Contribution of Cytidine Deaminase to Thymidylate Biosynthesis in Trypanosoma brucei: Intracellular Localization and Properties of the Enzyme.
Cytidine deaminase (CDA) is a pyrimidine salvage enzyme that catalyzes cytidine and deoxycytidine hydrolytic deamination to yield uridine and deoxyuridine. Here we report the biochemical characterization of Trypanosoma brucei CDA as an enzyme within the tetrameric class of the CDA family that efficiently deaminates cytidine, deoxycytidine, and the nucleoside analogue 5-methyl-2'-deoxycytidine. In line with previous studies, we show that RNA interference (RNAi)-mediated CDA depletion impairs T. brucei proliferation when grown in pyrimidine-deficient medium, while supplementation with thymidine or deoxyuridine restores growth, further underscoring the role of this enzyme in providing deoxyuridine for dUMP formation via thymidine kinase, the substrate required for de novo thymidylate biosynthesis. This observation contrasts with the existence in T. brucei of a dimeric deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), an essential enzyme that can produce dUMP via the hydrolysis of dUTP/dUDP. Thus, T. brucei dUTPase-null mutants are thymidine auxotrophs, suggesting that dUTPase might have a role in providing dUMP for thymidylate biosynthesis. We show that overexpression of human dCMP deaminase (DCTD), an enzyme that provides directly dUMP through dCMP deamination, does not reverse the lethal phenotype of dUTPase knockout cells, which further supports the notion that in T. brucei, CDA is uniquely involved in providing dUMP, while the main role of dUTPase would be the withdrawal of the excess of dUTP to avoid its incorporation into DNA. Furthermore, we report the mitochondrial localization of CDA, highlighting the importance of this organelle in pyrimidine metabolism.IMPORTANCE Cytidine deaminases (CDAs) catalyze the hydrolytic deamination of cytidine and deoxycytidine in the pyrimidine salvage pathway. In kinetoplastids, pyrimidine metabolism has been extensively studied as a source of potential drug targets, given the fact that many of the enzymes of the pathway are essential. Thymidylate (dTMP) synthesis in Trypanosoma brucei exhibits unique characteristics. Thus, it has been suggested that the production of dUMP, the substrate for dTMP formation, is solely dependent on cytidine deaminase and thymidine kinase. Here we characterize recombinant T. brucei CDA (TbCDA) and present evidence that indeed the alternative route for dUMP formation via deoxyuridine 5'-triphosphate nucleotidohydrolase does not have a prominent role in de novo dTMP formation. Furthermore, we provide a scheme for the compartmentalization of dTMP biosynthesis, taking into account the observation that CDA is located in the mitochondrion, together with available information on the intracellular localization of other enzymes involved in the dTTP biosynthetic pathway.


New approaches to superovulation in the cow.
There is continuing need to simplify bovine superovulation protocols without compromising embryo production. The control of follicular wave emergence and ovulation has facilitated donor management, but the most commonly used treatment, oestradiol, cannot be used in many parts of the world and mechanical removal of the dominant follicle is difficult to apply in the field. Other alternatives include gonadotrophin-releasing hormone (GnRH) or LH, but efficacy in groups of randomly cycling animals is variable. Another alternative is to increase the response to GnRH by inducing a persistent follicle and initiating FSH treatments following GnRH-induced ovulation. The number of transferable embryos following superovulation during the first follicular wave did not differ from that achieved 4 days after oestradiol benzoate and progesterone. To further simplify superovulation, FSH has been administered as a single intramuscular injection. Superovulation of beef donors with a single intramuscular injection of Folltropin-V (Bioniche Animal Health, Belleville, ON, Canada) diluted in a slow-release formulation resulted in embryo production comparable to that obtained using the traditional twice-daily protocol. The single intramuscular injection has the potential to reduce labour and handling and may be useful when handling stress is an impediment to success. These alternatives provide ways of facilitating widespread application of embryo transfer technologies.


ASD Traits Among Youth with Obsessive-Compulsive Disorder.
Research has shown high rates of comorbid psychiatric disorders among samples of youth with obsessive-compulsive disorder (OCD) (Farrell et al., Psychiatry Res 199(2):115-123, 2012; Lewin et al., Psychiatry Res 178(2):317-322, 2010; POTS Team, J Am Med Assoc 292(16):1969-1976, 2004). Autism and autistic traits co-occur at high rates within clinical samples of youth with OCD (Ivarsson and Melin in J Anxiety Disord 22(6):969-978, 2008; Stewart et al. in Child Psychiatry Hum Dev 1-9, 2016). This study extends the literature by examining the relationship between ASD traits, family accommodation, and functional impairment in a sample of youth with OCD across a wide age range (n = 80; aged 7-17 years). Results indicated that autistic traits, as measured by the social responsiveness scale (SRS), were elevated in 32.5% of youth (based on a T-score of 66T and above) relative to typically developing youth, as well as youth with non-autism-related psychiatric disorders (Constantino and Gruber in Social responsiveness scale, Western Psychogical Services, Torrance, 2012). Furthermore, 27.5% of youth scored within a moderate range (66T-75T) and 5% of youth scored within a severe range (76T or higher) on the SRS, typical of children with ASD (Constantino and Gruber in Social responsiveness scale, Western Psychogical Services, Torrance, 2012). Additionally, ASD traits were associated with greater functional impairment above OCD severity. Furthermore, family accommodation mediated the relationship between ASD traits and functional impairment. Implications of these findings are discussed in the context of clinical assessment and direction for further research.


Enhanced sound perception by widespread-onset neuronal responses in auditory cortex.
Accumulating evidence suggests that auditory cortical neurons exhibit widespread-onset responses and restricted sustained responses to sound stimuli. When a sound stimulus is presented to a subject, the auditory cortex first responds with transient discharges across a relatively large population of neurons, showing widespread-onset responses. As time passes, the activation becomes restricted to a small population of neurons that are preferentially driven by the stimulus, showing restricted sustained responses. The sustained responses are considered to have a role in expressing information about the stimulus, but it remains to be seen what roles the widespread-onset responses have in auditory information processing. We carried out numerical simulations of a neural network model for a lateral belt area of auditory cortex. In the network, dynamic cell assemblies expressed information about auditory sounds. Lateral excitatory and inhibitory connections were made between cell assemblies, respectively, by direct and indirect projections via interneurons. Widespread-onset neuronal responses to sound stimuli (bandpassed noises) took place over the network if lateral excitation preceded lateral inhibition, making a time widow for the onset responses. The widespread-onset responses contributed to the accelerating reaction time of neurons to sensory stimulation. Lateral interaction among dynamic cell assemblies was essential for maintaining ongoing membrane potentials near thresholds for action potential generation, thereby accelerating reaction time to subsequent sensory input as well. We suggest that the widespread-onset neuronal responses and the ongoing subthreshold cortical state, for which the coordination of lateral synaptic interaction among dissimilar cell assemblies is essential, may work together in order for the auditory cortex to quickly detect the sudden occurrence of sounds from the external environment.


Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin-proteasome pathway as a therapeutic target in poor prognosis tumors.
Malignant mesothelioma is an aggressive neoplastic proliferation derived from cells lining serosal membranes. The biological and clinical characteristics of epithelial type malignant mesothelioma are distinct from those of biphasic and sarcomatous type tumors. The goal of our study was to examine the molecular basis for this distinction. Microarray analysis confirmed that the molecular signatures of epithelial and biphasic histologic subtypes were distinct. Among the differentially expressed functional gene categories was the ubiquitin-proteasome pathway, which was upregulated in biphasic tumors. Cytotoxicity experiments indicated that 211H cells derived from biphasic tumors were synergistically sensitive to sequential combination regimens containing the proteasome inhibitor bortezomib and oxaliplatin. The mechanism of this synergistic response, which was not detected in cells of epithelial tumor origin, was apoptosis. Together, our results identify the ubiquitin-proteasome pathway as a biomarker of poor prognosis biphasic peritoneal mesothelioma tumors and suggest that proteasome inhibitors could increase the effectiveness of cytotoxic chemotherapy in this subset of patients.


Understanding frailty: a qualitative study of European healthcare policy-makers' approaches to frailty screening and management.
To elicit European healthcare policy-makers' views, understanding and attitudes about the implementation of frailty screening and management strategies and responses to stakeholders' views. Thematic analysis of semistructured qualitative interviews. European healthcare policy departments. Seven European healthcare policy-makers representing the European Union (n=2), UK (n=2), Italy (n=1), Spain (n=1) and Poland (n=1). Participants were sourced through professional networks and the European Commission Authentication Service website and were required to be in an active healthcare policy or decision-making role. Seven themes were identified. Our findings reveal a 'knowledge gap', around frailty and awareness of the malleability of frailty, which has resulted in restricted ownership of frailty by specialists. Policy-makers emphasised the need to recognise frailty as a clinical syndrome but stressed that it should be managed via an integrated and interdisciplinary response to chronicity and ageing. That is, through social co-production. This would require a culture shift in care with redeployment of existing resources to deliver frailty management and intervention services. Policy-makers proposed barriers to a culture shift, indicating a need to be innovative with solutions to empower older adults to optimise their health and well-being, while still fully engaging in the social environment. The cultural acceptance of an integrated care system theme described the complexities of institutional change management, as well as cultural issues relating to working democratically, while in signposting adult care, the need for a personal navigator to help older adults to access appropriate services was proposed. Policy-makers also believed that screening for frailty could be an effective tool for frailty management. There is potential for frailty to be managed in a more integrated and person-centred manner, overcoming the challenges associated with niche ownership within the healthcare system. There is also a need to raise its profile and develop a common understanding of its malleability among stakeholders, as well as consistency in how and when it is measured.


