Size-controllable dual drug-loaded silk fibroin nanospheres through a facile formation process.
The continual generation of drug resistance is a major challenge in clinical cancer chemotherapy. Combination drug therapy may overcome such limitations by minimizing the required dosage of each drug whilst achieving an enhancement of therapeutic efficacy. Regenerated silk fibroin (RSF) is a commonly used drug delivery platform due to its suitable biocompatibility, controllable biodegradability, and diverse material formats. Herein, dual drug-loaded RSF nanospheres were prepared using a facile and green method to deliver two anti-cancer drugs with distinct physical properties, namely hydrophobic paclitaxel (PTX) and hydrophilic doxorubicin (DOX). The particle size of the PTX/DOX-loaded RSF nanospheres was easily regulated, by varying the RSF and ethanol concentrations during the formation process, from approximately 100 to 600 nm, with subsequent applications in both intravenous and lymphatic chemotherapy. The drug release profile of both PTX and DOX in the PTX/DOX-loaded RSF nanospheres was found to be well controlled and sustained for over 7 days. Further, the dual drug-loaded RSF nanospheres exhibited a high cellular uptake via endocytosis. Importantly, the dual drug-loaded RSF nanospheres showed more efficient suppression of cancer cell growth than the single drug-loaded RSF nanospheres with either drug or the free drugs at the same concentration, particularly at a DOX/PTX ratio of 1 : 1. Thus, the prepared dual drug nanocarrier with a controllable particle size may have important clinical implications for combination chemotherapy.


Gene expression imputation across multiple brain regions provides insights into schizophrenia risk.
Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.


Panton-Valentine leukocidin expressing Staphylococcus aureus pneumonia managed with extracorporeal membrane oxygenation: experience and outcome.
Panton-Valentine leukocidin expressing Staphylococcus aureus pneumonia, an infection that affects predominantly young people, has a mortality rate of > 70% despite aggressive conventional management. Little information is available on the management of patients with Panton-Valentine leukocidin expressing S. aureus pneumonia with extracorporeal membrane oxygenation support. As a large extracorporeal membrane oxygenation center, we reviewed our experience and outcomes with Panton-Valentine Leukocidin expressing S. aureus pneumonia. Locally held register of all extracorporeal membrane oxygenation patients at Glenfield Hospital. Retrospective study including all patients with sputum-positive Panton-Valentine leukocidin expressing S. aureus pneumonia managed with extracorporeal membrane oxygenation support at a single extracorporeal membrane oxygenation center. On review of our database held from September 1989 until date, there were four patients with sputum-confirmed Panton-Valentine leukocidin expressing S. aureus pneumonia managed with extracorporeal membrane oxygenation. Refractory hypoxemia and/or uncompensated hypercapnia despite optimal conventional management were the indications for extracorporeal membrane oxygenation. After varying periods on extracorporeal membrane oxygenation with appropriate antibiotic and ancillary care, all four patients were discharged home. Panton-Valentine leukocidin expressing S. aureus pneumonia can cause severe, necrotizing pneumonia associated with acute respiratory distress syndrome, which can be particularly challenging to manage. Extracorporeal membrane oxygenation support permits low pressure lung ventilation, avoiding barotrauma to lungs made friable by Panton-Valentine leukocidin expressing S. aureus infection. Although this is a small number of patients, the results are encouraging.


A stress-responsive system for mitochondrial protein degradation.
We show that Ydr049 (renamed VCP/Cdc48-associated mitochondrial stress-responsive--Vms1), a member of an unstudied pan-eukaryotic protein family, translocates from the cytosol to mitochondria upon mitochondrial stress. Cells lacking Vms1 show progressive mitochondrial failure, hypersensitivity to oxidative stress, and decreased chronological life span. Both yeast and mammalian Vms1 stably interact with Cdc48/VCP/p97, a component of the ubiquitin/proteasome system with a well-defined role in endoplasmic reticulum-associated protein degradation (ERAD), wherein misfolded ER proteins are degraded in the cytosol. We show that oxidative stress triggers mitochondrial localization of Cdc48 and this is dependent on Vms1. When this system is impaired by mutation of Vms1, ubiquitin-dependent mitochondrial protein degradation, mitochondrial respiratory function, and cell viability are compromised. We demonstrate that Vms1 is a required component of an evolutionarily conserved system for mitochondrial protein degradation, which is necessary to maintain mitochondrial, cellular, and organismal viability.


Fracture diagnostics, unnecessary travel and treatment: a comparative study before and after the introduction of teleradiology in a remote general practice.
Teleradiology entails attainment of x-rays in one location, transfer over some distance and assessment at another location for diagnosis or consultation. This study documents fracture diagnostics, unnecessary trips to the hospital, treatment and number of x-rays for the years 2006 and 2009, before and after the introduction of teleradiology in a general practice on the island of Ameland in the north of the Netherlands. In a retrospective, descriptive, observational before and after study of the introduction of x-ray facilities in an island-based general practice, we compared the number of accurately diagnosed fractures, unnecessary trips, treatments and number of x-rays taken in 2006 when only a hospital x-ray facility was available 5 hours away with those in 2009 after an x-ray facility became available at a local general practice. All patients visiting a general practice on the island of Ameland in 2006 and 2009 with trauma and clinical suspicion of a fracture, dislocation or sprain were included in the study. The initial clinical diagnoses, including those based on the outcomes of x-rays, were compared for the two years and also whether the patients were treated at home or in hospital. A total of 316 and 490 patients with trauma visited a general practice in 2006 and 2009, respectively. Of these patients, 66 and 116 were found to have fractures or dislocations in the two years, respectively. In 2006, 83 x-rays were ordered; in 2009, this was 284. In 2006, 9 fractures were missed; in 2009, this was only 2. In 2006, 15 patients with fractures or dislocations were treated at the general practice; in 2009, this had increased to 77. Since the introduction of teleradiology the number of missed fractures in patients visiting the general practice with trauma and the number of the unnecessary trips to a hospital are reduced. In addition more patients with fractures and dislocations can be treated in the general practice as opposed to the hospital.


Structure-performance descriptors and the role of Lewis acidity in the methanol-to-propylene process.
The combination of well-defined acid sites, shape-selective properties and outstanding stability places zeolites among the most practically relevant heterogeneous catalysts. The development of structure-performance descriptors for processes that they catalyse has been a matter of intense debate, both in industry and academia, and the direct conversion of methanol to olefins is a prototypical system in which various catalytic functions contribute to the overall performance. Propylene selectivity and resistance to coking are the two most important parameters in developing new methanol-to-olefin catalysts. Here, we present a systematic investigation on the effect of acidity on the performance of the zeolite 'ZSM-5' for the production of propylene. Our results demonstrate that the isolation of Brønsted acid sites is key to the selective formation of propylene. Also, the introduction of Lewis acid sites prevents the formation of coke, hence drastically increasing catalyst lifetime.


Serious Games for Parkinson's Disease Fine Motor Skills Rehabilitation Using Natural Interfaces.
Parkinson's Disease rehabilitation can be long and boring being difficult to maintain patient engagement on therapy programs. Novel technologies are allowing computer games to be played throught natural interfaces. This paper presents the development and assessment of a system of serious games for fine motor skills rehabilitation using natural interfaces. The games were assessed throught a questionnaire that evaluated the game experience through seven components: immersion, flow, competence, tension, challenge and positive and negative affect. In addition, a conceptual framework for development of serious games for fine motor skills rehabilitation was proposed. The results from the quantitative questionnaire suggested that the player experience was positive on all components assessed. Also, player experience between the three games was statistically the same, implying that the games can be used with consistency in a physical therapy rehabilitation program.


Overview on the diversity of sounds produced by clownfishes (Pomacentridae): importance of acoustic signals in their peculiar way of life.
Clownfishes (Pomacentridae) are brightly colored coral reef fishes well known for their mutualistic symbiosis with tropical sea anemones. These fishes live in social groups in which there is a size-based dominance hierarchy. In this structure where sex is socially controlled, agonistic interactions are numerous and serve to maintain size differences between individuals adjacent in rank. Clownfishes are also prolific callers whose sounds seem to play an important role in the social hierarchy. Here, we aim to review and to synthesize the diversity of sounds produced by clownfishes in order to emphasize the importance of acoustic signals in their way of life. Recording the different acoustic behaviors indicated that sounds are divided into two main categories: aggressive sounds produced in conjunction with threat postures (charge and chase), and submissive sounds always emitted when fish exhibited head shaking movements (i.e. a submissive posture). Both types of sounds showed size-related intraspecific variation in dominant frequency and pulse duration: smaller individuals produce higher frequency and shorter duration pulses than larger ones, and inversely. Consequently, these sonic features might be useful cues for individual recognition within the group. This observation is of significant importance due to the size-based hierarchy in clownfish group. On the other hand, no acoustic signal was associated with the different reproductive activities. Unlike other pomacentrids, sounds are not produced for mate attraction in clownfishes but to reach and to defend the competition for breeding status, which explains why constraints are not important enough for promoting call diversification in this group.


The effectiveness of a neuromuscular prevention strategy to reduce injuries in youth soccer: a cluster-randomised controlled trial.
Soccer is a leading sport for participation and injury in youth. To examine the effectiveness of a neuromuscular prevention strategy in reducing injury in youth soccer players. Cluster-randomised controlled trial. Calgary soccer clubs (male or female, U13-U18, tier 1-2, indoor soccer). Eighty-two soccer teams were approached for recruitment. Players from 60 teams completed the study (32 training (n=380), 28 control (n=364)). The training programme was a soccer-specific neuromuscular training programme including dynamic stretching, eccentric strength, agility, jumping and balance (including a home-based balance training programme using a wobble board). The control programme was a standardised warm-up (static and dynamic stretching and aerobic components) and a home-based stretching programme. Previously validated injury surveillance included injury assessment by a study therapist. The injury definition was soccer injury resulting in medical attention and/or removal from a session and/or time loss. The injury rate in the training group was 2.08 injuries/1000 player-hours, and in the control group 3.35 injuries/1000 player-hours. Based on Poisson regression analysis, adjusted for clustering by team and covariates, the incidence rate ratios (IRR) for all injuries and acute onset injury were 0.62 (95% CI 0.39 to 0.99) and 0.57 (95% CI 0.35 to 0.91). Point estimates also suggest protection of lower extremity, ankle and knee sprain injuries (IRR=0.68 (95% CI 0.42 to 1.11), IRR=0.5 (95% CI 0.24 to 1.04) and IRR=0.38 (95% CI 0.08 to 1.75)). A neuromuscular training programme is protective of all injuries and acute onset injury in youth soccer players.


