samples were collected every hour for a period of 30 h in a fraction collector and analyzed by high-performance liquid chromatography-fluorometry after derivatization of the ALA. The iontophoretic ALA flux was studied as a function of the applied current density and the ALA concentration in the donor solution (1, 2.5 or 10% ALA). Depending on the ALA concentration in the donor cell, iontophoresis enhances the flux from close to the detection limit of 0.23 nmol cm(-2) h(-1) at zero current density (passive diffusion) to several hundred or thousand nanomoles per square centimeter per hour at current densities ranging from 100 to 1000 microA cm(-2). For example, interpolating our data we find that with an ALA concentration of 2% in the donor chamber, a current density of 0.255 mA cm(-2) transports 0.065 micromol cm(-2) ALA across the SC in 10 min (conditions of Rhodes et al. (1997), J. Invest. Dermatol. 108, 87-91). For passive diffusion we find that a 5 h topical application of 20% ALA results in the transport of 0.05 micromol cm(-2). Thus, the amount of ALA that passively diffuses through the SC in several hours, leading to therapeutic levels of protoporphyrin IX (PpIX) in the epidermis, can be delivered by iontophoresis in 10 min or less. However, because the formation of sufficient PpIX also requires several hours and also because the SC overlying skin lesions such as basal cell carcinoma (BCC) is not intact, the clinical benefit of topical ALA delivery by iontophoresis for PDT of BCC is yet to be established.


g:Profiler-a web server for functional interpretation of gene lists (2016 update).
Functional enrichment analysis is a key step in interpreting gene lists discovered in diverse high-throughput experiments. g:Profiler studies flat and ranked gene lists and finds statistically significant Gene Ontology terms, pathways and other gene function related terms. Translation of hundreds of gene identifiers is another core feature of g:Profiler. Since its first publication in 2007, our web server has become a popular tool of choice among basic and translational researchers. Timeliness is a major advantage of g:Profiler as genome and pathway information is synchronized with the Ensembl database in quarterly updates. g:Profiler supports 213 species including mammals and other vertebrates, plants, insects and fungi. The 2016 update of g:Profiler introduces several novel features. We have added further functional datasets to interpret gene lists, including transcription factor binding site predictions, Mendelian disease annotations, information about protein expression and complexes and gene mappings of human genetic polymorphisms. Besides the interactive web interface, g:Profiler can be accessed in computational pipelines using our R package, Python interface and BioJS component. g:Profiler is freely available at http://biit.cs.ut.ee/gprofiler/.


Polymorphism of the pig 2,4-dienoyl CoA reductase 1 gene (DECR1) and its association with carcass and meat quality traits.
We characterized the nearly complete coding sequence of the pig 2,4-dienoyl CoA reductase 1 (DECR1) gene, which encodes an enzyme involved in the beta-oxidation of polyunsaturated fatty enoyl-CoA esters and maps on a linoleic QTL located on Chromosome 4. Sequencing of a 937-bp fragment encompassing exons 2 and 10 revealed the existence of two missense SNP at exon 2 (C181 --> G181) and exon 5 (C458 -->G458). These two SNP are associated with Val (C) --> Leu (G) and Ser (C) --> Thr (G) conservative AA replacements at positions 61 and 153 of the DECR1 protein, respectively. Moreover, DECR1 genotyping in a representative sample of 184 pigs from the Large White, Pietrain, Iberian, Duroc, and Landrace breeds demonstrated the existence of disequilibrium linkage between these two SNP (Haplotype 1: C181C458; Haplotype 2: G181G458). An association analysis between DECR1 genotype and growth, carcass, and meat quality traits in a highly selected Landrace population (n = 470) revealed differences among genotypes for isocitrate dehydrogenase activity (highest posterior density [HPD] of 90%), longissimus thoracis pH (HPD of 95%), lightness (HPD of 90 to 95%), and redness (HPD of 95%). Because these associations were not consistently found in the three available genotype comparisons, we believe that exon 2 and 5 polymorphisms at the DECR1 gene might be in linkage disequilibrium with the true causal mutation influencing isocitrate dehydrogenase activity and muscle color and pH.


Long-term evaluation of the risk of recurrence after cerebral sinus-venous thrombosis.
The clinical course of cerebral sinus-venous thrombosis (CSVT) is largely unknown because prospective studies with a long follow-up and with the goal to assess thrombosis recurrence rate and predisposing factors for recurrence are lacking. One hundred forty-five patients with a first CSVT were followed up for a median of 6 years after discontinuation of anticoagulant treatment. End points were recurrent CSVT or other clinical manifestations of venous thromboembolism. CSVT recurred in 5 patients (3%) and other manifestations of venous thromboembolism (deep vein thrombosis of the lower limbs or pulmonary embolism) were seen in 10 additional patients (7%), for a recurrence rate of 2.03 per 100 person-years (95% confidence interval, 1.16 to 3.14) for all manifestations of venous thromboembolism and 0.53 per 100 person-years (95% confidence interval, 0.16 to 1.10) for CSVT. Nearly half of the recurrences occurred within the first year after discontinuation of anticoagulant therapy. Risk factors for recurrent venous thrombosis were male sex (adjusted hazard ratio, 9.66; 95% confidence interval, 2.86 to 32.7) and, for thromboses other than CSVT, severe thrombophilia resulting from antithrombin, protein C, protein S deficiency, anti-phospholipid antibodies, or combined abnormalities (adjusted hazard ratio, 4.71; 95% confidence interval, 1.34 to 16.5). The risk of recurrent CSVT is low and is higher in the first year after discontinuation of anticoagulant treatment and among men. Mild thrombophilia abnormalities are not associated with recurrent CSVT, but severe thrombophilia entails an increased risk of deep vein thrombosis of the lower limbs or pulmonary embolism.


Severe, traumatic soft-tissue loss in the antecubital fossa and proximal forearm associated with radial and/or median nerve palsy: nerve recovery after coverage with a pedicled latissimus dorsi muscle flap.
A total of 6 patients with complex, traumatic wounds of the antecubital fossa and proximal forearm were included in this study. All patients presented with radial and/or median nerve palsies in addition to their soft-tissue defect. Except for 1 patient with a 15-cm defect of the radial nerve, all other traumatized nerves appeared in-continuity at the time of surgery. However, the nerve injury was severe enough to induce Wallerian degeneration (i.e., axonotmesis in traumatized nerves in-continuity). Three patients required brachial artery reconstruction with a reverse saphenous vein graft. Wound coverage was accomplished using a pedicled latissimus dorsi muscle flap, which was covered with a split-thickness skin graft. Successful reconstruction was obtained in all patients. Follow-up ranged from 2 to 6 years. The range of motion at the elbow and forearm was considered excellent in 5 patients and good in the remaining patient who had an intra-articular fracture. Motor recovery of traumatized nerves in-continuity was observed in all but 1 patient who had persistent partial anterior interosseous nerve palsy. The grip strength of the injured hand measured 70% to 85% of the contralateral uninjured hand. Median nerve sensory recovery was excellent in all patients. The versatility of the pedicled latissimus dorsi muscle flap for coverage of these complex wounds with traumatized neurovascular bundles around the elbow is discussed.


Positive receptor feedback during lineage commitment can generate ultrasensitivity to ligand and confer robustness to a bistable switch.
Cytokines and lineage-specific transcription factors are critical molecular effectors for terminal differentiation during hematopoiesis. Intrinsic transcription factor activity is often believed to drive commitment and differentiation, whereas cytokine receptor signals have been implicated in the regulation of cell proliferation, survival, and differentiation. In erythropoiesis, recent experimental findings provide direct evidence that erythropoietin (Epo) can generate commitment cues via the erythropoietin receptor (EpoR); specifically, EpoR signaling leads to activation of the transcription factor GATA-1, which then triggers transcription of erythrocyte-specific genes. In particular, activated GATA-1 induces two positive feedback loops in the system through the enhanced expression of both inactive GATA-1 and EpoR, the latter of which is externally regulatable by Epo. Based upon this network architecture, we present a mathematical model of GATA-1 activation by EpoR, which bidirectionally links a lineage-specific receptor and transcription factor. Our deterministic model offers insight into stimulus-response relationships between Epo and several downstream effectors. In addition to the survival signals that EpoR provides, steady-state analysis of our model suggests that receptor upregulation during lineage commitment can also generate ultrasensitivity to Epo and bistability in GATA-1 activity. These system-level properties can induce a switch-like characteristic during differentiation and provide robustness to the mature state. The topology also suggests a novel mechanism for achieving robust bistability in a purely deterministic manner without molecular cooperativity. The analytical solution of a generalized, minimal model is provided and the significance of each of the two positive feedback loops is elucidated through bifurcation analysis. This network topology, or variations thereof, may link other receptor-transcription factor pairs and may therefore be of general relevance in cellular decision-making.


A prospective study of XELIRI plus bevacizumab as a first-line therapy in Japanese patients with unresectable or recurrent colorectal cancer (KSCC1101).
This study was designed to evaluate the efficacy and toxicity of XELIRI plus bevacizumab for the treatment of Japanese patients with unresectable or recurrent colorectal cancer (CRC). This was a multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated unresectable or recurrent CRC, presence of measurable lesions, ≥20 years of age, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients received bevacizumab (7.5 mg/kg on day 1) and XELIRI (irinotecan 200 mg/m2 on day 1 plus capecitabine 800 mg/m2 b.i.d. on days 1-14) every 3 weeks. The primary endpoint was the objective tumor response rate. A total of 36 patients were enrolled in this study from July 2011 to September 2012. One patient did not fulfill the eligibility criteria and one patient withdrew their consent before the start of the treatment protocol. The confirmed objective response rate was 58.8% (95% CI 35.1-70.2%). The median progression-free survival was 9.6 months (95% CI 5.1-11.1 months) and the median overall survival was 23.1 months (95% CI 11.3-36.7 months). The grade ≥3 adverse events that were frequently encountered in this study were neutropenia (31.4%), leukopenia (22.9%), diarrhea (22.9%), anemia (20.0%), anorexia (20.0%) and febrile neutropenia (17.2%). The frequency of grade 3/4 adverse events, such as neutropenia and leukopenia, was much higher in patients with a UGT1A1 polymorphism. A first-line therapy comprising XELIRI plus bevacizumab yielded a promising response rate. However, careful attention should be given to adverse clinical events in Japanese patients receiving treatment with unresectable or recurrent CRC.


