Protein phosphatase 2A activation as a therapeutic strategy for managing MYC-driven cancers.
The tumor suppressor protein phosphatase 2A (PP2A) is a serine/threonine phosphatase whose activity is inhibited in most human cancers. One of the best-characterized PP2A substrates is MYC proto-oncogene basic helix-loop-helix transcription factor (MYC), whose overexpression is commonly associated with aggressive forms of this disease. PP2A directly dephosphorylates MYC, resulting in its degradation. To explore the therapeutic potential of direct PP2A activation in a diverse set of MYC-driven cancers, here we used biochemical assays, recombinant cell lines, gene expression analyses, and immunohistochemistry to evaluate a series of first-in-class small-molecule activators of PP2A (SMAPs) in Burkitt lymphoma, KRAS-driven non-small cell lung cancer, and triple-negative breast cancer. In all tested models of MYC-driven cancer, the SMAP treatment rapidly and persistently inhibited MYC expression through proteasome-mediated degradation, inhibition of MYC transcriptional activity, decreased cancer cell proliferation, and tumor growth inhibition. Importantly, we generated a series of cell lines expressing PP2A-dependent phosphodegron variants of MYC and demonstrated that the antitumorigenic activity of SMAPs depends on MYC degradation. Collectively, the findings presented here indicate a pharmacologically tractable approach to drive MYC degradation by using SMAPs for the management of a broad range of MYC-driven cancers.


Cloning, cell-type specificity, and regulatory function of the mouse alpha(1B)-adrenergic receptor promoter.
The functionality of a 3422-base pair promoter fragment from the mouse alpha(1B)-adrenergic receptor (alpha(1B)AR) gene was examined. This fragment, cloned from a mouse genomic library, was found to have significant sequence homology to the known human and rat alpha(1B)AR promoters. However, the consensus motif of several key cis-acting elements is not conserved among the rat, human, and mouse genes, suggesting species specificity. Confirming fidelity of the murine promoter, robust in vitro expression of a chloramphenicol acetyltransferase (CAT) reporter was detected in known alpha(1B)AR-expressing BC(3)H1, NB41A3, and DDT(1)MF-2 cells transiently transfected with a promoter-CAT construct. Conversely, minimal CAT expression was detected in known alpha(1B)AR-negative RAT-1 and R3T3 cells. These findings were extended by transfecting the same promoter-CAT construct into various primary cell types. In support of the hypothesis that alpha(1)ARs are differentially expressed in the smooth muscle of the vasculature, primary cultures of superior mesenteric and renal artery vascular smooth muscle cells showed significantly stronger CAT expression than did vascular smooth muscle cells derived from pulmonary, femoral, and iliac arteries. Primary osteoblastic bone-forming cells, which are known to be alpha(1B)AR negative, showed minimal CAT expression. Indicating regulatory function through cis-acting elements, RAT-1, R3T3, NB41A3, BC(3)H1, and DDT(1)MF2 cells transfected with the promoter-CAT construct all showed increased CAT production when challenged with forskolin or hypoxic conditions. Additionally, tissue-specific regulation of the promoter was observed when cells were simultaneously challenged with both forskolin and hypoxia. These results collectively demonstrate that a 3.4-kb PvuII fragment of the murine alpha(1B)AR gene promoter can: 1) drive tissue-specific production of a CAT reporter in both clonal and primary cell lines; and 2) confer tissue-specific regulation of that CAT reporter when induced by challenge with forskolin and/or hypoxic conditions.


Selective Surface Charge Sign Reversal on Metallic Carbon Nanotubes for Facile Ultrahigh Purity Nanotube Sorting.
Semiconducting (semi-) single-walled carbon nanotubes (SWNTs) must be purified of their metallic (met-) counterparts for most applications including nanoelectronics, solar cells, chemical sensors, and artificial skins. Previous bulk sorting techniques are based on subtle contrasts between properties of different nanotube/dispersing agent complexes. We report here a method which directly exploits the nanotube band structure differences. For the heterogeneous redox reaction of SWNTs with oxygen/water couple, the aqueous pH can be tuned so that the redox kinetics is determined by the availability of nanotube electrons only at/near the Fermi level, as predicted quantitatively by the Marcus-Gerischer (MG) theory. Consequently, met-SWNTs oxidize much faster than semi-SWNTs and only met-SWNTs selectively reverse the sign of their measured surface zeta potential from negative to positive at the optimized acidic pH when suspended with nonionic surfactants. By passing the redox-reacted nanotubes through anionic hydrogel beads, we isolate semi-SWNTs to record high electrically verified purity above 99.94% ± 0.04%. This facile charge sign reversal (CSR)-based sorting technique is robust and can sort SWNTs with a broad diameter range.


Current advances in skin-on-a-chip models for drug testing.
Skin-on-a-chip models are highly desirable in drug testing compared to conventional 2D cell culture and animal models as they can replicate organ-specific 3D structural organization and physiological functions at a relatively low cost. To engineer a physiologically relevant skin model, human skin structures have been integrated onto microfluidic platforms to construct skin-on-a-chip systems that can mimic the complex in vivo situation. In this mini-review, we first briefly introduce some critical technologies employed to develop in vitro skin-on-a-chip models. We then review the applications of the state-of-the-art skin-on-a-chip models in drug testing, with a focus on using models of full-thickness skin equivalents (FTSEs), skin models with additional components such as vasculature, immune cells and hair follicles as well as multi-organ-on-a-chip models. Finally, we discuss some current challenges and future directions of development of complex, and in vivo-like skin-on-a-chip models.


Genome-wide association analysis of intra-specific QTL associated with the resistance for enteric septicemia of catfish.
Disease resistance is one of the most important traits for aquaculture industry. For catfish industry, enteric septicemia of catfish (ESC), caused by the bacterial pathogen Edwardsiella ictaluri, is the most severe disease, causing enormous economic losses every year. In this study, we used three channel catfish families with 900 individuals (300 fish per family) and the 690K catfish SNP array, and conducted a genome-wide association study to detect the quantitative trait loci (QTL) associated with ESC resistance. Three significant QTL, with two of located on LG1 and one on LG26, and three suggestive QTL located on LG1, LG3, and LG21, respectively, were identified to be associated with ESC resistance. With a well-assembled- and -annotated reference genome sequence, genes around the involved QTL regions were identified. Among these genes, 37 genes had known functions in immunity, which may be involved in ESC resistance. Notably, nlrc3 and nlrp12 identified here were also found in QTL regions of ESC resistance in the channel catfish × blue catfish interspecific hybrid system, suggesting this QTL was operating within both intra-specific channel catfish populations and interspecific hybrid backcross populations. Many of the genes of the Class I MHC pathway, for mediated antigen processing and presentation, were found in the QTL regions. The positional correlation found in this study and the expressional correlation found in previous studies indicated that Class I MHC pathway was significantly associated with ESC resistance. This study validated one QTL previously identified using the second and fourth generation of the interspecific hybrid backcross progenies, and identified five additional QTL among channel catfish families. Taken together, it appears that there are only a few major QTL for ESC disease resistance, making marker-assisted selection an effective approach for genetic improvements of ESC resistance.


Anti-inflammatory Effects of the Octapeptide NAP in Human Microbiota-Associated Mice Suffering from Subacute Ileitis.
The octapeptide NAP is well known for its neuroprotective properties. We here investigated whether NAP treatment could alleviate pro-inflammatory immune responses during experimental subacute ileitis. To address this, mice with a human gut microbiota were perorally infected with one cyst of Toxoplasma gondii (day 0) and subjected to intraperitoneal synthetic NAP treatment from day 1 until day 8 postinfection (p.i.). Whereas placebo (PLC) control animals displayed subacute ileitis at day 9 p.i., NAP-treated mice exhibited less pronounced pro-inflammatory immune responses as indicated by lower numbers of intestinal mucosal T and B lymphocytes and lower interferon (IFN)-γ concentrations in mesenteric lymph nodes. The NAP-induced anti-inflammatory effects were not restricted to the intestinal tract but could also be observed in extra-intestinal including systemic compartments, given that pro-inflammatory cytokines were lower in liver, kidney, and lung following NAP as compared to PLC application, whereas at day 9 p.i., colonic and serum interleukin (IL)-10 concentrations were higher in the former as compared to the latter. Remarkably, probiotic commensal bifidobacterial loads were higher in the ileal lumen of NAP as compared to PLC-treated mice with ileitis. Our findings thus further support that NAP might be regarded as future treatment option directed against intestinal inflammation.


CCN1 (Cyr61) Is Overexpressed in Human Osteoarthritic Cartilage and Inhibits ADAMTS-4 (Aggrecanase 1) Activity.
ADAMTS-4, also called aggrecanase 1, is considered to play a key role in aggrecan degradation in human osteoarthritic (OA) cartilage, but information about regulators of ADAMTS-4 aggrecanase activity remains limited. We undertook this study to search for molecules that modulate ADAMTS-4 activity. Molecules copurified with ADAMTS-4 from ADAMTS-4-transfected chondrocytic cells were sequenced by nanoscale liquid chromatography tandem mass spectrometry. Binding activity was determined by immunoprecipitation and solid-phase binding assay. Effects on ADAMTS-4 activity were examined by aggrecan digestion assay. Expression of the binding molecule in OA cartilage and chondrocytes was examined by immunohistochemistry and reverse transcription-polymerase chain reaction. We identified CCN1 (Cyr61) as an ADAMTS-4-binding protein and showed specific binding to the ADAMTS-4 cysteine-rich domain. Aggrecanase activity of ADAMTS-4 was inhibited by interaction with CCN1. Expression of messenger RNA for CCN1 was significantly higher in human OA cartilage than in normal cartilage. CCN1 was immunolocalized to chondrocytes in OA cartilage, showing direct correlations of immunoreactivity with the Mankin score of cartilage lesions and chondrocyte cloning. CCN1 and ADAMTS-4 were commonly coexpressed in clustered chondrocytes. CCN1 expression in OA chondrocytes was down-regulated by interleukin-1α (IL-1α) and up-regulated by transforming growth factor β (TGFβ). ADAMTS-4 expression was induced by treatment with IL-1α or TGFβ, but aggrecanase activity was detected only under stimulation with IL-1α. TGFβ-treated chondrocytes exhibited aggrecanase activity when CCN1 expression was knocked down. Our findings provide the first evidence that CCN1 suppresses ADAMTS-4 activity and that CCN1 overexpression is directly correlated with chondrocyte cloning in OA cartilage. Our results suggest that the TGFβ/CCN1 axis plays a role in chondrocyte cluster formation through inhibition of ADAMTS-4.


