Multicenter low energy transvenous atrial defibrillation (XAD) trial results in different subsets of atrial fibrillation.
This prospective, multicenter trial was aimed at defining efficacy and safety of low energy shocks during atrial fibrillation in a diverse cohort of patients. Experimental studies in sheep and preliminary data in humans have suggested that low energy internal shocks delivered between right atrial and coronary sinus electrode catheters may terminate atrial fibrillation. Biphasic 3/3-ms R wave synchronous shocks were delivered between two electrode catheters in the right atrium and coronary sinus. The defibrillation protocol started with a test shock of 20 V, and shocks increased in 40-V steps until restoration of sinus rhythm or a maximum of 400 V. Shock delivery was withheld after short RR intervals. In 141 patients with atrial fibrillation, the protocol was carried out under sedation in case the shock was associated with discomfort. The atrial arrhythmia was paroxysmal (< or = 7 days) in 50 patients, chronic (> 30 days) in 53, intermediate (> 7 days, < or = 30 days) in 18 and induced in 20. Underlying heart disease was present in 88 patients (62%). Paroxysmal atrial fibrillation was successfully terminated in 46 (92%) of 50 patients, chronic atrial fibrillation in 37 (70%) of 53, intermediate in 16 (89%) of 18 and induced in 16 (80%) of 20. Mean conversion threshold was 1.8 J (213 V) in the induced group, 2.0 J (229 V) in the paroxysmal group, 2.8 J (272 V) in the intermediate group and 3.6 J (311 V) in the chronic group. The conversion voltage was significantly (p < 0.001) higher in the chronic group than in the other groups of atrial fibrillation and increased significantly with the duration of atrial fibrillation and with left atrial size (p < 0.05). Of 1,779 R wave synchronized shocks delivered with a mean (+/-SD) preceding RR interval of 676 +/- 149 ms, no ventricular arrhythmia was induced. The latter may occur after unsynchronized shocks. Low energy transvenous shocks in patients with atrial fibrillation are effective and safe, provided that shocks are properly synchronized to R waves with preceding RR intervals that meet appropriate cycle length criteria. This study provides data that may be useful in the development of an implanted atrial defibrillator.


Ca(2+) channel blocker benidipine promotes coronary angiogenesis and reduces both left-ventricular diastolic stiffness and mortality in hypertensive rats.
The beneficial cardiac effects of some Ca(2+) channel blockers have been attributed to blood pressure reduction, but these pleiotropic effects require further investigation. We compared the effects of benidipine, which has beneficial cardiac effects, and nitrendipine, which does not, in an animal model of hypertensive diastolic heart failure (DHF). Male Dahl salt-sensitive rats were fed a high-salt diet from age 7 weeks to induce hypertension and were either vehicle or orally administered benidipine (3 mg/kg daily) or nitrendipine (10 mg/kg daily) from age 10 to 18 weeks. Control rats were maintained on a low-salt diet. In vehicle-treated rats, left-ventricular (LV) fractional shortening was preserved but LV end-diastolic pressure was increased, indicative of DHF. Benidipine and nitrendipine had similar antihypertensive effects and reduced both LV weight and cardiomyocyte hypertrophy. Benidipine reduced LV diastolic stiffness and mortality to a greater extent than did nitrendipine. Benidipine, but not nitrendipine, also reduced lung weight. The extent of interstitial fibrosis and the abundance of mRNAs for prohypertrophic, profibrotic, or proinflammatory genes in the left ventricle were reduced by benidipine and nitrendipine. Benidipine, but not nitrendipine, increased capillary density and restored the expression of hypoxia-inducible factor 1alpha, vascular endothelial growth factor, and endothelial nitric oxide synthase in the left ventricle. Benidipine reduced LV diastolic stiffness and increased survival, effects likely attributable predominantly to promotion of coronary angiogenesis rather than to attenuation of interstitial fibrosis. Benidipine may thus be more effective than purely L-type Ca(2+) channel blockers in preventing hypertensive DHF.


Implementation and Operational Research: Effects of CD4 Monitoring Frequency on Clinical End Points in Clinically Stable HIV-Infected Patients With Viral Suppression.
Current treatment guidelines for HIV infection recommend routine CD4 lymphocyte (CD4) count monitoring in patients with viral suppression. This may have a limited impact on influencing care as clinically meaningful CD4 decline rarely occurs during viral suppression. In a regional HIV observational cohort in the Asia-Pacific region, patients with viral suppression (2 consecutive viral loads <400 copies/mL) and a CD4 count ≥200 cells per microliter who had CD4 testing 6 monthly were analyzed. Main study end points were occurrence of 1 CD4 count <200 cells per microliter (single CD4 <200) and 2 CD4 counts <200 cells per microliter within a 6-month period (confirmed CD4 <200). A comparison of time with single and confirmed CD4 <200 with biannual or annual CD4 assessment was performed by generating a hypothetical group comprising the same patients with annual CD4 testing by removing every second CD4 count. Among 1538 patients, the rate of single CD4 <200 was 3.45/100 patient-years and of confirmed CD4 <200 was 0.77/100 patient-years. During 5 years of viral suppression, patients with baseline CD4 200-249 cells per microliter were significantly more likely to experience confirmed CD4 <200 compared with patients with higher baseline CD4 [hazard ratio, 55.47 (95% confidence interval: 7.36 to 418.20), P < 0.001 versus baseline CD4 ≥500 cells/μL]. Cumulative probabilities of confirmed CD4 <200 was also higher in patients with baseline CD4 200-249 cells per microliter compared with patients with higher baseline CD4. There was no significant difference in time to confirmed CD4 <200 between biannual and annual CD4 measurement (P = 0.336). Annual CD4 monitoring in virally suppressed HIV patients with a baseline CD4 ≥250 cells per microliter may be sufficient for clinical management.


Antimicrobial Stewardship - Do we need it in Pakistan?
In order to identify the literature and research available on development and implementation of Antimicrobial Stewardship Programme (ASP) in Pakistan, a systematic search of various electronic databases such as PubMed, Cochrane, CINAHL and PakMedinet from January 1, 2008 till November 2018 was conducted. Studies were included if they were focused around the development and implementation of the ASP within Pakistan. The search revealed that a significant knowledge gap exists regarding antimicrobial/antibiotic stewardship within Pakistan and not much is known about the current status of the development and implementation of antimicrobial stewardship programme. Only two research studies were found to be significant. Antimicrobial Stewardship Programme's development and implementation is highly essential and important. Currently, there exists a huge knowledge and systematic gap regarding ASP implementation at healthcare institutions.


COMBINE archive and OMEX format: one file to share all information to reproduce a modeling project.
With the ever increasing use of computational models in the biosciences, the need to share models and reproduce the results of published studies efficiently and easily is becoming more important. To this end, various standards have been proposed that can be used to describe models, simulations, data or other essential information in a consistent fashion. These constitute various separate components required to reproduce a given published scientific result. We describe the Open Modeling EXchange format (OMEX). Together with the use of other standard formats from the Computational Modeling in Biology Network (COMBINE), OMEX is the basis of the COMBINE Archive, a single file that supports the exchange of all the information necessary for a modeling and simulation experiment in biology. An OMEX file is a ZIP container that includes a manifest file, listing the content of the archive, an optional metadata file adding information about the archive and its content, and the files describing the model. The content of a COMBINE Archive consists of files encoded in COMBINE standards whenever possible, but may include additional files defined by an Internet Media Type. Several tools that support the COMBINE Archive are available, either as independent libraries or embedded in modeling software. The COMBINE Archive facilitates the reproduction of modeling and simulation experiments in biology by embedding all the relevant information in one file. Having all the information stored and exchanged at once also helps in building activity logs and audit trails. We anticipate that the COMBINE Archive will become a significant help for modellers, as the domain moves to larger, more complex experiments such as multi-scale models of organs, digital organisms, and bioengineering.


Effects of paternal and peripubertal stress on aggression, anxiety, and metabolic alterations in the lateral septum.
Early-life stress and biological predispositions are linked to mood and personality disorders related to aggressive behavior. We previously showed that exposure to peripubertal stress leads to increased anxiety-like behaviors and aggression against males and females, as well as increased aggression against females in their male offspring. Here, we investigated whether paternal (pS) and individual (iS) exposure to peripubertal stress may exert additive effects on the long-term programming of anxiety-like and aggressive behaviors in rats. Given the key role of the lateral septum (LS) in the regulation of anxiety and aggressive behaviors and the hypothesized alterations in balance between neural excitation and inhibition in aggression-related disorders, markers for these processes were examined in the LS. Peripubertal stress was applied both in naïve male rats and in the offspring of peripubertally stressed males, and anxiety-like and aggressive behaviors were assessed at adulthood. Proton magnetic resonance spectroscopy at 6-months, and post-mortem analysis of glutamic acid decarboxylase 67 (GAD67) at 12-months were conducted in LS. We confirmed that aggressive behavior was increased by pS and iS, while only iS increased anxiety-like behavior. Individual stress led to reduced GABA, confirmed by reduced GAD67 immunolabelling, and increased glutamate, N-acetyl-aspartate, phosphocholine and creatine; while pS specifically led to reduced phosphocreatine. pS and iS do not interact and exert a differential impact on the analyzed aspects of brain function and anxiety-like behaviors. These data support the view that early-life stress can affect the behavioral and neurodevelopmental trajectories of individuals and their offspring, which may involve different neurobiological mechanisms.


Catalytic reduction of nitric oxide with carbon monoxide on copper-cobalt oxides supported on nano-titanium dioxide.
A series of copper-cobalt oxides supported on nano-titanium dioxide were prepared for the reduction of nitric oxide with carbon monoxide and characterized using techniques such as XRD, BET and TPR. Catalyst CuCoOx/TiO2 with Cu/Co molar ratio of 1/2, Cu-Co total loading of 30% at the calcination temperature of 350 degrees C formed CuCo2O4 spinel and had the highest activity. NO conversion reached 98.9% at 200 degrees C. Mechanism of the reduction was also investigated, N2O was mainly yielded below 100 degrees C, while N2 was produced instead at higher temperature. O2 was supposed to accelerate the reaction between NOx and CO for its oxidation of NO to give more easily reduced NO2, but the oxidation of CO by O2 to CO2 decreased the speed of the reaction greatly. Either SO2 or H2O had no adverse impact on the activity of NO reduction; however, in the presence of both SO2 and H2O, the catalyst deactivated quickly.


