One-dimensional embedded cluster approach to modeling CdS nanowires.
We present an embedded cluster model to treat one-dimensional nanostructures, using a hybrid quantum mechanical/molecular mechanical (QM/MM) approach. A segment of the nanowire (circa 50 atoms) is treated at a QM level of theory, using density functional theory (DFT) with a hybrid exchange-correlation functional. This segment is then embedded in a further length of wire, treated at an MM level of theory. The interaction between the QM and MM regions is provided by an embedding potential located at the interface. Point charges are placed beyond the ends of the wire segment in order to reproduce the Madelung potential of the infinite system. We test our model on the ideal system of a CdS linear chain, benchmarking our results against calculations performed on a periodic system using a plane-wave DFT approach, with electron exchange and correlation treated at the same level of approximation in both methods. We perform our tests on pure CdS and, importantly, the system containing a single In or Cu impurity. We find excellent agreement in the determined electronic structure using the two approaches, validating our embedded cluster model. As the hybrid QM/MM model avoids spurious interactions between charged defects, it will be of benefit to the analysis of the role of defects in nanowire materials, which is currently a major challenge using a plane-wave DFT approach. Other advantages of the hybrid QM/MM approach over plane-wave DFT include the ability to calculate ionization energies with an absolute reference and access to high levels of theory for the QM region which are not incorporated in most plane-wave codes. Our results concur with available experimental data.


Dimerization of DNA methyltransferase 1 is mediated by its regulatory domain.
DNA methylation is a major epigenetic modification and plays a crucial role in the regulation of gene expression. Within the family of DNA methyltransferases (Dnmts), Dnmt3a and 3b establish methylation marks during early development, while Dnmt1 maintains methylation patterns after DNA replication. The maintenance function of Dnmt1 is regulated by its large regulatory N-terminal domain that interacts with other chromatin factors and is essential for the recognition of hemi-methylated DNA. Gelfiltration analysis showed that purified Dnmt1 elutes at an apparent molecular weight corresponding to the size of a dimer. With protein interaction assays we could show that Dnmt1 interacts with itself through its N-terminal regulatory domain. By deletion analysis and co-immunoprecipitations we mapped the dimerization domain to the targeting sequence TS that is located in the center of the N-terminal domain (amino acids 310-629) and was previously shown to mediate replication independent association with heterochromatin at chromocenters. Further mutational analyses suggested that the dimeric complex has a bipartite interaction interface and is formed in a head-to-head orientation. Dnmt1 dimer formation could facilitate the discrimination of hemi-methylated target sites as has been found for other palindromic DNA sequence recognizing enzymes. These results assign an additional function to the TS domain and raise the interesting question how these functions are spatially and temporarily co-ordinated.


S-Adenosyl-L-Homocysteine Hydrolase Inhibition by a Synthetic Nicotinamide Cofactor Biomimetic.
S-adenosyl-L-homocysteine (SAH) hydrolases (SAHases) are involved in the regulation of methylation reactions in many organisms and are thus crucial for numerous cellular functions. Consequently, their dysregulation is associated with severe health problems. The SAHase-catalyzed reaction is reversible and both directions depend on the redox activity of nicotinamide adenine dinucleotide (NAD+) as a cofactor. Therefore, nicotinamide cofactor biomimetics (NCB) are a promising tool to modulate SAHase activity. In the present in vitro study, we investigated 10 synthetic truncated NAD+ analogs against a SAHase from the root-nodulating bacterium Bradyrhizobium elkanii. Among this set of analogs, one was identified to inhibit the SAHase in both directions. Isothermal titration calorimetry (ITC) and crystallography experiments suggest that the inhibitory effect is not mediated by a direct interaction with the protein. Neither the apo-enzyme (i.e., deprived of the natural cofactor), nor the holo-enzyme (i.e., in the NAD+-bound state) were found to bind the inhibitor. Yet, enzyme kinetics point to a non-competitive inhibition mechanism, where the inhibitor acts on both, the enzyme and enzyme-SAH complex. Based on our experimental results, we hypothesize that the NCB inhibits the enzyme via oxidation of the enzyme-bound NADH, which may be accessible through an open molecular gate, leaving the enzyme stalled in a configuration with oxidized cofactor, where the reaction intermediate can be neither converted nor released. Since the reaction mechanism of SAHase is quite uncommon, this kind of inhibition could be a viable pharmacological route, with a low risk of off-target effects. The NCB presented in this work could be used as a template for the development of more potent SAHase inhibitors.


Heart rate as a marker of stress in ambulance personnel: a pilot study of the body's response to the ambulance alarm.
Studies have demonstrated the presence of stress and post-traumatic stress among ambulance personnel, but no previous research has focused on the body's reaction in the form of the change in heart rate of ambulance staff in association with specific occupational stress. The purpose of this study is to investigate whether work as an ambulance professional generates prolonged physiological arousal that can be measured by heart rate in different situations. Twenty participants carried a pulse-meter in the form of a wristwatch, which continuously measured and stored their heart rate 24 hours per day for a period of seven days. All ambulance alarms that occurred during the test period were recorded in journals, and the participants completed diaries and a questionnaire describing their experiences. The alarms were divided into different phases. Correlations between heart rate in the different phases were computed. Analysis of study data indicated a significant rise of heart rate unrelated to physical effort during an emergency alarm and response. This increased heart rate was noticed throughout the mission and it was not related to the length of experience the staff had in the ambulance profession. In addition, a non-significant trend suggested that alarms involving acutely ill children lead to an even higher increase in heart rate. In addition, this research showed that constant tension existed during sleep, while available for an emergency, indicated by a noticeable increase in heart rate during sleep at work compared to sleeping at home. A rise in heart rate was experienced during all acute emergency missions, regardless of a subject's experience, education, and gender. Missions by themselves generated a rate increase that did not seem to correlate with physical effort required during an emergency response. This study shows that working on an ambulance that responds to medical emergencies is associated with a prolonged physiological arousal.


Surface organization of a DPPC monolayer on concentrated SrCl2 and ZnCl2 solutions.
Transition metals are known to be enriched in organic-coated marine aerosols, but the impact these cations have on their surface properties is not well understood. Here the effect of Zn2+ enrichment on the surface properties of a dipalmitoylphosphatidylcholine (DPPC) monolayer was investigated and compared to that of the alkaline earth metal Sr2+, an ion not enriched in aerosols. Phase behavior of the DPPC film on concentrated aqueous solutions was probed with surface pressure-area isotherms while domain morphology was monitored with Brewster angle microscopy (BAM). Infrared reflection-absorption spectroscopy (IRRAS) and vibrational sum frequency generation (VSFG) spectroscopy were used to assess the impact of cations on the conformation and orientation of alkyl chains as well as the hydration state of the carbonyl and phosphatidylcholine (PC) moieties. Results of compression isotherms and BAM show that Zn2+ strongly interacts with DPPC molecules, and induces condensation of the monolayer while Sr2+ only weakly interacts with the monolayer in expanded phases. Conformational order and orientation of alkyl chains in the condensed phase are not significantly altered by either cation. IRRAS indicates that Sr2+ has weak interactions with the PC headgroup. Zn2+ ions cause dehydration of carbonyl groups and binds to the phosphate group in a 2 : 1 bridging complex. Findings here suggest that Sr2+ is not enriched in aerosols because it behaves similar to a monovalent ion and only weakly interacts with the monolayer, while enrichment of Zn2+ is due to strong binding to the lipid film.


Functional properties of spinach (Spinacia oleracea L.) phytochemicals and bioactives.
Overwhelming evidence indicates that diets rich in fruits and vegetables are protective against common chronic diseases, such as cancer, obesity and cardiovascular disease. Leafy green vegetables, in particular, are recognized as having substantial health-promoting activities that are attributed to the functional properties of their nutrients and non-essential chemical compounds. Spinach (Spinacia oleracea L.) is widely regarded as a functional food due to its diverse nutritional composition, which includes vitamins and minerals, and to its phytochemicals and bioactives that promote health beyond basic nutrition. Spinach-derived phytochemicals and bioactives are able to (i) scavenge reactive oxygen species and prevent macromolecular oxidative damage, (ii) modulate expression and activity of genes involved in metabolism, proliferation, inflammation, and antioxidant defence, and (iii) curb food intake by inducing secretion of satiety hormones. These biological activities contribute to the anti-cancer, anti-obesity, hypoglycemic, and hypolipidemic properties of spinach. Despite these valuable attributes, spinach consumption remains low in comparison to other leafy green vegetables. This review examines the functional properties of spinach in cell culture, animals and humans with a focus on the molecular mechanisms by which spinach-derived non-essential phytochemicals and bioactives, such as glycolipids and thylakoids, impart their health benefits.


The influence of natural barriers in shaping the genetic structure of Maharashtra populations.
The geographical position of Maharashtra state makes it rather essential to study the dispersal of modern humans in South Asia. Several hypotheses have been proposed to explain the cultural, linguistic and geographical affinity of the populations living in Maharashtra state with other South Asian populations. The genetic origin of populations living in this state is poorly understood and hitherto been described at low molecular resolution level. To address this issue, we have analyzed the mitochondrial DNA (mtDNA) of 185 individuals and NRY (non-recombining region of Y chromosome) of 98 individuals belonging to two major tribal populations of Maharashtra, and compared their molecular variations with that of 54 South Asian contemporary populations of adjacent states. Inter and intra population comparisons reveal that the maternal gene pool of Maharashtra state populations is composed of mainly South Asian haplogroups with traces of east and west Eurasian haplogroups, while the paternal haplogroups comprise the South Asian as well as signature of near eastern specific haplogroup J2a. Our analysis suggests that Indian populations, including Maharashtra state, are largely derived from Paleolithic ancient settlers; however, a more recent (∼10 Ky older) detectable paternal gene flow from west Asia is well reflected in the present study. These findings reveal movement of populations to Maharashtra through the western coast rather than mainland where Western Ghats-Vindhya Mountains and Narmada-Tapti rivers might have acted as a natural barrier. Comparing the Maharastrian populations with other South Asian populations reveals that they have a closer affinity with the South Indian than with the Central Indian populations.


