Electron beam excitation of surface plasmon polaritons.
In this paper, the excitations of surface plasmon polaritons (SPPs) by both perpendicular and parallel electron beam are investigated. The results of analytical theory and numerical calculation show that the mechanisms of these two excitations are essentially different, and the behavior and properties of SPPs in metal structures strongly depend on the methods of excitation. For the perpendicular excitation, SPPs contain plenty of frequency components, propagate with attenuation and are always accompanied with the transition radiation. Whereas for parallel excitation, SPPs waves are coherent, tunable, propagating without attenuation and the transition radiation does not occur. We also show that there are two modes for the parallel excited SPPs on the metal films and they all can be excited efficiently by the parallel moving electron beam. And the operating frequency of SPPs can be tuned in a large frequency range by adjusting the beam energy.


pIgR and PECAM-1 bind to pneumococcal adhesins RrgA and PspC mediating bacterial brain invasion.
Streptococcus pneumoniae is the main cause of bacterial meningitis, a life-threating disease with a high case fatality rate despite treatment with antibiotics. Pneumococci cause meningitis by invading the blood and penetrating the blood-brain barrier (BBB). Using stimulated emission depletion (STED) super-resolution microscopy of brain biopsies from patients who died of pneumococcal meningitis, we observe that pneumococci colocalize with the two BBB endothelial receptors: polymeric immunoglobulin receptor (pIgR) and platelet endothelial cell adhesion molecule (PECAM-1). We show that the major adhesin of the pneumococcal pilus-1, RrgA, binds both receptors, whereas the choline binding protein PspC binds, but to a lower extent, only pIgR. Using a bacteremia-derived meningitis model and mutant mice, as well as antibodies against the two receptors, we prevent pneumococcal entry into the brain and meningitis development. By adding antibodies to antibiotic (ceftriaxone)-treated mice, we further reduce the bacterial burden in the brain. Our data suggest that inhibition of pIgR and PECAM-1 has the potential to prevent pneumococcal meningitis.


Structural and electrophysiological dysfunctions due to increased endoplasmic reticulum stress in a long-term pacing model using human induced pluripotent stem cell-derived ventricular cardiomyocytes.
Long-term ventricular pacing has deleterious effects and becomes more significant when cumulative percent ventricular pacing (Cum%VP) exceeds 40% of time. However, cellular disturbances and pathways by which pacing leads to myocardial disorders are not well understood. Attempts to resolve these questions have been hampered by difficulties in obtaining human cardiac tissue and the inability to build a longer-lasting (lasting longer than weeks) pacing model in vitro. Human induced pluripotent stem cell-derived ventricular cardiomyocytes (VCMs) were cultured in the presence of electrical stimulation for 2 weeks. Quantitative structural and electrophysiological analyses were used to define the functional disturbances of pacing. Compared to controls, paced VCMs exhibited a remarkable reduction in the contractile protein expression, an increased apoptosis ratio and electrophysiological remodelling in a Cum%VP-dependent manner. Investigation of the protein expression levels revealed that long-term pacing universally activated both ER stress and downstream calpain. Moreover, the inhibition of calpain attenuated the adverse effects on the structural remodelling and increased the ICa, L in paced VCMs. The results demonstrated that pacing VCMs for 2 weeks in vitro led to a series of structural and electrophysiological dysfunctions. The increased ER stress and downstream calpain could be a central mechanism underlying the disease pathogenesis. This finding could represent a new therapeutic target in the management of long-term pacing patients.


Enrich: software for analysis of protein function by enrichment and depletion of variants.
Measuring the consequences of mutation in proteins is critical to understanding their function. These measurements are essential in such applications as protein engineering, drug development, protein design and genome sequence analysis. Recently, high-throughput sequencing has been coupled to assays of protein activity, enabling the analysis of large numbers of mutations in parallel. We present Enrich, a tool for analyzing such deep mutational scanning data. Enrich identifies all unique variants (mutants) of a protein in high-throughput sequencing datasets and can correct for sequencing errors using overlapping paired-end reads. Enrich uses the frequency of each variant before and after selection to calculate an enrichment ratio, which is used to estimate fitness. Enrich provides an interactive interface to guide users. It generates user-accessible output for downstream analyses as well as several visualizations of the effects of mutation on function, thereby allowing the user to rapidly quantify and comprehend sequence-function relationships. Enrich is implemented in Python and is available under a FreeBSD license at http://depts.washington.edu/sfields/software/enrich/. Enrich includes detailed documentation as well as a small example dataset. email@example.com; firstname.lastname@example.com Supplementary data is available at Bioinformatics online.


Endovascular treatment of a spinal dural arteriovenous malformation (DAVF).
We present a case of a patient with rapid loss of motor strength in his lower extremities. He became bedridden with bowel and bladder incontinence, and developed saddle anesthesia. MRI of the lumbar spine showed edema in the conus medullaris and multiple flow voids within the spinal canal. A spinal angiogram showed a dorsal Type I spinal AVF. This was treated successfully with Onyx 18 (eV3, Irvine, CA). The patient showed rapid post-procedure improvement, and at discharge from the hospital to a rehabilitation center he was fully ambulatory. At 3-year follow-up, the patient was found to ambulate without difficulty. He also had improved saddle anesthesia, and he was voiding spontaneously. There was no evidence of flow voids on repeat MRI of the lumbar spine. The video can be found here: http://youtu.be/SDYNIGNQIW8 .


[The psychopathology of Karl Jaspers: then and now].
The book entitled 'Allgemeine Psychopathologie' by the German psychiatrist-philosopher Karl Jaspers, first published in 1913, has had a lasting influence on the way in which psychiatry defines subjective psychiatric symptoms--phenomena. His psychopathology of meaningful connections, however, which purports to provide an empathic 'understanding' of the causes of mental disorders, is more controversial, particularly now that neurobiology claims it can explain all material causes. This article presents an enthusiastic summary of Jaspers' original work and culminates with a plea for a re-appraisal and revaluation of Jaspers phenomenology and methodological dualism. Jaspers' view on this subject is particularly important in our days of DSM-criteria, neuro-imaging and molecular biology.


The influence of the mandibular gonial angle on the occurrence of mandibular angle fracture.
Angle fractures represent the largest percentage of mandibular fractures. They pose as a unique entity because of their codependent morphological dynamic factors, rendering the understanding of the mechanism, and treatment challenging. The aim of this study was to analyze the association between the mandibular gonial angle and the risk of mandibular angle fracture while highlighting its clinical relevance. A retrospective analysis of radiographs of patients treated for mandibular fractures was done. The factors studied were as follows: the presence of a high gonial angle and an impacted third molar. The outcome was mandibular angle fracture. The gonial angle was measured using Planmeca Digital Software 3.7.0.R. Status of the third molar was also noted. Data obtained were analyzed using SPSS 22 (IBM Corp, Armonk, NY). The sample comprised 70 mandibular fractures (32 angle fractures and 38 non-angle fractures). The mean gonial angle in the angle fracture group was 128.5 ± 5.4º which was 10.2° larger than in the non-angle group (mean 118.5 ± 4.4º; P = 0.0001). Patients with a high gonial angle were 8.7 times more likely to sustain an angle fracture than those with normal or low gonial angles. A statistically significant relationship between the presence of impacted third molar and patients sustaining mandibular angle fractures was noted (P = 0.0001). Subjects with a high gonial angle and an impacted third molar are at an increased risk for mandibular angle fracture due to direct and indirect morphological factors.


The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy.
DNA damaging agents such as radiotherapy and gemcitabine are frequently used for the treatment of pancreatic cancer. However, these treatments typically provide only modest benefit. Improving the low survival rate for pancreatic cancer patients therefore remains a major challenge in oncology. Inhibition of the key DNA damage response kinase ATR has been suggested as an attractive approach for sensitization of tumor cells to DNA damaging agents, but specific ATR inhibitors have remained elusive. Here we investigated the sensitization potential of the first highly selective and potent ATR inhibitor, VE-821, in vitro. VE-821 inhibited radiation- and gemcitabine-induced phosphorylation of Chk1, confirming inhibition of ATR signaling. Consistently, VE-821 significantly enhanced the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and gemcitabine under both normoxic and hypoxic conditions. ATR inhibition by VE-821 led to inhibition of radiation-induced G 2/M arrest in cancer cells. Reduced cancer cell radiosurvival following treatment with VE-821 was also accompanied by increased DNA damage and inhibition of homologous recombination repair, as evidenced by persistence of γH2AX and 53BP1 foci and inhibition of Rad51 foci, respectively. These findings support ATR inhibition as a novel approach to improve the efficacy and therapeutic index of standard cancer treatments across a large proportion of pancreatic cancer patients.


Creating localized plasma waves by ionization of doped semiconductors.
Localized plasma waves can be generated by suddenly ionizing extrinsic semiconductors with spatially periodic dopant densities. The built-in electrostatic potentials at the metallurgical junctions, combined with electron density ripples, offer the exact initial condition for exciting long-lasting plasma waves upon ionization. This method can create plasma waves with a frequency between a few terahertz to subpetahertz without substantial damping. The lingering plasma waves can seed backward Raman amplification in a wide range of resonance frequencies up to the extreme ultraviolet regime. Chirped wave vectors and curved wave fronts allow focusing the amplified beam in both longitudinal and transverse dimensions. The main limitation to this method appears to be obtaining sufficiently low plasma density from solid-state materials to avoid collisional damping.


