Discovery of dominant and dormant genes from expression data using a novel generalization of SNR for multi-class problems.
The Signal-to-Noise-Ratio (SNR) is often used for identification of biomarkers for two-class problems and no formal and useful generalization of SNR is available for multiclass problems. We propose innovative generalizations of SNR for multiclass cancer discrimination through introduction of two indices, Gene Dominant Index and Gene Dormant Index (GDIs). These two indices lead to the concepts of dominant and dormant genes with biological significance. We use these indices to develop methodologies for discovery of dominant and dormant biomarkers with interesting biological significance. The dominancy and dormancy of the identified biomarkers and their excellent discriminating power are also demonstrated pictorially using the scatterplot of individual gene and 2-D Sammon's projection of the selected set of genes. Using information from the literature we have shown that the GDI based method can identify dominant and dormant genes that play significant roles in cancer biology. These biomarkers are also used to design diagnostic prediction systems. To evaluate the effectiveness of the GDIs, we have used four multiclass cancer data sets (Small Round Blue Cell Tumors, Leukemia, Central Nervous System Tumors, and Lung Cancer). For each data set we demonstrate that the new indices can find biologically meaningful genes that can act as biomarkers. We then use six machine learning tools, Nearest Neighbor Classifier (NNC), Nearest Mean Classifier (NMC), Support Vector Machine (SVM) classifier with linear kernel, and SVM classifier with Gaussian kernel, where both SVMs are used in conjunction with one-vs-all (OVA) and one-vs-one (OVO) strategies. We found GDIs to be very effective in identifying biomarkers with strong class specific signatures. With all six tools and for all data sets we could achieve better or comparable prediction accuracies usually with fewer marker genes than results reported in the literature using the same computational protocols. The dominant genes are usually easy to find while good dormant genes may not always be available as dormant genes require stronger constraints to be satisfied; but when they are available, they can be used for authentication of diagnosis. Since GDI based schemes can find a small set of dominant/dormant biomarkers that is adequate to design diagnostic prediction systems, it opens up the possibility of using real-time qPCR assays or antibody based methods such as ELISA for an easy and low cost diagnosis of diseases. The dominant and dormant genes found by GDIs can be used in different ways to design more reliable diagnostic prediction systems.


Influence of diurnal photosynthetic activity on the morphology, structure, and thermal properties of normal and waxy barley starch.
This study investigated the influence of diurnal photosynthetic activity on the morphology, molecular composition, crystallinity, and gelatinization properties of normal barley starch (NBS) and waxy barley starch (WBS) granules from plants cultivated in a greenhouse under normal diurnal (16h light) or constant light photosynthetic conditions. Growth rings were observed in all starch samples regardless of lighting conditions. The size distribution of whole and debranched WBS analyzed by gel-permeation chromatography did not appear to be influenced by the different lighting regimes, however, a greater relative crystallinity measured by wide-angle X-ray scattering and greater crystalline quality as judged by differential scanning calorimetry was observed under the diurnal lighting regime. NBS cultivated under the diurnal photosynthetic lighting regime displayed lower amylose content (18.7%), and shorter amylose chains than its counterpart grown under constant light. Although the relative crystallinity of NBS was not influenced by lighting conditions, lower onset, peak, and completion gelatinization temperatures were observed in diurnally grown NBS compared to constant light conditions. It is concluded that normal barley starch is less influenced by the diurnal photosynthetic lighting regime than amylose-free barley starch suggesting a role of amylose to prevent structural disorder and increase starch granule robustness against environmental cues.


Auxin transport in membrane vesicles from Cucurbita pepo L.
Association of (14)C-labelled indole-3-acetic acid (IAA) with membrane particles from zucchini (Cucurbita pepo L.) hypocotyls - previously described as "site III binding" (M. Jacobs and R. Hertel, 1978, Planta 142, 1-10) - is reinterpreted as a carrier-mediated uptake into closed and sealed vesicles driven by a pH gradient. Accumulation of the radioactive auxin is saturable, sensitive to the protonophore, carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (FCCP), and to nigericin, and requires a pH gradient across the membranes with proton concentration greater outside than inside. The pH gradient decays within 1-2 h at 4°C and can be restored by re-equilibration of the particle preparation at more alkaline pH followed by return to more acidic medium. Osmotic shock and sonication release the IAA from the vesicles. 1-N-naphthylphthalamic acid (NPA) and 2,3,5-triiodobenzoic acid (TIBA), both inhibitors of auxin transport in vivo, increase the amount of net IAA accumulation in the vesicles, presumably by blocking efflux. Analogs of NPA less active or inactive in vivo are respectively less active or inactive in vitro. It is proposed that these membrane particles are outside-out plasma membrane vesicles, and that they perform the essential functions of auxin transport according to the chemiosmotic theory, with a specific, saturable proton symport uptake and an export anion carrier which is inhibited by NPA and TIBA.


Optimization of the pulse-width of diode-pumped passively Q-switched mode-locked c-cut Nd:GdVO4 laser with a GaAs saturable absorber.
By considering the single-photon absorption and two-photon absorption processes in the GaAs saturable absorber, the coupled rate equations for a diode-pumped passively Q-switched and mode-locked (QML) laser with GaAs coupler under Gaussian approximation are given. These rate equations are solved numerically. The key parameters of an optimally coupled passively QML laser with the shortest pulse-width envelope are determined. These key parameters include the parameters of the gain medium, the saturable absorber, and the resonator, which can minimize the pulse-width of a singly Q-switched envelope. Sample calculations for a diode-pumped passively Q-switched mode-locked c-cut Nd:GdVO(4) laser with a GaAs coupler are presented to demonstrate that the shortest pulse-width envelope can be obtained by selecting the optimal small-signal transmission of the saturable absorber and the reflectivity of the output mirror.


Improved cognitive and motor development in a community-based intervention of psychosocial stimulation in northeast Brazil.
The aim of the study was to compare the development of children with and without a programme of psychosocial stimulation in 'control' and 'intervention' sites in a poorly resourced area of northeast Brazil. The sample (n = 156, born 1998) was from a larger cohort. The cohort was tested at 12 months (baseline) with the Bayley Scales of Infant Development. All children in the intervention site with a mental development index (MDI) and/or psychomotor development index (PDI) < or = 100 were enrolled. Each time such a child was enrolled, the next child tested in that site of the same sex and with an index of 101 to 115 was also enrolled, and the next two children matched for sex and scores of < or = 100 and 101 to 115 in the control sites were recruited in parallel. The intervention comprised 14 contacts between 13 and 17 months of age. All children were tested again at age 18 months. The intervention and control groups were similar at baseline for a range of socioeconomic, demographic, environmental, and biological variables, and their MDI and PDI were also similar. At 18 months, the mean differences between the intervention and control groups were + 9.4 points for MDI and + 8.2 points for PDI (p < 0.001 in each case). For children with an initial score of < or = 100, the mean difference between the intervened and control groups was + 11.2 points for MDI (p < 0.001), and + 10.8 points for PDI (p = 0.001). The intervention was thus associated with significant improvements in cognitive and motor development.


Isolation and chemical identification of lipid derivatives from avocado (Persea americana) pulp with antiplatelet and antithrombotic activities.
Platelets play a pivotal role in physiological hemostasis. However, in coronary arteries damaged by atherosclerosis, enhanced platelet aggregation, with subsequent thrombus formation, is a precipitating factor in acute ischemic events. Avocado pulp (Persea americana) is a good source of bioactive compounds, and its inclusion in the diet as a source of fatty acid has been related to reduced platelet aggregability. Nevertheless, constituents of avocado pulp with antiplatelet activity remain unknown. The present study aims to characterize the chemical nature of avocado constituents with inhibitory effects on platelet aggregation. Centrifugal partition chromatography (CPC) was used as a fractionation and purification tool, guided by an in vitro adenosine diphosphate (ADP), arachidonic acid or collagen-platelet aggregation assay. Antiplatelet activity was initially linked to seven acetogenins that were further purified, and their dose-dependent effects in the presence of various agonists were contrasted. This process led to the identification of Persenone-C (3) as the most potent antiplatelet acetogenin (IC₅₀=3.4 mM) among the evaluated compounds. In vivo evaluations with Persenone A (4) demonstrated potential protective effects against arterial thrombosis (25 mg kg⁻¹ of body weight), as coagulation times increased (2-fold with respect to the vehicle) and thrombus formation was attenuated (71% versus vehicle). From these results, avocado may be referred to as a functional food containing acetogenin compounds that inhibit platelet aggregation with a potential preventive effect on thrombus formation, such as those that occur in ischaemic diseases.


Relationship between visual acuity and retinal structures measured by spectral domain optical coherence tomography in patients with open-angle glaucoma.
We assessed the relationship between retinal structures measured by spectral-domain optical coherence tomography (SD-OCT) and visual acuity in open-angle glaucoma (OAG) patients. In this cross-sectional observational study, 186 eyes from 186 OAG patients were included. The participants underwent RTVue OCT for measurement of circumpapillary retinal nerve fiber layer (cpRNFL) thickness and macular ganglion cell complex (mGCC) thickness. The correlations between best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) parameters were evaluated using Pearson's partial correlation test and regression analysis. Receiver operating characteristic (ROC) curve analysis was performed to obtain a cutoff value for OCT parameters in detecting decreased visual acuity (BCVA < 0.7). Among RNFL parameters, average RNFL thickness (r = -0.447, P < 0.001) showed the highest correlation with BCVA, followed by superior hemisphere (r = -0.440, P <0.001), and TU1 (67.5°-90°, r = -0.427, P < 0.001), TU2 (45°-67.5°, r = -0.408, P < 0.001), and TL1 (90°-112.5°, r = -0.40, P < 0.001) sectors. When logMAR BCVA was plotted against average RNFL/ganglion cell complex (GCC) thickness, second-order polynomial models fit better than the linear model. The areas under the receiver operating characteristic curves (AUROCs) of the average RNFL/GCC thickness were 0.910 (95% confidence interval [CI], 0.856-0.965) and 0.874 (95% CI, 0.795-0.953), respectively. The relationship between BCVA and SD-OCT parameters were curvilinear, and significant correlations were noted only in eyes with severe glaucoma. The global average cpRNFL thickness showed the highest correlation with BCVA rather than TU1, TL1 sectors, or GCC parameters. Considering the wide variability of structure-visual acuity relationship in glaucoma patients, the clinicians should take other variables into account to predict the visual acuity in advanced glaucoma patients.