Regulation of TCL1 expression in B- and T-cell lymphomas and reactive lymphoid tissues.
Chromosomal rearrangements observed in T-cell prolymphocytic leukemia involve the translocation of one T-cell receptor gene to either chromosome 14q32 or Xq28, deregulating the expression of cellular protooncogenes of unknown function, such as TCL1 or its homologue, MTCP1. In the human hematopoietic system, TCL1 expression is predominantly observed in developing B lymphocytes, whereas its overexpression in T cells causes mature T-cell proliferation in transgenic mice. In this study, using a newly generated monoclonal antibody against recombinant TCL1 protein, we extended our analysis mainly by immunohistochemistry and also by fluorescence-activated cell sorting and Western blot to a large tumor lymphoma data bank including 194 cases of lymphoproliferative disorders of B- and T-cell origin as well as reactive lymphoid tissues. The results obtained show that in reactive lymphoid tissues, TCL1 is strongly expressed by a subset of mantle zone B lymphocytes and is expressed to a lesser extent by follicle center cells and by scattered interfollicular small lymphocytes. In B-cell neoplasia, TCL1 was expressed in the majority of the cases, including lymphoblastic lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma (60%), and primary cutaneous B cell lymphoma (55%). TCL1 expression was observed in both the cytoplasmic and nuclear compartments, as confirmed by Western blot analysis. Conversely, TCL1 was not expressed in Hodgkin/Reed-Sternberg cells, multiple myelomas, marginal zone B-cell lymphomas, CD30+ anaplastic large cell lymphoma, lymphoblastic T-cell lymphoma, peripheral T-cell lymphoma, and mycosis fungoides. These data indicate that TCL1 is expressed in more differentiated B cells, under both reactive and neoplastic conditions, from antigen committed B cells and in germinal center B cells and is down-regulated in the latest stage of B-cell differentiation.


Stripes disrupt odour attractiveness to biting horseflies: battle between ammonia, CO₂, and colour pattern for dominance in the sensory systems of host-seeking tabanids.
As with mosquitoes, female tabanid flies search for mammalian hosts by visual and olfactory cues, because they require a blood meal before being able to produce and lay eggs. Polarotactic tabanid flies find striped or spotted patterns with intensity and/or polarisation modulation visually less attractive than homogeneous white, brown or black targets. Thus, this reduced optical attractiveness to tabanids can be one of the functions of striped or spotty coat patterns in ungulates. Ungulates emit CO2 via their breath, while ammonia originates from their decaying urine. As host-seeking female tabanids are strongly attracted to CO2 and ammonia, the question arises whether the poor visual attractiveness of stripes and spots to tabanids is or is not overcome by olfactory attractiveness. To answer this question we performed two field experiments in which the attractiveness to tabanid flies of homogeneous white, black and black-and-white striped three-dimensional targets (spheres and cylinders) and horse models provided with CO2 and ammonia was studied. Since tabanids are positively polarotactic, i.e. attracted to strongly and linearly polarised light, we measured the reflection-polarisation patterns of the test surfaces and demonstrated that these patterns were practically the same as those of real horses and zebras. We show here that striped targets are significantly less attractive to host-seeking female tabanids than homogeneous white or black targets, even when they emit tabanid-luring CO2 and ammonia. Although CO2 and ammonia increased the number of attracted tabanids, these chemicals did not overcome the weak visual attractiveness of stripes to host-seeking female tabanids. This result demonstrates the visual protection of striped coat patterns against attacks from blood-sucking dipterans, such as horseflies, known to transmit lethal diseases to ungulates.


CK2 abrogates the inhibitory effects of PRH/HHEX on prostate cancer cell migration and invasion and acts through PRH to control cell proliferation.
PRH/HHEX (proline-rich homeodomain protein/haematopoietically expressed homeobox protein) is a transcription factor that controls cell proliferation, cell differentiation and cell migration. Our previous work has shown that in haematopoietic cells, Protein Kinase CK2-dependent phosphorylation of PRH results in the inhibition of PRH DNA-binding activity, increased cleavage of PRH by the proteasome and the misregulation of PRH target genes. Here we show that PRH and hyper-phosphorylated PRH are present in normal prostate epithelial cells, and that hyper-phosphorylated PRH levels are elevated in benign prostatic hyperplasia, prostatic adenocarcinoma, and prostate cancer cell lines. A reduction in PRH protein levels increases the motility of normal prostate epithelial cells and conversely, PRH over-expression inhibits prostate cancer cell migration and blocks the ability of these cells to invade an extracellular matrix. We show that CK2 over-expression blocks the repression of prostate cancer cell migration and invasion by PRH. In addition, we show that PRH knockdown in normal immortalised prostate cells results in an increase in the population of cells capable of colony formation in Matrigel, as well as increased cell invasion and decreased E-cadherin expression. Inhibition of CK2 reduces PRH phosphorylation and reduces prostate cell proliferation but the effects of CK2 inhibition on cell proliferation are abrogated in PRH knockdown cells. These data suggest that the increased phosphorylation of PRH in prostate cancer cells increases both cell proliferation and tumour cell migration/invasion.


Prospective randomized double-blind pilot study of site-specific consensus atlas implementation for rectal cancer target volume delineation in the cooperative group setting.
Variations in target volume delineation represent a significant hurdle in clinical trials involving conformal radiotherapy. We sought to determine the effect of a consensus guideline-based visual atlas on contouring the target volumes. A representative case was contoured (Scan 1) by 14 physician observers and a reference expert with and without target volume delineation instructions derived from a proposed rectal cancer clinical trial involving conformal radiotherapy. The gross tumor volume (GTV), and two clinical target volumes (CTVA, including the internal iliac, presacral, and perirectal nodes, and CTVB, which included the external iliac nodes) were contoured. The observers were randomly assigned to receipt (Group A) or nonreceipt (Group B) of a consensus guideline and atlas for anorectal cancers and then instructed to recontour the same case/images (Scan 2). Observer variation was analyzed volumetrically using the conformation number (CN, where CN = 1 equals total agreement). Of 14 evaluable contour sets (1 expert and 7 Group A and 6 Group B observers), greater agreement was found for the GTV (mean CN, 0.75) than for the CTVs (mean CN, 0.46-0.65). Atlas exposure for Group A led to significantly increased interobserver agreement for CTVA (mean initial CN, 0.68, after atlas use, 0.76; p = .03) and increased agreement with the expert reference (initial mean CN, 0.58; after atlas use, 0.69; p = .02). For the GTV and CTVB, neither the interobserver nor the expert agreement was altered after atlas exposure. Consensus guideline atlas implementation resulted in a detectable difference in interobserver agreement and a greater approximation of expert volumes for the CTVA but not for the GTV or CTVB in the specified case. Visual atlas inclusion should be considered as a feature in future clinical trials incorporating conformal RT.


Restructuring of the amphibian gut microbiota through metamorphosis.
Vertebrates maintain complex symbioses with a diverse community of microbes residing within their guts. The microbial players in these symbioses differ between major taxa of vertebrates, such that fish and amniotes maintain notably different communities. To date, there has not been a culture-independent inventory of an amphibian gut microbial community. Here, we compared gut microbial communities of tadpoles and frogs of the Northern leopard frog (Lithobates pipiens). We utilized Illumina sequencing, which allowed us to inventory more than 450 000 microbial sequences. We found that tadpoles and frogs differ markedly in the composition of their gut microbial communities, with tadpoles maintaining a community more similar to fish, whereas the frog community resembles that of amniotes. Additionally, frogs maintain a community with lower phylogenetic diversity compared with tadpoles. The significant restructuring of the microbiota is likely due to changes in diet as well as the large reorganization of the intestinal organ during metamorphosis. Overall, we propose that amphibians represent an important system in which to study regulation and selection of gut microbial communities.


Enhancement of angiotensin II type 1 receptor-associated protein in the paraventricular nucleus suppresses angiotensin II-dependent hypertension.
The renin-angiotensin system in the brain plays a pivotal role in modulating sympathetic nerve activity and contributes to the pathogenesis of hypertension. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R while suppressing pathological overactivation of AT1R signaling. However, the pathophysiological function of ATRAP in the brain remains unknown. Therefore, this study aims to investigate whether ATRAP in the paraventricular nucleus (PVN) is involved in neurogenic hypertension pathogenesis in Ang II-infused rats. The ATRAP/AT1R ratio, which serves as an indicator of tissue AT1R hyperactivity, tended to decrease within the PVN in the Ang II group than in the vehicle group. This suggests an Ang II-induced hyperactivation of the AT1R signaling pathway in the PVN. Lentiviral vectors were generated to stimulate ATRAP expression. At 6 weeks of age, rats were microinjected with LV-Venus (Venus-expressing lentivirus) or LV-ATRAP (Venus-ATRAP-expressing lentivirus). The rats were then randomly divided into four groups: (1) Vehicle/LV-Venus, (2) Vehicle/LV-ATRAP, (3) Ang II/LV-Venus, and (4) Ang II/LV-ATRAP. Two weeks after microinjection, vehicle or Ang II was administered systemically for 2 weeks. In the Ang II/LV-ATRAP group, systolic blood pressure at 1 and 2 weeks following administration was significantly lower than that in the Ang II/LV-Venus group. Furthermore, urinary adrenaline levels tended to decrease in the Ang II/LV-ATRAP group than in the Ang II/LV-Venus group. These findings suggest that enhanced ATRAP expression in the PVN suppresses Ang II-induced hypertension, potentially by suppressing hyperactivation of the tissue AT1R signaling pathway and, subsequently, sympathetic nerve activity.