Combination of Nonstructural Protein 1-Based Enzyme-Linked Immunosorbent Assays Can Detect and Distinguish Various Dengue Virus and Zika Virus Infections.
The recent outbreaks of Zika virus (ZIKV) and associated birth defects in regions of dengue virus (DENV) endemicity emphasize the need for sensitive and specific serodiagnostic tests. We reported previously that enzyme-linked immunosorbent assays (ELISAs) based on the nonstructural protein 1 (NS1) of DENV serotype 1 (DENV1) and ZIKV can distinguish primary DENV1, secondary DENV, and ZIKV infections. Whether ELISAs based on NS1 proteins of other DENV serotypes can discriminate various DENV and ZIKV infections remains unknown. We herein developed DENV2, DENV3, and DENV4 NS1 IgG ELISAs to test convalescent- and postconvalescent-phase samples from reverse transcription-PCR-confirmed cases, including 25 primary DENV1, 24 primary DENV2, 10 primary DENV3, 67 secondary DENV, 36 primary West Nile virus, 38 primary ZIKV, and 35 ZIKV with previous DENV infections as well as 55 flavivirus-naive samples. Each ELISA detected primary DENV infection with a sensitivity of 100% for the same serotype and 23.8% to 100% for different serotypes. IgG ELISA using a mixture of DENV1-4 NS1 proteins detected different primary and secondary DENV infections with a sensitivity of 95.6% and specificity of 89.5%. The ZIKV NS1 IgG ELISA detected ZIKV infection with a sensitivity of 100% and specificity of 82.9%. On the basis of the relative optical density ratio, the combination of DENV1-4 and ZIKV NS1 IgG ELISAs distinguished ZIKV with previous DENV and secondary DENV infections with a sensitivity of 91.7% to 94.1% and specificity of 87.0% to 95.0%. These findings have important applications to serodiagnosis, serosurveillance, and monitoring of both DENV and ZIKV infections in regions of endemicity.


Disaster planning for vulnerable populations: leveraging Community Human Service Organizations direct service delivery personnel.
Given the variability, complexities, and available resources for local vulnerable populations, it is clear that preparing effectively for catastrophic events cannot be accomplished with a single, simple template. Inclusion of Community Human Service Organizations' (CHSO's) direct service delivery personnel ensures that emergency disaster planning efforts for vulnerable populations are effective and responsive to unique needs and constraints. By leveraging existing local resources, it extends the preparedness system's reach to the whole community. CHSO personnel already perform community-based services and directly engage with vulnerable and special needs populations; typically they are on the front lines during an emergency event. Generally, however, the CHSOs, staff, and clients are neither adequately prepared for disasters nor well integrated into emergency systems. To address preparedness gaps identified during Hurricane Sandy, regional CHSO and local health department partners requested that the Columbia Regional Learning Center provide preparedness trainings for their agencies and staff responsible for vulnerable clients. Evaluation of this initiative was begun with a mixed-methods approach consisting of collaborative learning activities, a function-based assessment tool, and a 5 Steps to Preparedness module. Results from a survey were inclusive because of a low response rate but suggested satisfaction with the training format and content; increases in awareness of a client preparedness role; and steps toward improved personal, agency, and client preparedness. Direct service delivery personnel can leverage routine client interactions for preparedness planning and thus can contribute significantly to vulnerable population and community disaster readiness. Trainings that provide preparedness tools can help support this role. CHSO personnel are knowledgeable and have the expertise to assist clients in personal preparedness planning; yet, there are challenges around their ability and willingness to take on additional responsibilities.


Improving hospital care: are learning organizations the answer?
Hospital leaders are being challenged to become more consumer-oriented, more interprofessional in their approach to care and more focused on outcome measures and continuous quality improvement. The concept of the learning organization could provide the conceptual framework necessary for understanding and addressing these various challenges in a systematic way. The paper aims to discuss these issues. A scan of the literature reveals that this concept has been applied to hospitals and other health care institutions, but it is not known to what extent this concept has been linked to hospitals and with what outcomes. To bridge this gap, the question of whether learning organizations are the answer to improving hospital care needs to be considered. Hospitals are knowledge-intensive organizations in that there is a need for constant updating of the best available evidence and the latest medical techniques. It is widely acknowledged that learning may become the only sustainable competitive advantage for organizations, including hospitals. With the increased demand for accountability for quality care, fiscal responsibility and positive patient outcomes, exploring hospitals as learning organizations is timely and highly relevant to senior hospital administrators responsible for integrating best practices, interprofessional care and quality improvement as a primary means of achieving these outcomes. To date, there is a dearth of research on hospitals as learning organizations as it relates to improving hospital care.


A diffusion based study of population dynamics: Prehistoric migrations into South Asia.
A diffusion equation has been used to study migration of early humans into the South Asian subcontinent. The diffusion equation is tempered by a set of parameters that account for geographical features like proximity to water resources, altitude, and flatness of land. The ensuing diffusion of populations is followed in time-dependent computer simulations carried out over a period of 10,000 YBP. The geographical parameters are determined from readily-available satellite data. The results of our computer simulations are compared to recent genetic data so as to better correlate the migratory patterns of various populations; they suggest that the initial populations started to coalesce around 4,000 YBP before the commencement of a period of relative geographical isolation of each population group. The period during which coalescence of populations occurred appears consistent with the established timeline associated with the Harappan civilization and also, with genetic admixing that recent genetic mapping data reveal. Our results may contribute to providing a timeline for the movement of prehistoric people. Most significantly, our results appear to suggest that the Ancestral Austro-Asiatic population entered the subcontinent through an easterly direction, potentially resolving a hitherto-contentious issue.


Differential transcriptome analysis of intraarticular lesional vs intact cartilage reveals new candidate genes in osteoarthritis pathophysiology.
To elucidate disease-specific molecular changes in osteoarthritis (OA) by analyzing the differential gene expression profile of damaged vs intact cartilage areas within the same joint of patients with OA of the knee using a combination of a novel RNA extraction technique and whole-genome oligonucleotide arrays. The transcriptome of macroscopically affected vs intact articular cartilage as determined by visual assessment was analyzed using an optimized mill-based total RNA isolation directly from the tissue and high density synthetic oligonucleotide arrays. Articular cartilage samples were obtained from patients with OA of the knee. Expression of differentially regulated genes was validated by real-time quantitative polymerase chain reaction and immunohistochemistry. The amount of RNA obtained by the optimized extraction procedure was at least 1 microg per 500 mg of cartilage and fulfilled the common quality requirements. After hybridization onto HG-U133 Plus 2.0 GeneChips (Affymetrix), 28.6-51.7% of the probe sets on the microarray showed a detectable signal above the signal threshold in the individual samples. A subset of 411 transcripts, which appeared to be differentially expressed, was obtained when applying predefined filtering criteria. Of these, six genes were found to be up-regulated in the affected cartilage of all patients, including insulin-like growth factor binding protein 3 (IGFBP-3), wnt-1-inducible signaling protein 1 (WISP-1), aquaporin 1 (AQP-1), delta/notch-like EGF-repeat containing transmembrane (DNER), decay accelerating factor (DAF), complement factor I (IF). The optimized methodical approach reported here not only allows to determine area-specific gene expression profiles of intraindividually different low-RNA containing OA cartilage specimens. In addition, this study also revealed novel genes not yet reported to play a role in the pathophysiology of joint destruction in OA.


Social work at the Chinese Medicine system in Hong Kong: opportunities and challenges.
Dealing with health and disease is an area of concern for social workers. The establishment of medical social service in a health setting has more than 100 years of history in the USA and more than 60 years in Hong Kong. Despite the increasing popularity of Chinese Medicine (CM) used by the Hong Kong people, there has been no medical social service presence in the CM system. A pilot project demonstrated a successful interdisciplinary collaboration model between social work and CM irrespective of different social work methods, that is, individual work, groupwork, and community-based services. In this article, we will relate the opportunities and difficulties that we encountered in setting up the first medical social service in the CM system. Drawing on our experience, we found that both professions benefited from the interdisciplinary collaboration. CM was able to expand its scope of service to increase the service quality and promote primary health care in the community with the support of social work. Conversely, social workers found that CM is a good resource for providing innovative services to meet the various needs of the people in the community. There was also a ripple effect of incorporating CM elements into social service. The interface between the disciplines of social work and CM can widen the scope of their contributions on health. Implications for CM social service in social work will also be examined.


Proteomic comparison of Entamoeba histolytica and Entamoeba dispar and the role of E. histolytica alcohol dehydrogenase 3 in virulence.
The protozoan intestinal parasite Entamoeba histolytica infects millions of people worldwide and is capable of causing amebic dysentery and amebic liver abscess. The closely related species Entamoeba dispar colonizes many more individuals, but this organism does not induce disease. To identify molecular differences between these two organisms that may account for their differential ability to cause disease in humans, we used two-dimensional gel-based (DIGE) proteomic analysis to compare whole cell lysates of E. histolytica and E. dispar. We observed 141 spots expressed at a substantially (>5-fold) higher level in E. histolytica HM-1:IMSS than E. dispar and 189 spots showing the opposite pattern. Strikingly, 3 of 4 proteins consistently identified as different at a greater than 5-fold level between E. histolytica HM-1:IMSS and E. dispar were identical to proteins recently identified as differentially expressed between E. histolytica HM-1:IMSS and the reduced virulence strain E. histolytica Rahman. One of these was E. histolytica alcohol dehydrogenase 3 (EhADH3). We found that E. histolytica possesses a higher level of NADP-dependent alcohol dehydrogenase activity than E. dispar and that some EhADH3 can be localized to the surface of E. histolytica. Episomal overexpression of EhADH3 in E. histolytica trophozoites resulted in only subtle phenotypic differences in E. histolytica virulence in animal models of amebic colitis and amebic liver abscess, making it difficult to directly link EhADH3 levels to virulence differences between E. histolytica and less-pathogenic Entamoeba.


Studies on the propagation in vitro of poliomyelitis viruses. IV. Viral multiplication in a stable strain of human malignant epithelial cells (strain HeLa) derived from an epidermoid carcinoma of the cervix.
The cells of a human epithelial cancer cultivated en masse have been shown to support the multiplication of all three types of poliomyelitis virus. These cells (strain HeLa of Gey) have been maintained in vitro since their derivation from an epidermoid carcinoma of the cervix in February, 1951. As the virus multiplied it caused in from 12 to 96 hours degeneration and destruction of the cancer cells. The specific destructive effect of the virus was prevented by adding homotypic antibody to the cultures but not by adding heterotypic antibodies. Methods for the preparation of large numbers of replicate cultures with suspensions of strain HeLa cells were described. The cells in suspension were readily quantitated by direct counts in a hemocytometer. A synthetic solution that maintains cellular viability was employed for viral propagation. The experimental results demonstrate the usefulness of strain HeLa cells for (a) the quantitation of poliomyelitis virus, (b) the measurement of poliomyelitis antibodies, and (c) the production of virus.