Removal of the phage-shock protein PspB causes reduction of virulence in Salmonella enterica serovar Typhimurium independently of NRAMP1.
The phage-shock protein (Psp) system is believed to manage membrane stress in all Enterobacteriaceae and has recently emerged as being important for virulence in several pathogenic species of this phylum. The core of the Psp system consists of the pspA-D operon and the distantly located pspG gene. In Salmonella enterica serovar Typhimurium (S. Typhimurium), it has recently been reported that PspA is essential for systemic infection of mice, but only in NRAMP1(+) mice, signifying that attenuation is related to coping with divalent cation starvation in the intracellular environment. In the present study, we investigated the contribution of individual psp genes to virulence of S. Typhimurium. Interestingly, deletion of the whole pspA-D set of genes caused attenuation in both NRAMP1(+) and NRAMP1(-) mice, indicating that one or more of the psp genes contribute to virulence independently of NRAMP1 expression in the host. Investigations of single gene mutants showed that knock out of pspB reduced virulence in both types of mice, while deletion of pspA only caused attenuation in NRAMP1(+) mice, and deletion of pspD had a minor effect in NRAMP1(-) mice, while deletions of either pspC or pspG did not affect virulence. Experiments addressed at elucidating the role of PspB in virulence revealed that PspB is dispensable for uptake to and intracellular replication in cultured macrophages and resistance to complement-induced killing. Furthermore, the Psp system of S. Typhimurium was dispensable during pIV-induced secretin stress. In conclusion, our results demonstrate that removal of PspB reduces virulence in S. Typhimurium independently of host NRAMP1 expression, demonstrating that PspB has roles in intra-host survival distinct from the reported contributions of PspA.


The value of inpatient pharmaceutical counselling to elderly patients prior to discharge.
The use of medication and information discharge summaries (MIDS) has become a standard procedure in many hospitals. We have evaluated if these summaries, together with in-patient pharmaceutical counselling backed up with a simple medicine reminder card, may help with the delivery of seamless pharmaceutical care. Elderly patients prescribed more than four items discharged to their own home received the standard discharge policy including a recently introduced MIDS and medicine reminder card. Each patient's GP was sent a copy on discharge. Pre-discharge a pharmacist counselled study patients about their medicines and compliance. A research pharmacist visited patients in their home approximately 2-3 weeks and at 3 months post-discharge to determine their drug knowledge, compliance, home medicine stocks and any healthcare related events. Forty-three study and 40 control patients completed both visits. Their mean (s.d.) ages were 80.2 (5,7) and 81.1 (5,8) years and they were prescribed 7.1 (1.8) and 7.1 (2.3) items, respectively. At visit 1 knowledge (P < 0.01) and compliance (P < 0.001) was better in the study group. At visit 2 compliance had improved in the study group (P < 0.001). Unplanned visits to the GP and readmission to hospital amongst the study group were 19 and 5, respectively, which were both significantly less (P < 0.05) than 27 and 13 in the control group. At visit 2 for the study group the 24 unplanned GP visits and three re-admissions were significantly (P < 0.05) less than the respective 32 and 15 in the control group. At visit 1, two study group patients had altered their own medication compared with 10 control patients. At visit 2 these reduced to 0 and 4, respectively. In-patient pharmaceutical counselling, linked to a medication and information discharge summary and a medicine reminder card, contributed to better drug knowledge and compliance together with reduced unplanned visits to the doctor and re-admissions. A pharmaceutical domiciliary visit consolidated the improved healthcare outcomes.


Neurons of the inferior olive respond to broad classes of sensory input while subject to homeostatic control.
Purkinje cells in the cerebellum integrate input from sensory organs with that from premotor centres. Purkinje cells use a variety of sensory inputs relaying information from the environment to modify motor control. Here we investigated to what extent the climbing fibre inputs to Purkinje cells signal mono- or multi-sensory information, and to what extent this signalling is subject to recent history of activity. We show that individual climbing fibres convey multiple types of sensory information, together providing a rich mosaic projection pattern of sensory signals across the cerebellar cortex. Moreover, firing probability of climbing fibres following sensory stimulation depends strongly on the recent history of activity, showing a tendency to homeostatic dampening. Cerebellar Purkinje cells integrate sensory information with motor efference copies to adapt movements to behavioural and environmental requirements. They produce complex spikes that are triggered by the activity of climbing fibres originating in neurons of the inferior olive. These complex spikes can shape the onset, amplitude and direction of movements and the adaptation of such movements to sensory feedback. Clusters of nearby inferior olive neurons project to parasagittally aligned stripes of Purkinje cells, referred to as 'microzones'. It is currently unclear to what extent individual Purkinje cells within a single microzone integrate climbing fibre inputs from multiple sources of different sensory origins, and to what extent sensory-evoked climbing fibre responses depend on the strength and recent history of activation. Here we imaged complex spike responses in cerebellar lobule crus 1 to various types of sensory stimulation in awake mice. We find that different sensory modalities and receptive fields have a mild, but consistent, tendency to converge on individual Purkinje cells, with climbing fibres showing some degree of input-specificity. Purkinje cells encoding the same stimulus show increased events with coherent complex spike firing and tend to lie close together. Moreover, whereas complex spike firing is only mildly affected by variations in stimulus strength, it depends strongly on the recent history of climbing fibre activity. Our data point towards a mechanism in the olivo-cerebellar system that regulates complex spike firing during mono- or multi-sensory stimulation around a relatively low set-point, highlighting an integrative coding scheme of complex spike firing under homeostatic control.


Ctla-4 blockade plus adoptive T-cell transfer promotes optimal melanoma immunity in mice.
Immunotherapeutic approaches to the treatment of advanced melanoma have relied on strategies that augment the responsiveness of endogenous tumor-specific T-cell populations [eg, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade-mediated checkpoint inhibition] or introduce exogenously prepared tumor-specific T-cell populations [eg, adoptive cell transfer (ACT)]. Although both approaches have shown considerable promise, response rates to these therapies remain suboptimal. We hypothesized that a combinatorial approach to immunotherapy using both CTLA-4 blockade and nonlymphodepletional ACT could offer additive therapeutic benefit. C57BL/6 mice were inoculated with syngeneic B16F10 melanoma tumors transfected to express low levels of the lymphocytic choriomeningitis virus peptide GP33 (B16GP33), and treated with no immunotherapy, CTLA-4 blockade, ACT, or combination immunotherapy of CTLA-4 blockade with ACT. Combination immunotherapy resulted in optimal control of B16GP33 melanoma tumors. Combination immunotherapy promoted a stronger local immune response reflected by enhanced tumor-infiltrating lymphocyte populations, and a stronger systemic immune responses reflected by more potent tumor antigen-specific T-cell activity in splenocytes. In addition, whereas both CTLA-4 blockade and combination immunotherapy were able to promote long-term immunity against B16GP33 tumors, only combination immunotherapy was capable of promoting immunity against parental B16F10 tumors as well. Our findings suggest that a combinatorial approach using CTLA-4 blockade with nonlymphodepletional ACT may promote additive endogenous and exogenous T-cell activities that enable greater therapeutic efficacy in the treatment of melanoma.


Effects of long-term tai chi practice on balance and H-reflex characteristics.
The purpose of the present study was to examine the effects of long-term Tai Chi practice on postural balance and H-reflex. Sixteen healthy volunteers, eight with three or more years of experience in Tai Chi training (Tai Chi Group-TCG), and eight with no experience in Tai Chi training (Control Group-CG) participated in the study. Postural sways were measured under four experimental conditions: (1) Standing still with eyes open (EO); (2) Standing still with eyes closed (EC); (3) Standing and turning head to left and right with eyes open (EOT); and (4) Standing and turning head to left and right with eyes closed (ECT). Paired reflex depression (PRD) of the soleus muscle was measured under two conditions: supine and standing. Less significant postural sway was observed in the TCG than in the CG under four conditions including EO, EC, EOT, and ECT (p < 0.01). The TCG demonstrated 14.1%, 30.6%, 33.3% and 22.7% less postural sway, respectively. Significant PRD change from a supine to standing position was observed between TCG and CG (p < 0.05). A significant correlation between PRD change (from supine to standing) and years of Tai Chi practice was observed (r = 0.80, p < 0.05). The findings of this study support the positive effects of Tai Chi exercise on balance control under different conditions. Long-term Tai Chi exercisers also demonstrated different reflex modulation from a supine to standing position, and long-term Tai Chi practice may lead to a change of PRD modulation as neuroadaptation.


Health literacy in relation to cancer: addressing the silence about and absence of cancer discussion among Aboriginal people, communities and health services.
Cancer outcomes for Aboriginal Australians are poorer when compared with cancer outcomes for non-Aboriginal Australians despite overall improvements in cancer outcomes. One concept used to examine inequities in health outcomes between groups is health literacy. Recent research and advocacy have pointed to the importance of increasing health literacy as it relates to cancer among Aboriginal people. This study examined individual, social and cultural aspects of health literacy relevant to cancer among Aboriginal patients, carers and their health workers in New South Wales. Qualitative interviews were conducted with 22 Aboriginal people who had been diagnosed with cancer, 18 people who were carers of Aboriginal people with cancer and 16 healthcare workers (eight Aboriginal and eight non-Aboriginal health workers). Awareness, knowledge and experience of cancer were largely absent from people's lives and experiences until they were diagnosed, illustrating the need for cancer awareness raising among Aboriginal people, communities and services. Some beliefs about cancer (particularly equating cancer to death) differed from mainstream Western biomedical views of the body and cancer and this served to silence discussion on cancer. As such, these beliefs can be used to inform communication and help illuminate how beliefs can shape responses to cancer. Participants proposed some practical strategies that could work to fill absences in knowledge and build on beliefs about cancer. These results were characterised by a silence about cancer, an absence of discussions of cancer and an acknowledgement of an already full health agenda for Aboriginal communities. To promote health literacy in relation to cancer would require a multi-layered programme of work involving grass-roots community education, workers and Board members of Aboriginal community-controlled health organisations and speciality cancer services, with a particular focus on programmes to bridge community-based primary care and tertiary level cancer services.


