Accidental blood exposure: risk and prevention in interventional radiology.
There is a growing concern about the transmission of bloodborne pathogens during medical procedures among health care workers and patients. Over the last three decades, radiological services have undergone many changes with the introduction of new modalities. One of these new disciplines is interventional radiology (IR) which deals with procedures such as arteriography, image-guided biopsies, intravascular catheter insertions, angioplasty and stent placements. Despite these developments, the potential for accidental blood exposure and exposure to other infectious material continues to exist. Therefore, it is important for all radiologists who perform invasive procedures to observe specific recommendations for infection control. In this review, we look at the different policies for protection and universal standards on infection control.


[The history of the Zollinger-Ellison syndrome].
In 1955, the concept that an ulcerogenic islet cell tumor was responsible for a marked ulcer diathesis that led to gastric hyperacidity was proposed by myself and Ellison. Recently is was suggested that this concept marked the beginning of modern gastrointestinal endocrinology. Although these pancreatic ulcerogenic tumors are relatively uncommon, a survey in 1987 stated that inquiries about the tumor were the most common references requested from surgical journals. The original diagnostic triad proposed included a fulminating ulcer diathesis (12-hr secretion 2-3 liters), rapidly recurring ulceration despite adequate medical, surgical, and radiation therapy, and identification of a non-beta islet cell tumor of the pancreas. The non-beta islet cell was considered to be different from the cells producing insulinoma, which up to that time was thought to be the only type of islet cell tumor produced by the pancreas.


[Riboflavin biosynthesis in yeast as a model for estimating mechanisms of regulating synthesis of biologically active substances].
General principles of regulation of transcription in eucaryotic cells are characterized. Investigations on riboflavin biosynthesis and regulation of this process in yeasts are summarized. The data obtained permit to consider riboflavin biosynthesis control as an interesting and convenient model capable to estimate the mechanisms various transcription factors action. These investigations are required in order to reveal general features of vitamins and relative compounds biosynthesis regulation.


Artificial reefs and marine protected areas: a study in willingness to pay to access Folkestone Marine Reserve, Barbados, West Indies.
Artificial reefs in marine protected areas provide additional habitat for biodiversity viewing, and therefore may offer an innovative management solution for managing for coral reef recovery and resilience. Marine park user fees can generate revenue to help manage and maintain natural and artificial reefs. Using a stated preference survey, this study investigates the present consumer surplus associated with visitor use of a marine protected area in Barbados. Two hypothetical markets were presented to differentiate between respondents use values of either: (a) natural reefs within the marine reserve or (b) artificial reef habitat for recreational enhancement. Information was also collected on visitors' perceptions of artificial reefs, reef material preferences and reef conservation awareness. From a sample of 250 visitors on snorkel trips, we estimate a mean willingness to pay of US$18.33 (median-US$15) for natural reef use and a mean value of US$17.58 (median-US$12.50) for artificial reef use. The number of marine species viewed, age of respondent, familiarity with the Folkestone Marine Reserve and level of environmental concern were statistically significant in influencing willingness to pay. Regression analyses indicate visitors are willing to pay a significant amount to view marine life, especially turtles. Our results suggest that user fees could provide a considerable source of income to aid reef conservation in Barbados. In addition, the substantial use value reported for artificial reefs indicates a reef substitution policy may be supported by visitors to the Folkestone Marine Reserve. We discuss our findings and highlight directions for future research that include the need to collect data to establish visitors' non-use values to fund reef management.


Platelet P2Y12 receptors enhance signalling towards procoagulant activity and thrombin generation. A study with healthy subjects and patients at thrombotic risk.
Activated platelets participate in arterial thrombosis by forming aggregates and potentiating the coagulation through exposure of procoagulant phosphatidylserine. The function of the two receptors for ADP, P2Y(1) and P2Y(12), is well-established in aggregation, but is incompletely understood in the platelet procoagulant response. We established that, in PRP from healthy subjects, ADP accelerated and potentiated tissue factor induced thrombin generation exclusively via stimulation of P2Y(12) and not via P2Y(1) receptors. The P2Y(12) receptors also mediated the potentiating effect of PAR-1 stimulation on thrombin generation. Furthermore, ADP enhanced in a P2Y(12)-dependent manner the Ca(2+) response induced by thrombin, which was either added externally or generated in-situ. This ADP effect was in part dependent of phosphoinositide 3-kinase and was paralleled by increased phosphatidylserine exposure. In PRP from (young) patients with either stroke or type-II diabetes, platelet-dependent thrombin generation was similarly enhanced byADP or SFLLRN as in healthy subjects. In PRP from stroke patients of older age, the P2Y(12)-mediated contribution to thrombin generation was variably reduced by two weeks of clopidogrel medication. Remaining P2Y(12) activity after medication correlated with remaining P2Y(12)-dependent P-selectin exposure, i.e. Ca(2+)-dependent secretion, likely due to incomplete antagonism of P2Y(12) receptors. Together, these results indicate that physiological platelet agonists amplify phosphatidylserine exposure and subsequent thrombin generation by release of ADP and P2Y(12)-receptor stimulation. This P2Y(12) response is accomplished by a novel Ca(2+) signalling pathway. It is similarly active in platelets from control subjects and patients at thrombotic risk. Finally, the thrombogram method is useful for measuring incomplete P2Y(12) inhibition with clopidogrel.


MethBank: a database integrating next-generation sequencing single-base-resolution DNA methylation programming data.
DNA methylation plays crucial roles during embryonic development. Here we present MethBank (http://dnamethylome.org), a DNA methylome programming database that integrates the genome-wide single-base nucleotide methylomes of gametes and early embryos in different model organisms. Unlike extant relevant databases, MethBank incorporates the whole-genome single-base-resolution methylomes of gametes and early embryos at multiple different developmental stages in zebrafish and mouse. MethBank allows users to retrieve methylation levels, differentially methylated regions, CpG islands, gene expression profiles and genetic polymorphisms for a specific gene or genomic region. Moreover, it offers a methylome browser that is capable of visualizing high-resolution DNA methylation profiles as well as other related data in an interactive manner and thus is of great helpfulness for users to investigate methylation patterns and changes of gametes and early embryos at different developmental stages. Ongoing efforts are focused on incorporation of methylomes and related data from other organisms. Together, MethBank features integration and visualization of high-resolution DNA methylation data as well as other related data, enabling identification of potential DNA methylation signatures in different developmental stages and accordingly providing an important resource for the epigenetic and developmental studies.


Efficacy of myo-inositol in the clinical management of patients with asthenozoospermia.
The aim of this study was to analyze the effect of myo-inositol in combination with minerals and vitamin on sperm motility in patients affected by asthenozoospermia as index of Bulgarian population. One-hundred-nine men aged between 18 and 50 years with reduced sperm motility identified by routine semen analysis were enrolled in this study. After excluding any urological problems, three months of treatment with a supplementation based on myo-inositol and other minerals and vitamins (Andrositol, MLD trading, Bulgaria) was prescribed. The sperm motility was evaluated by statistical analysis. A significant improvement in sperm motility was reported in 85.32% of the patients. Furthermore, the average motility was improved from 20.31% (SD ± 8.5) to 27.98 (SD ± 9.69) after the treatment. In particular, 38 of these patients restored a normal sperm motility (34.86% of the patients) while 14 patients (12.84%) didn't show any beneficial effect and, even if any side effects were reported, 2 patients (1.84%) showed a worsened the motility. A treatment with Andrositol significantly improved sperm motility, increasing the likelihood of achieving a spontaneous pregnancy.


Factors Associated with Microalbuminuria Remission in Patients with Type 2 Diabetes: Importance of Early Intervention for Microalbuminuric Patients (TSUGARU STUDY).
The aim of this study was to clarify the rates of remission and progression for microalbuminuria in patients with type 2 diabetes (T2DM); and factors associated with remission and progression of diabetic nephropathy (DN). T2DM patients with a urinary albumin excretion (UAE) rate of 30-300 mg/gCr who were attending the medical clinic in the Tsugaru region in Japan were enrolled into this prospective, observational study for 36 months (N=317). We investigated the rate of remission (UAE <30 mg/g creatinine (Cr); normal albuminuria) and the rate of progression (UAE ≥300 mg/gCr; overt proteinuria) 36 months after study registration. The number of patients whose UAE levels were <30 mg/gCr (DN remission) at 36 months after registration was 64 (27.4%), and the number of patients whose UAE levels were ≥300 mg/gCr (DN progression) at 36 months after registration was 32 (13.7%). From multiple logistic regression analysis, the sole factor that contributed to remission at 36 months after registration was the UAE levels at registration (OR: 0.99; 95% CI: 0.98-1.00, p=0.003), and the factors that contributed to progression at 36 months after registration were the levels of UAE (OR: 1.01; 95% CI: 1.01-1.02, p=0.000) and systolic blood pressure (OR: 0.96; 95% CI: 0.93-1.00, p=0.033) at registration. Results suggest that patients with less severe microalbuminuria among microalbuminuric patients might more commonly experience DN remission and that earlier intervention is very important for promoting microalbuminuria remission in DN.