Longitudinal Associations of Neighborhood-level Racial Residential Segregation with Obesity Among Blacks.
Despite 50 years since the passage of the Fair Housing Act of 1968, the majority of black Americans continue to live in highly segregated communities. Differing exposure to obesogenic environments in segregated neighborhoods may contribute to racial disparities in obesity prevalence. We used prospective data from the Coronary Artery Risk Development in Young Adults (CARDIA) study to examine associations between levels of neighborhood-level racial residential segregation and incident obesity in black men and women. Obesity, determined by measured anthropometry, and residential segregation, measured using the local Gi*statistic, were recorded at baseline and follow-up at years 7, 10, 15, 20, and 25. We used marginal structural survival models to account for time-dependent confounding and for loss to follow-up. Black women living in highly segregated neighborhoods at the prior exam were 30% more likely to become obese during the follow-up period as compared with women living in neighborhoods with low levels of segregation after adjustment for sociodemographic and cardiovascular risk covariates (hazard ratio = 1.3 [95% confidence interval = 1.0, 1.7]). Cumulatively high exposure to segregation averaged across time points was associated with 50% higher hazard of obesity (hazard ratio = 1.5 [95% confidence interval = 1.0, 2.3]) among women. We observed few differences in obesity incidence among men by segregation levels. Fewer health-promoting resources, stressful neighborhood context, and social norms that are less stigmatizing of obesity may contribute to these findings, but more research on specific pathways leading from segregation to obesity is needed to understand differing patterns between men and women.


Do economic effects of the anti-COVID-19 lockdowns in different regions interact through supply chains?
To prevent the spread of COVID-19, many cities, states, and countries have 'locked down', restricting economic activities in non-essential sectors. Such lockdowns have substantially shrunk production in most countries. This study examines how the economic effects of lockdowns in different regions interact through supply chains, which are a network of firms for production, by simulating an agent-based model of production using supply-chain data for 1.6 million firms in Japan. We further investigate how the complex network structure affects the interactions between lockdown regions, emphasising the role of upstreamness and loops by decomposing supply-chain flows into potential and circular flow components. We find that a region's upstreamness, intensity of loops, and supplier substitutability in supply chains with other regions largely determine the economic effect of the lockdown in the region. In particular, when a region lifts its lockdown, its economic recovery substantially varies depending on whether it lifts the lockdown alone or together with another region closely linked through supply chains. These results indicate that the economic effect produced by exogenous shocks in a region can affect other regions and therefore this study proposes the need for inter-region policy coordination to reduce economic loss due to lockdowns.


The crucial role of the Aspergillus fumigatus siderophore system in interaction with alveolar macrophages.
Iron plays a central role in manifestation of infections for a variety of pathogens. To ensure an adequate supply with iron, Aspergillus fumigatus employs extra- and intracellular siderophores (low-molecular mass iron chelators), which are of importance for fungal growth in particular during iron starvation. Here we show that the lack of extracellular siderophores, and especially, the lack of the entire siderophore system cause in immunosuppressed mice in vivo (i) a reduced extracellular growth rate, (ii) a reduced intracellular growth rate in alveolar macrophages, and (iii) an increased susceptibility to conidial growth inhibition by alveolar macrophages. These data underline the crucial role of the fungal siderophore system not only for extracellular growth but also in the interaction with the host immune cells. Moreover, the hyphal growth rate within alveolar macrophages compared to extracellular lavage fluid was significantly decreased indicating that, besides elimination of fungal conidia, inhibition of pathogenic growth is a function of macrophages.


Identification of Seed Gall Nematodes of Agronomic and Regulatory Concern with PCR-RFLP of ITS1.
A molecular analysis of eight described species of seed gall nematode, along with six undescribed isolates from different hosts, has revealed a strong association between nucleotide sequence polymorphism and host status. Each anguinid nematode associated with a unique host produced a unique PCR-RFLP pattern for the ITS1 region. Anguina species that had been synonymized in the past, Anguina agrostis, A. funesta, and A. wevelli (Afrina wevelli), were readily discriminated. Two undescribed species from northern New South Wales and southeastern South Australia, reported to be vectors of Rathyaibacter toxicus in the disease called ''floodplain staggers,'' were differentiated by a single restriction enzyme, and both could be separated easily from A. funesta, the vector of R. toxicus in annual ryegrass toxicity. Other species differentiated in this study include A. agropyronifloris, A. graminis, A. microlaenae, A. pacificae, and undescribed species from host species Dactylis glomerata, Agrostis avenacea, Polypogon monospeliensis, Stipa sp., Astrebla pectinata, and Holcus lanatus. Phylogenetic analysis of the ITS1 region suggests that considerable anguinid genetic diversification has accompanied specialization on different host species.


Mice lacking renal chloride channel, CLC-5, are a model for Dent's disease, a nephrolithiasis disorder associated with defective receptor-mediated endocytosis.
Nephrolithiasis (kidney stones) affects 5-10% of adults and is most commonly associated with hypercalciuria, which may be due to monogenic renal tubular disorders. One such hypercalciuric disorder is Dent's disease, which is characterized by renal proximal tubular defects that include low molecular weight proteinuria, aminoaciduria and glycosuria, together with rickets in some patients. Dent's disease is due to inactivating mutations of the renal-specific voltage-gated chloride channel, CLC-5, which is expressed in the proximal tubule, thick ascending limb and collecting duct. The subcellular localization of CLC-5 to the proximal tubular endosomes has suggested a role in endocytosis, and to facilitate in vivo investigations of CLC-5 in Dent's disease we generated mice lacking CLC-5 by targeted gene disruption. CLC-5-deficient mice developed renal tubular defects which included low molecular weight (<70 kDa) proteinuria, generalized aminoaciduria that was more pronounced for neutral and polar amino acids, and glycosuria. They also developed hypercalciuria and renal calcium deposits and some had deformities of the spine. Furthermore, endocytosis as assessed by horseradish peroxidase uptake in the proximal tubule was severely impaired in CLC-5-deficient mice, thereby demonstrating a role for CLC-5 in endosomal uptake of low molecular weight proteins. Thus, CLC-5-deficient mice provide a model for Dent's disease and this will help in elucidating the function of this chloride channel in endocytosis and renal calcium homeostasis.


Specialist Osmia bees forage indiscriminately among hybridizing Balsamorhiza floral hosts.
Pollinators, even floral generalists (=polyleges), typically specialize during individual foraging bouts, infrequently switching between floral hosts. Such transient floral constancy restricts pollen flow, and thereby gene flow, to conspecific flowers in mixed plant communities. Where incipient flowering species meet, however, weak cross-fertility and often similar floral traits can yield mixed reproductive outcomes among pollinator-dependent species. In these cases, floral constancy by polyleges sometimes serves as an ethological mating barrier. More often, their foraging infidelities instead facilitate host introgression and hybridization. Many other bee species are oligolectic (taxonomic specialists for pollen). Oligoleges could be more discriminating connoisseurs than polyleges when foraging among their limited set of related floral hosts. If true, greater foraging constancy might ensue, contributing to positive assortative mating and disruptive selection, thereby facilitating speciation among their interfertile floral hosts. To test this Connoisseur Hypothesis, nesting females of two species of oligolectic Osmia bees were presented with randomized mixed arrays of flowers of two sympatric species of their pollen host, Balsamorhiza, a genus known for hybridization. In a closely spaced grid, the females of both species preferred the larger flowered B. macrophylla, evidence for discrimination. However, both species' females showed no floral constancy whatsoever during their individual foraging bouts, switching randomly between species proportional to their floral preference. In a wider spaced array in which the bouquets reflected natural plant spacing, foraging oligolectic bees often transferred pollen surrogates (fluorescent powders) both between conspecific flowers (geitonogamy and xenogamy) and between the two Balsamorhiza species. The Connoisseur Hypothesis was therefore rejected. Foraging infidelity by these oligolectic Osmia bees will contribute to introgression and hybridization where interfertile species of Balsamorhiza meet and flower together. A literature review reveals that other plant genera whose species hybridize also attract numerous oligolectic bees, providing independent opportunities to test the generality of this conclusion.


Population pharmacokinetics of subcutaneous C1-inhibitor for prevention of attacks in patients with hereditary angioedema.
Long-term prophylaxis with subcutaneous (SC) administration of a highly concentrated plasma-derived C1-esterase inhibitor (C1-INH) formulation was recently approved by the Food and Drug Administration for hereditary angioedema (HAE) attack prevention. To characterize the population pharmacokinetics of C1-INH (SC) (HAEGARDA® ; CSL Behring) in healthy volunteers and HAE patients, and assess the variability and influence of covariates on pharmacokinetics. C1-INH functional activity data obtained after administration of various C1-INH (intravenous; IV) and C1-INH (SC) doses from 1 study in healthy volunteers (n = 16) and 2 studies in subjects with HAE (n = 108) were pooled to develop a population pharmacokinetic model (NONMEM v7.2). Pharmacokinetic parameters derived from steady-state simulations based on the final model were also evaluated. C1-INH functional activity following C1-INH (SC) administration was described by a linear one-compartment model with first-order absorption and elimination, with inter-individual variability in all parameters tested. The mean population bioavailability of C1-INH (SC), and pharmacokinetic parameters for clearance (CL), volume of distribution, and absorption rate were estimated to be ~43%, 1.03 mL/hour/kg, 0.05 L/kg and 0.0146 hour-1 , respectively. The effect of bodyweight on CL of C1-INH functional activity was included in the final model, estimated to be 0.74. Steady-state simulations of C1-INH functional activity vs time profiles in 1000 virtual HAE patients revealed higher minimum functional activity (Ctrough ) levels after twice-weekly dosing with 40 IU/kg (~40%) and 60 IU/kg (~48%) compared with 1000 IU IV (~30%). Based on the population pharmacokinetic model, the median time to peak concentration was ~59 hours and the median apparent plasma half-life was ~69 hours. Twice-weekly bodyweight-adjusted dosing of C1-INH (SC) exhibits linear pharmacokinetics and dose-dependent increases in Ctrough levels at each dosing interval. In this analysis, SC dosing led to maintenance of higher Ctrough levels than IV dosing.