Discontinuing Antidepressants: How Can Clinicians Guide Patients and Drive Research?
Recent media reports have refocused attention on the syndromic manifestation experienced by some patients as they discontinue their antidepressant medication ("discontinuation syndrome"). This attention has been accompanied by criticisms that mainstream psychiatry has either ignored or minimized these symptoms and exposed patients to potentially harmful and addictive treatments. Yet, there has been very limited original research on the prevalence of discontinuation syndrome in the last decade. There is growing concern that labeling antidepressants as addictive may drive down the use of these medications and exacerbate the mental health crisis in which depression is often undiagnosed and undertreated. Hence, the onus of guiding patients through questions and concerns related to the use and discontinuation of antidepressants has fallen mainly on primary care and psychiatric clinicians. This report discusses some common decisional uncertainties relevant to antidepressant discontinuation and recommends a shared decision-making approach. Further, this report seeks to outline a roadmap for clinicians to drive research on this important yet understudied topic.


Esculentin-2CHa(1-30) and its analogues: stability and mechanisms of insulinotropic action.
The insulin-releasing effects, cellular mechanisms of action and anti-hyperglycaemic activity of 10 analogues of esculentin-2CHa lacking the cyclic C-terminal domain (CKISKQC) were evaluated. Analogues of the truncated peptide, esculentin-2CHa(1-30), were designed for plasma enzyme resistance and increased biological activity. Effects of those analogues on insulin release, cell membrane integrity, membrane potential, intracellular Ca2+ and cAMP levels were determined using clonal BRIN-BD11 cells. Their acute effects on glucose tolerance were investigated using NIH Swiss mice. d-Amino acid substitutions at positions 7(Arg), 15(Lys) and 23(Lys) and fatty acid (l-octanoate) attachment to Lys at position 15 of esculentin-2CHa(1-30) conveyed resistance to plasma enzyme degradation whilst preserving insulin-releasing activity. Analogues, [d-Arg7,d-Lys15,d-Lys23]-esculentin-2CHa(1-30) and Lys15-octanoate-esculentin-2CHa(1-30), exhibiting most promising profiles and with confirmed effects on both human insulin-secreting cells and primary mouse islets were selected for further analysis. Using chemical inhibition of adenylate cyclase, protein kinase C or phospholipase C pathways, involvement of PLC/PKC-mediated insulin secretion was confirmed similar to that of CCK-8. Diazoxide, verapamil and Ca2+ omission inhibited insulin secretion induced by the esculentin-2CHa(1-30) analogues suggesting an action on KATP and Ca2+ channels also. Consistent with this, the analogues depolarised the plasma membrane and increased intracellular Ca2+ Evaluation with fluorescent-labelled esculentin-2CHa(1-30) indicated membrane action, with internalisation; however, patch-clamp experiments suggested that depolarisation was not due to the direct inhibition of KATP channels. Acute administration of either analogue to NIH Swiss mice improved glucose tolerance and enhanced insulin release similar to that observed with GLP-1. These data suggest that multi-acting analogues of esculentin-2CHa(1-30) may prove useful for glycaemic control in obesity-diabetes.


Long-term treatment of severe obesity: are lifestyle interventions still an option?
Following lifestyle intervention programs based on dietary restriction and habitual physical activity, weight loss, however large, is reported to peak within six months. Despite maintenance protocols, only few cases continue to lose weight thereafter. The majority of cases regain weight and adherence to lifestyle changes are fostered by long-term contact with a supportive team. In general, surgical procedures are reported to produce much larger weight loss and to impact more favorably on long-term weight loss maintenance. Areas covered: We performed a PubMed search on lifestyle modification studies, focusing on the role of behavior programs for the long-term management of obesity in comparison with surgical procedures. Behaviorally-achieved weight loss outcomes can be improved by integrating standard behavior therapy with self-regulation cognitive skills, motivational interviewing and/or phone/internet-based recall systems. Expert commentary: Clinically-important long-term weight loss is achievable by behavior therapy in a small proportion of subjects with obesity, however severe, through personalized programs associating lifestyle modification interventions, with procedures aimed at developing commitment and responsibility skills. A new area of research is the integration of cognitive-behavior therapy with bariatric (metabolic) surgery, either pre- or post-operatively, to exploit long-term adherence to healthy diet and habitual physical activity.


The physiology underlying Roux-en-Y gastric bypass: a status report.
Obesity and its related comorbidities can be detrimental for the affected individual and challenge public health systems worldwide. Currently, the only available treatment options leading to clinically significant and maintained body weight loss and reduction in obesity-related morbidity and mortality are based on surgical interventions. This review will focus on two main clinical effects of Roux-en-Y gastric bypass (RYGB), namely body weight loss and change in eating behavior. Animal experiments designed to understand the underlying physiological mechanisms of these post-gastric bypass effects will be discussed. Where appropriate, reference will also be made to vertical sleeve gastrectomy. While caloric malabsorption and mechanical restriction seem not to be major factors in this respect, alterations in gut hormone levels are invariably found after RYGB. However, their causal role in RYGB effects on eating and body weight has recently been challenged. Other potential factors contributing to the RYGB effects include increased bile acid concentrations and an altered composition of gut microbiota. RYGB is further associated with remarkable changes in preference for different dietary components, such as a decrease in the preference for high fat or sugar. It needs to be noted, however, that in many cases, the question about the necessity of these alterations for the success of bariatric surgery procedures remains unanswered.


Enhancing the stability of porphyrin dye-sensitized solar cells by manipulation of electrolyte additives.
The use of porphyrin-based photosensitizers with superior light-harvesting properties has enabled the power conversion efficiency of dye-sensitized solar cells (DSCs) to reach 13 % under full sun illumination. However, a major limitation of such devices corresponds to the volatility of the solvent used so far for the electrolyte, which prevents practical applications. In this work, we describe a porphyrin-ionic liquid DSC, which not only affords the highest efficiency reported to date, but is also stable for more than 300 h under continuous full sun illumination at 60 °C. Furthermore, we identify a previously unreported pathway for device degradation, and show that the addition of N-methylbenzimidazole and a thiocyanate salt to the electrolyte is critical to obtaining long-lived devices.


Effects of pH and ionic composition on sorption/desorption of natural organic matter on zero-valent iron and magnetite nanoparticles.
Understanding the interactions between natural organic matter (NOM) and zero-valent iron nanoparticles (nano-Fe0) and magnetite nanoparticles (nano-Fe3O4) is essential for evaluating their performance in pollutant remediation, as well as determining their fate and transport in the environment. Batch experiments were performed to investigate the sorption/desorption behaviors of humic acid (HA) on commercially available nano-Fe0 and nano-Fe3O4. The sorption/desorption of HA on nano-Fe0 and nano-Fe3O4 were well described by both the Langmuir model and the modified Langmuir model. The adsorption capacities of HA were 8.77±0.31 mg C/g and 10.05±0.95 mg C/g for nano-Fe0 and nano-Fe3O4, respectively. The interactions of HA with nano-Fe0 and nano-Fe3O4 were highly pH-dependent. On one hand, nano-Fe0 had its maximum adsorption of 11.0 mg C/g HA at pH=3, which decreased to 0.6 mg C/g when pH increased to 11.9; on the other hand, alkaline condition enhanced HA desorption greatly. At pH=10.1, after 24 h desorption experiments, nearly 80% of initially adsorbed HA desorbed from the nanoparticles. The interactions of HA with nano-Fe0 and nano-Fe3O4 were also influenced by different ion compositions in solution. Divalent cations (e.g. Ca2+, Mg2+) enhanced HA adsorption significantly, while phosphate nearly eliminated HA adsorption and promoted significantly HA desorption.


Metabolism of 3-phenoxybenzoic acid and the enterohepatorenal disposition of its metabolites in the rat.
The absorption, metabolism and disposition of 3-phenoxybenzoic acid (3PBA) and its 4'-hydroxylated derivative (4'HO3PBA) have been investigated in intact and bile duct-cannulated rats. Both acids are rapidly and extensively eliminated in the urine as the O-sulfate ester of 4'HO3PBA (4'HOSO2O3PBA). Biliary excretion was 45% of the dose when 3PBA was administered at 100 mg/kg, compared with 16% at 10 mg/kg. The major biliary metabolites, identified by mass spectrometry, were 3PBA glucuronide and the ether and ester glucuronic acid conjugates of 4'HO3PBA. These biliary metabolites were of minor importance in the urine. At a dose of 100 mg/kg, an apparent excretion balance figure approximately 120%, as determined from the extent of elimination of radioactivity in the urine (72%) of intact animals and bile of cannulated rats (45%) (only 7% appeared in the feces), suggests that the biliary glucuronides decompose and/or are enzymically cleaved in the gastrointestinal tract to the respective benzoic acids. The latter are subsequently reabsorbed and undergo further metabolism, principally to the sulfate ester which is excreted in the urine. This enterohepatorenal disposition of 3PBA has been confirmed by suppression of the gut microflora with antibiotics in vivo, which dramatically reduces the extent of deconjugation of biliary glucuronides and hence reabsorption of the free benzoic acids. The deconjugation by gut bacteria has also been demonstrated in vitro.


A systematic review of help-seeking interventions for depression, anxiety and general psychological distress.
Depression and anxiety are treatable disorders, yet many people do not seek professional help. Interventions designed to improve help-seeking attitudes and increase help-seeking intentions and behaviour have been evaluated in recent times. However, there have been no systematic reviews of the efficacy or effectiveness of these interventions in promoting help-seeking. Therefore, this paper reports a systematic review of published randomised controlled trials targeting help-seeking attitudes, intentions or behaviours for depression, anxiety, and general psychological distress. Studies were identified through searches of PubMed, PsycInfo, and the Cochrane database in November 2011. Studies were included if they included a randomised controlled trial of at least one intervention targeting help-seeking for depression or anxiety or general psychological distress, and contained extractable data on help-seeking attitudes or intentions or behaviour. Studies were excluded if they focused on problems or conditions other than the target (e.g., substance use, eating disorder). Six published studies of randomised controlled trials investigating eight different interventions for help-seeking were identified. The majority of trials targeted young adults. Mental health literacy content was effective (d = .12 to .53) in improving help-seeking attitudes in the majority of studies at post-intervention, but had no effect on help-seeking behaviour (d = -.01, .02). There was less evidence for other intervention types such as efforts to destigmatise or provide help-seeking source information. Mental health literacy interventions are a promising method for promoting positive help-seeking attitudes, but there is no evidence that it leads to help-seeking behaviour. Further research investigating the effects of interventions on attitudes, intentions, and behaviour is required.