A Novel Method for Continuous, Noninvasive, Cuff-Less Measurement of Blood Pressure: Evaluation in Patients With Nonalcoholic Fatty Liver Disease.
One promising approach for a continuous, noninvasive, cuff-less ambulatory blood pressure (BP) monitor is to measure the pulse wave velocity or the inversely proportional pulse transit time (PTT), based on electrical and optical physiological measurements in the chest area. A device termed IsenseU-BP+ has been developed for measuring continuous BP, as well as other physiological data. The objective of this paper is to present results from the first clinical evaluation with a wide range of patients. The study was set up to verify whether IsenseU-BP+ can be used to measure raw signals with sufficient quality to derive PTT. Methods: The test protocol, run 23 times on 18 different patients with nonalcoholic fatty liver disease, includes both supine measurement at rest as well as measurements during indoor cycling. Changes in PTT were compared with the BP changes measured using validated reference sensors. Results: IsenseU-BP+ measured signals with good quality during rest on 17 of 18 patients despite the high diversity in age, body shape, and body mass index. Evaluation during cycling was difficult due to a lack of good reference measurements. IsenseU-BP+ measures PTT with high quality during supine rest and exercise and could therefore be suitable for deriving noninvasive continuous BP, although evaluation during exercise was limited due to inaccurate reference BP measurements. Continuous, noninvasive measurement of BP would be highly beneficial in a number of clinical settings. Systems currently considered as the gold standard for the investigation of hypertension carry considerable limitations, which could be overcome by the method proposed here.


Intervention Scalability Assessment Tool: A decision support tool for health policy makers and implementers.
Promising health interventions tested in pilot studies will only achieve population-wide impact if they are implemented at scale across communities and health systems. Scaling up effective health interventions is vital as not doing so denies the community the most effective services and programmes. However, there remains a paucity of practical tools to assess the suitability of health interventions for scale-up. The Intervention Scalability Assessment Tool (ISAT) was developed to support policy-makers and practitioners to make systematic assessments of the suitability of health interventions for scale-up. The ISAT was developed over three stages; the first stage involved a literature review to identify similar tools and frameworks that could be used to guide scalability assessments, and expert input to develop draft ISAT content. In the second stage, the draft ISAT tool was tested with end users. The third stage involved revising and re-testing the ISAT with end users to further refine the language and structure of the final ISAT. A variety of information and sources of evidence should be used to complete the ISAT. The ISAT consists of three parts. Part A: 'setting the scene' requires consideration of the context in which the intervention is being considered for scale-up and consists of five domains, as follows: (1) the problem; (2) the intervention; (3) strategic/political context; (4) evidence of effectiveness; and (5) intervention costs and benefits. Part B asks users to assess the potential implementation and scale-up requirements within five domains, namely (1) fidelity and adaptation; (2) reach and acceptability; (3) delivery setting and workforce; (4) implementation infrastructure; and (5) sustainability. Part C generates a graphical representation of the strengths and weaknesses of the readiness of the proposed intervention for scale-up. Users are also prompted for a recommendation as to whether the intervention (1) is recommended for scale-up, (2) is promising but needs further information before scaling up, or (3) does not yet merit scale-up. The ISAT fills an important gap in applied scalability assessment and can become a critical decision support tool for policy-makers and practitioners when selecting health interventions for scale-up. Although the ISAT is designed to be a health policy and practitioner tool, it can also be used by researchers in the design of research to fill important evidence gaps.


[Martorell Hypertensive Ischaemic Leg Ulcer].
Martorell hypertensive ischaemic leg ulcer (HYTILU) represents an important differential diagnosis of painful leg ulcerations. Stenotic subcutaneous arteriolosclerosis in patients with long-standing arterial hypertension finally leads to skin infarction. The typical histological changes are very similar in Martorell HYTILU and calciphylaxis. This raises the hypothesis that the two entities may have a common pathogenesis. Martorell HYTILU presents as an extremely painful ulcer that is regularly located at the laterodorsal lower leg or at the Achilles tendon. Because of its inflammatory and violaceous wound edges and its tendency to progression, clinicians unaware of the diagnosis Martorell HYTILU might misdiagnose pyoderma gangrenosum or necrotising cutaneous vasculitis start an immunosuppressive treatment and avoid surgical diagnostic and therapeutic procedures. Instead, necrosectomy and split skin grafting are the treatment of choice for Martorell HYTILU.


Individual patient data meta-analysis: a promising approach for evidence synthesis in reproductive medicine.
Systematic reviews and accompanying meta-analyses are the cornerstones of evidence-based medicine. Systematic reviews summarize clinical evidence; meta-analyses provide summary estimates of the treatment effect or the diagnostic test accuracy. Although deemed to provide the highest level of evidence, their clinical value is limited as they can only summarize aggregated data. In these meta-analyses the true variability of the treatment effects cannot be explored to the desired extent, because the meta-analyses cannot distinguish between patients with different clinical profiles. Systematic reviews and meta-analyses based on individual patient data (IPD), described as the 'gold standard' for systematic reviews are a promising approach that might overcome these limitations. IPD meta-analyses allow treatment effects and diagnostic accuracy to be estimated at the level of relevant patient subgroups. This enables researchers to investigate the effectiveness of treatment in patients with different profiles. In this article, we address the opportunities of systematic reviews and meta-analyses using IPD in reproductive medicine. We discuss its potential based on three clinical examples: single versus double embryo transfer in IVF, the diagnosis of tubal pathology and the prognostic value of ovarian reserve tests. We propose to show potential advantages of IPD systematic reviews and meta-analyses in providing stratified clinical evidence, which could improve medical care.


The therapeutic response of ER+/HER2- breast cancers differs according to the molecular Basal or Luminal subtype.
The genomics-based molecular classifications aim at identifying more homogeneous classes than immunohistochemistry, associated with a more uniform clinical outcome. We conducted an in silico analysis on a meta-dataset including gene expression data from 5342 clinically defined ER+/HER2- breast cancers (BC) and DNA copy number/mutational and proteomic data. We show that the Basal (16%) versus Luminal (74%) subtypes as defined using the 80-gene signature differ in terms of response/vulnerability to systemic therapies of BC. The Basal subtype is associated with better chemosensitivity, lesser benefit from adjuvant hormone therapy, and likely better sensitivity to PARP inhibitors, platinum salts and immune therapy, and other targeted therapies under development such as FGFR inhibitors. The Luminal subtype displays potential better sensitivity to CDK4/6 inhibitors and vulnerability to targeted therapies such as PIK3CA, AR and Bcl-2 inhibitors. Expression profiles are very different, showing an intermediate position of the ER+/HER2- Basal subtype between the ER+/HER2- Luminal and ER- Basal subtypes, and let suggest a different cell-of-origin. Our data suggest that the ER+/HER2- Basal and Luminal subtypes should not be assimilated and treated as a homogeneous group.


Emerging imaging technologies in dermatology: Part I: Basic principles.
Dermatologists rely primarily on clinical examination in combination with histopathology to diagnose conditions; however, clinical examination alone might not be sufficient for accurate diagnosis and skin biopsies have associated morbidity. With continued technological advancement, there are emerging ancillary imaging technologies available to dermatologists to aid in diagnosis and management. This 2-part review article will discuss these emerging technologies including: digital photographic imaging, confocal microscopy, optical coherence tomography, and high-frequency ultrasound, as well as several additional modalities in development. In this first installment, the authors describe the breadth of technologies available and the science behind them. Then, in the second article, the authors discuss the applications and limitations of these technologies and future directions.


Being in two minds: the neural basis of experiencing action crises in personal long-term goals.
Although the successful pursuit of long-term goals constitutes an essential prerequisite to personal development, health, and well-being, little research has been devoted to the understanding of its underlying neural processes. A critical phase in the pursuit of long-term goals is defined as an action crisis, conceptualized as the intra-psychic conflict between further goal pursuit and disengagement from the goal. In the present research, we applied an interdisciplinary (cognitive and neural) approach to the analysis of processes underlying the experience of an action crisis. In Study 1, a longitudinal field study, action crises in personal goals gave rise to an increased and unbiased (re)evaluation of the costs and benefits (i.e., rewards) of the goal. Study 2 was a magnetic resonance imaging study examining resting-state functional connectivity. The extent of experienced action crises was associated with enhanced fronto-accumbal connectivity signifying increased reward-related impact on prefrontal action control. Action crises, furthermore, mediated the relationship between a dispositional measure of effective goal pursuit (action orientation) and fronto-accumbal connectivity. The converging and complementary results from two methodologically different approaches advance the understanding of the neurobiology of personal long-term goals, especially with respect to the role of rewards in the context of goal-related conflicts.


Fecal microbiota transplantation in ulcerative colitis.
Fecal microbiota transplantation (FMT), a treatment aiming to restore dysbiosis by transferring stool from a healthy donor into the patient, has cure rates up to 90% in the management of recurrent Clostridium difficile (C. difficile) diarrhea. This paper tries to determine whether FMT is safe and effective in the treatment of ulcerative colitis, and what the potential characteristics could be of a 'super donor'. The PubMed database was searched using the term fecal microbiota transplantation inflammatory bowel disease. Only articles discussing the use of FMT in the treatment of ulcerative colitis were withheld. Finally, 31 original studies (10 case reports, 17 open label trials, 4 randomized controlled trials (RCTs)) and 1 meta-analysis were included. So far 4 RCTs have investigated the effectiveness of FMT in treating UC. Three RCTs reported a significant difference between FMT and a control group, achieving clinical remission in 24 to 44% of patients (vs. 5 to 20% of patients in control groups). The meta-analysis confirms that significantly more patients in the FMT-group achieve clinical remission in comparison to patients in the control group (p=0,01) : 42,1% vs. 22,6%. The composition of the gut microbiota plays an important role in the success of FMT-treatment. FMT seems to be a promising and safe therapy in the management of UC. Further research, with larger cohorts, will be needed to confirm this and to determine the optimal FMT procedure.


Nanogold plasmonic photocatalysis for organic synthesis and clean energy conversion.
This review provides the basic concepts, an overall survey and the state-of-the art of plasmon-based nanogold photocatalysis using visible light including fundamental understanding and major applications to organic reactions and clean energy-conversion systems. First, the basic concepts of localized surface plasmon resonance (LSPR) are recalled, then the major preparation methods of AuNP-based plasmonic photocatalysts are reviewed. The major part of the review is dedicated to the latest progress in the application of nanogold plasmonic photocatalysis to organic transformations and energy conversions, and the proposed mechanisms are discussed. In conclusion, new challenges and perspectives are proposed and analyzed.