HIV prevalence among adults in Rome: results of the MeDi (Measuring health Disparities in HIV prevention) survey. Part 2.
In Italy, out of 60 millions of inhabitants, 3000 (2700-4000) new HIV infections are estimated each year. As combined antiretroviral therapy (ART) prolongs life for HIV sufferers, the prevalence of HIV-infection is likely to increase over time. Few studies have assessed factors associated with being HIV positive in people accessing public outpatient clinics and, in particular, the influence of socio-economic circumstances on HIV prevalence. This study aims to evaluate the association between subjects' serostatus and socio-economic determinants measured at the individual and neighbourhood levels. Data from a large anonymous survey performed in 2012-2014 on more than 10 000 individuals 18-59 years old who underwent 21 public ambulatories in Rome were analysed. Subjects' socio-demographic characteristics, sexual orientation, number of sexual partners, HIV risk behaviour and HIV testing uptake were collected by a self-administered questionnaire. Level of area deprivation was measured at the postal code level by the index of social disadvantage (ISD). Multilevel Poisson regressions were carried out to take heterogeneity between clusters (post code and clinics) into account. Self-reported HIV-prevalence was 2.0% among subjects ever been tested (13.7% for the homosexual/lesbians 7.0% for the bisexual and 1.3% for the heterosexual). About 1% of subjects self-identified as low risk was HIV infected. This prevalence increased up to 2% in the age group 18-34 and up to 5% in the non-heterosexuals (i.e. self- identified homosexuals/lesbians and bisexuals). At the individual level, HIV-prevalence decreased linearly from lowest to highest levels of education. Living in a deprived neighbourhood was not associated with HIV-infection. Our study confirms high HIV prevalences among homosexuals/lesbians. Some infections occur in subjects who do not report high risk behaviours for HIV transmission.


Prevalence of markers of Q fever exposure in the Kimberley, Western Australia.
Although a large pastoral industry exists in the Kimberley region of Western Australia, there is no previously published information about the prevalence of immune markers for Q fever exposure in this region's population. This paper identifies the prevalence of, and factors associated with, positive immune markers of Q fever, and reports the uptake of Q fever vaccination by eligible subjects in the Kimberley region of Western Australia. Data regarding Q fever risk-factors were obtained using a standard questionnaire. Immunity and previous exposure to Q fever were assessed using both serology and a skin test, in accordance with accepted protocol. Fifty-nine subjects underwent Q fever pre-vaccination testing. The prevalence of a positive skin and/or blood test, indicating past exposure was 66 per cent (95% CI 52%-78%). After controlling for age and having lived on a farm at any time, employment in the pastoral industry was the only factor significantly associated with being skin and/or blood test positive (OR=24.6, 95% CI 3.0-204). Acceptance of vaccination was high, with 75 per cent of eligible subjects undergoing vaccination. The high prevalence of immune markers for Q fever in the Kimberley in this sample indicates that the disease is present in the region, despite the last recorded case being in 1986. Ensuring that Q fever vaccination is readily accessible to pastoralists, abattoir workers and other at-risk groups is a challenge that needs to be met by these industries and health services of the region.


The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease.
The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K(+) efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome-mediated interleukin (IL)-1β and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate crystal-induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome.


Sequencing Y chromosomes resolves discrepancy in time to common ancestor of males versus females.
The Y chromosome and the mitochondrial genome have been used to estimate when the common patrilineal and matrilineal ancestors of humans lived. We sequenced the genomes of 69 males from nine populations, including two in which we find basal branches of the Y-chromosome tree. We identify ancient phylogenetic structure within African haplogroups and resolve a long-standing ambiguity deep within the tree. Applying equivalent methodologies to the Y chromosome and the mitochondrial genome, we estimate the time to the most recent common ancestor (T(MRCA)) of the Y chromosome to be 120 to 156 thousand years and the mitochondrial genome T(MRCA) to be 99 to 148 thousand years. Our findings suggest that, contrary to previous claims, male lineages do not coalesce significantly more recently than female lineages.


Genetic characterization of four Austronesian-speaking populations.
Ascertaining the genetic relationships between Austronesian populations is paramount to understanding their dispersal throughout the islands of the Pacific and Indian Oceans. The start of the Austronesian expansion has been dated to approximately 6,000 years ago, and from linguistic and archeological evidence, the origin of this dispersal may have been the island of Formosa. Consequently, the Taiwanese aboriginal populations and their phylogenetic relationship to the Austronesian-speaking groups from Madagascar at the occidental fringes of the expansion are of great interest. In this study, allelic frequencies from six polymorphic point mutation loci were assessed in the Austronesian-speaking populations of Madagascar, the Atayal aborigines of Formosa, and the general populations of Bali and Java. These allelic frequencies were compared and analyzed with the corresponding values from eight other worldwide populations from geographically targeted regions. The group from Madagascar is genetically distinct from their east-African neighbor from Zimbabwe. Our data also indicates that the Ami and the Atayal aborigines in the island of Taiwan, which occupy adjacent territories, differ sharply genetically. Genetic differences were also found between the populations of Bali and Java, belying their geographical proximity. Our results indicate that the east-African population from Madagascar phylogenetically segregates intermediate between mainland east-African and east-Asian groups, corroborating linguistic data indicating the Austronesian influence on this population.


The NMR solution structure of the ion channel peptaibol chrysospermin C bound to dodecylphosphocholine micelles.
Chrysospermin C is a 19-residue peptaibol capable of forming transmembrane ion channels in phospholipid bilayers. The conformation of chrysospermin C bound to dodecylphosphocholine micelles has been solved using heteronuclear NMR spectroscopy. Selective 15N-labeling and 13C-labeling of specific alpha-aminoisobutyric acid residues was used to obtain complete stereospecific assignments for all eight alpha-aminoisobutyric acid residues. Structures were calculated using 339 distance constraints and 40 angle constraints obtained from NMR data. The NMR structures superimpose with mean global rmsd values to the mean structure of 0. 27 A (backbone heavy atoms) and 0.42 A (all heavy atoms). Chrysospermin C bound to decylphosphocholine micelles displays two well-defined helices at the N-terminus (residues Phe1-Aib9) and C-terminus (Aib13-Trp-ol19). A slight bend preceding Pro14, i.e. encompassing residues 10-12, results in an angle of approximately 38 degrees between the mean axes of the two helical regions. The bend structure observed for chrysospermin C is compatible with the sequences of all 18 long peptaibols and may represent a common 'active' conformation. The structure of chrysospermin C shows clear hydrophobic and hydrophilic surfaces which would be appropriate for the formation of oligomeric ion channels.


Effectiveness of a geriatric day hospital.
To determine whether there is a difference in the quality of life between elderly patients managed in a day hospital and those receiving conventional care. Randomized controlled trial; assessment upon entry to study and at 3, 6 and 12 months afterward. Geriatrician referral-based secondary care. A total of 113 consecutively referred elderly patients with deteriorating functional status believed to have rehabilitation potential; 55 were assessed and treated by an interdisciplinary team in a day hospital (treatment group), and 58 were assessed in an inpatient unit or an outpatient clinic or were discharged early with appropriate community services (control group). Barthel Index, Rand Questionnaire, Global Health Question and Geriatric Quality of Life Questionnaire (GQLQ). Eight study subjects and four control subjects died; the difference was insignificant. Functional status deteriorated over time in the two groups; although the difference was not significant there was less deterioration in the control group. The GQLQ scores indicated no significant difference between the two groups in the ability to perform daily living activities and in the alleviation of symptoms over time but did show a trend favouring the control group. The GQLQ scores did indicate a significant difference in favour of the control group in the effect of treatment on emotions (p = 0.009). The care received at the day hospital did not improve functional status or quality of life of elderly patients as compared with the otherwise excellent geriatric outpatient care.


SHARPIN regulates uropod detachment in migrating lymphocytes.
SHARPIN-deficient mice display a multiorgan chronic inflammatory phenotype suggestive of altered leukocyte migration. We therefore studied the role of SHARPIN in lymphocyte adhesion, polarization, and migration. We found that SHARPIN localizes to the trailing edges (uropods) of both mouse and human chemokine-activated lymphocytes migrating on intercellular adhesion molecule-1 (ICAM-1), which is one of the major endothelial ligands for migrating leukocytes. SHARPIN-deficient cells adhere better to ICAM-1 and show highly elongated tails when migrating. The increased tail lifetime in SHARPIN-deficient lymphocytes decreases the migration velocity. The adhesion, migration, and uropod defects in SHARPIN-deficient lymphocytes were rescued by reintroducing SHARPIN into the cells. Mechanistically, we show that SHARPIN interacts directly with lymphocyte-function-associated antigen-1 (LFA-1), a leukocyte counterreceptor for ICAM-1, and inhibits the expression of intermediate and high-affinity forms of LFA-1. Thus, SHARPIN controls lymphocyte migration by endogenously maintaining LFA-1 inactive to allow adjustable detachment of the uropods in polarized cells.