Isotopic evidence for the diet of an early hominid, Australopithecus africanus.
Current consensus holds that the 3-million-year-old hominid Australopithecus africanus subsisted on fruits and leaves, much as the modern chimpanzee does. Stable carbon isotope analysis of A. africanus from Makapansgat Limeworks, South Africa, demonstrates that this early hominid ate not only fruits and leaves but also large quantities of carbon-13-enriched foods such as grasses and sedges or animals that ate these plants, or both. The results suggest that early hominids regularly exploited relatively open environments such as woodlands or grasslands for food. They may also suggest that hominids consumed high-quality animal foods before the development of stone tools and the origin of the genus Homo.


Destigmatizing alcohol dependence: the requirement for an ethical (not only medical) remedy.
The disease model of alcohol dependence or "alcoholism" is often presented as the linchpin in addressing the condition successfully. It has been argued, for example, that adopting a medical approach will reduce the stigma that impedes the provision and acceptance of treatment. However, the medical paradigm has existed for many years without significantly affecting the negative social attitudes that surround dependence. I argue that a reductive scientific approach is not equipped to address the socioethical tensions that dependence creates. To lessen the stigmatization of dependence, it is important to integrate ethical analysis into policy debates on the condition.


Primary Cilia Are Dysfunctional in Obese Adipose-Derived Mesenchymal Stem Cells.
Adipose-derived mesenchymal stem cells (ASCs) have crucial functions, but their roles in obesity are not well defined. We show here that ASCs from obese individuals have defective primary cilia, which are shortened and unable to properly respond to stimuli. Impaired cilia compromise ASC functionalities. Exposure to obesity-related hypoxia and cytokines shortens cilia of lean ASCs. Like obese ASCs, lean ASCs treated with interleukin-6 are deficient in the Hedgehog pathway, and their differentiation capability is associated with increased ciliary disassembly genes like AURKA. Interestingly, inhibition of Aurora A or its downstream target the histone deacetylase 6 rescues the cilium length and function of obese ASCs. This work highlights a mechanism whereby defective cilia render ASCs dysfunctional, resulting in diseased adipose tissue. Impaired cilia in ASCs may be a key event in the pathogenesis of obesity, and its correction might provide an alternative strategy for combating obesity and its associated diseases.


The effect of simple interventions on paramedic aspirin administration rates.
To determine the baseline rate of aspirin administration by paramedics and to assess the effect of two interventions (protocol change and brief educational intervention) on that rate. The advanced life support transport provider's clinical database was retrospectively queried to identify calls involving adult patients with chest pain or paramedic impression of suspected cardiac event (possible acute coronary syndrome [ACS]). The study includes data from January 1, 1999, to June 30, 2002, which was divided into three distinct periods. Period 1 was the baseline, period 2 was after the protocol change intervention, and period 3 was after the brief educational intervention. The chest pain protocol indicates patients with chest pain should be treated with aspirin. During period 1, 548 of 3,635 (15.1%) patients with possible ACS received aspirin. During period 2, 1,941 of 7,236 (26.8%) patients with possible ACS received aspirin (chi(2) p<0.0001; odds ratio [OR]=2.06; 95% confidence interval [CI]=1.86-2.29). During period 3, 749 of 2,026 (37%) patients with possible ACS received aspirin (chi(2) p<0.0001; OR=1.60; 95% CI=1.44-1.78). Comparing period 1 with period 3, after both interventions, there was a 22% absolute improvement in aspirin administration rates (chi(2) p<0.0001; OR=3.30; 95% CI=2.91-3.76). Aspirin is underutilized in treating patients with suspected ACS. Two brief interventions can lead to modest increases in aspirin administration rates. Even after these interventions, aspirin administration rates remain low.


Dependency of the trans vivo delayed type hypersensitivity response on the action of regulatory T cells: implications for monitoring transplant tolerance.
The trans vivo delayed-type hypersensitivity (DTH) assay has been used for monitoring the immune status of clinical transplant recipients. Here we tested the hypothesis that the assay can reveal control of allograft rejection by CD25CD4 regulatory T cells (Treg). CBA.Ca (H2) recipients of heterotopic C57BL/10 (H2, B10) heart transplants were untreated or pretreated with anti-CD4 antibody and donor-specific blood. This protocol has been shown previously to induce operational tolerance to alloantigens that is dependent on CD25CD4 Treg. Four weeks after transplantation leukocytes were harvested and used for the trans vivo DTH assay. Cells were stimulated with irradiated B10 leukocytes or subcellular antigen and injected into ear pinnae of immune deficient CB17.SCID.beige hosts. Stimulation of leukocytes from recipients rejecting B10 cardiac allografts with recall alloantigen caused a "strong" swelling response, whereas similar stimulation of leukocytes from operationally tolerant mice resulted in significantly less swelling (n=17; P=0.003). When CD25 T cells were depleted from "tolerant" leukocytes, the swelling response triggered was similar to that obtained using cells from rejecting animals (P<0.001), while coinjection of purified CD25CD4 cells from tolerant recipients with rejecting cells suppressed the swelling response (P=0.007) to the level observed with cells from tolerant mice. Both the effector and the regulatory response were triggered by indirect allorecognition and blocking experiments showed that the regulation observed was dependent on cytoxic T lymphocyte antigen (CTLA) 4. The trans vivo DTH assay can be used to reveal regulation mediated by CD25CD4 T cells and is CTLA4 dependent.


Digital health and the biopolitics of the Quantified Self.
Recent years have witnessed an intensive growth of systems of measurement and an increasing integration of data processes into various spheres of everyday life. From smartphone apps that measure our activity and sleep, to digital devices that monitor our health and performance at the workplace, the culture of measurement is currently on the rise. Encouraged by movements such as the Quantified Self, whose motto is 'self knowledge through numbers', a growing number of people across the globe are embracing practices of self-quantification and tracking in the spirit of improving their wellbeing and productivity or charting their fitness progress. In this article, I examine the biopolitical aspects of the Quantified Self practices, exploring some of the ideologies and rationalities underlying self-tracking culture. I argue that such practices represent an instantiation of a 'biopolitics of the self' whereby the body is made amenable to management and monitoring techniques that often echo the ethos of neoliberalism. Rather than being restricted to an individualized form, self-tracking practices are also becoming part of a biosocial and communal phenomenon in which individuals are incited to share with others information about their physical activities and biodata. In exploring some examples of this data sharing culture, I critically address the extent to which the sharing of personal physical data can be seen as a 'solidaristic' act that can contribute to a larger Big Data ecosystem and inform the wider medical community and healthcare research and policy. I link this discussion to debates on 'data philanthropy', highlighting the emerging tension between philanthropic discourses of data sharing and issues of privacy. From here, I go on to discuss further ethical and political concerns, particularly in relation to data security and the marked shifts in healthcare responsibilities.


High HIV-1 incidence, correlates of HIV-1 acquisition, and high viral loads following seroconversion among MSM.
HIV-1 incidence estimates and correlates of HIV-1 acquisition in African MSM are largely unknown. Since 2005, HIV-1-uninfected men who reported sex with men and women (MSMW) or sex with men exclusively (MSME) were followed at scheduled visits for collection of behavioural and clinical examination data and plasma for HIV-1 testing. Urethral or rectal secretions were collected from symptomatic men to screen for gonorrhoea. Poisson regression methods were used to estimate adjusted incidence rate ratios to explore associations between risk factors and incident HIV-1 infection. Plasma viral loads (PVLs) were assessed over 2 years following seroconversion. Overall HIV-1 incidence in 449 men was 8.6 [95% confidence interval (CI) 6.7-11.0] per 100 person-years. Incidence was 5.8 (95% CI 4.2-7.9) per 100 person-years among MSMW, and 35.2 (95% CI 23.8-52.1) per 100 person-years among MSME. Unprotected sex, receptive anal intercourse, exclusive sex with men, group sex, and gonorrhoea in the past 6 months were strongly associated with HIV-1 acquisition, adjusted for confounders. PVL in seroconverters was more than 4 log10 copies/ml at 230 (73.4%) of 313 visits in MSMW and 153 (75.0%) of 204 visits in MSME. HIV-1 incidence is very high among MSM in coastal Kenya, and many seroconverters maintain high PVL for up to 2 years after infection. Effective HIV-1 prevention interventions, including treatment as prevention, are urgently needed in this population.


Association of Proteinuria and Incident Atrial Fibrillation in Patients With Intact and Reduced Kidney Function.
Early evidence suggests proteinuria is independently associated with incident atrial fibrillation (AF). We sought to investigate whether the association of proteinuria with incident AF is altered by kidney function. Retrospective cohort study using administrative healthcare databases in Ontario, Canada (2002-2015). A total of 736 666 patients aged ≥40 years not receiving dialysis and with no previous history of AF were included. Proteinuria was defined using the urine albumin-to-creatinine ratio (ACR) and kidney function by the estimated glomerular filtration rate (eGFR). The primary outcome was time to AF. Cox proportional models were used to determine the hazard ratio for AF censored for death, dialysis, kidney transplant, or end of follow-up. Fine and Grey models were used to determine the subdistribution hazard ratio for AF, with death as a competing event. Median follow-up was 6 years and 44 809 patients developed AF. In adjusted models, ACR and eGFR were associated with AF (P<0.0001). The association of proteinuria with AF differed based on kidney function (ACR × eGFR interaction, P<0.0001). Overt proteinuria (ACR, 120 mg/mmol) was associated with greater AF risk in patients with intact (eGFR, 120) versus reduced (eGFR, 30) kidney function (adjusted hazard ratios, 4.5 [95% CI, 4.0-5.1] and 2.6 [95% CI, 2.4-2.8], respectively; referent ACR 0 and eGFR 120). Results were similar in competing risk analyses. Proteinuria increases the risk of incident AF markedly in patients with intact kidney function compared with those with decreased kidney function. Screening and preventative strategies should consider proteinuria as an independent risk factor for AF.