Risk behaviors among HIV-positive gay and bisexual men at party-oriented vacations.
This study examined substance use (intended and actual), unprotected sex, and HIV disclosure practices (disclosure and questioning) among HIV-positive men who have sex with men (MSM) at two party-oriented vacations, where substance use and sexual risk may be heightened. A random sample of 489 MSM attending one of two party-oriented vacations participated in PartyIntents, a short-term longitudinal survey. Nearly half (47%) completed a follow-up assessment at the event or online for up to 2 weeks after the event. We examined rates of baseline intentions to use substances, actual substance use, and unprotected intercourse among HIV-positive men in attendance.Rates among HIV-negative men were estimated for comparison. Multiple logistic regression was used to assess the impact of illegal drug use and HIV status on unprotected anal intercourse (UAI). HIV-positive attendees (17%) were significantly more likely than HIV-negative attendees to use nitrite inhalants (or "poppers") (24.3% vs. 10.7%). HIV-positive attendees were also significantly more likely to have insertive UAI (64.3% vs. 34.1%) and receptive UAI (68.8% vs. 22.2%). Multivariate models showed associations between HIV status and illegal drug use with UAI (for HIV status, odds ratio [OR] = 4.5, p = .001; for any illegal drug use, OR = 16.4, p < .001). There was no evidence that the influence of drug use moderated risk by HIV status. Rates of HIV disclosure and questioning did not differ by HIV status. HIV-positive men attending these events engaged in higher rates of illegal drug use and sexual risk than HIV-negative men. Prevention campaigns targeting MSM at high-risk events should include messages geared toward HIV-positive men.


The 5α-reductase inhibitor finasteride reduces opioid self-administration in animal models of opioid use disorder.
Opioid use disorder (OUD) has become a leading cause of death in the United States, yet current therapeutic strategies remain highly inadequate. To identify potential treatments for OUD, we screened a targeted selection of over 100 drugs using a recently developed opioid self-administration assay in zebrafish. This paradigm showed that finasteride, a steroidogenesis inhibitor approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia, reduced self-administration of multiple opioids without affecting locomotion or feeding behavior. These findings were confirmed in rats; furthermore, finasteride reduced the physical signs associated with opioid withdrawal. In rat models of neuropathic pain, finasteride did not alter the antinociceptive effect of opioids and reduced withdrawal-induced hyperalgesia. Steroidomic analyses of the brains of fish treated with finasteride revealed a significant increase in dehydroepiandrosterone sulfate (DHEAS). Treatment with precursors of DHEAS reduced opioid self-administration in zebrafish in a fashion akin to the effects of finasteride. These results highlight the importance of steroidogenic pathways as a rich source of therapeutic targets for OUD and point to the potential of finasteride as a new treatment option for this disorder.


Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors.
In the present study we compared the affinity of various drugs for the high affinity "agonist-preferring" binding site of human recombinant 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors stably expressed in monoclonal mammalian cell lines. To ensure that the "agonist-preferring" conformation of the receptor was preferentially labelled in competition binding experiments, saturation analysis was conducted using antagonist and agonist radiolabels at each receptor. Antagonist radiolabels ([3H]-ketanserin for 5-HT(2A) receptor and [3H]-mesulergine for 5-HT(2B) and 5-HT(2C) receptor) bound to a larger population of receptors in each preparation than the corresponding agonist radiolabel ([125I]-DOI for 5-HT(2A) receptor binding and [3H]-5-HT for 5-HT(2B) and 5-HT(2C) receptor binding). Competition experiments were subsequently conducted against appropriate concentrations of the agonist radiolabels bound to the "agonist-preferring" subset of receptors in each preparation. These studies confirmed that there are a number of highly selective antagonists available to investigate 5-HT2 receptor subtype function (for example, MDL 100907, RS-127445 and RS-102221 for 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors respectively). There remains, however, a lack of highly selective agonists. (-)DOI is potent and moderately selective for 5-HT(2A) receptors, BW723C86 has poor selectivity for human 5-HT(2B) receptors, while Org 37684 and VER-3323 display some selectivity for the 5-HT(2C) receptor. We report for the first time in a single study, the selectivity of numerous serotonergic drugs for 5-HT2 receptors from the same species, in mammalian cell lines and using, exclusively, agonist radiolabels. The results indicate the importance of defining the selectivity of pharmacological tools, which may have been over-estimated in the past, and highlights the need to find more selective agonists to investigate 5-HT2 receptor pharmacology.


A path to improve colorectal cancer screening outcomes: faculty roundtable evaluation of cost-effectiveness and utility.
The American Journal of Managed Care® and Exact Sciences Corporation hosted a roundtable meeting to discuss the impact of colorectal cancer (CRC) screening modalities on improving patient outcomes. The roundtable participants were a diverse panel of experts, including primary care, gastroenterology, and oncology providers; experts in health outcomes research and health policy; and managed care executives with commercial and public payer experience. Participants discussed CRC prevention and treatment strategies, screening modalities and adherence, molecular diagnostics, patient navigation, evaluation of large data sets, managed care, outcomes research, quality improvement, and reimbursement policies. They focused on developing better value-based medical policies and payment procedures, identifying knowledge, practice, and access deficits related to CRC screening. Participants also provided suggestions on how to improve care quality and patient outcomes through effective evidence-based approaches. They also discussed costeffectiveness modeling for CRC screening, specifically the advantages and the real-world limitations of these models.


Real-time rotation estimation using histograms of oriented gradients.
This paper focuses on real-time rotation estimation for model-based automated visual inspection. In the case of model-based inspection, spatial alignment is essential to distinguish visual defects from normal appearance variations. Defects are detected by comparing the inspected object with its spatially aligned ideal reference model. Rotation estimation is crucial for the inspection of rotationally symmetric objects where mechanical manipulation is unable to ensure the correct object rotation. We propose a novel method for in-plane rotation estimation. Rotation is estimated with an ensemble of nearest-neighbor estimators. Each estimator contains a spatially local representation of an object in a feature space for all rotation angles and is constructed with a semi-supervised self-training approach from a set of unlabeled training images. An individual representation in a feature space is obtained by calculating the Histograms of Oriented Gradients (HOG) over a spatially local region. Each estimator votes separately for the estimated angle; all votes are weighted and accumulated. The final estimation is the angle with the most votes. The method was evaluated on several datasets of pharmaceutical tablets varying in size, shape, and color. The results show that the proposed method is superior in robustness with comparable speed and accuracy to previously proposed methods for rotation estimation of pharmaceutical tablets. Furthermore, all evaluations were performed with the same set of parameters, which implies that the method requires minimal human intervention. Despite the evaluation focused on pharmaceutical tablets, we consider the method useful for any application that requires robust real-time in-plane rotation estimation.


Forearc deformation and great subduction earthquakes: implications for cascadia offshore earthquake potential.
The maximum size of thrust earthquakes at the world's subduction zones appears to be limited by anelastic deformation of the overriding plate. Anelastic strain in weak forearcs and roughness of the plate interface produced by faults cutting the forearc may limit the size of thrust earthquakes by inhibiting the buildup of elastic strain energy or slip propagation or both. Recently discovered active strike-slip faults in the submarine forearc of the Cascadia subduction zone show that the upper plate there deforms rapidly in response to arc-parallel shear. Thus, Cascadia, as a result of its weak, deforming upper plate, may be the type of subduction zone at which great (moment magnitude approximately 9) thrust earthquakes do not occur.


Echinococcus multilocularis infection in the field vole (Microtus agrestis): an ecological model for studies on transmission dynamics.
We propose a model involving the oral inoculation of Echinococcus multilocularis eggs in a vole species and examine the infection dynamics in a dose-response experiment. Defined doses, 100 (n = 8), 500 (n = 5) and 1000 (n = 5) of E. multilocularis eggs were used to inoculate Microtus agrestis. Four female C57BL/6j mice were inoculated with 1000 eggs as positive controls. The groups inoculated with 100 and 500 eggs exhibited significantly higher lesion numbers, and relatively smaller lesion size was observed in the 1000 dose group. Undetectable abortive lesions may be responsible for some form of resource limitation early in the infection, resulting in lower lesion counts and size in the 1000 dose group. The C57BL/6j mice exhibited significantly fewer lesions than M. agrestis. The feasibility of measuring corticosterone (which has been shown to downregulate Th1 cytokines) in rodent hair and tumour necrosis factor (TNF) production in spleen cells was demonstrated by a positive correlation between corticosterone levels and higher lesion counts and TNF production in C57BL/6j, respectively. These results suggest that M. agrestis is more prone to a Th2 immune response than C57BL/6j, which is associated with E. multilocularis susceptibility and may explain why the parasite develops more slowly in murine models. This is the first data to suggest that M. agrestis is capable of supporting E. multilocularis transmission and thus may be suited as a model to describe the infection dynamics in an intermediate host that affects transmission under natural conditions.


[Manuel P. García and the history of the laryngoscope].
Many people have never heard of Manuel García; others know him as an artist and singing teacher of exceptional qualities; yet others had heard of him as an extraordinary researcher and the first scientist to investigate the voice. Manuel Patricio García is chiefly known as the man who invented the laryngeal mirror, the first person to carry out a dynamic assessment of phonation, and therefore the founder of laryngology. The main facts in his extensive biography are reviewed, covering his career as a singer, a teacher and a scientist; The invention of the laryngoscope and the "failed attempts"; his famous family, including his father, Manuel García, and his sisters María Malibrán and Paulina Viardot; and his extensive oeuvre.