Vascular Access Device Care and Management: A Comprehensive Organizational Approach.
The Infusion Nurses Society asserts that a comprehensive organizational approach to vascular access device (VAD) care and management is imperative to ensure safe and efficacious patient care. It is essential that each organization (1) develops policies and procedures to align VAD care and management with recognized standards of practice; (2) integrates unique aspects of organization-selected VAD care products into policies and procedures and establishes expectations for adherence to these organizational directives; (3) develops a framework for gathering and analyzing clinical data related to patient outcomes for VAD care and management; (4) utilizes quality outcome data to facilitate evidence-based best practices within the organization; and (5) evaluates and facilitates educational programming to validate clinician competency.


Spiroindoles as Potential Pharmacophores.
The spiroindole heterocyclic scaffold is found in many natural products and has been identified as an important bioactive agent. Over the past few decades, various spiroindole-containing compounds have been reported to possess biological properties and hence found in the structure of many synthetic pharmaceuticals. This mini-review describes the most promising examples of this class of compounds possessing biological activity including anticancer, anti-inflammatory, and antimicrobial activities. To the best of our knowledge, the earlier reviews did not cover the pharmaceutical properties of synthetic and naturally occurring spiroindoles; thus, the current review focuses on the biological activity of compounds containing the spiroindole scaffold.


Gum arabic reduces inflammation, oxidative, and nitrosative stress in the gastrointestinal tract of mice with chronic kidney disease.
The aim of this study was to investigate some biochemical indices of inflammation and oxidative and nitrosative stresses in the gastrointestinal tract of mice with experimental chronic kidney disease (CKD) and treated with gum arabic (GA). Male CD1 mice (n = 28) were randomly distributed into four groups and treated for four consecutive weeks: group 1: Control: received the same diet without treatment until the end of the study; group 2: Adenine: switched to a powder diet containing adenine (0.2% w/w in feed); group 3: Gum acacia (GA): given normal feed and GA in drinking water at a concentration of 15% w/v; and group 4: Adenine + GA: given adenine in the feed as in the second group plus GA in the drinking water at concentration of 15% w/v. CKD was induced to mice by adenine feeding and concomitantly treated with the prebiotic dietary fiber gum acacia, GA (15% in drinking water). Duodenal mucosa from CKD mice had significantly higher concentrations of TNF-alfa, IL- 6, and TGF-beta-1 and lipid peroxidation. Moreover, low concentrations of IL-10, some antioxidants (catalase, glutathione reductase, total antioxidant capacity, and superoxide dismutase), and nuclear factor erythroid 2-related factor 2 were found in the duodenum. The levels of nitrosative stress (nitrite, nitrate, and total nitrate) were significantly increased by CKD, as well as the concentrations of ammonia and urea creatinine in the cecal content. Concomitant GA treatment significantly mitigated these harmful effects. Taken together, GA reduces inflammation and duodenal oxidative and nitrosative stress in the gastrointestinal tract of mice with CKD.


Exposures recorded for participants in the UK Chemical Warfare Agent Human Research Programme, 1941-1989.
This study describes exposures to military veterans who participated between 1941 and 1989 in British research at Porton Down on the effects of exposure to chemical warfare agents and to defences against those agents. The study is part of a programme of epidemiological research initiated in response to service veterans' concerns about possible long-term health effects of their participation. All entries in 97 books held in the Porton Down historical experimental archive covering the years 1939-1989 were reviewed. For tests between April 1941 and December 1989, data were abstracted on chemicals used, with additional detail abstracted for tests involving vesicants and nerve agents. For tests recorded during 1939-1941, similar data were abstracted for a representative sample of tests. Historical data were abstracted for 17 303 veterans included in the cohort study of 18,276 servicemen who took part in tests at Porton Down between 1941 and 1989. The median number of days per veteran on which tests were carried out was 2 days. The median difference between the last and first day of testing was 4 days. A large number of chemicals were tested over this period (n = 492). The type of chemical tested varied over time. Exposures were often modified by respirator use or use of protective clothing or protective equipment. It was possible to assign a quantitative measure of cumulative exposure to 73% of veterans exposed to the vesicant sulphur mustard--3491 (34%) of exposed veterans had cumulative exposures > or =10.63 mg and for 70% of veterans exposed to the nerve agent sarin--658 (29%) of exposed veterans had cumulative exposures > or =15.0 mg min m(-3). Ninety-three per cent of veterans exposed to sulphur mustard were classified to a semi-quantitative scale of dermal effect--3771 (37%) had a vesicle or necrosed area, and 69% of veterans exposed to sarin could be categorized by change in blood cholinesterase activity--1033 (31%) had a depression in cholinesterase activity of > or =30%. The experimental archive at Porton Down has proved to be a rich source of data on tests conducted between 1941 and 1989. It has been possible to categorize most veterans according to date of test, chemical group, chemical, type of protection and, for certain chemicals, level of exposure and/or degree of acute toxicity. These categorizations have been used to assign veterans to exposure groups for epidemiological analysis.


Cross-language Neighborhood Effects in Learners Indicative of an Integrated Lexicon.
This study examined how acquisition of novel words from an unknown language (L2) is influenced by their orthographic similarity with existing native language (L1) words in beginning adult learners. Participants were tested in a two-alternative forced-choice recognition task and a typing production task as they learned to associate 80 L2 (pseudo)words with pictures depicting their meanings. There was no effect of L1 orthographic neighborhood density on accuracy in the two-alternative forced-choice task, but typing accuracy was higher for L2 words with many L1 neighbors in the earliest stages of learning. ERPs recorded during a language decision task before and after learning also showed differences as a function of L1 neighborhood density. Across sessions, L2 words with many L1 neighbors elicited slower responses and larger N400s than words with fewer L1 neighbors, suggesting that L1 neighbors continued to influence processing of the L2 words after learning (though to a lesser extent). Finally, ERPs recorded during a typing task after learning also revealed an effect of L1 neighborhood that began about 700 msec after picture onset, suggesting that the cross-language neighborhood effects cannot solely be attributed to bottom-up activation of L1 neighbors. Together, these results demonstrate that strategic associations between novel L2 words and existing L1 neighbors scaffold learning and result in interactions among cross-language neighbors, suggestive of an integrated L1-L2 lexicon.


Warfarin and vitamin K intake in the era of pharmacogenetics.
The considerable variability in the warfarin dose-response relationship between individuals, is explained mainly by genetic variation in its major metabolic (CYP2C9) and target (VKORC1) enzymes. Despite the predominance of pharmacogenetics, environmental factors also affect the pharmacokinetics and pharmacodynamics of warfarin, and are often overlooked. Among these factors, dietary and supplemental vitamin K consumption is a controllable contributor to within-, and between-patient variability of warfarin sensitivity. In this commentary we review the current role of vitamin K in warfarin anticoagulation therapy, with emphasis on the following: 1 The effect of dietary and supplemental vitamin K on warfarin anticoagulation, beyond the impact of genetic variability in CYP2C9 and VKORC1. We deal separately with the effects of vitamin K on warfarin dose requirements during the induction of therapy, as opposed to its effect on stability of anticoagulation control during maintenance therapy. 2 The role of vitamin K supplementation in warfarin treated patients with vitamin K deficiency as well as in patients with unstable warfarin anticoagulation, and 3 The role of therapeutic vitamin K in cases of warfarin over-anticoagulation.


Graphene-deposited photonic crystal fibers for continuous refractive index sensing applications.
We present a pilot demonstration of an optical fiber based refractive index (RI) sensor involving the deposition of graphene onto the surface of a segment of a photonic crystal fiber (PCF) in a fiber-based Mach-Zehnder Interferometer (MZI). The fabrication process is relatively simple and only involves the fusion splicing of a PCF between two single mode fibers. The deposition process relies only on the cold transfer of graphene onto the PCF segment, without the need for further physical or chemical treatment. The graphene overlay modified the sensing scheme of the MZI RI sensor, allowing the sensor to overcome limitations to its detectable RI range due to free spectral range issues. This modification also allows for continuous measurements to be obtained without the need for reference values for the range of RIs studied and brings to light the potential for simultaneous dual parameter sensing. The sensor was able to achieve a RI sensitivity of 9.4 dB/RIU for the RIs of 1.33-1.38 and a sensitivity of 17.5 dB/RIU for the RIs of 1.38-1.43. It also displayed good repeatability and the results obtained were consistent with the modeling.


Nondisseminated rhinosporidiosis with multisite involvement in the head and neck.
Rhinosporidiosis is a communicable disease prevalent in tropical countries that affects one or more mucocutaneous sites such as the nasal cavity, pharynx, skin, bronchus, genitals, and bone, in isolation or together. We report a case of multicentric rhinosporidiosis involving the nasal cavity, oropharynx, larynx, and cheek skin without disseminated disease outside the head and neck. Although the appearance of mucocutaneous lesions in our patient was similar to that of papilloma or neoplasm, the distinct clinicopathologic characteristics of the rhinosporidiosis guided us in managing the case successfully. In our own experience with 11 patients with rhinosporidiosis on whom we operated over the past 5 years, the nasal cavity and pharynx were the most commonly involved sites in the head and neck. Surgical excision of all lesions along with cauterization of the base and long-term dapsone therapy is the current standard of care for multicentric rhinosporidiosis.