Bladder dysfunction changes from underactive to overactive after experimental traumatic brain injury.
Although bladder dysfunction is common after traumatic brain injury (TBI), few studies have investigated resultant bladder changes and the detailed relationship between TBI and bladder dysfunction. The goal of this study was to characterize the effects of TBI on bladder function in an animal model. Fluid-percussion injury was used to create an animal model with moderate TBI. Female Sprague-Dawley rats underwent TBI, sham TBI or were not manipulated (naïve). All rats underwent filling cystometry while bladder pressure and external urethral sphincter electromyograms were simultaneously recorded 1 day, 1 week, 2 weeks, and 1 month after injury. One day after injury, 70% of the animals in the TBI group and 29% of the animals in the sham TBI group showed no bursting activity during urination. Compared to naïve rats, bladder function was mainly altered 1 day and 1 week after sham TBI, suggesting the craniotomy procedure affected bladder function mostly in a temporary manner. Compared to either naïve or sham TBI, bladder weight was significantly increased 1 month after TBI and collagen in the bladder wall was increased. Bladder function in the TBI group went from atonic 1 day post-TBI to overactive 1 month post-TBI, suggesting that TBI significantly affected bladder function.


Can motor control training lower the risk of injury for professional football players?
Among injuries reported by the Australian Football League (AFL), lower limb injuries have shown the highest incidence and prevalence rates. Deficits in the muscles of the lumbopelvic region, such as a smaller size of multifidus (MF) muscle, have been related to the occurrence of lower limb injuries in the preseason in AFL players. Motor control training programs have been effective in restoring the size and control of the MF muscle, but the relationship between motor control training and occurrence of injuries has not been extensively examined. This pre- and postintervention trial was delivered during the playing season as a panel design with three groups. The motor control program involved voluntary contractions of the MF, transversus abdominis, and pelvic floor muscles while receiving feedback from ultrasound imaging and progressed into a functional rehabilitation program. Assessments of muscle size and function were performed using magnetic resonance imaging and included the measurement of cross-sectional areas of MF, psoas, and quadratus lumborum muscles and the change in trunk cross-sectional area due to voluntarily contracting the transversus abdominis muscle. Injury data were obtained from club records. Informed consent was obtained from all study participants. A smaller size of the MF muscle (odds ratio [OR] = 2.38) or quadratus lumborum muscle (OR = 2.17) was predictive of lower limb injury in the playing season. At the time point when one group of players had not received the intervention (n = 14), comparisons were made with the combined groups who had received the intervention (n = 32). The risk of sustaining a severe injury was lower for those players who received the motor control intervention (OR = 0.09). Although there are many factors associated with injuries in AFL, motor control training may provide a useful addition to strategies aimed at reducing lower limb injuries.


Sex determination mechanisms in the Calliphoridae (blow flies).
The Calliphoridae or blow flies are a family of insects that occupy diverse habitats and perform important ecological roles, particularly the decomposition of animal remains. Some Calliphoridae species are also important in the forensic sciences, in agriculture (e.g. as livestock pests) and in medicine (e.g. maggot therapy). Calliphoridae provide striking examples in support of the hypothesis that sex determination regulatory gene hierarchies evolve in the reverse order, with the gene at the top being the most recently added. Unlike the model fly Drosophila melanogaster, where sex is determined by the number of X chromosomes, in the Australian sheep blow fly (Lucilia cuprina) sex is determined by a Y-linked male-determining gene (M). A different regulatory system appears to operate in the hairy maggot blow fly (Chrysomya rufifacies) where the maternal genotype determines sex. It is hypothesized that females heterozygous for a dominant female-determining factor (F/f) produce only female offspring and homozygous f/f females produce only sons. The bottom of the regulatory hierarchy appears to be the same in D. melanogaster and L. cuprina, with sex-specific splicing of doublesex transcripts being controlled by the female-specific Transformer (TRA) protein. We discuss a model that has been proposed for how tra transcripts are sex-specifically spliced in calliphorids, which is very different from D. melanogaster.


Cost-effectiveness of aspirin adjuvant therapy in early stage colorectal cancer in older patients.
Recent observational studies showed that post-operative aspirin use reduces cancer relapse and death in the earliest stages of colorectal cancer. We sought to evaluate the cost-effectiveness of aspirin as an adjuvant therapy in Stage I and II colorectal cancer patients aged 65 years and older. Two five-state Markov models were constructed separately for Stage I and II colorectal cancer using TreeAge Pro 2014. Two hypothetical cohorts of 10,000 individuals at a starting age of 65 years and with colorectal cancer in remission were put through the models separately. Cost-effectiveness of aspirin was evaluated against no treatment (Stage I and II) and capecitabine (Stage II) over a 20-year period from the United States societal perspective. Extensive one-way sensitivity analyses and multivariable Probabilistic Sensitivity Analyses (PSA) were performed. In the base case analyses, aspirin was cheaper and more effective compared to other comparators in both stages. Sensitivity analyses showed that no treatment and capecitabine (Stage II only) can be cost-effective alternatives if the utility of taking aspirin is below 0.909, aspirin's annual fatal adverse event probability exceeds 0.57%, aspirin's relative risk of disease progression is 0.997 or more, or when capecitabine's relative risk of disease progression is less than 0.228. Probabilistic Sensitivity Analyses (PSA) further showed that aspirin could be cost-effective 50% to 80% of the time when the willingness-to-pay threshold was varied from USD 20,000 to USD 100,000. Even with a modest treatment benefit, aspirin is likely to be cost-effective in Stage I and II colorectal cancer, thus suggesting a potential unique role in secondary prevention in this group of patients.


Identification of a 25 kDa polypeptide associated with the L antigen in low potassium-type sheep red cells.
Antisera to the L blood group antigen have been used, following radioiodination of low potassium-type sheep red cells and subsequent immunoprecipitation, to identify a polypeptide of the L antigen. Only LK, and not HK, cells express this 25 kDa component which is present in very low copy number.


Mental health and psychosocial support in humanitarian settings: linking practice and research.
This review links practice, funding, and evidence for interventions for mental health and psychosocial wellbeing in humanitarian settings. We studied practice by reviewing reports of mental health and psychosocial support activities (2007-10); funding by analysis of the financial tracking service and the creditor reporting system (2007-09); and interventions by systematic review and meta-analysis. In 160 reports, the five most commonly reported activities were basic counselling for individuals (39%); facilitation of community support of vulnerable individuals (23%); provision of child-friendly spaces (21%); support of community-initiated social support (21%); and basic counselling for groups and families (20%). Most interventions took place and were funded outside national mental health and protection systems. 32 controlled studies of interventions were identified, 13 of which were randomised controlled trials (RCTs) that met the criteria for meta-analysis. Two studies showed promising effects for strengthening community and family supports. Psychosocial wellbeing was not included as an outcome in the meta-analysis, because its definition varied across studies. In adults with symptoms of post-traumatic stress disorder (PTSD), meta-analysis of seven RCTs showed beneficial effects for several interventions (psychotherapy and psychosocial supports) compared with usual care or waiting list (standardised mean difference [SMD] -0·38, 95% CI -0·55 to -0·20). In children, meta-analysis of four RCTs failed to show an effect for symptoms of PTSD (-0·36, -0·83 to 0·10), but showed a beneficial effect of interventions (group psychotherapy, school-based support, and other psychosocial support) for internalising symptoms (six RCTs; SMD -0·24, -0·40 to -0·09). Overall, research and evidence focuses on interventions that are infrequently implemented, whereas the most commonly used interventions have had little rigorous scrutiny.


Ultrasound imaging velocimetry of the human vitreous.
Knowledge of vitreous motion in response to saccades is a prerequisite for understanding vitreous rheology. Purpose of present paper is to introduce Ultrasound Image Velocimetry of the human eye, measure scleral and vitreous velocity fields and test the reproducibility of the proposed technique. Twelve patients with varying diagnosis underwent Ocular Dynamic Ultrasound; scleral angular velocity (V(S)) was measured by 2 different operators and reproducibility calculated. Squared velocity of the vitreous (E), which is representative of kinetic energy per unit mass, was computed from velocity. The time evolution of the energy of the vitreous was described by its spatial average (E(S)), whereas spatial distribution was described by its time average (E(T)). Peak and average E(S), the ratio K(p) of the peak of the spatially averaged kinetic energy per unit mass to the maximum squared scleral angular velocity, vitreous motion onset time (T(O)) and vitreous motion decay time (T(D)) were also defined. Inter-operator reproducibility coefficient was 0.043 and correlation between operators was significant. V(S), peak and average E(S), K(p) ratio and T(D) differed among patients but not among operators. V(S) correlated with E(S) and T(D). E(S) and T(D) but not V(S), were significantly different in patients with Posterior Vitreous Detachment. Patients with retinal detachment showed significantly higher V(S) and E(S). K(p) was inversely correlated to age and refraction. Measures proved accurate and reproducible. E is related to V(S), retinal traction and mechanical stimulation. Identified variables varied with age, refraction pathologic conditions.


Fusion surface structure, function, and dynamics of gamete fusogen HAP2.
HAP2 is a class II gamete fusogen in many eukaryotic kingdoms. A crystal structure of Chlamydomonas HAP2 shows a trimeric fusion state. Domains D1, D2.1 and D2.2 line the 3-fold axis; D3 and a stem pack against the outer surface. Surprisingly, hydrogen-deuterium exchange shows that surfaces of D1, D2.2 and D3 closest to the 3-fold axis are more dynamic than exposed surfaces. Three fusion helices in the fusion loops of each monomer expose hydrophobic residues at the trimer apex that are splayed from the 3-fold axis, leaving a solvent-filled cavity between the fusion loops in each monomer. At the base of the two fusion loops, Arg185 docks in a carbonyl cage. Comparisons to other structures, dynamics, and the greater effect on Chlamydomonas gamete fusion of mutation of axis-proximal than axis-distal fusion helices suggest that the apical portion of each monomer could tilt toward the 3-fold axis with merger of the fusion helices into a common fusion surface.