Lateral epicondylalgia. A quantitative and qualitative analysis of interdisciplinary cooperation and treatment choice in the Swedish health care system.
Interdisciplinary cooperation is essential to develop a broad range of knowledge and skills. The aim of this study was to describe health care professionals' treatment choices, their cooperation with other professionals and their perceptions of potential risks regarding treatments of acute lateral epicondylalgia (LE). A quantitative descriptive study design with a summative approach to qualitative analysis. The ethical committee was asked verbally for approval but, as this study was performed to develop an organised way to treat LE, it did not require approval. The four ethical aspects information, consent, confidentiality and the use of the study materials were all addressed. All orthopaedic surgeons, general practitioners, physiotherapists and occupational therapists in a county. Questionnaire with 18 dichotomous, multiple-response, multiple-choice questions and three open-ended questions were analysed using quantitative cross-tab and qualitative content analysis with summative approach. The most common treatment choices were Non Steroidal Anti Inflammatory Drugs (NSAID), corticosteroid injections, training programmes, braces and ergonomics. Advantages from interdisciplinary cooperation were higher rated than disadvantages. The qualitative findings dealt with perceptions of interdisciplinary cooperation and resulted in three categories; right level of care, increased quality of care and decreased quality of care. Almost half of the physicians felt potential risks associated with their treatment methods. The qualitative findings dealt with perceptions of the potential risks and resulted in two categories: side effects and inadequate treatment. The number of responses varied because some of the respondents did not answered all of the questions. Interdisciplinary cooperation in the treatment of patients with acute LE benefits the patients by shortening the rehabilitation period and provides health care professionals the opportunity for an improved learning and exchanging experiences. These basic conditions must be met to improve health care quality.


Transport function and hepatocellular localization of mrp6 in rat liver.
The multidrug resistance-associated proteins (Mrps) constitute a family of cellular export pumps of the ATP-binding cassette transporter superfamily and play an important role in hepatobiliary excretion. We investigated the transport function and subcellular localization of mrp6, a novel member of the mrp family, in rat liver. Transport studies in vesicles isolated from mrp6 expressing Sf9 cells identified the anionic cyclopentapeptide and endothelin receptor antagonist BQ-123 as a substrate of mrp6 (K(m) approximately 17 microM). Besides BQ-123, which is also a substrate of mrp2 (K(m) approximately 124 microM), no other common substrates were found for mrp2, mrp6, and the canalicular bile salt export pump Bsep. The cyclic peptides endothelin I and Arg(8)-vasopressin were transported by mrp2 but not by mrp6. Using a polyclonal antiserum raised against a C-terminal peptide, mrp6 was found to be localized at the lateral and, to a lesser extent, at the canalicular plasma membrane of hepatocytes. The limited overlap of the substrate specificity with the canalicular export pumps mrp2 and Bsep indicates that mrp6 does not play a major role in canalicular organic anion excretion. However, its dual localization at the lateral and canalicular plasma membrane suggests that mrp6 might fulfill a "housekeeping" transport function involved in the regulation of paracellular and/or transcellular solute movement from blood into bile.


Beta-chemokine inhibition of monocytotropic HIV-1 infection. Interference with a postbinding fusion step.
The beta-chemokines RANTES, MIP-1 alpha, and MIP-1 beta have potent suppressive effects on HIV-1 infection resulting from an early postbinding block in virus fusion and entry. Inhibition was observed only with monocytotropic isolates and mapped to the V3 region of the HIV-1 envelope. RANTES did not inhibit virus expression in chronically infected cells or reduce initial virus attachment to the cell membrane. Inhibitory activity required RANTES binding to the target cell but not G protein-mediated signaling or protein tyrosine kinase activity. The results are consistent with a reversible competitive mechanism of virus inhibition that prevents a V3-associated postbinding step in membrane fusion. The data support a role for a RANTES chemokine receptor as a coreceptor for monocytotropic-HIV-1.


Analyzing the antiseptic capacity of silver-functionalized poly(ethylene glycol)-heparin hydrogels after human whole blood exposure.
Advanced blood contacting biomaterials are designed to combine antiseptic and anticoagulant functionalities. Here, we present a new in vitro methodology for the analysis of bacterial adhesion and growth after the preceding human whole blood incubation of the tested materials. Poly(styrene) surfaces as well as thrombin-responsive and non-responsive poly(ethylene glycol)-heparin hydrogel coatings, with and without silver functionalization, were analyzed with this approach using freshly drawn human whole blood and various human pathogens (Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli). Adsorbed blood proteins and adherent immune cells were observed to suppress bacterial colonization on poly(styrene) surfaces. Silver functionalization of responsive and non-responsive poly(ethylene glycol)-heparin hydrogels had no influence on microbial attachment but decreased bacterial proliferation and viability. Whole blood pre-incubation did not affect the antimicrobial properties of the tested silver-modified hydrogels. In sum, our introduced multistage incubation test revealed the antibacterial effects as well as antiseptic-permissive characteristics of blood-borne interfacial layers on polymeric biomaterials.


Reexploration for periampullary carcinoma: resectability, perioperative results, pathology, and long-term outcome.
This single-institution experience retrospectively reviews the outcomes of patients undergoing reexploration for periampullary carcinoma at a high-volume center. Many patients are referred to tertiary centers with periampullary carcinoma after their tumors were deemed unresectable at previous laparotomy. In carefully selected patients, tumor resection is often possible; however, the perioperative results and long-term outcome have not been well defined. From November 1991 through December 1997, 78 patients who underwent previous exploratory laparotomy and/or palliative surgery for suspected periampullary carcinoma underwent reexploration. The operative outcome, resectability rate, pathology, and long-term survival rate were compared with 690 concurrent patients who had not undergone previous exploratory surgery. Fifty-two of the 78 patients (67%) undergoing reexploration underwent successful resection by pancreaticoduodenectomy; the remaining 26 patients (34%) were deemed to have unresectable disease. Compared with the 690 patients who had not undergone recent related surgery, the patients in the reoperative group were similar with respect to gender, race, and resectability rate but were significantly younger. The distribution of periampullary cancers by site in the reoperative group undergoing pancreaticoduodenectomy (n = 52) was 60%, 19%, 15%, and 6% for pancreatic, ampullary, distal bile duct, and duodenal tumors, respectively. These figures were similar to the 65%, 14%, 16% and 5% for resectable periampullary cancers found in the primary surgery group (n = 460). Intraoperative blood loss and transfusion requirements did not differ between the two groups. However, the mean operative time was 7.4 hours in the reoperative group, significantly longer than in the control group. On pathologic examination, reoperative patients had smaller tumors, and the percentage of patients with positive lymph nodes in the resection specimen was significantly less. The incidence of positive margins was similar between the two groups. Postoperative lengths of stay, complication rates, and perioperative mortality rates were not higher in reoperative patients. The long-term survival rate was similar between the two resected groups, with a median survival of 24 months in the reoperative group and 20 months in those without previous exploration. These data demonstrate that patients undergoing reoperation for periampullary carcinoma have similar resectability, perioperative morbidity and mortality, and long-term survival rates as patients undergoing initial exploration. The results suggest that selected patients considered to have unresectable disease at previous surgery should undergo restaging and reexploration at specialized high-volume centers.


Beta-adrenergic modulation of cognitive flexibility during stress.
Stress-induced activation of the locus ceruleus-norepinephrine (LC-NE) system produces significant cognitive and behavioral effects, including enhanced arousal and attention. Improvements in discrimination task performance and memory have been attributed to this stress response. In contrast, for other cognitive functions that require cognitive flexibility, increased activity of the LC-NE system may produce deleterious effects. The aim of the present study was to determine the effect of pharmacological modulation of the LC-NE system on stress-induced impairments in cognitive flexibility performance in healthy individuals. Cognitive performance, plus psychological and physiological parameters for 16 adults without any history of anxiety disorders, was assessed during four test sessions: stress and no-stress, with each condition tested after administration of propranolol and placebo. The Trier Social Stress Test, a public-speaking and mental arithmetic stressor, was presented to participants for the stress sessions, whereas a similar, but nonstressful, control task (reading, counting) was utilized for the no-stress sessions. Tests of cognitive flexibility included lexical-semantic and associative problem-solving tasks (anagrams, Compound Remote Associates Test). Visuo-spatial memory and motor processing speed tests served as control tasks. Results indicate that (1) stress impaired performance on cognitive flexibility tasks, but not control tasks; (2) compared to placebo, cognitive flexibility improved during stress with propranolol. Therefore, psychological stress, such as public speaking, negatively impacts performance on tasks requiring cognitive flexibility in normal individuals, and this effect is reversed by beta-adrenergic antagonism. This may provide support for the hypothesis that stress-related impairments in cognitive flexibility are related to the noradrenergic system.


Cyclic peptide-capped gold nanoparticles for enhanced siRNA delivery.
Previously, we have reported the synthesis of a homochiral l-cyclic peptide [WR]5 and its use for delivery of anti-HIV drugs and biomolecules. A physical mixture of HAuCl4 and the peptide generated peptide-capped gold nanoparticles. Here, [WR]5 and [WR]5-AuNPs were tested for their efficiency to deliver a small interfering RNA molecule (siRNA) in human cervix adenocarcinoma (HeLa) cells. Flow cytometry investigation revealed that the intracellular uptake of a fluorescence-labeled non-targeting siRNA (200 nM) was enhanced in the presence of [WR]5 and [WR]5-AuNPs by 2- and 3.8-fold when compared with that of siRNA alone after 24 h incubation. Comparative toxicity results showed that [WR]5 and [WR]5-AuNPs were less toxic in cells compared to other available carrier systems, such as Lipofectamine.


Organic mercury compounds and autoimmunity.
Based on in vitro studies and short-term in vivo studies, all mercurials were for a long time considered as prototypic immunosuppressive substances. Recent studies have confirmed that organic mercurials such as methyl mercury (MeHg) and ethyl mercury (EtHg) are much more potent immunosuppressors than inorganic mercury (Hg). However, Hg interacts with the immune system in the presence of a susceptible genotype to cause immunostimulation, antinucleolar antibodies targeting fibrillarin, and systemic immune-complex (IC) deposits, a syndrome called Hg-induced autoimmunity (HgIA). Recent studies in mice with a susceptible genotype has revealed that the immunosuppressive effect of MeHg and EtHg will within 1-3 weeks be superseded by immunostimulation causing an HgIA-like syndrome. At equimolar doses of Hg, MeHg has the weakest immunostimulating, autoimmunogen, and IC-inducing effect, while the effect of thimerosal is similar to that of inorganic mercury. The immunosuppression is caused by the organic mercurials per se. Since they undergo rapid transformation to inorganic Hg, studies are being undertaken to delineate the importance of the organic substances per se and the newly formed inorganic Hg for induction of autoimmunity.