Highly stable cesium lead iodide perovskite quantum dot light-emitting diodes.
Recently, all-inorganic perovskites such as CsPbBr3 and CsPbI3, have emerged as promising materials for light-emitting applications. While encouraging performance has been demonstrated, the stability issue of the red-emitting CsPbI3 is still a major concern due to its small tolerance factor. Here we report a highly stable CsPbI3 quantum dot (QD) light-emitting diode (LED) with red emission fabricated using an improved purification approach. The device achieved decent external quantum efficiency (EQE) of 0.21% at a bias of 6 V and outstanding operational stability, with a L 70 lifetime (EL intensity decreases to 70% of starting value) of 16 h and 1.5 h under a constant driving voltage of 5 V and 6 V (maximum EQE operation) respectively. Furthermore, the device can work under a higher voltage of 7 V (maximum luminance operation) and retain 50% of its initial EL intensity after 500 s. These findings demonstrate the promise of CsPbI3 QDs for stable red LEDs, and suggest the feasibility for electrically pumped perovskite lasers with further device optimizations.


Utilization of bivalve shell-treated Zea mays L. (maize) husk leaf as a low-cost biosorbent for enhanced adsorption of malachite green.
In this work, two low-cost wastes, bivalve shell (BS) and Zea mays L. husk leaf (ZHL), were investigated to adsorb malachite green (MG) from aqueous solutions. The ZHL was treated with calcined BS to give the BS-ZHL, and its ability to adsorb MG was compared with untreated ZHL, calcined BS and Ca(OH)(2)-treated ZHL under several different conditions: pH (2-8), adsorbent dosage (0.25-2.5 g L(-1)), contact time (10-30 min), initial MG concentration (10-200 mg L(-1)) and temperature (303-323 K). The equilibrium studies indicated that the experimental data were in agreement with the Langmuir isotherm model. The use of 2.5 g L(-1) BS-ZHL resulted in the nearly complete removal of 200 mg L(-1) of MG with a maximum adsorption capacity of 81.5 mg g(-1) after 30 min of contact time at pH 6 and 323 K. The results indicated that the BS-ZHL can be used to effectively remove MG from aqueous media.


Liriomyza Leafminer (Diptera: Agromyzidae) Parasitoid Complex in Different Agroecological Zones, Seasons, and Host Plants in Kenya.
Liriomyza leafminers (Diptera: Agromyzidae) are severe pests of vegetables and ornamentals worldwide. Previous studies revealed low leafminer parasitism across different agroecological zones in Kenya. The present paper reports on the composition of leafminer parasitoids at different elevations, in different seasons, and on different host crops. Surveys were conducted monthly from January to November 2012, and nine parasitoid species were recovered. Total mean parasitism in the study sites was 31.23 ± 1.03% from a total of 20 different vegetable Liriomyza-infested crops belonging to seven families. Diglyphus isaea (Walker) (Hymenoptera: Eulophidae), Phaedrotoma scabriventris, a newly released parasitoid, and Opius dissitus Muesebeck (Hymenoptera: Braconidae) were the most abundant at all elevations, accounting for 67.3, 18.6, and 9.2% of total parasitoids, respectively. Elevation, season, and host crop significantly affected the parasitoid species present and their abundance. Diglyphus isaea was more abundant at the high- and mid-elevations at all seasons compared with the low-elevation, whereas the lower-elevation favored higher abundance of P. scabriventris and O. dissitus during the long rainy season compared with the high- and mid-elevations at all seasons. Of all the host crops surveyed, parasitoids were more abundant on tomato, local kidney bean, snow pea and French bean than other crops. The total parasitism rate observed in this study suggests a considerable improvement in leafminer parasitism compared with previous surveys in Kenya. The implications of these findings for leafminer management in vegetable and ornamental production in Kenya are discussed.


Design and fabrication of a high performance multilayer piezoelectric actuator with bending deformation.
A new bending mode multimorph actuator was designed and fabricated successfully by a multiple screen printing process. Unlike the conventional bimorph actuator in which the bend occurs in the thickness direction, the bend in the multimorph actuator occurs in the widthwise direction because of synchronistical deformation of each single monolithic layer in the multilayer structure. The theoretical analysis and experimental measurements were conducted to study the performance of this type of actuator, and a comparison was made with the conventional bimorph actuator. Larger displacement, higher resonance frequency, and much larger blocking force could be achieved with the multimorph actuator than with a bimorph actuator of similar dimensions. The multimorph actuator presented in this paper provides a valuable alternative for actuator applications beyond those available with the popular bimorph and longitudinal multilayer actuators.


Endothelin impairs ATP-sensitive K+ channel function after brain injury.
In piglets, pial arteries constrict, ATP-sensitive K+ (KATP) channel function is impaired, and cerebrospinal fluid endothelin-1 (ET-1) increases to 10(-10) M after brain injury [fluid percussion injury (FPI)]. Nitric oxide (NO) elicits dilation via guanosine 3',5'-cyclic monophosphate (cGMP) and KATP channel activation. This study was designed to characterize the relationship between ET-1 and impaired function of KATP channels after FPI. Injury was produced via the lateral FPI technique in piglets equipped with a closed cranial window. Cromakalim, a KATP agonist, produced dilation that was attenuated by FPI and partially restored by BQ-123, an ET-1 antagonist (11 +/- 1 and 23 +/- 2 vs. 2 +/- 1 and 4 +/- 1 vs. 8 +/- 1 and 17 +/- 2% for responses to 10(-8) and 10(-6) M cromakalim before FPI, after FPI, and after FPI with BQ-123, respectively). Because ET-1 constriction may antagonize dilation, separate experiments were conducted under conditions of equivalent baseline diameter in the absence and presence of ET-1 (10(-10) M). Cromakalim dilation was attenuated by ET-1 and partially restored by the protein kinase C (PKC) inhibitor staurosporine (12 +/- 1 and 28 +/- 1 vs. 2 +/- 1 and 21 +/- 3 vs. 9 +/- 1 and 29 +/- 2% for 10(-8) and 10(-6) M cromakalim, cromakalim with ET-1, and cromakalim with ET-1 + staurosporine, respectively). Similar interactions were observed with calcitonin gene-related peptide, 8-bromoguanosine 3',5'-cyclic monophosphate, and the NO releasers sodium nitroprusside and S-nitroso-N-acetylpenicillamine. These data show that ET-1 blunts KATP channel-, NO-, and cGMP-mediated dilation. These data suggest that ET-1 contributes to altered cerebral hemodynamics after FPI through impairment of KATP channel function via PKC activation.


Increasing complexity of farnesyltransferase inhibitors activity: role in chromosome instability.
Oncogenic Ras proteins have been seen as an important target for novel anticancer drugs. Due to the functional role of Ras farnesylation, fanesyltransferase (FTase) inhibition was thought to be a strategy for interfering with Ras-dependent transformation. When farnesylation is blocked, the function of Ras protein is severely impaired because of the inability of the nonfarnesylated protein to anchor to the membrane. Although it has been clearly demonstrated that FTase inhibitors (FTIs) inhibit Ras farnesylation, it is uncertain whether the antiproliferative effects of these compounds result exclusively from the effects on Ras. Moreover, no consensus has been reached as to the relevant targets(s) of FTIs that can explain their mosaic pharmacology. In searching for downstream targets for FTIs effects, CENP-E and CENP-F/mitosin were identified. Different studies showed that the inhibition of farnesylation interferes with CENP-E-microtubule association. In the presence of FTIs, chromosome alignment to the metaphase plate is delayed, suggesting that farnesylated proteins are involved in a step critical to bipolar spindle formation and chromosome alignment. An important question is whether these biological effects might contribute to the chemotherapeutic effects of the FTIs. However, FTIs, triggering the spindle checkpoint, might elevate the rate of cellular missegregation to levels that are incompatible with cell viability, as well as have a reduced (but still significant?) effect on checkpoint-proficient normal cells. As an example, RPR-115135 induced micronuclei (MN) increase in cancer cells displaying high chromosome instability (CIN) levels, whereas in normal cells it is devoid of activity. Cancer cells showing high CIN level might represent an ideal target for the activity of some FTIs.