Effects of omeprazole and genetic polymorphism of CYP2C19 on the clopidogrel active metabolite.
Clopidogrel is an antiplatelet agent widely used in cardiovascular diseases and an inactive prodrug that needs to be converted to an active metabolite in two sequential metabolic steps. Several CYP450 isoforms involved in these two steps have been described, although the relative contribution in vivo of each enzyme is still under debate. CYP2C19 is considered to be the major contributor to active metabolite formation. In the current study, net CYP2C19 contribution to the active metabolite formation was determined from exposure of the active metabolite in two clinical studies (one phase I study with well balanced genetic polymorphic populations and a meta-analysis with a total of 396 healthy volunteers) at different clopidogrel doses. CYP2C19 involvements were estimated to be from 58 to 67% in intermediate metabolizers (IMs), from 58 to 72% in extensive metabolizers (EMs), and from 56 to 74% in ultrarapid metabolizers (UMs), depending on the study and the dose. For this purpose, a static model was proposed to estimate the net contribution of a given enzyme to the secondary metabolite formation. This static model was compared with a dynamic approach (Simcyp model) and showed good consistency. In parallel, in vitro investigations showed that omeprazole is a mechanism-based inhibitor of CYP2C19 with K(I) of 8.56 μM and K(inact) of 0.156 min(-1). These values were combined with the net CYP2C19 contribution to the active metabolite formation, through a static approach, to predict the inhibitory effect at 80-mg omeprazole doses in EM, IM, and UM CYP2C19 populations, with good consistency, compared with observed clinical values.


Composition and transport properties of human ankle and knee cartilage.
The incidence of osteoarthritis is significantly higher in the knee as compared to the ankle, suggesting that differences in the properties of cartilage from these joints may contribute to the development of osteoarthritis. As an avascular tissue, articular cartilage depends primarily upon diffusion for molecular transport. The goal of this study was to determine if differences in the structure and composition between ankle and knee cartilage were also reflected as differences in solute transport properties. The diffusion coefficient and partition coefficient of a 70-kDa dextran molecule were measured in human ankle and knee articular cartilage using fluorescence recovery after photobleaching (FRAP) and were compared to the proteoglycan, collagen, water, and DNA contents within each zone. The mean partition coefficient was significantly lower in the ankle compared to the knee (0.010+/-0.002 vs. 0.022+/-0.003, p<0.01), but no differences in the diffusion coefficients were observed (34.6 +/- 0.9 microm(2)s(-1) vs. 35.4+/-2.4 microm(2)s(-1), p=0.70). Ankle cartilage exhibited higher proteoglycan content as well as a trend toward lower water content, suggesting that ankle cartilage has a smaller effective pore size than knee cartilage. These findings suggest that differences in the composition of ankle and knee cartilage contribute to a difference in the partition coefficient. The results of this study provide further support for the hypothesis that the transport properties of cartilage may play a role in the differences in the incidence of osteoarthritis in these joints by altering the effective concentration of growth factors and cytokines to which chondrocytes are exposed.


Radionuclide imaging of neurohormonal system of the heart.
Heart failure is one of the growing causes of death especially in developed countries due to longer life expectancy. Although many pharmacological and instrumental therapeutic approaches have been introduced for prevention and treatment of heart failure, there are still limitations and challenges. Nuclear cardiology has experienced rapid growth in the last few decades, in particular the application of single photon emission computed tomography (SPECT) and positron emission tomography (PET), which allow non-invasive functional assessment of cardiac condition including neurohormonal systems involved in heart failure; its application has dramatically improved the capacity for fundamental research and clinical diagnosis. In this article, we review the current status of applying radionuclide technology in non-invasive imaging of neurohormonal system in the heart, especially focusing on the tracers that are currently available. A short discussion about disadvantages and perspectives is also included.


Microprocessor mediates transcriptional termination of long noncoding RNA transcripts hosting microRNAs.
MicroRNAs (miRNAs) play a major part in the post-transcriptional regulation of gene expression. Mammalian miRNA biogenesis begins with cotranscriptional cleavage of RNA polymerase II (Pol II) transcripts by the Microprocessor complex. Although most miRNAs are located within introns of protein-coding transcripts, a substantial minority of miRNAs originate from long noncoding (lnc) RNAs, for which transcript processing is largely uncharacterized. We show, by detailed characterization of liver-specific lnc-pri-miR-122 and genome-wide analysis in human cell lines, that most lncRNA transcripts containing miRNAs (lnc-pri-miRNAs) do not use the canonical cleavage-and-polyadenylation pathway but instead use Microprocessor cleavage to terminate transcription. Microprocessor inactivation leads to extensive transcriptional readthrough of lnc-pri-miRNA and transcriptional interference with downstream genes. Consequently we define a new RNase III-mediated, polyadenylation-independent mechanism of Pol II transcription termination in mammalian cells.


Studies on physicochemical and nutritional properties of aerial parts of Cassia occidentalis L.
In the present, work chemical composition and nutritional value of aerial parts of Cassia occidentalis L. was studied. The aerial parts of C. occidentalis possess favorable physicochemical properties with good nutritional value, such as high energy value, crude fibers, and vitamin levels. The X-ray fluorescence spectrophotometry data revealed that the sample is rich in minerals, especially in Fe, Ca, K, and Mn. Further, minerals such as Mg, Zn, Cu, Na, P, and S are present in good amount and depicted the nutritional value of the selected material. The plant sample is rich in phytochemicals such as flavonoids, alkaloids, lignin, tannins, and phenols. The presence of phytochemical constituents was confirmed by gas chromatography-mass spectrometry profile and high-performance thin layer chromatography fingerprinting techniques. The findings stimulate the on-farm cultivation of C. occidentalis on a large scale to relieve the iron deficiency in local community, and it can be used as a dietary supplement to treat anemia.


MECHANISMS OF ENDOCRINOLOGY: Mechanisms of disease: the endocrinology of obstructive sleep apnoea.
Obstructive sleep apnoea (OSA) is a common disorder that is associated with serious comorbidities with a negative impact on quality of life, life expectancy and health costs. As OSA is related to obesity and is associated with sleep disruption, increased inflammation and oxidative stress, it is not surprising that OSA has an impact on the secretion of multiple hormones and is implicated in the development of many endocrine conditions. On the other hand, many endocrine conditions that can affect obesity and/or upper airways anatomy and stability have been implicated in the development or worsening of OSA. This bidirectional relationship between OSA and the endocrine system has been increasingly recognised in experimental and epidemiological studies and there are an increasing number of studies examining the effects of OSA treatment on endocrine conditions and vice versa. In this review article, we will critically appraise and describe the impact of OSA on the endocrine system including obesity, dysglycaemia, the pituitary, the thyroid, the adrenals, the reproductive system and the bones. In each section, we will assess whether a bidirectional relationship exists, and we will describe the potential underlying mechanisms. We have focused more on recent studies and randomised controlled trials where available and attempted to provide the information within clinical context and relevance.


Cross-sectional study of the burden of vector-borne and soil-transmitted polyparasitism in rural communities of Coast Province, Kenya.
In coastal Kenya, infection of human populations by a variety of parasites often results in co-infection or poly-parasitism. These parasitic infections, separately and in conjunction, are a major cause of chronic clinical and sub-clinical human disease and exert a long-term toll on economic welfare of affected populations. Risk factors for these infections are often shared and overlap in space, resulting in interrelated patterns of transmission that need to be considered at different spatial scales. Integration of novel quantitative tools and qualitative approaches is needed to analyze transmission dynamics and design effective interventions. Our study was focused on detecting spatial and demographic patterns of single- and co-infection in six villages in coastal Kenya. Individual and household level data were acquired using cross-sectional, socio-economic, and entomological surveys. Generalized additive models (GAMs and GAMMs) were applied to determine risk factors for infection and co-infections. Spatial analysis techniques were used to detect local clusters of single and multiple infections. Of the 5,713 tested individuals, more than 50% were infected with at least one parasite and nearly 20% showed co-infections. Infections with Schistosoma haematobium (26.0%) and hookworm (21.4%) were most common, as was co-infection by both (6.3%). Single and co-infections shared similar environmental and socio-demographic risk factors. The prevalence of single and multiple infections was heterogeneous among and within communities. Clusters of single and co-infections were detected in each village, often spatially overlapped, and were associated with lower SES and household crowding. Parasitic infections and co-infections are widespread in coastal Kenya, and their distributions are heterogeneous across landscapes, but inter-related. We highlighted how shared risk factors are associated with high prevalence of single infections and can result in spatial clustering of co-infections. Spatial heterogeneity and synergistic risk factors for polyparasitism need to be considered when designing surveillance and intervention strategies.


Work Ability Index of Shift Working Hospital Nurses in Jordan.
Despite the extensive literature on work ability, few studies have looked at variables associated with work ability of nurses working fixed versus rotating shifts. The study aims were to explore variables contributing to work ability and to examine the association of demographic, job satisfaction, and work shift to work ability. A cross-sectional design was utilized to assess work ability level and job satisfaction among nurses working 8 or 12 hour rotating or fixed shifts in Jordanian hospitals. The data collection tools were the Work Ability Index and the Mueller/McCloskey Satisfaction Scale. Data were analyzed to determine the extent to which job satisfaction, shift work, and demographic variables were associated with work ability. Work ability level was "moderate", while job satisfaction level was "moderately dissatisfied". A positive significant relationship was found between work ability and job satisfaction (r = 0.347, n = 349, p < 0.000). This relationship was higher for fixed-shift workers (r =.507) compared to rotating-shift workers (r = .299). Standard linear multiple regression analysis indicated that job satisfaction level predicted work ability level (β =.347, p = .000). The study confirmed that promoting job satisfaction leads to higher work ability, and thus, enhances the quality of care provided. The finding that job satisfaction is predictive of work ability has implications for training intervention.


Serum cystatin C level: An excellent predictor of mortality in patients with cirrhotic ascites.
Although serum cystatin C level is considered a more accurate marker of renal function in patients with liver cirrhosis, its prognostic efficacy remains uncertain. This study aimed to evaluate the prognostic efficacy of serum cystatin C level in patients with cirrhotic ascites. Patients with cirrhotic ascites from 15 hospitals were prospectively enrolled between September 2009 and March 2013. Cox regression analyses were performed to identify independent predictive factors of mortality and development of type 1 hepatorenal syndrome (HRS-1). In total, 350 patients were enrolled in this study. The mean age was 55.4 ± 10.8 years, and 267 patients (76.3%) were men. The leading cause of liver cirrhosis was alcoholic liver disease (64.3%), followed by chronic viral hepatitis (29.7%). Serum creatinine and cystatin C levels were 0.9 ± 0.4 mg/dL and 1.1 ± 0.5 mg/L, respectively. Multivariate analyses revealed that international normalized ratio and serum bilirubin, sodium, and cystatin C levels were independent predictors of mortality and international normalized ratio and serum sodium and cystatin C levels were independent predictors of the development of HRS-1. Serum creatinine level was not significantly associated with mortality and development of HRS-1 on multivariate analysis. Serum cystatin C level was an independent predictor of mortality and development of HRS-1 in patients with cirrhotic ascites, while serum creatinine level was not. Predictive models based on serum cystatin C level instead of serum creatinine level would be more helpful in the assessment of the condition and prognosis of patients with cirrhotic ascites.


