Subcellular dynamics of type II PKA in neurons.
Protein kinase A (PKA) plays multiple roles in neurons. The localization and specificity of PKA are largely controlled by A-kinase anchoring proteins (AKAPs). However, the dynamics of PKA in neurons and the roles of specific AKAPs are poorly understood. We imaged the distribution of type II PKA in hippocampal and cortical layer 2/3 pyramidal neurons in vitro and in vivo. PKA was concentrated in dendritic shafts compared to the soma, axons, and dendritic spines. This spatial distribution was imposed by the microtubule-binding protein MAP2, indicating that MAP2 is the dominant AKAP in neurons. Following cAMP elevation, catalytic subunits dissociated from the MAP2-tethered regulatory subunits and rapidly became enriched in nearby spines. The spatial gradient of type II PKA between dendritic shafts and spines was critical for the regulation of synaptic strength and long-term potentiation. Therefore, the localization and activity-dependent translocation of type II PKA are important determinants of PKA function.


Deep CNN Sparse Coding for Real Time Inhaler Sounds Classification.
Effective management of chronic constrictive pulmonary conditions lies in proper and timely administration of medication. As a series of studies indicates, medication adherence can effectively be monitored by successfully identifying actions performed by patients during inhaler usage. This study focuses on the recognition of inhaler audio events during usage of pressurized metered dose inhalers (pMDI). Aiming at real-time performance, we investigate deep sparse coding techniques including convolutional filter pruning, scalar pruning and vector quantization, for different convolutional neural network (CNN) architectures. The recognition performance has been assessed on three healthy subjects following both within and across subjects modeling strategies. The selected CNN architecture classified drug actuation, inhalation and exhalation events, with 100%, 92.6% and 97.9% accuracy, respectively, when assessed in a leave-one-subject-out cross-validation setting. Moreover, sparse coding of the same architecture with an increasing compression rate from 1 to 7 resulted in only a small decrease in classification accuracy (from 95.7% to 94.5%), obtained by random (subject-agnostic) cross-validation. A more thorough assessment on a larger dataset, including recordings of subjects with multiple respiratory disease manifestations, is still required in order to better evaluate the method's generalization ability and robustness.


Solitary mandibular metastasis as an initial manifestation of hepatocellular carcinoma.
Oral metastases from hepatocellular carcinoma are very rare. We encountered a case of hepatocellular carcinoma with a solitary metastasis to the mandible as an initial manifestation. The patient was a 76-year-old man who was admitted for left mandibular swelling. A biopsy specimen of mandible was suspected to be a metastatic tumor. The histological findings, abdominal computed tomography, bone scintigraphy, and F-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed it to be a solitary metastasis from hepatocellular carcinoma. As a result, he was diagnosed to have liver cirrhosis due to a hepatitis C virus infection and hepatocellular carcinoma with a solitary metastasis to the mandible. The primary lesion was treated with transcatheter arterial embolization (TAE), and the metastasis to the mandible was surgically resected. The patient survived for 9 months after treatment without recurrence.


Wnt disruption in colorectal polyps - the traditional serrated adenoma enters the fray.
The adenoma-carcinoma sequence describes the development of colorectal carcinoma (CRC) from benign colorectal precursor lesions. Molecular classification of established CRC has demonstrated considerable disease heterogeneity; however, as an emerging cancer frequently outgrows and destroys the initial precursor lesion, CRC molecular taxonomy can only be partially reconciled with histologically classified polyps. Thus, the molecular pathogenesis of some colorectal polyp types, including the traditional serrated adenoma (TSA), is still unclear. Now, candidate driver gene analysis of a cohort of different polyps reveals characteristic, but highly variable, mutations disrupting the Wnt signalling pathway across different histological polyp subtypes. How and when different precursor lesions acquire Wnt disruption reflects important distinctions in polyp biology, dependent on a combination of the dominant molecular pathway and the cell of origin of individual lesions. TSAs preferentially acquire ligand-dependent Wnt activating mutations, which means that the cancers that arise from these aggressive polyps may be sensitive to targeted Wnt inhibition. This paper demonstrates that applying next-generation sequencing technology to improve our understanding of colorectal precursor lesion molecular pathogenesis could also give important and translationally relevant insights into colorectal cancer biology. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Reactive Oxygen Species Affect Transglutaminase Activity and Regulate Hematopoiesis in a Crustacean.
Reactive oxygen species (ROS) serve as a prime signal in the commitment to hematopoiesis in both mammals and Drosophila In this study, the potential function of ROS during hematopoiesis in the crayfish Pacifastacus leniusculus was examined. The antioxidant N-acetylcysteine (NAC) was used to decrease ROS in both in vivo and in vitro experiments. An increase in ROS was observed in the anterior proliferation center (APC) after LPS injection. In the absence of NAC, the LPS-induced increase in ROS levels resulted in the rapid restoration of the circulating hemocyte number. In the presence of NAC, a delay in the recovery rate of the hemocyte number was observed. NAC treatment also blocked the spread of APC and other hematopoietic tissue (HPT) cells, maintaining these cells at an undifferentiated stage. Extracellular transglutaminase (TGase) has been shown previously to play a role in maintaining HPT cells in an undifferentiated form. In this study, we show that extracellular TGase activity increased when the ROS level in HPT or APC cells was reduced after NAC treatment. In addition, collagen, a major component of the extracellular matrix and a TGase substrate were co-localized on the HPT cell surface. Taken together, the results of this study show that ROS are involved in crayfish hematopoiesis, in which a low ROS level is required to maintain hematopoietic progenitor cells in the tissue and to reduce hemocyte release. The potential roles of TGase in this process are investigated and discussed.


A research agenda for geriatric emergency medicine.
The Research Agenda Setting Process (RASP), part of the American Geriatric Society's (AGS's) project "Increasing Geriatric Expertise in Surgical and Related Medical Specialties," was designed to define a research agenda for the geriatrics aspects of participating specialties. This paper presents a summary of the research agenda for emergency medicine. The RASP was developed by the AGS in conjunction with experts from the participating specialty organizations. A "content expert" (CE) for each specialty developed a Medline search strategy in conjunction with RAND Health librarians. The CE reviewed the search to identify papers that were germane to research in the emergency care of older patients. The CE and a senior writing group member drafted a paper that synthesized the current literature and suggested areas for further research. A panel consisting of AGS members and emergency physicians with geriatrics expertise reviewed this paper. The research agenda was further refined at a two-day retreat. Two senior geriatricians reviewed the resulting paper. The Medline search for emergency medicine resulted in a list of 3,348 articles; 299 articles were pertinent and reviewed. The search for trauma resulted in a list of 1,838 articles; 133 were reviewed. Research agenda items were defined for multiple topics within geriatric emergency medicine and trauma. A research agenda for geriatric emergency medicine has been developed, using a combination of review of current literature and expert opinion.


Assessment of Striatal Dopamine Transporter Binding in Individuals With Major Depressive Disorder: In Vivo Positron Emission Tomography and Postmortem Evidence.
Major depressive disorder (MDD) might involve dopamine (DA) reductions. The DA transporter (DAT) regulates DA clearance and neurotransmission and is sensitive to DA levels, with preclinical studies (including those involving inescapable stressors) showing that DAT density decreases when DA signaling is reduced. Despite preclinical data, evidence of reduced DAT in MDD is inconclusive. Using a highly selective DAT positron emission tomography (PET) tracer ([11C] altropane), DAT availability was probed in individuals with MDD who were not taking medication. Levels of DAT expression were also evaluated in postmortem tissues from donors with MDD who died by suicide. This cross-sectional PET study was conducted at McLean Hospital (Belmont, Massachusetts) and Massachusetts General Hospital (Boston) and enrolled consecutive individuals with MDD who were not taking medication and demographically matched healthy controls between January 2012 and March 2014. Brain tissues were obtained from the Douglas-Bell Canada Brain Bank. For the PET component, 25 individuals with current MDD who were not taking medication and 23 healthy controls recruited from McLean Hospital were included (all provided usable data). For the postmortem component, 15 individuals with depression and 14 healthy controls were considered. PET scan. Striatal and midbrain DAT binding potential was assessed. For the postmortem component, tyrosine hydroxylase and DAT levels were evaluated using Western blots. Compared with 23 healthy controls (13 women [56.5%]; mean [SD] age, 26.49 [7.26] years), 25 individuals with MDD (19 women [76.0%]; mean [SD] age, 26.52 [5.92] years) showed significantly lower in vivo DAT availability in the bilateral putamen and ventral tegmental area (Cohen d range, -0.62 to -0.71), and both reductions were exacerbated with increasing numbers of depressive episodes. Unlike healthy controls, the MDD group failed to show an age-associated reduction in striatal DAT availability, with young individuals with MDD being indistinguishable from older healthy controls. Moreover, DAT availability in the ventral tegmental area was lowest in individuals with MDD who reported feeling trapped in stressful circumstances. Lower DAT levels (and tyrosine hydroxylase) in the putamen of MDD compared with healthy controls were replicated in postmortem analyses (Cohen d range, -0.92 to -1.15). Major depressive disorder, particularly with recurring episodes, is characterized by decreased striatal DAT expression, which might reflect a compensatory downregulation due to low DA signaling within mesolimbic pathways.


Promoting effect of saccharin and DL-tryptophan in urinary bladder carcinogenesis.
The existence of at least two stages in bladder carcinogenesis was evaluated in male Fischer rats using N-[14-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) fed for six weeks at a level of 0.2% of the diet as the initiator. Sodium saccharin and DL-tryptophan were fed at levels of 5 and 2% of the diet, respectively, as possible promoting chemicals, and they were fed either immediately after FANFT administration or after six weeks of FANFT plus six weeks of control diet. All surviving rats were killed at the end of two years. Both chemicals significantly increased the incidence of bladder tumors following FANFT feeding compared to six weeks of FANFT feeding followed by control diet, and the results were similar whether saccharin or tryptophan feeding was started immediately after FANFT feeding was concluded or after a six-week delay. Saccharin was considerably more potent as a promoting agent than was tryptophan, inducing higher incidences of bladder tumors and having a shorter latent period. Long-term administration of FANFT induced a 100% incidence of bladder cancer. Sequential epithelial changes were observed by scanning and transmission electron microscopy as well as by light microscopy. Pleomorphic microvilli were present on the superficial cells of all tumors examined and on the surface cells of hyperplastic bladder epithelium after six weeks of FANFT plus six weeks of saccharin, but not after six weeks of FANFT and six weeks of control diet. Rats fed only saccharin tryptophan, or control diet did not have bladder tumors or pleomorphic microvilli on bladder epithelium. These data suggest that saccharin and tryptophan might act as tumor-promoting agents during bladder carcinogenesis.