Dissociation channel dependence on peptide size observed in electron capture dissociation of tryptic peptides.
Electron capture dissociation (ECD) of a series of five residue peptides led to the observation that these small peptides did not lead to the formation of the usual c/z ECD fragments, but to a, b, y, and w fragments. In order to determine how general this behavior is for small sized peptides, the effect of peptide size on ECD fragments using a complete set of ECD spectra from the SwedECD spectra database was examined. Analysis of the database shows that b and w fragments are favored for small peptide sizes and that average fragment size shows a linear relationship to parent peptide size for most fragment types. From these data, it appears that most of the w fragments are not secondary fragments of the major z ions, in sharp contrast with the proposed mechanism leading to these ions. These data also show that c fragment distributions depend strongly on the nature of C-terminal residue basic site: arginine leads to loss of short neutral fragments, whereas lysine leads to loss of longer neutral fragments. It also appears that b ions might be produced by two different mechanisms depending on the parent peptide size. A model for the fragmentation pathways in competition is proposed. These relationships between average fragment size and parent peptide size could be further exploited also for CID fragment spectra and could be included in fragmentation prediction algorithms.


Reduction in prevalence of invasive cervical cancer in KwaZulu-Natal, South Africa: impact of the human immunodeficiency virus epidemic.
The bulk of the human immunodeficiency virus (HIV) pandemic continues to ravage the developing world, especially sub-Saharan countries. The HIV seroprevalence among women with invasive cervical cancer varies in different parts of the world. A comparison of women with cervical cancer was undertaken for epidemiologic data in the province of KwaZulu-Natal, South Africa, which has the highest HIV prevalence. The two time periods of study were 1999 and 2003. The aim was to determine the trends of prevalence of invasive cervical cancer and HIV infection among such women. While the background prevalence of HIV infection among women with invasive cervical cancer in our setting has remained constant over the two time periods (21% and 21.8%), there has been a significant reduction in the number of women presenting with invasive cervical cancer to our center (672 to 271) over the two time periods, with no changes in other variables. On the contrary, the prevalence of HIV infection among antenatal attendees had risen from 32.5% to 38.5% in the 1999 and 2003 periods, respectively. Reasons for this dramatic trend are presented together with other epidemiologic data.


Measuring alcohol consumption using Timeline Followback in non-treatment-seeking medical clinic patients with and without HIV infection: 7-, 14-, or 30-day recall.
The measurement of alcohol consumption is an essential component of research in patients at risk for or infected with HIV. Daily estimation measures such as the Timeline Followback (TLFB) have been validated, yet the optimal time window and its performance in non-treatment-seeking medical clinic subjects and among those with HIV are not known. In 1,519 HIV-infected and 1,612 uninfected men receiving medical care in general medical or infectious disease clinics, we compared the association between 7-, 14-, and 30-day TLFB reports, obtained via telephone, of alcohol consumption using Spearman's correlation coefficients. To evaluate agreement between 7-, 14-, and 30-day reports of heavy episodic drinking, we evaluated percent agreement, sensitivity, and kappa statistics, considering 30-day report as the gold standard. The estimated prevalence of heavy episodic drinking was progressively higher for longer TLFB intervals (7 days: 6.3%; 14 days: 8.0%; 30 days: 9.5%). Correlation coefficients with 30- day TLFB were higher for 14 days (.94) than for 7 days (.86) overall (p < .001) and among HIV-infected (.94 vs. .86, p < .001) and uninfected (.95 vs. .87, p < 001). Correlations were similar by HIV status. When considered overall and by HIV status, the sensitivity, percent agreement, and kappa statistics are better for heavy episodic drinking based on 14 days compared with 7 days. A TLFB for alcohol consumption of 14 days is preferable to 7 days for non-treatment-seeking patients in medical clinics with and without HIV infection when compared with 30 days.


Static postural differences between neutral and flat feet in children with and without symptoms.
Flatfoot is a common variant of foot posture. Whilst usually benign, in some children flatfoot is accompanied by pain and functional complaints. Comparisons between the posture of asymptomatic and symptomatic flat feet are few. If a difference does exist, it may help understand symptoms and guide management. This paper investigated differences in lower limb posture between neutral and flat feet with and without symptoms during standing using the multi-segment Oxford Foot Model. 97 children between five and 18years old were assessed by a physiotherapist; each foot was classified into one of four categories: asymptomatic neutral (n=88), asymptomatic mild flatfoot (n=47), asymptomatic flatfoot (n=29), or symptomatic flatfoot (n=30). For each child, Oxford Foot Model markers were applied, and mean values of 11-Euler angles at the foot, ankle, and knee joints during standing were calculated. Analysis of variance and post-hoc tests were used to identify differences between groups. Hindfoot eversion was significantly increased (P<0.001) in children with asymptomatic and, to a greater extent, symptomatic flatfoot. The forefoot was significantly more abducted (P<0.001) in the symptomatic than asymptomatic groups, and in the flat than neutral group. The forefoot was more supinated relative to the hindfoot in the flatfoot groups (P=0.023), although post-hoc analysis did not identify specific group differences. Hindfoot eversion and forefoot abduction were much greater in the symptomatic population. The differences in foot alignment may relate to the presence of symptoms.


"Wii-Hab" in critically ill children: a pilot trial.
To evaluate the safety and feasibility of virtual reality (VR) exercise as a novel acute rehabilitation intervention in a Pediatric Critical Care Unit (PCCU) setting. Children aged 3-18 years with an anticipated PCCU stay > 48 hours, and baseline normal to moderate cognitive and functional disability were eligible. Exclusion criteria included: anticipated death, physical inability, or a contraindication to mobilization. Nintendo Wii™ Boxing was prescribed for a minimum of 10 minutes twice a day for 2 days. Primary outcomes were feasibility and safety. Of 21 eligible patients, 12 (57.1%) were enrolled and 8 completed the study. 41.7% (5/12) were males, and the median age was 11 (3,16) years. Four of the 8 participants who received the intervention were mechanically ventilated during Wii™ play. Participants used the Wii™ a median of 2 times (1,5) over the 2-day intervention period, for a median total duration of 54.5 (15, 224) minutes. There were no adverse events attributable to the intervention. Upper limb activity during Wii™ was significantly greater than the average daily activity (p=0.049). Grip strength did not change significantly from baseline (p=0.20). While the results of this pilot trial suggest that VR exercise may be safely applied in a subset of critically ill children, we observed several threats to its feasibility in this population.


Morphological analysis of the bone marrow biopsies derived from heparinized cadaveric organ donors before and after disconnecting from the respirator.
Hematopoietic stem cells (HSC) from unrelated HLA-matched heparinized cadaveric organ donors (HCOD) are an under-appreciated potential source of stem cells, which could be employed in hematopoietic transplants and/or gene therapy. In addition, these cells could also be transplanted along with solid organs in order to increase microchimerism and graft tolerance after transplantation. The aim of this study was to evaluate the morphological changes seen in the bone marrow biopsies derived from HCODs before and after disconnecting the donor from the respirator. The morphological time-kinetic analysis of the bone marrow biopsies along with functional clonogeneic studies performed on isolated cells collectively reveals that hematopoietic cells from HCOD for transplantological purposes should be harvested within 2 h after disconnecting the respirator. In addition, we noticed that an early sign of developing bone marrow hypoxia/necrosis is a decrease in the number of megakaryocytes visible on bone marrow biopsies.


Use of tablet personal computers for sensitive patient-reported information.
Notebook-style computers (e/Tablets) are increasingly replacing paper methods for collecting patient-reported information. Discrepancies in data between these methods have been found in oncology for sexuality-related questions. A study was performed to formulate hypotheses regarding causes for discrepant responses and to analyze whether electronic data collection adds value over paper-based methods when collecting data on sensitive topics. A total of 56 breast cancer patients visiting Duke Breast Clinic (North Carolina) participated by responding to 12 subscales of 5 survey instruments in electronic (e/Tablet) format and to a paper version of 1 of these surveys, at each visit. Twenty-one participants (38%) provided dissimilar responses on paper and electronic surveys to one item of the Functional Assessment of Cancer Therapy-General (FACT-G) Social Well-Being scale that asked patients to rate their satisfaction with their current sex life. Among these 21 patients were 8 patients who answered the question in the electronic environment, and 13 patients who answered both paper and electronic versions but with different responses. Eleven patients (29%) did not respond to the item on either e/Tablet or paper; 45 patients (80%) answered it on e/Tablet; and 37 patients (66%) responded on the paper version. The e/Tablet electronic system may provide a "safer" environment than paper questionnaires for cancer patients to answer private or highly personal questions on sensitive topics such as sexuality.


The unequal health of Europeans: successes and failures of policies.
Europe, with its 53 countries and divided history, is a remarkable but inadequately exploited natural laboratory for studies of the eff ects of health policy. In this paper, the fi rst in a Series about health in Europe, we review developments in population health in Europe, with a focus on trends in mortality, and draw attention to the main successes and failures of health policy in the past four decades. In western Europe, life expectancy has improved almost continuously, but progress has been erratic in eastern Europe, and, as a result, disparities in male life expectancy between the two areas are greater now than they were four decades ago. The falls in mortality noted in western Europe are associated with many different causes of death and show the combined eff ects of economic growth, improved health care, and successful health policies (eg, tobacco control, road traffic safety). Less favourable mortality trends in eastern Europe show economic and health-care problems and a failure to implement effective health policies. The political history of Europe has left deep divisions in the health of the population. Important health challenges remain in both western and eastern Europe and signify unresolved issues in health policy (eg, alcohol, food) and rising health inequalities within countries.


Phosphorylation of the actin binding protein Drebrin at S647 is regulated by neuronal activity and PTEN.
Defects in actin dynamics affect activity-dependent modulation of synaptic transmission and neuronal plasticity, and can cause cognitive impairment. A salient candidate actin-binding protein linking synaptic dysfunction to cognitive deficits is Drebrin (DBN). However, the specific mode of how DBN is regulated at the central synapse is largely unknown. In this study we identify and characterize the interaction of the PTEN tumor suppressor with DBN. Our results demonstrate that PTEN binds DBN and that this interaction results in the dephosphorylation of a site present in the DBN C-terminus--serine 647. PTEN and pS647-DBN segregate into distinct and complimentary compartments in neurons, supporting the idea that PTEN negatively regulates DBN phosphorylation at this site. We further demonstrate that neuronal activity increases phosphorylation of DBN at S647 in hippocampal neurons in vitro and in ex vivo hippocampus slices exhibiting seizure activity, potentially by inducing rapid dissociation of the PTEN:DBN complex. Our results identify a novel mechanism by which PTEN is required to maintain DBN phosphorylation at dynamic range and signifies an unusual regulation of an actin-binding protein linked to cognitive decline and degenerative conditions at the CNS synapse.