Open access publishers: The new players.
The essential role of journals as registries of scientific activity in all areas of knowledge justifies concern about their ownership and type of access. The purpose of this research is to analyze the main characteristics of publishers with journals that have received the DOAJ Seal. The specific objectives are a) to identify publishers and journals registered with the DOAJ Seal; b) to characterize those publishers; and c) to analyze their article processing fees. The research method involved the use of the DOAJ database, the Seal option and the following indicators: publisher, title, country, number of articles, knowledge area, article processing charges in USD, time for publication in weeks, and year of indexing in DOAJ. The results reveal a fast-rising oligopoly, dominated by Springer with 35% of the titles and PLOS with more than 20% of the articles. We've identified three models of expansion: a) a few titles with hundreds of articles; b) a high number of titles with a mix of big and small journals; and c) a high number of titles with medium-size journals. We identify a high number of titles without APCs (27%) in all areas while medicine was found to be the most expensive area. Commercial publishers clearly exercise control over the scope of journals and the creation of new titles, according to the interests of their companies, which are not necessarily the same as those of the scientific community or of society in general.


Pharmacological profile of progestins.
The synthetic progestins used so far for contraception and menopausal hormone therapy are derived either from testosterone (19-nortestosterone derivatives) or from progesterone (17-OH progesterone derivatives and 19-norprogesterone derivatives). Among the 19-nortestosterone derivatives, the estrane group include norethisterone (NET) and its metabolites, and the gonane group include levonorgestrel (LNG) and its derivatives. The later, including desogestrel (DSG) and its derivative etonogestrel, gestodene (GES) and norgestimate (norelgestromin), have been referred to as third-generation progestins. Several new progestins have been synthesized in the last decade and may be considered as a fourth-generation of progestins. Dienogest is referred to as a hybrid progestin being derived from the estrane group with a 17alpha-cyanomethyl group, and drospirenone derives from spirolactone. These two progestins have no androgenic effect but a partial antiandrogenic effect. The later exerts anti-mineralocorticoid effects. This property leads to a decreased salt and water retention and a lowering in blood pressure in users of pills containing this progestin. The 19-norprogesterone derivatives appear more specifically progestational and do not possess any androgenic, estrogenic or glucocorticoid activity. They are referred to as "pure" progestational molecules as they bind almost exclusively to the progesterone receptor (PR) and do not interfere with the other steroid receptor. This category includes, trimegestone, nomegestrol acetate and Nestorone is not active orally but proved to be a potent anti-ovulatory agent when given in implants, vaginal rings or percutaneous gel. Non-androgenic progestins would appear neutral on metabolic factors and on the vessels and would have the advantage of avoiding acnea. Progestins with antiandrogenic properties may also be used for the treatment of women with preexisting androgen related conditions. The progestins available for therapy exhibit profound differences according to their structure or metabolites and it is inappropriate to consider the various effects of the old and new molecules as class-effects.


Integration of ordinal and metric cues in depth processing.
J. Burge, M. A. Peterson, and S. E. Palmer (2005) reported that ordinal, configural cues of familiarity and convexity influence perceived depth even when unambiguous metric information in the form of binocular disparity is available. In their study, a shape that was both convex and familiar (i.e., a face) increased perceived depth in random dot stereograms if the shape was shown in the foreground and decreased perceived depth if it was shown in the background. It is generally assumed that luminance cues are necessary for pre-figural shape representation to influence figure-ground computations in this way (M. A. Peterson & B. S. Gibson, 1993); thus, Burge et al. (2005) had used a luminance edge. In this research, we asked whether configural cues need to be defined by luminance, contrast, or neither. For a sufficiently large disparity pedestal (about 2.5 arcmin), configural cues influenced perceived depth both for second-order contours and for contours defined only by disparity. The integration of ordinal and metric cues seems to be driven by the general saliency of the contours and not only by luminance information. This challenges the notion that the integration of such cues always needs to arise during figure-ground organization through early combinations of luminance-defined shape and binocular disparity.


Bayesian estimation of recent migration rates after a spatial expansion.
Approximate Bayesian computation (ABC) is a highly flexible technique that allows the estimation of parameters under demographic models that are too complex to be handled by full-likelihood methods. We assess the utility of this method to estimate the parameters of range expansion in a two-dimensional stepping-stone model, using samples from either a single deme or multiple demes. A minor modification to the ABC procedure is introduced, which leads to an improvement in the accuracy of estimation. The method is then used to estimate the expansion time and migration rates for five natural common vole populations in Switzerland typed for a sex-linked marker and a nuclear marker. Estimates based on both markers suggest that expansion occurred <10,000 years ago, after the most recent glaciation, and that migration rates are strongly male biased.


Ultrasonographic examination reduces the percentage of unsuccessful inseminations in dairy cows.
The objective of this study was to investigate whether confirmation of suitability for service by traditional methods, observation and transrectal palpation, is improved in cattle by additional ultrasonographic examination of the uterus and ovaries. The data from 600 lactating cows from Southern Germany submitted for the first service and alternately assigned to manual (group M, n = 301) and manual and sonographic examination (group S, n = 299) were evaluated. Cows of group M with a large, soft follicle with an estimated diameter of 12.0 to 22.5 mm, without a palpable CL (>10 mm), and with a contractile uterus without palpable content were considered suitable for service and inseminated. Cows of group S with a soft follicle measuring 12.0 to 22.5 mm, without a CL (>10 mm), and with a contractile uterus and no echoic content were inseminated. Pregnancy was determined by ultrasonography at 28 to 35 days after the first service. In group S, 10.9% fewer cows (P = 0.003) were considered suitable for service than in group M. The main reason (29.6%) for exclusion from service in group S was the presence of a CL greater than 10 mm in addition to a preovulatory follicle (12.0-22.5 mm), which was diagnosed less frequently in group M (4.5%; P < 0.0001). The first-service conception rate tended to be higher in group S than in group M (62.7% vs. 54.9%; P = 0.10), and the percentage of open cows, based on all cows submitted for service, was higher in group M than in group S (35.2% vs. 25.1%; P = 0.007). We concluded that sonographic examination of cows submitted for service facilitates the exclusion from service of proestrous and diestrous cows and reduces the number of pointless services.


Mathematical modeling of the thermal effects of irreversible electroporation for in vitro, in vivo, and clinical use: a systematic review.
Introduction: Irreversible electroporation (IRE) is a relatively new ablation method for the treatment of unresectable cancers. Although the main mechanism of IRE is electric permeabilization of cell membranes, the question is to what extent thermal effects of IRE contribute to tissue ablation.Aim: This systematic review reviews the mathematical models used to numerically simulate the heat-generating effects of IRE, and uses the obtained data to assess the degree of mild-hyperthermic (temperatures between 40 °C and 50 °C) and thermally ablative (TA) effects (temperatures exceeding 50 °C) caused by IRE within the IRE-treated region (IRE-TR).Methods: A systematic search was performed in medical and technical databases for original studies reporting on numerical simulations of IRE. Data on used equations, study design, tissue models, maximum temperature increase, and surface areas of IRE-TR, mild-hyperthermic, and ablative temperatures were extracted.Results: Several identified models, including Laplace equation for calculation of electric field distribution, Pennes Bioheat Equation for heat transfer, and Arrhenius model for thermal damage, were applied on various electrode and tissue models. Median duration of combined mild-hyperthermic and TA effects is 20% of the treatment time. Based on the included studies, mild-hyperthermic temperatures occurred in 30% and temperatures ≥50 °C in 5% of the IRE-TR.Conclusions: Simulation results in this review show that significant mild-hyperthermic effects occur in a large part of the IRE-TR, and direct thermal ablation in comparatively small regions. Future studies should aim to optimize clinical IRE protocols, maintaining a maximum irreversible permeabilized region with minimal TA effects.


A temporal analysis of QMR.
To understand better the trade-offs of not incorporating explicit time in Quick Medical Reference (QMR), a diagnostic system in the domain of general internal medicine, along the dimensions of expressive power and diagnostic accuracy. The study was conducted in two phases. Phase I was a descriptive analysis of the temporal abstractions incorporated in QMR's terms. Phase II was a pseudo-prospective controlled experiment, measuring the effect of history and physical examination temporal content on the diagnostic accuracy of QMR. For each QMR finding that would fit our operational definition of temporal finding, several parameters describing the temporal nature of the finding were assessed, the most important ones being: temporal primitives, time units, temporal uncertainty, processes, and patterns. The history, physical examination, and initial laboratory results of 105 consecutive patients admitted to the Pittsburgh University Presbyterian Hospital were analyzed for temporal content and factors that could potentially influence diagnostic accuracy (these included: rareness of primary diagnosis, case length, uncertainty, spatial/causal information, and multiple diseases). 776 findings were identified as temporal. The authors developed an ontology describing the terms utilized by QMR developers to express temporal knowledge. The authors classified the temporal abstractions found in QMR in 116 temporal types, 11 temporal templates, and a temporal hierarchy. The odds of QMR's making a correct diagnosis in high temporal complexity cases is 0.7 the odds when the temporal complexity is lower, but this result is not statistically significant (95% confidence interval = 0.27-1.83). QMR contains extensive implicit time modeling. These results support the conclusion that the abstracted encoding of time in the medical knowledge of QMR does not induce a diagnostic performance penalty.