Preventive effect of caffeine and curcumin on hepato-carcinogenesis in diethylnitrosamine-induced rats.
Chemopreventive effects of caffeine and curcumin were evaluated in the diethylnitrosamine (DEN)-induced hepatocarcinogenic rat model. Animals injected with DEN for 10 weeks (G2-10w) and 14 weeks (G2-14w) were hepato-carcinogenic rats. Animals injected with DEN and treated with curcumin and caffeine for 10 weeks (G3-10w, G4-10w) and 14 weeks (G3-14w, G4-14w) were compared with those in G2. Macroscopic and microscopic features suggested that treatment with caffeine, but not curcumin, for 10 and 14 weeks was effective in inhibiting DEN-induced hepatocarcinogenesis. Immunohistochemical and western blot analysis with proliferating cell nuclear antigen and glutathione S-transferase-P antibodies also showed that expression levels of these hepato-carcinogenic markers were more efficiently reduced by treatment with caffeine than curcumin. Our data demonstrate that caffeine could be a more potent compound than curcumin for prevention of hepatocarcinogenesis in DEN-induced rats.


Regional variations in Helicobacter pylori infection, gastric atrophy and gastric cancer risk: The ENIGMA study in Chile.
Regional variations in gastric cancer incidence are not explained by prevalence of Helicobacter pylori, the main cause of the disease, with several areas presenting high H. pylori prevalence but low gastric cancer incidence. The IARC worldwide H. pylori prevalence surveys (ENIGMA) aim at systematically describing age and sex-specific prevalence of H. pylori infection around the world and generating hypotheses to explain regional variations in gastric cancer risk. We selected age- and sex-stratified population samples in two areas with different gastric cancer incidence and mortality in Chile: Antofagasta (lower rate) and Valdivia (higher rate). Participants were 1-69 years old and provided interviews and blood for anti-H. pylori antibodies (IgG, VacA, CagA, others) and atrophy biomarkers (pepsinogens). H. pylori seroprevalence (Age-standardized to world population) and antibodies against CagA and VacA were similar in both sites. H. pylori seroprevalence was 20% among children <10 years old, 40% among 10-19 year olds, 60% in the 20-29 year olds and close to or above 80% in those 30+ years. The comparison of the prevalence of known and potential H. pylori cofactors in gastric carcinogenesis between the high and the low risk area showed that consumption of chili products was significantly higher in Valdivia and daily non-green vegetable consumption was more common in Antofagasta. Pepsinogen levels suggestive of gastric atrophy were significantly more common and occurred at earlier ages in Valdivia, the higher risk area. In a multivariate model combining both study sites, age, chili consumption and CagA were the main risk factors for gastric atrophy. The prevalence of H. pylori infection and its virulence factors was similar in the high and the low risk area, but atrophy was more common and occurred at younger ages in the higher risk area. Dietary factors could partly explain higher rates of atrophy and gastric cancer in Valdivia. The ENIGMA study in Chile contributes to better understanding regional variations in gastric cancer incidence and provides essential information for public health interventions.


Geometry, electronic structure and thermodynamic stability of intrinsic point defects in indium oxide.
Intrinsic point defects in indium oxide, including vacancies, interstitials as well as antisites, are studied by means of first-principles calculations within density functional theory using the generalized gradient approximation together with on-site corrections. Finite-size effects are corrected by an extrapolation procedure in order to obtain defect formation energies at infinite dilution. The results show that all intrinsic donor defects have shallow states and are capable of producing free electrons in the conduction band. This applies in particular to the oxygen vacancy. Since it has also a low formation energy, we find that the oxygen vacancy should be the major donor in this material explaining the n-type conductivity as well as the non-stoichiometry of indium oxide. In addition, we show that there are a wealth of oxygen dumbbell-like defects which are thermodynamically relevant under oxidizing conditions. Finally, we discuss defect induced changes of the electronic structure.


Identification of chloroplast genome loci suitable for high-resolution phylogeographic studies of Colocasia esculenta (L.) Schott (Araceae) and closely related taxa.
Recently, we reported the chloroplast genome-wide association of oligonucleotide repeats, indels and nucleotide substitutions in aroid chloroplast genomes. We hypothesized that the distribution of oligonucleotide repeat sequences in a single representative genome can be used to identify mutational hotspots and loci suitable for population genetic, phylogenetic and phylogeographic studies. Using information on the location of oligonucleotide repeats in the chloroplast genome of taro (Colocasia esculenta), we designed 30 primer pairs to amplify and sequence polymorphic loci. The primers have been tested in a range of intra-specific to intergeneric comparisons, including ten taro samples (Colocasia esculenta) from diverse geographical locations, four other Colocasia species (C. affinis, C. fallax, C. formosana, C. gigantea) and three other aroid genera (represented by Remusatia vivipara, Alocasia brisbanensis and Amorphophallus konjac). Multiple sequence alignments for the intra-specific comparison revealed nucleotide substitutions (point mutations) at all 30 loci and microsatellite polymorphisms at 14 loci. The primer pairs reported here reveal levels of genetic variation suitable for high-resolution phylogeographic and evolutionary studies of taro and other closely related aroids. Our results confirm that information on repeat distribution can be used to identify loci suitable for such studies, and we expect that this approach can be used in other plant groups.


Differential escape patterns within the dominant HLA-B*57:03-restricted HIV Gag epitope reflect distinct clade-specific functional constraints.
HLA-B*57:01 and HLA-B*57:03, the most prevalent HLA-B*57 subtypes in Caucasian and African populations, respectively, are the HLA alleles most protective against HIV disease progression. Understanding the mechanisms underlying this immune control is of critical importance, yet they remain unclear. Unexplained differences are observed in the impact of the dominant cytotoxic T lymphocyte (CTL) response restricted by HLA-B*57:01 and HLA-B*57:03 in chronic infection on the Gag epitope KAFSPEVIPMF (KF11; Gag 162 to 172). We previously showed that the HLA-B*57:03-KF11 response is associated with a >1-log-lower viral setpoint in C clade virus infection and that this response selects escape mutants within the epitope. We first examined the relationship of KF11 responses in B clade virus-infected subjects with HLA-B*57:01 to immune control and observed that a detectable KF11 response was associated with a >1-log-higher viral load (P = 0.02). No evidence of HLA-B*57:01-KF11-associated selection pressure was identified in previous comprehensive analyses of >1,800 B clade virus-infected subjects. We then studied a B clade virus-infected cohort in Barbados, where HLA-B*57:03 is highly prevalent. In contrast to findings for B clade virus-infected subjects expressing HLA-B*57:01, we observed strong selection pressure driven by the HLA-B*57:03-KF11 response for the escape mutation S173T. This mutation reduces recognition of virus-infected cells by HLA-B*57:03-KF11 CTLs and is associated with a >1-log increase in viral load in HLA-B*57:03-positive subjects (P = 0.009). We demonstrate functional constraints imposed by HIV clade relating to the residue at Gag 173 that explain the differential clade-specific escape patterns in HLA-B*57:03 subjects. Further studies are needed to evaluate the role of the KF11 response in HLA-B*57:01-associated HIV disease protection. HLA-B*57 is the HLA class I molecule that affords the greatest protection against disease progression in HIV infection. Understanding the key mechanism(s) underlying immunosuppression of HIV is of importance in guiding therapeutic and vaccine-related approaches to improve the levels of HIV control occurring in nature. Numerous mechanisms have been proposed to explain the HLA associations with differential HIV disease outcome, but no consensus exists. These studies focus on two subtypes of HLA-B*57 prevalent in Caucasian and African populations, HLA-B*57:01 and HLA-B*57:03, respectively. These alleles appear equally protective against HIV disease progression. The CTL epitopes presented are in many cases identical, and the dominant response in chronic infection in each case is to the Gag epitope KF11. However, there the similarity ends. This study sought to better understand the reasons for these differences and what they teach us about which immune responses contribute to immune control of HIV infection.


Heterogeneity in a mouse model of histiocytosis: transformation of Langerin+ dendritic cells, macrophages, and precursors.
Neoplastic diseases of macrophages (M phi) and dendritic cells (DC), collectively called histiocytoses, are relatively rare. The etiology of most forms of histiocytosis is poorly understood, and the development of animal models is crucial for further research in this field. Previously, an animal model for malignant histiocytosis (MH), involving transformed histiocytic cells, has been generated by infecting mice with malignant histiocytosis sarcoma virus (MHSV). However, increased insight into the heterogeneity of M phi and DC, and the associated reappraisal of human proliferative diseases involving these cells inspired us to re-evaluate the mouse model. We analyzed spleen, bone marrow, and lymph nodes of susceptible mice at various time points after infection. From day 11 onwards, a heterogeneous population of cells, consisting of CD8 alpha(+) Langerin(+) DC, ER-MP58(+) CD11b(+) myeloid precursor cells, CD169(+) metallophilic M phi, and CD71(hi) erythroblasts, was affected by viral transformation. In different mice, these subsets expanded at different rates in different organs, causing a variable disease profile in terminal stages. Cell lines, which were generated from MHSV-transformed tumors, showed a DC-like morphology and phenotype, and appeared to be arrested in different stages of maturation. Upon injection into healthy mice, different preferential homing patterns were observed for the various cell lines, and the cells acquired distinct phenotypes depending on the organ of homing. This indicates that these transformed cells adapt to their microenvironment by switching between precursor, DC/Langerhans cell, and M phi phenotypes. Our results demonstrate that the MHSV model represents a heterogeneous neoplastic disease with characteristics of M phi/DC sarcomas.