Chemical, electrochemical, and photochemical catalytic oxidation of water to dioxygen with mononuclear ruthenium complexes.
Four new Ru(II)-Cl and Ru(II)-H(2)O complexes containing the meridional 2,2':6',2"-terpyridine (trpy) ligand and the chelating 2-(5-phenyl-1H-pyrazol-3-yl)pyridine (H3p) ligand of general formula in- and out-[Ru(II) (trpy)(H3p)(X)](n+) (X=Cl, n=1; X=H(2)O, n=2) have been prepared, isolated and thoroughly characterized both in solution and in the solid state. In solution, all the complexes are characterized spectroscopically by UV/Vis and NMR, and their redox properties investigated by means of cyclic voltammetry, square wave voltammetry, and coulometry. In the solid state, monocrystal X-ray diffraction analysis was carried out for the in and out Ru-Cl complexes. The capacity of the Ru-aqua complexes to act as water oxidation catalysts (WOCs) was also investigated chemically, electrochemically, and photochemically. The performance of these complexes has also been compared to two previously described complexes of general formula in- and out-[Ru(II)(trpy)(Hbpp)(H(2)O)](2+) (Hbpp is 2,2'-(1H-pyrazole-3,5-diyl)dipyridine)), the capacity of which as WOCs had not been previously described.


Hematological findings in SARS patients and possible mechanisms (review).
Severe acute respiratory syndrome (SARS) is a new human infectious disease. The causative agent of SARS is a novel coronavirus (SARS-CoV). This report summarizes the hematological findings in SARS patients and proposes the possible mechanisms of SARS-CoV related abnormal hematopoiesis. Hematological changes in patients with SARS are common and include lymphopenia, thrombocytopenia and occasionally leukopenia. A significant decrease was also observed in peripheral CD4+ and CD8+ T lymphocyte subsets and it was related to onset of SARS. A number of potential mechanisms may be involved. The development of auto-immune antibodies or immune complexes triggered by viral infection may play a major role in inducing lymphopenia and thrombocytopenia. Moreover, SARS-CoV may also directly infect hematopoietic stem/progenitor cells via CD13 or CD66a inducing their growth inhibition and apoptosis. The receptor for group I and III CoV is aminopeptidase N (CD13). CD13 has been identified in human bone marrow CD34+ cells, platelets, megakaryocytes, myeloid cells, and erythroid cells, but not in lymphocytes. The common receptor for group II CoV is CEACAM1a (CD66a). CD66a is an adhesion molecule expressed on bone marrow CD34+ cells, platelets, granulocytes and activated lymphocytes. In addition, glucocorticoids could induce lymphopenia and the use of steroids may account for the decrease of lymphocytes in some SARS patients. The increased consumption of platelets and/or the decreased production of platelets in the damaged lungs are a potential alternative but often overlooked mechanism that can contribute to thrombocytopenia in severe critical pulmonary conditions.


Surgical quality assurance in head and neck cancer trials: an EORTC Head and Neck Cancer Group position paper based on the EORTC 1420 'Best of' and 24954 'larynx preservation' study.
Quality improvement of care for patients with head and neck cancer remains a constant objective for the multidisciplinary team of physicians managing these patients. The purpose of quality assurance (QA) for head and neck surgical oncology and surgical trials however differs. While QA for the general head and neck patient aims to improve global outcome through structural changes of health-care systems, QA for surgical trials pursues the goal to help providing meaningful results from a clinical trial through the definition of structure, process and outcome measures within the trial. Establishing a QA program for surgical trials is challenging largely due to the variation in the execution of surgical techniques. Within this article, we describe the surgical QA program, which was developed for the phase III European Organisation for Research and Treatment of Cancer (EORTC) 1420 study, a trial assessing swallowing function after transoral surgery compared with radiation therapy. We propose based on our experience to further develop surgical QA for surgical clinical trials by introducing two separate components, one adaptable and one non-adaptable. The adaptable is tailored to the scientific question and specific procedure; the non-adaptable consists of minimal structural requirements of the clinical unit to participate in surgical trials at EORTC as well as guidelines and incentives for protocol adherence based on our experience in EORTC 24954. Finally, we strongly believe that surgical QA designed for clinical trials may serve as a basis for the development of QA surgical guidelines in clinical practice.


Development of balanced nutrient management innovations in South Asia: Perspectives from Bangladesh, India, Nepal, and Sri Lanka.
Imbalanced application of fertilizers is a major fiscal and environmental problem in South Asia. We review fertilizer policies and extension efforts to promote the balanced application of nutrients in Bangladesh, India, Nepal, and Sri Lanka and draw 4 important lessons. (1) Fertilizer sector reforms need to be fiscally sustainable and politically feasible. Governments in South Asia have abolished fertilizer subsidies on multiple occasions, only to restore them a few years later. (2) The use of phosphate and potash did not decline much even after a sharp increase in their prices in India in 2011-12. Therefore, rationalizing subsidies, while necessary, may not be sufficient to ensure balanced use of fertilizers. Changing farmers' practice requires combining the right incentives with the right information. (3) Soil test based soil health cards (SHC) hold promise, but there is limited evidence on their utility. India's SHC program had very little impact on fertilizer use. (4) Direct cash transfer (DCT) of fertilizer subsidies can reduce distortions, but Sri Lanka's experience shows that implementing it is more challenging than universal subsidies. DCT requires the removal of price controls, integration of land records, farmer identity cards, a cash transfer system with universal coverage, and a competitive fertilizer retail sector.


The tetraspanin CD151 is required for Met-dependent signaling and tumor cell growth.
CD151, a transmembrane protein of the tetraspanin family, is implicated in the regulation of cell-substrate adhesion and cell migration through physical and functional interactions with integrin receptors. In contrast, little is known about the potential role of CD151 in controlling cell proliferation and survival. We have previously shown that β4 integrin, a major CD151 partner, not only acts as an adhesive receptor for laminins but also as an intracellular signaling platform promoting cell proliferation and invasive growth upon interaction with Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF). Here we show that RNAi-mediated silencing of CD151 expression in cancer cells impairs HGF-driven proliferation, anchorage-independent growth, protection from anoikis, and tumor progression in xenograft models in vivo. Mechanistically, we found that CD151 is crucially implicated in the formation of signaling complexes between Met and β4 integrin, a known amplifier of HGF-induced tumor cell growth and survival. CD151 depletion hampered HGF-induced phosphorylation of β4 integrin and the ensuing Grb2-Gab1 association, a signaling pathway leading to MAPK stimulation and cell growth. Accordingly, CD151 knockdown reduced HGF-triggered activation of MAPK but not AKT signaling cascade. These results indicate that CD151 controls Met-dependent neoplastic growth by enhancing receptor signaling through β4 integrin-mediated pathways, independent of cell-substrate adhesion.


Crossmodal correspondences: a tutorial review.
In many everyday situations, our senses are bombarded by many different unisensory signals at any given time. To gain the most veridical, and least variable, estimate of environmental stimuli/properties, we need to combine the individual noisy unisensory perceptual estimates that refer to the same object, while keeping those estimates belonging to different objects or events separate. How, though, does the brain "know" which stimuli to combine? Traditionally, researchers interested in the crossmodal binding problem have focused on the roles that spatial and temporal factors play in modulating multisensory integration. However, crossmodal correspondences between various unisensory features (such as between auditory pitch and visual size) may provide yet another important means of constraining the crossmodal binding problem. A large body of research now shows that people exhibit consistent crossmodal correspondences between many stimulus features in different sensory modalities. For example, people consistently match high-pitched sounds with small, bright objects that are located high up in space. The literature reviewed here supports the view that crossmodal correspondences need to be considered alongside semantic and spatiotemporal congruency, among the key constraints that help our brains solve the crossmodal binding problem.


Can the Results of Biodiversity-Ecosystem Productivity Studies Be Translated to Bioenergy Production?
Biodiversity experiments show that increases in plant diversity can lead to greater biomass production, and some researchers suggest that high diversity plantings should be used for bioenergy production. However, many methods used in past biodiversity experiments are impractical for bioenergy plantings. For example, biodiversity experiments often use intensive management such as hand weeding to maintain low diversity plantings and exclude unplanted species, but this would not be done for bioenergy plantings. Also, biodiversity experiments generally use high seeding densities that would be too expensive for bioenergy plantings. Here we report the effects of biodiversity on biomass production from two studies of more realistic bioenergy crop plantings in southern Michigan, USA. One study involved comparing production between switchgrass (Panicum virgatum) monocultures and species-rich prairie plantings on private farm fields that were managed similarly to bioenergy plantings. The other study was an experiment where switchgrass was planted in monoculture and in combination with increasingly species-rich native prairie mixtures. Overall, we found that bioenergy plantings with higher species richness did not produce more biomass than switchgrass monocultures. The lack of a positive relationship between planted species richness and production in our studies may be due to several factors. Non-planted species (weeds) were not removed from our studies and these non-planted species may have competed with planted species and also prevented realized species richness from equaling planted species richness. Also, we found that low seeding density of individual species limited the biomass production of these individual species. Production in future bioenergy plantings with high species richness may be increased by using a high density of inexpensive seed from switchgrass and other highly productive species, and future efforts to translate the results of biodiversity experiments to bioenergy plantings should consider the role of seeding density.