Distinct microbial populations exist in the mucosa-associated microbiota of sub-groups of irritable bowel syndrome.
There is increasing evidence to support a role for the gastrointestinal microbiota in the etiology of irritable bowel syndrome (IBS). Given the evidence of an inflammatory component to IBS, the mucosa-associated microbiota potentially play a key role in its pathogenesis. The objectives were to compare the mucosa-associated microbiota between patients with diarrhea predominant IBS (IBS-D), constipation predominant IBS (IBS-C) and controls using fluorescent in situ hybridization and to correlate specific bacteria groups with individual IBS symptoms. Forty-seven patients with IBS (27 IBS-D and 20 IBS-C) and 26 healthy controls were recruited to the study. Snap-frozen rectal biopsies were taken at colonoscopy and bacterial quantification performed by hybridizing frozen sections with bacterial-group specific oligonucleotide probes. Patients with IBS had significantly greater numbers of total mucosa-associated bacteria per mm of rectal epithelium than controls [median 218 (IQR - 209) vs 128 (121) P = 0.007], and this was chiefly comprised of bacteroides IBS [69 (67) vs 14 (41) P = 0.001] and Eubacterium rectale-Clostridium coccoides [52 (58) vs 25 (35) P = 0.03]. Analysis of IBS sub-groups demonstrated that bifidobacteria were lower in the IBS-D group than in the IBS-C group and controls [24 (32) vs 54 (88) vs 32 (35) P = 0.011]. Finally, amongst patients with IBS, the maximum number of stools per day negatively correlated with the number of mucosa-associated bifidobacteria (P < 0.001) and lactobacilli (P = 0.002). The mucosa-associated microbiota in patients with IBS is significantly different from healthy controls with increases in bacteroides and clostridia and a reduction in bifidobacteria in patients with IBS-D.


Comparison of the biological and biochemical activities of several members of the alphaherpesvirus ICP0 family of proteins.
Immediate-early protein ICP0 of herpes simplex virus type 1 (HSV-1) is an E3 ubiquitin ligase of the RING finger class that is required for efficient lytic infection and reactivation from latency. Other alphaherpesviruses also express ICP0-related RING finger proteins, but these have limited homology outside the core RING domain. Existing evidence indicates that ICP0 family members have similar properties, but there has been no systematic comparison of the biochemical activities and biological functions of these proteins. Here, we describe an inducible cell line system that allows expression of the ICP0-related proteins of bovine herpes virus type 1 (BHV-1), equine herpesvirus type 1 (EHV-1), pseudorabies virus (PRV), and varicella-zoster virus (VZV) and their subsequent functional analysis. We report that the RING domains of all the proteins have E3 ubiquitin ligase activity in vitro. The BHV-1, EHV-1, and PRV proteins complement ICP0-null mutant HSV-1 plaque formation and induce derepression of quiescent HSV-1 genomes to levels similar to those achieved by ICP0 itself. VICP0, the ICP0 expressed by VZV, was found to be extremely unstable, which limited its analysis in this system. We compared the abilities of the ICP0-related proteins to disrupt ND10, to induce degradation of PML and Sp100, to affect key components of the interferon signaling pathway, and to interfere with induction of interferon-stimulated genes. We found that the property that correlated most closely with their biological activities was the ability to preclude the recruitment of cellular ND10 proteins to sites closely associated with incoming HSV-1 genomes and early replication compartments.


Shear-induced platelet adherence and activation in an in-vitro dynamic multiwell-plate system.
Circulating blood cells are prone to varying flow conditions when contacting cardiovascular devices. For a profound understanding of the complex interplay between the blood components/cells and cardiovascular implant surfaces, testing under varying shear conditions is required. Here, we study the influence of arterial and venous shear conditions on the in vitro evaluation of the thrombogenicity of polymer-based implant materials.Medical grade poly(dimethyl siloxane) (PDMS), polyethylene terephthalate (PET) and polytetrafluoroethylene (PTFE) films were included as reference materials. The polymers were exposed to whole blood from healthy humans. Blood was agitated orbitally at low (venous shear stress: 2.8 dyne · cm-2) and high (arterial shear stress: 22.2 dyne · cm-2) agitation speeds in a well-plate based test system. Numbers of non-adherent platelets, platelet activation (P-Selectin positive platelets), platelet function (PFA100 closure times) and platelet adhesion (laser scanning microscopy (LSM)) were determined.Microscopic data and counting of the circulating cells revealed increasing numbers of material-surface adherent platelets with increasing agitation speed. Also, activation of the platelets was substantially increased when tested under the high shear conditions (P-Selectin levels, PFA-100 closure times). At low agitation speed, the platelet densities did not differ between the three materials. Tested at the high agitation speed, lowest platelet densities were observed on PDMS, intermediate levels on PET and highest on PTFE. While activation of the circulating platelets was affected by the implant surfaces in a similar manner, PFA closure times did not reflect this trend.Differences in the thrombogenicity of the studied polymers were more pronounced when tested at high agitation speed due to the induced shear stresses. Testing under varying shear stresses, thus, led to a different evaluation of the implant thrombogenicity, which emphasizes the need for testing under various flow conditions. Our data further confirmed earlier findings where the same reference implants were tested under static (and not dynamic) conditions and with fresh human platelet rich plasma instead of whole blood. This supports that the application of common reference materials may improve inter-study comparisons, even under varying test conditions.


20S RNA narnavirus defies the antiviral activity of SKI1/XRN1 in Saccharomyces cerevisiae.
20S RNA virus is a persistent positive strand RNA virus found in Saccharomyces cerevisiae. We previously observed that the virus generated in vivo from a launching vector possessed the correct RNA termini without extra sequences. Here we present evidence that the SKI1/XRN1 5'-exonuclease plays a major role in the elimination of the non-viral upstream sequences from the primary transcripts. The virus, once generated, however, is fairly unaffected by overexpression or deletion of SKI1/XRN1. By contrast, the copy number of the L-A double-stranded RNA virus in the same host is greatly increased by the deletion of SKI1/XRN1, and overexpression of the gene cured L-A virus from the cells at a high frequency. 20S RNA virus, unlike L-A virus, has a strong secondary structure at its 5'-end: the first four nucleotides are G, and they are buried at the bottom of a long stem structure, features known to inhibit the SKI1/XRN1 5'-exonuclease progression. Mutations that weakened the 5'-stem structure made 20S RNA virus vulnerable to SKI1/XRN1. These results, together with the data on L-A virus, indicate a strong anti-RNA virus activity of SKI1/XRN1. Given that 20S RNA virus resides and replicates in the cytoplasm without a protective capsid, our results suggest that the strong secondary structure at the 5'-end is crucial for the 20S RNA virus to evade the host SKI1/XRN1 defense.


Global Stroke Statistics 2019.
Data on stroke epidemiology and availability of hospital-based stroke services around the world are important for guiding policy decisions and healthcare planning. To provide the most current incidence, mortality and case-fatality data on stroke and describe current availability of stroke units around the world by country. We searched multiple databases (based on our existing search strategy) to identify new original manuscripts and review articles published between 1 June 2016 and 31 October 2018 that met the ideal criteria for data on stroke incidence and case-fatality. For data on the availability of hospital-based stroke services, we searched PubMed for all literature published up until 31 June 2018. We further screened reference lists, citation history of manuscripts and gray literature for this information. Mortality codes for International Classification of Diseases-9 and International Classification of Diseases-10 were extracted from the World Health Organization mortality database for each country providing these data. Population denominators were obtained from the World Health Organization, and when these were unavailable within a two-year period of mortality data, population denominators within a two-year period were obtained from the United Nations. Using country-specific population denominators and the most recent years of mortality data available for each country, we calculated both the crude mortality from stroke and mortality adjusted to the World Health Organization world population. Since our last report in 2017, there were two countries with new incidence studies, China (n = 1) and India (n = 2) that met the ideal criteria. New data on case-fatality were found for Estonia and India. The most current mortality data were available for the year 2015 (39 countries), 2016 (43 countries), and 2017 (7 countries). No new data on mortality were available for six countries. Availability of stroke units was noted for 63 countries, and the proportion of patients treated in stroke units was reported for 35/63 countries. Up-to-date data on stroke incidence, case-fatality, and mortality statistics provide evidence of variation among countries and changing magnitudes of burden among high and low-middle income countries. Reporting of hospital-based stroke units remains limited and should be encouraged.


(-)-baclofen and gamma-aminobutyric acid inhibit calcium currents in isolated retinal ganglion cells.
Of the various synaptic inputs known to converge upon retinal ganglion cells, the major inhibitory inputs are thought to be GABAergic. Although gamma-aminobutyric acid (GABA) is known to activate anion-selective ion channels in retinal ganglion cells, we have tested the possibility that GABA can also modulate cationic conductances in these cells, as seen in other central and peripheral neurons. Specifically, we have made whole-cell patch-clamp recordings to test whether voltage-gated calcium currents in isolated goldfish retinal ganglion cells are sensitive to GABAB receptor ligands. (-)-Baclofen and GABA inhibited calcium currents activated by moderately long depolarizations and, during large depolarizations (e.g., to 0 mV), also appeared to accelerate the rate of current decay. The calcium current inhibition induced by (-)-baclofen and GABA was not prevented by 2-hydroxysaclofen, phaclofen, or bicuculline, even though bicuculline suppressed a GABA-activated conductance in these cells. These results demonstrate the presence of baclofen- and GABA-sensitive calcium currents in vertebrate retinal ganglion cells as well as the coexistence of GABAA and GABAB receptors in individual retinal ganglion cells.