GM1 Gangliosidosis-A Mini-Review.
GM1 gangliosidosis is a progressive, neurosomatic, lysosomal storage disorder caused by mutations in the GLB1 gene encoding the enzyme β-galactosidase. Absent or reduced β-galactosidase activity leads to the accumulation of β-linked galactose-containing glycoconjugates including the glycosphingolipid (GSL) GM1-ganglioside in neuronal tissue. GM1-gangliosidosis is classified into three forms [Type I (infantile), Type II (late-infantile and juvenile), and Type III (adult)], based on the age of onset of clinical symptoms, although the disorder is really a continuum that correlates only partially with the levels of residual enzyme activity. Severe neurocognitive decline is a feature of Type I and II disease and is associated with premature mortality. Most of the disease-causing β-galactosidase mutations reported in the literature are clustered in exons 2, 6, 15, and 16 of the GLB1 gene. So far 261 pathogenic variants have been described, missense/nonsense mutations being the most prevalent. There are five mouse models of GM1-gangliosidosis reported in the literature generated using different targeting strategies of the Glb1 murine locus. Individual models differ in terms of age of onset of the clinical, biochemical, and pathological signs and symptoms, and overall lifespan. However, they do share the major abnormalities and neurological symptoms that are characteristic of the most severe forms of GM1-gangliosidosis. These mouse models have been used to study pathogenic mechanisms, to identify biomarkers, and to evaluate therapeutic strategies. Three GLB1 gene therapy trials are currently recruiting Type I and Type II patients (NCT04273269, NCT03952637, and NCT04713475) and Type II and Type III patients are being recruited for a trial utilizing the glucosylceramide synthase inhibitor, venglustat (NCT04221451).


The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis.
Patients in whom acid-fast bacilli smear-positive pulmonary tuberculosis was newly diagnosed were randomized to receive 400 mg moxifloxacin, 300 mg isonaizid, or 600 mg rifampin daily for 5 days. Sixteen-hour overnight sputa collections were made for the 2 days before and for 5 days of monotherapy. Bactericidal activity was estimated by the time taken to kill 50% of viable bacilli (vt50) and the fall in sputum viable count during the first 2 days designated as the early bactericidal activity (EBA). The mean vt50 of moxifloxacin was 0.88 days (95% confidence interval [CI], 0.43-1.33 days) and the mean EBA was 0.53 (95% CI 0.28-0.79). For the isoniazid group, the mean vt50 was 0.46 days (95% CI, 0.31-0.61 days) and the mean EBA was 0.77 (95% CI, 0.54-1.00). For rifampin, the mean vt50 was 0.71 days (95% CI, 0.48-0.95 days) and the mean EBA was 0.28 (95% CI, 0.15-0.41). Using the EBA method, isoniazid was significantly more active than rifampin (p < 0.01) but not moxifloxacin. Using the vt50 method, isoniazid was more active than both rifampin and moxifloxacin (p = 0.03). Moxifloxacin has an activity similar to rifampin in human subjects with pulmonary tuberculosis, suggesting that it should undergo further assessment as part of a short course regimen for the treatment of drug-susceptible tuberculosis.


Evolution of diversity in Albugo is driven by high host specificity and multiple speciation events on closely related Brassicaceae.
The Albuginaceae, responsible for white blister rust disease on various angiosperms, are obligate biotrophic oomycetes that are only distantly related to downy mildews (Peronosporaceae). Their diversity has been much underestimated during the past decades, mainly because of the paucity of morphological characters for species delimitation, which led to the application of a broad species concept. Recent phylogenetic analyses have revealed three new species within Albugo parasitic to Brassicaceae, but the overall evolution of these plant pathogens remains poorly understood. Especially the diversity of Albugo in various plant genera is almost completely unknown. Based on ITS and cox2 sequence data of 72 Albugo specimens, predominantly from herbarium archives, and focusing on the widespread genus Cardamine, a high degree of phylogenetic diversity was revealed in Albugo. In particular, the hypothesis that one host genus can be colonised by more than one white blister rust species is confirmed. In addition, it is revealed that there are hitherto overlooked lineages with close relationships to the generalist species Albugo candida. Evidence for at least three different species of Albugo infecting Cardamine is presented in this study. Based on molecular phylogenetic and morphological data three new white blister rust species are described, Albugo hohenheimia, Albugo hesleri, and Albugo leimonios infecting Cardamine hirsuta, Cardamine diphylla and Cardamine pratensis, respectively. The fact that these species each have different ecological niches, suggests that environmental factors may have played a role in the speciation process in Albugo. Our findings suggest that other larger genera of the Brassicaceae may harbour unrecognized white blister rust species and that only a small fraction of the true biodiversity of white blister rusts is known at present.


Post-transcriptional regulation of alpha-smooth muscle actin determines the contractile phenotype of Dupuytren's nodular cells.
The objective was to study Dupuytren's myofibroblast cells in constrained collagen matrices in order to more closely emulate their in vivo environment and, to correlate their contractility with alpha-smooth muscle actin (alpha-SMA) expression and determine if dermal fibroblasts regulate Dupuytren's myofibroblast phenotype. Isotonic and isometric force contraction by cells isolated from Dupuytren's nodules, palmar and non-palmar skin fibroblasts was measured in collagen matrices. The effect of co-culturing nodule cells with dermal fibroblasts on isometric contraction was examined. Isometric contraction was correlated with levels of alpha-SMA mRNA by pcr and protein by Western blotting, and alpha-SMA distribution assessed by immunofluorescence. Dupuytren's nodule cells exhibited similar levels of isotonic contraction to both palmar and non-palmar dermal fibroblasts. However, nodule cells generated high levels of isometric force (mean: 3.5 dynes/h), which continued to increase over 24 h to a maximum of 173 dynes. In contrast, dermal fibroblasts initially exhibited low levels of contraction (mean: 0.5 dynes/h) and reached tensional homeostasis on average after 15 h (range: 4-20 h), with a maximum force of 52 dynes. Although all three cell types had similar alpha-SMA mRNA levels, increased levels of alpha-SMA protein were observed in nodule cells compared to dermal fibroblasts. alpha-SMA localised to stress fibres in 35% (range: 26-50%) of nodule cells compared to only 3% (range:0-6%) of dermal fibroblasts. Co-cultures of Dupuytren's cells and dermal fibroblasts showed no contractile differences. The contractile phenotype of Dupuytren's myofibroblasts is determined by increased alpha-SMA protein distributed in stress fibres, not by cellular mRNA levels. Dupuytren's cell contractility is not influenced by dermal fibroblasts.


Dietary Chlorella vulgaris Ameliorates Altered Immunomodulatory Functions in Cyclophosphamide-Induced Immunosuppressive Mice.
Based on the well-known toxicity of cyclophosphamide (CYP) on the immune system, this research investigated the modulating effects of the long-term dietary Chlorella vulgaris (CV) supplementation on the immunosuppression induced by CYP in mice, in order to provide a novel dietary design to mitigate the side effects of CYP therapy. Control, CYP-treated, CYP + CV (6%), CYP + CV (12%) and CYP + CV (24%) were used for 6 weeks, CV supplement in diet recovered the significantly reduced immunological function in CYP treated mice. As CV may have a modulating function through the inducible expression of cytokines, we assayed the expressions of interleukin-2 (IL-2), interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Our results suggested that CYP significantly reduced the lymphocytes proliferation and phagocytic activities of macrophages, and stimulated the production of IL-2, IL-12, TNF-α and IFN-γ and that this impairment has been successfully adjusted by CV supplementation. Treatment with the algae also enhanced the natural killer (NK) cells cytotoxicity, and ameliorate histological changes of the spleen in CYP-treated mice. Therefore, as we found in this study, a diet supplemented with whole CV has beneficial effects on CVP-induced immunosuppression, through its immunomodulatory potential.


Calprotectin: from biomarker to biological function.
The incidence of inflammatory bowel diseases (IBD) emerged with Westernisation of dietary habits worldwide. Crohn's disease and ulcerative colitis are chronic debilitating conditions that afflict individuals with substantial morbidity and challenge healthcare systems across the globe. Since identification and characterisation of calprotectin (CP) in the 1980s, faecal CP emerged as significantly validated, non-invasive biomarker that allows evaluation of gut inflammation. Faecal CP discriminates between inflammatory and non-inflammatory diseases of the gut and portraits the disease course of human IBD. Recent studies revealed insights into biological functions of the CP subunits S100A8 and S100A9 during orchestration of an inflammatory response at mucosal surfaces across organ systems. In this review, we summarise longitudinal evidence for the evolution of CP from biomarker to rheostat of mucosal inflammation and suggest an algorithm for the interpretation of faecal CP in daily clinical practice. We propose that mechanistic insights into the biological function of CP in the gut and beyond may facilitate interpretation of current assays and guide patient-tailored medical therapy in IBD, a concept warranting controlled clinical trials.


Polarized thermal radiation by layer-by-layer metallic emitters with sub-wavelength grating.
Metallic thermal emitters consisting of two layers of differently structured nickel gratings on a homogeneous nickel layer are fabricated by soft lithography and studied for polarized thermal radiation. A thermal emitter in combination with a sub-wavelength grating shows a high extinction ratio, with a maximum value close to 5, in a wide mid-infrared range from 3.2 to 7.8 mum, as well as high emissivity up to 0.65 at a wavelength of 3.7 microm. All measurements show good agreement with theoretical predictions. Numerical simulations reveal that a high electric field exists within the localized air space surrounded by the gratings and the intensified electric-field is only observed for the polarizations perpendicular to the top sub-wavelength grating. This result suggests how the emissivity of a metal can be selectively enhanced at a certain range of wavelengths for a given polarization.


[Changes in the 24-hour rhythm of plasma melatonin in patients with liver cirrhosis--relation to sleep architecture].
To assess the 24 hr plasma melatonin profile as a marker of the output rhythm from the circadian clock and to study sleep diaries as reflection of subjective sleep quality in patients with liver cirrhosis. Prospective cohort study. A total of 14 subjects, 7 non-alcoholic cirrhotics and 7 age-, sex-, and educationally-matched controls. Exclusion criteria were factors that could affect melatonin levels (intercontinental travel, shift work, therapy with betablockers or corticosteroids). Plasma melatonin was measured every 30 min for 24 hr by radioimmuno assay and sleep recordings by polysomnography. Neuropsychological testing included visual reaction time. Trailmaking test A and B and the Digit Symbol Test. Sleep diaries were kept for the week prior to admission. Time of onset of melatonin rise was displaced from 19:50 +/- 26 min in the controls to 21:30 +/- 13 min (p = 0.013) in patients with liver cirrhosis. The time of peak melatonin levels was consistently and significantly delayed from 00:36 +/- 33 min in controls to 5:36 +/- 29 min (p < 0.001) in patients. Cirrhotic subjects showed markedly elevated melatonin levels during daytime, when melatonin is normally absent. Polysomnographic tracings showed no differences in patients and controls, but sleep diaries indicated more frequent nocturnal awakenings (p = 0.05) and daytime naps. A marked alteration of plasma melatonin rhythm is found in cirrhotic patients with subclinical hepatic encephalopathy. This disruption may reflect changes in the output of the circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. It is possible that some of the metabolic disturbances that lead to hepatic encephalopathy may also alter the function of the biological "clock".