The early consequences of myocardial ischaemia and their modification.
This paper attempts to review our studies on the early haemodynamic, metabolic and electrophysiological consequences of acute coronary artery ligation in an experimental model which allows the simultaneous assessment of blood flow and sampling of blood from both normal and acutely ischaemic zones of myocardium. 1. Using local coronary venous sampling, it has been observed that the major metabolic changes which occur in the ischaemic zone during the first 30 min after coronary artery ligation are increases in PCO2, decreases in pH and oxygen content, a shift in lactate handling from extraction to production and an efflux of K+. These changes were not observed in coronary sinus blood draining essentially nonischaemic zones of myocardium. 2. The major haemodynamic change produced by coronary artery ligation was cardiac depression (decreased stroke volume and cardiac work), unchanged LV dP/dt with an elevated filling pressure. 3. Acute ligation of the anterior descending branch of the left coronary artery, l.a.d., resulted in bursts of ventricular ectopic activity which was especially marked 10-20 min after ligation and which frequently resulted in ventricular fibrillation. The incidence of arrhythmias could be modified by the species of dog used, the anaesthetic employed, the arterial oxygen tension and the administration of several antiarrhythmic drugs. The possible relevance observed in the ischaemic myocardium, to the genesis of these arrhythmias is discussed. 4. The changes in the ST-segment of epicardial leads produced by short (3 min) occlusions of the l.a.d. were studied in mongrel dogs. Evidence is presented which suggests that the evolution of ST-segment elevation is linked to the efflux of K+ from ischaemic myocardial cells.


Vancomycin-resistant enterococci outside the health-care setting: prevalence, sources, and public health implications.
Although nosocomial acquisition and subsequent colonization of vancomycin-resistant enterococci (VRE), an emerging international threat to public health, has been emphasized in the United States, colonization among nonhospitalized persons has been infrequently documented. In contrast, in Europe, colonization appears to occur frequently in persons outside the health-care setting. An important factor associated with VRE in the community in Europe has been avoparcin, a glycopeptide antimicrobial drug used for years in many European nations at subtherapeutic doses as a growth promoter in food-producing animals. In Europe, evidence suggests that foodborne VRE may cause human colonization. Although avoparcin has never been approved for use in the United States, undetected community VRE transmission may be occurring at low levels. Further studies of community transmission of VRE in the United States are urgently needed. If transmission with VRE from unrecognized community sources can be identified and controlled, increased incidence of colonization and infection among hospitalized patients may be prevented.


Antimicrobial resistance in West Africa: a systematic review and meta-analysis.
Growing data suggest that antimicrobial-resistant bacterial infections are common in low- and middle-income countries. This review summarises the microbiology of key bacterial syndromes encountered in West Africa and estimates the prevalence of antimicrobial resistance (AMR) that could compromise first-line empirical treatment. We systematically searched for studies reporting on the epidemiology of bacterial infection and prevalence of AMR in West Africa within key clinical syndromes. Within each syndrome, the pooled proportion and 95% confidence interval were calculated for each pathogen-antibiotic pair using random-effects models. Among 281 full-text articles reviewed, 120 met the eligibility criteria. The majority of studies originated from Nigeria (70; 58.3%), Ghana (15; 12.5%) and Senegal (15; 12.5%). Overall, 43 studies (35.8%) focused on urinary tract infections (UTI), 38 (31.7%) on bloodstream infections (BSI), 27 (22.5%) on meningitis, 7 (5.8%) on diarrhoea and 5 (4.2%) on pneumonia. Children comprised the majority of subjects. Studies of UTI reported moderate to high rates of AMR to commonly used antibiotics including evidence of the emergence of cephalosporin resistance. We found moderate rates of AMR among common bloodstream pathogens to typical first-line antibiotics including ampicillin, cotrimoxazole, gentamicin and amoxicillin/clavulanate. Among S. pneumoniae strains isolated in patients with meningitis, levels of penicillin resistance were low to moderate with no significant resistance noted to ceftriaxone or cefotaxime. AMR was common in this region, particularly in hospitalized patients with BSI and both outpatient and hospitalized patients with UTI. This raises concern given the limited diagnostic capability and second-line treatment options in the public sector in West Africa.


Carbon-concentrating mechanisms in seagrasses.
Seagrasses are unique angiosperms that carry out growth and reproduction submerged in seawater. They occur in at least three families of the Alismatales. All have chloroplasts mainly in the cells of the epidermis. Living in seawater, the supply of inorganic carbon (Ci) to the chloroplasts is diffusion limited, especially under unstirred conditions. Therefore, the supply of CO2 and bicarbonate across the diffusive boundary layer on the outer side of the epidermis is often a limiting factor. Here we discuss the evidence for mechanisms that enhance the uptake of Ci into the epidermal cells. Since bicarbonate is plentiful in seawater, a bicarbonate pump might be expected; however, the evidence for such a pump is not strongly supported. There is evidence for a carbonic anhydrase outside the outer plasmalemma. This, together with evidence for an outward proton pump, suggests the possibility that local acidification leads to enhanced concentrations of CO2 adjacent to the outer tangential epidermal walls, which enhances the uptake of CO2, and this could be followed by a carbon-concentrating mechanism (CCM) in the cytoplasm and/or chloroplasts. The lines of evidence for such an epidermal CCM are discussed, including evidence for special 'transfer cells' in some but not all seagrass leaves in the tangential inner walls of the epidermal cells. It is concluded that seagrasses have a CCM but that the case for concentration of CO2 at the site of Rubisco carboxylation is not proven.


Acute and chronic nephrotoxicity of platinum nanoparticles in mice.
Platinum nanoparticles are being utilized in various industrial applications, including in catalysis, cosmetics, and dietary supplements. Although reducing the size of the nanoparticles improves the physicochemical properties and provides useful performance characteristics, the safety of the material remains a major concern. The aim of the present study was to evaluate the biological effects of platinum particles less than 1 nm in size (snPt1). In mice administered with a single intravenous dose of snPt1, histological analysis revealed necrosis of tubular epithelial cells and urinary casts in the kidney, without obvious toxic effects in the lung, spleen, and heart. These mice exhibited dose-dependent elevation of blood urea nitrogen, an indicator of kidney damage. Direct application of snPt1 to in vitro cultures of renal cells induced significant cytotoxicity. In mice administered for 4 weeks with twice-weekly intraperitoneal snPt1, histological analysis of the kidney revealed urinary casts, tubular atrophy, and inflammatory cell accumulation. Notably, these toxic effects were not observed in mice injected with 8-nm platinum particles, either by single- or multiple-dose administration. Our findings suggest that exposure to platinum particles of less than 1 nm in size may induce nephrotoxicity and disrupt some kidney functions. However, this toxicity may be reduced by increasing the nanoparticle size.


A Meta-Analysis of Postpartum Copper IUD Continuation Rates in Low- and Middle-Income Countries.
Long-acting reversible contraception (LARC) initiated immediately postpartum can reduce unintended or mistimed pregnancies, and contribute to proper pregnancy spacing. Data on use and continuation of postpartum LARC in low- and middle-income countries (LMIC) is limited. We searched PubMed, OVID, Embase, Google Scholar, Cochrane, POPLINE, Global Health (CABI), and LILACS databases for relevant terms. Studies of any design, published in English, were screened for relevance based on six-month continuation rates of postpartum LARC, location of study, and LARC insertion within 48 hours after vaginal or cesarean birth. We found no relevant studies of implant or hormonal intrauterine device (IUD). Therefore, analysis was limited to studies of the copper IUD only. Two authors used the Cochrane Public Health Group Data Extraction and Assessment Template to guide data extraction to estimate pooled six-month continuation rates, and the Cochrane Risk of Bias Tool for Randomized Controlled Trials and the National Heart, Lung, and Blood Institute (NHLBI) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies to rate the quality of the studies. A random-effects meta-analysis of proportions was performed. Immediate-postpartum copper IUDs have a six-month continuation rate of 87% (95% CI 80-92%) in LMIC. The pooled estimated rates of six-month adverse outcomes were 6% (95% CI 5-9%) for expulsion, 5% (95% CI 4-7%) for removal, and 0.2% (95% CI 0.0-0.9%) for infection. High six-month continuation rates and a low rate of adverse outcomes suggest immediate postpartum copper IUD insertion is a feasible and acceptable postpartum contraceptive option for women living in LMIC.


The Role of Neuronal Pentraxin 2 (NP2) in Regulating Glutamatergic Signaling and Neuropathology.
Pentraxins are a superfamily of evolutionarily conserved proteins that are characterized by their multimeric architecture and their calcium-dependent binding. They can be broadly grouped into two subfamilies: short pentraxins and long pentraxins. Pentraxins regulate many processes in the brain as well as the periphery. Neuronal pentraxin 2 (NP2/NPTX2), also known as neuronal activity-regulated pentraxin (Narp), is an immediate-early gene that has been shown to play a critical role in guiding synaptic plasticity. NP2 has been previously linked to excitatory neurotransmission, based on its ability to aggregate excitatory receptors in the central nervous system. The mechanisms mediating the effects of NP2 on excitatory neurotransmission remain unclear and warrants further investigation. This review article focuses on the biological features of NP2 and discusses the literature supporting a role for NP2 and other pentraxins in glutamatergic signaling. An analysis of evidence around the role of pentraxins in neuropathology is also reviewed.


Incidence of cases of ocular trauma admitted to hospital and incidence of blinding outcome.
To provide epidemiological data on the current burden of serious eye injuries utilising the hospital eye service, to inform the planning and provision of eye health care, and health and safety strategies for the prevention of ocular injuries. A prospective observational study was carried out of all patients with ocular trauma admitted to hospitals in Scotland, under the care of a consultant ophthalmologist, during a 1 year period. The population of Scotland represented the population at risk of injury. Visual outcome (Snellen visual acuity in the injured eye) was measured at the time of final discharge from ophthalmic care and at follow up. All ophthalmic departments in Scotland participated and a total of 415 residents of Scotland were admitted. The 1 year cumulative incidence of ocular trauma necessitating admission to hospital is estimated to be 8.14 per 100 000 population (95% CI 7.38 to 8.97). Some 13.2% (n = 26/197) of patients discharged from follow up had a poor visual outcome with a visual acuity less than 6/12 in the injured eye. Some 10.7% (21/197) patients at this time had a blinding outcome in the injured eye (visual acuity less than 6/60). No patient was registered blind or partially sighted during the study period. The home was the single most frequent place for blinding injuries to occur (52%, n = 11/21), followed by the workplace 24% (n = 5/21). The 1 year cumulative incidence of blinding outcome from serious ocular trauma is estimated to be 0.41 per 100 000 population per year (95% CI 0.26 to 0.64). The current burden of serious ocular trauma presenting to the hospital eye service has been quantified from this population based study, and for the first time, a direct estimate of the incidence of the subsequent blinding outcome from these injuries has been provided. Ocular trauma remains an important cause of avoidable and, predominantly, monocular visual morbidity (visual impairment and blindness), with over half of the blinding injuries now occurring in the home. Health education and safety strategies should now consider targeting the home for the prevention of the serious eye injuries in addition to the traditional work, sports, and leisure environments and their related activities.