Ovarian teratoma mimicking features of juvenile dermatomyositis in a child.
An 8-year-old girl complained for 4 months of right arm pain, weakness in both legs, difficulty in arising from a seated or squatting position, and 1 month of pain in her hips, ankles, and knees. On physical examination, she had weak neck flexors, weak proximal and abdominal muscles, and an assisted Gower maneuver; both knees and ankles were painful. Erythematous macules on her elbows, knees, and medial ankles were present without heliotrope rash or dilated eyelid capillaries. She had nail-fold erythema and decreased numbers of nail-fold capillary end-row loops (ERLs) (5.42 ERLs per mm [normal: ≥6.8 ERLs per mm]) without digital ulcers or tight skin. Laboratory testing revealed slightly elevated creatine phosphokinase (440 IU/L [normal: ≤199 IU/L]) and aldolase (11.7 U/L [normal: ≤8.6 U/L]) levels. Her eosinophilia (7.2%) was not characteristic of juvenile dermatomyositis. Rheumatologic evaluation included a positive antinuclear antibody test result (1:5120 titer), speckled pattern (normal: <80 titer), myositis-associated and -specific antibodies that showed indeterminate Mi-2, with the others negative, including p155/140, elevated immunoglobulin G (IgG) (1440 mg/dL [normal range: 608-1229]) and IgE (409 kU/L [normal: <160 kU/L]) levels, and normal levels of IgM and IgA. She had an increased neopterin level (20 nm/L [normal: <10 nm/L]) and decreased absolute count of CD3-CD56/16(+) natural killer cells (89 [lower normal limit: 138]). MRI of her thigh muscles revealed serpiginous increased T-2 signals consistent with inflammation and a complex round mass in the left pelvis. A muscle biopsy did not indicate juvenile dermatomyositis. Pelvic ultrasound confirmed a solid mass of the left ovary consistent with a mature teratoma. After surgical removal of the teratoma, the myositis, synovitis, and cutaneous findings resolved over 4 months without further therapy.


Rehabilitation service utilization in children and youth with cerebral palsy.
To describe the pattern of use of rehabilitation services in children and adolescents with cerebral palsy (CP), and to identify factors associated with use. In this study, parents of 91 school-age children and 167 adolescents with CP completed a questionnaire regarding educational and rehabilitation resources received within the last 6 months. Rehabilitation services included occupational therapy (OT), physical therapy (PT), speech language pathology (SLP), psychology and special education. Demographic characteristics were documented and developmental and functional status was assessed. Relationships between service utilization and sociodemographic factors, functioning and school setting were determined. Over half of children (53.2%) and adolescents (57.5%) were in regular schools; however, 41% of these required special education resources. The remainder (42.5-46.8%) was in special schools. The majority of children (84.6%) were receiving at least one rehabilitation service although this decreased (68.1%) in adolescence. PT and OT were most common and services were provided predominantly in the school setting. Services were primarily weekly direct interventions at school age, with weekly interventions or consultations most common for adolescents. Younger age was associated with service receipt at school age only. Children with greater motor limitations, lower IQ and greater activity limitations were more likely to receive OT, PT, SLP or special education. Children in segregated schools were significantly more likely to receive rehabilitation services, when compared with children in regular schools. The majority of children and youth received one or more services. Individuals with greater motor or cognitive challenges were more likely to receive a range of school-based services from rehabilitation specialists. When compared with children of school age, adolescents were less likely to receive services and when provided, services were more likely to be consultative. Services may need to be more optimally organized through childhood to enhance benefits to children with CP across activity limitation profiles.


Mutational definition of RNA-binding and protein-protein interaction domains of heterogeneous nuclear RNP C1.
The heterogeneous nuclear ribonucleoprotein (hn- RNP) C proteins, among the most abundant pre-mRNA-binding proteins in the eukaryotic nucleus, have a single RNP motif RNA-binding domain. The RNA-binding domain (RBD) is comprised of approximately 80-100 amino acids, and its structure has been determined. However, relatively little is known about the role of specific amino acids of the RBD in the binding to RNA. We have devised a phage display-based screening method for the rapid identification of amino acids in hnRNP C1 that are essential for its binding to RNA. The identified mutants were further tested for binding to poly(U)-Sepharose, a substrate to which wild type hnRNP C1 binds with high affinity. We found both previously predicted, highly conserved residues as well as additional residues in the RBD to be essential for C1 RNA binding. We also identified three mutations in the leucine-rich C1-C1 interaction domain near the carboxyl terminus of the protein that both abolished C1 oligomerization and reduced RNA binding. These results demonstrate that although the RBD is the primary determinant of C1 RNA binding, residues in the C1-C1 interaction domain also influence the RNA binding activity of the protein. The experimental approach we described should be generally applicable for the screening and identification of amino acids that play a role in the binding of proteins to nucleic acid substrates.


Effects of counter anions, P-substituents, and solvents on optical and photophysical properties of 2-phenylbenzo[b]phospholium salts.
In this work, we investigated the effects of counter anions, P-substituents, and solvents on the optical and photophysical properties of 2-phenylbenzo[b]phospholium salts in solution. A series of 2-phenylbenzo[b]phospholium salts was prepared by P-alkylation or P-phenylation of 1,2-diphenylbenzo[b]phosphole followed by anion exchange reactions. X-ray crystallographic analyses of six benzo[b]phospholium salts showed that each phosphorus center has an onium nature with an essentially tetrahedral geometry. 1H NMR and steady-state UV-vis absorption and fluorescence spectroscopic measurements of these phospholium salts revealed the pivotal role of counter-anion solvation. The observed results are discussed on the basis of the association-dissociation equilibrium between a contact ion pair (CIP) and a solvent-separated ion pair (SSIP) in solution. The hexafluorophosphates exist as SSIPs and emit intense fluorescence, irrespective of the P-substituents and solvents. In contrast, the iodides are present as SSIPs in methanol but exist as equilibrium mixtures of the two emitting species, SSIP and CIP, in dichloromethane. As a consequence, fluorescence intensities of the iodides varied significantly depending on the solvents, P-substituents, and solution concentrations. These findings were studied in more detail using time-resolved fluorescence spectroscopy and fluorescence titration measurements. The light-emitting properties of the 2-phenylbenzo[b]phospholium halides in the CIPs rely on heavy atom effects derived from the counter halide anions on the S1 state of the adjacent cationic benzo[b]phosphole π-systems. The present study suggests that 2-arylbenzo[b]phospholium salts would be promising scaffolds for developing new phosphole-based ionic fluorophores that are capable of responding to external stimuli such as anionic species and solvents.


MyD88 and retinoic acid signaling pathways interact to modulate gastrointestinal activities of dendritic cells.
Gut-associated dendritic cells (DC) metabolize vitamin A into all-trans retinoic acid (RA), which is required to induce lymphocytes to localize to the gastrointestinal tract and promotes the differentiation of Foxp3+ regulatory T cells and IgA antibody-secreting cells. We investigated whether RA functions in a positive-feedback loop in DC to induce its own synthesis. We measured levels of retinoids in intestinal tissues from mice and assessed the role of RA in the functional specialization of gut-associated DC in cell cultures and mice. We used pharmacologic antagonists to determine the signaling pathways involved in regulation of DC and used MyD88-/- mice to determine the contribution of Toll-like receptor signaling in RA-mediated effects on DC. The concentration of retinoids decreased in a proximal-to-distal gradient along the intestine, which correlated with the activity of gut-specific DC. Importantly, RA regulated the ability of gut-associated DC to produce RA, induce T cells to localize to the gastrointestinal tract, and generate regulatory T cells and IgA-secreting cells. RA was sufficient to induce its own production by extraintestinal DC in vitro and in vivo. RA-mediated regulation of DC required signaling through the mitogen-activated protein kinase signaling pathway and unexpectedly required MyD88, which is conventionally associated with Toll-like receptor, interleukin-1, and interleukin-18 signaling. RA is necessary and sufficient to induce DC to regulate T-cell localization to the gastrointestinal tract and IgA secretion. Our findings also indicate crosstalk between the RA receptor and MyD88-dependent Toll-like receptor signaling pathways.


The Oxford unicompartmental knee arthroplasty: a radiological perspective.
Unicompartmental knee arthroplasty (UKA) is increasingly being performed in both specialist centres as well as district hospitals. The radiologists should be aware of the required preoperative imaging, the normal appearance, and complications of this procedure. Unfortunately, very little is available in the radiology literature. This review aims to provide a radiological perspective to an already widely used procedure.


A mass spectrometric method for quantification of tryptophan-derived uremic solutes in human serum.
In addition to various physiologic roles, emerging evidence strongly points to pathogenic roles of tryptophan and of its metabolites, especially in diseases such as renal failure. Accurate estimation of levels of these metabolites in blood is important to mechanistically probe their contribution to disease pathogenesis, while clinically, such a panel can be used to risk stratify patients for a clinical phenotype. Herein, we describe a comprehensive liquid chromatography-mass spectrometry (LC/MS)-based method to determine the level of tryptophan and its metabolites (kynurenine, kynurenic acid, xanthurenic acid, anthranilic acid, indoxyl sulfate and indoxyl acetate). Human sera samples were processed through a C18 column followed by application of a binary gradient and quantitation by MS/MS. The linearity, lower limit of detection, inter- and intraassay variabilities and recovery were determined, yielding a precise, reproducible method for all the metabolites. Unlike previous studies, we further validated these methods in a well-characterized set of human sera from end stage renal disease patients compared to age-, gender- and ethnic-background matched human controls. Overall, we report an optimized LC/MS-based estimation of a comprehensive panel of tryptophan-derived metabolites with quality features within FDA standards, underscoring their readiness for translational use.


Structure and function of cohesin's Scc3/SA regulatory subunit.
Sister chromatid cohesion involves entrapment of sister DNAs by a cohesin ring created through association of a kleisin subunit (Scc1) with ATPase heads of Smc1/Smc3 heterodimers. Cohesin's association with chromatin involves subunits recruited by Scc1: Wapl, Pds5, and Scc3/SA, in addition to Scc2/4 loading complex. Unlike Pds5, Wapl, and Scc2/4, Scc3s are encoded by all eukaryotic genomes. Here, a crystal structure of Scc3 reveals a hook-shaped protein composed of tandem α helices. Its N-terminal domain contains a conserved and essential surface (CES) present even in organisms lacking Pds5, Wapl, and Scc2/4, while its C-terminal domain binds a section of the kleisin Scc1. Scc3 turns over in G2/M while maintaining cohesin's association with chromosomes and it promotes de-acetylation of Smc3 upon Scc1 cleavage.