Incidence of cancer among commercial airline pilots.
To describe the cancer pattern in a cohort of commercial pilots by follow up through the Icelandic Cancer Registry. This is a retrospective cohort study of 458 pilots with emphasis on subcohort working for an airline operating on international routes. A computerised file of the cohort was record linked to the Cancer Registry by making use of personal identification numbers. Expected numbers of cancer cases were calculated on the basis of number of person-years and incidences of cancer at specific sites for men provided by the Cancer Registry. Numbers of separate analyses were made according to different exposure variables. The standardised incidence ratio (SIR) for all cancers was 0.97 (95% confidence interval (95% CI) 0.62 to 1.46) in the total cohort and 1.16 (95% CI 0.70 to 1.81) among those operating on international routes. The SIR for malignant melanoma of the skin was 10.20, 95% CI 3.29 to 23.81 in the total cohort and 15.63, 95% CI 5.04 to 36.46 in the restricted cohort. Analyses according to number of block-hours and radiation dose showed that malignant melanomas were found in the subgroups with highest exposure estimates, the SIRs were 13.04 and 28.57 respectively. The SIR was 25.00 for malignant melanoma among those who had been flying over five time zones. The study shows a high occurrence of malignant melanoma among pilots. It is open to discussion what role exposure of cosmic radiation, numbers of block-hours flown, or lifestyle factors--such as possible excessive sunbathing--play in the aetiology of cancer among pilots. This calls for further and more powerful studies. The excess of malignant melanoma among those flying over five time zones suggests that the importance of disturbance of the circadian rhythm should be taken into consideration in future studies.


A Case of Metastatic CNS Melanoma of Unknown Primary Presenting with Seizures.
Seizures are a common occurrence. The goal of evaluating a seizure is to identify the etiology and to determine the likelihood of recurrence as well as guide management. We present a unique presentation of a 47-year-old female that presented with late onset seizures admitted due to status epilepticus. Brain magnetic resonance indicated diffuse supratentorial hemorrhagic lesions. Neurological workup including brain vessel imaging, CT chest, abdomen, and pelvis as well as CSF and serological workup for vasculitis failed to demonstrate the cause of her brain lesions. Ultimately, a brain biopsy showed metastatic melanoma of unknown primary origin.


Functional materials with self-healing properties: a review.
Self-healing materials (SHMs) have been a research hot topic in recent years owing to their greatly improved longevity and safety in practical applications. Recently, research on SHMs has gradually expanded from structural materials to functional materials. Functional materials with self-healing properties (FMSH) require simultaneous repairing not only of the mechanical properties but of the functionalities from damaged cracks or wounds. It is more challenging to introduce both self-healing properties and a particular functionality to materials owing to the difficulties of preparing the materials and their more complex healing mechanism. Herein, we summarize the recent progress that has been made in FMSH, put forward insights from the perspectives of material preparation and healing mechanisms and highlight future developments for FMSH.


Differentiation of the atrioventricular node, the atrioventricular bundle and the bundle branches in the bovine heart: an immunohistochemical and enzyme histochemical study.
The previous observations of differences between different cardiac regions (ventricular myocardium, atrial myocardium, Purkinje fibre system) with respect to the maturation of the M-line region and the establishment of mature metabolic characteristics, have been extended. It was found that M-line maturation proceeds differently also between different regions of the conduction system. The M-line proteins, myomesin and MM-creatine kinase, were detected earlier, by means of immunohistochemistry, in the AV bundle and bundle branch cells than in the AV node cells. Also, a difference was observed in large foetuses. Striations in the AV node were less evident than in the AV bundle and the bundle branches in sections incubated with antibodies against myomesin as well as against MM-creatine kinase. Using enzyme histochemistry it was observed that the differences in metabolic properties between the AV node, the AV bundle and the bundle branches on the one hand, and the ordinary myocardium on the other, of adult hearts, are not established at the early stages. No clear difference in activity of succinate dehydrogenase was seen between the conduction tissues and the ordinary myocardium in the foetal hearts, while the conduction tissues showed a lower activity in the adult hearts. Furthermore, the pattern of activity of mitochondrial glycerol-3-phosphate dehydrogenase between the conduction tissues and the atrial and ventricular myocardium was quite different in early foetal stages compared with the adult stage.


Rationale behind using valproic acid for Non-Hodgkin lymphoma: a biomolecular perspective.
Non-Hodgkin lymphoma (NHL) is a hematological malignancy with a high rate of relapse and refractory cases. It is believed to be caused by resistance to standard treatment modalities. Valproic acid (VPA), previously used as a broad-spectrum anticonvulsant drug, has been proposed for NHL owing to its action of epigenetic modification by inhibiting histone deacetylase. However, VPA studies on NHL are limited. This review describes the rationale behind the use of VPA for NHL treatment, particularly focusing on its molecular mechanism of action. This is a narrative review. The literature search strategy for indexed Scopus articles was performed randomly using PubMed and MEDLINE as the primary sources. No specific term was used. Several mechanisms are responsible for NHL development. VPA can modulate these mechanisms via epigenetic and nonepigenetic modifications. It may also have an impact on the proteins responsible for treatment resistance. The mechanisms of action of VPA in NHL are as follows: the induction of cell cycle arrest via the upregulation of cyclin-dependent protein kinase inhibitors; induction of Apo2 ligand or tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis; inactivation of B-cell lymphoma 6; inhibition of Janus kinase/signal transducer and activator of transcription, phosphoinositide 3-kinase/Akt, and nuclear factor kappa B signaling pathways; upregulation of tumor antigen as the primary target of immunotherapy; and strengthening of tumor immunosurveillance. Based on its biomolecular mechanism of action, VPA appears to be a promising initial treatment before initiating the standard treatment in patients with NHL to overcome resistance.


A non-opioid analgesic implant for sustained post-operative intraperitoneal delivery of lidocaine, characterized using an ovine model.
Appropriate management of post-operative pain is an ongoing challenge in surgical practice. At present, systemic opioid administration is routinely used for analgesia in the post-operative setting. However, due to significant adverse effects and potential for misuse, there is a perceived need for the development of alternative, opioid-sparing treatment modalities. Continuous infusion of local anesthetic into the peritoneum after major abdominal surgery reduces pain and opioid consumption, and enhances recovery from surgery. Here we describe a non-opioid, poly(ethylene-co-vinyl-acetate) intraperitoneal implant for the sustained delivery of local anesthetic following major abdominal surgery. A radio-opaque core had the required mechanical strength to facilitate placement and removal procedures. This core was enclosed by an outer shell containing an evenly dispersed local anesthetic, lidocaine. Sustained release of lidocaine was observed in an ovine model over days and the movement modelled between peritoneal fluid and circulating plasma. While desirably high levels of lidocaine were achieved in the peritoneal space these were several orders of magnitude higher than blood levels, which remained well below toxic levels. A pharmacokinetic model is presented that incorporates in vitro release data to describe lidocaine concentrations in both peritoneal and plasma compartments, predicting similar release to that suggested by lidocaine concentrations remaining in the device after 3 and 7 days in situ. Histological analysis revealed similar inflammatory responses following implantation of the co-extruded implant and a commercially used silicone drain after three days. This non-opioid analgesic implant provides sustained release of lidocaine in an ovine model and is suitable for moving onto first in human trials.


Immunoglobulin D multiple myeloma in our hospital--a rare occurrence.
Immunoglobulin (Ig) D multiple myeloma is a rare presentation, usually with an aggressive course and a poorer prognosis. It accounts for about 1-2% of newly diagnosed mulitple myeloma patients. Due to its rarity, reports on Ig D multiple myeloma are limited in the literature. We therefore present 4 cases of Ig D multiple myeloma in our hospital over a period of 8 years between 1990 to 1998. The average age of presentation of our patients was 44 years old with a female preponderance. Common presenting symptoms were appetite and weight loss and bone pain. Two patients presented with neurological symptoms and 2 with renal impairment. Three patients had an associated lambda paraproteinaemia and the fourth had a kappa paraproteinaemia. A common finding in Ig D myeloma is a small or no spike seen on serum electrophoresis together with heavy Bence Jones proteinuria. A review of the literature on Ig D myeloma is also presented.


Polo-like kinase 1 phosphorylation of p150Glued facilitates nuclear envelope breakdown during prophase.
Nuclear envelope breakdown (NEBD) is an essential step during the G2/M transition in higher eukaryotic cells. Increasing evidence supports the notion that both microtubules and microtubule-associated motor proteins are critical regulators of NEBD. Although it has been described that p150(Glued), the major component of the dynein/dynactin complex, localizes in the nuclear envelope during prophase, the exact role of p150(Glued) and its regulation during NEBD are largely elusive. Polo-like kinase 1 (Plk1), the best characterized Ser/Thr kinase, is involved in mitotic entry in several systems; however, the targets of Plk1 during NEBD are unknown. Herein, we show that in mammalian cells both Plk1 and p150(Glued) regulate NEBD and that Plk1 interacts with and phosphoryates p150(Glued) during NEBD at prophase. Using various approaches, we showed that Plk1 phosphorylates p150(Glued) at Ser-179 and that the pS179 epitope is generated at the nuclear envelope of prophase cells. Significantly, Plk1-mediated phosphorylation of p150(Glued) at Ser-179 positively regulates its accumulation at the nuclear envelope during prophase. Finally, we found that cells expressing the Plk1-unphosphorylatable mutant (p150(Glued)-S179A) arrest at G2, as indicated by reduced NEBD, increased levels of cyclin B and phospho-H3, but a decreased level of Cdc2 kinase activity. Taking these data together, we conclude that Plk1 phosphorylation of p150(Glued) might be one major pathway of NEBD regulation.