Cognitive performance among the elderly in relation to the intake of plant foods. The Hordaland Health Study.
Fruits and vegetables are among the most nutritious and healthy of foods, and are related to the prevention of many chronic diseases. The aim of the study was to examine the relationship between intake of different plant foods and cognitive performance in elderly individuals in a cross-sectional study. Two thousand and thirty-one elderly subjects (aged 70-74 years; 55% women) recruited from the general population in Western Norway underwent extensive cognitive testing and completed a comprehensive FFQ. The cognitive test battery covered several domains (Kendrick Object Learning Test, Trail Making Test--part A, modified versions of the Digit Symbol Test, Block Design, Mini-Mental State Examination and Controlled Oral Word Association Test). A validated and self-reported FFQ was used to assess habitual food intake. Subjects with intakes of >10th percentile of fruits, vegetables, grain products and mushrooms performed significantly better in cognitive tests than those with very low or no intake. The associations were strongest between cognition and the combined intake of fruits and vegetables, with a marked dose-dependent relationship up to about 500 g/d. The dose-related increase of intakes of grain products and potatoes reached a plateau at about 100-150 g/d, levelling off or decreasing thereafter, whereas the associations were linear for mushrooms. For individual plant foods, the positive cognitive associations of carrots, cruciferous vegetables, citrus fruits and high-fibre bread were most pronounced. The only negative cognitive association was with increased intake of white bread. In the elderly, a diet rich in plant foods is associated with better performance in several cognitive abilities in a dose-dependent manner.


A PDRMIP multi-model study on the impacts of regional aerosol forcings on global and regional precipitation.
Atmospheric aerosols such as sulfate and black carbon (BC) generate inhomogeneous radiative forcing and can affect precipitation in distinct ways compared to greenhouse gases (GHGs). Their regional effects on the atmospheric energy budget and circulation can be important for understanding and predicting global and regional precipitation changes, which act on top of the background GHG-induced hydrological changes. Under the framework of the Precipitation Driver Response Model Inter-comparison Project (PDRMIP), multiple models were used for the first time to simulate the influence of regional (Asian and European) sulfate and BC forcing on global and regional precipitation. The results show that, as in the case of global aerosol forcing, the global fast precipitation response to regional aerosol forcing scales with global atmospheric absorption, and the slow precipitation response scales with global surface temperature response. Asian sulphate aerosols appear to be a stronger driver of global temperature and precipitation change compared to European aerosols, but when the responses are normalised by unit radiative forcing or by aerosol burden change, the picture reverses, with European aerosols being more efficient in driving global change. The global apparent hydrological sensitivities of these regional forcing experiments are again consistent with those for corresponding global aerosol forcings found in the literature. However, the regional responses and regional apparent hydrological sensitivities do not align with the corresponding global values. Through a holistic approach involving analysis of the energy budget combined with exploring changes in atmospheric dynamics, we provide a framework for explaining the global and regional precipitation responses to regional aerosol forcing.


Histomorphological analysis of the urogenital diaphragm in elderly women: a cadaver study.
The objective of this study was to describe the histomorphological structure of the urogenital diaphragm in elderly women using a modern morphometric procedure. Biopsies were taken from the posterior margin of the urogenital diaphragm of 22 female cadavers (mean age, 87 years) using a 60-mm punch. Hematoxylin/eosin and Goldner sections were analyzed with the Cavalieri estimator. The mean thickness of the urogenital diaphragm was 5.5 mm. The main component was connective tissue. All biopsies contained smooth muscle. Eighteen biopsies contained more smooth muscle than striated muscle. In six of 22 biopsies, no striated muscle was found. The ratio of striated to smooth muscle to connective tissue was 1:2.3:13.3. Muscle fibers were dispersed in all parts of the urogenital diaphragm. The urogenital diaphragm of elderly women mainly consists of connective tissue. Smooth muscle was also found but to a lesser extent. The frequently used English term "perineal membrane" for the urogenital diaphragm is justified and well describes our findings in elderly women.


Large aperture segmented optics for space-to-ground communications.
A large aperture, moderate quality segmented optical array for use in noncoherent space-to-ground laser communications is determined as a function of resolution, diameter, focal length, and number of segments in the array. Secondary optics and construction tolerances are also discussed. Performance predictions show a typical receiver to be capable of megahertz communications at Mars distances during daylight operation.


Robust spatiotemporal matching of electronic slides to presentation videos.
We describe a robust and efficient method for automatically matching and time-aligning electronic slides to videos of corresponding presentations. Matching electronic slides to videos provides new methods for indexing, searching, and browsing videos in distance-learning applications. However, robust automatic matching is challenging due to varied frame composition, slide distortion, camera movement, low-quality video capture, and arbitrary slides sequence. Our fully automatic approach combines image-based matching of slide to video frames with a temporal model for slide changes and camera events. To address these challenges, we begin by extracting scale-invariant feature-transformation (SIFT) keypoints from both slides and video frames, and matching them subject to a consistent projective transformation (homography) by using random sample consensus (RANSAC). We use the initial set of matches to construct a background model and a binary classifier for separating video frames showing slides from those without. We then introduce a new matching scheme for exploiting less distinctive SIFT keypoints that enables us to tackle more difficult images. Finally, we improve upon the matching based on visual information by using estimated matching probabilities as part of a hidden Markov model (HMM) that integrates temporal information and detected camera operations. Detailed quantitative experiments characterize each part of our approach and demonstrate an average accuracy of over 95% in 13 presentation videos.


Evidence-based training and certification: the ERS thoracic ultrasound training programme.
Thoracic ultrasound has developed into an integral part of the respiratory physician's diagnostic and therapeutic toolbox, with high diagnostic accuracy for many diseases causing acute or chronic respiratory symptoms. However, it is vitally important that the operator has received the appropriate education and training to ensure a systematic and thorough examination, correct image interpretation, and that they then have the appropriate skills to integrate all the findings for patient benefit. In this review, we present the new European Respiratory Society thoracic ultrasound training programme, including a discussion of curriculum development, its implementation, and trainee evaluation. This programme enables participants to gain competence in thoracic ultrasound through structured, evidence-based training with robustly validated assessments and certification. The training programme consists of three components: an online, theoretical part (part 1), which is accessible all year; a practical course (part 2), with four courses held each year (two online courses and two on-site courses); and an examination (part 3) comprising an objective structured clinical examination (OSCE), which is hosted each year at the European Respiratory Society Congress.


Diagnostic performance and therapeutic impact of LightCycler SeptiFast assay in patients with suspected sepsis.
Rapid and reliable identification of pathogens is very important in the management of septic patients. We retrospectively evaluated the diagnostic accuracy and clinical utility of a multiplex real-time polymerase chain reaction (PCR) assay (SeptiFast (SF)) in patients with suspected sepsis in a tertiary care hospital in Tallinn, Estonia. A total of 160 blood samples from 144 patients were included in the study. SF results were compared with corresponding blood culture (BC) results. The concordance between SF and BC was 78.8%. The rate of positive results was significantly higher in SF than in BC (33.7% vs. 21.2%, respectively; p < 0.001). A total of 27 samples were found positive by both SF and BC, 27 by SF only, and seven by BC only. Of a total of 83 microorganisms detected SF identified 71, and BC 42 (p < 0.001). SF detected markedly more patients with candidemia: 11 patients were detected by SF compared to four patients by BC. Antimicrobial treatment was changed in 21 (38.9%) of 54 SF positive cases. In conclusion, our results demonstrated the high diagnostic accuracy of SF in detection of sepsis pathogens. In conjunction with its impact on therapeutic decisions, SF proved to be a useful adjunct to conventional blood culture in the diagnosis of sepsis etiology.


beta-Sheet structured beta-amyloid(1-40) perturbs phosphatidylcholine model membranes.
The disruption of intracellular calcium homeostasis plays a central role in the pathology of Alzheimer's disease, which is also characterized by accumulation of the amyloid-beta peptides Abeta40 and Abeta42. These amphipathic peptides may become associated with neuronal membranes and affect their barrier function, resulting in the loss of calcium homeostasis. This suggestion has been extensively investigated by exposing protein-free model membranes, either vesicles or planar bilayers, to soluble Abeta. Primarily unstructured Abeta has been shown to undergo a membrane-induced conformational change to either primarily beta-structure or helical structure, depending, among other factors, on the model membrane composition. Association of Abeta renders lipid bilayers permeable to ions but there is dispute whether this is due to the formation of discrete transmembrane ion channels of Abeta peptides, or to a non-specific perturbation of bilayer integrity by lipid head group-associated Abeta. Here, we have attempted incorporation of Abeta in the hydrophobic core of zwitterionic bilayers, the most simple model membrane system, by preparing proteoliposomes by hydration of a mixed film of Abeta peptides and phosphatidylcholine (PC) lipids. Despite the use of a solvent mixture in which Abeta40 and Abeta42 are almost entirely helical, the Abeta analogs were beta-structured in the resulting vesicle dispersions. When Abeta40-containing vesicles were fused into a zwitterionic planar bilayer, the typical irregular "single channel-like" conductance of Abeta was observed. The maximum conductance increased with additional vesicle fusion, while still exhibiting single channel-like behavior. Supported bilayers formed from Abeta40/PC vesicles did not exhibit any channel-like topological features, but the bilayer destabilized in time. Abeta40 was present primarily as beta-sheets in supported multilayers formed from the same vesicles. The combined observations argue for a non-specific perturbation of zwitterionic bilayers by surface association of small amphipathic Abeta40 assemblies.