A national clinical scenario-based survey of clinicians' attitudes towards fresh frozen plasma transfusion for critically ill patients.
It is known that 20-30% of fresh frozen plasma (FFP) is used in intensive care units (ICUs), but little is known about variations in decision making between clinicians in relation to coagulopathy management. Our aim was to describe ICU clinicians' beliefs and practice in relation to FFP treatment of non-bleeding coagulopathic critically ill patients. Two patient-based scenarios were developed and sent to 2700 members of two UK intensive care professional societies. Scenario 1 was a non-bleeding septic patient with coagulopathy; scenario 2 was a non-bleeding critically ill patient with hepatic cirrhosis and coagulopathy. Responses were sought in relation to FFP prophylaxis, and prior to central venous cannulation. A supplementary question asked clinicians' view of prophylaxis in relation to other ICU procedures. Two-thousand-and-seven-hundred clinicians were surveyed from whom 601 responses were received (22·3% response rate). For scenario 1 52% of respondents stated that they would never routinely administer prophylactic FFP, but this decreased to 9% when central venous cannulation was planned (P < 0·01). There was wide variation in the 'trigger' INR (international normalised ratio) value used prior to central vein cannulation, the most common range being 2·0-2·4. For scenario 2, responses were very similar. More than 80% of clinicians stated that they would routinely treat coagulopathy prior to lumbar puncture, epidural catheterisation, intracranial pressure monitoring and tracheostomy; and 54% prior to chest drain insertion. Our survey demonstrated a wide range of responses consistent with important variations in clinical practice and substantial clinical uncertainty in relation to FFP treatment for non-bleeding ICU patients.


Interplay of physics and evolution in the likely origin of protein biochemical function.
The intrinsic ability of protein structures to exhibit the geometric and sequence properties required for ligand binding without evolutionary selection is shown by the coincidence of the properties of pockets in native, single domain proteins with those in computationally generated, compact homopolypeptide, artificial (ART) structures. The library of native pockets is covered by a remarkably small number of representative pockets (∼400), with virtually every native pocket having a statistically significant match in the ART library, suggesting that the library is complete. When sequences are selected for ART structures based on fold stability, pocket sequence conservation is coincident to native. The fact that structurally and sequentially similar pockets occur across fold classes combined with the small number of representative pockets in native proteins implies that promiscuous interactions are inherent to proteins. Based on comparison of PDB (real, single domain protein structures found in the Protein Data Bank) and ART structures and pockets, the widespread assumption that the co-occurrence of global structure, pocket similarity, and amino acid conservation demands an evolutionary relationship between proteins is shown to significantly underestimate the random background probability. Indeed, many features of biochemical function arise from the physical properties of proteins that evolution likely fine-tunes to achieve specificity. Finally, our study suggests that a repertoire of thermodynamically (marginally) stable proteins could engage in many of the biochemical reactions needed for living systems without selection for function, a conclusion with significant implications for the origin of life.


Precise Tubular Braid Structures of Ultrafine Microwires as Neural Probes: Significantly Reduced Chronic Immune Response and Greater Local Neural Survival in Rat Cortex.
Braided multi-electrode probes (BMEPs) for neural interfaces comprise ultrafine microwire bundles interwoven into tubular braids. BMEPs provide highly flexible probes and tethers, and an open lattice structure with up to 24 recording/stimulating channels in precise geometries, currently all within a [Formula: see text] diameter footprint. This paper compares the long-term tissue effects of BMEPs ( [Formula: see text] wires) versus single conventional 50- [Formula: see text] wires, by testing nearby chronic immune response and neural survival in rat cortex. Four different types of electrodes were implanted in cortex in each of eight rats: 1) BMEP with tether; 2) tethered 50- [Formula: see text] wire; 3) BMEP without a tether; and 4) untethered 50- [Formula: see text] wire. Quantitative immunohistological statistical comparisons after eight weeks using GFAP, ED1, and NeuN staining clearly showed that both BMEP implants had significantly less tissue immune response and more neuronal survival than either of the 50- [Formula: see text] wires ( ) in each of the eight rats. Data strongly indicate that BMEP tissue responses are superior, and that BMEP designs partly alleviate chronic tissue inflammatory responses and neural losses. The flexible body, tether and open braid lattice, and finer wire diameters of BMEP designs may all contribute to reducing the biological long-term response.


CO(2) DIAL measurements of water vapor.
CO(2) lidars have heretofore been used to measure water vapor concentrations primarily using the 10R(20) line at 10.247 microm, which has a strong overlap with a water vapor absorption line. This paper discusses the use of that line as well as other CO(2) laser lines for which the absorption coefficients are weaker. The literature on measurement of water vapor absorption coefficients using CO(2) lasers is reviewed, and the results from four laboratories are shown to be generally consistent with each other after they are normalized to the same partial pressure, temperature, and ethylene absorption coefficient for the 1P(14) CO(2) laser line; however, the agreement with the Air Force Geophysics Laboratory's HITRAN and FASCOD 2 spectral data tapes is not good either for the water vapor absorption lines or for the water vapor continuum. Demonstration measurements of atmospheric water vapor have been conducted using the Mobile Atmospheric Pollutant Mapping System, a dual CO(2) lidar system using heterodyne detection. Results are discussed for measurements using three sets of laser line pairs covering a wide range of water vapor partial pressures.


Contrasting the Water Quality and Bacterial Community Patterns in Shallow and Deep Lakes: Manyas vs. Iznik.
The objectives of this study are to monitor the physicochemical properties of two freshwater lakes with different chemical characteristics and trophic status over a year (2019) and assess the bacterial diversity by a high-throughput sequencing method for a certain time. Carlson Trophic Index analysis revealed that, whereas the deep lake, Iznik Lake, (TSImean = 48.9) has mesotrophic characteristics, the shallow lake Manyas Lake (TSImean = 74.2) was found at a hypertrophic status. The most important parameters controlling water qualities in the lakes were temperature, alkalinity, and phosphate levels. Although the bacterial communities were dominated by the same phyla (Cyanobacteria, Bacteroidetes, Actinomicrobia, Proteobacteria, and Verrucomicrobia) in both lakes, the communities differed distinctly at the lower levels. Whereas Sporichthyaceae in Manyas Lake accounted for 10% of the total reads, the major share of the sequences was assigned to Cyanobacteria Family I (8%) in Iznik Lake. The hypertrophic Manyas Lake had a more diverse bacterial community rather than Iznik Lake and contained higher numbers of unique Operational Taxonomic Units.


Quantitative mitochondrial DNA copy number determination using droplet digital PCR with single-cell resolution.
Mitochondria are involved in a number of diverse cellular functions, including energy production, metabolic regulation, apoptosis, calcium homeostasis, cell proliferation, and motility, as well as free radical generation. Mitochondrial DNA (mtDNA) is present at hundreds to thousands of copies per cell in a tissue-specific manner. mtDNA copy number also varies during aging and disease progression and therefore might be considered as a biomarker that mirrors alterations within the human body. Here, we present a new quantitative, highly sensitive droplet digital PCR (ddPCR) method, droplet digital mitochondrial DNA measurement (ddMDM), to measure mtDNA copy number not only from cell populations but also from single cells. Our developed assay can generate data in as little as 3 h, is optimized for 96-well plates, and also allows the direct use of cell lysates without the need for DNA purification or nuclear reference genes. We show that ddMDM is able to detect differences between samples whose mtDNA copy number was close enough as to be indistinguishable by other commonly used mtDNA quantitation methods. By utilizing ddMDM, we show quantitative changes in mtDNA content per cell across a wide variety of physiological contexts including cancer progression, cell cycle progression, human T cell activation, and human aging.


Amino acid neurotoxins in feathers of the Lesser Flamingo, Phoeniconaias minor.
The Lesser Flamingo (Phoeniconaias minor) is known to use cyanobacteria (primarily Arthrospira) as a major food source in the East African Rift Valley lakes. Periodically, mass mortalities have occurred, associated with the cyanobacterial toxins (cyanotoxins), microcystins and anatoxin-a. Deposition of these cyanotoxins into P. minor feathers has been shown to occur, consistent with the presence of cyanotoxins in the livers, stomach and faecal contents after dietary intake. As cyanobacteria have been shown to also produce the neurotoxins β-N-methylamino-L-alanine (BMAA) and 2,4-diaminobutyric acid (DAB), stored wing feathers, previously recovered from flamingos which had been exposed to microcystins and anatoxin-a and had subsequently died, were analysed for these neurotoxic amino acids. Trace amounts of BMAA were detected in extracts from Lake Nakuru flamingo feathers, with DAB also present at concentrations between 3.5 and 8.5 μg g(-1) dry weight in feathers from both lakes. Toxin recovery by solid-phase extraction of feather digests was tested with spiked deuterated BMAA and showed good recovery when analysed by LC-MS/MS (80-94%). This is the first report of these neurotoxic amino acids in birds. We discuss the origin and significance of DAB, alongside other cyanotoxins of dietary origin, in the feathers of the Lesser Flamingo.


Autophagic dysregulation in glaucomatous trabecular meshwork cells.
Primary open angle glaucoma (POAG) is a degenerative disease commonly associated with aging and elevated intraocular pressure (IOP). Higher resistance to aqueous humor (AH) outflow through the trabecular meshwork (TM) generates the elevated IOP in POAG; unfortunately the underlying molecular mechanisms responsible for elevated resistance are unknown. It is widely accepted, however, that differences between normal and POAG TM tissues are presumably a consequence of cellular dysfunction. Here, we investigated the autophagic function and response to chronic oxidative stress in TM cells isolated from glaucomatous and age-matched donor eyes. Glaucomatous TM cells showed elevated senescence-associated-beta-galactosidase (SA-β-Gal) and cellular lipofuscin, together with decreased steady-state levels of LC3B-II, decreased levels of pRPS6K-T389 and reduced proteolysis of long-live proteins. Moreover, the glaucomatous cultures failed to activate autophagy when exposed to hyperoxic conditions. These results strongly suggest mTOR-dependent dysregulation of the autophagic pathway in cells isolated from the glaucomatous TM. Such dysregulated autophagic capacity can have a detrimental impact in outflow pathway tissue, i.e. mechanotransduction, and thus represent an important factor contributing to the progression of the disease.