Alternative Transcription at Venom Genes and Its Role as a Complementary Mechanism for the Generation of Venom Complexity in the Common House Spider.
The complex composition of venom, a proteinaceous secretion used by diverse animal groups for predation or defense, is typically viewed as being driven by gene duplication in conjunction with positive selection, leading to large families of diversified toxins with selective venom gland expression. Yet, the production of alternative transcripts at venom genes is often overlooked as another potentially important process that could contribute proteins to venom, and requires comprehensive datasets integrating genome and transcriptome sequences together with proteomic characterization of venom to be fully documented. In the common house spider, Parasteatoda tepidariorum, we used RNA sequencing of four tissue types in conjunction with the sequenced genome to provide a comprehensive transcriptome annotation. We also used mass spectrometry to identify a minimum of 99 distinct proteins in P tepidariorum venom, including at least 33 latrotoxins, pore-forming neurotoxins shared with the confamilial black widow. We found that venom proteins are much more likely to come from multiple transcript genes, whose transcripts produced distinct protein sequences. The presence of multiple distinct proteins in venom from transcripts at individual genes was confirmed for eight loci by mass spectrometry, and is possible at 21 others. Alternative transcripts from the same gene, whether encoding or not encoding a protein found in venom, showed a range of expression patterns, but were not necessarily restricted to the venom gland. However, approximately half of venom protein encoding transcripts were found among the 1,318 transcripts with strongly venom gland biased expression. Our findings revealed an important role for alternative transcription in generating venom protein complexity and expanded the traditional model of venom evolution.


[Developing the concept of neurosis (II): nosology and neurosis].
The apparition of the concept of "nervous alteration" in the XVII century, offers to psychiatry the possibility of a better and more solid development. Based on the Linneus idea of discrimination, description and classifications, nosologists constructed several ordinations of pathology. One of them, W. Cullen, using the nosologic method created the term "neurosis" to clarify these ideas in order to nervous alterations.


Anti-inflammatory effect by exclusive enteral nutrition (EEN) in a patient with juvenile idiopathic arthritis (JIA): brief report.
There is extensive evidence for influence of gut microbiota on health. Exclusive enteral nutrition (EEN) possibly changes gut microbiota, but the exact pathophysiological role is unknown. EEN has been shown to have an anti-inflammatory effect in children with Mb Crohn, an inflammatory bowel disease. The intestinal tract is very scarcely studied in children with juvenile idiopathic arthritis (JIA), but data points to an immunologically important role. The aim of this study was to explore if EEN had any anti-inflammatory effect in children with JIA. The first patient enrolled in the study was followed for 1 year. She had onset of severe polyarticular disease at 3.2 years of age, negative in RF, anti-CCP, ANA, and HLA-B27. She was included in the study at 7.4 years of age. Exclusive enteral nutrition was given in two periods of almost 7 weeks each, several months apart, during the year of the study. Clinical and laboratory status were assessed before, during, and after treatment periods. In this patient, EEN had remarkable anti-inflammatory effect that was sustained for months after each of two separate treatment periods. Exclusive enteral nutrition is a possible anti-inflammatory treatment in patients with JIA, but to what extent EEN is effective in other children with JIA needs to be explored, as well as the possible pathophysiological role of EEN in those children.


Traumatic Pneumothorax in a 58-Year-Old Man: A Case Report of a Rare Post-Acupuncture Adverse Event.
BACKGROUND The prevalence of chronic medical conditions continues to rise, as does the number of patients seeking alternative treatments for them. Chronic pain is a prevalent medical complaint and acupuncture often is used to treat it. The Chinese literature documents several adverse events (AEs) associated with acupuncture, including cardiac tamponade, pneumothorax, infection, and nerve injuries. These complications are rare and may be associated with anatomical characteristics of the patients and deep insertion of the acupuncture needles. Differences in body type, weight, height, sex, and muscle mass contribute to anatomical differences and the depth at which vital organs lie. Having a better understanding of these anatomical differences may alter the occurrence of such AEs. CASE REPORT A slim 58-year-old man who was treated for neck pain with acupuncture presented with 2-day history of moderate-severity pleuritic and sharp pain radiating from the left scapula to the midaxillary and retrosternal area. A left-sided pneumothorax was diagnosed on chest X-ray and the patient was treated with a chest tube. CONCLUSIONS This case underscores that acupuncture can result in complications such as a pneumothorax from puncture of the pleura. These types of AEs from acupuncture can be avoided with a better understanding of anatomical differences, including body mass index and variations in depth associated with body size, musculature, or skeletal structure. When placing the needles, it is crucial for practitioners to know that the depth at which vital organs lie may differ between patients.


Effect of coronary thrombolysis on the plasma concentration of osteonectin (SPARC, BM40) in patients with acute myocardial infarction.
Osteonectin is a phosphoglycoprotein exclusively located in bone and platelet alpha-granules. Human platelet-derived osteonectin is released into plasma after thrombin-induced activation. Recognizing the unique distribution of the osteonectin pool, we first sought to investigate whether osteonectin could serve as a sensitive marker of platelet activity, and identify patients with acute myocardial infarction (AMI). The second objective was to define the effects of thrombolytic therapy in these patients on the plasma concentrations of osteonectin at prespecified time points following attempted reperfusion. Osteonectin levels by ELISA were determined in AMI patients before thrombolysis and at 3, 6, 12, and 24 hours thereafter and compared with 12 healthy controls. At baseline, soluble osteonectin plasma levels were similar between controls (447. 7+/-20.6 ng/ml) and AMI patients (425.7+/-43.3 ng/mL; p=NS). A significant increase of the soluble osteonectin was observed at 3 hours after thrombolysis (519.4+/-26.9 ng/mL; p=0.03), and was followed by a decrease to baseline levels at 6 hours after attempted reperfusion. Contrary to expectations, the plasma osteonectin level in our pilot study was not a sensitive marker distinguishing patients with AMI. The early peak of soluble osteonectin at 3 hours after thrombolytic therapy is most likely not related to coronary thrombolysis per se but rather to the phasic changes of platelet activity during myocardial ischemia-reperfusion. The unquestionable platelet origin of this protein and the lack of elevated plasma levels of this alpha-granule constituent, challenge the postulate of uniform platelet activation in AMI patients.


Genetic Association of the Functional WDR4 Gene in Male Fertility.
Infertility is one of the important problems in the modern world. Male infertility is characterized by several clinical manifestations, including low sperm production (oligozoospermia), reduced sperm motility (asthenozoospermia), and abnormal sperm morphology (teratozoospermia). WDR4, known as Wuho, controls fertility in Drosophila. However, it is unclear whether WDR4 is associated with clinical manifestations of male fertility in human. Here, we attempted to determine the physiological functions of WDR4 gene. Two cohorts were applied to address this question. The first cohort was the general population from Taiwan Biobank. Genomic profiles from 68,948 individuals and 87 common physiological traits were applied for phenome-wide association studies (PheWAS). The second cohort comprised patients with male infertility from Wan Fang Hospital, Taipei Medical University. In total, 81 male participants were recruited for the genetic association study. Clinical records including gender, age, total testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total sperm number, sperm motility, and sperm morphology were collected. In the first cohort, results from PheWAS exhibited no associations between WDR4 genetic variants and 87 common physiological traits. In the second cohort, a total of four tagging single-nucleotide polymorphisms (tSNPs) from WDR4 gene (rs2298666, rs465663, rs2248490, and rs3746939) were selected for genotyping. We found that SNP rs465663 solely associated with asthenozoospermia. Functional annotations through the GTEx portal revealed the correlation between TT or TC genotype and low expression of WDR4. Furthermore, we used mouse embryonic fibroblasts cells from mwdr4 heterozygous (+/‒) mice for functional validation by western blotting. Indeed, low expression of WDR4 contributed to ROS-induced DNA fragmentation. In conclusion, our results suggest a critical role of WDR4 gene variant as well as protein expression in asthenozoospermia.


[Creativity and psychiatric disorders: exploring a marginal area].
Creativity is an important human quality on which many of man's achievements are based. To give a historical and cultural context, to facilitate meaningful scientific research into the link between creativity and psychiatric disorders. Review of relevant literature. The possibility of a link between creativity and psychiatric vulnerability was first discussed in antiquity. Modern interest in the subject stems from the romantic era and acquired a scientific aura in the 19th century. In the 20th century creativity and psychopathology became still further entangled as a result of the influence that mentally disturbed artists exerted on art. The history of the Prinzhorn collection illustrates many aspects of this interaction. Psychometric, psychodiagnostic and genetic research supports a link between creativity and psychiatric illness within the bipolar-psychotic continuum, with schizotypy/thymotypy as prototypes of creativity-related disorders. Evolutionary hypotheses connect the schizophrenia paradox to a survival advantage obtained as a result of enhanced creative ability. Neuro-aesthetics explains the neurologic correlates of the aesthetic experience on the basis of the features of the visual system. A specific challenge for scientific research in this complex and heterogeneous area is appropriate operationalisation of creativity and psychiatric illness within an truly artistic context. There is a continuing need for meaningful definitions and measurement instruments and for a multidisciplinary collaboration.


Src Inhibits the Hippo Tumor Suppressor Pathway through Tyrosine Phosphorylation of Lats1.
The Hippo pathway regulates cell proliferation, apoptosis, and stem cell self-renewal, and its inactivation in animal models causes organ enlargement followed by tumorigenesis. Hippo pathway deregulation occurs in many human cancers, but the underlying mechanisms are not fully understood. Here, we report tyrosine phosphorylation of the Hippo pathway tumor suppressor LATS1 as a mechanism underlying its regulation by cell adhesion. A tyrosine kinase library screen identified Src as the kinase to directly phosphorylate LATS1 on multiple residues, causing attenuated Mob kinase activator binding and structural alteration of the substrate-binding pocket in the kinase domain. Cell matrix adhesion activated the Hippo pathway effector transcription coactivator YAP partially through Src-mediated phosphorylation and inhibition of LATS1. Aberrant Src activation abolished the tumor suppressor activity of LATS1 and induced tumorigenesis in a YAP-dependent manner. Protein levels of Src in human breast cancer tissues correlated with accumulation of active YAP dephosphorylated on the LATS1 target site. These findings reveal tyrosine phosphorylation of LATS1 by Src as a novel mechanism of Hippo pathway regulation by cell adhesion and suggest Src activation as an underlying reason for YAP deregulation in tumorigenesis. Cancer Res; 77(18); 4868-80. ©2017 AACR.