Aqueous alkali halide solutions: can osmotic coefficients be explained on the basis of the ionic sizes alone?
We use the AMSA, associative mean spherical theory of associative fluids, to study ion-ion interactions in explicit water. We model water molecules as hard spheres with four off-center square-well sites and ions as charged hard spheres with sticky sites that bind to water molecules or other ions. We consider alkali halide salts. The choice of model parameters is based on two premises: (i) The strength of the interaction between a monovalent ion and a water molecule is inversely proportional to the ionic (crystal) diameter sigma(i). Smaller ions bind to water more strongly than larger ions do, taking into account the asymmetry of the cation-water and anion-water interactions. (ii) The number of contacts an ion can make is proportional to sigma2(i). In short, small ions bind waters strongly, but only a few of them. Large ions bind waters weakly, but many of them. When both a monovalent cation and anion are large, it yields a small osmotic coefficient of the salt, since the water molecules avoid the space in between large ions. On the other hand, salts formed from one small and one large ion remain hydrated and their osmotic coefficient is high. The osmotic coefficients, calculated using this model in combination with the integral equation theory developed for associative fluids, follow the experimental trends, including the unusual behavior of caesium salts.


Real-time kadanoff-baym approach to plasma oscillations in a correlated electron Gas
A nonequilibrium Green's functions approach to the collective response of correlated Coulomb systems at finite temperatures is presented. It is shown that solving Kadanoff-Baym-type equations of motion for the two-time correlation functions including the external perturbing field allows one to compute the plasmon spectrum with collision effects in a systematic and consistent way. The scheme has a "built-in" sum-rule preservation and is simpler to implement numerically than the equivalent equilibrium approach based on the Bethe-Salpeter equation.


Multimodal characterization of the bone-implant interface using Raman spectroscopy and nanoindentation.
Titanium implants are widely used in dental and orthopedic surgeries. Osseointegration phenomena lead to direct contact between bone tissue and the implant surface. The quality of the bone-implant interface (BII), resulting from the properties of newly formed bone, determines the implant stability. This study investigates the BII properties using a dedicated in vivo implant model consisting of a coin-shaped Ti-6Al-4V implant inserted in a rabbit femur for 10 weeks. A gap created below the implant was filled with newly formed bone tissue after healing. The properties of mature and newly formed bone tissues were compared using: i) Raman spectroscopy to assess the nanoscale compositional bone properties and ii) nanoindentation to quantify microscale elastic properties in site-matched regions. The mineral-to-matrix ratio, crystallinity (mineral size and lattice order), and the collagen cross-link ratio were significantly lower in newly formed bone tissue (e.g., a mineral-to-matrix ratio of 9.3 ± 0.5 for proline 853 cm-1) compared to mature bone (15.6 ± 1). Nanoindentation measurements gave Young's modulus of 12.8 ± 1.8 GPa for newly formed bone and 15.7 ± 2.3 GPa for mature bone. This multimodal and multiscale approach leads to a better understanding of osseointegration phenomena.


A probabilistic model of pre-erythrocytic malaria vaccine combination in mice.
Malaria remains one the world's most deadly infectious diseases, with almost half a million deaths and over 150 million clinical cases each year. An effective vaccine would contribute enormously to malaria control and will almost certainly be required for eventual eradication of the disease. However, the leading malaria vaccine candidate, RTS,S, shows only 30-50% efficacy under field conditions, making it less cost-effective than long-lasting insecticide treated bed nets. Other subunit malaria vaccine candidates, including TRAP-based vaccines, show no better protective efficacy. This has led to increased interest in combining subunit malaria vaccines as a means of enhancing protective efficacy. Mathematical models of the effect of combining such vaccines on protective efficacy can help inform optimal vaccine strategies and decision-making at all stages of the clinical process. So far, however, no such model has been developed for pre-clinical murine studies, the stage at which all candidate antigens and combinations begin evaluation. To address this gap, this paper develops a mathematical model of vaccine combination adapted to murine malaria studies. The model is based on simple probabilistic assumptions which put the model on a firmer theoretical footing than previous clinical models, which rather than deriving a relationship between immune responses and protective efficacy posit the relationship to be either exponential or Hill curves. Data from pre-clinical murine malaria studies are used to derive values for unknowns in the model which in turn allows simulations of vaccine combination efficacy and suggests optimal strategies to pursue. Finally, the ability of the model to shed light on fundamental biological variables of murine malaria such as the blood stage growth rate and sporozoite infectivity is explored.


Spinal Motoneuron TMEM16F Acts at C-boutons to Modulate Motor Resistance and Contributes to ALS Pathogenesis.
Neuronal Ca2+ entry elicited by electrical activity contributes to information coding via activation of K+ and Cl- channels. While Ca2+-dependent K+ channels have been extensively studied, the molecular identity and role of Ca2+-activated Cl- channels (CaCCs) remain unclear. Here, we demonstrate that TMEM16F governs a Ca2+-activated Cl- conductance in spinal motoneurons. We show that TMEM16F is expressed in synaptic clusters facing pre-synaptic cholinergic C-boutons in α-motoneurons of the spinal cord. Mice with targeted exon deletion in Tmem16f display decreased motor performance under high-demanding tasks attributable to an increase in the recruitment threshold of fast α-motoneurons. Remarkably, loss of TMEM16F function in a mouse model of amyotrophic lateral sclerosis (ALS) significantly reduces expression of an activity-dependent early stress marker and muscle denervation, delays disease onset, and preserves muscular strength only in male ALS mice. Thus, TMEM16F controls motoneuron excitability and impacts motor resistance as well as motor deterioration in ALS.


Dosimetric Performance of Poly(vinyl alcohol)/Silver Nanoparticles Hybrid Nanomaterials for Colorimetric Sensing of Gamma Radiation.
A colorimetric liquid sensor based on a poly(vinyl alcohol)/silver nanoparticle (PVA/AgNPs) hybrid nanomaterial was developed for gamma radiation in the range of 0−100 Gy. In this study, gamma rays (Cobalt-60 source) triggered the aggregation of AgNPs in a PVA/silver nitrate (AgNO3) hybrid solution. The color of this solution visibly changed from colorless to dark yellow. Absorption spectra of the PVA/AgNPs solution were analyzed by UV-Vis spectrophotometry in the range of 350−800 nm. Important parameters, such as pH and AgNO3 concentration were optimized. The accuracy, sensitivity, stability, and uncertainty of the sensor were investigated and compared to the reference standard dosimeter. Based on the spectrophotometric results, an excellent positive linear correlation (r = 0.998) between the absorption intensity and received dose was found. For the accuracy, the intra-class correlation coefficient (ICC) between the PVA/AgNPs sensor and the standard Fricke dosimeter was 0.998 (95%CI). The sensitivity of this sensor was 2.06 times higher than the standard dosimeter. The limit of detection of the liquid dosimeter was 13.4 Gy. Moreover, the overall uncertainty of this sensor was estimated at 4.962%, in the acceptable range for routine standard dosimeters (<6%). Based on its dosimetric performance, this new PVA/AgNPs sensor has potential for application as an alternative gamma sensor for routine dose monitoring in the range of 13.4−100 Gy.


Relaxation therapies for the management of primary hypertension in adults.
Lifestyle interventions are often recommended as initial treatment for mild hypertension, but the efficacy of relaxation therapies is unclear. To evaluate the effects of relaxation therapies on cardiovascular outcomes and blood pressure in people with elevated blood pressure. We searched the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, ISI Proceedings, ClinicalTrials.gov, Current Controlled Trials and reference lists of systematic reviews, meta-analyses and randomised controlled trials (RCTs) included in the review. RCTs of a parallel design comparing relaxation therapies with no active treatment, or sham therapy; follow-up >/=8 weeks; participants over 18 years, with raised systolic blood pressure (SBP) >/=140 mmHg or diastolic blood pressure (DBP) >/=85 mmHg); SBP and DBP reported at end of follow-up. participants were pregnant; participants received antihypertensive medication which changed during the trial. Two reviewers independently extracted data and assessed trial quality. Disagreements were resolved by discussion or a third reviewer. Random effects meta-analyses and sensitivity analyses were conducted. 29 RCTs, with eight weeks to five years follow-up, met our inclusion criteria; four were excluded from the primary meta-analysis because of inadequate outcome data. The remaining 25 trials assessed 1,198 participants, but adequate randomisation was confirmed in only seven trials and concealment of allocation in only one. Only one trial reported deaths, heart attacks and strokes (one of each). Meta-analysis indicated that relaxation resulted in small, statistically significant reductions in SBP (mean difference: -5.5 mmHg, 95% CI: -8.2 to -2.8, I2 =72%) and DBP (mean difference: -3.5 mmHg, 95% CI: -5.3 to -1.6, I2 =75%) compared to control. The substantial heterogeneity between trials was not explained by duration of follow-up, type of control, type of relaxation therapy or baseline blood pressure. The nine trials that reported blinding of outcome assessors found a non-significant net reduction in blood pressure (SBP mean difference: -3.2 mmHg, 95% CI: -7.7 to 1.4, I(2) =69%) associated with relaxation. The 15 trials comparing relaxation with sham therapy likewise found a non-significant reduction in blood pressure (SBP mean difference: -3.5 mmHg, 95% CI: -7.1 to 0.2, I(2) =63%). In view of the poor quality of included trials and unexplained variation between trials, the evidence in favour of causal association between relaxation and blood pressure reduction is weak. Some of the apparent benefit of relaxation was probably due to aspects of treatment unrelated to relaxation.