Comorbidity profiles among patients with recurrent aphthous stomatitis: A case-control study.
Recurrent aphthous stomatitis (RAS) is common and associated with certain comorbidities. The aim of this study was to investigate the prevalence of selected comorbidities in patients with RAUs and to compare the risks of comorbidity between the two cohorts of patients with or without RAUs based on the Taiwanese National Health Insurance Research Database. This case-control study included patients with recurrent aphthous stomatitis (the RAS cohort) and patients without recurrent aphthous stomatitis using 1:1 matching for year of index date, age, sex, monthly income, geographical location, and urbanization level (the non-RAS cohort). We calculated the prevalence of 31 medical comorbidities based on a modified version of the Elixhauser comorbidity index within 1 year before and after the index date. Conditional logistic regression was conducted to compare the risks of each comorbidity between the two cohorts. Compared with the non-RAS cohort, the RAS cohort had a significantly higher prevalence of 16 comorbidities, with 2% or higher prevalence difference for hyperlipidemia (2.9%), headaches (6.9%), liver diseases (2.8%), and peptic ulcers (5.4%). The adjusted odds ratios were >1.5 for headaches (1.92), migraines (1.62), hypothyroidism (1.50), rheumatoid arthritis (1.92), ankylosing spondylitis (1.94), systemic lupus erythematosus (1.82), liver diseases (1.51), peptic ulcers (1.69), hepatitis (1.62), depression (1.76), and psychoses (1.50). Patients with recurrent aphthous stomatitis were associated with increased risk of specific comorbidities. Physicians should screen for these comorbidities for early detection and treatment.


The effect of the serotonin transporter polymorphism (5-HTTLPR) on amygdala function: a meta-analysis.
The 5-HTTLPR polymorphism has been widely regarded as a potential genetic risk factor for affective disorders. Consistent with this, this polymorphism has been associated with altered amygdala responses at rest and in response to aversive stimuli. However, the strength of this association remains uncertain. We sought to synthesize existing data on the association between the 5-HTTLPR polymorphism and amygdala activation and ascertain the strength of evidence for this association. Meta-analytic techniques were applied to data from relevant published studies and unpublished data sets to obtain an estimate of the likely magnitude of effect of any association. The large number of studies allowed us to apply a formal test of publication bias, as well as explore the impact of various study-level characteristics on the magnitude of the observed effect size. Our meta-analysis indicated that there is a statistically significant but small effect of 5-HTTLPR on left and right amygdala activity. However, there was considerable between-study heterogeneity, which could not be fully accounted for by the study design and sample characteristics that we investigated. In addition, there was evidence of excess statistical significance among published studies. These findings indicate that the association between the 5-HTTLPR and amygdala activation is smaller than originally thought, and that the majority of previous studies have been considerably under powered to reliably demonstrate an effect of this size.


Survival in cohorts of asbestos cement workers and controls.
To measure the impact on survival of being exposed to asbestos cement dust. Survival of 866 asbestos cement workers and 755 controls was studied with Cox's proportional hazards regression models with age as the basic time variable. The effect of cumulative exposure up to the age of 40 was investigated in an internal analysis of 635 asbestos cement workers who had dose estimates. The death risk was higher for the asbestos cement workers than for the controls with a hazard ratio (HR) of 1.15 (95% confidence interval was 1.00 to 1.31). The increased risk found seemed to be confined to the period 20-40 years from start of employment. The estimates of the cohort effect were almost unaffected by adjustment for smoking habits. The estimates of the exposure effect rose with increasing dose (< 4 fibre-years/ml (f-y/ml): HR = 1.00, 4-9.9 f-y/ml: HR = 1.06, > or = 10 f-y/ml: HR = 1.35, for workers with at least five years of employment), and were higher when restricted only to deaths from malignant or non-malignant respiratory disease. However, none of the point estimates were significantly increased. Median age at death was two years lower in the high than in the low, exposure group. The results indicate that even a moderate asbestos exposure may shorten the median duration of life in an exposed population. Compared with the estimated effect on duration of life from ever being a smoker, that of ever being an asbestos cement worker was less, although that of having a high exposure was similar.


Role of wide/radical hysterectomy and pelvic lymph node dissection in endometrial cancer with cervical involvement.
The goal of this work was to assess retrospectively the role of wide/radical hysterectomy (RH) and pelvic lymph node dissection (LND) in endometrial cancer with cervical involvement. METHODS; From 1984 to 1993, 82 patients with endometrial cancer and cervical involvement were surgically managed at our institution. Of 57 patients with stage II (59%) or III (41%) disease receiving no preoperative therapy, 22 (39%) had simple hysterectomy (SH) and 35 (61%) had RH. Forty-four patients (77%) had pelvic LND, and 38 (67%) had adjuvant radiotherapy (RT). Median follow-up was 70 months. The 5-year disease-related survival (DRS) and recurrence-free survival (RFS) were 73 and 63%, respectively. Five-year DRS and RFS were 68 and 50%, respectively, in the SH group compared with 76% (P = 0.1) and 71% (P = 0.04) in the RH group. Distant recurrences occurred in 45% of patients with SH and in 23% with RH (P = 0.08). Local recurrence rates did not differ significantly. Considering only stage II tumors, we did not observe any recurrence among patients with negative nodes who had RH, irrespective of the administration of adjuvant RT. By contrast, adjuvant RT improved local control (even if not significantly) in stage II patients who had SH. Five-year DRS of stage III patients was 47%, but it was improved by adjuvant RT in the subgroup of patients who had RH. Independent variables associated with prognosis were stage III disease, deep myometrial invasion, RH, and adjuvant RT. RH and adjuvant RT appear to improve prognosis in endometrial cancer with cervical involvement. In particular, radical surgery alone is therapeutic in stage II patients with negative nodes, irrespective of the administration of RT. By contrast, RT can possibly improve local control in stage II patients who previously had SH. Overall, stage III patients have a poor prognosis that can be improved by a combination of radical surgery and adjuvant RT; however, associated therapy directed to extrapelvic sites is probably needed in patients with extrauterine disease.


Epidemiology of alcoholic liver disease in Denmark 2006-2011: a population-based study.
To describe incidence, prevalence, hospitalization rates and survival for alcoholic liver disease (ALD) in Denmark 2006-2011. Using nationwide healthcare registries we identified all Danish residents with a hospital diagnosis of ALD and computed standardized incidence, prevalence, and hospitalization rates in 2006-2011, age- and birth cohort-specific incidence for the 1930-1974 birth cohorts, and 1- and 5-year survival. In 2006-2011, the overall standardized ALD incidence decreased from 343 to 311 per 1,000,000 population per year. ALD incidence increased among women aged 65 years or older, but decreased in younger persons and men. Persons born in 1950-1959 had higher age-specific incidence than earlier and later birth cohorts. The prevalence (0.2% of the Danish adult population) and hospitalization rate were constant. The 1- and 5-year survival were 43 and 70%, respectively. In Denmark, persons born in 1950-1959 have had the highest age-specific incidence. The overall ALD incidence has been decreasing (along with per capita consumption). Despite increases in affordability during the study period, Denmark did not experience the increase in ALD seen, for example, in the UK. It is possible that this is due to the greater impact of government recommendations on safer drinking in Denmark than the UK.


Malaria risk factors in an endemic region of Sri Lanka, and the impact and cost implications of risk factor-based interventions.
In an 18-month study of malaria in a population of 1,875 residents in 423 houses in an endemic area in southern Sri Lanka, the risk of malaria was found to be 2.5-fold higher in residents of poorly constructed houses than in those living in houses of good construction type. In residents of poorly constructed houses but not in others, the risk was even greater when the house was located near a source of water that could act as a potential breeding place for malaria vector mosquitoes (P = 0.0001). Based on previous findings that confirmed that house construction type was itself a risk determinant, and not merely a marker of other behavioral factors, we have estimated the potential impact of two feasible interventions to reduce the risk of malaria: 1) the imposition of a buffer zone of 200 meters around bodies of water from which houses of poor construction were excluded, which was estimated to lead to a 21% reduction of the malaria incidence in the overall population and a 43% reduction in the relocated community; and 2) the conversion of houses of poor construction type located in the buffer zone to those of a good construction type, which was estimated to lead to a 36% reduction in the incidence rates in the whole population and a 76% reduction in the residents of houses whose construction type was improved. Taking into consideration the cost to the Government of malaria prevention, we estimated the worth of a Government's investment in improving house construction type. The investment in housing was estimated to be offset in 7.2 years by savings to the Government on malaria costs alone, and beyond this period, to bring a return on the Government's investment by way of savings to the malaria control program.


Analysis of respiratory syncytial virus strain variation in successive epidemics in one city.
The variability of respiratory syncytial virus isolates from five successive epidemics in an urban population was determined. A total of 187 isolates of respiratory syncytial virus from the southern part of Birmingham, United Kingdom, were classified into subgroups A and B and were then further assigned to genetic lineages. Allocation of isolates into lineages was achieved by reverse transcription of infected cell RNA and then PCR amplification of selected regions of the genome; PCR products were examined by restriction mapping or nucleotide sequencing of parts of the nucleoprotein gene, the small hydrophobic protein gene, and the attachment protein gene. Previous work has shown that estimations of genetic diversity by analysis of genes coding for proteins likely (attachment protein) and unlikely (nucleoprotein and small hydrophobic protein) to be under immune pressure gave concordant results. Six genetic lineages of subgroup A isolates have been defined by this procedure; these isolates differ by up to 20% in the amino acid sequences of their attachment proteins; likewise, subgroup B isolates can be divided into two categories by restriction mapping of parts of their nucleoprotein and attachment protein genes. The same genetic lineages appeared to be present worldwide during the same period. The analysis of isolates from successive epidemics showed that different lineages predominated in each epidemic and that not all lineages were present in every epidemic. Some lineages appeared to increase in numbers over several years and then decline, possibly indicating a buildup of resistance in the community to a particular genotype.


Cellular, Metabolic, and Developmental Dimensions of Whole-Body Regeneration in Hydra.
Here we discuss the developmental and homeostatic conditions necessary for Hydra regeneration. Hydra is characterized by populations of adult stem cells paused in the G2 phase of the cell cycle, ready to respond to injury signals. The body column can be compared to a blastema-like structure, populated with multifunctional epithelial stem cells that show low sensitivity to proapoptotic signals, and high inducibility of autophagy that promotes resistance to stress and starvation. Intact Hydra polyps also exhibit a dynamic patterning along the oral-aboral axis under the control of homeostatic organizers whose activity results from regulatory loops between activators and inhibitors. As in bilaterians, injury triggers the immediate production of reactive oxygen species (ROS) signals that promote wound healing and contribute to the reactivation of developmental programs via cell death and the de novo formation of new organizing centers from somatic tissues. In aging Hydra, regeneration is rapidly lost as homeostatic conditions are no longer pro-regenerative.