Tumours of the callosal area: problems and surgical strategies.
Tumours of the callosal area are quite common. However, those primarily located in this region which remain confined within the corpus callosum area not frequent. The introduction of intraoperative location devices, coupled with preoperative MR, CT and angiography, has further enhanced the operability of lesions of the deep area around the callosal body. On the basis of their site of origin, three groups of tumours can be identified: tumours originating from the corpus callosum (defined as properly callosal); tumours secondarily invading the corpus callosum; tumours affecting the corpus callosum because of their surgical approach. Various routes have been developed to reach the callosal area, the site and direction of growth of the tumour providing indications for the preferred approach. The commonest routes are the following: interhemispheric approach; transcerebral approach; transcallosal approach; the transcallosal approach to the ventricles offers a valuable corridor in the management of intraventricular tumours. It provides a rapid and safe access, without the attendant epilepsy that often follows the transcortical approach. The neuro-psychological effect of callosotomy are minimal and not affecting the daily activities of patients. Thus it is possible to reach remote regions through a narrow entry with very low neuro-psychological impact.


Comparison of four contingent valuation methods to estimate the economic value of a pneumococcal vaccine in Bangladesh.
To compare four contingent valuation elicitation methods as a means to estimate the value of a pneumococcal vaccine in Bangladesh and to test if the elicitation methods are subject to bias and if they produce valid responses. Three hundred sixty-one households with at least one child under 5 years of age were recruited in Dhaka, Bangladesh. Subjects were cluster-randomized to various elicitation methods: open-ended, dichotomous choice (at one of two asking prices), payment card (one of two cards with differing ranges). The dichotomous choice method was then followed up with a bidding game methodology, with the dichotomous choice price acting as the starting price for the bidding game. Analysis focused on summary statistics, demand curve estimation and multivariate regression analysis to test for validity and bias. Thirty-one households refused to participate, leaving a total of 330 participating households (a 91.4 percent response rate). Willingness to pay estimates varied significantly across the methods (p < .001), with average estimates varying between $2.34 and $18 (US). The open-ended elicitation method was found to produce highly inflated values that were insensitive to construct validity tests. The dichotomous choice method produced quantity (demand) estimates rather than value estimates, and there was some evidence of yea-saying. The payment card elicitation method was found to be affected by range bias. The bidding game elicitation method was found to be less sensitive to starting point bias and yea-saying. Different elicitation format do give rise to different demand curves; however, this may be partially due to the fact that they do not measure the same outcome. For example, the dichotomous choice format produces a demand curve, while the payment card, open-ended and bidding game produce inverse demand curves. All formats are prone to multiple biases. When choosing an elicitation format, it is important to first consider the purpose and use of the data. Each elicitation method has strengths and weaknesses and can be used for different purposes in technology assessment.


pH-Induced conformational change of ATPase inhibitor from yeast mitochondria. A proton magnetic resonance study.
The ATPase inhibitor from yeast, Saccharomyces cerevisiae, was found to strongly inhibit the ATPase activity when it was preincubated in an acidic pH region. This paper describes the conformational changes of the inhibitor in the acidic pH region, as studied by 1H NMR spectroscopy. In the pH range from 7.43 to 4.48, two conformations were detected. With lowering of the pH in this pH region, one conformation increased at the expense of the other. In the two conformations, His 39 had different pKa values which were determined at 23 degrees C to be 6.08 +/- 0.04 and 5.91 +/- 0.03 from the pH-titration curves of His 39. The exchange between the two conformations was reversible with pH and the rate of the conformational change was estimated to be slower than 22 s-1 at 23 degrees C as estimated by the line-widths (7.0 Hz) of the peaks from the C2-proton of His 39 in the two conformations. The equilibrium constant between the two conformations was dependent on the temperature. From the equilibrium constants in the temperature range from 23 to 45 degrees C, the apparent delta H'a of the conformational change was calculated to be 14 kcal/mol at pH 6.95. It was confirmed by 1H NMR spectra that at pH 6.95 the structure of the inhibitor was reversible with temperature at least below 80 degrees C. The reversibility is consistent with the high thermal stability of the protein.


Psychophysical and physiological evidence for parallel afferent pathways mediating the sensation of itch.
The neuronal pathways for itch have been characterized mainly based on responses to histamine. Intracutaneous application of histamine produces intense itch and a large area of axon-reflexive vasodilation ("flare") around the application site. Both phenomena are thought to be mediated through neuronal activity in itch-specific, mechanoinsensitive C-fiber afferents (CMi). However, mechanical and electrical stimuli that do not activate CMi fibers can cause the sensation of itch, and itch may occur without flare, suggesting that other neuronal itch pathways exist. Because cutaneous application of spicules from the plant Mucuna pruriens (cowhage) has been anecdotally reported to produce itch without flare, we performed psychophysical experiments to investigate whether the mechanisms underlying cowhage- and histamine-induced itch differ. Although histamine and cowhage produced itch of similar magnitude, the itch to cowhage was not correlated with the itch to histamine; some subjects had intense itch to cowhage and little itch to histamine and visa versa. Laser Doppler measurements of blood flow revealed that histamine led to a large area of vasodilation, whereas cowhage produced vasodilation restricted to the application site. Pretreatment of the skin with an antihistamine blocked the itch produced by histamine but did not prevent cowhage-induced itch. Desensitization of the skin with topical capsaicin abolished cowhage-induced itch but did not significantly alter histamine-induced itch. These findings indicate that cowhage itch is signaled through a population of capsaicin-sensitive afferent nerve fibers that is distinct from CMi fibers mediating histamine-induced itch. Cowhage may be useful to investigate the neural pathway mediating nonhistaminergic itch.


Pork products associated with human infection caused by an emerging phylotype of hepatitis E virus in England and Wales.
Since 2010, human hepatitis E infections have increased in England and Wales. Most cases are locally acquired and caused by hepatitis E virus genotype 3 (HEV G3). HEV G3 is linked to the consumption of pork products. The increase is associated with the emergence of a new phylotype, HEV G3-group 2 (G3-2, also known as G3abcdhij). Sixty individuals with confirmed hepatitis E infection and no history of travel outside the UK were recruited: 19 were infected with HEV G3-group 1 (G3-1 or G3efg) and 41 with G3-2. Epidemiological data relating to usual shopping habits and consumption of ham and sausages were analysed together with typing data to identify any associations with HEV phylotype. Study participants who purchased ham and/or sausage from a major supermarket were more likely to have HEV G3-2 infection (Relative risks 1·85, P = 0·06, CI 0·97-3·53). The HEV G3-2 phylotype has not been detected in indigenous UK pigs and it is suggested that human infections could be the result of consumption of products made from pork originating outside the UK. This does not infer blame on the supermarket but the epidemiology of HEV is dynamic and reflects complex animal husbandry practices which need to be explored further.


Parental history of myopia, sports and outdoor activities, and future myopia.
To identify whether parental history of myopia and/or parent-reported children's visual activity levels can predict juvenile-onset myopia. Survey-based data from Orinda Longitudinal Study of Myopia subjects from 1989 to 2001 were used to predict future myopia. Univariate and multiple logistic regression analyses were performed, and receiver operator characteristic (ROC) curves were generated. Differences among the areas under the ROC curves were compared using the method of multiple comparison with the best. Of the 514 children eligible for this analysis, 111 (21.6%) became myopic. Differences in the third grade between eventual myopes and nonmyopes were seen for the number of myopic parents (P < 0.001) and for the number of sports and outdoor activity hours per week (11.65 +/- 6.97 hours for nonmyopes vs. 7.98 +/- 6.54 hours for future myopes, P < 0.001). Analysis of the areas under the ROC curves showed three variables with a predictive value better than chance: the number of myopic parents, the number of sports and outdoor activity hours per week, and the number of reading hours per week. After controlling for sports and outdoor hours per week and parental myopia history, reading hours per week was no longer a statistically significant factor. The area under the curve for the parental myopia history and sports and outdoor activities model was 0.73. A significant interaction in the logistic model showed a differential effect of sport and outdoor activity hours per week based on a child's number of myopic parents. Parental history of myopia was an important predictor in univariate and multivariate models, with a differential effect of sports and outdoor activity hours per week based on the number of myopic parents. Lower amounts of sports and outdoor activity increased the odds of becoming myopic in those children with two myopic parents more than in those children with either zero or one myopic parent. The chance of becoming myopic for children with no myopic parents appears lowest in the children with the highest amount of sports and outdoor activity, compared with those with two myopic parents.


Dual protective role for glutathione S-transferase class pi against VCD-induced ovotoxicity in the rat ovary.
The occupational chemical 4-vinylcyclohexene diepoxide (VCD) selectively destroys ovarian small pre-antral follicles in rats and mice via apoptosis. Detoxification of VCD can occur through glutathione conjugation, catalyzed by glutathione S-transferase (GST) enzymes. Further, GST class pi (GSTp) can negatively regulate JNK activity through protein:protein interactions in extra-ovarian tissues. Dissociation of this protein complex in the face of chemical exposure releases the inhibition of pro-apoptotic JNK. Increased JNK activity during VCD-induced ovotoxicity has been shown in isolated ovarian small pre-antral follicles following in vivo dosing of rats (80mg/kg/day; 15days, i.p.). The present study investigated the pattern of ovarian GSTp expression during VCD exposure. Additionally, the effect of VCD on an ovarian GSTp:JNK protein complex was investigated. PND4 F344 rat ovaries were incubated in control medium+/-VCD (30muM) for 2-8days. VCD increased ovarian GSTp mRNA (P <0.05) relative to control on d4-d8; whereas GSTp protein was increased (P<0.05) on d6-d8. A GSTp:JNK protein complex was detected by immunoprecipitation and Western blotting in ovarian tissues. Relative to control, the amount of GSTp-bound JNK was increased (P=0.09), while unbound JNK was decreased (P<0.05) on d6 of VCD exposure. The VCD-induced decrease in unbound JNK was preceded by a decrease in phosphorylated c-Jun which occurred on d4. These findings are in support of a possible dual protective role for GSTp in the rat ovary, consisting of metabolism of VCD and inhibition of JNK-initiated apoptosis.