Measuring patient-reported outcomes in facial aesthetic patients: development of the FACE-Q.
To support the development of new techniques and technology in facial aesthetics, sophisticated ways of measuring outcomes are needed. The objective of this study was to develop the content of a set of patient-reported outcome (PRO) scales for use with facial aesthetic patients. A literature review, patient interviews, and input from experts working with facial aesthetic patients were used to develop a conceptual framework for the outcomes deemed important to facial aesthetic patients and to construct items and a set of preliminary PRO scales. The conceptual framework includes the following themes: satisfaction with facial appearance; health-related quality of life; recovery, early life impact, and adverse effects; and satisfaction with process of care. Separate scales were developed for all parts of the face (e.g., nose, ears, forehead, cheeks, etc.) rather than for particular facial procedures. This new PRO instrument, called the FACE-Q, contains multiple independently scoreable scales with preoperative and postoperative versions. Once psychometric evaluation is completed, the FACE-Q will provide researchers and physicians with the necessary tools to measure the impact and effectiveness of facial aesthetic procedures from the patients' perspective. The FACE-Q has the potential to support advocacy, quality metrics, and an evidence-based approach to facial aesthetic practice.


The effect of artificial sweetener on insulin secretion. 1. The effect of acesulfame K on insulin secretion in the rat (studies in vivo).
Acesulfame K is an artificial sweetener which has been used in the food industry for some years. As yet no metabolic effects have been reported. It was reported that the sweetener can induce a cephalic phase of insulin secretion. To analyse the mechanism of this phenomenon, we studied the effect of Acesulfame K on insulin secretion in vivo. Male Wistar rats, weighing 250-300 g were fasted overnight and anaesthetized with phenobarbital. A silicon catheter was inserted into the right cervical vein for injection of test substances and for obtaining blood samples. In some experiments, another catheter was inserted into the left cervical vein for continuous infusion. Blood samples were drawn at 0, 5, 10, 15, 30 and 60 min after injection, and at -10, 0, 10, 20, 30, 40, 60, 80, 100 and 120 min after the infusion started. Injection of Acesulfame K (150 mg/kg body weight) increased the plasma insulin concentration at 5 min from 27.3 +/- 3.0 microU/ml to 58.6 +/- 4.2 microU/ml without any significant change in the blood glucose. Infusion of Acesulfame K (20 mg/kg body weight/min) for one hour maintained the insulin concentration at a high level (about 85-100 microU/ml) during this period, and at the same time blood glucose was gradually reduced from 103.0 +/- 7.3 to 72.0 +/- 7.2 mg/dl. When using different amounts of Acesulfame K, the insulin secretion was stimulated in a dose-dependent fashion. The effect of Acesulfame K on insulin secretion was similar to that observed by injecting or infusing the same doses of glucose (150 mg/kg) body weight for injection and 20 mg/kg body weight/min for infusion), except that no hyperglycemia was observed with Acesulfame K.(ABSTRACT TRUNCATED AT 250 WORDS)


Cytogenetic analysis of an exposed-referent study: perchloroethylene-exposed dry cleaners compared to unexposed laundry workers.
Significant numbers of people are exposed to tetrachloroethylene (perchloroethylene, PCE) every year, including workers in the dry cleaning industry. Adverse health effects have been associated with PCE exposure. However, investigations of possible cumulative cytogenetic damage resulting from PCE exposure are lacking. Eighteen dry cleaning workers and 18 laundry workers (unexposed controls) provided a peripheral blood sample for cytogenetic analysis by whole chromosome painting. Pre-shift exhaled air on these same participants was collected and analyzed for PCE levels. The laundry workers were matched to the dry cleaners on race, age, and smoking status. The relationships between levels of cytological damage and exposures (including PCE levels in the shop and in workers' blood, packyears, cumulative alcohol consumption, and age) were compared with correlation coefficients and t-tests. Multiple linear regressions considered blood PCE, packyears, alcohol, and age. There were no significant differences between the PCE-exposed dry cleaners and the laundry workers for chromosome translocation frequencies, but PCE levels were significantly correlated with percentage of cells with acentric fragments (R2 = 0.488, p < 0.026). There does not appear to be a strong effect in these dry cleaning workers of PCE exposure on persistent chromosome damage as measured by translocations. However, the correlation between frequencies of acentric fragments and PCE exposure level suggests that recent exposures to PCE may induce transient genetic damage. More heavily exposed participants and a larger sample size will be needed to determine whether PCE exposure induces significant levels of persistent chromosome damage.


18F-fluoromisonidazole positron emission tomography before treatment is a predictor of radiotherapy outcome and survival prognosis in patients with head and neck squamous cell carcinoma.
To evaluate the usefulness of [(18)F]fluoromisonidazole ([(18)F]FMISO)-positron emission tomography (PET) prior to the treatment of head and neck squamous cell carcinoma. Seventeen patients with untreated HNSCC underwent pretreatment [(18)F]FMISO PET. Six of them underwent definitive surgery and the remaining 11 definitive (chemo-)radiotherapy. We evaluated 30 lesions from the 17 patients. SUVmax and tumor-to-muscle ratios (TMR) were measured as hypoxia indicators. Tumors equal to or above the median value were defined as tumor with high uptake of [(18)F]FMISO and those below as tumor with low uptake of [(18)F]FMISO in both indicators. Local control rates with radiotherapy, event-free survival and disease-specific survival (DSS) rates with radiotherapy or operation were compared. [(18)F]FMISO-PET imaging of 30 lesions resulted in a SUVmax median value of 2.3 and a TMR median value of 1.3. Local control rates with radiotherapy (20-month median follow-up duration) were significantly lower in the tumor group with high uptake of [(18)F]FMISO compared to the tumor group with low uptake of [(18)F]FMISO using either SUVmax or TMR as the hypoxic indicator (P = 0.02 and 0.04, respectively). DSS rate with radiotherapy or operation (21-month median follow-up duration) was significantly lower in the patient group with high uptake of [(18)F]FMISO compared to the patient group with low uptake of [(18)F]FMISO defined by SUVmax (P = 0.04), but was not by TMR (P = 0.57). Radiotherapy outcome and survival prognosis (radiotherapy or operation) in HNSCC may be predicted by carrying out [(18)F]FMISO PET before treatment.


[In Process Citation].
A large variety of local anaesthetics is widely used in dental clinic. Cautious application is essential in order to avoid adverse events of potentially lethal nature. The objective of this article is to present an overview of the mechanisms and to underline potentially lethal adverse effects and contraindications. The knowledge of specific side effects is vital in daily practice. An overview on specific products is accessible on www.kompendium.ch, however users have to be aware of the fact that this source may be incomplete.


[Tooth wear in Hindu betel nut chewers].
Literature data describe the impact of certain factors on oral health. Very well known is habitual chewing of different plant products, including tobacco, which depending on the geographical area and the substances used, have various names. It has been estimated that approximately 200 million residents of the West Pacific Rim and South-East Asia indulge in betel chewing. Betel is composed of a leaf of the betel pepper, lime, tobacco and the nut of the areca palm. This study aimed to assess the degree of abrasive changes in residents of the Korunalaya Leprosy Care Center. The examinations were carried out on 85 patients (45 females and 40 males), aged 35-95 years, at the local dental surgery. Patients had their teeth assessed and they were further interviewed as to the duration of their habit with regard to their sex and age (35-44; 45-64 and > or = 65 years). The abrasive changes were evaluated using Gerasimov's 7-degree scale. Interview data indicate that 71.76% of the patients were habitual betel chewers. Among female patients, third-degree abrasion was the most frequent change while among males--fifth degree (53.3% and 45.0%, respectively). The abrasive changes, increasing with age, can be attributed to the duration of betel chewing. It is worth noticing that a vegetarian diet can be a contributing factor to abrasion as most of the food consumed by Hindus are plants.


Review of Pasteuria penetrans: Biology, Ecology, and Biological Control Potential.
Pasteuria penetrans is a mycelial, endospore-forming, bacterial parasite that has shown great potential as a biological control agent of root-knot nematodes. Considerable progress has been made during the last 10 years in understanding its biology and importance as an agent capable of effectively suppressing root-knot nematodes in field soil. The objective of this review is to summarize the current knowledge of the biology, ecology, and biological control potential of P. penetrans and other Pasteuria members. Pasteuria spp. are distributed worldwide and have been reported from 323 nematode species belonging to 116 genera of free-living, predatory, plant-parasitic, and entomopathogenic nematodes. Artificial cultivation of P. penetrans has met with limited success; large-scale production of endospores depends on in vivo cultivation. Temperature affects endospore attachment, germination, pathogenesis, and completion of the life cycle in the nematode pseudocoelom. The biological control potential of Pasteuria spp. have been demonstrated on 20 crops; host nematodes include Belonolaimus longicaudatus, Heterodera spp., Meloidogyne spp., and Xiphinema diversicaudatum. Pasteuria penetrans plays an important role in some suppressive soils. The efficacy of the bacterium as a biological control agent has been examined. Approximately 100,000 endospores/g of soil provided immediate control of the peanut root-knot nematode, whereas 1,000 and 5,000 endospores/g of soil each amplified in the host nematode and became suppressive after 3 years.


Parasitology: United Kingdom National Quality Assessment Scheme.
To assess the results from parasitology laboratories taking part in a quality assessment scheme between 1986 and 1991; and to compare performance with repeat specimens. Quality assessment of blood parasitology, including tissue parasites (n = 444; 358 UK, 86 overseas), and faecal parasitology, including extra-intestinal parasites (n = 205; 141 UK, 64 overseas), was performed. Overall, the standard of performance was poor. A questionnaire distributed to participants showed that a wide range of methods was used, some of which were considered inadequate to achieve reliable results. Teaching material was distributed to participants from time to time in an attempt to improve standards. Since the closure of the IMLS fellowship course in 1972, fewer opportunities for specialised training in parasitology are available: more training is needed. Poor performance in the detection of malarial parasites is mainly attributable to incorrect speciation, misidentification, and lack of equipment such as an eyepiece graticule.