Hyperanxiety produced by periaqueductal gray injection of chondroitin sulphate glycosaminoglycan.
We examined the effects of chondroitin sulphate C (CSC) on fear and anxiety parameters following injection of the glycosaminoglycan into the dorsal periaqueductal gray. Rats with chronically implanted cannulae were administered CSC (0.4 or 4.0 nmol) or vehicle (saline, 0.2 microl) and exposed to the elevated plus-maze test of emotionality. Intra-periaqueductal gray injection of CSC produced a dose-dependent anxiogenic effect as indicated by reduced entries into and time spent on the open arms, fewer excursions into the end of the open arms and by increased stretched attend posture, flat back approach and closed arm peeping-out behaviour. The behavioural effects of CSC appeared to be anxioselective, since the glycosaminoglycan did not influence measures of general (exploratory) activity, such as number of entries into the enclosed arms and amount of scanning, rearing and grooming. The present results show that CSC can produce an anxiogenic-like profile after injection into the dorsal periaqueductal gray. This is the first such report implicating an endogenous matrix glycosaminoglycan in neural mechanisms governing fear and anxiety.


An evaluation of the satisfaction of midwives' working in midwifery group practice.
to examine changes in midwives' attitudes to their professional role following the introduction of midwifery group practice (MGP) (a caseload model of midwifery continuity of care provided to women of all risk levels) and to explore aspects of the model that were working well and those that were not working well. the questionnaire 'Attitudes to Professional Role' was used to measure midwives' satisfaction in terms of professional satisfaction, professional support, client interaction, and professional development. Open-ended questions were also included to offer an opportunity for midwives to expand on their experiences of working in the MGP model. The questionnaire was administered at five time points over the 18-month evaluation period. Round 1 was prior to the implementation of MGP, Rounds 2-4 were at three-month intervals, with Round 5 six months later. Analysis of the structured part of the questionnaire was undertaken by comparing mean scores of satisfaction ranging from -2 (very negative attitudes) to +2 (very positive attitudes), and the open-ended questions were analysed using qualitative content analysis. the Women's and Children's Hospital, Adelaide, South Australia. questionnaires were distributed to all midwives (n=15) working in MGP in Rounds 1, 2 and 3, and to the 12 midwives remaining from the original sample in Rounds 4 and 5. Fourteen questionnaires were returned in Round 1, 12 in Round 2, 10 in Round 3, nine in Round 4, and 10 in Round 5. overall, a positive change in attitudes to professional role was reflected in all sub-scales in the period between start-up and 18 months later; a reduction in scores occurred in Round 3. The mean increases were significant for all sub-scales apart from professional development. Five main themes were identified across the rounds in the content analysis: 'continuity of care', 'working pattern', 'working environment', 'collegiality' and 'issues relating to midwifery practice'. Midwives gained particular satisfaction from providing continuity of care and building relationships with women and their families, and through practising autonomously as a midwife. While there was a struggle to manage the hours worked and being on call, high levels of professional satisfaction were maintained. while there were aspects of MGP that midwives were not satisfied with and wanted to change, overall they were satisfied with the model. there is a need for ongoing evaluation in order to monitor the short- and long-term impact on midwives of working in a caseload model of continuity of midwifery care.


Cesar: cervical smear analyser and reader. A new approach to evaluating cells in cytological preparations.
Cesar presents an automated multiparameter approach to pattern recognition in the rapid detection of malignant cells from cervical and other cancers. Cells are cybernetically classified. They are collected into a container into which a nuclear stain may be incorporated and laid as a track on 35 mm. film using a disposable mapping pen device. The film track (Cytotrack) may be scanned using conventional optics and provision may be made for electronic sensing devices measuring a number of parameters, some of which are not normally used in conventional microscopy.


Social Status-Dependent Shift in Neural Circuit Activation Affects Decision Making.
In a social group, animals make behavioral decisions that fit their social ranks. These behavioral choices are dependent on the various social cues experienced during social interactions. In vertebrates, little is known of how social status affects the underlying neural mechanisms regulating decision-making circuits that drive competing behaviors. Here, we demonstrate that social status in zebrafish (Danio rerio) influences behavioral decisions by shifting the balance in neural circuit activation between two competing networks (escape and swim). We show that socially dominant animals enhance activation of the swim circuit. Conversely, social subordinates display a decreased activation of the swim circuit, but an enhanced activation of the escape circuit. In an effort to understand how social status mediates these effects, we constructed a neurocomputational model of the escape and swim circuits. The model replicates our findings and suggests that social status-related shift in circuit dynamics could be mediated by changes in the relative excitability of the escape and swim networks. Together, our results reveal that changes in the excitabilities of the Mauthner command neuron for escape and the inhibitory interneurons that regulate swimming provide a cellular mechanism for the nervous system to adapt to changes in social conditions by permitting the animal to select a socially appropriate behavioral response.SIGNIFICANCE STATEMENT Understanding how social factors influence nervous system function is of great importance. Using zebrafish as a model system, we demonstrate how social experience affects decision making to enable animals to produce socially appropriate behavior. Based on experimental evidence and computational modeling, we show that behavioral decisions reflect the interplay between competing neural circuits whose activation thresholds shift in accordance with social status. We demonstrate this through analysis of the behavior and neural circuit responses that drive escape and swim behaviors in fish. We show that socially subordinate animals favor escape over swimming, while socially dominants favor swimming over escape. We propose that these differences are mediated by shifts in relative circuit excitability.


Movement variability in stroke patients and controls performing two upper limb functional tasks: a new assessment methodology.
In the evaluation of upper limb impairment post stroke there remains a gap between detailed kinematic analyses with expensive motion capturing systems and common clinical assessment tests. In particular, although many clinical tests evaluate the performance of functional tasks, metrics to characterise upper limb kinematics are generally not applicable to such tasks and very limited in scope. This paper reports on a novel, user-friendly methodology that allows for the assessment of both signal magnitude and timing variability in upper limb movement trajectories during functional task performance. In order to demonstrate the technique, we report on a study in which the variability in timing and signal magnitude of data collected during the performance of two functional tasks is compared between a group of subjects with stroke and a group of individually matched control subjects. We employ dynamic time warping for curve registration to quantify two aspects of movement variability: 1) variability of the timing of the accelerometer signals' characteristics and 2) variability of the signals' magnitude. Six stroke patients and six matched controls performed several trials of a unilateral ('drinking') and a bilateral ('moving a plate') functional task on two different days, approximately 1 month apart. Group differences for the two variability metrics were investigated on both days. For 'drinking from a glass' significant group differences were obtained on both days for the timing variability of the acceleration signals' characteristics (p = 0.002 and p = 0.008 for test and retest, respectively); all stroke patients showed increased signal timing variability as compared to their corresponding control subject. 'Moving a plate' provided less distinct group differences. This initial application establishes that movement variability metrics, as determined by our methodology, appear different in stroke patients as compared to matched controls during unilateral task performance ('drinking'). Use of a user-friendly, inexpensive accelerometer makes this methodology feasible for routine clinical evaluations. We are encouraged to perform larger studies to further investigate the metrics' usefulness when quantifying levels of impairment.


Conventional dendritic cells are required for the activation of helper-dependent CD8 T cell responses to a model antigen after cutaneous vaccination with lentiviral vectors.
Cutaneous vaccination with lentiviral vectors generates systemic CD8 T cell responses that have the potential to eradicate tumors for cancer immunotherapy. However, although s.c. immunization with <1 million lentiviral particles clearly primes cytotoxic T cells, vaccination with much higher doses has routinely been used to define the mechanisms of T cell activation by lentiviral vectors. In particular, experiments to test presentation of lentiviral Ags by dendritic cells (DC) require injection of high viral titers, which may result in aberrant transduction of different DC populations. We exploited inducible murine models of DC depletion to investigate which DC prime the lentiviral response after s.c. immunization with low doses of lentiviral particles. In this article, we demonstrate that conventional DC are required to present Ag to CD8 T cells in draining lymph nodes. Langerhans cells are not required to activate the effector response, and neither Langerhans cells nor plasmacytoid DC are sufficient to prime Ag-specific T cells. Immunization drives the generation of endogenous long-lived memory T cells that can be reactivated to kill Ag-specific targets in the absence of inflammatory challenge. Furthermore, lentiviral vaccination activates expansion of endogenous CD4 Th cells, which are required for the generation of effector CD8 T cells that produce IFN-γ and kill Ag-specific targets. Collectively, we demonstrate that after cutaneous immunization with lentiviral particles, CD4-licensed lymph node conventional DC present Ag to CD8 T cells, resulting in the generation of protective endogenous antitumor immunity that may be effective for cancer immunotherapy.


Comparability of M mode echocardiographic long axis and short axis left ventricular function derivatives.
M mode echocardiographic anteroposterior indexes of left ventricular function derived from long and short axis parasternal planes were compared in one hundred cases. In all the disease groups studied the paired values were within acceptable statistical limits of comparability and interchangeability; that is they were within two standard deviations of the mean difference in both directions. Values from either plane can usually be considered as being representative of the expected values for the individual.


