Monoclonal antibody-based quantitation of poly(ethylene glycol)-derivatized proteins, liposomes, and nanoparticles.
Covalent attachment of poly(ethylene glycol) (PEG) molecules to drugs, proteins, and liposomes is a proven technology for improving their bioavailability, safety, and efficacy. Qualitative and quantitative analysis of PEG-derivatized molecules is important for both drug development and clinical applications. We previously reported the development of a monoclonal IgM antibody (AGP3) to PEG. We now describe a new IgG1 monoclonal antibody (E11) to PEG and show that it can be used in combination with AGP3 to detect and quantify PEG-derivatized molecules. Both antibodies bound the repeating subunits of the PEG backbone and could detect free PEG and PEG-modified proteins by ELISA, immunoblotting, and flow cytometry. Detection sensitivity increased with the length and the number of PEG chains on pegylated molecules. Both antibodies also efficiently accelerated the clearance of a PEG-modified enzyme in vivo. A sandwich ELISA in which E11/AGP3 were employed as the capture/detection antibodies was developed to detect PEG-modified proteins at concentrations as low as 1.2 ng/mL. In addition, the ELISA could also quantify, in the presence of 10% fetal bovine serum, free methoxy-PEG20,000, PEG2,000-quantum dots, and PEG2,000-liposomes at concentrations as low as 20 ng/mL (1.0 nM), 1.4 ng/mL (3.1 pM), and 2.4 ng/mL (3.13 nM phospholipids), respectively. Finally, we show that the sandwich ELISA could accurately measured the in vivo half-life of a PEG-modified enzyme. These antibodies should be generally applicable to the qualitative and quantitative analysis of all PEG-derivatized molecules.


A simplified, combined protocol versus standard treatment for acute malnutrition in children 6-59 months (ComPAS trial): A cluster-randomized controlled non-inferiority trial in Kenya and South Sudan.
Malnutrition underlies 3 million child deaths worldwide. Current treatments differentiate severe acute malnutrition (SAM) from moderate acute malnutrition (MAM) with different products and programs. This differentiation is complex and costly. The Combined Protocol for Acute Malnutrition Study (ComPAS) assessed the effectiveness of a simplified, unified SAM/MAM protocol for children aged 6-59 months. Eliminating the need for separate products and protocols could improve the impact of programs by treating children more easily and cost-effectively, reaching more children globally. A cluster-randomized non-inferiority trial compared a combined protocol against standard care in Kenya and South Sudan. Randomization was stratified by country. Combined protocol clinics treated children using 2 sachets of ready-to-use therapeutic food (RUTF) per day for those with mid-upper arm circumference (MUAC) < 11.5 cm and/or edema, and 1 sachet of RUTF per day for those with MUAC 11.5 to <12.5 cm. Standard care clinics treated SAM with weight-based RUTF rations, and MAM with ready-to-use supplementary food (RUSF). The primary outcome was nutritional recovery. Secondary outcomes included cost-effectiveness, coverage, defaulting, death, length of stay, and average daily weight and MUAC gains. Main analyses were per-protocol, with intention-to-treat analyses also conducted. The non-inferiority margin was 10%. From 8 May 2017 to 31 March 2018, 2,071 children were enrolled in 12 combined protocol clinics (mean age 17.4 months, 41% male), and 2,039 in 12 standard care clinics (mean age 16.7 months, 41% male). In total, 1,286 (62.1%) and 1,202 (59.0%), respectively, completed treatment; 981 (76.3%) on the combined protocol and 884 (73.5%) on the standard protocol recovered, yielding a risk difference of 0.03 (95% CI -0.05 to 0.10, p = 0.52; per-protocol analysis, adjusted for country, age, and sex). The amount of ready-to-use food (RUTF or RUSF) required for a child with SAM to reach full recovery was less in the combined protocol (122 versus 193 sachets), and the combined protocol cost US$123 less per child recovered (US$918 versus US$1,041). There were 23 (1.8%) deaths in the combined protocol arm and 21 (1.8%) deaths in the standard protocol arm (adjusted risk difference 95% CI -0.01 to 0.01, p = 0.87). There was no evidence of a difference between the protocols for any of the other secondary outcomes. Study limitations included contextual factors leading to defaulting, a combined multi-country power estimate, and operational constraints. Combined treatment for SAM and MAM is non-inferior to standard care. Further research should focus on operational implications, cost-effectiveness, and context (Asia versus Africa; emergency versus food-secure settings). This trial is complete and registered at ISRCTN (ISRCTN30393230). The trial is registered at ISRCTN, trial number ISRCTN30393230.


Pattern of Vascular Involvement in Egyptian Patients with Budd-Chiari Syndrome: Relation to Etiology and Impact on Clinical Presentation.
Budd-Chiari syndrome (BCS) is caused by hepatic venous outflow obstruction. This work aims to analyze the pattern of vascular involvement in Egyptian patients with BCS, demonstrates its relation to etiology and shows its impact on clinical presentation. The current retrospective study was conducted at The Tropical Medicine Department, Ain Shams University on one hundred Egyptian patients with confirmed diagnosis of primary BCS who were presented to the Budd-Chiari Study Group (BCSG) from April 2014 to May 2016 by collecting clinical, laboratory and radiological data from their medical records. Isolated hepatic vein occlusion (HVO) was the most common pattern of vascular involvement (43%), followed by combined HVO and inferior vena cava (IVC) compression by enlarged caudate lobe (32%), then combined HVO and IVC stenosis/webs (21%), and lastly isolated IVC occlusion (4%). Ascites was more significantly encountered in BCS patients with HVO than in those with isolated inferior vena cava (IVC) occlusion and patent HVs (P = 0.005). Abdominal pain was significantly encountered in patients with occluded three major HVs (P = 0.044). Behcet's disease was significantly detected in isolated IVC occlusion. Protein C deficiency was significantly detected in patients with combined HVO and IVC compression. Isolated HVs occlusion was the most common pattern of vascular involvement in Egyptian patients with primary BCS. Vascular pattern of involvement affected the clinical presentation and was related to the underlying thrombophilia in those patients.


An open tool for creating battery-electric vehicle time series from empirical data, emobpy.
There is substantial research interest in how future fleets of battery-electric vehicles will interact with the power sector. Various types of energy models are used for respective analyses. They depend on meaningful input parameters, in particular time series of vehicle mobility, driving electricity consumption, grid availability, or grid electricity demand. As the availability of such data is highly limited, we introduce the open-source tool emobpy. Based on mobility statistics, physical properties of battery-electric vehicles, and other customizable assumptions, it derives time series data that can readily be used in a wide range of model applications. For an illustration, we create and characterize 200 vehicle profiles for Germany. Depending on the hour of the day, a fleet of one million vehicles has a median grid availability between 5 and 7 gigawatts, as vehicles are parking most of the time. Four exemplary grid electricity demand time series illustrate the smoothing effect of balanced charging strategies.


High resolution helium ion scanning microscopy of the rat kidney.
Helium ion scanning microscopy is a novel imaging technology with the potential to provide sub-nanometer resolution images of uncoated biological tissues. So far, however, it has been used mainly in materials science applications. Here, we took advantage of helium ion microscopy to explore the epithelium of the rat kidney with unsurpassed image quality and detail. In addition, we evaluated different tissue preparation methods for their ability to preserve tissue architecture. We found that high contrast, high resolution imaging of the renal tubule surface is possible with a relatively simple processing procedure that consists of transcardial perfusion with aldehyde fixatives, vibratome tissue sectioning, tissue dehydration with graded methanol solutions and careful critical point drying. Coupled with the helium ion system, fine details such as membrane texture and membranous nanoprojections on the glomerular podocytes were visualized, and pores within the filtration slit diaphragm could be seen in much greater detail than in previous scanning EM studies. In the collecting duct, the extensive and striking apical microplicae of the intercalated cells were imaged without the shrunken or distorted appearance that is typical with conventional sample processing and scanning electron microscopy. Membrane depressions visible on principal cells suggest possible endo- or exocytotic events, and central cilia on these cells were imaged with remarkable preservation and clarity. We also demonstrate the use of colloidal gold probes for highlighting specific cell-surface proteins and find that 15 nm gold labels are practical and easily distinguishable, indicating that external labels of various sizes can be used to detect multiple targets in the same tissue. We conclude that this technology represents a technical breakthrough in imaging the topographical ultrastructure of animal tissues. Its use in future studies should allow the study of fine cellular details and provide significant advances in our understanding of cell surface structures and membrane organization.


Wellbeing and Arthritis Incidence: the Survey of Health, Ageing and Retirement in Europe.
A number of studies provide evidence for an association between psychosocial factors and risk of incident arthritis. Current evidence is largely limited to the examination of negative factors such as perceived stress, but positive factors such as subjective wellbeing may also play a role. The purpose of the current study was to investigate whether people with higher subjective wellbeing have a lower risk of developing arthritis. We used Cox proportional hazards regression to examine the prospective relationship between wellbeing (measured using the CASP-12) and incidence of arthritis over a 9-year period. The sample consisted of 13,594 participants aged ≥50 years from the Survey of Health, Ageing and Retirement in Europe. There was a significant association between greater wellbeing and reduced incident arthritis that was stronger at younger ages. In sex-adjusted analyses, for a standard deviation increase in CASP-12 score, the hazard ratios (95 % confidence intervals) for incident arthritis in people aged <65 and ≥65 years were 0.73 (0.69-0.77) and 0.80 (0.77-0.85), respectively. After further adjustment for other established risk factors, these associations were attenuated but remained significant in both age groups: the fully adjusted hazard ratios were 0.82 (0.77-0.87) and 0.88 (0.82-0.95), respectively. These results provide evidence for an association between greater wellbeing and reduced risk of incident arthritis and, more generally, support the theory that psychosocial factors are implicated in the aetiology of this disease. Future research needs to delineate the mechanisms underlying the association between wellbeing and arthritis risk.