Partner choice promotes cooperation: the two faces of testing with agent-based models.
Reciprocity is one of the most debated among the mechanisms that have been proposed to explain the evolution of cooperation. While a distinction can be made between two general processes that can underlie reciprocation (within-pair temporal relations between cooperative events, and partner choice based on benefits received), theoretical modelling has concentrated on the former, while the latter has been often neglected. We developed a set of agent-based models in which agents adopted a strategy of obligate cooperation and partner choice based on benefits received. Our models tested the ability of partner choice both to reproduce significant emergent features of cooperation in group living animals and to promote the evolution of cooperation. Populations formed by agents adopting a strategy of obligate cooperation and partner choice based on benefits received showed differentiated "social relationships" and a positive correlation between cooperation given and received, two common phenomena in animal cooperation. When selection across multiple generations was added to the model, agents adopting a strategy of partner choice based on benefits received outperformed selfish agents that did not cooperate. Our results suggest partner choice is a significant aspect of cooperation and provides a possible mechanism for its evolution.


Health effect of the New Nordic Diet in adults with increased waist circumference: a 6-mo randomized controlled trial.
The regional Mediterranean Diet has been associated with lower risk of disease. We tested the health effects of the New Nordic Diet (NND), which is a gastronomically driven regional, organic, and environmentally friendly diet, in a carefully controlled but free-living setting. A total of 181 centrally obese men and women, with a mean (range) age of 42 y (20-66 y), body mass index (in kg/m(2)) of 30.2 (22.6-47.3), and waist circumference of 100 cm (80-138 cm) were randomly assigned to receive either the NND (high in fruit, vegetables, whole grains, and fish) or an average Danish diet (ADD) for 26 wk. Participants received cookbooks and all foods ad libitum and free of charge by using a shop model. The primary endpoint was the weight change analyzed by both completer and intention-to-treat analyses. A total of 147 subjects [81% (NND 81%; ADD 82%)] completed the intervention. A high dietary compliance was achieved, with significant differences in dietary intakes between groups. The mean (±SEM) weight change was -4.7 ± 0.5 kg for the NND compared with -1.5 ± 0.5 kg for the ADD (adjusted difference: -3.2 kg; 95% CI: -4.6, -1.8 kg; P < 0.001) for the completer analysis, and the difference was -3.0 kg (95% CI: -4.0, -2.1 kg) for the intention-to-treat analysis. The NND produced greater reductions in systolic blood pressure (adjusted difference: -5.1 mm Hg; 95% CI: -8.2, -2.1 mm Hg) and diastolic blood pressure (adjusted difference: -3.2 mm Hg; 95% CI: -5.7, -0.8 mm Hg) than did the ADD. An ad libitum NND produces weight loss and blood pressure reduction in centrally obese individuals. This trial was registered at www.clinicaltrials.gov as NCT01195610.


Identification process in mass graves from the Spanish Civil War I.
The identification process of human skeletal remains exhumed from a mass grave from the Spanish Civil War (1936-1939) is presented. Information regarding the presumptive location of the grave and the presumptive number and identities of the persons buried in the grave was collected from interviews and written records from relatives and witnesses, as well as from research at the penitentiary archive. Antemortem individual data were collected from testimonies, and from research from penitentiary, army and civil archives. The consistency between data obtained from testimonies, archives, archaeology and osteology allowed a targeted approach to DNA typing based on the assumption of the finding of a closed synchronic group. Two were the first genetic studies requested: the first study focused in the identification of a family group presumptively buried in the grave, compatible with a group of four skeletons that were associated on the basis of dental non-metric traits; the second study focused on the identification of the youngest person presumptively buried at the grave, compatible with the biologically youngest skeleton exhumed. A complete match between 16 Y-STR loci was observed for the four skeletons, as well as a match between mtDNA profiles of the biologically youngest skeleton and the sister of the youngest person presumptively known to be buried in the grave. These results, together with the accumulated evidence, led to propose the identification of these five persons. To date, identifications have been proposed for 17 out of 46 skeletons exhumed from the grave.


Rectal cancer lateral lymph nodes: multicentre study of the impact of obturator and internal iliac nodes on oncological outcomes.
In patients with rectal cancer, enlarged lateral lymph nodes (LLNs) result in increased lateral local recurrence (LLR) and lower cancer-specific survival (CSS) rates, which can be improved with (chemo)radiotherapy ((C)RT) and LLN dissection (LLND). This study investigated whether different LLN locations affect oncological outcomes. Patients with low cT3-4 rectal cancer without synchronous distant metastases were included in this multicentre retrospective cohort study. All MRI was re-evaluated, with special attention to LLN involvement and response. More advanced cT and cN category were associated with the occurrence of enlarged obturator nodes. Multivariable analyses showed that a node in the internal iliac compartment with a short-axis (SA) size of at least 7 mm on baseline MRI and over 4 mm after (C)RT was predictive of LLR, compared with a post-(C)RT SA of 4 mm or less (hazard ratio (HR) 5.74, 95 per cent c.i. 2.98 to 11.05 vs HR 1.40, 0.19 to 10.20; P < 0.001). Obturator LLNs with a SA larger than 6 mm after (C)RT were associated with a higher 5-year distant metastasis rate and lowered CSS in patients who did not undergo LLND. The survival difference was not present after LLND. Multivariable analyses found that only cT category (HR 2.22, 1.07 to 4.64; P = 0.033) and margin involvement (HR 2.95, 1.18 to 7.37; P = 0.021) independently predicted the development of metastatic disease. Internal iliac LLN enlargement is associated with an increased LLR rate, whereas obturator nodes are associated with more advanced disease with increased distant metastasis and reduced CSS rates. LLND improves local control in persistent internal iliac nodes, and might have a role in controlling systemic spread in persistent obturator nodes.Members of the Lateral Node Study Consortium are co-authors of this study and are listed under the heading Collaborators.


An inexpensive retrospective standard setting method based on item facilities.
Standard setting is one of the most challenging aspects of assessment in high-stakes healthcare settings. The Angoff methodology is widely used, but poses a number of challenges, including conceptualisation of the just-passing candidate, and the time-cost of implementing the method. Cohen methodologies are inexpensive and rapid but rely on the performance of an individual candidate. A new method of standard setting, based on the entire cohort and every item, would be valuable. We identified Borderline candidates by reviewing their performance across all assessments in an academic year. We plotted the item scores of the Borderline candidates in comparison with Facility for the whole cohort and fitted curves to the resulting distribution. It is observed that for any given Item, an equation of the form y ≈ C. eFx where y is the Facility of Borderline candidates on that Item, x is the observed Item Facility of the whole cohort, and C and F are constants, predicts the probable Facility for Borderline candidates over the test, in other words, the cut score for Borderline candidates. We describe ways of estimating C and F in any given circumstance, and suggest typical values arising from this particular study: that C = 12.3 and F = 0.021. C and F are relatively stable, and that the equation y = 12.3. e0.021x can rapidly be applied to the item Facility for every item. The average value represents the cut score for the assessment as a whole. This represents a novel retrospective method based on test takers. Compared to the Cohen method which draws on one score and one candidate, this method draws on all items and candidates in a test. We propose that it can be used to standard set a whole test, or a particular item where the predicted Angoff score is very different from the observed Facility.


Diverse integrated ecosystem approach overcomes pandemic-related fisheries monitoring challenges.
The COVID-19 pandemic caused unprecedented cancellations of fisheries and ecosystem-assessment surveys, resulting in a recession of observations needed for management and conservation globally. This unavoidable reduction of survey data poses challenges for informing biodiversity and ecosystem functioning, developing future stock assessments of harvested species, and providing strategic advice for ecosystem-based management. We present a diversified framework involving integration of monitoring data with empirical models and simulations to inform ecosystem status within the California Current Large Marine Ecosystem. We augment trawl observations collected from a limited fisheries survey with survey effort reduction simulations, use of seabird diets as indicators of fish abundance, and krill species distribution modeling trained on past observations. This diversified approach allows for evaluation of ecosystem status during data-poor situations, especially during the COVID-19 era. The challenges to ecosystem monitoring imposed by the pandemic may be overcome by preparing for unexpected effort reduction, linking disparate ecosystem indicators, and applying new species modeling techniques.