Efficacy and tolerability of hypericum extract WS 5572 versus placebo in mildly to moderately depressed patients. A randomized double-blind multicenter clinical trial.
We have investigated the antidepressant efficacy and safety of Hypericum perforatum (St. John's wort) extract WS5572 in a double-blind, placebo-controlled multicenter clinical trial. 72 patients (WS 5572: 37, placebo: 35) with a diagnosis of mild to moderate major depressive disorder (according to DSM-IV criteria) were randomized in 42 days of treatment with either 300 mg WS5572 t.i.d. or placebo. The primary efficacy variable was the change of the 17-item Hamilton Depression Scale (HAMD) total score between baseline and double-blind treatment. The study was conducted with an adaptive interim analysis, which led to early stopping because convincing treatment efficacy could already be demonstrated. Group differences in favor of WS 5572 were descriptively apparent as early as day 7 of randomized treatment and were statistically significant at days 28 (p = 0.011) and day 42 (p < 0.001). Between baseline and treatment end, the HAMD total score decreased from 19.7 +/- 3.4 to 8.9 +/- 4.3 points in the Hypericum group and from 20.1 +/- 2.6 to 14.4 +/- 6.8 points in the placebo group (mean +/- SD). Responder rates were consistently higher in the Hypericum group. Comparable group differences in favor of WS 5572 were also found for von Zerssen's Depression Scale (D-S; self-rating), Clinical Global Impressions (CGI) and a global patient's self-assessment (GPA). Tolerability was very good in both groups, with no adverse drug reactions and no clinically relevant changes in safety parameters. The results indicate that Hypericum extract WS 5572 is an effective and well-tolerated drug for the treatment of mild to moderate major depressive disorder.


Epigenetic modifications as potential therapeutic targets in age-related macular degeneration and diabetic retinopathy.
Recently, aberrant epigenetic modifications have been identified in the pathogenesis of the posterior eye diseases, age-related macular degeneration (AMD) and diabetic retinopathy (DR). This has led to the development of alternative therapies that can alter aberrant chromatin-remodelling processes involved in AMD and DR. These novel therapeutic agents could help to ameliorate the challenges associated with current treatments that are limited by variable patient response and disease heterogeneity. However, research on the use of epigenetic-based therapies in these diseases is relatively young and, therefore, preclinical studies that evaluate their mechanism of action, specificity and adverse effects are warranted.


Nonlinear terahertz coherent excitation of vibrational modes of liquids.
We report the first coherent excitation of intramolecular vibrational modes via the nonlinear interaction of a TeraHertz (THz) light field with molecular liquids. A terahertz-terahertz-Raman pulse sequence prepares the coherences with a broadband, high-energy, (sub)picosecond terahertz pulse, that are then measured in a terahertz Kerr effect spectrometer via phase-sensitive, heterodyne detection with an optical pulse. The spectrometer reported here has broader terahertz frequency coverage, and an increased sensitivity relative to previously reported terahertz Kerr effect experiments. Vibrational coherences are observed in liquid diiodomethane at 3.66 THz (122 cm(-1)), and in carbon tetrachloride at 6.50 THz (217 cm(-1)), in exact agreement with literature values of those intramolecular modes. This work opens the door to 2D spectroscopies, nonlinear in terahertz field, that can study the dynamics of condensed-phase molecular systems, as well as coherent control at terahertz frequencies.


Coordinated regulation of amino sugar-synthesizing and -degrading enzymes in Escherichia coli K-12.
The intracellular concentration of the enzyme glucosamine-6-phosphate synthase, encoded by the gene glmS in Escherichia coli, is repressed about threefold by growth on the amino sugars glucosamine and N-acetylglucosamine. This regulation occurs at the level of glmS transcription. It is not due just to the presence of intracellular amino sugar phosphates, because mutations which derepress the genes of the nag regulon (coding for proteins involved in the uptake and metabolism of N-acetylglucosamine) also repress the expression of glmS in the absence of exogenous amino sugars.


Intestinal colonization potential of turbot (Scophthalmus maximus)- and dab (Limanda limanda)-associated bacteria with inhibitory effects against Vibrio anguillarum.
Of more than 400 bacteria isolated from turbot (Scophthalmus maximus), 89 have previously been shown to inhibit the in vitro growth of the fish pathogen Vibrio anguillarum. The aim of the present study was to investigate the potential of seven of these strains, as well as of intestinal isolates (four strains) from a closely related fish, dab (Limanda limanda), for colonizing farmed turbot as a means of protecting the host from infection by V. anguillarum. In addition, the inhibitory effect of these strains on the pathogen was further studied. Colonization potential was measured by the capacity of the strains to adhere to and grow in turbot intestinal mucus. These parameters were also used to investigate the potential of V. anguillarum to amplify in the turbot intestinal tract. Because of the observed rapid growth of V. anguillarum in intestinal mucus, it can be proposed that the intestinal tract is a site for V. anguillarum multiplication. Strains isolated from the intestine showed greater capacity for adhesion to and growth in fish intestinal mucus than did the pathogen and the skin mucus isolates. All of the isolates released metabolites into the culture medium that had inhibitory effects against V. anguillarum. The results are discussed with emphasis on administering bacteria of host origin to farmed turbot in order to control V. anguillarum-induced disease.


An adenylyl cyclase that functions during late development of Dictyostelium.
A variety of extracellular signals lead to the accumulation of cAMP which can act as a second message within cells by activating protein kinase A (PKA). Expression of many of the essential developmental genes in Dictyostelium discoideum are known to depend on PKA activity. Cells in which the receptor-coupled adenylyl cyclase gene, acaA, is genetically inactivated grow well but are unable to develop. Surprisingly, acaA(-) mutant cells can be rescued by developing them in mixtures with wild-type cells, suggesting that another adenylyl cyclase is present in developing cells that can provide the internal cAMP necessary to activate PKA. However, the only other known adenylyl cyclase gene in Dictyostelium, acgA, is only expressed during germination of spores and plays no role in the formation of fruiting bodies. By screening morphological mutants generated by Restriction Enzyme Mediated Integration (REMI) we discovered a novel adenylyl cyclase gene, acrA, that is expressed at low levels in growing cells and at more than 25-fold higher levels during development. Growth and development up to the slug stage are unaffected in acrA(-) mutant strains but the cells make almost no viable spores and produce unnaturally long stalks. Adenylyl cyclase activity increases during aggregation, plateaus during the slug stage and then increases considerably during terminal differentiation. The increase in activity following aggregation fails to occur in acrA(-) cells. As long as ACA is fully active, ACR is not required until culmination but then plays a critical role in sporulation and construction of the stalk.


Aquatic metagenomes implicate Thaumarchaeota in global cobalamin production.
Cobalamin (vitamin B12) is a complex metabolite and essential cofactor required by many branches of life, including most eukaryotic phytoplankton. Algae and other cobalamin auxotrophs rely on environmental cobalamin supplied from a relatively small set of cobalamin-producing prokaryotic taxa. Although several Bacteria have been implicated in cobalamin biosynthesis and associated with algal symbiosis, the involvement of Archaea in cobalamin production is poorly understood, especially with respect to the Thaumarchaeota. Based on the detection of cobalamin synthesis genes in available thaumarchaeotal genomes, we hypothesized that Thaumarchaeota, which are ubiquitous and abundant in aquatic environments, have an important role in cobalamin biosynthesis within global aquatic ecosystems. To test this hypothesis, we examined cobalamin synthesis genes across sequenced thaumarchaeotal genomes and 430 metagenomes from a diverse range of marine, freshwater and hypersaline environments. Our analysis demonstrates that all available thaumarchaeotal genomes possess cobalamin synthesis genes, predominantly from the anaerobic pathway, suggesting widespread genetic capacity for cobalamin synthesis. Furthermore, although bacterial cobalamin genes dominated most surface marine metagenomes, thaumarchaeotal cobalamin genes dominated metagenomes from polar marine environments, increased with depth in marine water columns, and displayed seasonality, with increased winter abundance observed in time-series datasets (e.g., L4 surface water in the English Channel). Our results also suggest niche partitioning between thaumarchaeotal and cyanobacterial ribosomal and cobalamin synthesis genes across all metagenomic datasets analyzed. These results provide strong evidence for specific biogeographical distributions of thaumarchaeotal cobalamin genes, expanding our understanding of the global biogeochemical roles played by Thaumarchaeota in aquatic environments.


Primary sequence of the Escherichia coli fadL gene encoding an outer membrane protein required for long-chain fatty acid transport.
The fadL gene of Escherichia coli encodes an outer membrane protein (FadL) that plays a central role in the uptake of exogenous long-chain fatty acids. The nucleotide sequence of the fadL gene revealed a single open reading frame of 1,344 bp encoding a protein with 448 amino acid residues and a molecular weight of 48,831. The transcriptional start, analyzed by primer extension, was shown to be 95 bp upstream from the translational start. Apparent -10 and -35 regions were found at -12 and -37 bp upstream from the transcriptional start. Three regions with hyphenated dyad symmetry (two between the transcriptional start and the translational start and one upstream from the -10 and -35 regions) were identified that may play a role in the expression of fadL. The protein product of the fadL gene contained a signal sequence and signal peptidase I cleavage site similar to that defined for other E. coli outer membrane proteins. The N-terminal sequence of mature FadL protein was determined by automated amino acid sequencing of protein purified from the outer membrane of a strain harboring fadL under the control of a T7 RNA polymerase-responsive promoter. This amino acid sequence, Ala-Gly-Phe-Gln-Leu-Asn-Glu-Phe-Ser-Ser, verified the signal peptidase I cleavage site on pre-FadL and confirmed the N-terminal amino acid sequence of FadL predicted from the DNA sequence. Mature FadL contained 421 amino acid residues, giving a molecular weight of 45,969. The amino acid composition of FadL deduced from the DNA sequence suggested that this protein contained an abundance of hydrophobic amino acid residues and lacked cysteinyl residues. The hydrophobic amino acids within FadL were predicted to contribute to at least five regions of the protein with an overall hydrophobic character. The amino acid sequence of FadL was used to search GenBank for other proteins with amino acid sequence homology. These data demonstrated that FadL and the heat-modifiable outer membrane protein P1 of Haemophilus influenzae type b were 60.5% conserved and 42.0% identical over 438 amino acid residues.