The sweating response of elite professional soccer players to training in the heat.
Sweat rate and sweat composition vary extensively between individuals, and quantification of these losses has a role to play in the individualisation of a hydration strategy to optimise training and competitive performance. Data were collected from 26 male professional football (soccer) players during one 90 min pre-season training session. This was the 2nd training session of the day, carried out between 19.30 and 21.00 h when the mean +/- SD environment was 32 +/- 3 degrees C, 20 +/- 5 %rh and WBGT 22 +/- 2 degrees C. Training consisted of interval running and 6-a-side games during which the average heart rate was 136 +/- 7 bpm with a maximum rate of 178 +/- 7 bpm (n = 19). Before and after training all players were weighed nude. During training all players had free access to sports drinks (Gatorade) and mineral water (Solan de Cabras). All drink bottles were weighed before and after training. Players were instructed to drink only from their own bottles and not to spit out any drink. No player urinated during the training session. Sweat was collected by patches from the chest, arm, back, and thigh of a subgroup of 7 players. These remained in place for the first 15 - 30 min of the training session, and sweat was analysed for sodium (Na (+)) and potassium (K (+)) concentration. Body mass loss was 1.23 +/- 0.50 kg (ranging from 0.50 to 2.55 kg), equivalent to dehydration of 1.59 +/- 0.61 % of pre-training body mass. The sweat volume lost was 2193 +/- 365 ml (1672 to 3138 ml), but only 972 +/- 335 ml (239 to 1724 ml) of fluid was consumed. 45 +/- 16 % of the sweat volume loss was replaced, but this ranged from 9 % to 73 %. The Na (+) concentration of the subgroup's sweat was 30.2 +/- 18.8 mmol/l (15.5 to 66.3 mmol/l) and Na (+) losses averaged 67 +/- 37 mmol (26 to 129 mmol). The K (+) concentration of the sweat was 3.58 +/- 0.56 mmol/l (2.96 to 4.50 mmol/l) and K (+) losses averaged 8 +/- 2 mmol (5 to 12 mmol). The drinking employed by these players meant that only 23 +/- 21 % of the sweat Na (+) losses were replaced: This ranged from replacing virtually none (when water was the only drink) to replacing 62 % when the sports drink was consumed. These elite soccer players did not drink sufficient volume to replace their sweat loss. This, however, is in accord with data in the literature from other levels of soccer players and athletes in other events. These measurements allow for an individualisation of the club's hydration strategy.


Transcranial magnetic motor evoked potentials in Great Danes with and without clinical signs of cervical spondylomyelopathy: association with neurological findings and magnetic resonance imaging.
Transcranial magnetic motor evoked potentials (TMMEPs) assess the functional integrity of the descending motor pathways, which are typically compromised in canine cervical spondylomyelopathy (CSM). The objective of this prospective study was to establish the reference ranges of TMMEP latency and amplitude in clinically normal (control) Great Danes (GDs), compare TMMEPs obtained in GDs with and without CSM, and determine whether there is any association between TMMEP data and severity of neurological signs or magnetic resonance imaging (MRI) findings. Twenty-nine client-owned GDs were enrolled (15 controls, 14 CSM-affected). All dogs underwent TMMEPs under sedation, and latencies and amplitudes were recorded from the extensor carpi radialis (ECR) and cranial tibial (CT) muscles. MRI of the cervical vertebral column was performed to evaluate the presence and severity of spinal cord (SC) compression, and the presence of SC signal changes. ECR and CT latencies were significantly longer in CSM-affected than control GDs. No significant differences between groups were found for amplitudes or neuronal path lengths. For the CT TMMEPs, CSM-affected GDs with moderate and severe clinical signs had significantly longer latencies than those with mild clinical signs. Significantly longer CT latencies were found in dogs with moderate and severe SC compression compared with dogs with mild compression. CT TMMEPs could not be recorded in 7/9 CSM-affected GDs with SC signal changes. These results provide a reference range for TMMEPs of clinically normal GDs. The use of TMMEPs is a valid ancillary test to assess the integrity of motor pathways in GDs with CSM.


Cryptosporidium infection, onsite wastewater systems and private wells in the arid Southwest.
Few prior studies have examined the potential health risks from transmission of enteric parasites via aquifers contaminated by wastewater from onsite systems. A cross-sectional study of 600 residents in households served with either onsite wastewater systems and private wells or city sewer/water systems in three different sites in central New Mexico compared serological responses to Cryptosporidium, a common waterborne infections agent. Study participants completed a short self-administered questionnaire with questions on demographic characteristics, characteristics of the onsite wastewater system and private well, and common risk factors associated with cryptosporidiosis. A sample of household tap water was collected, as well as a blood sample from each study participant to measure IgG responses to antigen groups for Cryptosporidium. Logistic regression analysis showed a significant association between having an onsite wastewater system and private well and the 27-kDa marker for Cryptosporidium in the River Valley site after adjusting for covariates (OR = 1.98; 95% CI = 1.11-3.55). This study, together with one prior study, suggests that the presence of onsite wastewater systems and private wells might be associated with an increased risk of Cryptosporidium infection.


A Survival Score for Patients Assigned to Palliative Radiotherapy for Metastatic Bladder Cancer.
To create a survival score for patients with metastatic bladder cancer. In 46 irradiated patients, six characteristics were evaluated for their association with survival: Age, gender, Karnofsky performance scale, initial stage (American Joint Committee on Cancer), number of metastatic sites, and interval between bladder cancer diagnosis and palliative radiotherapy. Characteristics showing a trend (p<0.15) were incorporated into the score. Six-month survival rates were divided by 10. Patients' scores were derived by totaling the scores of these characteristics. Performance scale (p=0.14), stage (p=0.055) and number of metastatic sites (p=0.10) showed a trend for association with survival. Patients' scores were 6, 7, 8, 10 or 12 points, with corresponding 6-month survival rates of 20%, 0%, 0%, 46% and 45% (p=0.038). Two groups were created, with 6-8 and with 10-12 points, with 6-month survival rates of 9% and 46% (p=0.002), respectively. A new survival score was developed. Patients with 6-8 points should receive less aggressive treatments for metastatic bladder cancer. Those with 10-12 points may receive more intensive approaches.


Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape.
Vertebrate Hox genes encode transcription factors operating during the development of multiple organs and structures. However, the evolutionary mechanism underlying this remarkable pleiotropy remains to be fully understood. Here, we show that Hoxd8 and Hoxd9, two genes of the HoxD complex, are transcribed during mammary bud (MB) development. However, unlike in other developmental contexts, their coexpression does not rely on the same regulatory mechanism. Hoxd8 is regulated by the combined activity of closely located sequences and the most distant telomeric gene desert. On the other hand, Hoxd9 is controlled by an enhancer-rich region that is also located within the telomeric gene desert but has no impact on Hoxd8 transcription, thus constituting an exception to the global regulatory logic systematically observed at this locus. The latter DNA region is also involved in Hoxd gene regulation in other contexts and strongly interacts with Hoxd9 in all tissues analyzed thus far, indicating that its regulatory activity was already operational before the appearance of mammary glands. Within this DNA region and neighboring a strong limb enhancer, we identified a short sequence conserved in therian mammals and capable of enhancer activity in the MBs. We propose that Hoxd gene regulation in embryonic MBs evolved by hijacking a preexisting regulatory landscape that was already at work before the emergence of mammals in structures such as the limbs or the intestinal tract.


Anatase titanium dioxide nanoparticles in mice: evidence for induced structural and functional sperm defects after short-, but not long-, term exposure.
Titanium dioxide (TiO 2 ) nanoparticles (TNPs) are widely used commercially and exist in a variety of products. To determine if anatase TNPs (ATNPs) in doses smaller than previously used reach the scrotum after entry in the body at a distant location and induce sperm defects, 100% ATNP (2.5 or 5 mg kg-1 body weight) was administered intraperitoneally to adult males for three consecutive days, followed by sacrifice 1, 2, 3, or 5 weeks later (long-) or 24, 48 or 120 h (short-term exposure). Transmission electron microscopy revealed the presence of ANTP in scrotal adipose tissues collected 120 h postinjection when cytokine evaluation showed an inflammatory response in epididymal tissues and fluid. At 120 h and up to 3 weeks postinjection, testicular histology revealed enlarged interstitial spaces. Significantly increased numbers of terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling-positive (apoptotic) germ (P = 0.002) and interstitial space cells (P = 0.04) were detected in treated males. Caudal epididymal sperm from the short-term, but not a long-term, arm showed significantly (P < 0.001) increased frequencies of flagellar abnormalities, excess residual cytoplasm (ERC), and unreacted acrosomes in treated versus controls (dose-response relationship). A novel correlation between ERC and unreacted acrosomes was uncovered. At 120 h, there were significant decreases in hyperactivated motility (P < 0.001) and mitochondrial membrane potential (P < 0.05), and increased reactive oxygen species levels (P < 0.00001) in treated versus control sperm. These results indicate that at 4-8 days postinjection, ANTP induce structural and functional sperm defects associated with infertility, and DNA damage via oxidative stress. Sperm defects were transient as they were not detected 10 days to 5 weeks postinjection.


Noradrenergic stimulation within midbrain raphe increases electrolyte excretion in rats.
The present study was carried out to assess the influence of noradrenergic stimulation of the midbrain dorsal (DRN) and median raphe nuclei (MRN) on urinary volume and electrolyte excretion in hydrated rats. Wistar rats were implanted with a guide cannula into the MRN or DRN and then submitted to two intragastric administrations of water in order to attain an increased diuresis. The following treatments were performed. (1) Intra-DRN microinjections of saline (0.2 microl), alpha(1)-adrenergic agonist phenylephrine (PHE, 0.49 and 4.9 nmol in 0.2 microl), alpha(2)-adrenergic antagonist idazoxan (IDZ, 0.42 and 4.2 nmol in 0.2 microl) or the alpha(1)-adrenergic antagonist prazosin (PRZ, 0.24 and 2.4 nmol in 0.2 microl). (2) Intra-MRN microinjections of saline, IDZ (4.2 nmol in 0.2 microl), PHE (4.9 nmol in 0.2 microl) or PRZ (2.4 nmol in 0.2 microl). Urine samples were subsequently collected over 120 min at 20 min intervals for photometric measurement of sodium and potassium. Intra-DRN administration of PHE and IDZ significantly increased the urinary volume, natriuresis and kaliuresis. Intra-DRN microinjection of a higher dose of PRZ reduced the urinary volume and both sodium and potassium excretion. Intra-MRN microinjections of PHE, IDZ or PRZ did not induce any significant effect on urinary volume or electrolyte excretion. These data suggest that the increase of tonic excitatory noradrenergic input conveyed to DRN influences the hydroelectrolyte homeostasis, possibly through 5-HTergic circuitry.