Perception-action loops of multiple agents: informational aspects and the impact of coordination.
Embodied agents can be conceived as entities perceiving and acting upon an external environment. Probabilistic models of this perception-action loop have paved the way to the investigation of information-theoretic aspects of embodied cognition. This formalism allows (i) to identify information flows and their limits under various scenarios and constraints, and (ii) to use informational quantities in order to induce the self-organization of the agent's behavior without any externally specified drives. This article extends the perception-action loop formalism to multiple agents. The multiple-access channel model is presented and used to identify the relationships between informational quantities of two agents interacting in the same environment. The central question investigated in this article is the impact of coordination. Information-theoretic limits on what can be achieved with and without coordination are identified. For this purpose, different abstract channels are studied, along with a concrete example of agents interacting in space. It is shown that, under some conditions, self-organizing systems based on information-theoretic quantities have a tendency to spontaneously generate coordinated behavior. Moreover, in the perspective of engineering such systems to achieve specific tasks, these information-theoretic limits put constraints on the amount of coordination that is required to perform the task, and consequently on the mechanisms that underlie self-organization in the system.


Transient reduction of mutans streptococci on tooth surfaces using a chlorhexidine-containing glass ionomer cement varnish.
Chlorhexidine (CHX) has been incorporated in polymer-based varnishes to reduce mutans streptococci (ms) by the sustained release of CHX. Such varnishes often adhere well to teeth initially but are easily peeled off. To be effective, repeated application is necessary. Glass ionomer (GI) cements interacts with tooth minerals to form a stronger bond, and the inherent brittleness of the cement makes it difficult to remove in large fragments. The fluoride content may also reduce demineralisation. The aim of this study was to observe whether ms could be reduced interproximally and in saliva by a single application of a GI cement containing 3.3% CHX gluconate (CHX-GI). After professional tooth cleaning and a mouth rinse for 2 min with 0.2% CHX, the teeth of six subjects were coated with CHX-GI cement. An additional six subjects were treated with a GI cement that did not contain CHX, and seven subjects received professional tooth cleaning only. Ms samples were taken interproximally with the tooth pick method before and after treatment. Interproximal levels were classified according to the number of colony-forming units (c.f.u.) found: 0, 1-20, 21-100, and > 100. Saliva ms were sampled with the Strip Mutans method. After four weeks, the interproximal levels of ms had decreased only in the CHX-GI group (p < 0.05). In this group 9 of 14 highly colonised sites (> 100 c.f.u.) remained reduced throughout this period. In the GI and the untreated group a slight increase of ms interproximally was seen after one week. The interproximal ms scores in all groups approached baseline levels after 8 weeks. There were no significant differences in saliva ms levels between the groups during the test period. GI cement may be a possible vehicle for CHX in reducing ms interproximally.


The Impact of Intraoperative Monitoring on Extent of Resection and Long-Term Neurological Outcomes: A Series of 39 Intramedullary Ependimomas.
To analyze the impact of intraoperative neurophysiological monitoring (IONM) on the extent of removal and long-term neurological outcomes in a series of grade II ependymomas. We retrospectively reviewed 88 consecutive patients who underwent surgical resection of an intramedullary spinal cord tumor (IMSCT) at the Clinic of Neurosurgery of the Clinical Center of Serbia in Belgrade between January 2012 and December 2017. In all, 39 patients (25 males and 14 females; mean age 46.16 years) with grade II ependymomas were enrolled in this study; the mean follow-up time was 49.84 months. The modified McCormick Scale (mMCS) was used to assess the short- and long-term outcomes, and the patients were divided into two groups based on whether they underwent IONM. The gross-total removal rate was 89.7%, and it was not influenced by use of IONM, location or tumor size. Upon admission,43.2% of the patients were dependent (grades IV and V), while 56.8% were independent (grades I, II and III), according to the mMCS. After 3 months of follow-up, 76.9% of the patients maintained or improved their neurological status, but this percentage was reduced after long-term follow-up. Total surgical resection with good neurological outcomes can be achieved in the vast majority of patients with grade II ependymomas; it is important to emphasize that the use of IONM allows acceptable extent of resection and provides better results in terms of functional outcomes, with lower morbidity rates. Therefore, no correlation was demonstrated between the decrease in the basal amplitudes of IONM and D-waves and poor neurological outcomes.


Detection of oxidized and glycated proteins in clinical samples using mass spectrometry--a user's perspective.
Proteins in human tissues and body fluids continually undergo spontaneous oxidation and glycation reactions forming low levels of oxidation and glycation adduct residues. Proteolysis of oxidised and glycated proteins releases oxidised and glycated amino acids which, if they cannot be repaired, are excreted in urine. In this review we give a brief background to the classification, formation and processing of oxidised and glycated proteins in the clinical setting. We then describe the application of stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry (LC-MS/MS) for measurement of oxidative and glycation damage to proteins in clinical studies, sources of error in pre-analytic processing, corroboration with other techniques - including how this may be improved - and a systems approach to protein damage analysis for improved surety of analyte estimations. Stable isotopic dilution analysis LC-MS/MS provides a robust reference method for measurement of protein oxidation and glycation adducts. Optimised pre-analytic processing of samples and LC-MS/MS analysis procedures are required to achieve this. Quantitative measurement of protein oxidation and glycation adducts provides information on level of exposure to potentially damaging protein modifications, protein inactivation in ageing and disease, metabolic control, protein turnover, renal function and other aspects of body function. Reliable and clinically assessable analysis is required for translation of measurement to clinical diagnostic use. Stable isotopic dilution analysis LC-MS/MS provides a "gold standard" approach and reference methodology to which other higher throughput methods such as immunoassay and indirect methods are preferably corroborated by researchers and those commercialising diagnostic kits and reagents. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn.


Nail dryer devices: a measured spectral irradiance and labelling review.
The popularity of nail beauty has increased during the last few years in Spain, as well as in other countries. Nowadays there are a large number of nail dryer devices in the market with ultraviolet (UV) fluorescent lamps, light emitting diodes (LED) or a combination of both. The different spectral emissions of each individual nail dryer device require particular nail polishes, which are polymerized by specific wavelengths and a controlled exposure time to achieve the desired results. We have measured and analyzed the emission of 28 nail dryer devices currently in use in Spanish beauty centers. The emission of each individual nail dryer device showed a particular spectral distribution and maximum intensity, especially those with fluorescent lamps or LED/UV combinations. About 30% of the devices emitted more UV-A radiation than that received in Barcelona at solar noon in summer. Nevertheless, in all cases the erythemal irradiance was low, similarly to ambient values at solar noon in winter or when the solar altitude is low. The erythemal doses corresponding to a typical session were, therefore, lower than those received from sunlight at summer midday at equivalent exposure times. The biological irradiances for photoaging (skin sagging and elastosis) showed high variability depending on the device, especially for fluorescent lamps. Since the emission of LED-based devices is centered in the visible region, erythemal and photoaging irradiances were low. An analysis of the labelling showed that 85% of the devices had a visible label, although 23% contained some errors, according to the EN 60335-1 guideline.


Standardized methods for assessing the imaging quality of intraocular lenses.
The relative merits of three standardized methods for assessing the imaging quality of intraocular lenses are discussed based on theoretical modulation-transfer-function calculations. The standards are ANSI Z80.7 1984 from the American National Standards Institute, now superseded by ANSI Z80.7 1994, and the proposed ISO 11979-2 from the International Organization for Standardization. They entail different test configurations and approval limits, respectively: 60% resolution efficiency in air, 70% resolution efficiency in aqueous humor, and 0.43 modulation at 100 line pairs/mm in a model eye. The ISO working group found that the latter corresponds to 60% resolution efficiency in air in a ring test among eight laboratories on a sample of 39 poly(methyl) methacrylate lenses and four silicone lenses spanning the power (in aqueous humor) range of 10-30 D. In both ANSI Z80.7 1994 and ISO 11979-2, a 60% resolution efficiency in air remains an optional approval limit. It is concluded that the ISO configuration is preferred, because it puts the intraocular lens into the context of the optics of the eye. Note that the ISO standard is tentative and is currently being voted on.


Binary Classification Using Neural and Clinical Features: An Application in Fibromyalgia With Likelihood-Based Decision Level Fusion.
Among several features used for clinical binary classification, behavioral performance, questionnaire scores, test results, and physical exam reports can be counted. Attempts to include neuroimaging findings to support clinical diagnosis are scarce due to difficulties in collecting such data, as well as problems in integration of neuroimaging findings with other features. The binary classification method proposed here aims to merge small samples from multiple sites so that a large cohort, which better describes the features of the disease can be built. We implemented a simple and robust framework for detection of fibromyalgia, using likelihood during decision level fusion. This framework supports sharing of classifier applications across clinical sites and arrives at a decision by fusing results from multiple classifiers. If there are missing opinions from some classifiers due to inability to collect their input features, such degradation in information is tolerated. We implemented this method using functional near infrared spectroscopy (fNIRS) data collected from fibromyalgia patients across three different tasks. Functional connectivity maps are derived from these tasks as features. In addition, self-reported clinical features are also used. Five classifiers are trained using k nearest neighborhood (kNN), linear discriminant analysis (LDA), and support vector machine (SVM). Fusion of classification opinions from multiple classifiers based on likelihood ratios outperformed individual classifier performances. When 2, 3, 4, and 5 different classifiers are fused, sensitivity, and specificity figures of 100% could be obtained based on the choice of the classifier set.