Ertapenem for the treatment of bloodstream infections due to ESBL-producing Enterobacteriaceae: a multinational pre-registered cohort study.
Data about the efficacy of ertapenem for the treatment of bloodstream infections (BSI) due to ESBL-producing Enterobacteriaceae (ESBL-E) are limited. We compared the clinical efficacy of ertapenem and other carbapenems in monomicrobial BSI due to ESBL-E. A multinational retrospective cohort study (INCREMENT project) was performed (ClinicalTrials.gov identifier: NCT01764490). Patients given monotherapy with ertapenem or other carbapenems were compared. Empirical and targeted therapies were analysed. Propensity scores were used to control for confounding; sensitivity analyses were performed in subgroups. The outcome variables were cure/improvement rate at day 14 and all-cause 30 day mortality. The empirical therapy cohort (ETC) and the targeted therapy cohort (TTC) included 195 and 509 patients, respectively. Cure/improvement rates were 90.6% with ertapenem and 75.5% with other carbapenems (P = 0.06) in the ETC and 89.8% and 82.6% (P = 0.02) in the TTC, respectively; 30 day mortality rates were 3.1% and 23.3% (P = 0.01) in the ETC and 9.3% and 17.1% (P = 0.01) in the TTC, respectively. Adjusted ORs (95% CI) for cure/improvement with empirical and targeted ertapenem were 1.87 (0.24-20.08; P = 0.58) and 1.04 (0.44-2.50; P = 0.92), respectively. For the propensity-matched cohorts it was 1.18 (0.43-3.29; P = 0.74). Regarding 30 day mortality, the adjusted HR (95% CI) for targeted ertapenem was 0.93 (0.43-2.03; P = 0.86) and for the propensity-matched cohorts it was 1.05 (0.46-2.44; P = 0.90). Sensitivity analyses were consistent except for patients with severe sepsis/septic shock, which showed a non-significant trend favouring other carbapenems. Ertapenem appears as effective as other carbapenems for empirical and targeted therapy of BSI due to ESBL-E, but further studies are needed for patients with severe sepsis/septic shock.


Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson's disease (NSTAPS study): a randomised controlled trial.
Patients with advanced Parkinson's disease often have rapid swings between mobility and immobility, and many respond unsatisfactorily to adjustments in pharmacological treatment. We assessed whether globus pallidus pars interna (GPi) deep brain stimulation (DBS) gives greater functional improvement than does subthalamic nucleus (STN) DBS. We recruited patients from five centres in the Netherlands who were aged 18 years or older, had idiopathic Parkinson's disease, and had, despite optimum pharmacological treatment, at least one of the following symptoms: severe response fluctuations, dyskinesias, painful dystonias, or bradykinesia. By use of a computer-generated randomisation sequence, we randomly assigned patients to receive either GPi DBS or STN DBS (1:1), applying a minimisation procedure according to drug use (levodopa equivalent dose <1000 mg vs ≥1000 mg) and treatment centre. Patients and study assessors (but not those who assessed adverse events) were masked to treatment allocation. We had two primary outcomes: functional health as measured by the weighted Academic Medical Center Linear Disability Scale (ALDS; weighted by time spent in the off phase and on phase) and a composite score for cognitive, mood, and behavioural effects up to 1 year after surgery. Secondary outcomes were symptom scales, activities of daily living scales, a quality-of-life questionnaire, the occurrence of adverse events, and drug use. We used the intention-to-treat principle for all analyses. This trial is registered with www.controlled-trials.com, number ISRCTN85542074. Between Feb 1, 2007, and March 29, 2011, we enrolled 128 patients, assigning 65 to GPi DBS and 63 to STN DBS. We found no statistically significant difference in either of our primary outcomes: mean change in weighted ALDS (3·0 [SD 14·5] in the GPi group vs 7·7 [23·2] in the STN group; p=0·28) and the number of patients with cognitive, mood, and behavioural side-effects (36 [58%] of 62 patients in the GPi group vs 35 [56%] of 63 patients in the STN group; p=0·94). Secondary outcomes showed larger improvements in off-drug phase in the STN group compared with the GPi group in the mean change in unified Parkinson's disease rating scale motor examination scores (20·3 [16·3] vs 11·4 [16·1]; p=0·03), the mean change in ALDS scores (20·3 [27·1] vs 11·8 [18·9]; p=0·04), and medication (mean levodopa equivalent drug reduction: 546 [SD 561] vs 208 [521]; p=0·01). We recorded no difference in the occurrence of adverse events between the two groups. Other secondary endpoints showed no difference between the groups. Although there was no difference in our primary outcomes, our findings suggest that STN could be the preferred target for DBS in patients with advanced Parkinson's disease. Stichting Internationaal Parkinson Fonds, Prinses Beatrix Fonds, and Parkinson Vereniging.


Maternal nutrition modifies trophoblast giant cell phenotype and fetal growth in mice.
Mammalian placentation is dependent upon the action of trophoblast cells at the time of implantation. Appropriate fetal growth, regulated by maternal nutrition and nutrient transport across the placenta, is a critical factor for adult offspring long-term health. We have demonstrated that a mouse maternal low-protein diet (LPD) fed exclusively during preimplantation development (Emb-LPD) increases offspring growth but programmes adult cardiovascular and metabolic disease. In this study, we investigate the impact of maternal nutrition on post-implantation trophoblast phenotype and fetal growth. Ectoplacental cone explants were isolated at day 8 of gestation from female mice fed either normal protein diet (NPD: 18% casein), LPD (9% casein) or Emb-LPD and cultured in vitro. We observed enhanced spreading and cell division within proliferative and secondary trophoblast giant cells (TGCs) emerging from explants isolated from LPD-fed females when compared with NPD and Emb-LPD explants after 24 and 48 h. Moreover, both LPD and Emb-LPD explants showed substantial expansion of TGC area during 24-48 h, not observed in NPD. No difference in invasive capacity was observed between treatments using Matrigel transwell migration assays. At day 17 of gestation, LPD- and Emb-LPD-fed conceptuses displayed smaller placentas and larger fetuses respectively, resulting in increased fetal:placental ratios in both groups compared with NPD conceptuses. Analysis of placental and yolk sac nutrient signalling within the mammalian target of rapamycin complex 1 pathway revealed similar levels of total and phosphorylated downstream targets across groups. These data demonstrate that early post-implantation embryos modify trophoblast phenotype to regulate fetal growth under conditions of poor maternal nutrition.


Reduced dermatopontin expression is a molecular link between uterine leiomyomas and keloids.
Uterine leiomyomas are prevalent estrogen-responsive clonal tumors, but the specific genetic alterations that contribute to their development have not been elucidated. To identify genes involved in the formation of leiomyomas, we used global expression profiling to compare clonal tumors with normal myometrium. Contrary to expectation, genes involved in estrogen action were not differentially expressed between leiomyoma and normal myometrium. Genes encoding extracellular-matrix proteins were prominently featured, suggesting their involvement in formation of a myofibroblast phenotype. Analysis of the extracellular matrix in the leiomyomas revealed a disordered collagen fibril orientation. Expression of the collagen-binding protein dermatopontin was found to be consistently decreased in leiomyoma by both reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time RT-PCR (mean underexpression = 9.41-fold) regardless of leiomyoma size, leiomyoma location, patient race, and patient age. This expression pattern was observed in 11 subjects and a total of 23 leiomyoma:myometrium pairs. Decreased expression of dermatopontin was also associated with keloid formation, a fibrotic disease that shares epidemiologic similarities with leiomyoma. Immunohistochemical studies of leiomyomas and keloids demonstrated reduced levels of dermatopontin in both tissues. In addition, ultrastructural analysis revealed that the orientation of the collagen fibrils in the keloid tissues strongly resembled that in the leiomyomas. Reduction in dermatopontin was associated with an increase in transforming growth factor-beta3 (TGFB3) mRNA levels in leiomyomas, whereas other genes involved in dermatopontin signaling were not differentially expressed. These findings suggest that leiomyoma development involves a myofibroblast cell phenotype characterized by dysregulation of genes encoding extracellular-matrix proteins. In particular, decreased expression of dermatopontin represents a molecular link between the leiomyoma and keloid phenotypes.


Strengthening early warning function of surveillance in the Republic of Serbia: lessons learned after a year of implementation.
The Republic of Serbia, with WHO support, has implemented an early warning system (ALERT) for priority communicable diseases, to complement the routine surveillance system which notifies individual confirmed cases. The results of its evaluation, conducted one year after implementation is presented here. ALERT relies on notification of 11 syndromes by primary care facilities. Data is analysed weekly at district level and transmitted to national epidemiologists. ALERT is perceived to be a simple and flexible tool. Acceptability is higher at national level than at district level. Some districts perceive ALERT as a parallel system poorly connected to control measures. Sensitivity of ALERT in detecting cases of meningitis is 93%, and 37% for cases of hepatitis. Retrospective analysis of ALERT data identified 9 outbreaks, 5 of which had been recognized by epidemiologists. ALERT was the timeliest system for detecting 4 outbreaks identified by both systems. ALERT was useful for triggering timely investigation and control of outbreaks of hantavirus and salmonellosis and for detecting the start of the influenza season. However, ALERT did not detect clusters of brucellosis and tularaemia targeted by the unexplained fever syndrome. This evaluation underlined the need for a global review of surveillance activities when implementing new components such as ALERT. While control measures based on notification of individual confirmed cases are well understood and implemented, the investigation and verification process that should result from an increase in ALERT syndromes is not fully understood. Field epidemiology training programmes, such as the EPIET programme, are best suited to bring about this change of perspective.