Mapping stakeholders of the Palestinian Health Research System: a qualitative study.
There is a growing international and regional interest in Health Research Systems (HRSs) in light of a global strategy for HRS stakeholders' (HRSSHs) active involvement. HRSSHs in Palestine have rarely been investigated with regard to uncertainties. This study aimed to analyse perceptions of HRSSHs in order to understand their roles and involvement, identify gaps, and offer policy solutions for stakeholders' engagement in the Palestinian HRS. This qualitative study targeted three local Palestinian health sectors, government, academia, and local and international agencies. Data were collected through 52 in-depth interviews (IDIs) and 6 focus group discussions (FGDs) and then analysed using MAXQDA 12 software. Participants and institutions were selected purposively based on a set of criteria and peer review. The overall HRS stakeholders' roles were unsatisfactory, with low involvement from society, the private sector, local and international sectors. The role of academia and the Ministry of Health is vital but observed moderate in health research while that of international agencies is weak due to conflicting agendas and lack of a guiding body. Most universities have poor representation in public decision-making and scarcity in health research potential and capacity. Interest-power imbalance among stakeholders is reported where political, organizational, and technical shortfalls were indicative of weak roles and low involvement, along with a lack of health research culture, structure, resources, defined roles, and network. Tackling the inadequate roles, interests' disparity, and poor involvement of HRSSHs is imperative for HRS strengthening. Redefining HRSSHs' roles and involving all stakeholders is key through strategic dialogue, consolidated leadership, and resource mobilization.


Optimizing the Management Algorithm for Esophageal Dysphagia After Index Endoscopy: Cost-Effectiveness and Cost-Minimization Analysis.
Guidelines advise esophageal motility testing for dysphagia when structural disorders are ruled out, but cost concerns impede adoption. We evaluated cost-effective positioning of esophageal motility testing in the algorithm to evaluate esophageal dysphagia. We developed a decision analytic model comparing 3 strategies: (i) esophageal manometry, (ii) screening impedance planimetry followed by esophageal manometry if needed, or (iii) nonalgorithmic usual care. Diagnostic test accuracy was adapted to expected rates of esophageal motility disorders in general gastroenterology populations. We modeled routine testing for all patients with nonstructural/mechanical dysphagia compared with selective testing with strong suspicion for achalasia. Cost outcomes were defined on national commercial and Medicare datasets stratified on age and sex. Health outcomes were modeled on populations with achalasia. The time horizon was 1 year. Motility testing was preferred over nonalgorithmic usual care due to cost savings rather than health gains. To commercial insurers, routine esophageal manometry for nonstructural/mechanical dysphagia would be cost-saving below a reimbursed cost of $2,415. Screening impedance planimetry would be cost saving below a reimbursed cost of $1,130. The limit for reimbursed costs would be lower for patients older than 65 years to achieve cost savings mainly due to insurance. Sex did not significantly influence cost-effectiveness. Patients and insurers preferred routine screening impedance planimetry before manometry when the index of suspicion for achalasia was below 6%. Aligning with practice guidelines, routine esophageal motility testing seems cost saving to patients and insurers compared with nonalgorithmic usual care to evaluate nonstructural/mechanical dysphagia. Choice of testing should be guided by index of suspicion.


Bidirectional alteration of insulin receptor affinity by different forms of physical exercise.
Insulin binding of monocytes and erythrocytes was studied in untrained male volunteers after 15 min of exhaustive bicycle exercise (EE) and several days later after moderate exercise (ME) for 90 min. Insulin receptor affinity decreased after EE in monocytes (26.4% decrease; P less than 0.01) and in erythrocytes (10.4%; P less than 0.05) with no change in receptor number. After ME, however, binding to monocytes was enhanced by 15.2% (P less than 0.05) due to increased receptor affinity. The number of circulating monocytes was markedly increased after both forms of exercise, averaging 105% after EE and 57% after ME. The bidirectional effect on monocyte insulin binding could be reproduced in vitro by incubation of preexercise cells with post-exercise serum: 12.4% (P less than 0.05) decrease with EE serum and 6.1% (P less than 0.05) increase with ME serum. The effect was prevented by overnight dialysis. These results suggest that physical exercise not only entails adjustment of serum insulin but also of cellular hormone sensitivity, presumably through the mediation of low-molecular-weight serum components.


Defining and Measuring Safety Climate: A Review of the Construction Industry Literature.
Safety climate measurements can be used to proactively assess an organization's effectiveness in identifying and remediating work-related hazards, thereby reducing or preventing work-related ill health and injury. This review article focuses on construction-specific articles that developed and/or measured safety climate, assessed safety climate's relationship with other safety and health performance indicators, and/or used safety climate measures to evaluate interventions targeting one or more indicators of safety climate. Fifty-six articles met our inclusion criteria, 80% of which were published after 2008. Our findings demonstrate that researchers commonly defined safety climate as perception based, but the object of those perceptions varies widely. Within the wide range of indicators used to measure safety climate, safety policies, procedures, and practices were the most common, followed by general management commitment to safety. The most frequently used indicators should and do reflect that the prevention of work-related ill health and injury depends on both organizational and employee actions. Safety climate scores were commonly compared between groups (e.g. management and workers, different trades), and often correlated with subjective measures of safety behavior rather than measures of ill health or objective safety and health outcomes. Despite the observed limitations of current research, safety climate has been promised as a useful feature of research and practice activities to prevent work-related ill health and injury. Safety climate survey data can reveal gaps between management and employee perceptions, or between espoused and enacted policies, and trigger communication and action to narrow those gaps. The validation of safety climate with safety and health performance data offers the potential for using safety climate measures as a leading indicator of performance. We discuss these findings in relation to the related concept of safety culture and offer suggestions for future research and practice including (i) deriving a common definition of safety climate, (ii) developing and testing construction-specific indicators of safety climate, and (iii) focusing on construction-specific issues such as the transient workforce, subcontracting, work organization, and induction/acculturation processes.


Pharmacoepidemiology and gastroenterology: a close couple.
The discipline of pharmacoepidemiology has always been strongly linked with the problem of gastrointestinal injury caused by non-steroidal anti-inflammatory drugs, and has led to a close liaison between gastroenterology and pharmacoepidemiology. This paper discusses three important areas of pharmacoepidemiological interest relevant to gastroenterologists: confounding by indication and channeling bias, drug exposure patterns, and postmarketing surveillance studies. (i) Drug prescribing is associated with a patient's prognosis and disease status, called indication for treatment. These patient disease characteristics can drive drug channeling in risk populations and create confounded drug-effect associations. (ii) Drug exposure is the result of the 'natural' experiment of pharmacotherapy over time. Reliable information on the time-sequence of events in relation to drug exposure is required to evaluate both beneficial and adverse effects of drug therapy. (iii) Postmarketing surveillance studies provide intensive learning about drug effects when large spectra of patients with various medical backgrounds, prognoses, co-morbidity, and the like, are exposed to the drug. Information on drug use and patient outcomes in 'real life' populations is necessary to bridge normal practice experiments with randomized clinical trials.


An unusual case of active tuberculosis of the oesophagus in an adult.
A case is reported of a 56-year-old woman of Libyan origin presenting with dysphagia, retrosternal pain and weight loss. Oesophago-gastroduodenoscopy revealed an ulcerated tumor in the upper oesophagus strongly suggesting a malignancy. A positive Mendel-Mantoux test along with histological evidence of epitheloid cell granulomas and clinical findings consistent with pulmonary and lymph node tuberculosis led to the presumptive diagnosis of oesophageal tuberculosis. The diagnosis was later confirmed by positive bacteriological cultures of oesophageal biopsies and gastric washings. It is very unusual for dysphagia to be the presenting symptom of active adult tuberculosis. Oesophageal tuberculosis is extremely rare and must be distinguished predominantly from oesophageal carcinoma.


Relationship between functional disability and costs one and two years post stroke.
Stroke affects mortality, functional ability, quality of life and incurs costs. The primary objective of this study was to estimate the costs of stroke care in Sweden by level of disability and stroke type (ischemic (IS) or hemorrhagic stroke (ICH)). Resource use during first and second year following a stroke was estimated based on a research database containing linked data from several registries. Costs were estimated for the acute and post-acute management of stroke, including direct (health care consumption and municipal services) and indirect (productivity losses) costs. Resources and costs were estimated per stroke type and functional disability categorised by Modified Rankin Scale (mRS). The results indicated that the average costs per patient following a stroke were 350,000SEK/€37,000-480,000SEK/€50,000, dependent on stroke type and whether it was the first or second year post stroke. Large variations were identified between different subgroups of functional disability and stroke type, ranging from annual costs of 100,000SEK/€10,000-1,100,000SEK/€120,000 per patient, with higher costs for patients with ICH compared to IS and increasing costs with more severe functional disability. Functional outcome is a major determinant on costs of stroke care. The stroke type associated with worse outcome (ICH) was also consistently associated to higher costs. Measures to improve function are not only important to individual patients and their family but may also decrease the societal burden of stroke.