Test performance of PET-CT for mediastinal lymph node staging of pulmonary carcinoid tumours.
Positron emission tomography-CT (PET-CT) is one of the initial mediastinal staging modality for non-small cell lung cancer; however, the clinical utility in carcinoid tumours is uncertain. We sought to determine the test performance of PET-CT for mediastinal lymph node staging of pulmonary carcinoid tumours. We collated data from seven institutions, performing a retrospective search on pathological databases for a consecutive series of patients who underwent thoracic surgery (with lymph nodal dissection) for carcinoid tumours with preoperative PET-CT staging. PET-CT results were compared with the reference standard of pathologic results obtained from lymph node dissection and test performance reported using sensitivity and specificity. From November 1999 to January 2013, 247 patients from seven institutions underwent surgery for carcinoid tumours with a corresponding preoperative PET-CT scan. The mean age of the patients was 61 (SD 15, range 73) and 84 were male patients (34%). The pathologic subtype was typical carcinoid in 217 patients (88%) and atypical carcinoid in 30 patients (12%). Results from lymph node dissection were obtained in 207 patients. The calculated sensitivity and specificity of PET-CT to identify mediastinal lymph node disease was 33% (95% CI 4% to 78%) and 94% (95% CI 89% to 97%), respectively. Our results indicate that PET-CT has a poor sensitivity but good specificity to detect the presence of mediastinal lymph node metastases in pulmonary carcinoid tumours. Mediastinal lymph node metastases cannot be ruled out with negative PET-CT uptake, and if the absence of mediastinal lymph node disease is a prerequisite for directing management, tissue sampling should be undertaken.


A boundary current drives synchronous growth of marine fishes across tropical and temperate latitudes.
Entrainment of growth patterns of multiple species to single climatic drivers can lower ecosystem resilience and increase the risk of species extinction during stressful climatic events. However, predictions of the effects of climate change on the productivity and dynamics of marine fishes are hampered by a lack of historical data on growth patterns. We use otolith biochronologies to show that the strength of a boundary current, modulated by the El Niño-Southern Oscillation, accounted for almost half of the shared variance in annual growth patterns of five of six species of tropical and temperate marine fishes across 23° of latitude (3000 km) in Western Australia. Stronger flow during La Niña years drove increased growth of five species, whereas weaker flow during El Niño years reduced growth. Our work is the first to link the growth patterns of multiple fishes with a single oceanographic/climate phenomenon at large spatial scales and across multiple climate zones, habitat types, trophic levels and depth ranges. Extreme La Niña and El Niño events are predicted to occur more frequently in the future and these are likely to have implications for these vulnerable ecosystems, such as a limited capacity of the marine taxa to recover from stressful climatic events.


Identification of pure and mixed basophil colonies in culture of human peripheral blood and marrow cells.
We present a colony assay system that allows in situ identification of human basophil/mast cell (basophil) colonies. In methylcellulose culture, in the presence of phytohemagglutinin-leukocyte conditioned media (PHA-LCM), human peripheral blood and bone marrow cells form colonies that can be distinguished by their unique morphological characteristics. Pure basophil colonies are diffuse, small colonies containing small, round, highly refractile cells. These characteristics of the constituent cells led us to the observation that a significant number of basophils are found in combination with eosinophils. The mixed eosinophil/basophil colonies have the distinctive elements of pure eosinophil and pure basophil colonies. Usually, these are diffuse colonies with compact clusters of slightly larger, darker-appearing cells. We also found colonies that contained basophils and neutrophils/monocytes, but this type could not be consistently identified by in situ morphology. Cytochemical analysis confirmed the metachromatic nature of the granules in the basophils. The presence of IgE receptors on the cells was documented by indirect immunofluorescent staining after passive sensitization with purified human IgE. Peripheral blood cells from six healthy volunteers formed 5.7 +/- 1.0 (mean +/- SEM) pure colonies in 2 X 10(5) cells. Cultures of bone marrow cells from patients with various types of anemia had 9.0 +/- 1.5 colonies in 10(5) cells. This is the first description of a colony assay system for in situ identification of a pure population of basophilic granulocytes.


Effects of causal networks on the structure and stability of resource allocation trait correlations.
Discovering the mechanisms by which genetic variation influences phenotypes is integral to understanding life-history evolution. Models describing causal relationships among traits in a developmental hierarchy provide a functional basis for understanding the correlations often observed among life-history traits. In this paper, we evaluate a developmental network model of life-history traits based on the perennial herb Arabidopsis lyrata, evaluate phenotypic, genetic, and environmental covariance matrices obtained under different scenarios of quantitative trait locus (QTL) effects in simulated crosses, test the efficacy of structural equation modeling to identify the correct basis for multiple-trait QTL effects, and compare model predictions with field data. We found that the trait network constrained the phenotypic covariance patterns to varying degrees, depending on which traits were directly affected by QTLs. Genetic and environmental covariance matrices were strongly correlated only when direct QTL effects were spread over many traits. Structural equation models that included all simulated traits correctly identified traits directly affected by QTLs, but heuristic search algorithms found several network structures other than the correct one that also fit the data closely. Estimated correlations among a subset of traits in F(2) data from field studies corresponded closely to model predictions when simulated QTLs affected traits known to differ between the parental populations. Our results show that causal trait network models can unify several aspects of quantitative genetic theory with empirical observations on genetic and phenotypic covariance patterns, and that incorporating trait networks into genetic analysis offers promise for elucidating mechanisms of life history evolution.


Predispersal home range shift of an ocelot Leopardus pardalis (Carnivora: Felidae) on Barro Colorado Island, Panama.
Home range shifts prior to natal dispersal have been rarely documented, yet the events that lead a subadult to abandon a portion of its home range and venture into unfamiliar territories, before eventually setting off to look for a site to reproduce, are probably related to the causes of dispersal itself. Here, we used a combination of manual radio-tracking and an Automated Radio Telemetry System to continuously study the movements of a subadult male ocelot (Leopardus pardalis), a solitary carnivore with sex-biased dispersal, on Barro Colorado Island, Panama, for 18 months from May 2003 through October 2004. The subadult ocelot's parents were also radio-tracked to record possible parent-offspring interactions within their home ranges. At the age of ca. 21 months the subadult gradually began to shift its natal home range, establishing a new one used until the end of the study, in an area that had previously been used by another dispersing subadult male. Only three parent-offspring interactions were recorded during the four months around the time the range-shift occurred. The apparent peaceful nature of these encounters, along with the slow transition out of a portion of his natal home range, suggest the subadult was not evicted from his natal area by his parents. The timing of the shift, along with the subadult's increase in weight into the weight range of adult ocelots four months after establishing the new territory, suggests that predispersal home range shifts could act as a low risk and opportunistic strategy for reaching adult size, while minimizing competition with parents and siblings, in preparation for an eventual dispersal into a new breeding territory.


A Low-Strain Potassium-Rich Prussian Blue Analogue Cathode for High Power Potassium-Ion Batteries.
Most of the cathode materials for potassium ion batteries (PIBs) suffer from poor structural stability due to the large ionic radius of K+ , resulting in poor cycling stability. Here we report a low-strain potassium-rich K1.84 Ni[Fe(CN)6 ]0.88 ⋅0.49 H2 O (KNiHCF) as a cathode material for PIBs. The as-prepared KNiHCF cathode can deliver reversible discharge capacity of 62.8 mAh g-1 at 100 mA g-1 , with a high discharge voltage of 3.82 V. It can also achieve a superior rate performance of 45.8 mAh g-1 at 5000 mA g-1 , with a capacity retention of 88.6 % after 100 cycles. The superior performance of KNiHCF cathode results from low-strain de-/intercalation mechanism, intrinsic semiconductor property and low potassium diffusion energy barrier. The high power density and long-term stability of KNiHCF//graphite full cell confirmed the feasibility of K-rich KNiHCF cathode in PIBs. This work provides guidance to develop Prussian blue analogues as cathode materials for PIBs.


How Did the Number and Type of Injuries in Patients Presenting to a Regional Level I Trauma Center Change During the COVID-19 Pandemic with a Stay-at-home Order?
During a pandemic, it is paramount to understand volume changes in Level I trauma so that with appropriate planning and reallocation of resources, these facilities can maintain and even improve life-saving capabilities. Evaluating nonaccidental and accidental trauma can highlight potential areas of improvement in societal behavior and hospital preparedness. These critical questions were proposed to better understand how healthcare leaders might adjust surgeon and team coverage of trauma services as well as prepare from a system standpoint what resources will be needed during a pandemic or similar crisis to maintain services. (1) How did the total observed number of trauma activations, defined as patients who meet mechanism of injury requirements which trigger the notification and aggregation of the trauma team upon entering the emergency department, change during a pandemic and stay-at-home order? (2) How did the proportion of major mechanisms of traumatic injury change during this time period? (3) How did the proportion and absolute numbers of accidental versus nonaccidental traumatic injury in children and adults change during this time period? This was a retrospective study of trauma activations at a Level I trauma center in New Orleans, LA, USA, using trauma registry data of all patients presenting to the trauma center from 2017 to 2020. The number of trauma activations during a government mandated coronavirus 2019 (COVID-19) stay-at-home order (from March 20, 2020 to May 14, 2020) was compared with the expected number of activations for the same time period from 2017 to 2019, called "predicted period". The expected number (predicted period) was assumed based on the linear trend of trauma activations seen in the prior 3 years (2017 to 2019) for the same date range (March 20, 2020 to May 14, 2020). To define the total number of traumatic injuries, account for proportion changes, and evaluate fluctuation in accidental verses nonaccidental trauma, variables including type of traumatic injury (blunt, penetrating, and thermal), and mechanism of injury (gunshot wound, fall, knife wound, motor vehicle collision, assault, burns) were collected for each patient. There were fewer total trauma activations during the stay-at-home period than during the predicted period (372 versus 532 [95% CI 77 to 122]; p = 0.016). The proportion of penetrating trauma among total activations was greater during the stay-at-home period than during the predicted period (35% [129 of 372] versus 26% [141 of 532]; p = 0.01), while the proportion of blunt trauma was lower during the stay-at-home period than during the predicted period (63 % [236 of 372] versus 71% [376 of 532]; p = 0.02). The proportion of gunshot wounds in relation to total activations was greater during the stay-at-home period than expected (26% [97 of 372] versus 18% [96 of 532]; p = 0.004). There were fewer motor vehicle collisions in relation to total activations during the stay-at-home period than expected (42% [156 of 372] versus 49% [263 of 532]; p = 0.03). Among total trauma activations, the stay-at-home period had a lower proportion of accidental injuries than the predicted period (55% [203 of 372] versus 61% [326 of 532]; p = 0.05), and there was a greater proportion of nonaccidental injuries than the predicted period (37% [137 of 372] versus 27% [143 of 532]; p < 0.001). In adults, the stay-at-home period had a greater proportion of nonaccidental injuries than the predicted period (38% [123 of 328] versus 26% [123 of 466]; p < 0.001). There was no difference between the stay-at-home period and predicted period in nonaccidental and accidental injuries among children. Data from the trauma registry at our region's only Level I trauma center indicate that a stay-at-home order during the COVID-19 pandemic was associated with a 70% reduction in the number of traumatic injuries, and the types of injuries shifted from more accidental blunt trauma to more nonaccidental penetrating trauma. Non-accidental trauma, including gunshot wounds, increased during this period, which suggest community awareness, crisis de-escalation strategies, and programs need to be created to address violence in the community. Understanding these changes allows for adjustments in staffing schedules. Surgeons and trauma teams could allow for longer shifts between changeover, decreasing viral exposure because the volume of work would be lower. Understanding the shift in injury could also lead to a change in specialists covering call. With the often limited availability of orthopaedic trauma-trained surgeons who can perform life-saving pelvis and acetabular surgery, this data may be used to mitigate exposure of these surgeons during pandemic situations. Level III, therapeutic study.