The "noncompliant" transplant patient: a persistent ethical dilemma.
The term noncompliant patient may evoke the image of a difficult, demanding, and troublesome patient. In the transplant environment, patients who are unable or unwilling to adhere to a prescribed plan of treatment raise a number of medical, ethical, and other concerns with respect to individual patient care. Their behavior also raises questions of justice and fairness, especially in light of the limited numbers of transplantable organs available and the very large number of people who are waiting for a transplant. Patients who are unable to do what is necessary to maintain a transplanted organ may create a moral dilemma for the healthcare providers who treat them. This article will (1) attempt to develop a more complete understanding of "patient noncompliance," (2) address concerns that arise both before and after the transplant, and (3) suggest strategies for dealing with noncompliant patients.


Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy.
In addition to inducing a self-limited myopathy, statin use is associated with an immune-mediated necrotizing myopathy (IMNM), with autoantibodies that recognize ∼200-kd and ∼100-kd autoantigens. The purpose of this study was to identify these molecules to help clarify the disease mechanism and facilitate diagnosis. The effect of statin treatment on autoantigen expression was addressed by immunoprecipitation using sera from patients. The identity of the ∼100-kd autoantigen was confirmed by immunoprecipitation of in vitro-translated 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) protein. HMGCR expression in muscle was analyzed by immunofluorescence. A cohort of myopathy patients was screened for anti-HMGCR autoantibodies by enzyme-linked immunosorbent assay and genotyped for the rs4149056 C allele, a predictor of self-limited statin myopathy. Statin exposure induced expression of the ∼200-kd/∼100-kd autoantigens in cultured cells. HMGCR was identified as the ∼100-kd autoantigen. Competition experiments demonstrated no distinct autoantibodies recognizing the ∼200-kd protein. In muscle biopsy tissues from anti-HMGCR-positive patients, HMGCR expression was up-regulated in cells expressing neural cell adhesion molecule, a marker of muscle regeneration. Anti-HMGCR autoantibodies were found in 45 of 750 patients presenting to the Johns Hopkins Myositis Center (6%). Among patients ages 50 years and older, 92.3% had taken statins. The prevalence of the rs4149056 C allele was not increased in patients with anti-HMGCR. Statins up-regulate the expression of HMGCR, the major target of autoantibodies in statin-associated IMNM. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response even after statins are discontinued. These studies demonstrate a mechanistic link between an environmental trigger and the development of sustained autoimmunity. Detection of anti-HMGCR autoantibodies may facilitate diagnosis and direct therapy.


Outpatient laser ablation of non-muscle-invasive bladder cancer: is it safe, tolerable and cost-effective?
To evaluate the safety, tolerability and effectiveness of outpatient (office-based) laser ablation (OLA), with local anaesthetic, for non-muscle-invasive bladder cancer (NMIBC) in an elderly population with and without photodynamic diagnosis (PDD). To compare the cost-effectiveness of OLA of NMIBC with that of inpatient cystodiathermy (IC). We conducted a prospective cohort study of patients with NMIBC treated with OLA by one consultant surgeon between March 2008 and July 2011 A subgroup of patients had PDD before undergoing OLA. Safety and effectiveness were determined by complications (In the immediate post operative period, at three days and at three months), patient tolerability (visual analogue score) and recurrence rates. The long-term costs and cost-effectiveness of OLA and IC of NMIBC were evaluated using Markov modeling. A total of 74 OLA procedures (44 white-light, 30 PDD) were carried out in 54 patients. The mean (range) patient age was 77 (52-95) years. More than half of the patients had more than three comorbidities. Previous tumour histology ranged from G1pTa to T3. One patient had haematuria for 1 week which settled spontaneously and did not require hospital admission. There were no other complications. The procedure was well tolerated with pain scores of 0-2/10. Additional lesions were found in 21% of patients using PDD that were not found using white light. At 3 months, the percentage of patients who had recurrence after OLA with white light and OLA with PDD were 10.6 and 4.3%, respectively. At 1 year, 65.1% and 46.9% of patients had recurrence. The cost of OLA was found to be much lower than that of IC (£538 vs £1474), even with the addition of PDD (£912 vs £1844). Over the course of a patient's lifetime, OLA was more clinically effective, measured in quality-adjusted life-years (QALY), than IC (0.147 [sd 0.059]) and less costly (£2576.42 [sd £7293.07]). At a cost-effectiveness threshold of £30,000/QALY, as set by the National Institute for Health and Care Excellence, there was an 82% probability that OLA was cost-effective. This is the first study to demonstrate the long-term cost-effectiveness of OLA of NMIBC. The results support the use of OLA for the treatment of NMIBC, especially in the elderly.


The role of significant others in adolescent diabetes: a qualitative study.
The purpose of this study was to explore perceptions of how diabetes influences adolescents' perceptions of quality of life in general and their relationships with parents, peers, school, and their physician. The authors recruited adolescents between the ages of 13 and 18 years living with type 1 diabetes mellitus from a midwestern metropolitan area. Qualitative analysis of the focus group data followed a set procedure: (1) audio review of the tapes, (2) reading through the transcriptions, (3) discussions among investigators, (4) determination of conceptual themes, and (5) assignment of relevant responses to appropriate thematic constructs. The 5 focus groups involved 31 adolescents. From the discussions that occurred within the 5 focus groups, the following themes were identified: personal perceptions of living with diabetes (which included living with diabetes, testing and injections, and blood sugar fluctuations), impact on relationships (which included relationships with their parents, their friends/peers, and their physician), and impact on school. Diabetes in adolescence is fraught with equal and opposite demands. One consequence of this internal push/pull is that adolescents become more afraid to do appropriate developmental activities. This can have a significant impact on their normal progression to independence and adulthood, ironically at odds with the increased responsibility they have had to assume throughout their lives to care for their disease. Much of the clinical time and research still focuses on the devices of diabetes care: testing and treatment. While these are important tools in improving the outcomes of people with diabetes, they will have little impact on the adolescent until the developmental consequences of diabetes on their lives are simultaneously addressed.


Representation of action in occipito-temporal cortex.
A fundamental question for social cognitive neuroscience is how and where in the brain the identities and actions of others are represented. Here we present a replication and extension of a study by Kable and Chatterjee [Kable, J. W., & Chatterjee, A. Specificity of action representations in the lateral occipito-temporal cortex. Journal of Cognitive Neuroscience, 18, 1498-1517, 2006] examining the role of occipito-temporal cortex in these processes. We presented full-cue movies of actors performing whole-body actions and used fMRI to test for action- and identity-specific adaptation effects. We examined a series of functionally defined regions, including the extrastriate and fusiform body areas, the fusiform face area, the parahippocampal place area, the lateral occipital complex, the right posterior superior temporal sulcus, and motion-selective area hMT+. These regions were analyzed with both standard univariate measures as well as multivoxel pattern analyses. Additionally, we performed whole-brain tests for significant adaptation effects. We found significant action-specific adaptation in many areas, but no evidence for identity-specific adaptation. We argue that this finding could be explained by differences in the familiarity of the stimuli presented: The actions shown were familiar but the actors performing the actions were unfamiliar. However, in contrast to previous findings, we found that the action adaptation effect could not be conclusively tied to specific functionally defined regions. Instead, our results suggest that the adaptation to previously seen actions across identities is a widespread effect, evident across lateral and ventral occipito-temporal cortex.


[The role of food-specific IgG antibody test in diagnosis and treatment of mild recurrent aphthous ulcer].
To evaluate the role of food-specific IgG antibody test in the treatment of mild recurrent aphthous ulcer. Seven hundred and ninety nine mild recurrent aphthous ulcer patients and 762 normal persons were enrolled in the experimental and control group respectively, based on the criteria for inclusion and exclusion. The blood serum samples of them were obtained to detect food-specific IgG antibody by enzyme-linked immunosorbent assay. The positive rates were then compared by Chi-square test between 2 groups using SPSS 17.0 software package. The experimental group was further analyzed based on age, gender, course, interval period, number of ulcer, allergy history, etc. Food rotation was applied in strong positive patients for food-specific IgG antibody. The positive rate was 45.2% in the experimental group and 40.9% in the control group(P=0.101). The positive rate was significantly higher in young patients (51.3%) and patients with short interval (83.9%). Food rotation could prolong the interval period from 13.00 days to 14.77 days in general but did not reduce the ulcer number significantly. Food-specific IgG antibody test may be helpful for the treatment of young or frequent patients with mild recurrent aphthous ulcer.