Electrogenic colonic ion transport in Hirschsprung's disease: reduced secretion to the neural secretagogues acetylcholine and iloprost.
The effects of the abnormal innervation in Hirschsprung's disease on colonic ion transport were examined in vitro using Ussing chambers. The response of the mucosal/submucosal preparations to different secretagogues were investigated in aganglionic and ganglionic rectosigmoid and transverse colon from children with Hirschsprung's disease and compared with normally innervated colon from children with anorectal anomalies. Basal values were similar in aganglionic and ganglionic rectosigmoid colon. Neurally mediated secretion with iloprost (10(-6) M) and acetylcholine (900 and 9 microM) was considerably reduced in aganglionic colon compared with normally innervated ganglionic colon. The ganglionic colon proximal to the aganglionic colon also had a reduced response to acetylcholine despite a normal acetylcholinesterase staining pattern. The responses to Escherichia coli STa enterotoxin (50 MU/ml) and isobutylmethylxanthine (10(-3) M) were similar in ganglionic and aganglionic colon. The response to STa enterotoxin was not changed by the nerve blocking agent tetrodotoxin (10(-6) M). The data show that colonocytes from aganglionic colon are capable of a normal secretory response if stimulated directly by cAMP or cGMP acting secretagogues but secretion in response to neurally mediated secretagogues is impaired. The hypertrophied acetylcholinesterase positive nerve fibres that infiltrate the aganglionic colon are likely to contribute to the reduced secretion to acetylcholine.


Green tea averts age-dependent decline of hippocampal signaling systems related to antioxidant defenses and survival.
We previously found that prolonged consumption of green tea (GT), a rich source of antioxidant polyphenols, protected proteins and lipids against oxidation and reduced lipofuscin deposition in the rat hippocampal formation as well as improving spatial memory during aging. In this work, we sought to investigate whether GT treatment could interfere with age-related changes in redox status and cellular signaling systems related to oxidative stress and survival in the same brain region. To address this issue, five male Wistar rats were fed with GT from 12 to 19 months of age and results were compared to those obtained from controls age 19 months (C-19 M). A third group of rats was evaluated at 12 months of age to provide baseline data. At completion of the specified time points, the glutathione levels and antioxidant enzyme activities, the activation of the transcription factors cyclic AMP response element-binding (CREB) and nuclear factor-kappaB (NF-kappaB, p50 and p65 subunits), and the levels of brain-derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (Bcl-2) were measured in hippocampal formations. GT-treated rats presented higher reduced and lower oxidized glutathione levels and displayed favorable alterations in antioxidant enzyme activities compared to C-19 M animals. In addition, GT increased CREB activation and the levels of BDNF and Bcl-2, but had no effect on activation of NF-kappaB subunits, relative to age-matched controls. We conclude that long-term GT ingestion improves antioxidant systems and activates CREB in the aging rat hippocampal formation, leading to neuroprotection mediated by downstream upregulation of BDNF and Bcl-2.


Clinical Utility of Rapid EGFR Genotyping in Advanced Lung Cancer.
Targeted therapy is the cornerstone of treatment of advanced EGFR-mutant non-small-cell lung cancer (NSCLC). Next-generation sequencing (NGS), the preferred method for genotyping, typically requires several weeks. Here, we assessed workflows designed to rapidly identify patients with actionable EGFR mutations and reduce time to initiation (TTI) of epidermal growth factor receptor (EGFR)-directed therapy. We performed rapid testing for EGFR L858R mutations and exon 19 deletions on paraffin-embedded or frozen section biopsy specimens from newly diagnosed patients with metastatic NSCLC by using an EGFR-specific assay (rapid test). To determine clinical utility, we assessed concordance with NGS results, turnaround time, and TTI of EGFR therapy, and we evaluated reimbursement data. Between January 2015 and September 2017, we performed 243 rapid EGFR tests and identified EGFR mutations in 43 patients (18%). With NGS results as a reference, sensitivity and specificity of the rapid EGFR polymerase chain reaction assay were 98% and 100%, respectively. The median turnaround time for NGS was 14 days, compared with 7 days for rapid testing (P < .001). In the rapid group, 95% of patients received an EGFR inhibitor in the first-line setting. The median TTI of EGFR therapy was significantly shorter in the rapid cohort when compared with 121 historical cases (22 v 37 days; P = .01). Escalation of the initiative into an interdisciplinary ultra-rapid next-day frozen-section workflow for highly symptomatic patients (n = 8) resulted in a reduction in the median (± standard deviation) turnaround time to 1 ± 0.4 days and allowed several patients to initiate therapy within 1 week of biopsy. An extended 9-month clinical evaluation phase confirmed operational sustainability (turnaround times: ultra-rapid, 0.81 ± 0.4 days; rapid, 3 ± 1.5 days), and a 63% reimbursement rate indicated financial sustainability. Rapid genotyping facilitates earlier initiation of EGFR-directed therapies without compromising NGS workflows.


What Should Junior Doctors Know about the Drugs they Frequently Prescribe? A Delphi Study among Physicians in the Netherlands.
The aim of this study was to identify the information about commonly prescribed drugs that junior doctors should know in order to prescribe rationally in daily practice, defined as essential drug knowledge (EDK). A two-round Internet Delphi study was carried out involving general practitioners from one practice cluster, and registrars and consultants from two Dutch academic and eight teaching hospitals. A preliminary list of 377 potential EDK items for three commonly prescribed drugs was assessed on a dichotomous scale; an item was considered EDK if at least 80% consensus was reached. The consensus list of EDK items was discussed by the research team to identify similarities between the three drugs, with a view to forming a list of general EDK items applicable to other commonly prescribed drugs. Sixty experts considered 93 of the 377 items (25%) as EDK. These items were then used to form a list of 10 general EDK items. The list of EDK items identified by primary and secondary care doctors could be used in medical curricula and training programmes and for assessing the prescribing competence of future junior doctors. Further research is needed to evaluate the generalizability of this list for other commonly prescribed drugs.


Prognostic relevance of lymph node ratio following pancreaticoduodenectomy for pancreatic cancer.
The presence or absence of lymph node metastases is known to be an important prognostic factor for patients with pancreatic cancer. Few studies have investigated the ratio of the number of lymph nodes harboring metastatic cancer to the total number of lymph nodes examined (lymph node ratio [LNR]) with regard to outcome after pancreaticoduodenectomy for ductal cancer of the pancreas. Between 1995 and 2005, a total of 905 patients underwent pancreaticoduodenectomy for pancreatic adenocarcinoma. Demographics, operative data, number of lymph nodes evaluated, number of lymph nodes with metastatic carcinoma, LNR, pathologic margin status, and long-term survival were analyzed. There were 187 (20.7%) of the 905 patients who had negative peripancreatic lymph nodes (N0), whereas 718 (79.3%) of the 905 patients had lymph node metastases (N1). The median number of lymph nodes evaluated in the N0 group was 15 versus 18 in the N1 group (P = .12). At median follow-up of 24 months, the median survival for all patients was 17.4 months, and the 5-year actuarial survival rate was 16.1%. Patients with lymph node metastases had a shorter median overall survival (16.5 months) compared with patients with negative lymph nodes (25.3 months; P = .001). Compared with the total number of lymph nodes examined or total number of lymph node metastases, LNR was the most compelling predictor of survival. As the LNR increased, median overall survival decreased (LNR = 0, 25.3 months; LNR > 0 to 0.2, 21.7 months; LNR > 0.2 to 0.4, 15.3 months; LNR > 0.4, 12.2 months; P = .001). After adjusting for other factors associated with survival, LNR remained an independent predictor of overall survival (P < .001). After pancreaticoduodenectomy for adenocarcinoma of the pancreas, LNR was one of the most powerful predictors of survival. LNR should be considered when stratifying patients in future clinical trials.


Efficacy of decontamination and sterilization of a single-use single-incision laparoscopic surgery port.
To determine the efficacy of decontamination and sterilization of a disposable port intended for use during single-incision laparoscopy. 5 material samples obtained from each of 3 laparoscopic surgery ports. Ports were assigned to undergo decontamination and ethylene oxide sterilization without bacterial inoculation (negative control port), with bacterial inoculation (Staphylococcus aureus, Escherichia coli, and Mycobacterium fortuitum) and without decontamination and sterilization (positive control port), or with bacterial inoculation followed by decontamination and ethylene oxide sterilization (treated port). Each port underwent testing 5 times; during each time, a sample of the foam portion of each port was obtained and bacteriologic culture testing was performed. Bacteriologic culture scores were determined for each port sample. None of the treated port samples had positive bacteriologic culture results. All 5 positive control port samples had positive bacteriologic culture results. One negative control port sample had positive bacteriologic culture results; a spore-forming Bacillus sp organism was cultured from that port sample, which was thought to be an environmental contaminant. Bacteriologic culture scores for the treated port samples were significantly lower than those for the positive control port samples. Bacteriologic culture scores for the treated port samples were not significantly different from those for negative control port samples. Results of this study indicated standard procedures for decontamination and sterilization of a single-use port intended for use during singleincision laparoscopic surgery were effective for elimination of inoculated bacteria. Reuse of this port may be safe for laparoscopic surgery of animals.


Measuring components of family planning program effort.
The measures of family planning program effort developed by Lapham and Mauldin have played a key role in family planning program analysis, but surprisingly little is known about them. This article investigates the measurement of family planning program effort based on data reflecting conditions circa 1982 in 100 developing countries. Using confirmatory factor analytic techniques, it tests some hypotheses implicit in the work of Mauldin and Lapham. Since the data do not fully support these hypotheses, an alternative conceptualization is proposed that consists of eight rather than four components. The discussion focuses on the expanded set of components and includes an assessment of the empirical indicators associated with them.