Molecular stripping, targets and decoys as modulators of oscillations in the NF-κB/IκBα/DNA genetic network.
Eukaryotic transcription factors in the NF-κB family are central components of an extensive genetic network that activates cellular responses to inflammation and to a host of other external stressors. This network consists of feedback loops that involve the inhibitor IκBα, numerous downstream functional targets, and still more numerous binding sites that do not appear to be directly functional. Under steady stimulation, the regulatory network of NF-κB becomes oscillatory, and temporal patterns of NF-κB pulses appear to govern the patterns of downstream gene expression needed for immune response. Understanding how the information from external stress passes to oscillatory signals and is then ultimately relayed to gene expression is a general issue in systems biology. Recently, in vitro kinetic experiments as well as molecular simulations suggest that active stripping of NF-κB by IκBα from its binding sites can modify the traditional systems biology view of NF-κB/IκBα gene circuits. In this work, we revise the commonly adopted minimal model of the NF-κB regulatory network to account for the presence of the large number of binding sites for NF-κB along with dissociation from these sites that may proceed either by passive unbinding or by active molecular stripping. We identify regimes where the kinetics of target and decoy unbinding and molecular stripping enter a dynamic tug of war that may either compensate each other or amplify nuclear NF-κB activity, leading to distinct oscillatory patterns. Our finding that decoys and stripping play a key role in shaping the NF-κB oscillations suggests strategies to control NF-κB responses by introducing artificial decoys therapeutically.


Impact of molecular imaging on the diagnostic process in a memory clinic.
[(11)C]Pittsburgh compound B ([(11)C]PIB) and [(18)F]-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) PET measure fibrillar amyloid-β load and glucose metabolism, respectively. We evaluated the impact of these tracers on the diagnostic process in a memory clinic population. One hundred fifty-four patients underwent paired dynamic [(11)C]PIB and static [(18)F]FDG PET scans shortly after completing a standard dementia screening. Two-year clinical follow-up data were available for 39 patients. Parametric PET images were assessed visually and results were reported to the neurologists responsible for the initial diagnosis. Outcome measures were (change in) clinical diagnosis and confidence in that diagnosis before and after disclosing PET results. [(11)C]PIB scans were positive in 40 of 66 (61%) patients with a clinical diagnosis of Alzheimer's disease (AD), 5 of 18 (28%) patients with frontotemporal dementia (FTD), 4 of 5 (80%) patients with Lewy body dementia, and 3 of 10 (30%) patients with other dementias. [(18)F]FDG uptake patterns matched the clinical diagnosis in 38 of 66 (58%) of AD patients, and in 6 of 18 (33%) FTD patients. PET results led to a change in diagnosis in 35 (23%) patients. This only occurred when prior diagnostic certainty was <90%. Diagnostic confidence increased from 71 ± 17% before to 87 ± 16% after PET (p < .001). Two-year clinical follow-up (n = 39) showed that [(11)C]PIB and [(18)F]FDG predicted progression to AD for patients with mild cognitive impairment, and that the diagnosis of dementia established after PET remained unchanged in 96% of patients. In a memory clinic setting, combined [(11)C]PIB and [(18)F]FDG PET are of additional value on top of the standard diagnostic work-up, especially when prior diagnostic confidence is low.


Fiber optic SPR biosensing of DNA hybridization and DNA-protein interactions.
In this paper we present a fiber optic surface plasmon resonance (SPR) sensor as a reusable, cost-effective and label free biosensor for measuring DNA hybridization and DNA-protein interactions. This is the first paper that combines the concept of a fiber-based SPR system with DNA aptamer bioreceptors. The fibers were sputtered with a 50nm gold layer which was then covered with a protein repulsive self-assembled monolayer of mixed polyethylene glycol (PEG). Streptavidin was attached to the PEG's carboxyl groups to serve as a versatile binding element for biotinylated ssDNA. The ssDNA coated SPR fibers were first evaluated as a nucleic acid biosensor through a DNA-DNA hybridization assay for a random 37-mer ssDNA. This single stranded DNA showed a 15 nucleotides overlap with the receptor ssDNA on the SPR fiber. A linear calibration curve was observed in 0.5-5 microM range. A negative control test did not reveal any significant non-specific binding, and the biosensor was easily regenerated. In a second assay the fiber optic SPR biosensor was functionalized with ssDNA aptamers against human immunoglobulin E. Limits of detection (2nM) and quantification (6nM) in the low nanomolar range were observed. The presented biosensor was not only useful for DNA and protein quantification purposes, but also to reveal the binding kinetics occurring at the sensor surface. The dissociation constant between aptamer and hIgE was equal to 30.9+/-2.9nM. The observed kinetics fully comply with most data from the literature and were also confirmed by own control measurements.


An Insight into Z-Drug Abuse and Dependence: An Examination of Reports to the European Medicines Agency Database of Suspected Adverse Drug Reactions.
Although originally marketed as safe alternatives to the habit-forming benzodiazepines, growing numbers of zaleplon, zolpidem, and zopiclone ("Z-drugs") clinical concerns relating to their potential of abuse, dependence, and withdrawal have been reported over time. We aimed here at assessing these issues analyzing datasets of adverse drug reactions provided by the European Medicines Agency through the EudraVigilance system. Analyzing the adverse drug reactions databases of each Z-drug, descriptive analyses have been performed on cases and proportional reporting ratios (PRRs) computed. An overall number of 33 240 (e.g., 23 420 zolpidem; 9283 zopiclone; and 537 zaleplon) misuse-, abuse-, dependence-, and withdrawal-related adverse drug reactions, corresponding to some 6246 unique patients given Z-drugs, were here identified. Cases were studied and described, including demographic characteristics and clinical data such as concomitant drugs, doses, routes of administration, and outcomes of the reactions (being fatalities recorded). Considering PRR values and in comparison with zopiclone, zolpidem was more frequently involved in both misuse/abuse and withdrawal issues. Zolpidem and zopiclone presented with the same dependence risk, but zopiclone was most involved in overdose adverse drug reactions. Compared with zaleplon, zopiclone presented higher dependence and overdose-related issues but slightly lower misuse/abuse and withdrawal PRR values. Current data may only represent a gross underestimate of the real prevalence of Z-drug misuse. Caution should be exercised when prescribing those molecules, especially for patients with psychiatric illnesses and/or history of drug abuse. We recommend the need to invest in proactive pharmacovigilance activities to better and promptly detect, understand, and prevent any possible misuse potential of prescribed medications.


Injured workers' perception of loss and gain in the return to work process.
When a worker is injured at work, he has to face a tough decision-making process about when and how to return to work (RTW). This study tests how the prospect theory can be applied to influence the injured workers' perceptions about this important choice. One hundred forty-one injured workers were presented with wage- and pain-related information in four different message framing (negatively or positively) and precision (smaller or larger number) conditions. After exposure to the specific combination of this wage and pain information, the participants were asked to express intentions to RTW in terms of perceived chance, confidence, and anticipated sick leave duration. When asked to predict their RTW outcome, 101 participants (72.3%) responded favorably, whereas only 40 (27.7%) indicated an expectation for staying on sick leave. The present results did not show significant differences in the participants' responses to the positively and negatively framed information about wage and pain. However, it was noted that the control group that was presented with positive framing for both "wage" and "pain" information showed higher scores in expectation and confidence for RTW, whereas the Ambivalent Group that had both negative messages showed lower scores. Seventy-nine participants who had ≥60% perceived improvement in condition were selected for further analysis, and those who were presented with "wage loss" information rated significantly higher perceived chance of RTW than those in the "pain gain" group. More in-depth investigation is warranted on this topic, with a larger sample of injured workers to investigate the effects of message framing on the decision-making process about RTW.


Cell cycle studies on the mode of action of yeast K28 killer toxin.
The virally encoded K28 killer toxin of Saccharomyces cerevisiae kills sensitive cells by a receptor-mediated process. DNA synthesis is rapidly inhibited, cell viability is lost more slowly and cells eventually arrest, apparently in the S phase of the cell cycle with a medium-sized bud, a single nucleus in the mother cell and a pre-replicated (1n) DNA content. Cytoplasmic microtubules appear normal, and no spindle is detectable. Arrest of a sensitive haploid yeast strain by alpha-factor at START gave complete protection for at least 4 h against a toxin concentration that killed non-arrested cells at the rate of one log each 2.5 h. Cells released from alpha-factor arrest were killed by toxin at a similar rate; arrest occurred with medium-sized buds within the same cell cycle. Cells arrested by hydroxyurea, with unreplicated DNA, or by the spindle poison methylbenzimidazol-2yl-carbamate, with unseparated chromosomes, both arrest at the checkpoint at the G2/M boundary; these arrested cells were not protected against toxin, losing about one log of viability every 4 h. Following release from the cell cycle block, a majority of these toxin-exposed cells progressed through the cell cycle and arrested in the following S-phase, again with medium-sized buds. Killing by K28 toxin apparently requires entry into the nuclear division and bud cycles, but can result from inhibition of either early or late events in these cycles. Morphogenesis in moribund cells is uniformly blocked in early S-phase with an immature bud. Toxin action causes either independent blockage of both DNA synthesis and the budding cycle, or inhibits some unknown step required for both events.


Lectio Divina: A Preliminary Evaluation of a Chaplaincy Program.
This participant outcome evaluation serves as a preliminary investigation into the effects of lectio divina, a chaplaincy service representing a form of focused Scripture reading. A sample of n = 19 patients who participated in this service at a Department of Veterans Affairs Medical Center in upstate New York was screened at baseline and 30-days follow-up using the Duke University Religion Index, Berg Spiritual Injury Scale, and a screening question for thoughts of harming self or others. These measures were used to assess the intended outcomes of enhanced religiosity, ameliorated spiritual injury, and decreased thoughts of violence. Data were collected through retrospective clinical chart reviews. The outcomes of enhanced religiosity or decreased thoughts of violence were not observed in this sample population. Ameliorated spiritual injury was observed in veterans with substantial engagement in lectio divina (>2 sessions) as well as those who endorsed thoughts of harming self or others.


Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation.
Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC.


Usual therapy improves perianal Crohn's disease as measured by a new disease activity index. McMaster IBD Study Group.
Troublesome perianal disease occurs in approximately 35% of patients with Crohn's disease, yet conventional disease activity indices do not reflect the severity of this feature. To assess the degree of impairment and response to therapy, we identified five simple elements and graded each on a 5-point Likert scale in 37 patients at 124 visits. At each visit a Crohn's Disease (CDAI) or Simple Activity Index (HBDAI), Perianal Disease Activity Index (PDAI), and treatment were recorded. The PDAI was validated against physician (MDGA) and patient (PGA) global assessments, and treatment was prescribed for the perianal disease. Measurement error was evaluated in 19 patients who were clinically stable at two consecutive visits. The ability of the PDAI to detect important clinical change was tested in 20 subjects exhibiting a change on PGA at consecutive visits. There were strong correlations between PDAI, MDGA, and PGA scores at all visits (R = 0.66-0.72; p < 0.001), whereas the CDAI and HBDAI correlated poorly with PDAI (R < 0.23). Physicians prescribed more aggressive therapy for higher PDAI scores (r = 0.53). Mean PDAI scores between visits in clinically stable subjects were not significantly different [5.58 +/- 2.79 (initial); 5.42 +/- 2.55 (follow-up); p = 0.63]. PDAI significantly improved between visits when the perianal disease had improved (PDAI score difference 3.05 +/- 2.96; P = .0002). We conclude that the PDAI is simple and clinically useful for patient management. It should now be assessed in a clinical trial.


Ocular straylight in the normal pseudophakic eye.
To assess normal values for straylight in the pseudophakic eye as a function of age and to develop a model to predict the improvement in straylight after lens extraction based on preoperative straylight levels. Rotterdam Ophthalmic Institute, Rotterdam, the Netherlands. Review with retrospective cross-study analysis. A literature review was performed to identify relevant papers on straylight and pseudophakia with no patient comorbidities. Sixteen papers met the eligibility criteria and were included in the analysis. The postoperative results were used to define the norm for straylight in pseudophakia. Straylight improvement after lens replacement was assessed by evaluation of preoperative and postoperative values. The age effect was incorporated to determine a model for straylight improvement. The mean postoperative straylight value derived from 16 studies (1869 eyes) was 1.21 log units ± 0.21 (SD). Age dependence could be assessed from 13 studies (1533 eyes), resulting in the straylight age-norm curve in pseudophakic eyes as follows: Straylight value = 0.0044 × age + 0.89 with ± 0.42 log units of 95% confidence interval. A strong correlation was observed between preoperative straylight and its improvement after lens extraction, yielding the following relationship: Straylight improvement = 1.04 × preoperative straylight value - 0.006 × age - 0.84. A norm for straylight in the pseudophakic eye was developed that is considerably different from the previously published norm for the phakic eye. The new pseudophakic norm can be used clinically to predict the straylight value after lens replacement and as a reference criterion for clinical studies. The Netherlands Academy of Arts and Sciences owns a patent on straylight measurement, with Dr. van den Berg as the inventor, and licenses that to Oculus Optikgeräte GmbH for the C-Quant instrument. No author has a financial or proprietary interest in any material or method mentioned.


Periodontal disease among indigenous people in the Amazon rain forest.
People are not all equally susceptible to periodontitis. To understand the epidemiology and natural history of this disease, it is important to study populations with varying genetic backgrounds and environmental exposures. Characterize the periodontal condition of a sample of indigenous adults in a remote region of the Amazon rain forest and determine the association of periodontal disease with various demographic, behavioral and environmental factors. A cross-sectional evaluation of 244 subjects aged 20-70 years was conducted. Pocket depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), plaque and calculus were assessed for the Ramfjord index teeth. These people had high levels of plaque, calculus and BOP. The mean PD was rather shallow (2.45 mm in 20-29 year-olds to 2.73 mm in 50+ year-olds) and did not increase significantly with age. Mean CAL (0.57 mm in 20-29 year-olds and 2.26 mm in 50+ year-olds) and mean location of the free gingival margin in relation to the cemento-enamel junction changed significantly with age (p<0.0001). Multivariate analysis revealed that increasing age, bleeding on probing and calculus scores were positively associated with mean CAL (p<0.01). Sex, ethnicity, level of modern acculturation, use of coca or tobacco paste, frequency of dental visits and plaque were not associated with mean CAL. Periodontal disease in these people was mainly associated with gingival recession rather than deep pockets. Most people had clinical attachment loss but despite poor oral hygiene and extensive gingival inflammation, they did not have very severe periodontal destruction.


High-Intensity Statins Benefit High-Risk Patients: Why and How to Do Better.
Review of the US and European literature indicates that most patients at high risk for atherosclerotic cardiovascular disease (ASCVD are not treated with high-intensity statins, despite strong clinical-trial evidence of maximal statin benefit. High-intensity statins are recommended for 2 categories of patients: those with ASCVD (secondary prevention) and high-risk patients without clinical ASCVD. Most patients with ASCVD are candidates for high-intensity statins, with a goal for low-density lipoprotein cholesterol reduction of 50% or greater. A subgroup of patients with ASCVD are at very high risk and can benefit by the addition of nonstatin drugs (ezetimibe with or without bile acid sequestrant or bempedoic acid and/or a proprotein convertase subtilisin/kexin type 9 inhibitor). High-risk primary prevention patients are those with severe hypercholesterolemia, diabetes with associated risk factors, and patients aged 40 to 75 years with a 10-year risk for ASCVD of 20% or greater. In patients with a 10-year risk of 7.5% to less than 20%, coronary artery calcium scoring is an option; if the coronary artery calcium score is 300 or more Agatston units, the patient can be up-classified to high risk. If high-intensity statin treatment is not tolerated in high-risk patients, a reasonable approach is to combine a moderate-intensity statin with ezetimibe. In very high-risk patients, proprotein convertase subtilisin/kexin type 9 inhibitors lower low-density lipoprotein cholesterol levels substantially and hence reduce risk as well.


Kinase patent space visualization using chemical replacements.
Here we present a methodology for characterizing the structure of patented chemical space. This approach identifies those chemical replacements that can connect sets of exemplified compounds in individual patents. Chemists can then search these replacements to help them discover the architecture within their patent space of interest. To demonstrate the utility of such an approach, we characterize a set of kinase inhibitors from patents and literature and find that many companies' patents can be understood to be straightforward modifications of competitors' patents. By reapplying these same chemical themes to other related compound series, novel, biologically active compounds can be discovered.


Properties of two forms of DNA polymerase delta from calf thymus.
Purified calf thymus DNA polymerases delta I and II each have an associated 3' to 5' exonuclease but otherwise resemble DNA polymerase alpha in size, biochemical kinetic parameters, and the presence of DNA primase [Crute, J. J., Wahl, A. F., & Bambara, R. A. (1986) Biochemistry 25, 26-36]. Here we demonstrate a functional association of polymerase and exonuclease with each delta form. Furthermore, we show that the exonuclease can be dissociated from DNA polymerase delta I but does not appear to be removable from DNA polymerase delta II. Polymerases delta I, delta II, and alpha are equally sensitive to the inhibitor aphidicolin, suggesting a similarity in active site structure. In comparison with DNA polymerase alpha and delta II, DNA polymerase delta I has intermediate sensitivity to 2-(p-n-butylanilino)-2'-deoxyadenosine 5'-triphosphate (BuAdATP) or N2-(p-n-butylphenyl)-2'-deoxyguanosine 5'-triphosphate (BuPdGTP). The activity of the DNA primase of the delta II enzyme is insensitive to BuAdATP whereas 1.0 microM of this inhibitor will decrease the activity of the DNA primase of the alpha and delta I enzymes approximately 50%. Two monoclonal antibodies that potently inhibit DNA polymerase alpha are only slightly inhibitory to DNA polymerase delta I and are ineffective at inhibiting DNA polymerase delta II. DNA polymerase delta II had been previously found to be nearly inactive on nuclease-treated calf thymus DNA, relative to its activity on homopolymeric DNA. We find that addition of purified calf histone proteins or spermidine can greatly enhance synthesis by this enzyme on activated calf DNA.


Mechanics of the carotid artery wall and baroreflex sensitivity after acute ethanol administration in young healthy volunteers.
The effects of ethanol administered orally (300 mg/kg in 250 ml of water) or intravenously (7.5 mg.min(-1).kg(-1) in 250 ml of saline over 40 min) on common carotid haemodynamics, wall mechanics and baroreflex sensitivity were compared with the effects of the intravenous infusion of 250 ml of saline. Ethanol or saline was administered to 10 healthy volunteers after 30 min of supine rest, and measurements were obtained 40 min (median; range 34-46 min) after administration. After ethanol administration, the plasma alcohol level rose from 0 to 0.3+/-0.07 g/l. Mean arterial blood pressure had risen slightly at 20 min, but was normalized by 40 min, the time at which the haemodynamic study was performed. Heart rate decreased after infusion of either saline or alcohol, but was unchanged after oral ethanol administration. Both oral and intravenous ethanol administration were associated with significant decreases in baroreflex sensitivity, carotid shear stress and blood velocity, compared with resting values, while the mean carotid artery diameter was increased, and blood viscosity and mean blood flow were unchanged. No changes were observed in these parameters after saline administration. Ethanol, administered either intravenously or orally, increased the stiffness of the carotid artery and decreased the pulsatility (systo-diastolic changes) of its diameter. A direct, statistically significant correlation was found between the decrease in shear stress and the decrease in baroreflex heart rate control sensitivity after both modes of alcohol administration, while no such correlation was found between the increase in the Peterson elastic modulus and the decrease in carotid diameter pulsatility on the one hand or the decrease in baroreflex sensitivity on the other. In conclusion, reduced shear stress associated with vasodilatation of the carotid artery wall may contribute to the decrease in baroreflex sensitivity observed after acute ethanol administration.