A longitudinal twin study of 1-year prevalence of major depression in women.
This study seeks to clarify the etiologic importance and temporal stability of the genetic and environmental risk factors for 1-year prevalence of major depression (1YP-MD) in women. One-year prevalence of major depression was personally assessed, using DSM-III-R criteria, at two time points a minimum of 1 year apart. Both members of 938 adult female-female twin pairs ascertained from the population-based Virginia Twin Registry. The correlation in liability to 1YP-MD was much greater in monozygotic (MZ) than in dizygotic (DZ) twins at time 1 alone, time 2 alone, or at either time 1 or time 2. Model fitting suggested that the liability to 1YP-MD was due to additive genes and individual specific environment with a heritability of 41% to 46% and was not biased by violations of the equal environment assumption. Jointly analyzing both times of assessment using a longitudinal twin model suggested that, over a 1-year period, genetic effects on the liability to 1YP-MD were entirely stable, while environmental effects were entirely occasion specific. These results suggest that: (1) genetic factors play a moderate etiologic role in the 1YP-MD, (2) the temporal stability of the liability to major depression in adult women is largely or entirely genetic in origin, and (3) environmental factors play a significant role in the etiology of major depression, but their effects are generally transitory and do not result in enduring changes in the liability to illness.


Delusions and Responsibility for Action: Insights from the Breivik Case.
What factors should be taken into account when attributing criminal responsibility to perpetrators of severe crimes? We discuss the Breivik case, and the considerations which led to holding Breivik accountable for his criminal acts. We put some pressure on the view that experiencing certain psychiatric symptoms or receiving a certain psychiatric diagnosis is sufficient to establish criminal insanity. We also argue that the presence of delusional beliefs, often regarded as a key factor in determining responsibility, is neither necessary nor sufficient for criminal insanity.


Predicting severe outcomes in Covid-19 related illness using only patient demographics, comorbidities and symptoms.
Development of a risk-stratification model to predict severe Covid-19 related illness, using only presenting symptoms, comorbidities and demographic data. We performed a case-control study with cases being those with severe disease, defined as ICU admission, mechanical ventilation, death or discharge to hospice, and controls being those with non-severe disease. Predictor variables included patient demographics, symptoms and past medical history. Participants were 556 patients with laboratory confirmed Covid-19 and were included consecutively after presenting to the emergency department at a tertiary care center from March 1, 2020 to April 21, 2020 RESULTS: Most common symptoms included cough (82%), dyspnea (75%), and fever/chills (77%), with 96% reporting at least one of these. Multivariable logistic regression analysis found that increasing age (adjusted odds ratio [OR], 1.05; 95% confidence interval [CI], 1.03-1.06), dyspnea (OR, 2.56; 95% CI: 1.51-4.33), male sex (OR, 1.70; 95% CI: 1.10-2.64), immunocompromised status (OR, 2.22; 95% CI: 1.17-4.16) and CKD (OR, 1.76; 95% CI: 1.01-3.06) were significant predictors of severe Covid-19 infection. Hyperlipidemia was found to be negatively associated with severe disease (OR, 0.54; 95% CI: 0.33-0.90). A predictive equation based on these variables demonstrated fair ability to discriminate severe vs non-severe outcomes using only this historical information (AUC: 0.76). Severe Covid-19 illness can be predicted using data that could be obtained from a remote screening. With validation, this model could possibly be used for remote triage to prioritize evaluation based on susceptibility to severe disease while avoiding unnecessary waiting room exposure.


Disposed to distraction: genetic variation in the cholinergic system influences distractibility but not time-on-task effects.
Both the passage of time and external distraction make it difficult to keep attention on the task at hand. We tested the hypothesis that time-on-task and external distraction pose independent challenges to attention and that the brain's cholinergic system selectively modulates our ability to resist distraction. Participants with a polymorphism limiting cholinergic capacity (Ile89Val variant [rs1013940] of the choline transporter gene SLC5A7) and matched controls completed self-report measures of attention and a laboratory task that measured decrements in sustained attention with and without distraction. We found evidence that distraction and time-on-task effects are independent and that the cholinergic system is strongly linked to greater vulnerability to distraction. Ile89Val participants reported more distraction during everyday life than controls, and their task performance was more severely impacted by the presence of an ecologically valid video distractor (similar to a television playing in the background). These results are the first to demonstrate a specific impairment in cognitive control associated with the Ile89Val polymorphism and add to behavioral and cognitive neuroscience studies indicating the cholinergic system's critical role in overcoming distraction.


Identity, regulation and in vivo function of gut NKp46+RORγt+ and NKp46+RORγt- lymphoid cells.
The gut is a major barrier against microbes and encloses various innate lymphoid cells (ILCs), including two subsets expressing the natural cytotoxicity receptor NKp46. A subset of NKp46(+) cells expresses retinoic acid receptor-related orphan receptor γt (RORγt) and produces IL-22, like lymphoid tissue inducer (LTi) cells. Other NKp46(+) cells lack RORγt and produce IFN-γ, like conventional Natural Killer (cNK) cells. The identity, the regulation and the in vivo functions of gut NKp46(+) ILCs largely remain to be unravelled. Using pan-genomic profiling, we showed here that small intestine (SI) NKp46(+)RORγt(-) ILCs correspond to SI NK cells. Conversely, we identified a transcriptional programme conserved in fetal LTi cells and adult SI NKp46(+)RORγt(+) and NKp46(-)RORγt(+) ILCs. We also demonstrated that the IL-1β/IL-1R1/MyD88 pathway, but not the commensal flora, drove IL-22 production by NKp46(+)RORγt(+) ILCs. Finally, oral Listeria monocytogenes infection induced IFN-γ production in SI NK and IL-22 production in NKp46(+)RORγt(+) ILCs, but only IFN-γ contributed to control bacteria dissemination. NKp46(+) ILC heterogeneity is thus associated with subset-specific transcriptional programmes and effector functions that govern their implication in gut innate immunity.


Photo-structuring of As(2)S(3) glass by femtosecond irradiation.
The nonlinear absorption coefficient of As(2)S(3) glass has been measured to be 2.0 cm/GW for femtosecond pulses at 800 nm. Femtosecond laser structuring via two photon absorption in bulk As(2)S(3) glass by erasable and permanent photo-darkening is demonstrated using both holographic and direct multi-beam laser writing.


Evaluation of single-pigment shift model of anomalous trichromacy.
The spectral sensitivity of the visual photopigments, the interobserver variability in color judgments, and the spectral locus of unique yellow provide three major problems for accounts of X-chromosomal-linked anomalous trichromacy. According to the single-pigment hypothesis, the primary defect in anomalous trichromacy is a wavelength shift in the peak sensitivity of one of the three visual photopigments. We show that this shift results in reduction of the anomalous trichromat's r-g opponent chromatic channel. The distribution of response variability in Rayleigh equation match widths due to factors other than the spectral characteristics of the photopigments is similar in normal and anomalous trichromats. When normal and anomalous trichromats make hue estimations of sets of stimuli designed to contain similar chromatic information, their judgments show similar variability. Calculation of the r-g opponent chromatic channel can provide correct predictions of the spectral loci for unique yellow for anomalous trichromats.


The roles of buckled geometry and water environment in the excitonic properties of graphitic C3N4.
The exciton plays a crucial role in two-dimensional materials involved in photocatalytic water splitting, where its properties are determined not only by the material itself, but also by the surrounding water environment. By the framework of many-body perturbation theory, we investigated the excitonic effects in pure and water-adsorbed g-C3N4. It is shown that the excitonic properties are very sensitive to the geometry of g-C3N4 and the adsorption of water molecules. Firstly, the optical band gap, i.e. the first bright excitonic energy of pure g-C3N4 decreases remarkably from a high symmetry planar structure (3.8 eV) to a P1 buckled configuration (2.7 eV). Secondly, the hydrogen bonds between water and g-C3N4 induce the generation of interface excitons. With a reduced binding energy (at least 0.2 eV), interface excitons can contribute to a more efficient separation of electrons and holes. Our work provides an insight into the excitation mechanism of 2D photocatalysts in a real environment.


The Degree of Early Life Stress Predicts Decreased Medial Prefrontal Activations and the Shift from Internally to Externally Guided Decision Making: An Exploratory NIRS Study during Resting State and Self-Oriented Task.
Early life stress (ELS), an important risk factor for psychopathology in mental disorders, is associated neuronally with decreased functional connectivity within the default mode network (DMN) in the resting state. Moreover, it is linked with greater deactivation in DMN during a working memory task. Although DMN shows large amplitudes of very low-frequency oscillations (VLFO) and strong involvement during self-oriented tasks, these features' relation to ELS remains unclear. Therefore, our preliminary study investigated the relationship between ELS and the degree of frontal activations during a resting state and self-oriented task using near-infrared spectroscopy (NIRS). From 22 healthy participants, regional hemodynamic changes in 43 front-temporal channels were recorded during 5 min resting states, and execution of a self-oriented task (color-preference judgment) and a control task (color-similarity judgment). Using a child abuse and trauma scale, ELS was quantified. We observed that ELS showed a negative correlation with medial prefrontal cortex (MPFC) activation during both resting state and color-preference judgment. In contrast, no significant correlation was found between ELS and MPFC activation during color-similarity judgment. Additionally, we observed that ELS and the MPFC activation during color-preference judgment were associated behaviorally with the rate of similar color choice in preference judgment, which suggests that, for participants with higher ELS, decisions in the color-preference judgment were based on an external criterion (color similarity) rather than an internal criterion (subjective preference). Taken together, our neuronal and behavioral findings show that high ELS is related to lower MPFC activation during both rest and self-oriented tasks. This is behaviorally manifest in an abnormal shift from internally to externally guided decision making, even under circumstances where internal guidance is required.