Impaired quality of life 5 years after bile duct injury during laparoscopic cholecystectomy: a prospective analysis.
To assess the impact of bile duct injury (BDI) sustained during laparoscopic cholecystectomy on physical and mental quality of life (QOL). The incidence of BDI during laparoscopic cholecystectomy has decreased but remains as high as 1.4%. Data on the long-term outcome of treatment in these patients are scarce, and QOL after BDI is unknown. One hundred six consecutive patients (75 women, median age 44 +/- 14 years) were referred between 1990 and 1996 for treatment of BDI sustained during laparoscopic cholecystectomy. Outcome was evaluated according to the type of treatment used (endoscopic or surgical) and the type of injury. Objective outcome (interventions, hospital admissions, laboratory data) was evaluated, a questionnaire was filled out, and a QOL survey was performed (using the SF-36). Risk factors for a worse outcome were calculated. Median follow-up time was 70 months (range 37-110). The objective outcome of endoscopic treatment (n = 69) was excellent (94%). The result of surgical treatment (n = 31) depended on the timing of reconstruction (overall success 84%; in case of delayed hepaticojejunostomy 94%). Five patients underwent interventional radiology with a good outcome. Despite this excellent objective outcome, QOL appeared to be both physically and mentally reduced compared with controls (P <.05) and was not dependent on the type of treatment used or the severity of the injury. The duration of the treatment was independently prognostic for a worse mental QOL. Despite the excellent functional outcome after repair, the occurrence of a BDI has a great impact on the patient's physical and mental QOL, even at long-term follow-up.


Nitric Oxide Production in the Striatum and Cerebellum of a Rat Model of Preterm Global Perinatal Asphyxia.
Encephalopathy due to perinatal asphyxia (PA) is a major cause of neonatal morbidity and mortality in the period around birth. Preterm infants are especially at risk for cognitive, attention and motor impairments. Therapy for this subgroup is limited to supportive care, and new targets are thus urgently needed. Post-asphyxic excitotoxicity is partially mediated by excessive nitric oxide (NO) release. The aims of this study were to determine the timing and distribution of nitric oxide (NO) production after global PA in brain areas involved in motor regulation and coordination. This study focused on the rat striatum and cerebellum, as these areas also affect cognition or attention, in addition to their central role in motor control. NO/peroxynitrite levels were determined empirically with a fluorescent marker on postnatal days P5, P8 and P12. The distributions of neuronal NO synthase (nNOS), cyclic guanosine monophosphate (cGMP), astroglia and caspase-3 were determined with immunohistochemistry. Apoptosis was additionally assessed by measuring caspase-3-like activity from P2-P15. On P5 and P8, increased intensity of NO-associated fluorescence and cGMP immunoreactivity after PA was apparent in the striatum, but not in the cerebellum. No changes in nNOS immunoreactivity or astrocytes were observed. Modest changes in caspase-3-activity were observed between groups, but the overall time course of apoptosis over the first 11 days of life was similar between PA and controls. Altogether, these data suggest that PA increases NO/peroxynitrite levels during the first week after birth within the striatum, but not within the cerebellum, without marked astrogliosis. Therapeutic benefits of interventions that reduce endogenous NO production would likely be greater during this time frame.


Heritability of serum iron, ferritin and transferrin saturation in a genetically isolated population, the Erasmus Rucphen Family (ERF) Study.
Iron has been implicated in the pathogenesis of various disorders. Mutations in the HFE gene are associated with an increase in serum iron parameters. The aim of this study was to estimate the heritability in serum iron parameters explained by HFE. Ninety families (980 subjects) were included in the present analysis. Heritability estimation was conducted using the variance component method. The likelihood ratio test was used to compare models. Phenotypic and genetic correlations between serum iron parameters were calculated. The heritability (h(2) +/- SE) estimates were 0.23 +/- 0.07 (p < 0.0001) for iron, 0.29 +/- 0.09 (p < 0.0001) for ferritin and 0.28 +/- 0.07 (p < 0.0001) for transferrin saturation while adjusting for age, age(2) and sex. The HFE genotypes explained between 2 to 6% of the sex and age-adjusted variance in serum iron, ferritin and transferrin saturation. There was a high genetic correlation between serum iron parameters, suggesting pleiotropy between these traits. A substantial proportion of the variance of iron, ferritin and transferrin saturation can be explained by additive genetic effects, independent of sex and age. The HFE genotypes explained a considerable proportion of serum iron parameters and may be an important factor in the complex iron network.


Bayesian Estimation of Causal Direction in Acyclic Structural Equation Models with Individual-specific Confounder Variables and Non-Gaussian Distributions.
Several existing methods have been shown to consistently estimate causal direction assuming linear or some form of nonlinear relationship and no latent confounders. However, the estimation results could be distorted if either assumption is violated. We develop an approach to determining the possible causal direction between two observed variables when latent confounding variables are present. We first propose a new linear non-Gaussian acyclic structural equation model with individual-specific effects that are sometimes the source of confounding. Thus, modeling individual-specific effects as latent variables allows latent confounding to be considered. We then propose an empirical Bayesian approach for estimating possible causal direction using the new model. We demonstrate the effectiveness of our method using artificial and real-world data.


Novel TPP-riboswitch activators bypass metabolic enzyme dependency.
Riboswitches are conserved regions within mRNA molecules that bind specific metabolites and regulate gene expression. TPP-riboswitches, which respond to thiamine pyrophosphate (TPP), are involved in the regulation of thiamine metabolism in numerous bacteria. As these regulatory RNAs are often modulating essential biosynthesis pathways they have become increasingly interesting as promising antibacterial targets. Here, we describe thiamine analogs containing a central 1,2,3-triazole group to induce repression of thiM-riboswitch dependent gene expression in different E. coli strains. Additionally, we show that compound activation is dependent on proteins involved in the metabolic pathways of thiamine uptake and synthesis. The most promising molecule, triazolethiamine (TT), shows concentration dependent reporter gene repression that is dependent on the presence of thiamine kinase ThiK, whereas the effect of pyrithiamine (PT), a known TPP-riboswitch modulator, is ThiK independent. We further show that this dependence can be bypassed by triazolethiamine-derivatives that bear phosphate-mimicking moieties. As triazolethiamine reveals superior activity compared to pyrithiamine, it represents a very promising starting point for developing novel antibacterial compounds that target TPP-riboswitches. Riboswitch-targeting compounds engage diverse endogenous mechanisms to attain in vivo activity. These findings are of importance for the understanding of compounds that require metabolic activation to achieve effective riboswitch modulation and they enable the design of novel compound generations that are independent of endogenous activation mechanisms.


The presence of emphysema further impairs physiologic function in patients with idiopathic pulmonary fibrosis.
Emphysema, especially in the upper lobes, is frequently observed in association with idiopathic pulmonary fibrosis (IPF). However, the combination of emphysema plus IPF has received little attention. To investigate the additional functional impairment from emphysema in IPF patients. Twenty-one patients (mean age 66 y, 20 men) (Group I) who had both IPF (mean 35% of total lung volume) and emphysema (mean 14% of total lung volume) were compared to a group of 21 subjects who had IPF but no emphysema (Group II). The groups were matched for (among other criteria) the total extent of disease. Pulmonary function tests, Medical Research Council dyspnea score, 6-min walk test, and radiographic extents of both IPF and emphysema were obtained for each patient. The Composite Physiologic Index was calculated. In the total population (n = 42), the independent contributions of IPF and emphysema to several physiologic variables were investigated by using stepwise multiple regression analysis. Despite the limited extent of emphysema, Groups I and II had similar physiologic impairment. Only residual volume and total lung capacity were significantly higher in Group I. According to stepwise multiple regression analysis, the extent of IPF and either the presence or the extent of emphysema in the total population were independent and significant predictors of dyspnea score, 6-min walk test, P(aO2), forced expiratory volume in the first second (FEV(1)), forced vital capacity (FVC), FEV1/FVC, the diffusing capacity of the lung for carbon monoxide, carbon monoxide diffusing capacity adjusted for alveolar volume (gas-transfer coefficient), and residual volume. The Composite Physiologic Index was closely related to the extent of IPF (r = 0.65, p < 0.0001) and to the dyspnea score (rho = 0.59, p < 0.0001). In former smokers with IPF, the presence and the extent of emphysema have a profound influence on physiologic function in terms of both further impairment and confounding effects.


Staphylococcus capitis isolated from prosthetic joint infections.
Further knowledge about the clinical and microbiological characteristics of prosthetic joint infections (PJIs) caused by different coagulase-negative staphylococci (CoNS) may facilitate interpretation of microbiological findings and improve treatment algorithms. Staphylococcus capitis is a CoNS with documented potential for both human disease and nosocomial spread. As data on orthopaedic infections are scarce, our aim was to describe the clinical and microbiological characteristics of PJIs caused by S. capitis. This retrospective cohort study included three centres and 21 patients with significant growth of S. capitis during revision surgery for PJI between 2005 and 2014. Clinical data were extracted and further microbiological characterisation of the S. capitis isolates was performed. Multidrug-resistant (≥3 antibiotic groups) S. capitis was detected in 28.6 % of isolates, methicillin resistance in 38.1 % and fluoroquinolone resistance in 14.3 %; no isolates were rifampin-resistant. Heterogeneous glycopeptide-intermediate resistance was detected in 38.1 %. Biofilm-forming ability was common. All episodes were either early post-interventional or chronic, and there were no haematogenous infections. Ten patients experienced monomicrobial infections. Among patients available for evaluation, 86 % of chronic infections and 70 % of early post-interventional infections achieved clinical cure; 90 % of monomicrobial infections remained infection-free. Genetic fingerprinting with repetitive sequence-based polymerase chain reaction (rep-PCR; DiversiLab®) displayed clustering of isolates, suggesting that nosocomial spread might be present. Staphylococcus capitis has the potential to cause PJIs, with infection most likely being contracted during surgery or in the early postoperative period. As S. capitis might be an emerging nosocomial pathogen, surveillance of the prevalence of PJIs caused by S. capitis could be recommended.