S-adenosylmethionine decarboxylase from Leishmania donovani. Molecular, genetic, and biochemical characterization of null mutants and overproducers.
The polyamine biosynthetic enzyme, S-adenosylmethionine decarboxylase (ADOMETDC) has been advanced as a potential target for antiparasitic chemotherapy. To investigate the importance of this protein in a model parasite, the gene encoding ADOMETDC has been cloned and sequenced from Leishmania donovani. The Delta adometdc null mutants were created in the insect vector form of the parasite by double targeted gene replacement. The Delta adometdc strains were incapable of growth in medium without polyamines; however, auxotrophy could be rescued by spermidine but not by putrescine, spermine, or methylthioadenosine. Incubation of Delta adometdc parasites in medium lacking polyamines resulted in a drastic increase of putrescine and glutathione levels with a concomitant decrease in the amounts of spermidine and the spermidine-containing thiol trypanothione. Parasites transfected with an episomal ADOMETDC construct were created in both wild type and Delta adometdc parasites. ADOMETDC overexpression abrogated polyamine auxotrophy in the Delta adometdc L. donovani. In addition, ADOMETDC overproduction in wild type parasites alleviated the toxic effects of 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (MDL 73811), but not pentamidine, berenil, or methylglyoxyl bis(guanylhydrazone), all inhibitors of ADOMETDC activities in vitro. The molecular, biochemical, and genetic characterization of ADOMETDC establishes that it is essential in L. donovani promastigotes and a potential target for therapeutic validation.


Effects of Target Signal Shape and System Dynamics on Feedforward in Manual Control.
The human controller (HC) in manual control of a dynamical system often follows a visible and predictable reference path (target). The HC can adopt a control strategy combining closed-loop feedback and an open-loop feedforward response. The effects of the target signal waveform shape and the system dynamics on the human feedforward dynamics are still largely unknown, even for common, stable, vehicle-like dynamics. This paper studies the feedforward dynamics through computer model simulations and compares these to system identification results from human-in-the-loop experimental data. Two target waveform shapes are considered, constant velocity ramp segments and constant acceleration parabola segments. Furthermore, three representative vehicle-like system dynamics are considered: 1) a single integrator (SI); 2) a second-order system; and 3) a double integrator. The analyses show that the HC utilizes a combined feedforward/feedback control strategy for all dynamics with the parabola target, and for the SI and second-order system with the ramp target. The feedforward model parameters are, however, very different between the two target waveform shapes, illustrating the adaptability of the HC to task variables. Moreover, strong evidence of anticipatory control behavior in the HC is found for the parabola target signal. The HC anticipates the future course of the parabola target signal given extensive practice, reflected by negative feedforward time delay estimates.


Behavioral aspects of solid waste management: A systematic review.
Over the past three decades, research on the established linkages between solid waste management and psychological models has progressed rapidly. This informs statutory bodies that wish to design an effective solid waste management system. To further address this crucial task, this paper examined the existing literature on behavioral approaches applied to the study of solid waste. Through a systematic literature review approach, we identified, analyzed, and synthesized available literature across various geographical regions. Based on an analysis of 80 articles, we found that high-income countries (61%) are overrepresented in the existing literature, in which the USA (44%) has contributed the most. Most articles targeted recycling behavior (59%) by applying individual behavior theories (90%), in which the theory of planned behavior was widely tested (46%). In addition, 65% of the articles conducted model testing and 51% conducted empirical studies, revealing a dearth of evaluation studies in the literature. Cluster analyses revealed that psychological factors, comprising 34 variables, were extensively used, allowing future researchers to explore relevant variables from inter-disciplinary domains by adopting a pragmatic paradigm approach. In summary, this review identified four research gaps, recommended paths for future research, and concluded by highlighting the need of investigating social elements to tackle solid waste issues. Implications: The systematic review presented in this paper is an original contribution to the aforementioned body of knowledge. It makes the case for more researchers, teachers, and students to undertake behavioral projects, thus creating awareness among citizens to participate in waste management activities. The research gaps identified here also highlight the scope for future studies in under-explored areas and in the implementation of pro-environmental models to build a clean and green environment. Furthermore, the findings facilitate the formulation of pro-environmental laws, regulations, and policies in developing countries, where there is a higher need for strict environmental regulations focused on sustainability.


Electrostatic potential distribution of the gene V protein from Ff phage facilitates cooperative DNA binding: a model of the GVP-ssDNA complex.
The crystal structure of the gene V protein (GVP) from the Ff filamentous phages (M13, fl, fd) has been solved for the wild-type and two mutant (Y41F and Y41H) proteins at high resolution. The Y41H mutant crystal structure revealed crystal packing interactions, which suggested a plausible scheme for constructing the polymeric protein shell of the GVP-single-stranded DNA (ssDNA) complex (Guan Y, et al., 1994, Biochemistry 33:7768-7778). The electrostatic potentials of the isolated and the cooperatively formed protein shell have been calculated using the program GRASP and they revealed a highly asymmetric pattern of the electrostatic charge distribution. The inner surface of the putative DNA-binding channel is positively charged, whereas the opposite outer surface is nearly neutral. The electrostatic calculation further demonstrated that the formation of the helical protein shell enhanced the asymmetry of the electrostatic distribution. A model of the GVP-ssDNA complex with the n = 4 DNA-binding mode could be built with only minor conformational perturbation to the GVP protein shell. The model is consistent with existing biochemical and biophysical data and provides clues to the properties of GVP, including the high cooperatively of the protein binding to ssDNA. The two antiparallel ssDNA strands form a helical ribbon with the sugar-phosphate backbones at the middle and the bases pointing away from each other. The bases are stacked and the Phe 73 residue is intercalated between two bases. The optimum binding to a tetranucleotide unit requires the participation of four GVP dimers, which may explain the cooperativity of the GVP binding to DNA.


Screening of novel excipients for freeze-dried protein formulations.
The typical excipients used as bulking agents and lyoprotectants for freeze-drying are usually limited to only a few selected substances, such as sucrose and mannitol. Considering the sheer diversity amongst proteins, it is doubtful that this limited choice should, in every case, provide the best possible option in order to achieve the most stable product. In this work, a screening of 12 proteins with 64 excipients was conducted in order to increase the knowledge space of potential excipients. Three critical quality attributes (CQAs) of the freeze-dried products, namely the solid state, the cake appearance and the protein integrity based on changes in tryptophan fluorescence were investigated by high throughput X-ray powder diffraction, image analysis and intrinsic fluorescence spectroscopy, respectively. It was found, that in some cases the excipient had a dominating influence on the CQAs, whilst in other cases the CQAs were primarily protein dependent, or that the CQAs were dependent on the combination of both. In the course of this investigation, a general view of potentially relevant excipients, and their interplay with various proteins, was obtained, thereby furthermore paving the way for the use of novel freeze-drying excipients.


A transcription factor IIA-binding site differentially regulates RNA polymerase II-mediated transcription in a promoter context-dependent manner.
RNA polymerase II (pol II) is required for the transcription of all protein-coding genes and as such represents a major enzyme whose activity is tightly regulated. Transcriptional initiation therefore requires numerous general transcriptional factors and cofactors that associate with pol II at the core promoter to form a pre-initiation complex. Transcription factor IIA (TFIIA) is a general cofactor that binds TFIID and stabilizes the TFIID-DNA complex during transcription initiation. Previous studies showed that TFIIA can make contact with the DNA sequence upstream or downstream of the TATA box, and that the region bound by TFIIA could overlap with the elements recognized by another factor, TFIIB, at adenovirus major late core promoter. Whether core promoters contain a DNA motif recognized by TFIIA remains unknown. Here we have identified a core promoter element upstream of the TATA box that is recognized by TFIIA. A search of the human promoter database revealed that many natural promoters contain a TFIIA recognition element (IIARE). We show that the IIARE enhances TFIIA-promoter binding and enhances the activity of TATA-containing promoters, but represses or activates promoters that lack a TATA box. Chromatin immunoprecipitation assays revealed that the IIARE activates transcription by increasing the recruitment of pol II, TFIIA, TAF4, and P300 at TATA-dependent promoters. These findings extend our understanding of the role of TFIIA in transcription, and provide new insights into the regulatory mechanism of core promoter elements in gene transcription by pol II.


A Role for the Mre11-Rad50-Xrs2 Complex in Gene Expression and Chromosome Organization.
Mre11-Rad50-Xrs2 (MRX) is a highly conserved complex with key roles in various aspects of DNA repair. Here, we report a new function for MRX in limiting transcription in budding yeast. We show that MRX interacts physically and colocalizes on chromatin with the transcriptional co-regulator Mediator. MRX restricts transcription of coding and noncoding DNA by a mechanism that does not require the nuclease activity of Mre11. MRX is required to tether transcriptionally active loci to the nuclear pore complex (NPC), and it also promotes large-scale gene-NPC interactions. Moreover, MRX-mediated chromatin anchoring to the NPC contributes to chromosome folding and helps to control gene expression. Together, these findings indicate that MRX has a role in transcription and chromosome organization that is distinct from its known function in DNA repair.


Nutrition Risk Measured Online in Community-Living Older Australians.
Many community-living older adults experience the condition of malnutrition and the causes are complex and multi-factorial. This study examined nutrition risk in a sample of community-living older Australians (n = 77, age ≥65 years) using an online, self-administered survey consisting of two validated questionnaires (SCREEN II and SF-12). We found a significant relationship between health status and nutrition risk; those with higher self-rated health status had lower nutrition risk. Forty percent of the participants were categorized at high nutritional risk, 26% at moderate nutritional risk and 34% not at nutritional risk. The most common nutrition risk factors were: (i) weight perception (perceiving weight to be more than it should); (ii) food avoidance; (iii) low intake of milk, milk products and alternatives; and (iv) finding meal preparation a chore. Many nutrition-risk factors were consistent with population survey data highlighting the need for greater awareness of nutritional requirements for healthy ageing.


Emergency management of children with severe sepsis in the United Kingdom: the results of the Paediatric Intensive Care Society sepsis audit.
To audit current UK practice of the management of severe sepsis in children against the 2002 American College of Critical Care Medicine/Pediatric Advanced Life Support (ACCM-PALS) guideline. Prospective observational study. 17 UK paediatric intensive care units (PICUs) and two UK PICU transport services. 200 children accepted for PICU admission within 12 h of arrival in hospital, whether or not successfully transported to a PICU, with a discharge diagnosis of sepsis or suspected sepsis. Medical interventions, physiological and laboratory data to determine the presence or absence of shock, inter-hospital transfer times, predicted mortality (using the Paediatric Index of Mortality, version 2 (PIM2) scoring system) and observed mortality. 34/200 (17%) children died following referral. Although children defined as being in shock received significantly more fluid (p<0.001) than those who were not in shock, overall fluid and inotrope management suggested by the 2002 ACCM-PALS guideline was not followed in 62% of shocked children. Binary logistic regression analysis demonstrated that the odds ratio for death, if shock was present at PICU admission, was 3.8 (95% CI 1.4 to 10.2, p = 0.008). The presence of shock at PICU admission is associated with an increased risk of death. Despite clear consensus guidelines for the emergency management of children with severe sepsis and septic shock, most children received inadequate fluid resuscitation and inotropic support in the crucial few hours following presentation.