Granule associated DNase in T4 and T8 lymphocytes from patients with autoimmune diseases.
The presence of a DNase activity associated with secretion granules was detected in T4 and T8 lymphocytes from patients with autoimmune diseases. This activity was much higher in primary biliary cirrhosis (PBC) than in Graves' disease (GD) and multiple sclerosis (MS) or in healthy subjects. This granule associated DNase activity was Ca(2+)-dependent, inhibited by Zn2+, and higher at low pH; its molecular weight corresponded to 66kDa; it was more active with double-strand than single-strand DNA. Judging from its properties this enzyme differed from the three types of endonucleases described as involved in DNA fragmentation (DNase I, DNase II and NUC18). Flow cytometry analysis of T lymphocytes showed that DNase activity associated with CD4+ lymphocyte granules correlated with the ratio CD4+CD45RO+/CD4+CD45RA+ (memory and cytotoxic cells/naive cells, inducers of suppression). In contrast, T8 lymphocyte DNase activity correlated with the proportion of CD4+ lymphocytes with CD4+CD45RA- phenotype (helpers and inducers of cytotoxicity). The possible role of this DNase activity in the mechanisms of lysis or apoptosis mediated by CTL is discussed. We suggest that this DNase activity could be implicated in some of the alterations of the autoimmune response depending on cytotoxic T lymphocytes or T cell inducers of apoptosis.


The effectiveness of multidisciplinary rehabilitation in the treatment of fibromyalgia: a randomized controlled trial.
To assess the effectiveness of multidisciplinary rehabilitation in the treatment of fibromyalgia in comparison to standard medical care. Seventy-nine men and women were randomly assigned to one of two groups. The intervention group consisted of a rheumatologist and physical therapist intake and discharge, 18 group supervised exercise therapy sessions, 2 group pain and stress management lectures, 1 group education lecture, 1 group dietary lecture, and 2 massage therapy sessions. The control group consisted of standard medical care with the patients' family physician. Outcome measures included self-perceived health status, pain-related disability, average pain intensity, depressed mood, days in pain, hours in pain, prescription and nonprescription medication usage, and work status. Outcomes were measured at the end of the 6-week intervention and at 15-month follow-up. Thirty-five out of 43 patients from the intervention group and 36 out of 36 patients from the control group completed the study. There were no statistically significant differences between the 2 groups prior to intervention. Intention-to-treat analysis revealed that the intervention group, in comparison to the control group, experienced statistically significant changes at intervention completion in self-perceived health status, average pain intensity, pain related disability, depressed mood, days in pain, and hours in pain, but no significant differences in nonprescription drug use, prescription drug use, or work status. At 15 months, all health outcomes retained their significance except health status. Nonprescription and prescription drug use demonstrated significant reductions at 15 months. Binary logistic regression indicated that long-term changes in Pain Disability Index were influenced by long-term exercise adherence and income status. Positive health-related outcomes in this mostly unresponsive condition can be obtained with a low-cost, group multidisciplinary intervention in a community-based, nonclinical setting.


Long-term use of daily subcutaneous low molecular weight heparin in cancer patients with venous thromboembolism: why hesitate any longer?
Cancer disease inducing an acquired hypercoagulable state is a well-established feature. Venous thromboembolism (VTE) occurs in 4% to 20% of the patients and is the second cause of mortality in cancer; VTE incidence is four to six times higher in cancer patients compared to other patients. In the last 10 years, important randomised clinical trials have clearly demonstrated that long-term use of daily subcutaneous low molecular weight heparin (LMWH) is more efficient than Vitamin K antagonists to treat VTE in cancer patients. First Italian, then American and more recently French national guidelines recommend the use of LMWH for 3 to 6 months for curative treatment of VTE in cancer patients with a clearly high level (A) of evidence. Despite convincing data, many physicians have not yet modified their clinical practice, doubting the tolerability of such a long period of subcutaneous injections. In fact, LMWH long-term use appears well tolerated and may also increase cancer patient survival. The aim of this review is to present the scientific rationale for long-term daily subcutaneous LMWH in cancer patients, and to reinforce the favourable benefit/tolerance tolerability ratio with this specific antithrombotic strategy.


Mating-type control in Saccharomyces cerevisiae: isolation and characterization of mutants defective in repression by a1-alpha 2.
The alpha 2 protein, the product of the MAT alpha 2 cistron, represses various genes specific to the a mating type (alpha 2 repression), and when combined with the MATa1 gene product, it represses MAT alpha 1 and various haploid-specific genes (a1-alpha 2 repression). One target of a1-alpha 2 repression is RME1, which is a negative regulator of a/alpha-specific genes. We have isolated 13 recessive mutants whose a1-alpha 2 repression is defective but which retain alpha 2 repression in a genetic background of ho MATa HML alpha HMRa sir3 or ho MAT alpha HMRa HMRa sir3. These mutations can be divided into three different classes. One class contains a missense mutation, designated hml alpha 2-102, in the alpha 2 cistron of HML, and another class contains two mat alpha 2-202, in the MAT alpha locus. These three mutants each have an amino acid substitution of tyrosine or acid substitution of tyrosine or phenylalanine for cysteine at the 33rd codon from the translation initiation codon in the alpha 2 cistron of HML alpha or MAT alpha. The remaining 10 mutants make up the third class and form a single complementation group, having mutations designated aar1 (a1-alpha 2 repression), at a gene other than MAT, HML, HMR, RME1, or the four SIR genes. Although a diploid cell homozygous for the aarl and sir3 mutations and for the MATa, HML alpha, and HMRa alleles showed alpha mating type, it could sporulate and gave rise to asci containing four alpha mating-type spores. These facts indicate that the domain for alpha2 repression is separable from that for a1-alpha2 protein interaction or complex formation in the alpha2 protein and that an additional regulation gene, AAR1, is associated with the a1-alpha2 repression of the alpha1 cistron and haploid-specific genes.


The effectiveness, safety and epidemiology of the use of acarbose in the treatment of patients with type II diabetes mellitus. A model of medicine-based evidence.
To assess the efficacy, safety and extent of perceived indications of acarbose, a new antidiabetic agent, under routine clinical practice conditions in an unselected Northern Italian population of type II diabetic patients. The study population was assigned to three different groups according to the physician's clinical judgement: group A (acarbose considered as an elective treatment); group B (acarbose considered to be of uncertain benefit): group C (acarbose deemed not to be appropriate). Group B patients were randomized either to continue their standard treatment or to add acarbose to it. Patients with type II diabetes mellitus were recruited from 17 diabetes outpatient clinics from one Italian region (Lombardy). A total of 1027 patients were recruited (group A: 283; group C: 494; group B: 250, of whom 124 were randomly assigned to standard treatment + acarbose and 126 to standard treatment alone). Acarbose was administered for 1 year at a median dose of 100 mg 3 times daily. Drug efficacy was evaluated in terms of mean HbAlc, pre- and post-prandial glycaemic values. Additional endpoints were the proportion of patients with HbA1c levels below 8% at the end of the study period and the proportion of subjects who needed a modification in the standard treatment. The safety and tolerability profiles of the drug were also investigated. Data on HbA1c, fasting and post-prandial blood glucose levels were analysed over time using repeated-measures analysis [Generalized Estimating Equation (GEE) models]. The analysis of Group B showed that, after treatment for 1 year, the mean reduction in HbA1c levels in the acarbose group with respect to the control group was 0.30% (95% confidence limits -0.60 +0.02; P = 0.07), while the mean reduction in post-prandial glycaemia was 17 mg-dl(-1) (95% c.l. -33.5 -0.8; P = 0.04). No difference resulted for fasting blood glucose levels. When looking at the baseline HbA1c levels, it emerged that the mean benefit associated with the use of acarbose was 0.14% (95% c.l. -0.6 +0.28; P = 0.5) in patients with HbAlc levels below 8%, 0.28% (95% c.l. -0.6 +0.05; P = 0.09) in those with values between 8% and 9.9% and 0.65% (95% c.l. -1.36 +0.06; P = 0.07) in those with values > or =10%. Only patients treated with diet+/-oral anti-diabetic agents (OAA) benefited from acarbose treatment (mean benefit = 0.37%, 95% c.l. -0.65 -0.08), while no effect was shown for insulin-treated subjects. The proportion of patients with HbA1c below 8% increased from 31% to 44% in the acarbose group and from 40% to 45% in the control group (absolute difference between baseline and end-of-study values = 8.0% in favour of acarbose-treated patients; P = 0.058). Patients treated with acarbose were significantly more likely to undergo a dose reduction in concomitant diabetic treatments compared with the control group; they were also less likely to require an increase in the dose of standard treatment and to start insulin during the study period. One third of the patients could not assume the drug for the whole study period, mainly due to gastrointestinal side-effects. The design adopted in this study allowed an integrated evaluation of the overall effectiveness of acarbose in clinical practice. The benefits of the drug in an unselected population of non-insulin-dependent diabetes mellitus (NIDDM) patients are significant but of marginal clinical relevance. Only a better definition of the subgroups of patients who are more likely to benefit from long-term treatment, particularly through possible postponement of secondary OAA failure, will allow a reliable definition of the cost-effectiveness of this complementary component of anti-diabetic strategy.


Does "community social capital" contribute to population health?
Robert Putnam showed that a social capital index, created as a weighted sum of 14 variables chosen to describe the civic degree of sociability and community mindedness, is correlated with many community outcomes, such as education, child well-being, crime, and the total mortality rate. Although correlation does not establish causation, we can find that in a large number of studies this index, a selection of its elements, or similar measures register as significantly correlated with health variables, virtually always in a direction consistent with the hypothesis that social capital improves health. The potential benefit of this relationship is substantial, especially if it proves to be robust to differences in time and place, statistical contexts, and ultimately if the relation can be supported to be causal. This paper subjects the social capital and health hypothesis to an expanded set of rigorous tests, which, by surviving, it becomes stronger or, by failing, its weaknesses are better revealed. The paper seeks to extend this body of research by a combination of study characteristics that are each relatively unusual in social capital and health research. Though causality cannot be established by these tests, the work shows that the association of social capital with health is quite robust when challenged in the following ways: (1) seven different health measures are studied, including five mortality rates; (2) the 48 contiguous states are observed at six points in time covering the years from 1978 to 1998 over four year intervals, thus forming a panel; (3) the multivariate tests feature economic variables from the production of health literature; and (4) a statistical method (instrumental variables) is applied to account for the possibility that omitted variables are confounding the social capital estimates. The results and the discussion find cases for which the social capital and health hypothesis performs only weakly, but, on the whole, the hypothesis is remarkably robust to these variations.