Planned postradiotherapy neck dissection in patients with advanced head and neck cancer.
Metastatic neck nodes in patients with squamous cell carcinoma of the head and neck are most commonly managed by surgery, radiotherapy, or combined-modality therapy. For combined-modality cases, the sequencing of surgery and radiotherapy is generally guided by which modality is considered preferable for treatment of the primary tumor. A postradiotherapy neck dissection is often considered for those patients with > N1 disease in which the primary is treated with radiotherapy alone. Between February 1991 and October 1995, 25 patients with node-positive squamous cell carcinoma of the head and neck were treated with planned unilateral (n = 22) or bilateral (n = 3) neck dissection following high-dose radiotherapy. The primary tumor sites included: tongue base (n = 11), tonsil (n = 6), nasopharynx (n = 3), pyriform sinus (n = 2), supraglottic larynx, (n = 1), soft palate (n = 1), and unknown head and neck primary (n = 1). The specific nodal stage breakdown of the 28 individual neck dissections (25 patients) was N1 (n = 1), N2A (n = 5), N2B (n = 15), N3 (n = 7). Nineteen of the 28 neck dissections (68%) demonstrated no evidence of residual carcinoma. Of the nine positive neck dissections, six revealed malignant cells in a single nodal echelon. The 1- and 2-year rate of neck control in all 25 patients was 100% and 93%, respectively. The 1- and 2-year disease-specific survival for all 25 patients was 83% and 60%, respectively. With a minimum follow-up of 2 years, 64% of the 25 patients remain alive with no evidence of disease or dead of non-cancer causes. In this series of postradiotherapy neck dissections, two thirds of the dissections demonstrated no evidence of residual tumor (19/28, or 68%). However, there was not a direct correlation between pretreatment nodal size (neck staging), radiation dose delivered, and the likelihood of achieving a cancer-free neck dissection. Only one of 28 postradiotherapy neck dissections identified tumor outside of nodal stations II-IV. The predictable pattern of residual disease in pathologically positive cases suggests that a selective neck dissection encompassing levels II-IV may be appropriate in a majority of patients.


DrugE-Rank: improving drug-target interaction prediction of new candidate drugs or targets by ensemble learning to rank.
Identifying drug-target interactions is an important task in drug discovery. To reduce heavy time and financial cost in experimental way, many computational approaches have been proposed. Although these approaches have used many different principles, their performance is far from satisfactory, especially in predicting drug-target interactions of new candidate drugs or targets. Approaches based on machine learning for this problem can be divided into two types: feature-based and similarity-based methods. Learning to rank is the most powerful technique in the feature-based methods. Similarity-based methods are well accepted, due to their idea of connecting the chemical and genomic spaces, represented by drug and target similarities, respectively. We propose a new method, DrugE-Rank, to improve the prediction performance by nicely combining the advantages of the two different types of methods. That is, DrugE-Rank uses LTR, for which multiple well-known similarity-based methods can be used as components of ensemble learning. The performance of DrugE-Rank is thoroughly examined by three main experiments using data from DrugBank: (i) cross-validation on FDA (US Food and Drug Administration) approved drugs before March 2014; (ii) independent test on FDA approved drugs after March 2014; and (iii) independent test on FDA experimental drugs. Experimental results show that DrugE-Rank outperforms competing methods significantly, especially achieving more than 30% improvement in Area under Prediction Recall curve for FDA approved new drugs and FDA experimental drugs. http://datamining-iip.fudan.edu.cn/service/DrugE-Rank firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Self-consistent tumor control probability and normal tissue complication probability models based on generalized EUD.
Traditional methods to compute the tumor control probability (TCP) or normal tissue complication probability (NTCP) typically require a heterogeneous radiation dose distribution to be converted into a simple uniform dose distribution with an equivalent biological effect. Several power-law type dose-volume-histogram reduction schemes, particularly Niemierko's generalized equivalent uniform dose model [Med. Phys. 26, 1000 (1999)], have been proposed to achieve this goal. In this study, we carefully examine the mathematical outcome of these schemes. We demonstrate that (1) for tumors, with each tumor cell independently responding to local radiation dose, a closed-form analytical solution for tumor survival fraction and TCP can be obtained; (2) for serial structured normal tissues, an exponential power-law form relating survival to functional sub-unit (FSU) radiation is required, and a closed-form analytical solution for the related NTCP is provided; (3) in the case of a parallel structured normal tissue, when NTCP is determined solely by the number of the surviving FSUs, a mathematical solution is available only when there is a non-zero threshold dose and/or a finite critical dose defining the radiotherapy response. Some discussion is offered for the partial irradiation effect on normal tissues in this category; (4) for normal tissues with alternative architectures, where the radiation response of FSU is inhomogeneous, there is no exact global mathematical solution for SF or NTCP within the available schemes. Finally, numerical fits of our models to some experimental data are also presented.


An identified motoneuron with variable fates in embryonic zebrafish.
Every trunk hemisegment of the zebrafish is innervated by 3 identified primary motoneurons whose development can be observed directly in living embryos. In this paper, we describe another identified neuron that is part of this system. Unlike the other primary motoneurons which are present in all trunk hemisegments, this cell is present in slightly less than half of the trunk hemisegments. Additionally, this cell has at least 2 different fates: it may become a primary motoneuron and arborize in an exclusive muscle territory, or it may die during embryonic development. We have named this cell VaP, for variable primary. We show that the presence of VaP does not affect the early development of the other primary motoneurons in the same hemisegment. Moreover, we show that ablation of both VaP and caudal primary does not alter pathfinding by another identified primary motoneuron.


Two- to 4-Year Followup of a Short Stem THA Construct: Excellent Fixation, Thigh Pain a Concern.
Short stem cementless femoral components were developed to aid insertion through smaller incisions, preserve metaphyseal bone, and potentially decrease or limit the incidence of thigh pain. Despite some clinical success, the senior author (DDG) believed a higher percentage of his patients who had received a cementless short stem design were experiencing thigh pain, which, coupled with concerns about bone ingrowth fixation, motivated the review of this case series. (1) What is the proportion of patients treated with a short stem cementless THA femoral component that develop thigh pain and what are the hip scores of this population? (2) What are the radiographic results, specifically with respect to bone ingrowth fixation and stress shielding, of this design? (3) Are there particular patient or procedural factors that are associated with thigh pain with this short stem design? Two hundred sixty-one primary THAs were performed in 238 patients by one surgeon between November 2010 and August 2012. During this time period, all patients undergoing primary THA by this surgeon received the same cementless short titanium taper stem. Seven patients (eight hips) died and five patients (five hips) were lost to followup, leaving 226 patients (248 hips) with a mean followup of 3 years (range, 2-5 years). Patients rated their thigh pain during activity or rest at final followup on a 10-point visual analog scale. Harris hip scores (HHS) were obtained at every clinic appointment. Thigh pain was evaluated at the final followup or by contacting the patient by phone. Radiographs were evaluated for bone-implant fixation, bone remodeling, and osteolysis. An attempt was made to correlate thigh pain with patient demographics, implant specifications, or radiographic findings. Seventy-six percent of hips (180 of 238) had no thigh pain, 16% of hips (37 of 238) had mild thigh pain, and 9% (21 of 238) had moderate or severe thigh pain. Preoperatively, mean HHS was 47 (SD, 16) and at last followup, mean HHS was 88 (SD, 13). There were two femoral revisions, one for severe thigh pain and the other for infection. All but two components demonstrated bone ingrowth fixation (99%). Femoral stress shielding was mild in 64% of hips (135 of 212), moderate in 0.5% (one of 212), and severe in no hips. There is an inverse linear relationship between age and severity of thigh pain (r = -0.196; p < 0.0024). Although reliable fixation was achieved and good HHS were attained, the frequency and severity of thigh pain with this short cementless stem were concerning. The surgeon has subsequently abandoned this short stem design and returned to a conventional length stem. Future study direction might investigate the biomechanical grounds for the thigh pain associated with this stem design. Level IV, therapeutic study.


Do we have a "best practice" for treating high altitude pulmonary edema?
High-altitude pulmonary edema (HAPE) is a rare, but potentially fatal, non-cardiogenic pulmonary edema that affects unacclimatized lowlanders ascending to altitudes above 2500 m. A review of the literature on the disease suggests that a wide range of strategies is employed for treatment purposes. This situation raises questions as to whether a "best practice" exists for treating HAPE and whether clinicians are using greater measures than necessary to ensure good outcomes. This review considers these issues in greater detail, examining the current state of research and clinical practice in HAPE treatment, addressing important questions raised by documented treatment practices, such as the utility of beta agonists, acetazolamide and diuretics and, finally, proposing reasonable, parsimonious treatment approaches that reflect the setting in which the patient is being treated.


Monocyte-dependent oncostatin M and TNF-alpha synergize to stimulate unopposed matrix metalloproteinase-1/3 secretion from human lung fibroblasts in tuberculosis.
Leukocyte-derived matrix metalloproteinases (MMP) are implicated in the tissue destruction characteristic of tuberculosis (TB). The contribution of lung stromal cells to MMP activity in TB is unknown. Oncostatin M (OSM) is an important stimulus to extrapulmonary stromal MMP induction, but its role in regulation of pulmonary MMP secretion or pathophysiology of TB is unknown. We investigated OSM secretion from Mycobacterium tuberculosis (Mtb)-infected human monocytes/macrophages and the networking effects of such OSM on lung fibroblast MMP secretion. Mtb increased monocyte OSM secretion dose dependently in vitro. In vivo tuberculous granulomas immunostained positively for OSM. Further, conditioned media from Mtb-infected monocytes (CoMTb) induced monocyte OSM secretion (670 +/- 55 versus 166 +/- 14 pg/mL in controls), implicating an autocrine loop. Mtb-induced OSM secretion was prostaglandin (PG) sensitive, and required activation of surface G-protein coupled receptors. OSM induction was ERK MAP kinase dependent, p38-requiring but JNK-independent. OSM synergized with TNF-alpha, a key cytokine in TB granuloma formation, to stimulate pulmonary fibroblast MMP-1/-3 secretion, while suppressing secretion of tissue inhibitors of metalloproteinases-1/-2. In summary, Mtb infection of monocytes results in PG-dependent OSM secretion, which synergizes with TNF-alpha to drive functionally unopposed fibroblast MMP-1/-3 secretion, demonstrating a previously unrecognized role for OSM in TB.