Using a Virtual Reality Social Network During Awake Craniotomy to Map Social Cognition: Prospective Trial.
In awake craniotomy, it is possible to temporarily inactivate regions of the brain using direct electrical stimulation, while the patient performs neuropsychological tasks. If the patient shows decreased performance in a given task, the neurosurgeon will not remove these regions, so as to maintain all brain functions. The objective of our study was to describe our experience of using a virtual reality (VR) social network during awake craniotomy and discuss its future applications for perioperative mapping of nonverbal language, empathy, and theory of mind. This was a single-center, prospective, unblinded trial. During wound closure, different VR experiences with a VR headset were proposed to the patient. This project sought to explore interactions with the neuropsychologist's avatar in virtual locations using a VR social network as an available experience. Three patients experienced VR. Despite some limitations due to patient positioning during the operation and the limitation of nonverbal cues inherent to the app, the neuropsychologist, as an avatar, could communicate with the patient and explore gesture communication while wearing a VR headset. With some improvements, VR social networks can be used in the near future to map social cognition during awake craniotomy. ClinicalTrials.gov NCT03010943; https://clinicaltrials.gov/ct2/show/NCT03010943 (Archived at WebCite at http://www.webcitation.org/70CYDil0P).


Cortical and retinal defects caused by dosage-dependent reductions in VEGF-A paracrine signaling.
To determine the function of VEGF-A in nervous system development, we have utilized the Nestin promoter-driven Cre recombinase transgene, in conjunction with a conditional and hypomorphic VEGF-A allele, to lower VEGF-A activity in neural progenitor cells. Mice with intermediate levels of VEGF-A activity showed decreased blood vessel branching and density in the cortex and retina, resulting in a thinner retina and aberrant structural organization of the cortex. Severe reductions in VEGF-A led to decreases in vascularity and subsequent hypoxia, resulting in the specific degeneration of the cerebral cortex and neonatal lethality. Decreased neuronal proliferation and hypoxia was evident at E11.5, leading to increased neuronal apoptosis in the cortex by E15.5. In order to address whether the observed changes in the structural organization of the nervous system were due to a direct and autocrine role of VEGF-A on the neural population, we conditionally inactivated the main VEGF-A receptor, Flk1, specifically in neuronal lineages, by using the Nestin Cre transgene. The normality of these mice ruled out the possibility that VEGF-A/Flk1 signaling has a significant autocrine role in CNS development. VEGF-A dosage is therefore a critical parameter regulating the density of the vascular plexus in the developing CNS that is in turn a key determinant in the development and architectural organization of the nervous system.


Search for alkanes of 15 to 30 carbon atom length.
A 50-gram sample of lunar fines was subjected to stepwise extraction in a mixture of benzene and methanol while intact, after being pulverized, and after being digested in hydrofluoric acid. None of these three extracts contained detectable quantities of C(15) to C(30) alkanes. No C(15) to C(30) alkane was present in this lunar sample at a concentration exceeding I part per billion by weight.


Democratic integration: self-organized integration of adaptive cues.
Sensory integration or sensor fusion -- the integration of information from different modalities, cues, or sensors -- is among the most fundamental problems of perception in biological and artificial systems. We propose a new architecture for adaptively integrating different cues in a self-organized manner. In Democratic Integration different cues agree on a result, and each cue adapts toward the result agreed on. In particular, discordant cues are quickly suppressed and recalibrated, while cues having been consistent with the result in the recent past are given a higher weight in the future. The architecture is tested in a face tracking scenario. Experiments show its robustness with respect to sudden changes in the environment as long as the changes disrupt only a minority of cues at the same time, although all cues may be disrupted at one time or another.


Chimpanzee females queue but males compete for social status.
Dominance hierarchies are widespread in animal social groups and often have measureable effects on individual health and reproductive success. Dominance ranks are not static individual attributes, however, but instead are influenced by two independent processes: 1) changes in hierarchy membership and 2) successful challenges of higher-ranking individuals. Understanding which of these processes dominates the dynamics of rank trajectories can provide insights into fitness benefits of within-sex competition. This question has yet to be examined systematically in a wide range of taxa due to the scarcity of long-term data and a lack of appropriate methodologies for distinguishing between alternative causes of rank changes over time. Here, we expand on recent work and develop a new likelihood-based Elo rating method that facilitates the systematic assessment of rank dynamics in animal social groups, even when interaction data are sparse. We apply this method to characterize long-term rank trajectories in wild eastern chimpanzees (Pan troglodytes schweinfurthii) and find remarkable sex differences in rank dynamics, indicating that females queue for social status while males actively challenge each other to rise in rank. Further, our results suggest that natal females obtain a head start in the rank queue if they avoid dispersal, with potential fitness benefits.


Dual effects of the Nrf2 inhibitor for inhibition of hepatitis C virus and hepatic cancer cells.
We previously showed that knockdown of nuclear factor E2-related factor 2 (Nrf2) resulted in suppression of hepatitis C virus (HCV) infection. In this study, whether brusatol, an Nrf2 inhibitor, has dual anti-HCV and anticancer effects was explored. The anti-HCV effect of brusatol was investigated by analyzing HCV RNA and proteins in a hepatic cell line persistently-infected with HCV, HPI cells, and by analyzing HCV replication in a replicon-replicating hepatic cell line, OR6 cells. Then, dual anti-HCV and anticancer effects of brusatol and enhancement of the effects by the combination of brusatol with anticancer drugs including sorafenib, which has been reported to have the dual effects, were then investigated. Brusatol suppressed the persistent HCV infection at both the RNA and protein levels in association with a reduction in Nrf2 protein in the HPI cells. Analysis of the OR6 cells treated with brusatol indicated that brusatol inhibited HCV persistence by inhibiting HCV replication. Combination of brusatol with an anticancer drug not only enhanced the anticancer effect but also, in the case of the combination with sorafenib, strongly suppressed HCV infection. Brusatol has dual anti-HCV and anticancer effects and can enhance the comparable effects of sorafenib. There is therefore the potential for combination therapy of brusatol and sorafenib for HCV-related hepatocellular carcinoma.


Time-frequency analysis using damped-oscillator pseudo-wavelets: Application to electrophysiological recordings.
The damped-oscillator pseudo-wavelet is presented as a method of time-frequency analysis along with a new spectral density measure, the data power. An instantaneous phase can be defined for this pseudo-wavelet, and it is easily inverted. The data power measure is tested on both computer generated data and in vivo intrahippocampal electrophysiological recordings from a rat. The data power spectral density is found to give better time and frequency resolution than the more conventional total energy measure, and additionally shows intricate time-frequency structure in the rat that is altered in association with the emergence of epilepsy. With epileptogenesis, the baseline theta oscillation is severely degraded and is absorbed into a broader gamma band. There are also broad 600 Hz and 2000 Hz bands which localize to hippocampal layers that are distinct from those of the theta and gamma bands. The 600 Hz band decreases in prominence with epileptogenesis while the 2000 Hz band increases in prominence. The origins of these high frequency bands await further study. In general, we find that the damped-oscillator pseudo-wavelet is easy to use and is particularly suitable for problems where a wide range of oscillator frequencies is expected.


Effects of self-reported hearing or vision impairment on depressive symptoms: a population-based longitudinal study.
The aims of this study were to investigate the effects of either hearing, vision or dual sensory impairment on depressive symptoms and to identify subgroups that are vulnerable and significantly affected. Data from the 2006-2014 Korean Longitudinal Study of Aging (KLoSA) were used and a total of 5832 individuals were included in this study. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D10) scale. Sensory impairment was assessed according to the levels of self-reported hearing or vision, which were categorised as either good (excellent, very good or good) or poor (fair or poor). The changes in hearing or vision from records of previous survey were investigated. Changes from good to poor, which indicates new onset, were defined as hearing impairment or vision impairment. Interactions of changes in hearing and vision were considered in the analysis. Dual sensory impairment was indicated when hearing impairment and vision impairment both developed at the same time. Demographic, socioeconomic and health-related factors were considered as potential confounders and were adjusted for in the generalised estimating equation model. Individuals with hearing impairment demonstrated significantly more severe depressive symptoms [β = 0.434, standard errors (s.e.) = 0.097, p < 0.001] than those who had good hearing. Those with vision impairment also showed significantly elevated depressive symptoms (β = 0.253, s.e. = 0.058, p < 0.001) than those with good vision. When the interactions between hearing and vision were considered, participants with dual sensory impairment showed significantly more severe depressive symptoms (β = 0.768, s.e. = 0.197, p < 0.001) than those with good hearing and vision. The effect of a single and dual sensory impairment on depressive symptoms was significant in both sexes and across age groups, except for vision impairment in male participants. Hearing, vision and dual sensory impairment are significantly associated with depressive symptoms. Our results suggest that treatment or rehabilitation of either hearing or vision impairment would help prevent depression.


Substance use among patients in specialized mental health services in Norway: prevalence and patient characteristics based on a national census.
The aim of this study was to investigate the clinical and demographic variation in the prevalence of substance use among the general psychiatric population in Norway. A national census in psychiatric institutions and outpatient clinics was conducted. Data were returned for 2358 inpatients (response rate, 65%) and 23,167 outpatients (response rate, 60%). Substance use was measured based on substance use disorder diagnosis or reported substance use in the last 4 weeks (alcohol 2-4 days a week or more frequently/illicit drug use). Regression analyses controlling for demographic and sociodemographic characteristics were carried out. Substance use was identified in 32.4% of inpatients and 13.9% of outpatients. The most frequently reported substances used were alcohol, sedatives and cannabis. Among inpatients, the prevalence of substance use was highest in patients with schizophrenia, personality disorders and anxiety disorders. Among outpatients, the prevalence was highest in patients with schizophrenia and other psychoses. Inpatients with anxiety disorders and outpatients with schizophrenia and other psychoses had a significantly higher risk of substance use than other patients. In both samples, the prevalence of substance use was higher among males, 24 to 29-year-olds and the most socially deprived. This study provides further knowledge about patients at risk for co-morbid substance abuse and poor treatment outcomes. Clinicians may consider targeting patients with schizophrenia and other psychoses, young males and those who are socially deprived in efforts to prevent emerging substance abuse and improve outcomes.