Impacts of biological invasions: what's what and the way forward.
Study of the impacts of biological invasions, a pervasive component of global change, has generated remarkable understanding of the mechanisms and consequences of the spread of introduced populations. The growing field of invasion science, poised at a crossroads where ecology, social sciences, resource management, and public perception meet, is increasingly exposed to critical scrutiny from several perspectives. Although the rate of biological invasions, elucidation of their consequences, and knowledge about mitigation are growing rapidly, the very need for invasion science is disputed. Here, we highlight recent progress in understanding invasion impacts and management, and discuss the challenges that the discipline faces in its science and interactions with society.


An examination of the psychological aspects of bite marks.
The intent of this paper is to present some psychological threads which appear to be operative for the perpetrator of bite marks. In the catalogue of multiple motivations, there appears to be a current theme of power, control, potency, and the attempt to have a psychological symbolization of the perpetrator's omniscient capacity for absorbing life essences. In an examination of these highly complex needs, the modern perpetrator appears to act out consistently with cultural biases coupled with immediate psychological needs which have pressed for expression. Due to a pattern of psychologically expressed ritualism, the perpetrator will often inadvertently leave important psychological clues at the crime scene. The attack style, mode of death, characteristics of the victim, etc.--these components reveal the information on the type of psychological needs that the perpetrator is trying to satisfy. In the cases of bite marks associated with violent crime, it becomes crucial to an "investigator" what type of personality characteristics are welded together to form this kind of need complex. After reviewing cases reported in the literature and after conducting psychological interviews with perpetrators, three major groups of perpetrators seem to be apparent. The first group is motivated out of an anger track, the second group is motivated out of sadistic biting, and the third is out of the more traditional "cannibal complex" motif.


Isolation and properties in culture of human adrenal capillary endothelial cells.
The isolation of human adrenal capillary endothelial (HACE) cells without resort to fluorescence activated cell sorting is described, together with their properties in culture. HACE cells were isolated by plating collagenase digests at high dilution in the presence of endothelial cell growth supplement, followed by clonal selection of endothelial colonies. HACE cells exhibit a typical endothelial 'cobblestone' morphology at confluence and formed 'tubes' when seeded onto 'Matrigel'. They are positive for human MHC1, and the endothelial markers ENDOCAM (CD31) and weakly CD34, they also take up dil-acetyl low density lipoprotein but are negative for Factor VIII. Their growth is strongly stimulated by FGF and inhibited by TGF-beta I. Like their much studied bovine counterparts they are robust in culture, retaining the properties described up to senescence. HACE cells provide a readily available alternative to human umbilical vein endothelial cells in that they are easily isolated pure and in quantity. They should be particularly useful in studies where human capillary, as opposed to large vessel endothelium, is required.


Phase II study of RC-160 (vapreotide), an octapeptide analogue of somatostatin, in the treatment of metastatic breast cancer.
RC-160 (octastatin/vapreotide) is a potent octapeptide analogue of somatostatin with growth inhibitory activity in experimental tumours in vitro and in vivo, including breast cancer. We evaluated the efficacy and tolerability of high-dose RC-160, 3 mg day(-1) on week 1 increased to 4.5 mg day(-1) for weeks 2-4 and subsequently 6 mg day(-1) until the end of treatment, administered by continuous subcutaneous infusion in the management of 14 women with previously treated metastatic breast cancer. The age range was 37-80 years (median 58.5 years) and performance status 0-2. The treatment was well tolerated with no dose reductions being required. No grade 3 or 4 toxicities were seen. Abscess formation developed at the infusion site in eight patients and erythema and discomfort was seen in a further three patients. A significant reduction in IGF-I levels occurred by day 7 and was maintained throughout the treatment. The lowest dose of RC-160 produced the maximal IGF-I response. Although there was no reduction in prolactin levels in patients whose baseline levels were normal, elevated prolactin levels found in three patients fell to within the normal range 7 days after commencing RC-160 treatment. A small but significant rise in fasting blood glucose levels was also recorded, the highest level on treatment being 7.6 mmol l(-1). No objective tumour responses were observed, all patients showing disease progression within 3 months of commencing treatment. These findings demonstrate that high-dose RC-160, administered as a continuous subcutaneous infusion, can reduce serum levels of the breast growth factors IGF-I and prolactin but is ineffective in the management of metastatic breast cancer. Encouraging preclinical anti-tumour activity and the favourable toxicity profile in patients suggest the merit of future studies combining RC-160 with anti-oestrogen, cytotoxic and anti-angiogenic agents.


Use of integrated technology in team sports: a review of opportunities, challenges, and future directions for athletes.
Integrated technology (IT), which includes accelerometers, global positioning systems (GPSs), and heart rate monitors, has been used frequently in public health. More recently, IT data have been used in sports settings to assess training and performance demands. However, the impact of IT in sports settings is yet to be evaluated, particularly in field-based team sports. This narrative-qualitative review provides an overview of the emerging impact of IT in sports settings. Twenty electronic databases (e.g., Medline, SPORTdiscus, and ScienceDirect), print publications (e.g., Signal Processing Magazine and Catapult Innovations news releases), and internet resources were searched using different combinations of keywords as follows: accelerometers, heart rate monitors, GPS, sport training, and field-based sports for relevant articles published from 1990 to the present. A total of 114 publications were identified, and 39 that examined a field-based team sport using a form of IT were analyzed. The articles chosen for analysis examined a field-based team sport using a form of IT. The uses of IT can be divided into 4 categories: (a) quantifying movement patterns (n = 22), (b) assessing the differences between demands of training and competition (n = 12), (c) measuring physiological and metabolic responses (n = 16), and (d) determining a valid definition for velocity and a sprint effort (n = 8). Most studies used elite adult male athletes as participants and analyzed the sports of Australian Rules football, field hockey, cricket, and soccer, with sample sizes between 5 and 20 participants. The limitations of IT in a sports setting include scalability issues, cost, and the inability to receive signals within indoor environments. Integrated technology can contribute to significant improvements in the preparation, training, and recovery aspects of field-based team sports. Future research should focus on using IT with female athlete populations and developing resources to use IT indoors to further enhance individual and team performances.


A melting pot of Old World begomoviruses and their satellites infecting a collection of Gossypium species in Pakistan.
CLCuD in southern Asia is caused by a complex of multiple begomoviruses (whitefly transmitted, single-stranded [ss]DNA viruses) in association with a specific ssDNA satellite; Cotton leaf curl Multan betasatellite (CLCuMuB). A further single ssDNA molecule, for which the collective name alphasatellites has been proposed, is also frequently associated with begomovirus-betasatellite complexes. Multan is in the center of the cotton growing area of Pakistan and has seen some of the worst problems caused by CLCuD. An exhaustive analysis of the diversity of begomoviruses and their satellites occurring in 15 Gossypium species (including G. hirsutum, the mainstay of Pakistan's cotton production) that are maintained in an orchard in the vicinity of Multan has been conducted using φ29 DNA polymerase-mediated rolling-circle amplification, cloning and sequence analysis. The non-cultivated Gossypium species, including non-symptomatic plants, were found to harbor a much greater diversity of begomoviruses and satellites than found in the cultivated G. hirsutum. Furthermore an African cassava mosaic virus (a virus previously only identified in Africa) DNA-A component and a Jatropha curcas mosaic virus (a virus occurring only in southern India) DNA-B component were identified. Consistent with earlier studies of cotton in southern Asia, only a single species of betasatellite, CLCuMuB, was identified. The diversity of alphasatellites was much greater, with many previously unknown species, in the non-cultivated cotton species than in G. hirsutum. Inoculation of newly identified components showed them to be competent for symptomatic infection of Nicotiana benthamiana plants. The significance of the findings with respect to our understanding of the role of host selection in virus diversity in crops and the geographical spread of viruses by human activity are discussed.


Yoga: a biobehavioral approach to reduce symptom distress in women with urge urinary incontinence.
Urge urinary incontinence is a debilitating chronic condition that poses challenges for affected women and the clinicians who care for them. Multicomponent behavioral therapies have shown promise in allowing women to manage their symptoms. New evidence suggests an underlying pathophysiologic inflammatory process for urge urinary incontinence, and complementary therapies that address the psychoneuroimmunology component may improve the health and quality of life for the millions of women with this condition. Yoga, a mind-body therapy, has been shown to reduce inflammation and may help improve symptoms of urge urinary incontinence. More research is necessary to demonstrate the effectiveness of yoga to reduce urge urinary incontinence symptom burden and improve quality of life.


Allowing variance may enlarge the safe operating space for exploited ecosystems.
Variable flows of food, water, or other ecosystem services complicate planning. Management strategies that decrease variability and increase predictability may therefore be preferred. However, actions to decrease variance over short timescales (2-4 y), when applied continuously, may lead to long-term ecosystem changes with adverse consequences. We investigated the effects of managing short-term variance in three well-understood models of ecosystem services: lake eutrophication, harvest of a wild population, and yield of domestic herbivores on a rangeland. In all cases, actions to decrease variance can increase the risk of crossing critical ecosystem thresholds, resulting in less desirable ecosystem states. Managing to decrease short-term variance creates ecosystem fragility by changing the boundaries of safe operating spaces, suppressing information needed for adaptive management, cancelling signals of declining resilience, and removing pressures that may build tolerance of stress. Thus, the management of variance interacts strongly and inseparably with the management of resilience. By allowing for variation, learning, and flexibility while observing change, managers can detect opportunities and problems as they develop while sustaining the capacity to deal with them.