Coupled activity-dependent trafficking of synaptic SK2 channels and AMPA receptors.
Small conductance Ca(2+)-activated K(+) type 2 (SK2) channels are expressed in the postsynaptic density of CA1 neurons where they are activated by synaptically evoked Ca(2+) influx to limit the size of EPSPs and spine Ca(2+) transients. At Schaffer collateral synapses, the induction of long-term potentiation (LTP) increases the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR)-mediated contribution to synaptic transmission and decreases the synaptic SK2 channel contribution through protein kinase A-dependent channel endocytosis. Using a combination of electrophysiology and immunoelectron microscopy in mice, the relationship between the dynamics of spine SK2 channels and AMPARs was investigated. Unlike AMPARs, synaptic SK2 channels under basal conditions do not rapidly recycle. Furthermore, SK2 channels occupy a distinct population of endosomes separate from AMPARs. However, blocking vesicular exocytosis or the delivery of synaptic GluA1-containing AMPARs during the induction of LTP blocks SK2 channel endocytosis. By approximately 2 h after the induction of LTP, synaptic SK2 channel expression and function are restored. Thus, LTP-dependent endocytosis of SK2 is coupled to LTP-dependent AMPA exocytosis, and the approximately 2 h window after the induction of LTP during which synaptic SK2 activity is absent may be important for consolidating the later phases of LTP.


Role of long-chain polyunsaturated fatty acids in neurodevelopment and growth.
There has been intense interest in the role of the n-3 long-chain polyunsaturated fatty acid (LCPUFA) docosahexaenoic acid (DHA, 22:6n-3), in growth and development of infants. In 2009, there are at least twelve published randomized controlled trials (RCT) assessing the effects of LCPUFA supplementation of infant formula for preterm infants and seventeen RCTs involving formula-fed term infants. In addition, at least five RCTs have investigated the effect of DHA supplementation during pregnancy and/or lactation on infant and early child development. Collectively, the published literature has demonstrated no harm of dietary LCPUFA for infants regardless of whether they are born preterm or at term. However, developmental benefit is more consistently observed in infants born preterm. This may be explained by the fact that DHA accretion to neural tissues peaks during the fetal brain growth spurt in the last trimester of pregnancy. Infants born preterm are denied the full gestation period to accumulate DHA and are at risk of incomplete DHA accumulation. New research is focused on the timing and dose of DHA supplementation needed to optimize developmental outcomes.


Role of central interneurons in habituation of swimming activity in the medicinal leech.
Swimming activity evoked by light tactile stimulation of a body wall flap in dissected leech preparations undergoes habituation (5). In this study, we examine the activity of several interneurons (cell 204, cell 205, the S cell, and cell 208) during habituation trials to study further the neuronal mechanisms that mediate this decline in responsiveness. Light tactile stimulation of the leech body wall evoked initially a marked excitatory response in cell 204 homologs (segmental swim-initiating neurons) that preceded the initiation of swimming activity. This response decreased over the course of repeated stimulus trials; however, no marked decline in cell 204 activity accompanied the cessation of swim initiation. A similar activity pattern was observed in cell 205. Thus the habituation of swimming activity to stroking of the body wall is not due solely to reduced input to cell 204 and cell 205. The early activity of cell 204 was not correlated to the duration of subsequent swim episodes. However, the impulse frequency of cell 204 during swim episodes was negatively correlated to the period of swim cycles. This correlation between cell 204 activity and cycle period occurred both within individual episodes as well as between trials in a habituation series. Direct stimulation of cell 204 with current pulses evoked swimming activity reliably for an average of 72 trials. Therefore, habituation that results from stroking the body wall (which occurs after approximately 6 trials) is not mediated by plasticity in the connections between cell 204 and the swim oscillator. The S cell fired repeatedly in response to light tactile stimulation. This response declined with repeated trials. Intense intracellular stimulation of the S cell was sufficient to initiate swimming activity in some preparations. The magnitude and duration of the excitation required to initiate swimming by this means were far greater, however, than that which occurred during stroking the body wall. The response of cell 208 (a swim oscillator cell) to body wall stimulation during habituation trials was variable; usually an initial hyperpolarization was followed by some depolarization. No aspect of this response correlated with the onset of habituation. Our results are consistent with the idea that cell 204 and cell 205 are part of the pathway that mediates swimming activity in response to light tactile stimulation of the leech body wall, and that habituation occurs, in part, as the result of reduced sensory input to this cell.(ABSTRACT TRUNCATED AT 400 WORDS)


Adult chronic myelomonocytic leukemia with trisomy 11: a case report.
Chronic myelomonocytic leukemia (cmml) is an indolent disease in the category of myelodysplastic and myeloproliferative neoplasms, which can often evolve into acute leukemic neoplasms. Although cytogenetic abnormalities such as trisomy 8 or absence of chromosome Y are well known, few reports about cmml with trisomy 11 have been published. Here, we report a case of cmml with trisomy 11 as the sole chromosomal abnormality, resulting in a very poor outcome. Based on a bone marrow specimen, cmml-1 with trisomy 11 was diagnosed in a 79-year-old man presenting with anemia and atypical peripheral blood cells. Because of the patient's age, he was followed without receiving anticancer treatment. Two months after his diagnosis, the patient's leucocytosis and anemia rapidly worsened, with increasing numbers of immature peripheral cells, which was strongly suggestive of leukemic transformation. Because of acute kidney injury superimposed on chronic kidney disease that led to poor performance status, cytotoxic chemotherapy was not considered feasible, and the patient was transferred to a hospice care facility.


Spectroscopy of 3, 4, 9, 10-perylenetetracarboxylic dianhydride (PTCDA) attached to rare gas samples: clusters vs. bulk matrices. II. Fluorescence emission spectroscopy.
The interaction between 3, 4, 9, 10-perylenetetracarboxylic dianhydride (PTCDA) molecules and solid rare gas samples is studied by means of fluorescence emission spectroscopy. Laser-excited PTCDA-doped large argon, neon, and para-hydrogen clusters along with PTCDA embedded in helium nanodroplets are spectroscopically characterized with respect to line broadening and shifting. A fast non-radiative relaxation is observed before a radiative decay in the electronic ground state takes place. In comparison, fluorescence emission studies of PTCDA embedded in bulk neon and argon matrices result in much more complex spectral signatures characterized by a splitting of the different emission lines. These can be assigned to the appearance of site isomers of the surrounding matrix lattice structure.


Computerized management of diabetes: a synthesis of controlled trials.
Computerized management of diabetes is the use of information technology to improve diabetic patient outcomes. The computer can be used to provide educational information to patients and facilitate the storage and transmittal of clinical data between patients and clinicians. The objective of this paper was to evaluate computerized management of diabetes in changing the health outcomes. Clinical trial reports were identified through systematic electronic database and manual searches. Four eligibility criteria were applied: diabetes clinical area; prospective, contemporaneously controlled clinical trial with random assignment of the intervention; computer generated information for patients in the intervention group and no similar intervention in the control group; and measurement of effect on the outcome of care (health status, social functioning, patient/family satisfaction). Data were abstracted using a standardized abstraction form and the quality of methodology was scored. Of 15 eligible clinical trials, 12 (80%) reported positive outcomes or significant benefits. A total of 48 outcome measures were reported, an average of 3.2/study. Significantly improved clinical outcomes included Hemoglobin A1c (HbA1c), blood glucose, and hypoglycemic events. Patient-computer interaction appears to be a valuable supplement to interaction with clinicians. Considering the need to enhance patient participation in the care of chronic illnesses, initial evidence indicates computers can play a more significant role in the future.


Fermented rice bran prevents atopic dermatitis in DNCB-treated NC/Nga mice.
The fermentation of natural plants has a favorable effect on the functional and biological activities of living systems. These include anti-oxidative, anti-inflammatory, and anti-platelet aggregation activities. This is attributed to the chemical conversion of the parent plants to functional constituents, which show more potent biological activity. In our study, rice bran along with oriental medicinal plants (Angelicae gigantis, Cnidium officinale, Artemisia princeps, and Camellia sinensis) was fermented by Lactobacillus rhamnosus and Pichia deserticola (FRBE). We evaluated the effects of oral administration of FRBE on atopic dermatitis in 1-chloro-2,4-dinitrobenzene (DNCB)-treated NC/Nga mice. FRBE significantly ameliorated the macroscopic and microscopic appearance of skin lesions in DNCB-induced atopic dermatitis and reduced levels of serum immunoglobulin E and the differential white blood cell count. In addition, it reduced skin thickness compared to that of atopic dermatitis-affected skin. FRBE treatment also reduced mast cell incorporation in skin lesions of atopic dermatitis. The total cell number in dorsal skin tissue and the axillary lymph node increased following DNCB application, and this was normalized by FRBE treatment. Moreover, it decreased the levels of CD8(+) helper T cells and Gr-1(+)/CD11b(+) B cells in peripheral blood mononuclear cells and skin lesions in DNCB-induced atopic dermatitis. Using real-time polymerase chain reaction analysis, we demonstrated that FRBE significantly inhibited mRNA expression of cytokines (e.g., interleukin-5 and interleukin-13) and cyclooxygenase-2 in AD skin lesions. These results suggest that FRBE could be a valuable herbal remedy for the treatment of atopic dermatitis.


Scattering mueller matrix of an ensemble of variously shaped small particles.
A description is given of an analytical solution to the scattering Mueller matrix of an ensemble of small particles that may be of different shape, size, composition, and structure. It is derived within the framework of the generalized multiparticle Mie solution (GMM). Provided that all individual T matrices of a group of particles are known analytically or can be computed accurately, light scattering by an arbitrary configuration of these particles can be predicted precisely for both fixed and random orientations. In practical implementations, the applicability of the solution is limited by the size of individual particles only, and there is no restriction on the overall dimension of an ensemble. This multiparticle-scattering formulation of the GMM has been implemented in several public-domain computer codes. In practical calculations, the maximum total number of particles in an ensemble that can be handled depends on the largest size of the individual components and the availability of computer memory.