Development of a halothane-adrenaline arrhythmia model using in vivo Guinea pigs.
In vivo antiarrhythmic effects of diltiazem hydrochloride and nifekalant hydrochloride, a pure class III antiarrhythmic drug (Vaughan Williams' classification), on adrenaline induced ventricular arrhythmias were examined in halothane anesthetized guinea pigs. Continuous adrenaline infusion (12.5 microg/kg per min) induced ventricular arrhythmias. Arrhythmogenicity was significantly increased with vagotomy and higher concentration of halothane. After injection of diltiazem at 0.5 mg/kg, the arrhythmic ratio (the number of ventricular ectopic beats divided by the total heart beats) was significantly reduced compared with the predrug control value (0.69 vs 0.04, P<0.05). No significant change of arrhythmic ratio was observed after injection of nifekalant (0.57 vs 0.61, ns). After administration of nifekalant, the mean minimum adrenaline infusion rate that induced ventricular arrhythmia decreased from 9.29 to 6.43 microg/kg per min. On the other hand, before administration of diltiazem, the mean arrhythmogenic rate of adrenaline was 8.50 microg/kg per min, but ventricular arrhythmias were no longer induced during continuous infusion of diltiazem at 0.5 mg/kg per min. These results were qualitatively consistent with previous experiments using the canine halothane-adrenaline model. In conclusion, the halothane-adrenaline arrhythmia model using the in vivo guinea pig is useful for screening drugs with potential anti- or pro-arrhythmic properties.


Ten lessons learned from conducting an adherence intervention trial.
Clinical practice research provides a unique opportunity to care for a diverse patient population in various health care system settings. Federal study of Adherence to Medications in the Elderly (FAME) was the first prospective observational and randomized controlled trial to implement effective strategies to enhance medication adherence and health outcomes in older patients using polypharmacy. Ten lessons learned from conducting this adherence intervention trial are described: (1) Link the trial to existing clinical work, (2) Begin with a thorough understanding of medication adherence, (3) Ensure that trial highlights individualized intervention, (4) Tailor inclusion criteria and study duration to target population, (5) Employ a range of outcomes linked to meaningful clinical effects, (6) Win the support of the multidisciplinary team and the administration, (7) Promote team work, (8) Consider the potential limitations, (9) Seize the grant opportunities, and (10) Share the findings.


Qualitative membrane enzyme immunoassay for detection of cytomegalovirus antibody.
A new qualitative membrane immunoassay for use in detecting IgG antibodies to cytomegalovirus (CMV) was compared with a standard microplate enzyme immunoassay (EIA). A total of 179 patients were tested by the EIA for IgG- and IgM-specific antibodies to CMV and then compared with the new membrane immunoassay. Among the 179 sera, five specimens were repeatably invalid. Among the 174 evaluable sera, 128 (73.6%) were positive for IgG antibody to CMV by the EIA method. Of these 128 sera, the Transtat-CMV was positive in 124 (96.9%). The remaining 46 sera were negative for IgG antibodies by both methods. The Transtat-CMV membrane immunoassay appears to be a reliable and easily used method not requiring additional equipment or extended incubation times. As a qualitative-only assay, it cannot be used for diagnosis.


Functional disability 5 years after acute respiratory distress syndrome.
There have been few detailed, in-person interviews and examinations to obtain follow-up data on 5-year outcomes among survivors of the acute respiratory distress syndrome (ARDS). We evaluated 109 survivors of ARDS at 3, 6, and 12 months and at 2, 3, 4, and 5 years after discharge from the intensive care unit. At each visit, patients were interviewed and examined; underwent pulmonary-function tests, the 6-minute walk test, resting and exercise oximetry, chest imaging, and a quality-of-life evaluation; and reported their use of health care services. At 5 years, the median 6-minute walk distance was 436 m (76% of predicted distance) and the Physical Component Score on the Medical Outcomes Study 36-Item Short-Form Health Survey was 41 (mean norm score matched for age and sex, 50). With respect to this score, younger patients had a greater rate of recovery than older patients, but neither group returned to normal predicted levels of physical function at 5 years. Pulmonary function was normal to near-normal. A constellation of other physical and psychological problems developed or persisted in patients and family caregivers for up to 5 years. Patients with more coexisting illnesses incurred greater 5-year costs. Exercise limitation, physical and psychological sequelae, decreased physical quality of life, and increased costs and use of health care services are important legacies of severe lung injury.


Identification and expression of mRNAs encoding bursicon in the plesiomorphic central nervous system of Homarus gammarus.
Ecdysis in arthropods is a complex process, regulated by many neurohormones, which must be released in a precisely coordinated manner. In insects, the ultimate hormone involved in this process is the cuticle tanning hormone, bursicon. Recently, this hormone has been identified in crustaceans. To further define the distribution of bursicon in crustacean nervous systems, and to compare hormone structures within the sub-phylum, cDNAs encoding both bursicon subunits were cloned and sequenced from the nervous system of the European lobster, Homarus gammarus, and expression patterns including those for CCAP determined using in-situ hybridisation, quantitative RT-PCR and immunohistochemistry. Full-length cDNAs encoded bursicon subunits of 121 amino acids (Average M(r): 13365.48) for Burs α, 115 amino acids (Average M(r): 12928.54) for Burs β. Amino acid sequences were most closely related to those of crabs, and for Burs β the sequence was identical to that of the American lobster, Homarus americanus. Complete co-localisation with CCAP in the VNC was seen. Copy numbers burs α, burs β and CCAP mRNAs were between 0.5 and 1.5 × 10(5) for both bursicon subunits, 0.5-6 × 10(5) per cdn neurone for CCAP. The terminal abdominal ganglia (AG 6-8) contained about 52 cdn-type neurons, making it the largest bursicon producing region in the CNS. Double labelling IHC using recombinant Carcinus Burs α and CCAP antisera demonstrated complete co-localisation in the VNC. On the basis of the results obtained, it is proposed that CCAP and bursicon release occur simultaneously during ecdysis in crustaceans.


Aerobiology and its role in the transmission of infectious diseases.
Aerobiology plays a fundamental role in the transmission of infectious diseases. As infectious disease and infection control practitioners continue employing contemporary techniques (e.g., computational fluid dynamics to study particle flow, polymerase chain reaction methodologies to quantify particle concentrations in various settings, and epidemiology to track the spread of disease), the central variables affecting the airborne transmission of pathogens are becoming better known. This paper reviews many of these aerobiological variables (e.g., particle size, particle type, the duration that particles can remain airborne, the distance that particles can travel, and meteorological and environmental factors), as well as the common origins of these infectious particles. We then review several real-world settings with known difficulties controlling the airborne transmission of infectious particles (e.g., office buildings, healthcare facilities, and commercial airplanes), while detailing the respective measures each of these industries is undertaking in its effort to ameliorate the transmission of airborne infectious diseases.


Isolation and characterization of a stable activation intermediate of the lysosomal aspartyl protease cathepsin D.
Procathepsin D is the intracellular aspartyl protease precursor of cathepsin D, a major lysosomal enzyme. Procathepsin D is rapidly processed inside the cell, and, thus, examination of its proteolyic activation and structure has been difficult. To study this proenzyme, a nonglycosylated form of the human fibroblast procathepsin D was expressed in Escherichia coli, refold in vitro, and purified by affinity chromatography on pepstatinyl agarose. Sequence analysis of the refolded, autoactivated enzyme allowed determination of the autoproteolytic cleavage site. The sequence surrounding this cleavage site between residues LeuP26 and IleP27 (in the "pro" region) resembled the first cleavage site found during activation of other aspartyl proteases. Thus, the autoactivated procathepsin D is analogous to the pepsin activation intermediate, which has been termed pseudopepsin. The enzymatic activity, thermal and pH stability, and fluorescence spectra of pseudocathepsin D were compared to mature, predominantly two-chain, cathepsin D isolated from human placenta. The results indicated that pseudocathepsin D and mature enzyme have a similar Km toward a peptide substrate and cleave a protein substrate at identical sites. Temperature stability of the recombinant enzyme was similar to that of the tissue-derived enzyme. However, the recombinant enzyme had increased stability at low pH when compared to the glycosylated tissue-derived two-chain cathepsin D. Fluorescence spectra of the recombinant and tissue-derived enzymes were identical. Thus, the absence of asparagine-linked oligosaccharides and the presence of the remaining segment of propeptide did not significantly alter the structural and enzymatic properties of the enzyme.


Influenza and influenza-like syndromes: the subjects' beliefs, the attitude to prevention and treatment, and the impact in Italian general population.
Influenza and influenza-like syndromes (I-LSs) are infectious diseases occurring on a seasonal basis which can lead to upper (URTI) and lower respiratory tract illness (LRTI) of different severity. The approach to these disorders is unfortunately not uniform. Aim of the study was to investigate real-life people beliefs, the attitude to their prevention and treatment, and their impact in general population. A cross-sectional survey via Computer Assisted Telephone Interview (CATI) was carried out using a specific questionnaire investigating influenza episode rates, subjects behavior in case of influenza and I-LSs, and prescribed therapy. 1,202 subjects completed the questionnaire: median age was 46, 49% male, 20% active smokers. 57% of respondents experienced at least one episode of influenza or I-LS in the previous 12 months; episodes were usually home-managed, shorter than 2 weeks and more frequent in fall and winter (73% of the total). GP resulted the first health-care option (56%); almost 3% of respondents referred to the emergency room, and hospitalization occurred in 1%. Mucolytics resulted the most prescribed drugs (55%) followed by antibiotics and aerosol therapy (37-38%). Even if more than 70% of subjects considered vaccination essential, only 14% received influenza vaccination yearly and almost 60% had never received vaccination. Approximately 36% of respondents regarded homeopathy (namely Oscillococcinum) as an helpful alternative because of perceived as safer. Seasonal prevalence of I-LSs and influenza partially overlap. As virus identification is not a common procedure in daily practice, only a clinical discrimination is possible. Antibiotic prescription is still too high and largely inappropriate. Influenza vaccination is strongly encouraged, but different strategies are also used. Other approaches are receiving increasing attention in general population, and subjects' willingness to spend out-of-pocket for effective remedies is also increasing. The discrepancy between subjects' beliefs and health care actions likely reflects the insufficiency of institutional preventive strategies. In general, the approach to influenza and I-LSs appear variable and highly dependent of subjects' and their GPs' cultural beliefs.