Evidence-based review for patients undergoing elective hip and knee replacement.
The objective of this study was to evaluate the evidence for different interventions in the preoperative, perioperative and post-operative care for people undergoing elective total hip (THR) and knee (TKR) replacement surgery. A multidisciplinary working group comprising consumers, managers and clinicians from the areas of orthopaedics, rheumatology, aged care and rehabilitation evaluated randomized controlled trials (RCTs) and systematic reviews/meta-analyses concerning aspects of preoperative, perioperative and post-operative clinical care periods for THR/TKR through systematic searching of Medline, Embase, CENTRAL and the Cochrane Database of Systematic Reviews from May 2007 to April 2011. Multiple reviewers determined study eligibility and one or more members extracted primary study findings. The body of evidence were assessed and specific recommendations made according to NHMRC guidelines. Twenty-five aspects were identified for review. Recommendations for 16 of 25 areas of care were made: impact of waiting, multidisciplinary preparation, preoperative exercise, smoking cessation, interventions for comorbid conditions, predictors of outcome, clinical pathways, implementation of a blood management programme, antibiotic prophylaxis, regional anaesthesia and analgesia, use of a tourniquet in knee replacement, venous thromboembolism prophylaxis, early post-operative cryotherapy, early mobilization and continuous passive motion. In the post-operative period, study heterogeneity across all aspects of care precluded specific recommendations. There was a deficiency in the quality of the evidence supporting key aspects of the continuum of care for primary THR/TKR surgery. Consequently, recommendations were limited. Prioritization and funding for research into areas likely to impact clinical practice and patient outcomes after elective joint replacement surgery are the next important steps.


Effect of Fluvoxamine on Amyloid-β Peptide Generation and Memory.
Alzheimer's disease is characterized by abnormal amyloid-β (Aβ) peptide accumulation beginning decades before symptom onset. An effective prophylactic treatment aimed at arresting the amyloidogenic pathway would therefore need to be initiated prior to the occurrence of Aβ pathology. The SIGMAR1 gene encodes a molecular chaperone that modulates processing of the amyloid-β protein precursor (AβPP). Fluvoxamine is a selective serotonin reuptake inhibitor and a potent SIGMAR1 agonist. We therefore hypothesized that fluvoxamine treatment would reduce Aβ production and improve cognition. We firstly investigated the impact of SIGMAR1 on AβPP processing, and found that overexpression and knockdown of SIGMAR1 significantly affected γ-secretase activity in SK-N-MC neuronal cells. We then tested the impact of fluvoxamine on Aβ production in an amyloidogenic cell model, and found that fluvoxamine significantly reduced Aβ production by inhibiting γ-secretase activity. Finally, we assessed the efficacy of long-term treatment (i.e., ∼8 months) of 10 mg/kg/day fluvoxamine in the J20 amyloidogenic mouse model; the treatment was initiated prior to the occurrence of predicted Aβ pathology. Physical examination of the animals revealed no overt pathology or change in weight. We conducted a series of behavioral tests to assess learning and memory, and found that the fluvoxamine treatment significantly improved memory function as measured by novel object recognition task. Two other tests revealed no significant change in memory function. In conclusion, fluvoxamine has a clear impact on γ-secretase activity and AβPP processing to generate Aβ, and may have a protective effect on cognition in the J20 mice.


Evaluation of a community pharmacy-based intervention for improving patient adherence to antihypertensives: a randomised controlled trial.
The majority of patients using antihypertensive medications fail to achieve their recommended target blood pressure. Poor daily adherence with medication regimens and a lack of persistence with medication use are two of the major reasons for failure to reach target blood pressure. There is no single intervention to improve adherence with antihypertensives that is consistently effective. Community pharmacists are in an ideal position to promote adherence to chronic medications. This study aims to test a specific intervention package that could be integrated into the community pharmacy workflow to enable pharmacists to improve patient adherence and/or persistence with antihypertensive medications--Hypertension Adherence Program in Pharmacy (HAPPY). The HAPPY trial is a multi-centre prospective randomised controlled trial. Fifty-six pharmacies have been recruited from three Australian states. To identify potential patients, a software application (MedeMine CVD) extracted data from a community pharmacy dispensing software system (FRED Dispense). The pharmacies have been randomised to either 'Pharmacist Care Group' (PCG) or 'Usual Care Group' (UCG). To check for 'Hawthorne effect' in the UCG, a third group of patients 'Hidden Control Group' (HCG) will be identified in the UCG pharmacies, which will be made known to the pharmacists at the end of six months. Each study group requires 182 patients. Data will be collected at baseline, three and six months in the PCG and at baseline and six months in the UCG. Changes in patient adherence and persistence at the end of six months will be measured using the self-reported Morisky score, the Tool for Adherence Behaviour Screening and medication refill data. To our knowledge, this is the first research testing a comprehensive package of evidence-based interventions that could be integrated into the community pharmacy workflow to enable pharmacists to improve patient adherence and/or persistence with antihypertensive medications. The unique features of the HAPPY trial include the use of MedeMine CVD to identify patients who could potentially benefit from the service, control for the 'Hawthorne effect' in the UCG and the offer of the intervention package at the end of six months to patients in the UCG, a strategy that is expected to improve retention. Australian New Zealand Clinical Trial Registry ACTRN12609000705280.


Power estimation for gene-longevity association analysis using concordant twins.
Statistical power is one of the major concerns in genetic association studies. Related individuals such as twins are valuable samples for genetic studies because of their genetic relatedness. Phenotype similarity in twin pairs provides evidence of genetic control over the phenotype variation in a population. The genetic association study on human longevity, a complex trait that is under control of both genetic and environmental factors, has been confronted by the small sample sizes of longevity subjects which limit statistical power. Twin pairs concordant for longevity have increased probability for carrying beneficial genes and thus are useful samples for gene-longevity association analysis. We conducted a computer simulation to estimate the power of association study using longevity concordant twin pairs. We observed remarkable power increases in using singletons from longevity concordant twin pairs as cases in comparison with cases of sporadic proband. A similar power would require doubled sample sizes for fraternal twins than for identical twins who are concordant for longevity suggesting that longevity concordant identical twins are more efficient samples than fraternal twins. We also observed an approximate of 2- to 3-fold increase in sample sizes needed for longevity cutoff at age 90 as compared with that at age 95. Overall, our results showed high value of twins in genetic association studies on human longevity.


Linkage-specific conformational ensembles of non-canonical polyubiquitin chains.
Polyubiquitination is a critical protein post-translational modification involved in a variety of processes in eukaryotic cells. The molecular basis for selective recognition of the polyubiquitin signals by cellular receptors is determined by the conformations polyubiquitin chains adopt; this has been demonstrated for K48- and K63-linked chains. Recent studies of the so-called non-canonical chains (linked via K6, K11, K27, K29, or K33) suggest they play important regulatory roles in growth, development, and immune system pathways, but biophysical studies are needed to elucidate the physical/structural basis of their interactions with receptors. A first step towards this goal is characterization of the conformations these chains adopt in solution. We assembled diubiquitins (Ub2) comprised of every lysine linkage. Using solution NMR measurements, small-angle neutron scattering (SANS), and in silico ensemble generation, we determined population-weighted conformational ensembles that shed light on the structure and dynamics of the non-canonical polyubiquitin chains. We found that polyubiquitin is conformationally heterogeneous, and each chain type exhibits unique conformational ensembles. For example, K6-Ub2 and K11-Ub2 (at physiological salt concentration) are in dynamic equilibrium between at least two conformers, where one exhibits a unique Ub/Ub interface, distinct from that observed in K48-Ub2 but similar to crystal structures of these chains. Conformers for K29-Ub2 and K33-Ub2 resemble recent crystal structures in the ligand-bound state. Remarkably, a number of diubiquitins adopt conformers similar to K48-Ub2 or K63-Ub2, suggesting potential overlap of biological function among different lysine linkages. These studies highlight the potential power of determining function from elucidation of conformational states.


Variable left-hemisphere language and orthographic lateralization reduces right-hemisphere face lateralization.
It is commonly believed that, in right-handed individuals, words and faces are processed by distinct neural systems: one in the left hemisphere (LH) for words and the other in the right hemisphere (RH) for faces. Emerging evidence suggests, however, that hemispheric selectivity for words and for faces may not be independent of each other. One recent account suggests that words become lateralized to the LH to interact more effectively with language regions, and subsequently, as a result of competition with words for representational space, faces become lateralized to the RH. On this interactive account, left-handed individuals, who as a group show greater variability with respect to hemispheric language dominance, might be expected to show greater variability in their degree of RH lateralization of faces as well. The current study uses behavioral measures and ERPs to compare the hemispheric specialization for both words and faces in right- and left-handed adult individuals. Although both right- and left-handed groups demonstrated LH over RH superiority in discrimination accuracy for words, only the right-handed group demonstrated RH over LH advantage in discrimination accuracy for faces. Consistent with this, increased right-handedness was related to an increase in RH superiority for face processing, as measured by the strength of the N170 ERP component. Interestingly, the degree of RH behavioral superiority for face processing and the amplitude of the RH N170 for faces could be predicted by the magnitude of the N170 ERP response to words in the LH. These results are discussed in terms of a theoretical account in which the typical RH face lateralization fails to emerge in individuals with atypical language lateralization because of weakened competition from the LH representation of words.


Adult male nutrition and reproductive success in Drosophila melanogaster.
Explanations for the maintenance of variation in reproductive traits influenced by seminal fluid accessory gland proteins (Acps) in male Drosophila melanogaster include nontransitivity in the outcome of sperm competition and/or condition dependence of the traits involved. We investigated the effects of adult male nutrition (five diets) on the expression of Acp- and sperm- mediated traits. We found novel, nonlinear effects, with females showing lower levels of refractoriness to remating after mating with males held on the lowest and highest yeast diets. There were no significant effects of adult male nutrition on male paternity share, but there was a striking, nonlinear effect on second male progeny production, with males kept on intermediate yeast diets fathering the highest number of offspring. Such "bell shaped" responses of life-history traits to nutrition have only previously been reported for longevity. Consistent with previous reports, males maintained on low protein diets had lower premating success and gained fewer rematings with nonvirgins. We show novel and body size independent effects of adult male nutrition on traits influenced by Acps and sperm, which do not fit current condition-dependent handicap models and can affect the strength of sexual selection acting upon such fitness-related traits.