Regional variation in use of exogenous and endogenous glomerular filtration rate (GFR) markers in Sweden.
Markers of renal function (glomerular filtration rate (GFR)) are frequently used in the Swedish health care. GFR is usually estimated based on plasma creatinine concentration, but plasma cystatin C concentration, creatinine clearance, iohexol clearance, and (51)Cr-EDTA clearance are also used. These markers are all part of the daily patient care, but there is little specific information on the clinical use of these markers. The aim of this study was to compare the use of these various GFR markers in different parts of Sweden and potential changes over time. Retrospective study using questionnaires to collect information for the years 2006-2009 divided per county on the specific use of GFR markers with type of test reports. Plasma/serum creatinine concentration (96%) is by far the dominating GFR marker in Sweden, while cystatin C concentration (3.5%), creatinine clearance (0.1%), iohexol clearance (0.1%), and 51Cr-EDTA clearance (0.1%) are less frequently used. The use of GFR markers, including creatinine, continues to increase on a national level with the exception of creatinine clearance and 51Cr-EDTA clearance. There were considerable variations between different counties in the use of GFR markers and the type of test reports that the laboratories provided. The inter-county variations of GFR markers used in Sweden are large and indicate that savings associated with optimized test utilization in this regard could be substantial. Regional habits and traditions are likely to influence the variations in GFR marker use.


Structure of human pancreatic lipase-related protein 2 with the lid in an open conformation.
Access to the active site of pancreatic lipase (PL) is controlled by a surface loop, the lid, which normally undergoes conformational changes only upon addition of lipids or amphiphiles. Structures of PL with their lids in the open and functional conformation have required cocrystallization with amphiphiles. Here we report two crystal structures of wild-type and unglycosylated human pancreatic lipase-related protein 2 (HPLRP2) with the lid in an open conformation in the absence of amphiphiles. These structures solved independently are strikingly similar, with some residues of the lid being poorly defined in the electron-density map. The open conformation of the lid is however different from that previously observed in classical liganded PL, suggesting different kinetic properties for HPLRP2. Here we show that the HPLRP2 is directly inhibited by E600, does not present interfacial activation, and acts preferentially on substrates forming monomers or small aggregates (micelles) dispersed in solution like monoglycerides, phospholipids and galactolipids, whereas classical PL displays reverse properties and a high specificity for unsoluble substrates like triglycerides and diglycerides forming oil-in-water interfaces. These biochemical properties imply that the lid of HPLRP2 is likely to spontaneously adopt in solution the open conformation observed in the crystal structure. This open conformation generates a large cavity capable of accommodating the digalactose polar head of galactolipids, similar to that previously observed in the active site of the guinea pig PLRP2, but absent from the classical PL. Most of the structural and kinetic properties of HPLRP2 were found to be different from those of rat PLRP2, the structure of which was previously obtained with the lid in a closed conformation. Our findings illustrate the essential role of the lid in determining the substrate specificity and the mechanism of action of lipases.


MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins.
Using highly sensitive microarray-based procedures, we identified eight microRNAs (miRNAs) showing robust differential expression between 31 laser-capture-microdissected nasopharyngeal carcinomas (NPCs) and 10 normal healthy nasopharyngeal epithelial samples. In particular, miRNA mir-29c was expressed at one-fifth the levels in tumors as in normal epithelium. In NPC tumors, the lower mir-29c levels correlated with higher levels of multiple mRNAs whose 3' UTRs can bind mir-29c at target sequences conserved across many vertebrates. In cultured cells, introduction of mir-29c down-regulated these genes at the level of mRNA and inhibited expression of luciferase encoded by vectors having the 3' UTRs of these genes. Moreover, for each of several genes tested, mutating the mir-29c target sites in the 3' UTR abrogated mir-29c-induced inhibition of luciferase expression. Most of the mir-29c-targeted genes identified encode extracellular matrix proteins, including multiple collagens and laminin gamma1, that are associated with tumor cell invasiveness and metastatic potential, prominent characteristics of NPC. Thus, we identify eight miRNAs differentially expressed in NPC and demonstrate the involvement of one in regulating genes involved in metastasis.


Beyond formalized plans: User involvement in support in daily living - users' and support workers' experiences.
User involvement, based on respect and carried out through dialogue, has been shown to lead to increased self-respect, self-confidence and positive identity. In Sweden, the Social Service Act requires that interventions be designed and implemented together with the individual concerned. The basic criterion for social support is prolonged severe mental illness (usually at least 6 months), with no criteria for specific diagnosis or institutional history. The most common form of social support is 'support in daily living', a community care intervention for people aged 18 years or older who have their own homes and living arrangements. This article aims to deepen our understanding of user involvement at the individual level in the provision of an ongoing social work intervention. What elements of user involvement can be found in users' and support workers' descriptions of helpful support in daily living? Qualitative interviews were conducted with 18 users, who had experienced support in daily living as helpful, and 16 interviews with the users' support workers. Three major, interconnected themes emerged: Constant dialogue; Framing the flexibility, in relation to formalized intervention plans and regulations; The importance of 'small things', decisions concerning daily life. Both users and support workers described user involvement at the individual, micro-level to be an integral part of helpful support in daily living. It was possible to create a space for dialogue and co-creation in which users were involved in formulating and deciding the contents of their support at an informal level, to influence their own everyday lives. While a formal framework of rules, restrictions and plans surrounds meetings between users and professionals, a facilitating factor may be the absence of too detailed plans and regulations, leaving trust to users and professionals and their capacity to manage most of the choices they have to make.


Immobilization of gold nanoparticles on living cell membranes upon controlled lipid binding.
We present a versatile and controlled route to immobilize gold nanoparticles (NPs) on the surface of living cells, while preserving the sensing and optothermal capabilities of the original colloid. Our approach is based on the controlled and selective binding of Au NPs to phospholipids prior to cell incubation. We show that in the presence of the cells the lipid-bound Au NPs are delivered to the cellular membrane and that their diffusion is rather slow and spatially limited, as a result of lipid binding. Avoiding nonspecific membrane labeling, this approach is of general application to several types of colloids and cells and thereby provides a platform for controlled plasmonic and optothermal investigations of living cell membranes.


Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage-A Systematic Review.
Fibrinogen levels drop early in postpartum hemorrhage (PPH), and low fibrinogen levels predict outcomes. There is increasing interest in replacing fibrinogen early in severe PPH and this systematic review's aim was to assess if early fibrinogen replacement therapy improves outcomes in severe PPH. We searched the following databases from inception to June 2019: CDSR and CENTRAL (The Cochrane Library), MEDLINE, Embase, CINAHL, PubMed, Transfusion Evidence Library, LILACS, Web of Science Conference Proceedings Citation Index-Science, ClinicalTrials.gov and the WHO International Clinical Trials Registry Portal. We included randomized (RCT) and well-designed controlled observational studies where fibrinogen replacement therapy was given early (within 90 minutes of bleeding) compared with standard protocol in pregnant women > 24 weeks' gestation who developed PPH, defined as estimated blood loss ≥500 mL up to 24 hours post-delivery. Two independent reviewers extracted and reviewed the data on the primary outcome of allogeneic blood transfusion at 24 hours after intervention and secondary outcomes including all-cause mortality, rate of thrombosis, and the need for surgical and non-surgical interventions. We identified 5 eligible studies: 2 completed (total of 299 women) RCTs comparing fibrinogen concentrate with placebo, and 3 ongoing RCTs. There was no completed study assessing cryoprecipitate transfusion. There was variation of: timings of intervention administration; severity of PPH; fibrinogen doses and use of tranexamic acid. There was insufficient evidence that early administration of fibrinogen in PPH reduces the need for allogeneic blood transfusion at 24 hours (risk ratio 0.83 (95% CI 0.54-1.26), P = 0.38) (2 trials, 299 participants) or improves other outcomes. Both studies were underpowered to answer our outcomes. There is a lack of evidence that early fibrinogen replacement therapy improves outcomes in PPH. Future studies are needed to address this, underpinned by data on the optimal fibrinogen dose, protocol-driven approaches versus targeted therapy, and cost-effectiveness of cryoprecipitate versus fibrinogen concentrate therapy in PPH.


Image reconstruction in microwave tomography using a dielectric Debye model.
In this paper, quantitative dielectric image reconstruction based on broadband microwave measurements is investigated. A time-domain-based algorithm is derived where Debye model parameters are reconstructed in order to take into account the strong dispersive behavior found in biological tissue. The algorithm is tested with experimental and numerical data in order to verify the algorithm and to investigate improvements in the reconstructed image resulting from the improved description of the dielectric properties of the tissue when using broadband data. The comparison is made in relation to the more commonly used conductivity model. For the evaluation, two examples were considered, the first was a lossy saline solution and the second was less lossy tap water. Both liquids are strongly dispersive and used as a background medium in the imaging examples. The results show that the Debye model algorithm is of most importance in the tap water for a bandwidth of more than 1.5 GHz. Also the saline solution exhibits a dispersive behavior but since the losses restrict the useful bandwidth, the Debye model is of less significance even if somewhat larger and stronger artifacts can be seen in the conductivity model reconstructions.


The effect of gestational undernutrition on maternal weight change and fetal weight in lines of mice selected for different growth characteristics.
The present study investigated whether the genetic growth characteristics (fast or slow growing, lean or fat) of a mother influences her ability to partition nutrients to developing offspring. A total of sixty-one pregnant mice of three selected lines were used: fast-growing, relatively fat (FF, n 19); fast-growing, relatively lean (FL, n 23); and normal growth, relatively lean (NL, n 19). On day 1 of pregnancy, mice were given either ad libitum access to food (control (C): n 32) or pair-fed at 80 % of C intake (restricted (R): n 29). Feed intake and dam weight were measured daily. The weight of the mouse, organs, mammary tissue and the weight of fetuses and placentas were determined at day 18 of gestation. Overall, R dams gained less than half the weight of C dams during gestation. NL dams gained the most weight, and FF dams gained the least weight (P < 0·001). R dams in the fast-growing lines mobilised significantly more body fat during gestation than the NL line (P < 0·001) and had a greater reduction in mammary tissue growth. The relative weight of the litter increased in R dams of the FF line but was reduced in both the lean lines. Undernutrition reduced fetal and placental weight, and reduced placental efficiency in all the lines. The reduction was least in the FF line and greatest in the FL line. The data suggest that selection of animals for different growth characteristics alters their response to undernutrition during pregnancy, the relatively fat line was better able to buffer its offspring from the effects of undernutrition than the lean lines, regardless of their underlying rate of growth.