Recurrent respiratory infections in children: a study in clinical practice.
Recurrent respiratory infections (RRI) are very frequent in childhood. RRI are commonly associated with some co-morbidities and typical clinical features. This study aimed to test the hypothesis whether an ENT visit could identify predicting factors for IRR.Globally, 1,002 children (550 males, mean age 5.77 years) were consecutively visited at an ENT clinic. Clinical visit, nasal endoscopy, and skin prick test were performed in all patients. RRI were present in 633 (63.5%) children. Some parameters were predicting factor for RRI: male gender (OR=1.68), tonsil and adenoid volume, even if partially for some volume grading. On the other hand, familiar atopy (OR=0.68), acute otitis media (OR=0.29), and certain tonsil and adenoid size (OR range 0.61-0-47) seemed to be protecting factor for RRI. This real-life study showed that during an ENT visit it is possible to identify some predictive factors involved in RRI: some seem to be protective, whereas other seem to be predisposing.


The establishment of the photo management system for orthodontics and its clinical application.
It is necessary for orthodontists to collect and analyze the patients' photographic data. By conventional methods, these photo data were commonly saved on film, which were frail and often resulted in data loss. Furthermore, it is not convenient for the orthodontists to consult and study these data during clinical research. A critical problem thus arises in managing these photo data scientifically. The computer technique and picture processing method were employed in the present study to establish the Photo Management System for Orthodontics (PMSO), which makes the administration of patients' photo data more scientific, convenient, and effective than before. This system is characterized as follows: (1) Clinical orthodontists designed and programmed the system, which is "close to clinical reality and serves the clinic". Orthodontists can easily use it without any training course. (2) The images can be imported from many devices, such as digital cameras, scanners, and electronic data storage media such as floppy disks. (3) Even two groups of photos (four images) could be displayed in the same window for comparison and study. This function allows orthodontists to easily observe the differences in the same patient's photos at different stages, which is important to obtain comprehensive knowledge of the patient. (4) The network technique makes it possible for the photos to be shared. The orthodontists can get the patients' photos through the network without going to the radiology department or the imaging room. (5) It is helpful for orthodontic research since the photos can be exported easily in different ways. (6) This is shared software; orthodontists can use it for free.


Peer review in 18th-century scientific journalism.
Although the beginnings of "peer review" are frequently associated with the Royal Society of London when it took over official responsibility for the Philosophical Transactions in 1752, antecedents of peer review practices go back to the 17th century. Despite the differences in the academic, social, intellectual, and economic environments of the 18th century and today, we can find interesting and instructive similarities in the way early editors defined and exercised their prerogatives and responsibilities. These concerns extend to ideas and practices that are closely related to what we call peer review or refereeing today.


HIV infection and lymphoma.
The incidence of lymphoma in patients with HIV infection greatly exceeds that of the general population. The increased risk for lymphoma appears related to multiple factors, including the transforming properties of the retrovirus itself, the immunosuppression and cytokine dysregulation that results from the disease, and, most importantly, opportunistic infections with other lymphotrophic herpes viruses such as Epstein-Barr virus and human herpesvirus 8. Histologically lymphomas fall into three groups: (1) those also occurring in immunocompetent patients; (2) those occurring more specifically in HIV-positive patients; and (3) those also occurring in patients with other forms of immunosuppression. Aggressive lymphomas account for the vast majority cases. They frequently present with advanced stage, bulky disease with high tumour burden and, typically, involve extranodal sites. Clinical outcome appears to be worse than in similar aggressive lymphomas in the general population. However, following the introduction of highly active antiretroviral therapy, the risk for developing lymphoma in the context of HIV infection has decreased and the clinical outcome has improved.


Interstitial Fibrosis Restricts Osmotic Water Transport in Encapsulating Peritoneal Sclerosis.
Encapsulating peritoneal sclerosis (EPS) is a rare but severe complication of peritoneal dialysis (PD) characterized by extensive fibrosis of the peritoneum. Changes in peritoneal water transport may precede EPS, but the mechanisms and potential predictive value of that transport defect are unknown. Among 234 patients with ESRD who initiated PD at our institution over a 20-year period, 7 subsequently developed EPS. We evaluated changes in peritoneal transport over time on PD in these 7 patients and in 28 matched controls using 3.86% glucose peritoneal equilibration tests. Compared with long-term PD controls, patients with EPS showed early loss of ultrafiltration capacity and sodium sieving before the onset of overt EPS. Multivariate analysis revealed that loss of sodium sieving was the most powerful predictor of EPS. Compared with long-term PD control and uremic peritoneum, EPS peritoneum showed thicker submesothelial fibrosis, with increased collagen density and a greater amount of thick collagen fibers. Reduced osmotic conductance strongly correlated with the degree of peritoneal fibrosis, but not with vasculopathy. Peritoneal fibrosis was paralleled by an excessive upregulation of vascular endothelial growth factor and endothelial nitric oxide synthase, but the expression of endothelial aquaporin-1 water channels was unaltered. Our findings suggest that an early and disproportionate reduction in osmotic conductance during the course of PD is an independent predictor of EPS. This functional change is linked to specific alterations of the collagen matrix in the peritoneal membrane of patients with EPS, thereby validating the serial three-pore membrane/fiber matrix and distributed models of peritoneal transport.


Bending sensor combining multicore fiber with a mode-selective photonic lantern.
A bending sensor is demonstrated using the combination of a mode-selective photonic lantern (PL) and a multicore fiber. A short section of three-core fiber with strongly coupled cores is used as the bend sensitive element. The supermodes of this fiber are highly sensitive to the refractive index profiles of the cores. Small bend-induced changes result in drastic changes of the supermodes, their excitation, and interference. The multicore fiber is spliced to a few-mode fiber and excites bend dependent amounts of each of the six linearly polarized (LP) modes guided in the few-mode fiber. A mode selective PL is then used to demultiplex the modes of the few-mode fiber. Relative power measurements at the single-mode PL output ports reveal a high sensitivity to bending curvature and differential power distributions according to bending direction, without the need for spectral measurements. High direction sensitivity is demonstrated experimentally as well as in numerical simulations. Relative power shifts of up to 80% have been measured at radii of approximately 20 cm, and good sensitivity was observed with radii as large as 10 m, making this sensing system useful for applications requiring both large and small curvature measurements.


Enhancement of semiconducting single-wall carbon-nanotube photoluminescence.
Photoluminescence properties of semiconducting single-wall carbon-nanotube (s-SWNT) thin films with different metallic single-wall carbon-nanotube (m-SWNT) concentrations are reported. s-SWNT purified samples are obtained by polymer-assisted selective extraction. We show that the presence of a few m-SWNTs in the sample generates a drastic quenching of the emission. Therefore, the highly purified s-SWNT film is a strongly luminescent material and a good candidate for future applications in photonics, such as near-IR emitters, modulators, and detectors.


Leukocyte counts and activation in spontaneously hypertensive and normotensive rats.
The etiology for the progressive organ injury in hypertension is largely speculative. Recent studies have shown that leukocytes play a key role in several cardiovascular diseases. As an initial step toward investigating the role of leukocytes in hypertension, we measured leukocyte counts and spontaneous activation of granulocytes of freshly drawn unseparated blood samples in spontaneously hypertensive rats and in their normotensive counterpart, Wistar-Kyoto rats. The animals were derived from one breeder in the United States and from two breeders in Europe. Total leukocyte counts in young, mature, and old hypertensive rats were 50-100% above the controls. The number of granulocytes in mature and old spontaneously hypertensive rats in more than 100% elevated compared with control rats. In young hypertensive rats the mean granulocyte count was only slightly elevated. The number of spontaneously activated granulocytes, as detected by the nitroblue tetrazolium reduction, increases with age in both species; in mature spontaneously hypertensive rats, it is more than 300% above the values in the controls. Furthermore, in mature hypertensive rats the number of monocytes, activated monocytes, and the lymphocyte count are also significantly elevated over the values in the normotensive controls. It is proposed that these elevated leukocyte counts may constitute an enhanced risk for organ injury in the spontaneously hypertensive rat.


Pulmonary macrophages: key players in the innate defence of the airways.
Macrophages are the most numerous immune-cells present in the lung environment under homoeostatic conditions and are ideally positioned to dictate the innate defence of the airways. Pulmonary macrophage populations are heterogeneous and demonstrate remarkable plasticity, owing to variations in origin, tissue residency and environmental influences. Lung macrophage diversity facilitates considerable specialisation, aids efficient responses to environmental signals and allows rapid alterations in phenotype and physiology in response to a plethora of cytokines and microbial signals. This review describes pulmonary macrophage origins, phenotypes, roles in diseases of the airways and implications for the treatment of respiratory disease.