Antimicrobial activity of plant compounds against Salmonella Typhimurium DT104 in ground pork and the influence of heat and storage on the antimicrobial activity.
Salmonella enterica is a predominant foodborne pathogen that causes diarrheal illness worldwide. A potential method of inhibiting pathogenic bacterial growth in meat is through the introduction of plant-derived antimicrobials. The objectives of this study were to investigate the influence of heat (70°C for 5 min) and subsequent cold storage (4°C up to 7 days) on the effectiveness of oregano and cinnamon essential oils and powdered olive and apple extracts against Salmonella enterica serovar Typhimurium DT104 in ground pork and to evaluate the activity of the most effective antimicrobials (cinnamon oil and olive extract) at higher concentrations in heated ground pork. The surviving Salmonella populations in two groups (heated and unheated) of antimicrobial-treated pork were compared. Higher concentrations of the most effective compounds were then tested (cinnamon oil at 0.5 to 1.0% and olive extract at 3, 4, and 5%) against Salmonella Typhimurium in heated ground pork. Samples were stored at 4°C and taken on days 0, 3, 5, and 7 for enumeration of survivors. The heating process did not affect the activity of antimicrobials. Significant 1.3- and 3-log reductions were observed with 1.0% cinnamon oil and 5% olive extract, respectively, on day 7. The minimum concentration required to achieve . 1-log reduction in Salmonella population was 0.8% cinnamon oil or 4% olive extract. The results demonstrate the effectiveness of these antimicrobials against multidrug-resistant Salmonella Typhimurium in ground pork and their stability during heating and cold storage. The most active formulations have the potential to enhance the microbial safety of ground pork.


Haemodynamic simulation of aneurysm coiling in an anatomically accurate computational fluid dynamics model: technical note.
Computational fluid dynamics (CFD) is a numerical technique that is used for studying haemodynamic parameters in cerebral aneurysms. As it is now possible to represent an anatomically accurate intracranial aneurysm in a computational model, we have attempted to simulate its endosaccular occlusion with coils and demonstrate the haemodynamic changes induced. This is the first attempt to use this particular porous medium-based method for coiling simulation in a CFD model, to our knowledge. Datasets from a rotational 3-D digital subtraction angiogram of a recently ruptured anterior communicating aneurysm were converted into a 3-D geometric model and the discretized data were processed using the computational technique developed. Coiling embolisation simulation was achieved by impediment of flow through a porous medium with characteristics following a series of embolisation coils. Haemodynamic parameters studied were: pressure distribution on the vessel wall, blood velocity and blood flow patterns. Significant haemodynamic changes were detected after deployment of the first coil. Similar, but less dramatic changes occurred during subsequent stages of coiling. The blood flow patterns became less vortical in the aneurysm sac as velocity decreased to stagnation and the wall pressure at the fundus was gradually reduced. Furthermore, the haemodynamic characteristics developed at the area of the neck remnant could form the basis for assessing the likelihood of delayed coil compaction and aneurysm regrowth. Appropriate computational techniques show great promise in simulating the haemodynamic behaviour of the various stages in coil embolisation and may be a potentially valuable tool in interventional planning and procedural decision-making.


Outcome of conservation surgery for laryngeal carcinoma: an 8-year trial.
The purpose of this report is to review the experience of our institution with conservative surgery for laryngeal cancer. In this retrospective study, a review was made of 85 patients treated with conservation surgery between 1998 and 2005. At least 2 years of follow-up period (mean 46.6 months) was achieved for all the patients. We evaluated age, tobacco and alcohol intake, T stage, histopathological differentiation and localization of tumor, subglottic extension, anterior commissure invasion, vocal cord mobility, surgical margins, type of surgery applied, and post-operative radiotherapy (pRT) applied. Local control and 2-year survival rates were estimated. We managed with horizontal, vertical, and horizontovertical laryngectomies in 55, 26, and 4 patients, respectively. 28 patients were scheduled to have pRT. The actuarial and overall local control rates were 82.4 and 94.1%, respectively. On univariable analysis, significant factors for increased recurrences were positive resection margins, low differentiation of tumor, alcohol consumption and incompletion of the planned pRT. The 2-year survival rate was 60 and 95.7% for patients with and without local recurrence, respectively. Conservation surgery is a safe procedure for laryngeal cancer in proper endications.


A comparison of neuropsychiatric and cognitive profiles in delirium, dementia, comorbid delirium-dementia and cognitively intact controls.
Delirium and dementia have overlapping features that complicate differential diagnosis. Delirium symptoms overshadow dementia symptoms when they co-occur, but delirium phenomenology in comorbid cases has not been compared to both conditions alone. Consecutive adults with DSM-IV delirium, dementia, comorbid delirium-dementia and cognitively intact controls were assessed using the Revised Delirium Rating Scale (DRS-R98) and Cognitive Test for Delirium (CTD). Delirium and comorbid delirium-dementia groups had comparable DRS-R98 and CTD total scores, which were greater than in dementia or control groups. On the DRS-R98, multiple non-cognitive symptoms, inattention and disorientation were more severe in delirium groups compared with dementia-alone. Patients with dementia differed from both delirium groups on the CTD test of attention. Spatial span backwards was significantly lower in all patients with cognitive impairment (delirium, comorbid delirium-dementia, dementia alone) compared to controls, whereas spatial span forwards distinguished delirium groups from dementia. Delirium phenomenology is similar with or without comorbid dementia. A wide range of neuropsychiatric symptoms distinguish delirium from dementia. Spatial span forward is disproportionately diminished in delirium suggesting usefulness as a differentiating screening test.


An Application of Artificial Intelligence to Diagnostic Imaging of Spine Disease: Estimating Spinal Alignment From Moiré Images.
The use of artificial intelligence (AI) as a tool supporting the diagnosis and treatment of spinal diseases is eagerly anticipated. In the field of diagnostic imaging, the possible application of AI includes diagnostic support for diseases requiring highly specialized expertise, such as trauma in children, scoliosis, symptomatic diseases, and spinal cord tumors. Moiré topography, which describes the 3-dimensional surface of the trunk with band patterns, has been used to screen students for scoliosis, but the interpretation of the band patterns can be ambiguous. Thus, we created a scoliosis screening system that estimates spinal alignment, the Cobb angle, and vertebral rotation from moiré images. In our system, a convolutional neural network (CNN) estimates the positions of 12 thoracic and 5 lumbar vertebrae, 17 spinous processes, and the vertebral rotation angle of each vertebra. We used this information to estimate the Cobb angle. The mean absolute error (MAE) of the estimated vertebral positions was 3.6 pixels (~5.4 mm) per person. T1 and L5 had smaller MAEs than the other levels. The MAE per person between the Cobb angle measured by doctors and the estimated Cobb angle was 3.42°. The MAE was 4.38° in normal spines, 3.13° in spines with a slight deformity, and 2.74° in spines with a mild to severe deformity. The MAE of the angle of vertebral rotation was 2.9°±1.4°, and was smaller when the deformity was milder. The proposed method of estimating the Cobb angle and AVR from moiré images using a CNN is expected to enhance the accuracy of scoliosis screening.


Transplantation of umbilical cord blood after myeloablative therapy: analysis of engraftment.
The possibility that umbilical cord and placental blood from an HLA-identical sibling might produce stable donor-derived lymphohematopoietic engraftment was tested in a patient with juvenile chronic myelogenous leukemia (JCML). After conditioning with high-dose busulfan and cyclophosphamide, cryopreserved umbilical cord blood, containing 0.5 x 10(8) nucleated cells/kg and 2.7 x 10(4) colony forming units-granulocyte, macrophage (CFU-GM)/kg, was infused. A leukocyte count greater than 1,000/microL, absolute neutrophil count (ANC) greater than 500/microL, and platelet count greater than 20,000/microL (untransfused) were observed on days 39, 39, and 47 after transplantation, respectively. Donor cell engraftment was documented in the peripheral blood and bone marrow by cytogenetic analysis, restriction fragment length polymorphism (RFLP), and polymerase chain reaction (PCR) as early as day 21. Furthermore, the donor origin of each lymphohematopoietic lineage (ie, CD5+ T cells, CD19/20+ B cells, CFU-GM, and burst-forming unit-erythrocyte [BFU-E]) was confirmed. On day 200, assays of the peripheral blood and bone marrow showed an abnormal proliferation of CFU-GM at low seeding densities in the absence of exogenous growth factors, as well as a hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), both pathophysiologic characteristics of JCML. Recurrent disease was confirmed histologically on day 225. Together, these results demonstrate that umbilical cord blood contains sufficient numbers of hematopoietic stem cells necessary for the engraftment of leukemia patients treated with myeloablative therapy and that the detection of "spontaneous" CFU-GM and hypersensitivity to GM-CSF after treatment is a marker of residual or recurrent disease in patients with JCML.


Health and socioeconomic effects of groundwater arsenic contamination in rural Bangladesh: new evidence from field surveys.
This report discusses the health and socioeconomic problems that have recently emerged in the Bangladesh countryside because of arsenic contamination of the groundwater. A survey found that men in rural households are generally found to be more susceptible to arsenicosis than women. The survey also indicated that villagers with lower annual income are more likely to experience arsenicosis. About 60 percent of the respondents indicated a willingness to pay up to a dollar of their monthly income for safe water. More than 70 percent of women were found to be willing to walk for five minutes to collect safe water. Awareness campaigns conducted over the last decade seem to have been effective for villagers. Overall, findings from the survey paint a picture of a gradually evolving social and health scenario in rural Bangladesh that health officials must heed to safeguard the public health of the rural public.


Predictors of Bloodstream Infection in Patients Presenting With Cardiovascular Implantable Electronic Device Pocket Infection.
Generator pocket infection is the most frequent presentation of cardiovascular implantable electronic device (CIED) infection. We aim to identify predictors of underlying bloodstream infection (BSI) in patients presenting with CIED pocket infection. We retrospectively reviewed all adults with CIED pocket infection cared for at our institution from January 2005 through January 2016. The CIED pocket infection cases were then subclassified as with or without associated BSI. Variables with P values <.05 at univariate analysis were included in a multivariable model to identify independent predictors of underlying BSI. We screened 429 cases of CIED infection, and 95 met the inclusion criteria. Of these, 68 cases (71.6%) were categorized as non-BSI and 27 (28.4%) as BSI. There were no statistically significant differences in patient comorbid conditions or device characteristics between the 2 groups. In multivariable analysis, the presence of systemic inflammatory response syndrome criteria (tachycardia, tachypnea, fever or hypothermia, and leukocytosis or leukopenia) and hypotension were independent predictors of underlying BSI in patients presenting with CIED pocket infection. Overall, patients in the non-BSI group who did not receive pre-extraction antibiotics had a higher frequency of positive intraoperative pocket/device cultures than those with pre-extraction antibiotic exposure (79.4% vs 58.6%; P = .06). Patients with CIED pocket infection who meet systemic inflammatory response syndrome criteria and/or are hypotensive at admission are more likely to have underlying BSI and should be started on empiric antibiotics after blood cultures are obtained. If these features are absent, it may be reasonable to withhold empiric antibiotics to optimize yield of pocket/device cultures during extraction.