Ethical considerations on the complicity of psychologists and scientists in torture.
The long-standing debate on medical complicity in torture has overlooked the complicity of cognitive scientists-psychologists, psychiatrists and neuroscientists-in the practice of torture as a distinct phenomenon. In this paper, we identify the risk of the re-emergence of torture as a practice in the USA, and the complicity of cognitive scientists in these practices. We review arguments for physician complicity in torture. We argue that these defences fail to defend the complicity of cognitive scientists. We address objections to our account, and then provide recommendations for professional associations in resisting complicity in torture. Arguments for cognitive scientist complicity in torture fail when those actions stem from the same reasons as physician complicity. Cognitive scientist involvement in the torture programme has, from the outset, been focused on the outcomes of interrogation rather than supportive care. Any possibility of a therapeutic relationship between cognitive therapists and detainees is fatally undermined by therapists' complicity with torture. Professional associations ought to strengthen their commitment to refraining from engaging in any aspect of torture. They should also move to protect whistle-blowers against torture programmes who are members of their association. If the political institutions that are supposed to prevent the practice of torture are not strengthened, cognitive scientists should take collective action to compel intelligence agencies to refrain from torture.


Usefulness of liver test and controlled attenuation parameter in detection of nonalcoholic fatty liver disease in patients with chronic renal failure and coronary heart disease.
In recent years, nonalcoholic fatty liver disease (NAFLD) was recognized as an important factor in chronic kidney disease (CKD) pathogenesis. The concentrations of serum aminotransferases in both chronic dialysis and chronic renal failure (CRF) patients most commonly fall within the lower end of the range of normal values. The aim of the present study was to investigate the usefulness of four liver tests and four biological scores in detection of NAFLD in comparison with transient elastography (TE) findings in different groups of patients. The study was cross-sectional analysis collected data from a single tertiary care center. Of 202 patents there were 52 patients with CKD, 50 patients with end-stage renal disease (ESRD) treated with haemodialysis (HD), 50 renal transplant recipients (RTRs) and 50 patients with proven coronary heart disease (CHD). Fifty sex- and age-matched individuals without NAFLD and with normal liver and kidney function tests served as controls. With the help of TE (FibroScan®, Echosense SA, Paris, France), liver stiffness was selected as the parameter to quantify liver fibrosis and Controlled Attenuation Parameter (CAP) was used to detect and quantify liver steatosis. According to the CAP findings 76.9 %CKD patients, 82 %HD patients, 74 %RTRs and 69.1 % CHD patients had CAP > 238 dB.m(-1) and thus by definition NAFLD. We have found that ALT, AST and GGT levels were positively correlated with CAP values while ALT and AST showed positive correlation with liver stiffness acquired with TE only in CHD patients. According to TE findings APRI (AUC 0.796) and FIB-4 (AUC 0.790) scores were correlated with the presence of fibrosis, while HIS score was correlated with the presence of steatosis (AUC 0.867) only in CHD patients. Liver tests and biological scores are not useful for NAFLD detection in CRF patients. TE with CAP provides the opportunity of noninvasive screening for NAFLD as well as liver fibrosis in patients with CRF.


Evolution of eumalacostracan development-new insights into loss and reacquisition of larval stages revealed by heterochrony analysis.
Within Malacostraca (Crustacea), direct development and development through diverse forms of larvae are found. Recent investigations suggest that larva-related developmental features have undergone heterochronic evolution in Malacostraca. In the light of current phylogenetic hypotheses, the free-swimming nauplius larva was lost in the lineage leading to Malacostraca and evolved convergently in the malacostracan groups Dendrobranchiata and Euphausiacea. Here we reconstruct the evolutionary history of eumalacostracan (Malacostraca without Phyllocarida) development with regard to early appendage morphogenesis, muscle and central nervous system development, and determine the heterochronic transformations involved in changes of ontogenetic mode. Timing of 33 developmental events from the different tissues was analyzed for six eumalacostracan species (material for Euphausiacea was not available) and one outgroup, using a modified version of Parsimov-based genetic inference (PGi). Our results confirm previous suggestions that the event sequence of nauplius larva development is partly retained in embryogenesis of those species which do not develop such a larva. The ontogenetic mode involving a nauplius larva was likely replaced by direct development in the malacostracan stem lineage. Secondary evolution of the nauplius larva of Dendrobranchiata from this ancestral condition, involved only a very small number of heterochronies, despite the drastic change of life history. In the lineage leading to Peracarida, timing patterns of nauplius-related development were lost. Throughout eumalacostracan evolution, events related to epidermal and neural tissue development were clearly less affected by heterochrony than events related to muscle development. Weak integration between mesodermal and ectodermal development may have allowed timing in muscle formation to be altered independently of ectodermal development. We conclude that heterochrony in muscle development played a crucial role in evolutionary loss and secondary evolution of a nauplius larva in Malacostraca.


The MRSA-import in ICUs is an important predictor for the occurrence of nosocomial MRSA cases.
Nosocomial infections with methicillin-resistant Staphylococcus aureus (MRSA) account for increased morbidity, mortality and healthcare costs in critically ill patients worldwide. The intensive care unit (ICU) component of the German surveillance system for nosocomial infections (Krankenhaus-Infektions-Surveillance-System, KISS) has been supplemented with a module targeting the surveillance of multiresistant pathogens [Multiresistente Erreger (MRE)-KISS] in order to account for the increasing burden of antibiotic-resistant bacteria. The aim of this study was to assess the association between structural and organizational characteristics of ICUs and the number of nosocomial MRSA cases. Data were derived from routine data collected in the frame of the national surveillance system of nosocomial infections (ICU- and MRE-KISS) from January 2007 to December 2008 and from a questionnaire inquiring about structure and process parameters. One hundred and forty ICUs performing active screening have been included. Process parameters such as isolation of MRSA patients, decolonization procedures and introduction of MRSA alert systems have been implemented by the majority of the ICUs, whereas the application mode of screening procedures and pre-emptive isolation measures is heterogeneous. Multivariable analysis using negative binominal regression models shows that a stay on a medical ICU has a protective effect (incidence rate ratio, 0.42; 95% confidence interval, 0.24-0.74; p = 0.003), whereas the imported MRSA incidence is significantly associated with the number of nosocomial MRSA cases (incidence rate ratio, 1.74; 95% confidence interval, 1.23-2.45; p = 0.002). Structure and process parameters do not show any effect. ICU type and imported MRSA incidence should be considered for benchmarking between hospitals.


Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells.
Many tumor-associated antigens are derived from nonmutated "self" proteins. T cells infiltrating tumor deposits recognize self-antigens presented by tumor cells and can be expanded in vivo with vaccination. These T cells exist in a functionally tolerant state, as they rarely result in tumor eradication. We found that tumor growth and lethality were unchanged in mice even after adoptive transfer of large numbers of T cells specific for an MHC class I-restricted epitope of the self/tumor antigen gp100. We sought to develop new strategies that would reverse the functionally tolerant state of self/tumor antigen-reactive T cells and enable the destruction of large (with products of perpendicular diameters of >50 mm2), subcutaneous, unmanipulated, poorly immunogenic B16 tumors that were established for up to 14 d before the start of treatment. We have defined three elements that are all strictly necessary to induce tumor regression in this model: (a) adoptive transfer of tumor-specific T cells; (b) T cell stimulation through antigen-specific vaccination with an altered peptide ligand, rather than the native self-peptide; and (c) coadministration of a T cell growth and activation factor. Cells, vaccination, or cyto-kine given alone or any two in combination were insufficient to induce tumor destruction. Autoimmune vitiligo was observed in mice cured of their disease. These findings illustrate that adoptive transfer of T cells and IL-2 can augment the function of a cancer vaccine. Furthermore, these data represent the first demonstration of complete cures of large, established, poorly immunogenic, unmanipulated solid tumors using T cells specific for a true self/tumor antigen and form the basis for a new approach to the treatment of patients with cancer.


Subcellular fractionation studies of human gastric antrum: localization of the mucosal peptide hormones.
1. Analytical subcellular fractionation techniques have been applied to endoscopic human gastric antral biopsies to study the localization of gastrin, somatostatin, vasoactive intestinal peptide and the properties of the principal subcellular organelles. 2. The peptide hormones, detected by radioimmunoassay, showed particulate localizations with single peaks in the density gradients for somatostatin (modal density 1.23) and vasoactive intestinal peptide (modal density 1.17). Gastrin showed a more complex distribution with a distinct peak (modal density 1.18) and a substantial shoulder extending into the denser regions of the gradient. 3. The following organelles, characterized by their marker enzymes, were located in the density gradients: plasma membrane (5'-nucleotidase), mitochondria (malate dehydrogenase), peroxisomes (catalase), lysosomes (beta-N-acetyl-D-glucosaminidase), endoplasmic reticulum (neutral alpha-aminidase), cytosol (lactate dehydrogenase). 4. This technique can be applied to investigate disease of the gastric antrum at a subcellular level.


Structure of the FH2 domain of Daam1: implications for formin regulation of actin assembly.
Daam1 (dishevelled-associated activator of morphogenesis-1) is a diaphanous-related formin first studied as a novel dishevelled binding protein and shown to be crucial for the planar cell polarity (PCP) pathway in Xenopus. Daam1, like other formins, directs nucleation and elongation of new actin filaments using its conserved formin-homology-2 (FH2) domain. Here we report the crystal structure of a large C-terminal fragment of human Daam1 containing the FH2 domain. The structure, determined at 2.25 A resolution using the single-wavelength anomalous diffraction (SAD) phasing method, reveals a "tethered dimer" architecture that is similar to that previously described for the FH2 domain of the yeast formin Bni1, which shares approximately 21% sequence identity with Daam1. Despite the overall similarity with the dimeric FH2 domain of Bni1 and with a truncated monomeric structure of mDia1, the Daam1 FH2 structure reveals a number of differences in secondary structure elements and in the "lasso/post" dimerization interface that may be functionally important. Most strikingly, the two halves of the crystallographic dimer pack together in a manner that occludes their actin binding surfaces. This "locked" conformation is stabilized by two novel, interacting beta-strands formed by the ends of the linkers that connect the two sides of the dimer. The Daam1 FH2 domain has weak actin assembly activity as compared with other mammalian formins, but mutations that disrupt the beta-strand lock increase activity about tenfold to a level comparable to other formins, suggesting that this occluded conformation may represent an auto-inhibited conformation of the Daam1 FH2 domain.