Low-carbohydrate diets and prostate cancer: how low is "low enough"?
Previous studies indicate that carbohydrate intake influences prostate cancer biology, as mice fed a no-carbohydrate ketogenic diet (NCKD) had significantly smaller xenograft tumors and longer survival than mice fed a Western diet. As it is nearly impossible for humans to consume and maintain NCKD, we determined whether diets containing 10% or 20% carbohydrate kcal showed similar tumor growth as NCKD. A total of 150 male severe combined immunodeficient mice were fed a Western diet ad libitum, injected with the human prostate cancer cell line LAPC-4, and then randomized 2 weeks later to one of three arms: NCKD, 10% carbohydrate, or 20% carbohydrate diets. Ten mice not injected were fed an ad libitum low-fat diet (12% fat kcal) serving as the reference in a modified-paired feeding protocol. Mice were sacrificed when tumors reached 1,000 mm(3). Despite consuming extra calories, all mice receiving low-carbohydrate diets were significantly lighter than those receiving a low-fat diet (P < 0.04). Among the low-carbohydrate arms, NCKD-fed mice were significantly lighter than the 10% or 20% carbohydrate groups (P < 0.05). Tumors were significantly larger in the 10% carbohydrate group on days 52 and 59 (P < 0.05), but at no other point during the study. Diet did not affect survival (P = 0.34). There were no differences in serum insulin-like growth factor-I or insulin-like growth factor binding protein-3 at sacrifice among the low-carbohydrate arms (P = 0.07 and P = 0.55, respectively). Insulin was significantly lower in the 20% carbohydrate arm (P = 0.03). LAPC-4 xenograft mice fed a low-carbohydrate diet (10-20% carbohydrate kcal) had similar survival as mice consuming NCKD (0% carbohydrate kcal).


Two vibrio splendidus related strains collaborate to kill Crassostrea gigas: taxonomy and host alterations.
For several years, strains phenotypically related to Vibrio splendidus have been associated with mortality outbreaks of molluscs. A former study on Crassostrea gigas demonstrated the genetic diversity of V. splendidus strains associated with diseased animals. Another study suggested that different strains may act in an additive/synergistic way leading to higher C. gigas mortality rates. Here, a strain pair (31+32) was characterised at taxonomic and virulence levels. Using a polyphasic approach, these strains were confirmed to be V. splendidus-related, without a clear discrimination between V. kanaloae and V. pomeroyi since hybridisation rates with both these strains were above 70 %. Following experimental infection of C. gigas by injection in the adductor muscle or in the pallial cavity, the host alterations induced were described. After injection of strains 31 and/or 32, bacteria were localised at the periphery of the muscle and induced extensive lesions of the translucent part of the adductor muscle. Muscle alterations were of 3 kinds: (1) presence of isolated rounded muscular fibres containing non-homogenous granular material and surrounded by a translucent halo; (2) presence of non-homogenous granular material in the cytoplasm of entire muscle bands; (3) affection of wide muscle areas with extremely condensed muscle fibres. Infiltration associated with these lesions was notably absent in the vast majority of the individuals.


Paid Caregiver Communication With Homebound Older Adults, Their Families, and the Health Care Team.
Although paid caregivers (e.g., home health aides and home care workers) provide essential care for homebound older adults with serious illness in their homes, little is known about how and to whom paid caregivers communicate about the health needs they encounter. This study explored how paid caregivers (i) communicate when older adults experience symptoms or clinical changes and (ii) interact with the health care team. We conducted separate one-on-one, semi-structured interviews (n = 30) lasting 40-60 min with homebound older adults (or their proxies if they had cognitive impairment) and their paid caregivers (provided they had worked with the older adult for ≥8 hr per week for ≥6 months). Interviews were audio-recorded, transcribed, and coded. Thematic analysis identified four themes: (i) older adults or their families were the gatekeepers to paid caregiver communication with the health care team; (ii) communication between older adults, their families, and paid caregivers was enhanced when close relationships were present; (iii) paid caregivers responded to health care team inquiries but rarely communicated proactively; and (4) most older adults, families, and paid caregivers were satisfied with existing paid caregiver communication with the health care team. Rather than discuss concerns with the health care team, paid caregivers communicated directly with older adults or their families about the health needs they encounter. Understanding how communication occurs in the home is the first step to maximizing the potentially positive impact of paid caregivers on the health of older adults living at home.


Noninvasive imaging and quantification of bile salt hydrolase activity: From bacteria to humans.
The microbiome-produced enzyme bile salt hydrolase (BSH) plays a central role in human health, but its function remains unclear due to the lack of suitable methods for measuring its activity. Here, we have developed a novel optical tool based on ultrasensitive bioluminescent imaging and demonstrated that this assay can be used for quick and cost-effective quantification of BSH activity across a broad range of biological settings including pure enzymes and bacteria, intact fecal slurries, and noninvasive imaging in live animals, as well as for the assessment of BSH activity in the entire gastrointestinal tract of mice and humans. Using this assay, we showed that certain types of prebiotics are capable of increasing BSH activity of the gut microbiota in vivo and successfully demonstrated potential application of this assay as a noninvasive diagnostic test to predict the clinical status of inflammatory bowel disease (IBD) patients.


Estrogen receptor-positive mammary tumorigenesis in TGFalpha transgenic mice progresses with progesterone receptor loss.
We characterized the novel NRL-transforming growth factor alpha (NRL-TGFalpha) transgenic mouse model in which growth factor - steroid receptor interactions were explored. The NRL promoter directs transgene expression to mammary ductal and alveolar cells and is nonresponsive to estrogen manipulations in vitro and in vivo. NRL-TGFalpha mice acquire proliferative hyperplasias as well as cystic and solid tumors. Quantitative transcript analysis revealed a progressive decrease in estrogen receptor alpha (ER) and progesterone receptor (PR) mRNA levels with tumorigenesis. However, ER protein was evident in all lesion types and in surrounding stromal cells using immunohistochemistry. PR protein was identified in normal epithelial cells and in very few cells of small epithelial hyperplasias, but never in stromal or tumor cells. Prophylactic ovariectomy significantly delayed tumor development and decreased incidence. Finally, while heterozygous (+/-) p53 mice did not acquire mammary lesions, p53+/- mice carrying the NRL-TGFalpha transgene developed ER negative/PR negative undifferentiated carcinomas. These data demonstrate that unregulated TGFalpha expression in the mammary gland leads to oncogenesis that is dependent on ovarian steroids early in tumorigenesis. Resulting tumors resemble a clinical phenotype of ER+/PR-, and when combined with a heterozygous p53 genotype, ER-/PR-.


Appropriate margin for lumpectomy excision of invasive breast cancer.
The management of patients with early-stage breast cancer has evolved over time, with the understanding that tumor biology, and not just disease burden, impact local control. Local control is greatly improved with systemic therapy, providing an opportunity to decrease the morbidity of local therapy in women with invasive breast cancer. In women undergoing breast-conserving therapy, which consists of lumpectomy and whole-breast irradiation, there has been a lack of consensus as to what constitutes a negative margin. Current evidence indicates that wider margins do not reduce local recurrence compared to "no tumor on ink". In this article, we will review the available data on the relationship between margin status and local control for invasive breast cancer, and discuss the impact of molecular subtypes and systemic therapy on local control.


The early phase of a bacterial insertion sequence infection.
Bacterial insertion sequences are the simplest form of autonomous mobile DNA. It is unknown whether they need to have beneficial effects to infect and persist in bacterial populations, or whether horizontal gene transfer suffices for their persistence. We address this question by using branching process models to investigate the critical, early phase of an insertion sequence infection. We find that the probability of a successful infection is low and depends linearly on the difference between the rate of horizontal gene transfer and the fitness cost of the insertion sequences. Our models show that the median time to extinction of an insertion sequence that dies out is very short, while the median time for a successful infection to reach a modest population size is very long. We conclude that horizontal gene transfer is strong enough to allow the persistence of insertion sequences, although infection is an erratic and slow process.


Nonself help: how immunology might reframe the Enlightenment.
The classical immunological paradigm is predicated on the body's ability to recognize and eliminate "nonself." However, the "self–nonself" model has yet to facilitate any resolution of the field's major concerns, and may thus prove to be of limited use. Merely discarding it is no solution, as the juxtaposition of "self" and "nonself" persists in research, in clinical settings, and in everyday practice despite the best efforts of theoretical immunologists. Instead, the very conception of "selfhood" may prove to be key. Replacing immunology's prior and persistent "self" with less static concepts derived from non-Western contexts not only resolves immunology's famous paradoxes but also offers a new and more accurate model that allows immunology to reframe what may become an outmoded Enlightenment construct of "self." In such a new paradigm, immunology's well-known system of protection and defense is replaced with a view in which nonself becomes less the body's enemy than its primary mechanism for the creative assimilation of difference. This incorporative model—in which the "immune system" functions more as a search engine than as an expeller of difference—both resolves outstanding paradoxes, and complies more accurately with contemporary knowledge and research practice.


Mobilizing Policy (In)Capacity to Fight COVID-19: Understanding Variations in State Responses.
The objective of this collection of essays is to gain insights into the different national-level state responses to COVID-19 around the world and the conditions that shaped them. The pandemic offers a natural experiment wherein the policy problem governments faced was the same but the responses they made were different, creating opportunities for comparison of both the kinds of policy tools being used and the factors that accounted for their choice. Accordingly, after surveying on-line databases of policy tools used in the pandemic and subjecting these to topic modelling to reveal the characteristics of a 'standard' national pandemic response, we discuss the similarities and differences found in specific responses. This is done with reference to the nature and level of policy capacity of respective governments, highlighting the critical roles played by (in)adequate preparation and lesson-drawing from past experiences with similar outbreaks or crises. Taken together the articles show how the national responses to the COVID-19 pandemic were shaped by the opportunity and capacity each government had to learn from previous pandemics and their capacity to operationalize and build political support for the standard portfolio of policy measures deployed to deal with the crisis. However, they also show how other factors such as the nature of national leadership, the organization of government and civil society, and blindspots towards the vulnerabilities of certain population segments also helped to shape policy responses to the pandemic.