Sensitivity of global terrestrial ecosystems to climate variability.
The identification of properties that contribute to the persistence and resilience of ecosystems despite climate change constitutes a research priority of global relevance. Here we present a novel, empirical approach to assess the relative sensitivity of ecosystems to climate variability, one property of resilience that builds on theoretical modelling work recognizing that systems closer to critical thresholds respond more sensitively to external perturbations. We develop a new metric, the vegetation sensitivity index, that identifies areas sensitive to climate variability over the past 14 years. The metric uses time series data derived from the moderate-resolution imaging spectroradiometer (MODIS) enhanced vegetation index, and three climatic variables that drive vegetation productivity (air temperature, water availability and cloud cover). Underlying the analysis is an autoregressive modelling approach used to identify climate drivers of vegetation productivity on monthly timescales, in addition to regions with memory effects and reduced response rates to external forcing. We find ecologically sensitive regions with amplified responses to climate variability in the Arctic tundra, parts of the boreal forest belt, the tropical rainforest, alpine regions worldwide, steppe and prairie regions of central Asia and North and South America, the Caatinga deciduous forest in eastern South America, and eastern areas of Australia. Our study provides a quantitative methodology for assessing the relative response rate of ecosystems--be they natural or with a strong anthropogenic signature--to environmental variability, which is the first step towards addressing why some regions appear to be more sensitive than others, and what impact this has on the resilience of ecosystem service provision and human well-being.


Regulation of cellular response to oncogenic and oxidative stress by Seladin-1.
Expression of multiple oncogenes and inactivation of tumour suppressors is required to transform primary mammalian cells into cancer cells. Activated Ha-RasV12 (Ras) is usually associated with cancer, but it also produces paradoxical premature senescence in primary cells by inducing reactive oxygen species followed by accumulation of tumour suppressors p53 and p16(INK4a) (ref. 4). Here we identify, using a direct genetic screen, Seladin-1 (also known as Dhcr24) as a key mediator of Ras-induced senescence. Following oncogenic and oxidative stress, Seladin-1 binds p53 amino terminus and displaces E3 ubiquitin ligase Mdm2 from p53, thus resulting in p53 accumulation. Additionally, Seladin-1 associates with Mdm2 independently of p53, potentially affecting other Mdm2 targets. Ablation of Seladin-1 causes the bypass of Ras-induced senescence in rodent and human fibroblasts, and allows Ras to transform these cells. Wild-type Seladin-1, but not mutants that disrupt its association with either p53 or Mdm2, suppresses the transformed phenotype. The same mutants are also inactive in directing p53-dependent oxidative stress response. These results show an unanticipated role for Seladin-1, previously implicated in Alzheimer's disease and cholesterol metabolism, in integrating cellular response to oncogenic and oxidative stress.


Uniformly stable backpropagation algorithm to train a feedforward neural network.
Neural networks (NNs) have numerous applications to online processes, but the problem of stability is rarely discussed. This is an extremely important issue because, if the stability of a solution is not guaranteed, the equipment that is being used can be damaged, which can also cause serious accidents. It is true that in some research papers this problem has been considered, but this concerns continuous-time NN only. At the same time, there are many systems that are better described in the discrete time domain such as population of animals, the annual expenses in an industry, the interest earned by a bank, or the prediction of the distribution of loads stored every hour in a warehouse. Therefore, it is of paramount importance to consider the stability of the discrete-time NN. This paper makes several important contributions. 1) A theorem is stated and proven which guarantees uniform stability of a general discrete-time system. 2) It is proven that the backpropagation (BP) algorithm with a new time-varying rate is uniformly stable for online identification and the identification error converges to a small zone bounded by the uncertainty. 3) It is proven that the weights' error is bounded by the initial weights' error, i.e., overfitting is eliminated in the proposed algorithm. 4) The BP algorithm is applied to predict the distribution of loads that a transelevator receives from a trailer and places in the deposits in a warehouse every hour, so that the deposits in the warehouse are reserved in advance using the prediction results. 5) The BP algorithm is compared with the recursive least square (RLS) algorithm and with the Takagi-Sugeno type fuzzy inference system in the problem of predicting the distribution of loads in a warehouse, giving that the first and the second are stable and the third is unstable. 6) The BP algorithm is compared with the RLS algorithm and with the Kalman filter algorithm in a synthetic example.


Promoter hypermethylation of tumor suppressor genes in urine from kidney cancer patients.
Kidney cancer confined by the renal capsule can be surgically cured in the majority of cases, whereas the prognosis for patients with advanced disease at presentation remains poor. Novel strategies for early detection are therefore needed. Molecular DNA-based tests have successfully used the genetic alterations that initiate and drive tumorigenesis as targets for the early detection of several types of cancer in bodily fluids, including urine. Using sensitive methylation-specific PCR, we screened matched tumor DNA and sediment DNA from preoperative urine specimens obtained in 50 patients with kidney tumors, representing all major histological types, for hypermethylation status of a panel of six normally unmethylated tumor suppressor genes VHL, p16/CDKN2a, p14ARF, APC, RASSF1A, and Timp-3. Hypermethylation of at least one gene was found in all 50 tumor DNAs (100% diagnostic coverage) and an identical pattern of gene hypermethylation found in the matched urine DNA from 44 of 50 patients (88% sensitivity), including 27/30 cases of stage I disease. In contrast, hypermethylation of the genes in the panel was not observed in normal kidney tissue or in urine from normal healthy individuals and patients with benign kidney disease (100% specificity). Hypermethylation of VHL was found only in clear cell, whereas hypermethylation of p14ARF, APC, or RASSF1A was more frequent in nonclear cell tumors, which suggested that the panel might facilitate differential diagnosis. We conclude that promoter hypermethylation is a common and early event in kidney tumorigenesis and can be detected in the urine DNA from patients with organ-confined renal cancers of all histological types. Methylation-specific PCR may enhance early detection of renal cancer using a noninvasive urine test.


The effects of visual display distance on eye accommodation, head posture, and vision and neck symptoms.
Determine the effects of display viewing distance on both the visual and musculoskeletal systems while the text height is held constant across viewing distances. The distance from the eyes to a computer display may affect visual and neck comfort. If the angular size of the characters remains the same, it is recommended that the display be placed at a farther viewing distance (e.g., 70-100 cm). However, in common usage, the character sizes are not adjusted based on viewing distance. Participants under the age of 35 years (N = 24) performed visually demanding tasks using a computer display for 2 hr each at three viewing distances (mean: 52.4, 73.0, and 85.3 cm) while torso and head posture were tracked. At the end of each task, eye accommodation was measured and symptoms were recorded. The near distance was associated with significantly less blurred vision, less dry or irritated eyes, less headache, and improved convergence recovery when compared with the middle and far distances. Participants moved their torsos and heads closer to the monitor at the far distance. If the computer screen character sizes are close to the limits of visual acuity, it is recommended that the computer monitor be positioned between the near (52 cm) and middle (73 cm) distance from the eyes. The location of a computer display should take into account the size of the characters on the screen and the visual acuity of the user.


DNA vaccine based on conserved HA-peptides induces strong immune response and rapidly clears influenza virus infection from vaccinated pigs.
Swine influenza virus (SIVs) infections cause a significant economic impact to the pork industry. Moreover, pigs may act as mixing vessel favoring genome reassortment of diverse influenza viruses. Such an example is the pandemic H1N1 (pH1N1) virus that appeared in 2009, harboring a combination of gene segments from avian, pig and human lineages, which rapidly reached pandemic proportions. In order to confront and prevent these possible emergences as well as antigenic drift phenomena, vaccination remains of vital importance. The present work aimed to evaluate a new DNA influenza vaccine based on distinct conserved HA-peptides fused with flagellin and applied together with Diluvac Forte as adjuvant using a needle-free device (IntraDermal Application of Liquids, IDAL®). Two experimental pig studies were performed to test DNA-vaccine efficacy against SIVs in pigs. In the first experiment, SIV-seronegative pigs were vaccinated with VC4-flagellin DNA and intranasally challenged with a pH1N1. In the second study, VC4-flagellin DNA vaccine was employed in SIV-seropositive animals and challenged intranasally with an H3N2 SIV-isolate. Both experiments demonstrated a reduction in the viral shedding after challenge, suggesting vaccine efficacy against both the H1 and H3 influenza virus subtypes. In addition, the results proved that maternally derived antibodies (MDA) did not constitute an obstacle to the vaccine approach used. Moreover, elevated titers in antibodies both against H1 and H3 proteins in serum and in bronchoalveolar lavage fluids (BALFs) was detected in the vaccinated animals along with a markedly increased mucosal IgA response. Additionally, vaccinated animals developed stronger neutralizing antibodies in BALFs and higher inhibiting hemagglutination titers in sera against both the pH1N1 and H3N2 influenza viruses compared to unvaccinated, challenged-pigs. It is proposed that the described DNA-vaccine formulation could potentially be used as a multivalent vaccine against SIV infections.


Systematic review of machine learning for diagnosis and prognosis in dermatology.
Background: Software systems using artificial intelligence for medical purposes have been developed in recent years. The success of deep neural networks (DNN) in 2012 in the image recognition challenge ImageNet LSVRC 2010 fueled expectations of the potential for using such systems in dermatology.Objective: To evaluate the ways in which machine learning has been utilized in dermatology to date and provide an overview of the findings in current literature on the subject.Methods: We conducted a systematic review of existing literature, identifying the literature through a systematic search of the PubMed database. Two doctors assessed screening and eligibility with respect to pre-determined inclusion and exclusion criteria.Results: A total of 2175 publications were identified, and 64 publications were included. We identified eight major categories where machine learning tools were tested in dermatology. Most systems involved image recognition tools that were primarily aimed at binary classification of malignant melanoma (MM). Short system descriptions and results of all included systems are presented in tables.Conclusions: We present a complete overview of artificial intelligence implemented in dermatology. Impressive outcomes were reported in all of the identified eight categories, but head-to-head comparison proved difficult. The many areas of dermatology where we identified machine learning tools indicate the diversity of machine learning.


Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells.
Evi-1 has been recognized as one of the dominant oncogenes associated with murine and human myeloid leukemia. Here, we show that hematopoietic stem cells (HSCs) in Evi-1-deficient embryos are severely reduced in number with defective proliferative and repopulating capacity. Selective ablation of Evi-1 in Tie2(+) cells mimics Evi-1 deficiency, suggesting that Evi-1 function is required in Tie2(+) hematopoietic stem/progenitors. Conditional deletion of Evi-1 in the adult hematopoietic system revealed that Evi-1-deficient bone marrow HSCs cannot maintain hematopoiesis and lose their repopulating ability. In contrast, Evi-1 is dispensable for blood cell lineage commitment. Evi-1(+/-) mice exhibit the intermediate phenotype for HSC activity, suggesting a gene dosage requirement for Evi-1. We further demonstrate that disruption of Evi-1 in transformed leukemic cells leads to significant loss of their proliferative activity both in vitro and in vivo. Thus, Evi-1 is a common and critical regulator essential for proliferation of embryonic/adult HSCs and transformed leukemic cells.


Musical experience and the aging auditory system: implications for cognitive abilities and hearing speech in noise.
Much of our daily communication occurs in the presence of background noise, compromising our ability to hear. While understanding speech in noise is a challenge for everyone, it becomes increasingly difficult as we age. Although aging is generally accompanied by hearing loss, this perceptual decline cannot fully account for the difficulties experienced by older adults for hearing in noise. Decreased cognitive skills concurrent with reduced perceptual acuity are thought to contribute to the difficulty older adults experience understanding speech in noise. Given that musical experience positively impacts speech perception in noise in young adults (ages 18-30), we asked whether musical experience benefits an older cohort of musicians (ages 45-65), potentially offsetting the age-related decline in speech-in-noise perceptual abilities and associated cognitive function (i.e., working memory). Consistent with performance in young adults, older musicians demonstrated enhanced speech-in-noise perception relative to nonmusicians along with greater auditory, but not visual, working memory capacity. By demonstrating that speech-in-noise perception and related cognitive function are enhanced in older musicians, our results imply that musical training may reduce the impact of age-related auditory decline.


Autoradiographic analysis of the distribution of vasoactive intestinal peptide binding sites in the vertebrate central nervous system: a phylogenetic study.
The distribution of vasoactive intestinal peptide (VIP) binding sites in the brain of several vertebrate species was examined by in vitro autoradiography on slide-mounted sections. This study included fish, frog, snake, pigeon, rat, mouse, guinea pig, cat and monkey brain. A fully characterized, monoiodinated form of vasoactive intestinal peptide (M-125I-VIP), which maintains the biological activity of the native peptide in the central nervous system (CNS), was used throughout the study. Among the lower vertebrate species, no significant specific binding was found in the fish brain, whereas in the frog and snake brain, specific VIP binding sites were observed, mainly in the telencephalon. In the pigeon brain, high densities of VIP binding sites were localized in the hyperstriatum, neostriatum, archistriatum, hippocampal area, dorsolateral cortical area and in the optic tectum. Ectostriatum and paleostriatum augmentatum displayed lower densities of specific binding. In mammals, the highest concentrations of VIP binding sites were observed in the rodent brain. In the rat, mouse and guinea pig brain, high densities were detected in the olfactory bulb, external layers of the cerebral cortex, dentate gyrus, midline thalamic nuclei, geniculate nuclei, some hypothalamic nuclei, superior colliculus and locus coeruleus. Intermediate densities were found in amygdala, caudate-putamen, septum and nucleus accumbens, CA1-CA3 fields of the hippocampus and central gray. The cerebellum of these species presented high densities of VIP binding sites, with species to species differences in their localization. The non-specific binding was, however, increased in the rodent cerebellum. Lower densities of VIP binding sites were observed in the cat and monkey CNS. In these two species, the non-specific binding was considerably higher than in the lower mammals brain. In the cat and monkey brain, as in the lower mammals, the highest densities were revealed in the neocortex, dentate gyrus, thalamic nuclei and some midbrain structures including substantia nigra and locus coeruleus. In all the species studied, the white matter was never labeled with M-125I-VIP. This study suggests that VIP binding sites appear relatively early in the evolution of the vertebrate CNS. The most important densities of specific VIP binding sites are observed in the pigeon and rodent brain, whereas the cat and monkey present a marked increase in non-specific binding. It is interesting to note that the distribution of VIP binding sites as revealed by autoradiography is quite conservative in terms of evolution and indicates an association, although non-exclusive, of VIP receptors with brain regions involved in the processing of specific sensory inputs.


The neural mechanisms underlying the influence of pavlovian cues on human decision making.
In outcome-specific transfer, pavlovian cues that are predictive of specific outcomes bias action choice toward actions associated with those outcomes. This transfer occurs despite no explicit training of the instrumental actions in the presence of pavlovian cues. The neural substrates of this effect in humans are unknown. To address this, we scanned 23 human subjects with functional magnetic resonance imaging while they made choices between different liquid food rewards in the presence of pavlovian cues previously associated with one of these outcomes. We found behavioral evidence of outcome-specific transfer effects in our subjects, as well as differential blood oxygenation level-dependent activity in a region of ventrolateral putamen when subjects chose, respectively, actions consistent and inconsistent with the pavlovian-predicted outcome. Our results suggest that choosing an action incompatible with a pavlovian-predicted outcome might require the inhibition of feasible but nonselected action-outcome associations. The results of this study are relevant for understanding how marketing actions can affect consumer choice behavior as well as for how environmental cues can influence drug-seeking behavior in addiction.


Normal adult performance on constructional praxis training tasks.
This study used a balanced factorial design to examine the performance of normal young adults on a parquetry block assembly task that occupational therapists use to treat constructional deficits in adults. Ninety-six 18- to 34-year-old right-handed college students or college graduates (48 men and 48 women) were tested. Independent variables were subjects' sex, presence or absence of color on the model design card, and amount of detail on the model design card. Dependent variables were speed and accuracy of design construction. Results of a factorial analysis of variance with the three variables showed that the subjects' total time scores were significantly related to their sex and to the presence or absence of color and the amount of detail on the design card. Interaction effects were significant for sex by amount of detail and for color by amount of detail. The results were used to generate clinical performance criteria and graded levels of difficulty for this modality. The subjects' learning and test behaviors were examined to generate ideas for treatment and for future research.


Testing cosmogonic models with gravitational lensing.
Gravitational lensing provides a strict test of cosmogonic models because it is directly sensitive to mass inhomogeneities. Detailed numerical propagation of light rays through a universe that has a distribution of inhomogeneities derived from the standard CDM (cold dark matter) scenario, with the aid of massive, fully nonlinear computer simulations, was used to test the model. It predicts that more widely split quasar images should have been seen than were actually found. These and other inconsistencies rule out the Cosmic Background Explorer (COBE)-normalized CDM model with density parameter Omega = 1 and the Hubble constant (H(o)) = 50 kilometers second(-1) megaparsec(-1); but variants of this model might be constructed, which could pass the stringent tests provided by strong gravitational lensing.


Echinocandin antifungal drugs in fungal infections: a comparison.
This review compares the pharmacology, spectrum of antifungal activity, pharmacokinetic and pharmacodynamic properties, safety and clinical efficacy of the three licensed echinocandins: caspofungin, micafungin and anidulafungin. Echinocandins inhibit the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall, and represent a valuable treatment option for fungal infections. The echinocandins exhibit potent in vitro and in vivo fungicidal activity against Candida species, including azole-resistant pathogens. For all agents, strains with drug minimum inhibitory concentrations (MICs) of ≤ 2 μg/mL are considered susceptible; the MIC at which 90% of isolates tested were inhibited (MIC₉₀) values are typically <2 μg/mL but 100-fold higher MIC₉₀ values are seen with Candida parapsilosis (1-2 μg/mL) and Candida guilliermondii (1-4 μg/mL). Activity is comparable between the three agents, although limited data indicate that anidulafungin may have low MICs against C. parapsilosis and Candida glabrata strains that demonstrate elevated MICs to caspofungin and micafungin. All three drugs have good fungistatic activity against Aspergillus spp., although minimal effective concentrations of micafungin and anidulfungin are 2- to 10-fold lower than those for caspofungin. Synergistic/additive in vitro effects of echinocandins when combined with a polyene or azole have been observed. Clinical resistance to the echinocandins is rare despite case reports of caspofungin resistance in several Candida spp. Resistance has been attributed to mutations in the FKS1 gene within two hot spot regions, leading to amino acid substitutions, mostly at position 645 (serine), yet not all FKS1 mutants have caspofungin MICs of >2 μg/mL. Of the three echinocandins, the in vitro 'paradoxical effect' (increased growth at supra-MIC drug concentrations) is observed least often with anidulafungin. All echinocandins have low oral bioavailability, and distribute well into tissues, but poorly into the CNS and eye. Anidulafungin is unique in that it undergoes elimination by chemical degradation in bile rather than via hepatic metabolism, has a lower maximum concentration and smaller steady state under the concentration-time curve but longer half-life than caspofungin or micafungin. In children, dosing should be based on body surface area. Daily doses of caspofungin (but not micafungin and anidulafungin) should be decreased (from 50 to 35 mg) in moderate liver insufficiency. All echinocandins display concentration-dependent fungicidal (for Candida) or fungistatic (for Aspergillus) activity. The postantifungal effect is 0.9-20 hours against Candida and <0.5 hours against Aspergillus. The echinocandins are well tolerated with few serious drug-drug interactions since they are not appreciable substrates, inhibitors or inducers of the cytochrome P450 or P-glycoprotein systems. In parallel with the greater clinical experience with caspofungin, this agent has a slightly higher potential for adverse effects/drug-drug interactions, with the least potential observed for anidulafungin. Caspofungin (but not micafungin or anidulafungin) dosing should be increased if coadministered with rifampicin and there are modest interactions of caspofungin with calcineurin inhibitors. All three agents are approved for the treatment of oesophageal candidiasis, candidaemia and other select forms of invasive candidiasis. Only micafungin is licensed for antifungal prophylaxis in stem cell transplantation, whereas caspofungin is approved for empirical therapy of febrile neutropenia. Caspofungin has been evaluated in the salvage and primary therapy of invasive aspergillosis. Combination regimens incorporating an echinocandin showing promise in the treatment of aspergillosis. However, echinocandins remain expensive to use.