Non-invasive assessment of coronary artery disease with CT coronary angiography and SPECT: a novel dose-saving fast-track algorithm.
To validate a new low-dose and rapid stepwise individualized algorithm for non-invasive assessment of ischemic coronary artery disease by sequential use of prospectively ECG-triggered low-dose CT coronary angiography (CTCA) and low-dose single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI). Forty patients referred for elective invasive coronary angiography (CA) were prospectively enrolled to undergo a comprehensive non-invasive evaluation with low-dose CTCA and a dose-reduced stress/rest SPECT-MPI scan (using dedicated reconstruction algorithms for low count scans). The following algorithm was reviewed: CTCA first, followed by a stress-only MPI if a coronary stenosis (> or = 50% diameter narrowing) or equivocal findings were observed. Only abnormal stress MPI scans were followed by rest MPI. The accuracy of the individualized algorithm to predict coronary revascularization and its mean effective radiation dose were assessed. CTCA documented CAD in 18 and equivocal findings in two patients, thus, requiring additional stress MPI scans. Of these, 16 were abnormal, therefore requiring a rest MPI scan, revealing ischemia in 15 patients. Sensitivity, specificity, negative and positive predictive value, and accuracy of the individualized algorithm for predicting coronary revascularization was 93.3%, 96.0%, 96.0%, 93.3% and 95.0% on a per-patient base. The mean effective radiation dose was significantly lower for the individualized (4.8 +/- 3.4 mSv) versus the comprehensive method (8.1 +/- 1.5 mSv) resulting in a total population radiation dose reduction of 132.6 mSv. This new individualized low-dose algorithm allows rapid and accurate prediction of invasive CA findings and of treatment decision with minimized radiation dose.


Relationship between Initial Telomere Length, Initial Telomerase Activity, Age, and Replicative Capacity of Nucleus Pulposus Chondrocytes in Human Intervertebral Discs: What Is a Predictor of Replicative Potential?
There is evidence that telomere length (TL), telomerase activity (TA), and age are related to the replicative potential of human nucleus pulposus chondrocytes (NPCs). However, it has not yet been established if any of these factors can serve as predictors of the replicative potential of NPCs. To establish predictors of the replicative potential of NPCs, we evaluated potential relationships between replicative capacity of NPCs, initial TL (telomere length at the first passage), initial TA (telomerase activity at the first passage), and age. Nucleus pulposus specimens were obtained from 14 patients of various ages undergoing discectomy. NPCs were serially cultivated until the end of their replicative lifespans. Relationships among cumulative population doubling level (PDL), initial TL, initial TA, and age were analyzed. Initial TA was negatively correlated with age (r = -0.674, P = 0.008). However, no correlation between initial TL and age was observed. Cumulative PDL was also negatively correlated with age (r = -0.585, P = 0.028). Although the cumulative PDL appeared to increase with initial TL or initial TA, this trend was not statistically significant. In conclusion, age is the sole predictor of the replicative potential of human NPCs, and replicative potential decreases with age. Initial TL and initial TA are not predictors of replicative potential, and can serve only as reference values.


CRISPR Editing of Mutant IDH1 R132H Induces a CpG Methylation-Low State in Patient-Derived Glioma Models of G-CIMP.
Mutations in isocitrate dehydrogenases 1 and 2 (IDH) occur in the majority of World Health Organization grade II and III gliomas. IDH1/2 active site mutations confer a neomorphic enzyme activity producing the oncometabolite D-2-hydroxyglutarate (D-2HG), which generates the glioma CpG island methylation phenotype (G-CIMP). While IDH1/2 mutations and G-CIMP are commonly retained during tumor recurrence, recent work has uncovered losses of the IDH1 mutation in a subset of secondary glioblastomas. Cooccurrence of the loss of the mutant allele with extensive methylation changes suggests a possible link between the two phenomena. Here, we utilize patient-derived IDH1R132H/WT glioma cell lines and CRISPR-Cas9-mediated gene knockout to model the genetic loss of IDH1 R132H, and characterize the effects of this deletion on DNA methylation. After D-2HG production has been abolished by deletions within the IDH1 alleles, these models show persistent DNA hypermethylation at seven CpG sites previously used to define G-CIMP-positivity in patient tumor samples. Despite these defining G-CIMP sites showing persistent hypermethylation, we observed a genome-wide pattern of DNA demethylation, enriched for CpG sites located within open sea regions of the genome, as well as in CpG-island shores of transcription start sites, after loss of D-2HG production. These results suggest that inhibition of D-2HG from genetic deletion of IDH alleles is not sufficient to reverse hypermethylation of all G-CIMP-defining CpG sites, but does result in more demethylation globally and may contribute to the formation of a G-CIMP-low-like phenotype. IMPLICATIONS: These findings show that loss of the IDH1 mutation in malignant glioma cells leads to a pattern of DNA methylation alterations, and shows plausibility of IDH1 mutation loss being causally related to the gain of a G-CIMP-low-like phenotype.


Ethylene oxide neurotoxicity: a cluster of 12 nurses with peripheral and central nervous system toxicity.
Ethylene oxide (EO) is commonly used to sterilize heat-sensitive products used by hospital patients and personnel. Ethylene chlorohydrin (EC), a by-product, is considered highly toxic. We report a cluster of 12 operating-room nurses and technicians who developed symptoms after a 5-month exposure to high levels of EO and EC in disposable surgical gowns. All patients reported a rash on the wrist where contact was made with the gowns, headaches, and hand numbness with weakness. Ten of 12 patients complained of memory loss. Neurologic evaluation revealed neuropathy on examination in nine of the 12 patients, elevated vibration threshold in four of nine, abnormal pressure threshold in 10 of 11, atrophy on head MRI in three of 10, and neuropathy on conduction studies in four of 10. Neuropsychological testing demonstrated mild cognitive impairment in four of six patients. Sural nerve biopsy in the most severely affected patient showed findings of axonal injury. Several patients in this group display signs of peripheral and CNS dysfunction following exposure to EO. Possible mechanisms of neurotoxicity include direct exposure of peripheral nerves through cutaneous absorption and central involvement through inhalation and vascular dissemination. The frequency of central and peripheral nervous system symptoms, supported by objective testing in these EO-exposed patients, suggests other healthcare personnel may be at similar risk.


Cervical stitch (cerclage) for preventing preterm birth in singleton pregnancy.
Cervical cerclage is a well-known surgical procedure carried out during pregnancy. It involves positioning of a suture (stitch) around the neck of the womb (cervix), aiming to give a mechanical support to the cervix and thereby reducing the risk of preterm birth. The effectiveness and safety of this procedure remains controversial. To assess whether the use of cervical stitch in singleton pregnancy at high risk of pregnancy loss based on a woman's history and/or ultrasound finding of 'short cervix' and/or physical exam improves subsequent obstetric care and fetal outcome. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2011) and reference lists of identified studies. We included all randomised trials of cervical suturing in singleton pregnancies carried out when pregnancy was considered to be at sufficiently high risk of pregnancy loss for cerclage to be potentially indicated. We included any study that compared cerclage with either no treatment or any alternative intervention. Three review authors independently assessed trials for inclusion. Two review authors independently assessed risk of bias and extracted data. Data were checked for accuracy. We included 12 trials (involving 3328 women). When cerclage was compared with no treatment, there was no statistically significant difference in perinatal deaths (8.4% versus 10.7%) (risk ratio (RR) 0.78; 95% confidence interval (CI) 0.61 to 1.00; eight trials, 2391 women) and neonatal morbidity (9.6% versus 10.2%) (RR 0.95; 95% CI 0.63 to 1.43; four trials, 818 women), despite significant reduction in preterm births (average RR 0.80; 95% CI 0.69 to 0.95; nine trials, 2898 women). Cervical cerclage was associated with the higher rate of maternal side effects (vaginal discharge and bleeding, pyrexia) (average RR 2.25; 95% CI 0.89 to 5.69; three trials, 953 women). Caesarean section rates were significantly higher after cervical cerclage (RR 1.19; 95% CI 1.01 to 1.40; 8 trials, 2817 women).There was no evidence of any important differences across all prespecified clinical subgroups (history-indicated, ultrasound-indicated)One study that compared cerclage with weekly intramuscular injections of 17 α-hydroxyprogesterone caproate in women with a short cervix detected by transvaginal ultrasound, failed to reveal any obvious differences in obstetric and neonatal outcomes between the two management strategies.Two studies compared the benefits of performing cerclage based on previous history with cerclage, only if the cervix was found to be short on transvaginal ultrasound. There was no significant difference in any of the primary and secondary outcomes. Compared with no treatment, cervical cerclage reduces the incidence of preterm birth in women at risk of recurrent preterm birth without statistically significant reduction in perinatal mortality or neonatal morbidity and uncertain long-term impact on the baby. Ceasarean section is more likely in women who had cervical suture inserted during pregnancy.The decision on how best to minimise the risk of recurrent preterm birth in women at risk, either because of poor history of a short or dilated cervix, should be 'personalised', based on the clinical circumstances, the skill and expertise of the clinical team and, most importantly, woman's informed choice.


Dynamic nuclear polarization studies of nitroxyl spin probes in agarose gel using Overhauser-enhanced magnetic resonance imaging.
Agarose is a tissue-equivalent material and its imaging characteristics similar to those of real tissues. Hence, the dynamic nuclear polarization studies of 3-carboxy-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl (carboxy-PROXYL) in agarose gel were carried out. The dynamic nuclear polarization parameters such as spin lattice relaxation time, longitudinal relaxivity, leakage factor, saturation parameter and coupling parameter were estimated for 2 mM carboxy-PROXYL in phosphate-buffered saline solution and water/agarose mixture (99 : 1). From these results, the spin probe concentration was optimized as 2 mM, and the reduction in enhancement was observed for carboxy-PROXYL in water/agarose mixture (99 : 1) compared with phosphate-buffered saline solution. Phantom imaging was also performed with 2 mM concentration of carboxy-PROXYL in various concentrations of agarose gel at various radio frequency power levels. The results from the dynamic nuclear polarization measurements agree well with the phantom imaging results. These results pave the way for designing model system for human tissues suited to the biological applications of electron spin resonance/Overhauser-enhanced magnetic resonance imaging.