Comparison of the caudal and lumbar approaches to the epidural space.
To investigate the accuracy of placement of epidural injections using the lumbar and caudal approaches. To identify which factors, if any, predicted successful placement. 200 consecutive patients referred to a pain clinic for an epidural injection of steroid were randomly allocated to one of two groups. Group L had a lumbar approach to the epidural space and group C a caudal approach to the epidural space. Both groups then had epidurography performed using Omnipaque and an image intensifier to determine the position of the needle. Body mass index (BMI), grade of operator, and route of injection were predictors of a successful placement. 93% of lumbar and 64% of caudal epidural injections were correctly placed (p< 0.001). 97% of lumbar and 85% of caudal epidural injections clinically thought to be correctly placed were confirmed radiographically. For epidural injections where the clinical impression was "maybe", 91% of lumbar injections, but only 45% of caudal injections were correctly placed. Obesity was associated with a reduced chance of successful placement (odds ratio (OR) 0.34 (95% confidence interval (CI) 0.17 to 0.72) BMI >30 v BMI <30). A more senior grade of operator was associated with a reduced chance of successful placement (OR 0.16 (95% CI 0.03 to 0.89) consultant v other). However, small numbers may have accounted for the latter result. The weight of the patient and intended approach need to be considered when deciding the method used to enter the epidural space. In the non-obese patient, lumbar epidural injections can be accurately placed without x ray screening, but caudal epidural injections, to be placed accurately, require x ray screening no matter what the weight of the patient.


The effects of dietary cholesterol-lowering on psychological symptoms: a randomised controlled study.
The relationship of plasma cholesterol-reducing interventions to emotional states, such as depression and hostility, remains a topic of debate. The present study employed a randomised, controlled design, and was conducted at a clinical research center to test the effect of dietary cholesterol-lowering on psychological symptoms. Ten women and eight men were randomly assigned to one of two counterbalanced diet cycles (low-fat versus high-fat diet; isocaloric; 6 weeks each; separated by a washout period). Analyses for repeated measures revealed that the low-fat diet significantly reduced total, LDL and HDL cholesterol, when compared with baseline and the high-fat diet. As expected, weight remained unchanged. Ratings of depression, hostility and global severity of psychological symptoms as measured by the SCL-90-R also improved significantly on the low-fat, high-complex carbohydrate diet when compared with baseline. These results suggest that plasma cholesterol-lowering in the context of a low-fat, high-complex carbohydrate diet may have a beneficial effect on psychological symptoms.


A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects.
Animal studies suggest a positive role for nicotinamide riboside (NR) on insulin sensitivity and hepatic steatosis in models of obesity and type 2 diabetes. NR, an NAD+ precursor, is a member of the vitamin B-3 family now available as an over-the-counter supplement. Although data from preclinical trials appear consistent, potential effects and safety need to be evaluated in human clinical trials. The aim of this study was to test the safety of dietary NR supplementation over a 12-wk period and potential to improve insulin sensitivity and other metabolic parameters in obese, insulin-resistant men. In an investigator-initiated randomized, placebo-controlled, double-blinded, and parallel-group designed clinical trial, forty healthy, sedentary men with a body mass index (BMI) > 30 kg/m2, age-range 40-70 y were randomly assigned to 12 wk of NR (1000 mg twice daily) or placebo. We determined the effects of NR supplementation on insulin sensitivity by a hyperinsulinemic euglycemic clamp and substrate metabolism by indirect calorimetry and labeled substrates of tritiated glucose and palmitate. Body composition and fat mass distribution were determined by whole-body dual-energy X-ray absorptiometry (DXA) and MRI scans, and measurements of intrahepatic lipid content were obtained by MR spectroscopy. Insulin sensitivity, endogenous glucose production, and glucose disposal and oxidation were not improved by NR supplementation. Similarly, NR supplementation had no effect on resting energy expenditure, lipolysis, oxidation of lipids, or body composition. No serious adverse events due to NR supplementation were observed and safety blood tests were normal. 12 wk of NR supplementation in doses of 2000 mg/d appears safe, but does not improve insulin sensitivity and whole-body glucose metabolism in obese, insulin-resistant men. This trial was registered at clinicaltrials.gov as NCT02303483.


Papillary fill response in single-tooth implants using abutments of different geometry.
To evaluate the influence of abutment geometry on papillary fill in the esthetic zone in a delayed crown protocol. Twenty-six subjects received two non-adjacent endosseous implants in the esthetic zone. Functional temporary crowns were installed 17-19 weeks later, using conventional (control) and curved (experimental) abutments. The abutments were randomized in each patient independently. Final crowns were cemented after 2 months (T0). Standard intraoral photographs and radiographs were made to evaluate papillary fill after 12 months (T12). The interproximal papilla fill was measured by means of the papilla index score (PIS) and related to the maximum bone level between the implant and the adjacent root as well as the peri-implant marginal bone level at T12, both measured radiographically. No statistically significant difference between the experimental and the control group could be demonstrated (P = 0.25). Ordinal regression analysis showed a positive correlation between the maximum bone level and papilla fill (P < 0.01) and a negative correlation between the peri-implant marginal bone level and papilla fill (P < 0.05). A concave abutment does not exhibit a better fill of the papilla compared with a straight abutment in single-tooth implant placement using a delayed protocol in the esthetic zone after 12 months of function.


Noninvasive detection of vertebral artery dissection.
We sought to identify the use of duplex and transcranial Doppler sonography in the noninvasive diagnosis of vertebral dissection. Ten patients with a diagnosis of symptomatic vertebral artery dissection confirmed by cerebral angiography were retrospectively analyzed. Computed tomographic scanning and magnetic resonance imaging together delineated lateral medullary or cerebellar infarcts in 7 patients. Angiography documented a total of 21 vertebral artery lesions (16 stenoses and 5 occlusions), with 7 of 10 patients having multiple sites of vertebral artery dissection. Vertebral Doppler was abnormal in 8 of the 10 patients. A high resistance signal in the relevant vertebral artery was found in 6 patients, no flow in a well-imaged vertebral artery in 1, and bilateral retrograde vertebral artery flow in 1 patient. Transcranial Doppler was abnormal in only 2 patients, with reduced pulsatility index in 1 and high resistance vertebral signal in another. A hyperintense intramural signal of the affected vertebral artery by magnetic resonance imaging was documented in 1 patient in whom Doppler sonography was nondiagnostic. Vertebral artery dissection can be detected and monitored by noninvasive vertebral Doppler and magnetic resonance imaging in the setting of a clinically suggestive presentation.


Basins of coexistence and extinction in spatially extended ecosystems of cyclically competing species.
Microscopic models based on evolutionary games on spatially extended scales have recently been developed to address the fundamental issue of species coexistence. In this pursuit almost all existing works focus on the relevant dynamical behaviors originated from a single but physically reasonable initial condition. To gain comprehensive and global insights into the dynamics of coexistence, here we explore the basins of coexistence and extinction and investigate how they evolve as a basic parameter of the system is varied. Our model is cyclic competitions among three species as described by the classical rock-paper-scissors game, and we consider both discrete lattice and continuous space, incorporating species mobility and intraspecific competitions. Our results reveal that, for all cases considered, a basin of coexistence always emerges and persists in a substantial part of the parameter space, indicating that coexistence is a robust phenomenon. Factors such as intraspecific competition can, in fact, promote coexistence by facilitating the emergence of the coexistence basin. In addition, we find that the extinction basins can exhibit quite complex structures in terms of the convergence time toward the final state for different initial conditions. We have also developed models based on partial differential equations, which yield basin structures that are in good agreement with those from microscopic stochastic simulations. To understand the origin and emergence of the observed complicated basin structures is challenging at the present due to the extremely high dimensional nature of the underlying dynamical system.


Identifying protein interaction subnetworks by a bagging Markov random field-based method.
Identification of differentially expressed subnetworks from protein-protein interaction (PPI) networks has become increasingly important to our global understanding of the molecular mechanisms that drive cancer. Several methods have been proposed for PPI subnetwork identification, but the dependency among network member genes is not explicitly considered, leaving many important hub genes largely unidentified. We present a new method, based on a bagging Markov random field (BMRF) framework, to improve subnetwork identification for mechanistic studies of breast cancer. The method follows a maximum a posteriori principle to form a novel network score that explicitly considers pairwise gene interactions in PPI networks, and it searches for subnetworks with maximal network scores. To improve their robustness across data sets, a bagging scheme based on bootstrapping samples is implemented to statistically select high confidence subnetworks. We first compared the BMRF-based method with existing methods on simulation data to demonstrate its improved performance. We then applied our method to breast cancer data to identify PPI subnetworks associated with breast cancer progression and/or tamoxifen resistance. The experimental results show that not only an improved prediction performance can be achieved by the BMRF approach when tested on independent data sets, but biologically meaningful subnetworks can also be revealed that are relevant to breast cancer and tamoxifen resistance.


Frequency of bleb manipulations after trabeculectomy surgery.
To quantify the type and frequency of postoperative bleb manipulations undertaken after modern glaucoma surgery. Bleb manipulations were recorded after trabeculectomy surgery on 119 consecutive patients with at least 1 year of follow-up. The type of intervention and time after surgery were recorded. Statistical analysis identified success rates at various intraocular pressure (IOP) cut-off definitions and identified factors that increased the risk for bleb manipulation. In all, 78.2% of trabeculectomies were followed by some form of bleb manipulation. Almost 49% of blebs underwent massage and a similar number required at least one suture removal, 31.1% required at least one 5-fluorouracil (5-FU) injection and 25.2% required at least one needling and 5-FU injection. The median time to the first intervention for massage, suture removal, 5-FU injection, and needling and 5-FU injection were 1, 14, 14 and 43 days, respectively. IOP measurements were higher at all follow-up time points in the intervention group. Failure to achieve specific IOP target pressures was also generally poorer in the 5-FU, and needling and 5-FU intervention groups. Postoperative intervention is a frequent occurrence after modern glaucoma surgery. This requires intensive postoperative follow-up and is a labour-intensive undertaking. Despite interventions in our group of patients, IOP in the intervention group was always higher than in the group that required no intervention.