Skin blood vessels are simultaneously innervated by sensory, sympathetic, and parasympathetic fibers.
Despite the known major role of skin blood vessel innervation in blood flow control, particularly in disease, little information on the co-innervation of blood vessels by sensory and autonomic fibers and the relationships of these fibers to one another is available. To fill this gap, we performed a light and electron microscopic analysis of the innervation of skin vessels by sensory and autonomic fibers by using the rat and monkey lower lips as a model. In rats, double-labeling immunocytochemistry revealed that combinations of fibers immunoreactive for substance P (SP) and dopamine-beta-hydroxylase (DbetaH), SP and vesicular acetylcholine transporter (VAChT), as well as DbetaH and VAChT occurred only around blood vessels in the lower dermis. All fiber types travelled in parallel and in close proximity to one another. In the upper dermis, blood vessels were innervated by SP-containing fibers only. Although nerve terminals displayed synaptic vesicles, synaptic specializations were never observed, suggesting that, in this territory, these fibers do not establish synaptic contacts. Quantification of the distance between the various immunoreactive terminals and their presumptive targets (smooth muscle cells and endothelial cells) revealed that both sympathetic and parasympathetic fibers were significantly closer to the endothelial cell layer and smooth muscle cells compared with sensory fibers. In monkeys, double-labeling immunocytochemistry was performed for SP-DbetaH and SP-VAChT only. The results obtained are similar to those found in rats; however, the fiber density was greater in monkeys. Our findings suggest that the regulation of skin microcirculation might be the result of the coordinated functions of sensory and autonomic fibers.


Mutation of rat Zp2 causes ROS-mediated oocyte apoptosis.
In this study, we investigated a gene-edited (Zp2MT/MT) rat model of infertility caused by the failure to express the zona pellucida glycoprotein 2 (ZP2) due to the significant reduction of mRNA amount. We examined the defects in the zona pellucida (ZP) caused by ZP2 nullification and the influence of these defects on aspects of oocyte development, including apoptosis and fertilization ability. To investigate the cause of the influence to the oocytes' development, we evaluated the morphology of follicular transzonal projections (TZPs), known as 'bridges', which mediate the bidirectional signaling between the oocyte and surrounding granulosa cells and the level of reactive oxygen species (ROS) in ovulated eggs. Our results showed that two types of ZP defects were generated in the Zp2MT/MT rat,that is, ZP intact but thinned and ZP cracked (or even absent). The fertilization rate of the ovulated eggs reduced in both types, while increased oocyte apoptosis was observed only in the latter type. Moreover, the increased oocyte apoptosis rate correlated closely with the reduction in follicular TZPs and increased ROS levels in ovulated egg. In conclusion, nullification of rat ZP2 destroyed the integrity of the ZP, impaired the bidirectional signaling between the oocyte and surrounding granulosa cells. Therefore, the resulting infertility likely occurs via elevation of oxidative stress and oocytes apoptosis.


Drosophila melanogaster SL2 cells contain a hypoxically inducible DNA binding complex which recognises mammalian HIF-binding sites.
Nuclear extracts from Drosophila SL2 cells were found to contain a hypoxically inducible complex capable of binding to hypoxia response elements from mammalian genes. This complex (HIF-D) resembled mammalian hypoxia inducible factor (HIF-1) in DNA sequence specificity, abrogation of induction by cycloheximide, induction by desferrioxamine and redox sensitivity of DNA binding. However, HIF-D was not induced by cobalt and was less sensitive to phosphatase than HIF-1. Endogenous phosphoglycerate kinase mRNA in SL2 cells showed similar inducible characteristics to HIF-D. These findings are evidence that the mammalian HIF-1 dependent system of oxygen regulated gene expression has a functional homologue in Drosophila.


Colorectal cancer: from prevention to personalized medicine.
Colorectal cancer (CRC) is a very heterogeneous disease that is caused by the interaction of genetic and environmental factors. CRC develops through a gradual accumulation of genetic and epigenetic changes, leading to the transformation of normal colonic mucosa into invasive cancer. CRC is one of the most prevalent and incident cancers worldwide, as well as one of the most deadly. Approximately 1235108 people are diagnosed annually with CRC, and 609051 die from CRC annually. The World Health Organization estimates an increase of 77% in the number of newly diagnosed cases of CRC and an increase of 80% in deaths from CRC by 2030. The incidence of CRC can benefit from different strategies depending on its stage: health promotion through health education campaigns (when the disease is not yet present), the implementation of screening programs (for detection of the disease in its early stages), and the development of nearly personalized treatments according to both patient characteristics (age, sex) and the cancer itself (gene expression). Although there are different strategies for screening and although the number of such strategies is increasing due to the potential of emerging technologies in molecular marker application, not all strategies meet the criteria required for screening tests in population programs; the three most accepted tests are the fecal occult blood test (FOBT), colonoscopy and sigmoidoscopy. FOBT is the most used method for CRC screening worldwide and is also the primary choice in most population-based screening programs in Europe. Due to its non-invasive nature and low cost, it is one of the most accepted techniques by population. CRC is a very heterogeneous disease, and with a few exceptions (APC, p53, KRAS), most of the genes involved in CRC are observed in a small percentage of cases. The design of genetic and epigenetic marker panels that are able to provide maximum coverage in the diagnosis of colorectal neoplasia seems a reasonable strategy. In recent years, the use of DNA, RNA and protein markers in different biological samples has been explored as strategies for CRC diagnosis. Although there is not yet sufficient evidence to recommend the analysis of biomarkers such as DNA, RNA or proteins in the blood or stool, it is likely that given the quick progression of technology tools in molecular biology, increasingly sensitive and less expensive, these tools will gradually be employed in clinical practice and will likely be developed in mass.


Spatial Bayesian latent factor regression modeling of coordinate-based meta-analysis data.
Now over 20 years old, functional MRI (fMRI) has a large and growing literature that is best synthesised with meta-analytic tools. As most authors do not share image data, only the peak activation coordinates (foci) reported in the article are available for Coordinate-Based Meta-Analysis (CBMA). Neuroimaging meta-analysis is used to (i) identify areas of consistent activation; and (ii) build a predictive model of task type or cognitive process for new studies (reverse inference). To simultaneously address these aims, we propose a Bayesian point process hierarchical model for CBMA. We model the foci from each study as a doubly stochastic Poisson process, where the study-specific log intensity function is characterized as a linear combination of a high-dimensional basis set. A sparse representation of the intensities is guaranteed through latent factor modeling of the basis coefficients. Within our framework, it is also possible to account for the effect of study-level covariates (meta-regression), significantly expanding the capabilities of the current neuroimaging meta-analysis methods available. We apply our methodology to synthetic data and neuroimaging meta-analysis datasets.


JC virus detection and JC virus-specific immunity in natalizumab-treated multiple sclerosis patients.
The use of natalizumab in multiple sclerosis (MS) may favour JC virus reactivation; this phenomenon is usually asymptomatic but can, albeit rarely, evolve into frank progressive multifocal leucoencephalopathy (PML). JCV-specific CD8+ T lymphocytes were evaluated by flow cytometry over a 24-month period in 24 natalizumab-treated MS patients in whom JCV DNA was or was not detected in blood using quantitative real-time polymerase chain reaction; all these cases were asymptomatic. Perforin- and grazymes-containing VP-1-specific CD8+ T lymphocytes were reduced whereas CD107a-expressing cells were increased in JCV positive patients, suggesting an active degranulation of these cells; naïve CD8+ T lymphocytes were also decreased whereas memory cells were increased in patients in whom JCV reactivation was observed. The presence of a CD8+ T lymphocyte-mediated effector immune response offers a greater insight into reactivation of JCV and its clinical sequelae, and may help the monitoring of patients on natalizumab therapy.


Liver receptor homolog 1 contributes to intestinal tumor formation through effects on cell cycle and inflammation.
Liver receptor homolog 1 (LRH-1) is an orphan nuclear receptor that synergizes with beta-catenin/T cell factor 4 signaling to stimulate intestinal crypt cell renewal. We evaluated here the impact of haploinsufficiency of LRH-1 on intestinal tumorigenesis by using two independent mouse models of human colon tumorigenesis. Haploinsufficiency of LRH-1 blunts intestinal tumorigenesis in the ApcMin/+ mice, a genetic model of intestinal cancer. Likewise, Lrh-1+/- mice are protected against the formation of aberrant crypt foci in the colon of mice exposed to the carcinogen azoxymethane. LRH-1 gene expression is reduced in tumors that express elevated levels of the proinflammatory cytokine TNF-alpha. Reciprocally, decreased LRH-1 expression in Lrh-1+/- mice attenuates TNF-alpha expression. Compared with normal human colon, expression and subcellular localization of LRH-1 is significantly altered in neoplastic colon. In combination, these data suggest a role of LRH-1 in the initiation of intestinal tumorigenesis both by affecting cell cycle control as well as through its impact on inflammatory pathways.


Informal care-giving and mental ill-health - differential relationships by workload, gender, age and area-remoteness in a UK region.
Informal care-giving can be a demanding role which has been shown to impact on physical, psychological and social well-being. Methodological weaknesses including small sample sizes and subjective measures of mental health have led to inconclusive evidence about the relationship between informal care-giving and mental ill-health. This paper reports on a study carried out in a UK region which investigated the relationship between informal care-giving and mental ill-health. The analysis was conducted by linking three data sets, the Northern Ireland Longitudinal Study, the Northern Ireland Enhanced Prescribing Database and the Proximity to Service Index from the Northern Ireland Statistics and Research Agency. Our analysis used both a subjective measure of mental ill-health, i.e. a question asked in the 2011 Census, and an objective measure, whether the respondents had been prescribed antidepressants by a General Practitioner between 2010 and 2012. We applied binary logistic multilevel modelling to these two responses to test whether, and for what sub-groups of the population, informal care-giving was related to mental ill-health. The results showed that informal care-giving per se was not related to mental ill-health, although there was a strong relationship between the intensity of the care-giving role and mental ill-health. Females under 50, who provided over 19 hours of care, were not employed or worked part-time and who provided care in both 2001 and 2011 were at a statistically significantly elevated risk of mental ill-health. Caregivers in remote areas with limited access to shops and services were also at a significantly increased risk as evidenced by prescription rates for antidepressants. With community care policies aimed at supporting people to remain at home, the paper highlights the need for further research in order to target resources appropriately.