Individuals With Knee Osteoarthritis Demonstrate Interlimb Asymmetry in Pedaling Power During Stationary Cycling.
Cycling is commonly prescribed for physical rehabilitation of individuals with knee osteoarthritis (OA). Despite the known therapeutic benefits, no research has examined interlimb symmetry of power output during cycling in these individuals. We investigated the effects of external workload and cadence on interlimb symmetry of crank power output in individuals with knee OA versus healthy controls. A total of 12 older participants with knee OA and 12 healthy sex- and age-matched controls were recruited. Participants performed 2-minute bouts of stationary cycling at 4 workload-cadence conditions (75 W at 60 rpm, 75 W at 90 rpm, 100 W at 60 rpm, and 100 W at 90 rpm). Power output contribution of each limb toward total crank power output was computed over 60 crank cycles from the effective component of pedal force, which was perpendicular to the crank arm. Across the workload-cadence conditions, the knee OA group generated significantly higher power output with the severely affected leg compared with the less affected leg (10% difference; P = .02). Healthy controls did not show interlimb asymmetry in power output (0.1% difference; P > .99). For both groups, interlimb asymmetry was unaffected by external workload and cadence. Our results indicate that individuals with knee OA demonstrate interlimb asymmetry in crank power output during stationary cycling.


Quantitative genomics of locomotor behavior in Drosophila melanogaster.
Locomotion is an integral component of most animal behaviors, and many human health problems are associated with locomotor deficits. Locomotor behavior is a complex trait, with population variation attributable to many interacting loci with small effects that are sensitive to environmental conditions. However, the genetic basis of this complex behavior is largely uncharacterized. We quantified locomotor behavior of Drosophila melanogaster in a large population of inbred lines derived from a single natural population, and derived replicated selection lines with different levels of locomotion. Estimates of broad-sense and narrow-sense heritabilities were 0.52 and 0.16, respectively, indicating substantial non-additive genetic variance for locomotor behavior. We used whole genome expression analysis to identify 1,790 probe sets with different expression levels between the selection lines when pooled across replicates, at a false discovery rate of 0.001. The transcriptional responses to selection for locomotor, aggressive and mating behavior from the same base population were highly overlapping, but the magnitude of the expression differences between selection lines for increased and decreased levels of behavior was uncorrelated. We assessed the locomotor behavior of ten mutations in candidate genes with altered transcript abundance between selection lines, and identified seven novel genes affecting this trait. Expression profiling of genetically divergent lines is an effective strategy for identifying genes affecting complex behaviors, and reveals that a large number of pleiotropic genes exhibit correlated transcriptional responses to multiple behaviors.


Sonoelastography for 1,786 non-palpable breast masses: diagnostic value in the decision to biopsy.
To evaluate the diagnostic value of sonoelastography by correlation with histopathology compared with conventional ultrasound on the decision to biopsy. Prospectively determined BI-RADS categories of conventional ultrasound and elasticity scores from strain sonoelastography of 1786 non-palpable breast masses (1,523 benign and 263 malignant) in 1,538 women were correlated with histopathology. The sensitivity and specificity of two imaging techniques were compared regarding the decision to biopsy. We also investigated whether there was a subset of benign masses that were recommended for biopsy by B-mode ultrasound but that had a less than 2% malignancy rate with the addition of sonoelastography. The mean elasticity score of malignant lesions was higher than that of benign lesions (2.94 ± 1.10 vs. 1.78 ± 0.81) (P < 0.001). In the decision to biopsy, B-mode ultrasound had higher sensitivity than sonoelastography (98.5% vs. 93.2%) (P < 0.001), whereas sonoelastography had higher specificity than B-mode ultrasound (42.6% vs. 16.3%) (P < 0.001). BI-RADS category 4a lesions with an elasticity score of 1 had a malignancy rate of 0.8%. Sonoelastography has higher specificity than B-mode ultrasound in the differentiation between benign and malignant masses and has the potential to reduce biopsies with benign results. • Sonoelastography has higher specificity than B-mode ultrasound in distinguishing benign from malignant masses. • Sonoelastography could potentially help reduce the number of biopsies with benign results. • Lesion stiffness on sonoelastography correlated with the malignant potential of the lesion.


Novel SPAST deletion and reduced DPY30 expression in a Spastic Paraplegia type 4 kindred.
The hereditary spastic paraplegias (HSPs) are pleiomorphic disorders of motor pathway and a large number of affected genes have been discovered. Yet, mutations in SPG4/SPAST represent the most frequent molecular etiology in autosomal dominant (AD) patients and sporadic cases. We describe a large, AD-HSP Sardinian family where 5 out of several living members harbored a novel deletion affecting also the 5'UTR of SPAST and resulting in reduced expression of DPY30, the gene located upstream SPAST in a head-to-head manner. A 54-year-old woman manifested leg stiffness at age 39 and required a cane to walk at age 50. Neurological examination disclosed mild spasticity and weakness in the legs, hyperreflexia in all limbs, and bilateral Babinski sign. She also complained of urinary urgency, but no additional neurological symptoms or signs were detected at examination. The clinical examination of 24 additional relatives disclosed three further affected individuals, two men and one woman. In the four symptomatic patients the initial manifestations were walking abnormalities and leg stiffness with a mean age at onset (SD) of 46.75 (5.44) years (range 39-51). The mean disease duration was 13.2 (13.4) years (range 6-35), and it correlated well with clinical severity (SPRS score) (r = 0.975, p = 0.005). One patient was confined to bed and displayed knee and ankle contractures, another case needed a cane to walk, and two individuals were able to walk without aids. Interestingly, a patient had also had a miscarriage during her first pregnancy.Gene testing revealed an heterozygous deletion spanning from the 5'-UTR to intron 4 of SPAST in the affected individuals and in one clinically unaffected woman. In three affected patients, the deletion also determined low mRNA levels of SPAST and DPY30, a component of the Set1-like multiprotein histone methyltransferase complex located upstream, head-to-head with SPAST. Together with data described in a Japanese family, our findings seem to suggest that genes close to spastin might be candidates in modulating the clinical phenotype. This report endorses future research on the role of neighboring genes as potential players in SPG4 disease variability.


Classification of team sport activities using a single wearable tracking device.
Wearable tracking devices incorporating accelerometers and gyroscopes are increasingly being used for activity analysis in sports. However, minimal research exists relating to their ability to classify common activities. The purpose of this study was to determine whether data obtained from a single wearable tracking device can be used to classify team sport-related activities. Seventy-six non-elite sporting participants were tested during a simulated team sport circuit (involving stationary, walking, jogging, running, changing direction, counter-movement jumping, jumping for distance and tackling activities) in a laboratory setting. A MinimaxX S4 wearable tracking device was worn below the neck, in-line and dorsal to the first to fifth thoracic vertebrae of the spine, with tri-axial accelerometer and gyroscope data collected at 100Hz. Multiple time domain, frequency domain and custom features were extracted from each sensor using 0.5, 1.0, and 1.5s movement capture durations. Features were further screened using a combination of ANOVA and Lasso methods. Relevant features were used to classify the eight activities performed using the Random Forest (RF), Support Vector Machine (SVM) and Logistic Model Tree (LMT) algorithms. The LMT (79-92% classification accuracy) outperformed RF (32-43%) and SVM algorithms (27-40%), obtaining strongest performance using the full model (accelerometer and gyroscope inputs). Processing time can be reduced through feature selection methods (range 1.5-30.2%), however a trade-off exists between classification accuracy and processing time. Movement capture duration also had little impact on classification accuracy or processing time. In sporting scenarios where wearable tracking devices are employed, it is both possible and feasible to accurately classify team sport-related activities.


Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model.
Understanding the host pathways that define susceptibility to Severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) infection and disease are essential for the design of new therapies. Oxygen levels in the microenvironment define the transcriptional landscape, however the influence of hypoxia on virus replication and disease in animal models is not well understood. In this study, we identify a role for the hypoxic inducible factor (HIF) signalling axis to inhibit SARS-CoV-2 infection, epithelial damage and respiratory symptoms in the Syrian hamster model. Pharmacological activation of HIF with the prolyl-hydroxylase inhibitor FG-4592 significantly reduced infectious virus in the upper and lower respiratory tract. Nasal and lung epithelia showed a reduction in SARS-CoV-2 RNA and nucleocapsid expression in treated animals. Transcriptomic and pathological analysis showed reduced epithelial damage and increased expression of ciliated cells. Our study provides new insights on the intrinsic antiviral properties of the HIF signalling pathway in SARS-CoV-2 replication that may be applicable to other respiratory pathogens and identifies new therapeutic opportunities.


Polyp measurement with CT colonography: multiple-reader, multiple-workstation comparison.
The risk of invasive colorectal cancer in colorectal polyps correlates with lesion size. Our purpose was to define the most accurate methods for measuring polyp size at CT colonography (CTC) using three models of workstations and multiple observers. Six reviewers measured 24 unique polyps of known size (5, 7, 10, and 12 mm), shape (sessile, flat, and pedunculated), and location (straight or curved bowel segment) using CTC data sets obtained at two doses (5 mAs and 65 mAs) and a previously described colonic phantom model. Reviewers measured the largest diameter of polyps on three proprietary workstations. Each polyp was measured with lung and soft-tissue windows on axial, 2D multiplanar reconstruction (MPR), and 3D images. There were significant differences among measurements obtained at various settings within each workstation (p < 0.0001). Measurements on 2D images were more accurate with lung window than with soft-tissue window settings (p < 0.0001). For the 65-mAs data set, the most accurate measurements were obtained in analysis of axial images with lung window, 2D MPR images with lung window, and 3D tissue cube images for Wizard, Advantage, and Vitrea workstations, respectively, without significant differences in accuracy among techniques (0.11 < p < 0.59). The mean absolute error values for these optimal settings were 0.48 mm, 0.61 mm, and 0.76 mm, respectively, for the three workstations. Within the ultralow-dose 5-mAs data set the best methods for Wizard, Advantage, and Vitrea were axial with lung window, 2D MPR with lung window, and 2D MPR with lung window, respectively. Use of nearly all measurement methods, except for the Vitrea 3D tissue cube and the Wizard 2D MPR with lung window, resulted in undermeasurement of the true size of the polyps. Use of CTC computer workstations facilitates accurate polyp measurement. For routine CTC examinations, polyps should be measured with lung window settings on 2D axial or MPR images (Wizard and Advantage) or 3D images (Vitrea). When these optimal methods are used, these three commercial workstations do not differ significantly in acquisition of accurate polyp measurements at routine dose settings.