Primary hyperparathyroidism: diagnosis and management.
To review the manifestations of primary hyperparathyroidism and the available treatment strategies. The epidemiologic and pathologic features of this endocrine disorder are outlined. Guidelines for surgical intervention are discussed, and the effectiveness of various medical treatments is summarized. Primary hyperparathyroidism, a common disorder, is diagnosed on the basis of hypercalcemia in the presence of increased parathyroid hormone levels as measured by immunoassay. Clinical manifestations are variable with many patients being asymptomatic at the time of diagnosis. Patients with severe disease require definitive surgical treatment. Surgical cure rates are high--approximately 95% in experienced hands. Indications for surgery include a serum calcium of more than 2.9 mmol/L (12 mg/dL), osteoporosis, recurrent renal stones, and parathyroid carcinoma. As well, it is recommend in individuals younger than 50 years of age. Patients with mild disease may have a benign natural history and may not have progression to severe disease. Asymptomatic individuals with mild hypercalcemia and close to normal bone mass and renal function may be managed medically, particularly those who are over the age of 50 years. Medical management includes ensuring adequate hydration and avoiding volume depletion. Estrogen therapy is valuable in postmenopausal women without contraindications to hormone replacement. Calcitonin has been shown to decrease serum calcium levels on a short-term basis. Bisphosphonates are also potential treatment options and require further study. Calcium-mimetic agents also may become valuable in the medical management of primary hyperparathyroidism in the near future. As primary hyperparathyroidism is being increasingly detected at an asymptomatic stage, medical therapy is assuming a greater role in the effective management of this common condition.


Excited-state proton transfer in complexes of poly(methacrylic acid) with dodecyltrimethylammonium chloride.
Proton-transfer reactions in aqueous solutions of poly(methacrylic acid) (PMA) were studied using a fluorescent probe and Fourier transform infrared (FTIR) spectroscopy. Protolytic photodissociation of 1-hydroxypyrene (HP) in water was found to be very slow. The PMA polyanion appeared to be very inefficient as a proton acceptor in the excited-state reaction with HP. However, a drastic increase in the deprotonation efficiency was observed in PMA solutions with the same pH values close to neutral when dodecyltrimethylammonium chloride (DTAC) was added. The protonated form of HP, as well as its anion, was shown to be solubilized in polyion-covered micelles. Time-resolved fluorescence data suggested at least two localization sites with different reactivities toward PMA. FTIR spectroscopy was used to quantify the degree of ionization of PMA in PMA-DTAC mixtures. The IR data indicated that protolytic dissociation of PMA could be well described by the Henderson-Hasselbach equation with an apparent pK of 6.6. In contrast, the fluorescent data revealed cooperative protonation of the PMA groups interacting with HP localized within surfactant assemblies. This selective protonation at a pH close to neutral may be associated with a conformational transition in the polymer-surfactant complex.


6-thioguanine: a drug with unrealized potential for cancer therapy.
Sixty years ago, 6-thioguanine (6-TG) was introduced into the clinic. We suggest its full potential in therapy may not have been reached. In this paper, we contrast 6-TG and the more widely used 6-mercaptopurine; discuss 6-TG metabolism, pharmacokinetics, dosage and schedule; and summarize many of the early studies that have shown infrequent but nevertheless positive results with 6-TG treatment of cancers. We also consider studies that suggest that combinations of 6-TG with other agents may enhance antitumor effects. Although not yet tested in man, 6-TG has recently been proposed to treat a wide variety of cancers with a high frequency of homozygous deletion of the gene for methylthioadenosine phosphorylase (MTAP), often codeleted with the adjacent tumor suppressor CDKN2A (p16). Among the cancers with a high frequency of MTAP deficiency are leukemias, lymphomas, mesothelioma, melanoma, biliary tract cancer, glioblastoma, osteosarcoma, soft tissue sarcoma, neuroendocrine tumors, and lung, pancreatic, and squamous cell carcinomas. The method involves pretreatment with the naturally occurring nucleoside methylthioadenosine (MTA), the substrate for the enzyme MTAP. MTA pretreatment protects normal host tissues, but not MTAP-deficient cancers, from 6-TG toxicity and permits administration of doses of 6-TG that are much higher than can now be safely administered. The combination of MTA/6-TG has produced substantial shrinkage or slowing of growth in two different xenograft human tumor models: lymphoblastic leukemia and metastatic prostate carcinoma with neuroendocrine features. Further development and a clinical trial of the proposed MTA/6-TG treatment of MTAP-deficient cancers seem warranted.


Low cholesterol is not always good: low cholesterol levels are associated with decreased serotonin and increased aggression in fish.
The inverse relationship between serum cholesterol and levels of aggression led to the cholesterol-serotonin hypothesis. According to this hypothesis, low dietary cholesterol intake leads to depressed central serotonergic activity, which is associated with increased aggression. Here we present the hypothesis about the evolutionary origins of low cholesterol and aggressive behavior, investigating the relationship between low levels of plasma cholesterol and aggressive behavior in fish. We used Nile tilapia (Oreochromis niloticus), a species of aggressive fish with a clear dominant subordinate relation, as an experimental model. The fish were treated with statin, a cholesterol-lowering drug. Aggressive behavior, brain serotonin (5-HT) concentrations, 5-hydroxyindoleacetic acid (5-HIAA, the major 5-HT metabolite) and plasma cholesterol were analyzed after chronic administration of statin. Our results show that fish treated with statin exhibited reduced plasma cholesterol, reduced telencephalic indexes of 5-HIAA/5-HT and increased aggressive behavior compared to control fish. These results indicate that changes in plasma cholesterol may affect neurochemical processes underlying aggressive behavior in fish, suggesting an evolutionary mechanism conserved among vertebrates. Such mechanisms may be important for the control of aggression in many vertebrate species, not just mammals, as has been demonstrated so far.


Association of primary ovarian insufficiency with a specific human leukocyte antigen haplotype (A*24:02-C*03:03-B*35:01) in Japanese women.
Primary ovarian insufficiency (POI) is a heterogeneous condition defined by the triad of oligo/amenorrhea, elevated gonadotropins and estrogen deficiency in women under the age of 40 years. Although autoimmune abnormalities appear to be involved in the development of POI, there are only a few studies with respect to human leukocyte antigen (HLA). The objective of this study was to identify an HLA allele(s) and/or haplotype(s) constituting a susceptibility factor(s) for POI. We examined 83 Japanese women with apparently idiopathic isolated POI. For controls, Japanese HLA reference data registered in the HLA Laboratory were utilized. No significant association was found for a total of 94 alleles for HLA-A, B, C, DRB1, and DQB1 loci, after both stringent Bonferroni correction and less stringent Benjamini- Hochberg (B-H) correction for multiple comparisons. By contrast, of 86 haplotypes identified for MHC class I (HLA-A, B, and C) and 31 haplotypes detected for MHC class II (HLA-DRB1 and DQB1), a single haplotype (A*24:02-C*03:03-B*35:01) remained significant after Bonferroni and B-H corrections (frequency: 4.82% in women with POI and 1.06% in the control data; p = 0.00049). The results imply that a specific HLA haplotype (A*24:02-C*03:03-B*35:01) constitutes a susceptibility factor for apparently isolated POI in Japanese women.


Factors Associated With Home Visits in a 5-Year Study of Acute Respiratory Distress Syndrome Survivors.
Participant retention is vital for longitudinal studies. Home visits may increase retention, but little is known about the subset of patients they benefit. To evaluate patient-related variables associated with home visits. In a 5-year, longitudinal, multisite, prospective study of 195 survivors of acute respiratory distress syndrome, in-person assessments were conducted at a research clinic. Home visits were offered to participants who could not attend the clinic. Associations between having a home visit, prior follow-up visit status, and baseline and in-hospital patient variables were evaluated with multivariable, random-intercept logistic regression models. The association between home visits and patients' posthospital clinical status was evaluated with a subsequent regression model adjusted for these variables. Participants had a median age of 49 years and were 56% male and 58% White. The following had independent associations with home visits (adjusted odds ratio [95% CI]): age (per year: 1.03 [1.00-1.05]) and immediately preceding visit incomplete (2.46 [1.44-4.19]) or at home (8.24 [4.57-14.86]). After adjustment for prior-visit status and baseline and hospitalization variables, these posthospital patient outcome variables were associated with a subsequent home visit: instrumental activities of daily living (≥ 2 vs < 2 dependencies: 2.32 [1.29-4.17]), EQ-5D utility score (per 0.1-point decrease: 1.15 [1.02-1.30]), and 6-minute walk test (per 10-percentage-point decrease in percent-predicted distance: 1.50 [1.26-1.79]). Home visits were important for retaining older and more physically impaired study participants, helping reduce selection bias caused by excluding them.


Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism.
Causes of autism are unknown. Associations with maternal nutritional factors and their interactions with gene variants have not been reported. Northern California families were enrolled from 2003 to 2009 in the CHARGE (CHildhood Autism Risks from Genetics and Environment) population-based case-control study. Children aged 24-60 months were evaluated and confirmed to have autism (n = 288), autism spectrum disorder (n = 141), or typical development (n = 278) at the University of California-Davis Medical Investigation of Neurodevelopmental Disorders Institute using standardized clinical assessments. We calculated adjusted odds ratios (ORs) for associations between autism and retrospectively collected data on maternal vitamin intake before and during pregnancy. We explored interaction effects with functional genetic variants involved in one-carbon metabolism (MTHFR, COMT, MTRR, BHMT, FOLR2, CBS, and TCN2) as carried by the mother or child. Mothers of children with autism were less likely than those of typically developing children to report having taken prenatal vitamins during the 3 months before pregnancy or the first month of pregnancy (OR = 0.62 [95% confidence interval = 0.42-0.93]). Significant interaction effects were observed for maternal MTHFR 677 TT, CBS rs234715 GT + TT, and child COMT 472 AA genotypes, with greater risk for autism when mothers did not report taking prenatal vitamins periconceptionally (4.5 [1.4-14.6]; 2.6 [1.2-5.4]; and 7.2 [2.3-22.4], respectively). Greater risk was also observed for children whose mothers had other one-carbon metabolism pathway gene variants and reported no prenatal vitamin intake. Periconceptional use of prenatal vitamins may reduce the risk of having children with autism, especially for genetically susceptible mothers and children. Replication and mechanistic investigations are warranted.