Age effect in expert cognitive flexibility in Guinea baboons (Papio papio).
Cognitive flexibility in non-human primates is traditionally measured with the conceptual set shifting task (CSST). In our laboratory, Guinea baboons (N = 24) were continuously tested with a CSST task during approximately 10 years. Our task involved the presentation of three stimuli on a touch screen all made from 3 possible colours and 3 shapes. The subjects had to touch the stimulus containing the stimulus dimension (e.g., green) that was constantly rewarded until the stimulus dimension changed. Analysis of perseveration responses, scores and response times collected during the last two years of testing (approximately 1.6 million trials) indicate (1) that the baboons have developed an "expert" form of cognitive flexibility and (2) that their performance was age-dependent, it was at a developing stage in juveniles, optimal in adults, declining in middle-aged, and strongly impaired in the oldest age group. A direct comparison with the data collected by Bonté , Flemming & Fagot (2011) on some of the same baboons and same task as in the current study indicates that (3) the performance of all age groups has improved after 10 years of training, even for the now old individuals. All these data validate the use of non-human primates as models of human cognitive flexibility and suggest that cognitive flexibility in humans has a long evolutionary history.


Difficulty buying food, BMI, and eating habits in young children.
To determine whether parent report of difficulty buying food was associated with child body mass index (BMI) z-score or with eating habits in young children. This was a cross-sectional study in primary care offices in Toronto, Ontario. Subjects were children aged 1-5 years and their caregivers, recruited through the TARGet Kids! Research Network from July 2008 to August 2011. Regression models were developed to test the association between parent report of difficulty buying food because of cost and the following outcomes: child BMI z-score, parent's report of child's intake of fruit and vegetables, fruit juice and sweetened beverages, and fast food. Confounders included child's age, sex, birth weight, maternal BMI, education, ethnicity, immigration status, and neighbourhood income. The study sample consisted of 3333 children. Data on difficulty buying food were available for 3099 children, and 431 of these (13.9%) were from households reporting difficulty buying food. There was no association with child BMI z-score (p = 0.86). Children from households reporting difficulty buying food (compared with never having difficulty buying food) had increased odds of consuming three or fewer servings of fruits and vegetables per day (odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.03-1.69), more than one serving of fruit juice/sweetened beverage per day (OR: 1.60, 95% CI: 1.28-2.00), and, among children 1-2 years old, one or more servings of fast food per week (OR: 2.91, 95% CI: 1.67-5.08). Parental report of difficulty buying food is associated with less optimal eating habits in children but not with BMI z-score.


The difficulty of determining the route of intraocular penetration of gentamicin after subconjunctival injection in the rabbit.
In small animals such as the rabbit the ratio of eye size to body size is much larger than it is in humans. Accordingly, periocular injection of antibodies in this animal model results in significantly higher serum concentrations than does a comparable does in a human. To assess the effect of the systemic drug component on ocular penetration, we compared the levels of gentamicin in ocular tissues and fluids of the rabbit following injection of 20 mg by subconjunctival or intramuscular routes. Blood levels of gentamicin were similar with the two routes of administration. In normal rabbit eyes, no antibiotic was detectable in the vitreous humor for the first 3 hr after either subconjunctival or intramuscular injection. By 6 hr, low vitreous levels of drug were detectable after subconjunctival, but not after intramuscular, injection. Because these concentrations were so close to the threshold of sensitivity of the assay, it was not clear that the difference between the routes was significant in normal eyes. In infected eyes, the concentrations of gentamicin in the vitreous were similar after subconjunctival and intramuscular injection. These data indicate that the penetration of gentamicin in to the infected vitreous humor of rabbits after subconjunctival injection could be attributed as well to hematogenous carriage as to direct penetration. The problem in distinguishing systemic from direct transport with periocular injections may be inherent in any small animal model in which the ratio of eye size to body size is high.


Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein.
alpha-Synucleinopathies are neurodegenerative disorders that range pathologically from the demise of select groups of nuclei to pervasive degeneration throughout the neuraxis. Although mounting evidence suggests that alpha-synuclein lesions lead to neurodegeneration, this remains controversial. To explore this issue, we generated transgenic mice expressing wild-type and A53T human alpha-synuclein in CNS neurons. Mice expressing mutant, but not wild-type, alpha-synuclein developed a severe and complex motor impairment leading to paralysis and death. These animals developed age-dependent intracytoplasmic neuronal alpha-synuclein inclusions paralleling disease onset, and the alpha-synuclein inclusions recapitulated features of human counterparts. Moreover, immunoelectron microscopy revealed that the alpha-synuclein inclusions contained 10-16 nm wide fibrils similar to human pathological inclusions. These mice demonstrate that A53T alpha-synuclein leads to the formation of toxic filamentous alpha-synuclein neuronal inclusions that cause neurodegeneration.


Discriminative control of saccade latencies.
Recent studies have demonstrated that saccadic reaction times (SRTs) are influenced by the temporal regularities of dynamic environments (Vullings & Madelain, 2018). Here, we ask whether discriminative control (i.e., the possibility to use external stimuli signaling the future state of the environment) of latencies in a search task might be established using reinforcement contingencies. Eight participants made saccades within 80-750 ms toward a target displayed among distractors. We constructed two latency classes, "short" and "long," using the first and last quartiles of the individual baseline distributions. We then used a latency-contingent display paradigm in which finding the visual target among other items was made contingent upon specific SRTs. For a first group, the postsaccadic target was displayed only following short latencies with leftward saccades, and following long latencies with rightward saccades. The opposite was true for a second group. When short- and long-latency saccades were reinforced (i.e., the target was displayed) depending on the saccade direction, median latencies differed by 74 ms on average (all outside the 98% null hypothesis confidence intervals). Posttraining, in the absence of reinforcement, we still observed strong differences in latency distributions, averaging 64 ms for leftward versus rightward saccades. Our results demonstrate the discriminative control of SRTs, further supporting the effects of reinforcement learning for saccade. This study reveals that saccade triggering is finely controlled by learned temporal and spatial properties of the environment using predictive mechanisms.


Incidence and recurrent work-related violence towards healthcare workers and subsequent health effects. A one-year follow-up study.
The aim of the present study was to analyse the incidence of violence and threats of violence during the first year at work after graduating as a healthcare worker, the risk of re-exposure and health effects among respondents previously exposed to violence or threats. We analysed baseline data from 5,696 healthcare students and conducted prospective multinomial regression analyses following 2,847 respondents during their first year of employment. At baseline we found that nearly a third of the respondents had been exposed to violence or threats of violence, 8.7% during trainee periods. At follow-up, we found that 24.6% of the healthcare workers had been exposed to violence and 33.4% to threats during the first year at work after graduation. Exposure to violence or threats during trainee periods was a strong predictor of violence (Odds ratio (OR)=3.3) and threats (OR=4.2) at follow-up. The results showed that violence or threats in previous jobs or at other places had a significant impact on the health of the victims at follow-up independent of gender, age, sense of coherence, self-efficacy and health at baseline. Exposure during trainee periods had a small but not quite significant (p=0.06) impact on the health of the victims at follow-up. The study shows a high risk of violence and threats of violence among healthcare workers during training and the first year at work after graduation, indicating a need for violence prevention planning involving both college and workplaces.


Brief report: School exclusion drug use and delinquency in adolescence.
Fifty-one young people aged 14-15 years considered to be at a high risk to substance abuse and exhibiting antisocial behavior, primarily because they longer attended mainstream school, participated in this research by completing a questionnaire to measure drug use and delinquent behaviour. The findings suggest that many of them may have already developed a high propensity to drug abuse and antisocial behaviour compared with their peers in mainstream education. As they were all excluded from school, they were not accessing school based prevention programmes delivered to their contemporaries at school suggesting that additional and specialized resources are required to fully meet their needs.


An optimal transition path for controlling greenhouse gases.
Designing efficient policies to slow global warming requires an approach that combines economic tools with relations from the natural sciences. The dynamic integrated climate-economy (DICE) model presented here, an intertemporal general-equilibrium model of economic growth and climate change, can be used to investigate alternative approaches to slowing climate change. Evaluation of five policies suggests that a modest carbon tax would be an efficient approach to slow global warming, whereas rigid emissions- or climate-stabilization approaches would impose significant net economic costs.


Cyclosporine nephrotoxicity in type 1 diabetic patients. A 7-year follow-up study.
To evaluate kidney function 7 years after the end of treatment with cyclosporine A (CsA) (initial dosage of 9.3 tapered off to 7.0 mg.kg-1.day-1) in young patients (mean age 20 years) with newly diagnosed type 1 diabetes participating in a randomized, double-blind, placebo-controlled CsA trial. In this study, 21 patients received CsA for 12.5 +/- 4.0 months (mean +/- SD) and 19 patients received placebo for 14.4 +/- 3.8 months. The two groups were similar with regard to mean arterial blood pressure (BP), urinary albumin excretion rate (UAER), serum creatinine, and estimated glomerular filtration rate (GFR [Cockcroft and Gault]) at initiation of CsA treatment (baseline). HbA1c (mean +/- SEM) during 7 years of follow-up was also the same: 8.7 +/- 0.4 vs. 8.3 +/- 0.4% in the CsA and placebo groups, respectively. During the 7 years after cessation of study medication, two CsA group patients and one control patient were lost to follow-up. One placebo-treated patient developed IgA nephropathy (biopsy proven) and was excluded. Four CsA-treated patients developed persistently elevated UAER > 30 mg/24 h (n = 3 with microalbuminuria), whereas all the 17 placebo-treated patients had normal UAER (< 30 mg/24 h) after 7 years of follow-up. At the end of follow-up, the CsA group had a more pronounced rise in UAER: 2.5-fold (95% CI 1.4-4.5) higher than baseline value vs. 1.1-fold (0.7-1.7) in the placebo-treated group (P < 0.05). Estimated GFR (ml.min-1.1.73 m-2) declined from baseline to end of follow-up (1994) by 6.3 +/- 6.0 in the former CsA group, whereas it rose by 7.4 +/- 5.0 in the placebo group (P = 0.05). In 1994, 24-h blood pressure was nearly the same: 131/77 +/- 4/2 vs. 127/75 +/- 2/2 mmHg (NS) in the CsA and placebo groups, respectively. Five randomly selected CsA-treated patients had a kidney biopsy performed shortly after the CsA treatment was stopped. Interstitial fibrosis/tubular atrophy and/or arteriolopathy were present in two subjects who both subsequently developed persistent microalbuminuria. The results of our 7-year follow-up study suggested that short-lasting CsA treatment in young, newly diagnosed type 1 diabetic patients accelerated the rate of progression in UAER and tended to induce a loss in kidney function. Longer term follow-up is mandatory to clarify whether CsA-treated patients are at increased risk of developing clinical nephropathy.