Mortality at ages 50-59 and deprivation at early and late stages of the life course in Wales.
Most previous studies have examined the association between mortality and deprivation at only one point in time. However, risk accumulates over the life course. The design of the study was ecological. Its aims were to explain inequalities in total and cause-specific mortality between geographical areas in relation to the lifestyle and health behaviours of the resident populations and the area levels of deprivation in 1981 and in 1921-40. Data on health behaviour from the 1985 Heartbeat Wales Community Survey were evaluated in light of Welsh mortality rates for the period 1981-99, 1981 census data on socioeconomic position and the infant mortality rates in 1921-40. Negative binomial models were carried out to investigate the district-level association of mortality with deprivation (infant mortality in 1921-40, Carstairs score in 1981, combined index of deprivation) independently from the personal habits and characteristics of the resident population. There was an increased risk of death in deprived areas compared with more wealthy ones. Both infant mortality (a proxy of material deprivation during the time in which the 50-59-year-old individuals were born or were children) and Carstairs scores (a proxy of deprivation during adulthood) were strongly associated with recent mortality. Deprivation had stronger effects in women than in men, the only exception being the effects of later life deprivation on lung cancer. Area characteristics at different points of time may help to explain geographical inequality in mortality.


Sublethal Endpoints in Non-target Organism Testing for Insect-Active GE Crops.
Historically, genetically engineered (GE) plants that have incorporated genes conferring insect protection have primarily used Cry proteins derived from Bacillus thuringiensis (Bt) to achieve their insecticidal phenotype. As a result, regulators have developed a level of familiarity and confidence in reviewing plants incorporating these insecticidal proteins. However, new technologies have been developed that produce GE plants that incorporate pest protection by triggering an RNA interference (RNAi) response or proteins other than Bt Cry proteins. These technologies have new modes of action. Although the overall assessment paradigm for GE plants is robust, there are ongoing discussions about the appropriate tests and measurement endpoints needed to inform non-target arthropod assessment for technologies that have a different mode of action than the Bt Cry proteins. As a result, increasing attention is being paid to the use of sublethal endpoints and their value for environmental risk assessment (ERA). This review focuses on the current status and history of sublethal endpoint use in insect-active GE crops, and evaluates the future use of sublethal endpoints for new and emerging technologies. It builds upon presentations made at the Workshop on Sublethal Endpoints for Non-target Organism Testing for Non-Bt GE Crops (Washington DC, USA, 4-5 March 2019), and the discussions of government, academic and industry scientists convened for the purpose of reviewing the progress and status of sublethal endpoint testing in non-target organisms.


Cyclin D1 and estrogen receptor messenger RNA levels are positively correlated in primary breast cancer.
The CCND1 gene, encoding the cell cycle regulatory protein cyclin D1, maps to chromosome 11q13, a locus that is amplified in about 13% of breast cancers. Because several studies have indicated a relationship between 11q13 amplification and markers of phenotype including estrogen receptor (ER) status, we tested the relationship between CCND1 and ER gene expression in 364 primary breast cancers using Northern blot analysis. Seventy-three % of samples were positive for ER mRNA, and cyclin D1 mRNA levels in the ER-positive group were significantly higher than those in the ER-negative group (P = 0.0001). When the samples were divided into quartiles of cyclin D1 expression, 58% of samples were ER positive in the lowest quartile and 87% in the highest quartile. The tumors expressing the highest levels of cyclin D1 (7%) were all ER positive. Furthermore, ER mRNA levels in the half with lower cyclin D1 mRNA were significantly less than in the half with higher cyclin D1 levels (P = 0.0001). Using simple regression analysis, there was a significant positive correlation between cyclin D1 and ER mRNA levels in the total population (P = 0.0001). This study demonstrates that cyclin D1 mRNA and ER mRNA are positively correlated in primary breast cancer, but the functional relationship between these genes remains to be elucidated.


A New TRADDition in intracellular antiviral signaling.
To effectively defeat viral infection, a mammalian host must detect the presence of viruses and activate a robust antiviral response, which is mediated by cytokines known as type I interferons (IFNs). Much excitement has been generated by the discovery of the retinoic acid-induced gene 1-like helicase (RLH) pathway, which detects RNA-containing viruses in the cytoplasm and activates the type I IFN response. A study now describes a role for the tumor necrosis factor receptor (TNFR)-associated death domain (TRADD) in the antiviral response and sheds new light on how the RLH signaling complex is organized upon viral infection.


Plant Stress Granules: Trends and Beyond.
Stress granules (SGs) are dynamic membrane-less condensates transiently assembled through liquid-liquid phase separation (LLPS) in response to stress. SGs display a biphasic architecture constituted of core and shell phases. The core is a conserved SG fraction fundamental for its assembly and consists primarily of proteins with intrinsically disordered regions and RNA-binding domains, along with translational-related proteins. The shell fraction contains specific SG components that differ among species, cell type, and developmental stage and might include metabolic enzymes, receptors, transcription factors, untranslated mRNAs, and small molecules. SGs assembly positively correlates with stalled translation associated with stress responses playing a pivotal role during the adaptive cellular response, post-stress recovery, signaling, and metabolic rewire. After stress, SG disassembly releases mRNA and proteins to the cytoplasm to reactivate translation and reassume cell growth and development. However, under severe stress conditions or aberrant cellular behavior, SG dynamics are severely disturbed, affecting cellular homeostasis and leading to cell death in the most critical cases. The majority of research on SGs has focused on yeast and mammals as model organism. Nevertheless, the study of plant SGs has attracted attention in the last few years. Genetics studies and adapted techniques from other non-plant models, such as affinity capture coupled with multi-omics analyses, have enriched our understanding of SG composition in plants. Despite these efforts, the investigation of plant SGs is still an emerging field in plant biology research. In this review, we compile and discuss the accumulated progress of plant SGs regarding their composition, organization, dynamics, regulation, and their relation to other cytoplasmic foci. Lastly, we will explore the possible connections among the most exciting findings of SGs from mammalian, yeast, and plants, which might help provide a complete view of the biology of plant SGs in the future.


Antibody therapy for rheumatoid arthritis.
High-quality monoclonal antibodies (mAbs) with specificity for relevant disease molecules can now be produced in abundance. Anti-tumour necrosis factor-alpha therapies have set a new standard for symptom control in rheumatoid arthritis, and blockade of tumour necrosis factor has the potential to protect joints from structural damage. Other targets for therapeutic antibodies include the cytokines interleukin (IL)-1, IL-6, IL-8, IL-15, IL-17 and IL-18. In addition, there is preliminary evidence for the clinical efficacy of both keliximab, a mAb targeting the T cell antigen CD4, and rituximab, a chimeric mAb against the B cell antigen CD20 and CTLA4-Ig, which blocks the CD28/B7 interaction. Phase III studies have yet to be undertaken for these novel biological agents, and it is unclear whether any of these agents will have true disease-modifying capabilities.


Enkephalins and immune inflammatory reactions.
Methionine-enkephalin (Met-Enk) and leucine-enkephalin (Leu-Enk) belong to family of opioid peptides. In vivo studies on immunomodulating activity of enkephalins performed in the rat revealed the following: (a) both neuropentapeptides showed a dual, dose-dependent effect, i.e., high doses suppressed while low doses potentiated immune responses; (b) Met-Enk is more potent immunomodulator than Leu-Enk; (c) high doses of Met-Enk suppressed immune inflammatory reactions, such as systemic anaphylactic shock, Arthus and delayed hypersensitivity skin reactions to protein antigen, allograft rejection, adjuvant arthritis, and experimental allergic encephalomyelitis. Met-Enk is more efficient when applied intracerebroventricularly. A preliminary clinical trial showed that intrathecally given Met-Enk exerted a beneficial effect on 13 patients with chronic severe progressive multiple sclerosis.


Improving data collection, documentation, and workflow in a dementia screening study.
A clinical study team performing three multicultural dementia screening studies identified the need to improve data management practices and facilitate data sharing. A collaboration was initiated with librarians as part of the National Library of Medicine (NLM) informationist supplement program. The librarians identified areas for improvement in the studies' data collection, entry, and processing workflows. The librarians' role in this project was to meet needs expressed by the study team around improving data collection and processing workflows to increase study efficiency and ensure data quality. The librarians addressed the data collection, entry, and processing weaknesses through standardizing and renaming variables, creating an electronic data capture system using REDCap, and developing well-documented, reproducible data processing workflows. NLM informationist supplements provide librarians with valuable experience in collaborating with study teams to address their data needs. For this project, the librarians gained skills in project management, REDCap, and understanding of the challenges and specifics of a clinical research study. However, the time and effort required to provide targeted and intensive support for one study team was not scalable to the library's broader user community.


High-repetition-rate chirped-pulse-amplification thin-disk laser system with joule-level pulse energy.
We are reporting on the development of a diode-pumped chirped-pulse-amplification (CPA) laser system based on Yb:YAG thin-disk technology with a repetition rate of 100 Hz and output pulse energy in the joule range. The focus lies with the first results of the preamplifier--a regenerative amplifier (RA) and a multipass amplifier (MP). The system consists of a front end including the CPA stretcher followed by an amplifier chain based on Yb:YAG thin-disk amplifiers and the CPA compressor. It is developed in the frame of our x-ray laser (XRL) program and fulfills all requirements for pumping a plasma-based XRL in grazing incidence pumping geometry. Of course it can also be used for other interesting applications. With the RA pulse energies of more than 165 mJ can be realized. At a repetition rate of 100 Hz a stability of 0.8% (1sigma) over a period of more than 45 min has been measured. The optical-to-optical efficiency is 14%. The following MP amplifier can increase the pulse energy to more than 300 mJ. A nearly bandwidth-limited recompression to less than 2 ps could be demonstrated.