Biophysical and pharmacological characterization of voltage-gated calcium currents in turtle auditory hair cells.
Hair cell calcium channels regulate membrane excitability and control synaptic transmission. The present investigations focused on determining whether calcium channels vary between hair cells of different characteristic frequencies or if multiple channel types exist within a hair cell, each serving a different function. To this end, turtle auditory hair cells from high- (317 +/- 27 Hz) and low-frequency (115 +/- 6 Hz) positions were voltage clamped using the whole-cell recording technique, and calcium currents were characterized based on activation, inactivation and pharmacological properties. Pharmacological sensitivity to dihydropyridines (nimodipine, Bay K 8644), benzothiazepines (diltiazem) and acetonitrile derivatives (verapamil, D600) and the insensitivity to non-L-type calcium channel antagonists support the conclusion that only L-type calcium channels were present. Fast activation rise times (< 0.5 ms), hyperpolarized half-activation potentials and a relative insensitivity to nimodipine suggest the channels were of the alpha1D (CaV1.3) variety. Although no pharmacological differences were found between calcium currents obtained from high- and low-frequency cells, low-frequency cells activated slightly faster and at hyperpolarized potentials, with half-activating voltages of -43 +/- 1 mV compared to -35 +/- 1 mV. Inactivation was observed in both high- and low-frequency cells. The time course of inactivation required three time constants for a fit. Long depolarizations could result in complete inactivation. The voltage of half-inactivation was -40 +/- 2 mV for high-frequency cells and -46 +/- 2 mV for low-frequency cells. Calcium channel inactivation did not significantly alter hair cell electrical resonant properties elicited from protocols where the membrane potential was hyperpolarized or depolarized prior to characterizing the resonance. A bell-shaped voltage dependence and modest sensitivities to intracellular calcium chelators and external barium ions suggest that inactivation was calcium dependent.


Intersectionality Research for Transgender Health Justice: A Theory-Driven Conceptual Framework for Structural Analysis of Transgender Health Inequities.
Transgender people experience intersecting forms of social marginalization and are disproportionately affected by health inequities. We elucidate a novel conceptual framework for transgender health research that theorizes the constructs and pathways through which social inequities produce health inequities for transgender populations. Drawing on theories of intersectionality and structural injustice, Intersectionality Research for Transgender Health Justice (IRTHJ) posits that social and health inequities affecting transgender populations are the result of status quo power relations produced within and between oppressive structures, institutional systems, and socio-structural processes. The IRTHJ framework delineates three main actions for improving transgender health research: (i) name intersecting power relations, (ii) disrupt the status quo, and (iii) center embodied knowledge. The authors show how IRTHJ provides tools for researchers to transform the design, implementation, and interpretation of transgender health research, and they discuss implications for programs, policy, and action for transgender health justice.


Single origin and subsequent diversification of central Andean endemic Umbilicaria species.
We studied an Andean endemic group of species of the lichen-forming fungal genus Umbilicaria from the subalpine and low-alpine zone, with their biogeographic center in Bolivia and Peru. A number of species and varieties have been described from this element, but apparent instability in several morphological traits has made it difficult to precisely delimit taxa. Based on DNA sequences of nuclear ITS, LSU and mitochondrial SSU from extensive collections from Argentina, Bolivia, Chile, Colombia, Ecuador and Peru, we present here a molecular phylogenetic analysis of this Andean endemic element within genus Umbilicaria. All analyses (MP, ML and Bayesian) support a single origin for the element and a division into two major groups characterized by different apothecium types: the Umbilicaria dichroa group and U. calvescens group. Taxa U. krempelhuberi, U. peruviana and U. subcalvescens are nested withinn U. calvescens and are treated as conspecific with the latter species. The endemic element shares a most recent common ancestor with the Umbilicaria vellea group, which has a worldwide distribution and contains several asexually reproducing (sorediate) species. Independent reversals to sexual reproduction might explain the evolution of two types of apothecia in this monophyletic endemic lineage. A number of cosmopolitan, mostly high-alpine, species of Umbilicaria also present in the central Andes are related only remotely to the endemic element and do not exhibit speciation into endemics. Because the An-dean element dominates the Umbilicaria habitats of the low- and subalpine zones we propose that the founder colonized the Andes at a time when the mountains had not yet reached their current elevation while the high-alpine species arrived more recently.


Population status of a cryptic top predator: an island-wide assessment of tigers in Sumatran rainforests.
Large carnivores living in tropical rainforests are under immense pressure from the rapid conversion of their habitat. In response, millions of dollars are spent on conserving these species. However, the cost-effectiveness of such investments is poorly understood and this is largely because the requisite population estimates are difficult to achieve at appropriate spatial scales for these secretive species. Here, we apply a robust detection/non-detection sampling technique to produce the first reliable population metric (occupancy) for a critically endangered large carnivore; the Sumatran tiger (Panthera tigris sumatrae). From 2007-2009, seven landscapes were surveyed through 13,511 km of transects in 394 grid cells (17×17 km). Tiger sign was detected in 206 cells, producing a naive estimate of 0.52. However, after controlling for an unequal detection probability (where p = 0.13±0.017; ±S.E.), the estimated tiger occupancy was 0.72±0.048. Whilst the Sumatra-wide survey results gives cause for optimism, a significant negative correlation between occupancy and recent deforestation was found. For example, the Northern Riau landscape had an average deforestation rate of 9.8%/yr and by far the lowest occupancy (0.33±0.055). Our results highlight the key tiger areas in need of protection and have led to one area (Leuser-Ulu Masen) being upgraded as a 'global priority' for wild tiger conservation. However, Sumatra has one of the highest global deforestation rates and the two largest tiger landscapes identified in this study will become highly fragmented if their respective proposed roads networks are approved. Thus, it is vital that the Indonesian government tackles these threats, e.g. through improved land-use planning, if it is to succeed in meeting its ambitious National Tiger Recovery Plan targets of doubling the number of Sumatran tigers by 2022.


Impact of smoking and other lifestyle factors on life expectancy among japanese: findings from the Japan Collaborative Cohort (JACC) Study.
A number of lifestyle factors, including smoking and drinking, are known to be independently associated with all-cause mortality. However, it might be more effective in motivating the public to adopt a healthier lifestyle if the combined effect of several lifestyle factors on all-cause mortality could be demonstrated in a straightforward manner. We examined the combined effects of 6 healthy lifestyle behaviors on all-cause mortality by estimating life expectancies at 40 and 60 years of age among 62 106 participants in a prospective cohort study with a 14.5-year follow-up. The healthy behaviors selected were current nonsmoking, not heavily drinking, walking 1 hour or more per day, sleeping 6.5 to 7.4 hours per day, eating green leafy vegetables almost daily, and having a BMI between 18.5 to 24.9. At age 40, we found a 10.3-year increase in life expectancy for men and a 8.3-year increase for women who had all 6 healthy behaviors, as compared with those who had only 0 to 2 healthy behaviors. Increases of 9.6 and 8.2 years were observed for men and women, respectively, at age 60 with all 6 healthy behaviors. When comparing currently nonsmoking individuals with 0 to 1 healthy behaviors, the life expectancy of smokers was shorter in both men and women, even if they maintained all 5 other healthy behaviors. Among individuals aged 40 and 60 years, maintaining all 6 healthy lifestyle factors was associated with longer life expectancy. Smokers should be encouraged to quit smoking first and then to maintain or adopt the other 5 lifestyle factors.


Cueing vocabulary during sleep increases theta activity during later recognition testing.
Neural oscillations in the theta band have repeatedly been implicated in successful memory encoding and retrieval. Several recent studies have shown that memory retrieval can be facilitated by reactivating memories during their consolidation during sleep. However, it is still unknown whether reactivation during sleep also enhances subsequent retrieval-related neural oscillations. We have recently demonstrated that foreign vocabulary cues presented during sleep improve later recall of the associated translations. Here, we examined the effect of cueing foreign vocabulary during sleep on oscillatory activity during subsequent recognition testing after sleep. We show that those words that were replayed during sleep after learning (cued words) elicited stronger centroparietal theta activity during recognition as compared to noncued words. The reactivation-induced increase in theta oscillations during later recognition testing might reflect a strengthening of individual memory traces and the integration of the newly learned words into the mental lexicon by cueing during sleep.


Cost effectiveness of tiotropium for chronic obstructive pulmonary disease: a systematic review of the evidence.
Tiotropium has been shown to reduce exacerbations and improve quality of life for patients with chronic obstructive pulmonary disease (COPD), a lung disease characterized by a persistent and progressive airflow limitation. To present a systematic literature review of the cost effectiveness of treatment with tiotropium compared with other currently used treatments for COPD. A systematic search was performed via PubMed, the Cochrane database, and EMBASE from 2002 to 2009. Methods and results by study design and by country were compared. Seventeen studies were included in the review. Study designs were characterized as follows: modeling based on clinical trial data, and empirical analysis based on either clinical trial or observational data. Comparing monotherapy regimens (12 studies), all study designs found that treatment with tiotropium was associated with lower costs for hospitalisation and other non-drug services. Total costs, including the costs of maintenance drugs, were lower with tiotropium in some, but not all, of the studies. Tiotropium was shown to be cost effective based on commonly accepted benchmark values. Limitations of the review included the wide variety of outcome measures used in different studies, the limited number of observational database studies for monotherapy, and limited data for combination therapy regimens. The main conclusions of the economic evaluations derived from clinical trial data at the time of product approval and from later observational data reflecting clinical use are similar: use of tiotropium monotherapy is associated with lower hospital and other non-drug costs and better health outcomes and is either cost saving or cost effective compared with other maintenance monotherapies.