Using global statistical tests in long-term Parkinson's disease clinical trials.
Parkinson's disease (PD) impairments are multidimensional, making it difficult to choose a single primary outcome when evaluating treatments to stop or lessen the long-term decline in PD. We review commonly used multivariate statistical methods for assessing a treatment's global impact, and we highlight the novel Global Statistical Test (GST) methodology. We compare the GST to other multivariate approaches using data from two PD trials. In one trial where the treatment showed consistent improvement on all primary and secondary outcomes, the GST was more powerful than other methods in demonstrating significant improvement. In the trial where treatment induced both improvement and deterioration in key outcomes, the GST failed to demonstrate statistical evidence even though other techniques showed significant improvement. Based on the statistical properties of the GST and its relevance to overall treatment benefit, the GST appears particularly well suited for a disease like PD where disability and impairment reflect dysfunction of diverse brain systems and where both disease and treatment side effects impact quality of life. In future long term trials, use of GST for primary statistical analysis would allow the assessment of clinically relevant outcomes rather than the artificial selection of a single primary outcome.


Reassortant low-pathogenic avian influenza H5N2 viruses in African wild birds.
To investigate the presence and persistence of avian influenza virus in African birds, we monitored avian influenza in wild and domestic birds in two different regions in Nigeria. We found low-pathogenic avian influenza (LPAI) H5N2 viruses in three spur-winged geese (Plectropterus gambensis) in the Hadejia-Nguru wetlands. Phylogenetic analyses revealed that all of the genes, except the non-structural (NS) genes, of the LPAI H5N2 viruses were more closely related to genes recently found in wild and domestic birds in Europe. The NS genes formed a sister group to South African and Zambian NS genes. This suggested that the Nigerian LPAI H5N2 viruses found in wild birds were reassortants exhibiting an NS gene that circulated for at least 7 years in African birds and is part of the African influenza gene pool, and genes that were more recently introduced into Africa from Eurasia, most probably by intercontinental migratory birds. Interestingly the haemagglutinin and neuraminidase genes formed a sister branch to highly pathogenic avian influenza (HPAI) H5N2 strains found in the same wild bird species in the same wetland only 1 year earlier. However, they were not the closest known relatives of each other, suggesting that their presence in the wetland resulted from two separate introductions. The presence of LPAI H5N2 in wild birds in the Hadejia-Nguru wetlands, where wild birds and poultry occasionally mix, provides ample opportunity for infection across species boundaries, with the potential risk of generating HPAI viruses after extensive circulation in poultry.


Cross-species protein interactome mapping reveals species-specific wiring of stress response pathways.
The fission yeast Schizosaccharomyces pombe has more metazoan-like features than the budding yeast Saccharomyces cerevisiae, yet it has similarly facile genetics. We present a large-scale verified binary protein-protein interactome network, "StressNet," based on high-throughput yeast two-hybrid screens of interacting proteins classified as part of stress response and signal transduction pathways in S. pombe. We performed systematic, cross-species interactome mapping using StressNet and a protein interactome network of orthologous proteins in S. cerevisiae. With cross-species comparative network studies, we detected a previously unidentified component (Snr1) of the S. pombe mitogen-activated protein kinase Sty1 pathway. Coimmunoprecipitation experiments showed that Snr1 interacted with Sty1 and that deletion of snr1 increased the sensitivity of S. pombe cells to stress. Comparison of StressNet with the interactome network of orthologous proteins in S. cerevisiae showed that most of the interactions among these stress response and signaling proteins are not conserved between species but are "rewired"; orthologous proteins have different binding partners in both species. In particular, transient interactions connecting proteins in different functional modules were more likely to be rewired than conserved. By directly testing interactions between proteins in one yeast species and their corresponding binding partners in the other yeast species with yeast two-hybrid assays, we found that about half of the interactions that are traditionally considered "conserved" form modified interaction interfaces that may potentially accommodate novel functions.


Evaluating the impact of handling and logger attachment on foraging parameters and physiology in southern rockhopper penguins.
Logger technology has revolutionised our knowledge of the behaviour and physiology of free-living animals but handling and logger attachments may have negative effects on the behaviour of the animals and their welfare. We studied southern rockhopper penguin (Eudyptes chrysocome) females during the guard stage in three consecutive breeding seasons (2008/09-2010/11) to evaluate the effects of handling and logger attachment on foraging trip duration, dive behaviour and physiological parameters. Smaller dive loggers (TDRs) were used in 2010/11 for comparison to larger GPS data loggers used in all three seasons and we included two categories of control birds: handled controls and PIT control birds that were previously marked with passive integrative transponders (PITs), but which had not been handled during this study. Increased foraging trip duration was only observed in GPS birds during 2010/11, the breeding season in which we also found GPS birds foraging further away from the colony and travelling longer distances. Compared to previous breeding seasons, 2010/11 may have been a period with less favourable environmental conditions, which would enhance the impact of logger attachments. A comparison between GPS and TDR birds showed a significant difference in dive depth frequencies with birds carrying larger GPS data loggers diving shallower. Mean and maximum dive depths were similar between GPS and TDR birds. We measured little impact of logger attachments on physiological parameters (corticosterone, protein, triglyceride levels and leucocyte counts). Overall, handling and short-term logger attachments (1-3 days) showed limited impact on the behaviour and physiology of the birds but care must be taken with the size of data loggers on diving seabirds. Increased drag may alter their diving behaviour substantially, thus constraining them in their ability to catch prey. Results obtained in this study indicate that data recorded may also not represent their normal dive behaviour.


DNA primase-DNA polymerase alpha assembly from mouse FM3A cells. Purification of constituting enzymes, reconstitution, and analysis of RNA priming as coupled to DNA synthesis.
The mouse DNA primase-DNA polymerase alpha complex can be resolved with buffer containing 50% ethylene glycol (Suzuki, M., Enomoto, T., Hanaoka, F., and Yamada, M. (1985) J. Biochem. (Tokyo) 98, 581-584). The dissociated primase and DNA polymerase alpha have been purified sufficiently that there was no cross-contamination with each other. By the use of thus isolated DNA primase and DNA polymerase alpha in addition to DNA primase-DNA polymerase alpha complex, we have studied primer RNA synthesis and DNA elongation separately as well as the coupled reaction of the initiation and elongation of DNA chains. In the absence of deoxyribonucleoside triphosphates, the isolated primase synthesized oligoribonucleotides of an apparent length of 7-11 nucleotides (monomeric oligomer) and multiples of a modal length of 9-10 nucleotides (multimeric oligomer) and fd phage single-stranded circular DNA. Monomeric and dimeric oligomers were synthesized processively, and trimeric and larger oligomers were produced by repeated cycles of processive synthesis. The primase complexed with DNA polymerase alpha mainly synthesized monomeric and a small amount of dimeric oligomers. In the presence of deoxyribonucleoside triphosphates at concentrations above 10 microM, the DNA primase-DNA polymerase alpha complex exclusively synthesized monomeric oligomers only, which were utilized as primers for DNA synthesis. On the other hand, the products synthesized by the isolated primase were qualitatively unchanged as compared with those synthesized in the absence of DNA precursors. When the synthesis of oligomers by the isolated primase was coupled with DNA elongation by the addition of the primase-free DNA polymerase alpha, the synthesis of dimeric oligomers was inhibited as a result of efficient DNA elongation from monomeric oligomers.


Comparison of anterior and posterior surgical approaches in the treatment of ventral spinal hemangioblastomas in patients with von Hippel-Lindau disease.
Von Hippel-Lindau (VHL) disease is an autosomal-dominant neoplastic syndrome with manifestations in multiple organs, which is evoked by the deletion or mutation of a tumor suppressor gene on chromosome 3p25. Spinal hemangioblastomas (40% of VHL disease-associated lesions of the central nervous system) arise predominantly in the posterior aspect of the spinal cord and are often associated with an intraspinal cyst. Rarely, the tumor develops in the anterior aspect of the spinal cord. Ventral spinal hemangioblastomas are a surgical challenge because of difficult access and because vessels feeding the tumor originate from the anterior spinal artery. The goal of this study was to clarify whether an anterior or posterior surgical approach is better for management of hemangioblastomas of the ventral spinal cord. . The authors performed a retrospective analysis of clinical outcomes and findings on magnetic resonance (MR) imaging studies in eight patients (two women and six men with a mean age of 34 +/- 15 years) who underwent resection of ventral spinal hemangioblastomas (nine tumors: five cervical and four thoracic). Two surgical approaches were used to resect these tumors. A posterior approach was selected to treat five patients (laminectomy and posterior myelotomy in four patients and the posterolateral approach in one patient); an anterior approach (corpectomy and arthrodesis) was selected to treat the remaining three patients. Immediately after surgery, the ability to ambulate remained unchanged in patients in whom an anterior approach had been performed, but deteriorated significantly in patients in whom a posterior approach had been used, because of motor weakness (four of five patients) and/or proprioceptive sensory loss (three of five patients). This difference in ambulation, despite significant improvements over time among patients in the posterior access group, remained significant 6 months after surgery. In all cases, MR images revealed complete resection of the tumor and in five patients significant or complete resolution of the intramedullary cyst was demonstrated (present in six of eight patients). The outcomes of these eight patients with hemangioblastomas of the ventral spinal cord indicate that both immediate and long-term results are better when an anterior approach is selected for resection.


The making of might-have-beens: effects of free will belief on counterfactual thinking.
Counterfactual thoughts are based on the assumption that one situation could result in multiple possible outcomes. This assumption underlies most theories of free will and contradicts deterministic views that there is only one possible outcome of any situation. Three studies tested the hypothesis that stronger belief in free will would lead to more counterfactual thinking. Experimental manipulations (Studies 1-2) and a measure (Studies 3-4) of belief in free will were linked to increased counterfactual thinking in response to autobiographical (Studies 1, 3, and 4) and hypothetical (Study 2) events. Belief in free will also predicted the kind of counterfactuals generated. Belief in free will was associated with an increase in the generation of self and upward counterfactuals, which have been shown to be particularly useful for learning. These findings fit the view that belief in free will is promoted by societies because it facilitates learning and culturally valued change.