Serum progesterone levels could predict diagnosis, completion and complications of miscarriage.
Low serum progesterone levels were strongly correlated with miscarriages in several publications and with completion of miscarriage in one paper. This study evaluated several parameters, predominantly serum progesterone, as predictors for miscarriages, their swift non-surgical completion and their complications. Suspected or confirmed non-viable pregnancies with available concomitant serum progesterone measurements were retrospectively reviewed. The performance of serum progesterone, either alone or combined with other parameters, to predict viability, surgical removal and delay of non-surgical evacuation of non-viable pregnancy and complications, was analysed by logistic regression combined with Akaike and Bayesian information criteria, likelihood, receiver operated characteristic (ROC) curves, Mann-Whitney test and Fisher's exact test. From 151 included pregnancies, 104 (68.9 %) were non-viable with 91 completions of miscarriage without surgery. The probability of viability was correlated linearly and curvilinearly with serum progesterone (p < 0.001). The probability of surgical removal, and the delay before non-surgical evacuation, showed a linear relationship with progesterone. No complication occurred when progesterone levels remained below 10 μg/L, while its rates were 9.5 % of non-viable pregnancies with progesterone levels between 10 and 20 μg/L and 26.7 % of cases with progesterone levels above 20 μg/L. Combined with progesterone, either "parity" or "history of miscarriage" improved the prediction of viability, "history of supra-isthmic uterine surgery" improved the prediction of surgery and "history of miscarriage" improved the prediction of delayed non-surgical evacuations. Serum progesterone can probably predict the odds of miscarriages, surgical removal, delayed non-surgical evacuation and complications, with potential improvements when different predictors are combined.


Optimal rebinning of time-of-flight PET data.
Time-of-flight (TOF) positron emission tomography (PET) scanners offer the potential for significantly improved signal-to-noise ratio (SNR) and lesion detectability in clinical PET. However, fully 3D TOF PET image reconstruction is a challenging task due to the huge data size. One solution to this problem is to rebin TOF data into a lower dimensional format. We have recently developed Fourier rebinning methods for mapping TOF data into non-TOF formats that retain substantial SNR advantages relative to sinograms acquired without TOF information. However, mappings for rebinning into non-TOF formats are not unique and optimization of rebinning methods has not been widely investigated. In this paper we address the question of optimal rebinning in order to make full use of TOF information. We focus on FORET-3D, which approximately rebins 3D TOF data into 3D non-TOF sinogram formats without requiring a Fourier transform in the axial direction. We optimize the weighting for FORET-3D to minimize the variance, resulting in H(2)-weighted FORET-3D, which turns out to be the best linear unbiased estimator (BLUE) under reasonable approximations and furthermore the uniformly minimum variance unbiased (UMVU) estimator under Gaussian noise assumptions. This implies that any information loss due to optimal rebinning is as a result only of the approximations used in deriving the rebinning equation and developing the optimal weighting. We demonstrate using simulated and real phantom TOF data that the optimal rebinning method achieves variance reduction and contrast recovery improvement compared to nonoptimized rebinning weightings. In our preliminary study using a simplified simulation setup, the performance of the optimal rebinning method was comparable to that of fully 3D TOF MAP.


Psychiatric disorders in children and adolescents in a middle-income Latin American country.
Child and adolescent mental health has scarcely been studied in developing countries, though it is an important aspect of health. Mental health problems in youth often continue into adulthood if not diagnosed or treated in time. The Sistema de Evaluación de Niños y Adolescentes (SENA) [Child and Adolescent Evaluation System] was used to evaluate mental health indicators in a sample of students in Northern Chile. Two age-appropriate versions of the assessment were applied to a total sample of 5043 students, which included an elementary education sample of 1953 schoolchildren from fourth grade through sixth grade (ages 8 to 13 years), and a Secondary School sample of 3090 schoolchildren from seventh grade (the last year of elementary school) through the last year of Secondary school (senior high school) (ages 12 to 19 years). For each group, the version of the assessment used was determined by the students' grade level. Both samples included municipal, government-subsidized, and private schools. In this student population, depression, anxiety, and behavioral disorders were the main mental health problems identified, and indicators revealed a progressive increase in cases over the years, coinciding with the global epidemiological scenario. Males showed a greater presence of externalizing behaviors related to mental health problems associated with aggression and defiant behavior. However, females showed the highest number of mental health issues overall, especially regarding problems related to internalization. There are significant differences between school types. Our sample population analysis indicates that early intervention is necessary for the diagnosis and treatment of youth, with the goal of reducing the probability that psychiatric disorders will be prolonged, evolving, and worsening in adulthood.


Electronic control of friction in silicon pn junctions.
A remarkable dependence of the friction force on carrier concentration was found on doped silicon substrates. The sample was a nearly intrinsic n-type Si(100) wafer patterned with 2-micrometer-wide stripes of highly B-doped p-type material. The counter surface was the tip of an atomic force microscope coated with conductive titanium nitride. The local carrier concentration was controlled through application of forward or reverse bias voltages between the tip and the sample in the p and the n regions. Charge depletion or accumulation resulted in substantial differences in friction force. The results demonstrate the capability to electronically control friction in semiconductor devices, with potential applications in nanoscale machines containing moving parts.


Ecological and Fitness Correlates of Personality in a Long-lived Terrestrial Turtle.
An individual's behavioral tendencies (i.e., personality or temperament) can influence its interactions with the environment and thus have important ecological and evolutionary consequences for animal populations. Boldness, defined as an individual's tendency to engage in risk-taking activities, is a phenotypically variable trait linked with numerous behavioral and fitness outcomes in free-ranging animals. We examined variation and repeatability of boldness and other behavioral characteristics in two wild Eastern Box Turtle (Terrapene carolina carolina) populations using radiotelemetry, and assessed fitness correlates of boldness over multiple years. We observed large amounts of among-individual variation and within-individual consistency (i.e., repeatability) of boldness as measured by their head emergence latency following a standardized confinement assay. Individuals were also consistent in several in-field behaviors including movement rate, home range size, and date of emergence from overwintering refuges. Individuals with shorter head emergence latencies (i.e., bolder turtles) had larger home ranges, emerged earlier from overwintering dormancy, and experienced moderately lower survival compared with shy individuals. Boldness did not affect time spent within the thermal preference range, somatic growth rates, or the frequency of mating or same-sex aggressive encounters. Boldness and its effects on in-field behaviors differed between sexes and populations, and the relationship between boldness and survival was temporally variable. Our results suggest possible intrinsic behavioral types in T. c. carolina and highlight the importance of long-term and multipopulation studies when examining ecological and evolutionary processes that shape personality phenotypes in turtles.


Comparison of in-situ and ex-situ catalytic pyrolysis in a micro-reactor system.
In this study, we compared ex-situ catalytic pyrolysis (CP) and in-situ CP of hybrid poplar in a micro-reactor system. When both pyrolysis and catalysis were performed at 700 °C, the carbon yield of olefins was greater for ex-situ CP than for in-situ CP (17.4% vs. 5.4%). On the other hand, in-situ CP produced more aromatic hydrocarbons than ex-situ CP (26.1% vs. 18.9%). The remarkably high yield of olefins from ex-situ CP indicates the potential of exploiting the process to preferentially produce olefins as a primary product from biomass, with aromatics being the secondary products. The carbon yield of carbonaceous residues from ex-situ CP was 18.6% compared to 31.3% for in-situ CP. Substantial carbon was deposited as char during ex-situ CP, which could be easily recovered as by-product, simplifying catalyst regeneration. The effects of catalyst loading, pyrolysis temperature and catalysis temperature on product distributions for ex-situ CP were also investigated. Our results showed that catalyst temperature strongly affected product distribution. While high catalyst temperature enhanced both olefin and aromatic production, yield of olefin increased to a greater extent than did aromatics. Neither pyrolysis temperature nor catalyst loadings had significant effect on product distribution for ex-situ CP.


Synapsin-dependent reserve pool of synaptic vesicles supports replenishment of the readily releasable pool under intense synaptic transmission.
Synapsins are abundant synaptic vesicle (SV)-associated proteins thought to mediate synaptic vesicle mobility and clustering at most synapses. We used synapsin triple knock-out (TKO) mice to examine the morphological and functional consequences of deleting all synapsin isoforms at the calyx of Held, a giant glutamatergic synapse located in the auditory brain stem. Quantitative three-dimensional (3D) immunohistochemistry of entire calyces showed lower amounts of the synaptic vesicle protein vGluT1 while the level of the active zone marker bassoon was unchanged in TKO terminals. Examination of brain lysates by ELISA revealed a strong reduction in abundance of several synaptic vesicle proteins, while proteins of the active zone cytomatrix or postsynaptic density were unaffected. Serial section scanning electron microscopy of large 3D-reconstructed segments confirmed a decrease in the number of SVs to approximately 50% in TKO calyces. Short-term depression tested at stimulus frequencies ranging from 10 to 300 Hz was accelerated only at frequencies above 100 Hz and the time course of recovery from depression was slowed in calyces lacking synapsins. These results reveal that in wild-type synapses, the synapsin-dependent reserve pool contributes to the replenishment of the readily releasable pool (RRP), although accounting only for a small fraction of the SVs that enter the RRP. In conclusion, our results suggest that synapsins may be required for normal synaptic vesicle biogenesis, trafficking and immobilization of synaptic vesicles, yet they are not essential for sustained high-frequency synaptic transmission at the calyx terminal.


[Immunotherapy of chronic inflammatory demyelinating polyneuropathy].
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated disease of the peripheral nervous system with an estimated prevalence of 1-2/100,000. The clinical presentation is heterogeneous, but the most common form causes symmetrical progressive or relapsing weakness affecting proximal and distal muscles. CIDP is among the most treatable peripheral nerve disorders and corticosteroids, plasmapheresis and intravenous immunoglobulin have been shown to be effective in short-term prospective, randomized controlled trials. Data however indicate that approximately one-third of patients do not respond to these treatment modalities, nor do they provide equivalent evidence for a durable clinical response. There is a lack of good quality controlled trials of any other immunosuppressive agent, but cyclophosphamide and cyclosporin may be of value in patients with poor response to first-line modalities. Alternatively, the use of combination therapy may increase the efficacy in unresponsive patients. This review highlights the current status of CIDP treatment trials and discusses the significance of any therapeutic option in terms of efficacy, tolerability and cost-effects.