Anti-osteoporotic constituents from Indian medicinal plants.
The objective of this study was to determine the in vitro osteogenic activities of selected medicinal plants used traditionally in India. The compounds isolated from three plants viz. Allophylus serratus, Cissus quadrangularis and Vitex negundo were evaluated for their in vitro osteogenic activities. Primary cultures of osteoblasts were used to determine the effects of these components on osteoblast functions. Five of the fourteen compounds isolated led to increase in osteoblast differentiation and mineralization. These findings lend support to the use of Allophylus serratus, Cissus quadrangularis and Vitex negundo in traditional medicine.


Hepatocyte growth factor/MET and CD44 in colorectal cancer: partners in tumorigenesis and therapy resistance.
Intestinal epithelial self-renewal is a tightly controlled process, which is critically dependent on WNT signalling. Aberrant activation of the WNT pathway in intestinal stem cells (ISCs) results in constitutive transcription of target genes, which collectively drive malignant transformation in colorectal cancer (CRC). However, the contribution of individual genes to intestinal homeostasis and tumorigenesis often is incompletely defined. Here, we discuss converging evidence indicating that the receptor tyrosine kinase (RTK) MET and its ligand hepatocyte growth factor (HGF) play a major role in the intestinal damage response, as well as in intestinal tumorigenesis, by controlling the proliferation, survival, motility, and stemness of normal and neoplastic intestinal epithelial cells. These activities of MET are promoted by specific CD44 isoforms expressed by ISCs. The accrued data indicate that MET and the EGFR have overlapping roles in the biology of intestinal epithelium and that metastatic CRCs can exploit this redundancy to escape from EGFR-targeted treatments, co-opting HGF/MET/CD44v signalling. Hence, targeting both pathways may be required for effective treatment of (a subset of) CRCs. The RTK identity of MET, the distinctive 'plasminogen-like' structure and activation mode of its ligand HGF, and the specific collaboration of MET with CD44, provide several unique targeting options, which merit further exploration.


Pooled Amplicon Deep Sequencing of Candidate Plasmodium falciparum Transmission-Blocking Vaccine Antigens.
Polymorphisms within Plasmodium falciparum vaccine candidate antigens have the potential to compromise vaccine efficacy. Understanding the allele frequencies of polymorphisms in critical binding regions of antigens can help in the designing of strain-transcendent vaccines. Here, we adopt a pooled deep-sequencing approach, originally designed to study P. falciparum drug resistance mutations, to study the diversity of two leading transmission-blocking vaccine candidates, Pfs25 and Pfs48/45. We sequenced 329 P. falciparum field isolates from six different geographic regions. Pfs25 showed little diversity, with only one known polymorphism identified in the region associated with binding of transmission-blocking antibodies among our isolates. However, we identified four new mutations among eight non-synonymous mutations within the presumed antibody-binding region of Pfs48/45. Pooled deep sequencing provides a scalable and cost-effective approach for the targeted study of allele frequencies of P. falciparum candidate vaccine antigens.


The use of probabilistic decision models in technology assessment : the case of total hip replacement.
There is increasing recognition that decision modelling is central to health technology assessment and, in particular, to analyses to support formal decision making regarding the funding of the use of new technologies. In part, the key role of decision analysis stems from the need to handle multiple sources of uncertainty in the available evidence. The use of probabilistic decision analysis is a means of reflecting the parameter uncertainty in models and presenting this in a comprehensible manner to decision makers. In this article, we demonstrate the potential role of probabilistic models using the case study of total hip replacement surgery.A cost-effectiveness model was constructed to compare the Charnley and Spectron hip prostheses in terms of lifetime costs and quality-adjusted life-years (QALYs). Revision rates were estimated from the Swedish National Total Hip Arthroplasty Register (1992-2000); the risk of revision with the Spectron prosthesis relative to the Charnley prosthesis was 0.67 (95% confidence interval [CI] 0.32, 1.02) for early revisions and 0.26 (95% CI 0.07, 0.46) for late revisions. This lower revision risk resulted in the Spectron generating more QALYs than the Charnley prosthesis. Based on mean costs and QALYs, the Spectron results in cost savings in younger patients, and generates incremental cost-effectiveness ratios of between pound1000 and pound16 000 in older patient groups. The probabilistic results from the model indicated that, if it is assumed that decision makers are willing to pay up to pound20 000 per additional QALY, the probability of the Spectron being the more cost-effective prosthesis ranged between 70% and 100%, depending on the age and sex of the patient.This article looks at the application of probabilistic decision modelling using total hip replacement as a case study to emphasis the need for decision models to quantify all sources of parameter uncertainty and to clearly distinguish parameter uncertainty from subgroup heterogeneity.


From informed consent to informed request: strengthening shared decisionmaking.
Obtaining valid consent is regarded as essential before there can be an ethically or legally appropriate medical intervention. The justification is, simply, that patient autonomy should be respected. The patient's body is hers, and she has a right to do with it what she chooses. In order for that choice to be real, it has to be a choice made by a patient who is competent to make it. That competence has two elements. First, the patient must have the cognitive hardware and software necessary to receive, retain and process the information, weighing the benefits and the burdens of the proposed treatment against each other. Second, the inputs must be the relevant ones: the information to be processed must be (i) accurate and (ii) sufficient.


Patients' perceptions of barriers for participation in nursing care.
In many Western countries as in Sweden, patients have legal right to participate in own care individually adjusted to each patient's wishes and abilities. There are still few empirical studies of patients' perceptions of barriers for participation. Accordingly, there is a need to identify what may prevent patients from playing an active role in own nursing care. Such knowledge is highly valuable for the nursing profession when it comes to implementation of individual patient participation. To explore barriers for patient participation in nursing care with a special focus on adult patients with experience of inpatient physical care. Data were collected through 6 focus groups with 26 Swedish informants recruited from physical inpatient care as well as discharged patients from such a setting. A content analysis with qualitative approach of the tape-recorded interview material was made. The ethics of scientific work was adhered to. Each study participant gave informed consent after verbal and written information. The Ethics Committee of Göteborg University approved the study. The barriers for patient participation were identified as four categories: Facing own inability, meeting lack of empathy, meeting a paternalistic attitude and sensing structural barriers, and their 10 underlying subcategories. Our study contributes knowledge and understanding of patients' experiences of barriers for participation. The findings point to remaining structures and nurse attitudes that are of disadvantage for patients' participation. The findings may increase the understanding of patient participation and may serve as an incentive in practice and nursing education to meet and eliminate these barriers, in quality assurance of care, work organization and further research.


Three IgA myeloma immunoglobulins from the BALB/ mouse: precipitation with pneumococcal C polysaccharide.
Three of 64 IgA immunoglobuilins, derived from plasma cell tumors induced by mineral oil in BALB/c mice, precipitated with species-specific pneumococcus C polysaccharide. A related antigen was also found in group O and some group H streptococci. A difference in ability to precipitate a C polysaccharide from a pneumococcus type XIV was demonstrated between protein 603 which did precipitate and protein 167 which did not precipitate this polysaccharide. Studies of the 167 and 603 proteins showed differences in electrophoretic mobility and polypeptide chains. The antigen-combining site of the 167 and 603 proteins resided on the papain-digestion Fab fragment.


Seabream growth hormone receptor: molecular cloning and functional studies of the full-length cDNA, and tissue expression of two alternatively spliced forms.
A full-length clone of the growth hormone receptor (GHR) was isolated from a cDNA library constructed from the liver of black seabream (Acanthopagrus schlegeli). The seabream GHR (sbGHR) cDNA sequence encodes a transmembrane protein of 640 amino acids (aa) possessing the characteristic motifs and architectural design of GHRs of other species. When compared to the other fish GHRs, it is most homologous to another marine fish species, the turbot, where the aa identity is 79.3%. But the sbGHR sequence is more remotely related to the goldfish GHR (51.6% aa identity) and the salmonid GHRs (approximately 46-48% aa identities). Phylogenetic comparison with other known GHRs indicates that the fish GHRs constitute a distinct group among the different vertebrate classes. The aa identities between sbGHR and other GHRs are low, being around 40% with mammalian GHRs, around 45% with avian and reptilian GHRs, and less than 35% with Xenopus GHR. CHO cells transfected with the sbGHR cDNA can be stimulated to proliferate by recombinant seabream growth hormone (sbGH). In addition, the transfected cells can transactivate a co-expressed mammalian serine protease inhibitor (Spi) 2.1 promoter upon stimulation by sbGH. These functional assays indicated that the fish receptor can interact with its homologous ligand to evoke the downstream post-receptor events. Reverse transcription-polymerase chain reaction (RT-PCR) and genomic PCR using a pair of gene-specific primers revealed the expression of two alternatively spliced forms of sbGHR in various tissues of the fish. A 93-bp intron, unique to the sbGHR gene and not found in any other known GHR genes, is alternatively spliced to give rise to two forms of receptor mRNA transcripts. The two forms of the receptor are differentially expressed among the different tissues of the fish.


Crosstalk analysis of aligned and misaligned free-space optical interconnect systems.
We present an analysis of crosstalk in aligned and misaligned free-space optical interconnect (FSOI) systems. On the basis of a generalized diffraction integral formula, an analytical expression of irradiation distribution for FSOI systems and a convenient approach to calculate crosstalk noise signal ratios (CNSR) are proposed. Simulations are performed to analyze the factors affecting the CNSR. The analyses indicate that small beam quality factor and wide channel pitch will significantly improve performance of the FSOIs. Furthermore, the displacement of the transmitter microlens array will affect the interconnection distance much more significantly than that of the receiver microlens array.