Optimization of selection of chain amine scrubbers for CO2 capture.
In order to optimize the selection of a suitable amine molecule for CO2 scrubbers, a series of ab initio calculations were performed at the B3LYP/6-31+G(d,p) level of theory. Diethylenetriamine was used as a simple chain amine. Methyl and hydroxyl groups served as examples of electron donors, and electron withdrawing groups like trifluoromethyl and nitro substituents were also evaluated. Interaction distances and binding energies were employed as comparison operators. Moreover, natural bond orbital (NBO) analysis, namely the second order perturbation approach, was applied to determine whether the amine-CO2 interaction is chemical or physical. Different sizes of substituents affect the capture ability of diethylenetriamine. For instance, trifluoromethyl shields the nitrogen atom to which it attaches from the interaction with CO2. The results presented here provide a means of optimizing the choice of amine molecules for developing new amine scrubbers.


High-risk behaviors and their association with awareness of HIV status among participants of a large-scale prevention intervention in Athens, Greece.
Aristotle was a seek-test-treat intervention during an outbreak of human immunodeficiency virus (HIV) infection among people who inject drugs (PWID) in Athens, Greece that started in 2011. The aims of this analysis were: (1) to study changes of drug injection-related and sexual behaviors over the course of Aristotle; and (2) to compare the likelihood of risky behaviors among PWID who were aware and unaware of their HIV status. Aristotle (2012-2013) involved five successive respondent-driven sampling rounds of approximately 1400 PWID each; eligible PWID could participate in multiple rounds. Participants were interviewed using a questionnaire, were tested for HIV, and were classified as HIV-positive aware of their status (AHS), HIV-positive unaware of their status (UHS), and HIV-negative. Piecewise linear generalized estimating equation models were used to regress repeatedly measured binary outcomes (high-risk behaviors) against covariates. Aristotle recruited 3320 PWID (84.5% males, median age 34.2 years). Overall, 7110 interviews and blood samples were collected. The proportion of HIV-positive first-time participants who were aware of their HIV infection increased from 21.8% in round A to 36.4% in the last round. The odds of dividing drugs at least half of the time in the past 12 months with a syringe someone else had already used fell from round A to B by 90% [Odds Ratio (OR) (95% Confidence Interval-CI): 0.10 (0.04, 0.23)] among AHS and by 63% among UHS [OR (95% CI): 0.37 (0.19, 0.72)]. This drop was significantly larger (p = 0.02) among AHS. There were also decreases in frequency of injection and in receptive syringe sharing in the past 12 months but they were not significantly different between AHS (66 and 47%, respectively) and UHS (63 and 33%, respectively). Condom use increased only among male AHS from round B to the last round [OR (95% CI): 1.24 (1.01, 1.52)]. The prevalence of risky behaviors related to drug injection decreased in the context of Aristotle. Knowledge of HIV infection was associated with safer drug injection-related behaviors among PWID. This highlights the need for comprehensive interventions that scale-up HIV testing and help PWID become aware of their HIV status.


Nifedipine gastrointestinal therapeutic system (GITS) as an alternative to slow-release for tocolysis--tolerance and pharmacokinetic profile.
To determine nifedipine plasma concentrations after a loading dose of nifedipine 10mg capsules, 40 mg over 1h followed by slow-release tablets (60 mg/d) versus gastrointestinal therapeutic system (GITS) tablets (90 mg/d) for tocolysis. Prospective study in 14 pregnant women treated for threatened preterm labor. Following capsule administration there was a rapid rise in plasma concentration of drug achieving a peak of 97.5 microg/l (median) at 1h, then declined to 59.5 microg/l (median) at 5h. The concentration measured at 7200 min (120 h) was non-significantly higher in the slow-release group (median 25.5, range 6.9-67.2 microg/l) than in the GITS group (median 14.6, range 6.0-20.0 microg/l). Area under the curve (AUC) increased with the applied dose in both groups in a linear regression. Headache was more frequent in the slow-release group than in the GITS group (P=0.001). GITS tablets 90 mg/d are an alternative dosage regimen to previous used slow-release tablets 60 mg/d for tocolysis with similar pharmacokinetic profile and a good tolerance. However, tocolysis with GITS tablets is simpler than that with slow-release tablets and may be associated with a higher compliance. GITS tablets are therefore also qualified for home monitoring.


CYP24A1 and CYP27B1 Polymorphisms, Concentrations of Vitamin D Metabolites, and Odds of Colorectal Adenoma Recurrence.
Development of colorectal adenoma and cancer are associated with low circulating 25-hydroxyvitamin D [25(OH)D] levels. However, less is known regarding colorectal neoplasia risk and variation in CYP27B1 or CYP24A1, genes encoding the enzymes responsible for the synthesis and catabolism of 1α,25-hydroxyvitamin D [1,25(OH)2D]. This study examined associations between CYP27B1 and CYP24A1 polymorphisms, circulating 25(OH)D and 1,25(OH)2D concentrations, and colorectal adenoma recurrence in a pooled sample from 2 clinical trials (n = 1,188). Nominal associations were observed between increasing copies of the T allele in CYP24A1 rs927650 and 25(OH)D concentrations (P = 0.02); as well as colorectal adenoma recurrence, with odds ratios (95% confidence intervals) of 1.30 (0.99-1.70) and 1.38 (1.01-1.89) for heterozygotes and minor allele homozygotes, respectively (P = 0.04). In addition, a statistically significant relationship between CYP24A1 rs35051736, a functional polymorphism, and odds for advanced colorectal adenoma recurrence was observed (P < 0.001). Further, nominally statistically significant interactions were observed between rs2296241 and 25(OH)D as well as rs2762939 and 1,25(OH)2D (P(interaction) = 0.10, respectively). Overall, CYP24A1 polymorphisms may influence the development of advanced lesions, and modify the effect of vitamin D metabolites on adenoma recurrence. Further study is necessary to characterize the differences between circulating vitamin D metabolite measurements compared to cellular level activity in relation to cancer risk.


Ornithine-containing lipids of some Pseudomonas species.
Ornithine-containing lipids purified by thin-layer chromatography were found to represent 2-15% of the total extractable cellular lipids in two or three strains each of four Pseudomonas species: P. aeruginosa, P. fluorescens, P. stutzeri and P. cepacia. The structures of the ornithine-containing lipids were elucidated by chemical analysis, thin-layer chromatography, gas-liquid chromatography, gas-liquid chromatography/mass spectrometry (electron impact or secondary ion) and infrared absorption spectroscopy. At least six molecular species of ornithine-containing lipids were present in common in all of the preparations of the four Pseudomonas species. The structure which was the most abundantly in P. fluorescens (about 60% of the total amount of the ornithine-containing lipid) was 3-hydroxyhexadecanoic acid amide-linked to ornithine and esterified to hexadecanoic acid. In addition to this structure, 3-hydroxyoctadecenoic acid amide-linked to ornithine and esterified to hexadecanoic acid was a dominant structure in the ornithine-containing lipids of P. aeruginosa, P. stutzeri or P. cepacia. In P. cepacia, another ornithine-containing lipids with a terminal polar fatty acid, 3-hydroxyhexadecanoic acid amide-linked to ornithine and esterified to 2-hydroxynonadecacyclopropanoic acid or 2-hydroxyoctadecenoic acid, was found; its content, which represented 8-11% of the total extractable cellular lipids, was higher than that of the ornithine-containing lipids with a terminal nonpolar fatty acid. These ornithine-containing lipids exhibited hemagglutinating activity. Additionally, it was very interesting that hydroxy fatty acids included in the ornithine-containing lipids were not found in the phospholipids which represented more than 80% of the total extractable cellular lipids.


Product design, semantics and emotional response.
This paper explores theoretical issues in ergonomics related to semantics and the emotional content of design. The aim is to find answers to the following questions: how to design products triggering "happiness" in one's mind; which product attributes help in the communication of positive emotions; and finally, how to evoke such emotions through a product. In other words, this is an investigation of the "meaning" that could be designed into a product in order to "communicate" with the user at an emotional level. A literature survey of recent design trends, based on selected examples of product designs and semantic applications to design, including the results of recent design awards, was carried out in order to determine the common attributes of their design language. A review of Good Design Award winning products that are said to convey and/or evoke emotions in the users has been done in order to define good design criteria. These criteria have been discussed in relation to user emotional responses and a selection of these has been given as examples.


A Systematic Review and Meta-Analysis of Health Utilities in Patients With Chronic Hepatitis C.
Chronic hepatitis C (CHC) is among the most burdensome infectious diseases in the world. Health utilities are a valuable tool for quantifying this burden and conducting cost-utility analysis. Our study summarizes the available data on utilities in CHC patients. This will facilitate analyses of CHC treatment and elimination strategies. We searched MEDLINE, Embase, and the Cochrane Library for studies measuring utilities in CHC patients. Utilities were pooled by health state and utility instrument using meta-analysis. A further analysis used meta-regression to adjust for the effects of clinical status and methodological variation. Fifty-one clinical studies comprising 15 053 patients were included. Based on the meta-regression, patients' utilities were lower for more severe health states (predicted mean EuroQol-5D-3L utility for mild/moderate CHC: 0.751; compensated cirrhosis: 0.671; hepatocellular carcinoma: 0.662; decompensated cirrhosis: 0.602). Patients receiving interferon-based treatment had lower utilities than those on interferon-free treatment (0.647 vs 0.733). Patients who achieved sustained virologic response (0.786) had higher utilities than those with mild to moderate CHC. Utilities were substantially higher for patients in experimental studies compared to observational studies (coefficient: +0.074, P < .05). The time tradeoff instrument was associated with the highest utilities, and the Health Utilities Index 3 was associated with the lowest utilities. Chronic hepatitis C is associated with a significant impairment in global health status, as measured by health utility instruments. Impairment is greater in advanced disease. Experimental study designs yield higher utilities-an effect not previously documented. Curative therapy can alleviate the burden of CHC, although further research is needed in certain areas, such as the long-term impacts of treatment on utilities.