Primary choriocarcinoma of the vulva.
Primary extrauterine choriocarcinoma is very rare, found mostly in the genital tract (tube, cervix, ovary, vagina). Other sites such as lungs, gastrointestinal tract, heart, brain and submentum also have been reported. A 31-year-old woman presented with abnormal uterine bleeding 6 weeks after her last menstrual cycle. Her HCG titer level was 900 mIu/ml. She underwent dilation and curettage (D & C). Pathology failed to reveal any chorionic villi. Further evaluation was done, including a second D & C, laparoscopy, exploratory laparotomy, CT, MRI and ultrasound which all failed to define a source for the elevated HCG titer which subsequently rose to 95,000 mIu/ml 130 days after her last menstrual cycle. At that time a vulvar mass was observed. Fine needle aspiration (FNA) was positive for choriocarcinoma. The patient was treated with one course of methotrexate 60 mg intramuscularly every other day for 5 days. Actinomycin-D 0.5 mg given intravenously daily for 5 days was added to courses 2-7. Radiotherapy (4000 rads) was applied concomitant with the chemotherapy. The remainder of the mass was subsequently excised. The patient has remained with no evidence of disease for 10 years. This is the first case report of primary vulvar choriocarcinoma.


Play and developmental outcomes in infant siblings of children with autism.
We observed infant siblings of children with autism later diagnosed with ASD (ASD siblings; n = 17), infant siblings of children with autism with and without other delays (Other Delays and No Delays siblings; n = 12 and n = 19, respectively) and typically developing controls (TD controls; n = 19) during a free-play task at 18 months of age. Functional, symbolic, and repeated play actions were coded. ASD siblings showed fewer functional and more non-functional repeated play behaviors than TD controls. Other Delays and No Delays siblings showed more non-functional repeated play than TD controls. Group differences disappeared with the inclusion of verbal mental age. Play as an early indicator of autism and its relationship to the broader autism phenotype is discussed.


Structured Neonatal Point-of-Care Ultrasound Training Program.
Point-of-care ultrasound (POC US) has been increasingly used by intensive care physicians. Growing use of POC US necessitates defining distinct clinical indications for its application, as well as structured POC US training programs. Homogeneous approach to POC US education combined with rigorous quality assurance should further enable POC US to become standard-of-care clinical tool. This study aimed to present the first, innovative, and structured POC US program in neonatal-perinatal medicine field. In addition, we reviewed the availability of the POC US training programs across different medical specialties. Available English-language publications on POC US training programs in general and neonatal-perinatal medicine were reviewed in this study. Mounting body of evidence suggests improved procedural completion rates, as well as clinical decision making with the use of POC US. However, limited research supported the existence of structured, comprehensive POC US programs. It was recognized that medical institutions need to develop syllabuses, teach, and credential increasing number of health care professionals in the use of POC US. We defined intuitive educational strategy that encompasses POC US clinical indications, educational curriculum, scanning protocols, competence evaluation, and finally credentialing process. In addition, we offered description of the imaging quality assurance, as well as POC US coding, and reimbursement. Future efforts need to be dedicated to the ongoing development of neonatal POC US as a clinical instrument. It should allow for eventual paradigm change and improved effectiveness in management of critically ill neonates.


Individual Lesion-Level Meta-Analysis Comparing Various Doses of Intracoronary Bolus Injection of Adenosine With Intravenous Administration of Adenosine for Fractional Flow Reserve Assessment.
Intravenous infusion of adenosine is considered standard practice for fractional flow reserve (FFR) assessment but is associated with adverse side-effects and is time-consuming. Intracoronary bolus injection of adenosine is better tolerated by patients, cheaper, and less time-consuming. However, current literature remains fragmented and modestly sized regarding the equivalence of intracoronary versus intravenous adenosine. We aim to investigate the relationship between intracoronary adenosine and intravenous adenosine to determine FFR. We performed a lesion-level meta-analysis to compare intracoronary adenosine with intravenous adenosine (140 µg/kg per minute) for FFR assessment. The search was conducted in accordance to the Preferred Reporting for Systematic Reviews and Meta-Analysis statement. Lesion-level data were obtained by contacting the respective authors or by digitization of scatterplots using custom-made software. Intracoronary adenosine dose was defined as; low: <40 µg, intermediate: 40 to 99 µg, and high: ≥100 µg. We collected 1972 FFR measurements (1413 lesions) comparing intracoronary with intravenous adenosine from 16 studies. There was a strong correlation (correlation coefficient =0.915; P<0.001) between intracoronary-FFR and intravenous-FFR. Mean FFR was 0.81±0.11 for intracoronary adenosine and 0.81±0.11 for intravenous adenosine (P<0.001). We documented a nonclinically relevant mean difference of 0.006 (limits of agreement: -0.066 to 0.078) between the methods. When stratified by the intracoronary adenosine dose, mean differences between intracoronary and intravenous-FFR amounted to 0.004, 0.011, or 0.000 FFR units for low-dose, intermediate-dose, and high-dose intracoronary adenosine, respectively. The present study documents clinically irrelevant differences in FFR values obtained with intracoronary versus intravenous adenosine. Intracoronary adenosine hence confers a practical and patient-friendly alternative for intravenous adenosine for FFR assessment.


Lck and the nature of the T cell receptor trigger.
Exactly how ligand binding 'triggers' T cell receptor (TCR) phosphorylation is unclear. It has been proposed that ligand engagement by the TCR somehow activates the Src kinase Lck, which in turn phosphorylates the receptor. Recent data, however, suggest instead that a significant fraction of the Lck in resting T cells is already activated and that the proportion of active Lck does not change during the early stages of T cell activation. We argue that, caveats notwithstanding, these new observations offer support for the 'kinetic-segregation' model of TCR triggering, which involves spatial reorganization of signalling proteins upon ligand binding and requires a fraction of Lck to be active in resting T cells.


Cortisol levels are positively associated with pup-feeding rates in male meerkats.
In societies of cooperative vertebrates, individual differences in contributions to offspring care are commonly substantial. Recent attempts to explain the causes of this variation have focused on correlations between contributions to care and the protein hormone prolactin, or the steroid hormone testosterone. However, such studies have seldom considered the importance of other hormones or controlled for non-hormonal factors that are correlative with both individual hormone levels and contributions to care. Using multivariate statistics, we show that hormone levels explain significant variation in contributions to pup-feeding by male meerkats, even after controlling for non-hormonal effects. However, long-term contributions to pup provisioning were significantly and positively correlated with plasma levels of cortisol rather than prolactin, while plasma levels of testosterone were not related to individual patterns of pup-feeding. Furthermore, a playback experiment that used pup begging calls to increase the feeding rates of male helpers gave rise to parallel increases in plasma cortisol levels, whilst prolactin and testosterone levels remained unchanged. Our findings confirm that hormones can explain significant amounts of variation in contributions to offspring feeding, and that cortisol, not prolactin, is the hormone most strongly associated with pup-feeding in cooperative male meerkats.


Differential effects of N-acetyl-2-aminofluorene and N-2-aminofluorene adducts on the conformational change in the structure of DNA polymerase I (Klenow fragment).
The carcinogen N-acetyl-2-aminofluorene forms two major DNA adducts: the N-(2'-deoxyguanosin-8-yl)-2-acetylaminofluorene adduct (dG-C8-AAF) and its deacetylated derivative, the N-(2'-deoxyguanosin-8-yl)-2-aminofluorene adduct (dG-C8-AF). It is well established that the AAF adduct is a very strong block for DNA synthesis in vitro while the AF adduct is more easily bypassed. In an effort to understand the molecular mechanism of this phenomenon, the structure of the complex of an exonuclease-deficient Escherichia coli DNA polymerase I (Klenow fragment) bound to primer-templates containing either an AF or AAF adduct in or near the active site was probed by nuclease and protease digestion analyses. The results of these experiments suggest that positioning the AAF adduct in the polymerase active site strongly inhibits the conformational change that is required for the insertion of a nucleotide. Similar experiments with AF-modified primer-templates shows a much less pronounced effect. The inhibition of the conformational change by either adduct is not detected if they are positioned in the single-stranded part of the template just one nucleotide before the active site. These findings may explain the different abilities of these lesions to block DNA synthesis.


Cinaciguat, a soluble guanylate cyclase activator for the potential treatment of acute heart failure.
The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine-3',5'-monophosphate (cGMP) pathway plays an important role in cardiovascular regulation by producing vasodilation and inhibiting platelet aggregation and vascular smooth muscle proliferation. The NO/SGC/cGMP pathway is disrupted in patients with heart failure as a result of a decrease in NO bioavailability and an increase in NO-insensitive forms of sGC, resulting in insufficient vasodilation. Drugs that activate sGC in a NO-independent manner may provide considerable therapeutic advantages in treating these patients. Cinaciguat (BAY-58-2667), currently in development by Bayer AG, preferentially activates sGC in its oxidized or heme-free state, when the enzyme is insensitive to both NO and nitrovasodilators. Cinaciguat exhibits potent vasodilator and antiplatelet activity, a long-lasting antihypertensive effect and a hemodynamic profile similar to that of nitrates. In clinical trials in patients with acute decompensated heart failure, cinaciguat potently unloaded the heart, increased cardiac output and renal blood flow, and preserved renal function and sodium and water excretion without further neurohumoral activation. The pharmacokinetics of cinaciguat demonstrated dose-proportionality with low individual variability and a low incidence of adverse events. The phase I and II clinical trials performed with cinaciguat so far, however, are insufficient to provide convincing evidence on the efficacy and safety of the drug. Thus, caution should be exerted before extrapolating the present preliminary data to the clinical practice.