Aberrant expression of CPSF1 promotes head and neck squamous cell carcinoma via regulating alternative splicing.
Alternative mRNA splicing increases protein diversity, and alternative splicing events (ASEs) drive oncogenesis in multiple tumor types. However, the driving alterations that underlie the broad dysregulation of ASEs are incompletely defined. Using head and neck squamous cell carcinoma (HNSCC) as a model, we hypothesized that the genomic alteration of genes associated with the spliceosome may broadly induce ASEs across a broad range of target genes, driving an oncogenic phenotype. We identified 319 spliceosome genes and employed a discovery pipeline to identify 13 candidate spliceosome genes altered in HNSCC using The Cancer Genome Atlas (TCGA) HNSCC data. Phenotypic screens identified amplified and overexpressed CPSF1 as a target gene alteration that was validated in proliferation, colony formation, and apoptosis assays in cell line and xenograft systems as well as in primary HNSCC. We employed knockdown and overexpression assays followed by identification of ASEs regulated by CPSF1 overexpression to identify changes in ASEs, and the expression of these ASEs was validated using RNA from cell line models. Alterations in expression of spliceosome genes, including CPSF1, may contribute to HNSCC by mediating aberrant ASE expression.


Activation of integrins in endothelial cells by fluid shear stress mediates Rho-dependent cytoskeletal alignment.
Fluid shear stress is a critical determinant of vascular remodeling and atherogenesis. Both integrins and the small GTPase Rho are implicated in endothelial cell responses to shear but the mechanisms are poorly understood. We now show that shear stress rapidly stimulates conformational activation of integrin alpha(v)beta3 in bovine aortic endothelial cells, followed by an increase in its binding to extracellular cell matrix (ECM) proteins. The shear-induced new integrin binding to ECM induces a transient inactivation of Rho similar to that seen when suspended cells are plated on ECM proteins. This transient inhibition is necessary for cytoskeletal alignment in the direction of flow. The results therefore define the role of integrins and Rho in a pathway leading to endothelial cell adaptation to flow.


Two Fe-S clusters catalyze sulfur insertion by radical-SAM methylthiotransferases.
How living organisms create carbon-sulfur bonds during the biosynthesis of critical sulfur-containing compounds is still poorly understood. The methylthiotransferases MiaB and RimO catalyze sulfur insertion into tRNAs and ribosomal protein S12, respectively. Both belong to a subgroup of radical-S-adenosylmethionine (radical-SAM) enzymes that bear two [4Fe-4S] clusters. One cluster binds S-adenosylmethionine and generates an Ado• radical via a well-established mechanism. However, the precise role of the second cluster is unclear. For some sulfur-inserting radical-SAM enzymes, this cluster has been proposed to act as a sacrificial source of sulfur for the reaction. In this paper, we report parallel enzymological, spectroscopic and crystallographic investigations of RimO and MiaB, which provide what is to our knowledge the first evidence that these enzymes are true catalysts and support a new sulfation mechanism involving activation of an exogenous sulfur cosubstrate at an exchangeable coordination site on the second cluster, which remains intact during the reaction.


Functional consequences of pre- and postsynaptic expression of synaptic plasticity.
Growing experimental evidence shows that both homeostatic and Hebbian synaptic plasticity can be expressed presynaptically as well as postsynaptically. In this review, we start by discussing this evidence and methods used to determine expression loci. Next, we discuss the functional consequences of this diversity in pre- and postsynaptic expression of both homeostatic and Hebbian synaptic plasticity. In particular, we explore the functional consequences of a biologically tuned model of pre- and postsynaptically expressed spike-timing-dependent plasticity complemented with postsynaptic homeostatic control. The pre- and postsynaptic expression in this model predicts (i) more reliable receptive fields and sensory perception, (ii) rapid recovery of forgotten information (memory savings), and (iii) reduced response latencies, compared with a model with postsynaptic expression only. Finally, we discuss open questions that will require a considerable research effort to better elucidate how the specific locus of expression of homeostatic and Hebbian plasticity alters synaptic and network computations.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'.


Errors of Classification With Potassium Blood Testing: The Variability and Repeatability of Critical Clinical Tests.
To understand the performance of a currently used clinical blood test with regard to the frequency and size of variation of the results. From November 29, 2012, through November 29, 2013, patients were recruited at 65 sites as part of a previously reported clinical trial (ClinicalTrials.gov Identifier: NCT01737697). Eligible outpatients who had been fasting for at least 8 hours underwent venous phlebotomy at baseline, 30 minutes, and 60 minutes to measure plasma potassium levels in whole blood using a point-of-care device (i-STAT, Abbott Laboratories). We analyzed the results to assess their variability and frequency of pseudohyperkalemia and pseudonormokalemia. A total of 1170 patients were included in this study. Absolute differences between pairs of measurements from different time points ranged from 0 to 2.5 mmol/L, with a mean difference of 0.26 mmol/L. The mean percentage differences were approximately 5% with an SD of 5%. Approximately 12% of differences between repeated fasting potassium blood test results were above 0.5 mmol/L (33% of the normal range), and 20% of patients (234) had at least one difference greater than 0.5 mmol/L. In 44.0% of the patients with a hyperkalemic average value (true hyperkalemia) (302 of 686), at least one blood test result was in the normal range (pseudonormokalemia), and in 30.2% of the patients with a normal average value (146 of 484), at least one blood test result was elevated (pseudohyperkalemia). Expected variability and errors exist with potassium blood tests, even when conditions are optimized. Pseudohyperkalemia and pseudonormokalemia are common, indicating a need for thoughtful clinical interpretation of unexpected test results.


Tantalum(v) 1,3-propanediolate β-diketonate solution as a precursor to sol-gel derived, metal oxide thin films.
Tantalum oxide is ubiquitous in everyday life, from capacitors in electronics to ion conductors for electrochromic windows and electrochemical storage devices. Investigations into sol-gel deposition of tantalum oxide, and its sister niobium oxide, has accelerated since the 1980s and continues to this day. The aim of this study is to synthesize a near UV sensitive, air stable, and low toxicity tantalum sol-gel precursor solution for metal oxide thin films - these attributes promise to reduce manufacturing costs and allow for facile mass production. By utilizing 1D and 2D nuclear magnetic resonance, this study shows that by removing ethanol from the precursor solution at a relatively low temperature and pressure, decomposition of the photosensitive complex can be minimized while obtaining a precursor solution with sufficient stability for storage and processing in the atmosphere. The solution described herein is further modified for inkjet printing, where multiple material characterization techniques demonstrate that the solution can be utilized in low temperature, photochemical solution deposition of tantalum oxide, which is likely amorphous. Tested substrates include amorphous silica, crystalline silicon wafer, and gold/titanium/PET foil. The hope is that these results may spark future investigations into electronic, optical, and biomedical device fabrication with tantalum oxide, and potentially niobium oxide, based films using the proposed synthesis method.


Behavioral and neuroimaging evidence for a contribution of color and texture information to scene classification in a patient with visual form agnosia.
A common notion is that object perception is a necessary precursor to scene perception. Behavioral evidence suggests, however, that scene perception can operate independently of object perception. Further, neuroimaging has revealed a specialized human cortical area for viewing scenes that is anatomically distinct from areas activated by viewing objects. Here we show that an individual with visual form agnosia, D.F., who has a profound deficit in object recognition but spared color and visual texture perception, could still classify scenes and that she was fastest when the scenes were presented in the appropriate color. When scenes were presented as black-and-white images, she made a large number of errors in classification. Functional magnetic resonance imaging revealed selective activation in the parahippocampal place area (PPA) when D.F. viewed scenes. Unlike control observers, D.F. demonstrated higher activation in the PPA for scenes presented in the appropriate color than for black-and-white versions. The results demonstrate that an individual with profound form vision deficits can still use visual texture and color to classify scenes-and that this intact ability is reflected in differential activation of the PPA with colored versions of scenes.


Left ventricular failure induced by long-term hypertension in rats.
To determine whether the duration of hypertension is an essential component in the evolution of myocardial dysfunction, renal artery constriction was performed in male Fischer 344 rats at 4 months of age, and in vivo global cardiac performance of sham-operated and experimental animals was evaluated 8 months later. Systemic arterial blood pressure increased to 173 +/- 5 mm Hg 2 weeks after the arteries were clipped and remained elevated for the following 5 months. Blood pressure decreased over the remaining 3 months to a value not significantly different from control rats that were killed, 132 +/- 4 mm Hg. After 8 months of renovascular hypertension, we observed that the elevated level of systolic arterial pressure was accompanied by a distinct absence of left ventricular hypertrophy when measured at the ventricular weight level. Moreover, left ventricular end-diastolic pressure increased in hypertensive animals from 6.0 to 24.0 mm Hg while peak left ventricular pressure was identical to controls. In addition, peak +dP/dt and -dP/dt were depressed in hypertensive animals. Although stroke volume was unaltered, cardiac output in renal artery clipped animals was depressed by 34% while total peripheral resistance was elevated by 50%. Ventricular chamber remodeling in the hearts of hypertensive animals was evidenced as a 19% increase in the transverse and a 16% increase in the longitudinal axes of the left ventricle with a 27% diminution of wall thickness. Myocardial damage, in the form of myocyte loss and replacement fibrosis, increased in the hearts of hypertensive animals resulting in a ninefold augmentation in the volume fraction of collagen within the ventricular wall. These alterations in the architectural properties of chamber geometry coupled with the abnormalities in contractile performance resulted in a severe reduction in ejection fraction from 82% to 47% and a marked elevation in transmural diastolic and systolic stress in hypertensive animals. The gradient in stress across the ventricular wall, from epicardium to endocardium, revealed a direct correlation with the regional distribution of myocardial damage. In conclusion, the loading state of the myocardium, tissue injury, and myocardial fibrosis all appear to be critical determinants in the genesis of left ventricular failure in long-term pressure overload.