Nanometer-size alpha-PbO(2)-type TiO(2) in garnet: A thermobarometer for ultrahigh-pressure metamorphism
A high-pressure phase of titanium dioxide (TiO(2)) with an alpha-PbO(2)-type structure has been identified in garnet of diamondiferous quartzofeldspathic rocks from the Saxonian Erzgebirge, Germany. Analytical electron microscopy indicates that this alpha-PbO(2)-type TiO(2) occurred as an epitaxial nanometer-thick slab between twinned rutile bicrystals. Given a V-shaped curve for the equilibrium phase boundary of alpha-PbO(2)-type TiO(2) to rutile, the stabilization pressure of alpha-PbO(2)-type TiO(2) should be 4 to 5 gigapascals at 900 degrees to 1000 degrees C. This suggests a burial of continental crustal rocks to depths of at least 130 kilometers. The alpha-PbO(2)-type TiO(2) may be a useful pressure and temperature indicator in the diamond stability field.


The effect of room size and general ventilation on the relationship between near and far-field concentrations.
Measurements of personal exposure level are generally greater than or equal to concentrations found at some fixed location in the body of the workroom. This article presents a theoretical analysis of such differences using a simple model of exposure, implemented as a two-compartment mass balance model with a constant emission rate. Simulated exposure levels (termed the near-field) and the concentration at a fixed location (the far-field) were obtained for five room sizes (30 to 3000 m3), each with five general ventilation rates (0.3 to 30 air-changes per hour) and three levels of air movement in the vicinity of the worker (generally 3 to 30 m3/min). The ratio of near- to far-field concentrations from the simulations ranged from unity in small poorly ventilated rooms to 24 in large well ventilated areas, which compares favorably with actual measurement data. The predicted concentrations obtained in small rooms (< 100 m3) with less than one air-change per hour were almost 40 times higher than in larger rooms. The results from these simulations have been used to modify the original exposure model to better reflect the likely effect of general ventilation on workers' exposure.


Dietary intervention to lower serum cholesterol.
Dietary intervention to lower serum LDL-cholesterol (LDL-C) is effective, yet underutilised in general practice. This report summarises the findings of an expert roundtable convened to review the evidence relating to dietary interventions to lower serum LDL-C. Interventions that lower LDL-C lower the risk of cardiovascular disease. Comprehensive dietary intervention is indicated in all patients with an absolute 5 year risk for coronary disease of 10% or greater. Short term trials indicate that these interventions have the potential to lower LDL-C by approximately 20%. A year long trial has shown mean LDL-C lowering of 13%, with about one-third of subjects achieving a reduction greater than 20%, highlighting the importance of adherence to dietary advice. The most effective dietary strategies are replacing saturated and trans fatty acids with poly- and monounsaturated fats and increasing intake of plant sterols. Losing weight and increasing soluble fibre and soy protein intake can also lower serum cholesterol and may be considered when recommending a nutritionally balanced, cholesterol lowering diet. Motivational interviewing by general practitioners can improve the effectiveness of brief, behaviour orientated advice and dietary counselling to lower serum cholesterol.


Neuroblastoma arising from an unresected sacrococcygeal teratoma in a child.
Malignant transformation of a germ cell tumor, referring to the occurrence of somatic, nongerm cell malignancy within a germ cell tumor is a rare entity. The authors report a case of malignant transformation of an unreseceted sacrococcygeal teratoma to neuroblastoma in a 6-year-old girl and discuss this case in the light of relevant literature. This case shows that complete resection of germ cell tumor is necessary to prevent malignant transformation. In addition, when malignant transformation occurs, the treatment strategy must include surgery together with histology adapted systemic chemotherapy.


Integrative Molecular Analysis of Patients With Advanced and Metastatic Cancer.
We developed a precision medicine program for patients with advanced cancer using integrative whole-exome sequencing and transcriptome analysis. Five hundred fifteen patients with locally advanced/metastatic solid tumors were prospectively enrolled, and paired tumor/normal sequencing was performed. Seven hundred fifty-nine tumors from 515 patients were evaluated. Most frequent tumor types were prostate (19.4%), brain (16.5%), bladder (15.4%), and kidney cancer (9.2%). Most frequently altered genes were TP53 (33%), CDKN2A (11%), APC (10%), KTM2D (8%), PTEN (8%), and BRCA2 (8%). Pathogenic germline alterations were present in 10.7% of patients, most frequently CHEK2 (1.9%), BRCA1 (1.5%), BRCA2 (1.5%), and MSH6 (1.4%). Novel gene fusions were identified, including a RBM47-CDK12 fusion in a metastatic prostate cancer sample. The rate of clinically relevant alterations was 39% by whole-exome sequencing, which was improved by 16% by adding RNA sequencing. In patients with more than one sequenced tumor sample (n = 146), 84.62% of actionable mutations were concordant. Integrative analysis may uncover informative alterations for an advanced pan-cancer patient population. These alterations are consistent in spatially and temporally heterogeneous samples.


Experience-dependent induction of hypnagogic images during daytime naps: a combined behavioural and EEG study.
This study characterizes hypnagogic hallucinations reported during a polygraphically recorded 90-min daytime nap following or preceding practice of the computer game Tetris. In the experimental group (N = 16), participants played Tetris in the morning for 2 h during three consecutive days, while in a first control group (N = 13, controlling the effect of experience) participants did not play any game, and in a second control group (N = 14, controlling the effect of anticipation) participants played Tetris after the nap. During afternoon naps, participants were repetitively awakened 15, 45, 75, 120 or 180 s after the onset of S1, and were asked to report their mental content. Reports content was scored by three judges (inter-rater reliability 85%). In the experimental group, 48 out of 485 (10%) sleep-onset reports were Tetris-related. They mostly consisted of images and sounds with very little emotional content. They exactly reproduced Tetris elements or mixed them with other mnemonic components. By contrast, in the first control group, only one report out of 107 was scored as Tetris-related (1%), and in the second control group only three reports out of 112 were scored as Tetris-related (3%; between-groups comparison; P = 0.006). Hypnagogic hallucinations were more consistently induced by experience than by anticipation (P = 0.039), and they were predominantly observed during the transition of wakefulness to sleep. The observed attributes of experience-related hypnagogic hallucinations are consistent with the particular organization of regional brain activity at sleep onset, characterized by high activity in sensory cortices and in the default-mode network.


Diverse inhibitory projections from the cerebellar interposed nucleus.
The cerebellum consists of parallel circuit modules that contribute to diverse behaviors, spanning motor to cognitive. Recent work employing cell-type-specific tracing has identified circumscribed output channels of the cerebellar nuclei (CbN) that could confer tight functional specificity. These studies have largely focused on excitatory projections of the CbN, however, leaving open the question of whether inhibitory neurons also constitute multiple output modules. We mapped output and input patterns to intersectionally restricted cell types of the interposed and adjacent interstitial nuclei in mice. In contrast to the widespread assumption of primarily excitatory outputs and restricted inferior olive-targeting inhibitory output, we found that inhibitory neurons from this region ramified widely within the brainstem, targeting both motor- and sensory-related nuclei, distinct from excitatory output targets. Despite differences in output targeting, monosynaptic rabies tracing revealed largely shared afferents to both cell classes. We discuss the potential novel functional roles for inhibitory outputs in the context of cerebellar theory.


Differential proteome analysis of Chikungunya virus-infected new-born mice tissues reveal implication of stress, inflammatory and apoptotic pathways in disease pathogenesis.
Chikungunya infection is a major disease of public health concern. The recurrent outbreaks of this viral disease and its progressive evolution demands a potential strategy to understand major aspects of its pathogenesis. Unlike other alphaviruses, Chikungunya virus (CHIKV) pathogenesis is poorly understood. In every consecutive outbreak, some new symptoms associated with virulence and disease manifestations are being reported such as neurological implication, increased severity and enhanced vector competence. In order to unravel the mechanism of the disease process, proteomic analysis was performed to evaluate the host response in CHIKV-infected mice tissues. Comparative analysis of the multiple gels representing the particular tissue extract from mock and CHIKV-infected tissues revealed a drastic reprogramming of physiological conditions through 35 and 15 differentially expressed proteins belonging to different classes such as stress, inflammation, apoptosis, urea cycle, energy metabolism, etc. from liver and brain, respectively. Based on the alterations obtained in the CHIKV mouse model, most of the aspects of CHIKV infection such as disease severity, neurological complications, disease susceptibility and immunocompetence could be defined. This is the first report unravelling the complicated pathways involved in the mechanism of Chikungunya disease pathogenesis employing proteomic approach.


Cell arrangement impacts metabolic activity and antibiotic tolerance in Pseudomonas aeruginosa biofilms.
Cells must access resources to survive, and the anatomy of multicellular structures influences this access. In diverse multicellular eukaryotes, resources are provided by internal conduits that allow substances to travel more readily through tissue than they would via diffusion. Microbes growing in multicellular structures, called biofilms, are also affected by differential access to resources and we hypothesized that this is influenced by the physical arrangement of the cells. In this study, we examined the microanatomy of biofilms formed by the pathogenic bacterium Pseudomonas aeruginosa and discovered that clonal cells form striations that are packed lengthwise across most of a mature biofilm's depth. We identified mutants, including those defective in pilus function and in O-antigen attachment, that show alterations to this lengthwise packing phenotype. Consistent with the notion that cellular arrangement affects access to resources within the biofilm, we found that while the wild type shows even distribution of tested substrates across depth, the mutants show accumulation of substrates at the biofilm boundaries. Furthermore, we found that altered cellular arrangement within biofilms affects the localization of metabolic activity, the survival of resident cells, and the susceptibility of subpopulations to antibiotic treatment. Our observations provide insight into cellular features that determine biofilm microanatomy, with consequences for physiological differentiation and drug sensitivity.