Next-generation sequencing for BCR-ABL1 kinase domain mutations in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A position paper.
Emergence of clones carrying point mutations in the BCR-ABL1 kinase domain (KD) is a common mechanism of resistance to tyrosine kinase inhibitor (TKI)-based therapies in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Sanger sequencing (SS) is the most frequently used method for diagnostic BCR-ABL1 KD mutation screening, but it has some limitations-it is poorly sensitive and cannot robustly identify compound mutations. Next-generation sequencing (NGS) may overcome these problems. NSG is increasingly available and has the potential to become the method of choice for diagnostic BCR-ABL1 KD mutation screening. A group discussion within an ad hoc constituted Panel of Experts has produced a series of consensus-based statements on the potential value of NGS testing before and during first-line TKI-based treatment, in relapsed/refractory cases, before and after allo-stem cell transplantation, and on how NGS results may impact on therapeutic decisions. A set of minimal technical and methodological requirements for the analysis and the reporting of results has also been defined. The proposals herein reported may be used to guide the practical use of NGS for BCR-ABL1 KD mutation testing in Ph+ ALL.


Aminoacyl-tRNA synthetases, the genetic code, and the evolutionary process.
The aminoacyl-tRNA synthetases (AARSs) and their relationship to the genetic code are examined from the evolutionary perspective. Despite a loose correlation between codon assignments and AARS evolutionary relationships, the code is far too highly structured to have been ordered merely through the evolutionary wanderings of these enzymes. Nevertheless, the AARSs are very informative about the evolutionary process. Examination of the phylogenetic trees for each of the AARSs reveals the following. (i) Their evolutionary relationships mostly conform to established organismal phylogeny: a strong distinction exists between bacterial- and archaeal-type AARSs. (ii) Although the evolutionary profiles of the individual AARSs might be expected to be similar in general respects, they are not. It is argued that these differences in profiles reflect the stages in the evolutionary process when the taxonomic distributions of the individual AARSs became fixed, not the nature of the individual enzymes. (iii) Horizontal transfer of AARS genes between Bacteria and Archaea is asymmetric: transfer of archaeal AARSs to the Bacteria is more prevalent than the reverse, which is seen only for the "gemini group. " (iv) The most far-ranging transfers of AARS genes have tended to occur in the distant evolutionary past, before or during formation of the primary organismal domains. These findings are also used to refine the theory that at the evolutionary stage represented by the root of the universal phylogenetic tree, cells were far more primitive than their modern counterparts and thus exchanged genetic material in far less restricted ways, in effect evolving in a communal sense.


The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration.
Neurodegenerative illnesses such as Parkinson and Alzheimer disease are an increasingly prevalent problem in aging societies, yet no therapies exist that retard or prevent neurodegeneration. Dominant missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD), but the mechanisms by which mutant forms of LRRK2 disrupt neuronal function and cause cell death remain poorly understood. We report that LRRK2 interacts with the death adaptor Fas-associated protein with death domain (FADD), and that in primary neuronal culture LRRK2-mediated neurodegeneration is prevented by the functional inhibition of FADD or depletion of caspase-8, two key elements of the extrinsic cell death pathway. This pathway is activated by disease-triggering mutations, which enhance the LRRK2-FADD association and the consequent recruitment and activation of caspase-8. These results establish a direct molecular link between a mutant PD gene and the activation of programmed cell death signaling, and suggest that FADD/caspase-8 signaling contributes to LRRK2-induced neuronal death.


Palliative patients cared for at home by PAMINO-trained and other GPs - health-related quality of life as measured by QLQ-C15-PAL and POS.
To maintain patients' quality of life is one of the major goals in palliative home care provided by general practitioners (GPs). GPs need adequate training to care for palliative patients. The paper seeks to evaluate whether a specific training in Germany (PAMINO) has any improving impact on the care of palliative patients and their health-related quality of life. From September 2007 until June 2009, GPs and their palliative care patients with cancer participated in a study to evaluate palliative courses for GPs offered by a regional palliative care initiative (PAMINO). For a period of six months at most or until death, patients were asked monthly to judge their quality of life on the Quality of Life Questionnaire Core 15 Palliative (QLQ-C15-PAL) of the European Organization for Research and Treatment of Cancer (EORTC) and on the Palliative Care Outcome Scale (POS). The 'Overall quality of life' scale of the QLQ-C15-PAL takes values between 0 and 100 with higher values indicating a higher quality of life. The POS sum scale takes values between 0 and 40 with higher values indicating worse care outcomes. Patients cared for by PAMINO-trained GPs and patients cared for by other GPs (control group) are compared using t-tests for differences in group means. One hundred patients participated in the study; 96 patients filled out the questionnaires at least once. On the QLQ-C15-PAL, mean quality of life of the patient groups of PAMINO-trained and other GPs were 37.7 (SD = 25.5) and 39.4 (SD = 26.3) (p = .76), respectively. On the POS, respective mean values of 13.6 (SD = 5.8) and 12.0 (SD = 6.5) (p = .26) were given. Patients cared for by a PAMINO-trained GP did not report better quality of life and care outcomes than patients cared for by other general practitioners. Patients cared for by PAMINO-trained and other GPs in our study did not report differences in quality of life. Quality of life and care outcomes of all patients were better than of palliative patients in institutional or specialized care, emphasizing the ability of GPs to provide adequate care for these vulnerable patients. However, conclusions need to be drawn cautiously since the study had a small sample size. Current Controlled Trials ISRCTN78021852.


The burden of brain diseases in Europe.
The burden [as defined by the World Health Organisation (WHO)] of brain diseases (neurological, neurosurgical and psychiatric diseases together) is very high and yet resources spent on these diseases are not necessarily commensurate with the extent of this burden. However, hard data on the burden of brain diseases in Europe have not previously been easily accessible. The Global Burden of Disease (GBD) 1990 study conducted jointly by the WHO, Harvard University and the World Bank provided new measures that are now becoming universally accepted and have been used also in a repeat study: The GBD 2000. The key parameter of the study is disability adjusted life years (DALY), which is the sum of years of life lost (YLL) caused by premature death and years of life lived with disability (YLD). In the present report, data from the GBD 2000 study and from the World Health Report 2001 on brain diseases is extracted for the territory of Europe. This territory corresponds roughly to the membership countries of the European Federation of Neurological Societies. The WHO's Report has a category called neuropsychiatric diseases, which comprises the majority but not all the brain diseases. In order to gather all brain diseases, stroke, meningitis, half of the burden of injuries and half of the burden of congenital abnormalities are added. Throughout Europe, 23% of the years of healthy life is lost and 50% of YLD are caused by brain diseases. Regarding the key summary measure of lost health, DALY, 35% are because of brain diseases. The fact that approximately one-third of all burden of disease is caused by brain diseases should have an impact on resource allocation to teaching, reasearch, health care and prevention. Although other factors are also of importance, it seems reasonable that one-third of the curriculum at medical school should deal with the brain and that one-third of life science funding should go to basic and clinical neuroscience. In addition, resource allocation to prevention, diagnosis and treatment of brain diseases should be increased to approach, at least, one-third of health care expenditure. With the present data on hand, neurologists, neurosurgeons, psychiatrists, patient organizations and basic neuroscientists have a better possibility to increase the focus on the brain.


Mitigating Anticipated Effects of Systematic Errors Supports Sister-Group Relationship between Xenacoelomorpha and Ambulacraria.
Xenoturbella and the acoelomorph worms (Xenacoelomorpha) are simple marine animals with controversial affinities. They have been placed as the sister group of all other bilaterian animals (Nephrozoa hypothesis), implying their simplicity is an ancient characteristic [1, 2]; alternatively, they have been linked to the complex Ambulacraria (echinoderms and hemichordates) in a clade called the Xenambulacraria [3-5], suggesting their simplicity evolved by reduction from a complex ancestor. The difficulty resolving this problem implies the phylogenetic signal supporting the correct solution is weak and affected by inadequate modeling, creating a misleading non-phylogenetic signal. The idea that the Nephrozoa hypothesis might be an artifact is prompted by the faster molecular evolutionary rate observed within the Acoelomorpha. Unequal rates of evolution are known to result in the systematic artifact of long branch attraction, which would be predicted to result in an attraction between long-branch acoelomorphs and the outgroup, pulling them toward the root [6]. Other biases inadequately accommodated by the models used can also have strong effects, exacerbated in the context of short internal branches and long terminal branches [7]. We have assembled a large and informative dataset to address this problem. Analyses designed to reduce or to emphasize misleading signals show the Nephrozoa hypothesis is supported under conditions expected to exacerbate errors, and the Xenambulacraria hypothesis is preferred in conditions designed to reduce errors. Our reanalyses of two other recently published datasets [1, 2] produce the same result. We conclude that the Xenacoelomorpha are simplified relatives of the Ambulacraria.


New Horizons for the Study of Dietary Fiber and Health: A Review.
Dietary fibre has been consumed for centuries with known health benefits, but defining dietary fibre is a real challenge. From a functional perspective, dietary fibre is described as supporting laxation, attenuating blood glucose responses and assisting with cholesterol lowering. The problem is different types of dietary fibre have different effects, and new effects are increasingly observed, such as the influence on gut microbiota. Thus, a single definition may need to be described in more generic terms. Rather than being bound by a few functional definitions, we may need to embrace the possibilities of new horizons, and derive a working definition of dietary fibre based on a set of conceptual principles, rather than the limited definitions we have to date. To begin this process, a review of individual fibre types and their physiological effects would be helpful. Dietary fibre is a complex group of substances, and there is a growing interest in specific effects linked to fibre type. Different fractions of dietary fibre have different physiological properties, yet there is a paucity of literature covering the effects of all fibres. This paper describes a range of individual fibre types and identifies gaps in the literature which may expose new directions for a working definition of dietary fibre.