Initial speech problems in patients treated with multiple zygomatic implants.
The aim of this study was to investigate the speech ability of patients treated with multiple zygomatic implants. This technique can be used in patients with severe atrophy of the maxilla when there is insufficient residual bone in the anterior region for placement of conventional implants. Between 2004 and 2008, audio recordings were performed in patients treated with fixed dental prostheses (FDP) supported by multiple zygomatic implants. Patients with extensive resorption of the basal bone of the maxilla (Cawood and Howell Class VI) were included in the study. No bone grafts were used. Audio recordings were conducted before treatment (pretreatment), within 1 week after the FDP was inserted (1 week posttreatment), and then again after 4 months (4 months posttreatment). Perceptual evaluations of the recordings were performed by a panel of speech and language pathologists (n = 3), and the patients' subjective views of speech quality were investigated on the three different occasions. Seven consecutive patients were treated with a total of 28 zygomatic implants and five conventional implants. All patients received a FDP. According to the evaluations by professionals, five of the seven patients, all of whom wore a removable conventional denture prior to treatment, had normal speech before treatment. One patient could not be evaluated by the professionals because of medical impairment. In five of the six remaining patients, a mild deterioration in articulation was registered at 1 week posttreatment, and these problems remained after 4 months. Patients' subjective views reflected a dramatic improvement in speech at 1 week posttreatment for the two patients presenting with the highest degree of maxillary bone resorption. The three patients who reported completely normal speech before treatment all experienced a drop in their ability at 1 week posttreatment. Four patients displayed a similar pattern after treatment according to the professionals' opinions and the patients' subjective reports. A mild deterioration in speech can be anticipated in patients subjected to treatment with a FDP supported by multiple zygomatic implants.


Continuous morphological variation correlated with genome size indicates frequent introgressive hybridization among Diphasiastrum species (Lycopodiaceae) in Central Europe.
Introgressive hybridization is an important evolutionary process frequently contributing to diversification and speciation of angiosperms. Its extent in other groups of land plants has only rarely been studied, however. We therefore examined the levels of introgression in the genus Diphasiastrum, a taxonomically challenging group of Lycopodiophytes, using flow cytometry and numerical and geometric morphometric analyses. Patterns of morphological and cytological variation were evaluated in an extensive dataset of 561 individuals from 57 populations of six taxa from Central Europe, the region with the largest known taxonomic complexity. In addition, genome size values of 63 individuals from Northern Europe were acquired for comparative purposes. Within Central European populations, we detected a continuous pattern in both morphological variation and genome size (strongly correlated together) suggesting extensive levels of interspecific gene flow within this region, including several large hybrid swarm populations. The secondary character of habitats of Central European hybrid swarm populations suggests that man-made landscape changes might have enhanced unnatural contact of species, resulting in extensive hybridization within this area. On the contrary, a distinct pattern of genome size variation among individuals from other parts of Europe indicates that pure populations prevail outside Central Europe. All in all, introgressive hybridization among Diphasiastrum species in Central Europe represents a unique case of extensive interspecific gene flow among spore producing vascular plants that cause serious complications of taxa delimitation.


Determinants of green growth in developed and developing countries.
Considering the need for environmental sustainability while ensuring economic growth and development by 2030, this study uses data on 123 developed and developing countries to examine factors that influence green growth. The empirical results show that economic development positively influences green growth. However, trade openness is detrimental to green growth. Regarding energy-related factors, we find energy consumption negatively affecting green growth, but renewable energy consumption significantly improves green growth. In further analysis, we find that the influence of these factors differs between developed and developing countries. The result implies that countries at a different development level will require different strategies in achieving the Sustainable Development Goals in 2030. The results are robust to alternative identification strategies such as the System Generalised Method of Movement, which accounts for potential endogeneity.


Selective bird predation on the peppered moth: the last experiment of Michael Majerus.
Colour variation in the peppered moth Biston betularia was long accepted to be under strong natural selection. Melanics were believed to be fitter than pale morphs because of lower predation at daytime resting sites on dark, sooty bark. Melanics became common during the industrial revolution, but since 1970 there has been a rapid reversal, assumed to have been caused by predators selecting against melanics resting on today's less sooty bark. Recently, these classical explanations of melanism were attacked, and there has been general scepticism about birds as selective agents. Experiments and observations were accordingly carried out by Michael Majerus to address perceived weaknesses of earlier work. Unfortunately, he did not live to publish the results, which are analysed and presented here by the authors. Majerus released 4864 moths in his six-year experiment, the largest ever attempted for any similar study. There was strong differential bird predation against melanic peppered moths. Daily selection against melanics (s ≈ 0.1) was sufficient in magnitude and direction to explain the recent rapid decline of melanism in post-industrial Britain. These data provide the most direct evidence yet to implicate camouflage and bird predation as the overriding explanation for the rise and fall of melanism in moths.


A novel debridement device for the treatment of hard-to-heal wounds: a prospective trial.
Debridement, the removal of nonviable tissue, forms the foundation of wound care practice. Clinicians have a variety of debridement methods at their disposal: sharp, biologic, enzymatic, autolytic and mechanical. The choice of debridement technique depends on the patient care setting, ulcer type and the clinician's experience, training, comfort level and licensure. This prospective study evaluated a novel debridement instrument, EZ-Debride (MDM Ventures, US). Cutting flutes on the head of the tool permit uniform removal of dead tissue while lessening the risk of deeper injury. It may also minimise pain during the debridement procedure. Subjects with hard-to-heal wounds, drawn from a single wound care centre, participated in this institutional review board-approved prospective clinical study. Pain was measured before, during and after debridement using a numerical scale. Assessment of bacterial burden using fluorescence imaging (MolecuLight, Canada) was performed before and after debridement. Enrolment of 10 male and 12 female subjects, with a total of 28 wounds, was carried out over a two-month period by two investigators at a single institution. The average age of subjects was 64 years (range: 22-95 years). The average wound duration was 29 weeks (range: 6-142 weeks). Wound types included diabetic foot, venous leg and pressure ulcers, post-surgical and traumatic wounds. The average pain score at the time of enrolment was 3.9. Subjects reported an average increase in pain with debridement of 0.6 points (range: 0-8). Fluorescence imaging demonstrated a reduction in bacterial load in 69% of cases, with complete resolution in 19% of wounds. Haemostasis was achieved with direct pressure in all cases and the only adverse event was a wound infection that occurred four days after debridement. The results suggest that this novel debridement tool can safely remove nonviable tissue with minimal discomfort and reduce bacterial burden similar to results achieved by sharp debridement.


Camptothecin blocks memory of conditioned avoidance in the goldfish.
Intracranial injection of 10 to 75 micrograms of camptothecin, a plant alkaloid that blocks RNA synthesis in eucaryotic cells, blocks incorporation of tritiated uridine into RNA in the goldfish brain. Injection of 10 to 50 micrograms of the drug within 1.5 hours of training results in greatly diminished memory, tested 1 week later. Injection of the drug 5 or 24 hours after training produces no measurable effect on retention of the learned response.


Serum albumin and body weight as biomarkers for the antemortem identification of bone and gastrointestinal disease in the common marmoset.
The increasing use of the common marmoset (Callithrix jacchus) in research makes it important to diagnose spontaneous disease that may confound experimental studies. Bone disease and gastrointestinal disease are two major causes of morbidity and mortality in captive marmosets, but currently no effective antemortem tests are available to identify affected animals prior to the terminal stage of disease. In this study we propose that bone disease and gastrointestinal disease are associated disease entities in marmosets and aim to establish the efficacy of several economical antemortem tests in identifying and predicting disease. Tissues from marmosets were examined to define affected animals and unaffected controls. Complete blood count, serum chemistry values, body weight, quantitative radiographs, and tissue-specific biochemical markers were evaluated as candidate biomarkers for disease. Bone and gastrointestinal disease were associated, with marmosets being over seven times more likely to have either concurrent bone and gastrointestinal disease or neither disease as opposed to lesions in only one organ system. When used in tandem, serum albumin <3.5 g/dL and body weight <325 g identified 100% of the marmosets affected with concurrent bone and gastrointestinal disease. Progressive body weight loss of 0.05% of peak body weight per day predicted which marmosets would develop disease prior to the terminal stage. Bone tissue-specific tests, such as quantitative analysis of radiographs and serum parathyroid hormone levels, were effective for distinguishing between marmosets with bone disease and those without. These results provide an avenue for making informed decisions regarding the removal of affected marmosets from studies in a timely manner, preserving the integrity of research results.


cAMP, Ca2+, pHi, and NO Regulate H-like Cation Channels That Underlie Feeding and Locomotion in the Predatory Sea Slug Pleurobranchaea californica.
A systems approach to regulation of neuronal excitation in the mollusc Pleurobranchaea has described novel interactions of cyclic AMP-gated cation current (INa,cAMP), Ca2+, pHi, and NO. INa,cAMP appears in many neurons of feeding and locomotor neuronal networks. It is likely one of the family of hyperpolarization-activated, cyclic-nucleotide-gated currents (h-current) of vertebrate and invertebrate pacemaker networks. There are two isoforms. Ca2+ regulates both voltage dependence and depolarization-sensitive inactivation in both isoforms. The Type 1 INa,cAMP of the feeding network is enhanced by intracellular acidification. A direct dependence of INa,cAMP on cAMP allows the current to be used as a reporter on cAMP concentrations in the cell, and from there to the intrinsic activities of the synthetic adenyl cyclase and the degradative phosphodiesterase. Type 2 INa,cAMP of the locomotor system is activated by serotonergic inputs, while Type 1 of the feeding network is thought to be regulated peptidergically. NO synthase activity is high in the CNS, where it differs from standard neuronal NO synthase in not being Ca2+ sensitive. NO acidifies pHi, potentiating Type 1, and may act to open proton channels. A cGMP pathway does not mediate NO effects as in other systems. Rather, nitrosylation likely mediates its actions. An integrated model of the action of cAMP, Ca2+, pHi, and NO in the feeding network postulates that NO regulates proton conductance to cause neuronal excitation in the cell body on the one hand, and relief of activity-induced hyperacidification in fine dendritic processes on the other.