Partitioning of Catechol Derivatives in Lipid Membranes: Implications for Substrate Specificity to Catechol-O-methyltransferase.
We have utilized multiparametric surface plasmon resonance and impendance-based quartz crystal microbalance instruments to study the distribution coefficients of catechol derivatives in cell model membranes. Our findings verify that the octanol-water partitioning coefficient is a poor descriptor of the total lipid affinity for small molecules which show limited lipophilicity in the octanol-water system. Notably, 3-methoxytyramine, the methylated derivative of the neurotransmitter dopamine, showed substantial affinity to the lipids despite its nonlipophilic nature predicted by octanol-water partitioning. The average ratio of distribution coefficients between 3-methoxytyramine and dopamine was 8.0. We also found that the interactions between the catechols and the membranes modeling the cell membrane outer leaflet are very weak, suggesting a mechanism other than the membrane-mediated mechanism of action for the neurotransmitters at the postsynaptic site. The average distribution coefficient for these membranes was one-third of the average value for pure phosphatidylcholine membranes, calculated using all compounds. In the context of our previous work, we further theorize that membrane-bound enzymes can utilize membrane headgroup partitioning to find their substrates. This could explain the differences in enzyme affinity between soluble and membrane-bound isoforms of catechol-O-methyltransferase, an essential enzyme in catechol metabolism.


Rehabilitation and Disability Spectrum From Adverse Childhood Experience: The Impact of the Movement Cognition and Narration of Emotions Treatment (MCNT) Version 2.0.
Adverse Childhood Experiences (ACE) are associated with an increased risk of cerebral, behavioral, and cognitive outcomes, and vulnerability to develop a Borderline Intellectual Functioning (BIF). BIF is characterized by an intelligence quotient (IQ) in the range 70-85, poor executive functioning, difficulties in emotion processing, and motor competencies. All these difficulties can lead to mental and/or neurodevelopmental disorders that require long-term care. Accordingly, we developed an intensive and multidomain rehabilitation program for children with ACE and BIF, termed the Movement Cognition and Narration of emotions Treatment (MCNT1.0). The efficacy of MCNT1.0 on cognitive and social functioning was demonstrated with a previously reported randomized controlled trial (RCT). To extend the impact of the treatment also to the motor domain a new version, called MCNT2.0, was implemented. The present study aims to verify the feasibility of MCNT2.0 and its effects on the motor domain. A quasi-experimental approach was used in which a group of 18 children with ACE and BIF were consecutively recruited and participated in the MCNT 2.0 program. Participants were compared with the MCNT1.0 group as an active comparator, using the dataset of the RCT. The two groups received a full evaluation comprising: the Wechsler Intelligent Scale for Children-IV (WISC-IV), the Movement-ABC (M-ABC), the Test of Gross Motor Development (TGMD), the Social Skills from Vineland Adaptive Behavioral Scale-II (VABS-II) and the Child Behavior Check List 6-18 (CBCL). An ANCOVA was carried out on changes in the scale scores from baseline with age and baseline score as covariates. Results showed a mean adherence to treatment of 0.85 (sd = 0.07), with no differences between groups in IQ, and Social Skills changes, while greater improvements for motor abilities were shown in the MCNT 2.0 group: M-ABC (p = 0.002), and TGMD (p = 0.002). Finally, greater improvement in the CBCL scale was observed in the MCNT 1.0 group (p = 0.002). Results indicate that due to its positive effects on cognitive, social participation and motor domains, MCNT2.0 may represent a protective factor against maladaptive outcomes of children with ACE and BIF.


Placebo controlled trial of enteric coated pancreatin microsphere treatment in patients with unresectable cancer of the pancreatic head region.
Impeded flow of pancreatic juice due to mechanical obstruction of the pancreatic duct in patients with cancer of the pancreatic head region causes exocrine pancreatic insufficiency with steatorrhoea and creatorrhoea. This may contribute to the profound weight loss that often occurs in these patients. To investigate whether pancreatic enzyme replacement therapy prevents this weight loss. Twenty one patients with unresectable cancer of the pancreatic head region with suspected pancreatic duct obstruction, a biliary endoprosthesis in situ, and a Karnofsky performance status greater than 60. Randomised double blind trial of eight weeks with either placebo or high dose enteric coated pancreatin enzyme supplementation. All patients received dietary counselling. The mean difference in the percentage change of body weight was 4.9% (p = 0.02, 95% confidence interval for the difference: 0.9 to 8.9). Patients on pancreatic enzymes gained 1.2% (0.7 kg) body weight whereas patients on placebo lost 3.7% (2.2 kg). The fat absorption coefficient in patients on pancreatic enzymes improved by 12% whereas in placebo patients it dropped by 8% (p = 0.13, 95% confidence interval for the difference: -6 to 45). The daily total energy intake was 8.42 MJ in patients on pancreatic enzymes and 6.66 MJ in placebo patients (p = 0.04, 95% confidence interval for the difference: 0.08 to 3.44). Weight loss in patients with unresectable cancer of the pancreatic head region and occlusion of the pancreatic duct can be prevented, at least for the period immediately after insertion of a biliary endoprosthesis, by high dose enteric coated pancreatin enzyme supplementation in combination with dietary counselling.


Molecular epidemiology of coronavirus in faeces of Brazilian calves and Peruvian camelid herds.
The enteric disorders represent a serious hazard for bovine and camelid breeding. The aim of this study was to examine the frequency of detection and molecular characteristics of enteric coronavirus (CoV) infections in cattle, alpaca, and llama herds bred in family-based farms in Brazil and Peru. Stool samples were collected from calves from Brazil and camelids from Peru for detection and characterization of CoV by reverse transcription polymerase chain reaction (RT-PCR) and sequence analysis. 46.5% (47/101) samples from calves and 26.8% (70/261) from alpaca tested positive for CoV. All strains belong to lineage A1 of the Betacoronavirus genus. Phylogenetic analysis showed high identity between CoV strains detected in calves and alpacas. This study characterised CoV strains from dairy cattle herds in the state of Rio de Janeiro, Brazil, and indicated that this virus is spread among the state herds. The results also indicate widespread circulation of CoV among the alpacas of Cuzco, Peru.


Prostaglandin E2 induces DNA hypermethylation in gastric cancer in vitro and in vivo.
Rationale: Prostaglandin E2 (PGE2) is a pro-inflammatory eicosanoid up-regulated in gastric cancer (GC). However, its impact on epigenetic dysfunction in the process of gastric carcinogenesis is unknown. In this study, we investigate the role of PGE2 in DNA methylation in gastric epithelium in vitro, in mice, and humans. Methods: PGE2-induced DNMT3B and DNA methylation was determined in gastric cell lines and COX-2 transgenic mice. Effect of COX-2 inhibition on DNA methylation was evaluated in a randomized controlled trial. Efficacy of combined COX-2/PGE2 and DNMT inhibition on GC growth was examined in cell lines and mice models. Results: PCR array analysis of PGE2-treated GC cells revealed the up-regulation of DNMT3B, a de novo DNA methyltransferase. In GC cells, PGE2 induced DNMT3B expression and activity, leading to increased methylated cytosine (5mC) and promoter methylation of tumor suppressive genes (MGMT and CNR1). Consistently, Cox-2 (rate-limiting enzyme for PGE2 biosynthesis) transgenic expression in mice significantly induced Dnmt3b expression, increased 5mC content, and promoted Mgmt promoter methylation. We retrospectively analyzed the 5mC content of 42 patients with intestinal metaplasia (a precancerous lesion of GC) treated with a COX-2 specific inhibitor Rofecoxib or placebo for 2 years, revealing that the COX-2 inhibitor significantly down-regulated 5mC levels (N=42, P=0.009). Collectively, these data indicate that PGE2 is closely related to DNA hypermethylation in vitro and in vivo. Using genome-wide 450K methylation array, we identified chromosomal genes (POT1, ATM and HIST1H2AA) were preferentially methylated by PGE2. Biofunctional work revealed that POT1 functions as a tumor suppressor. Finally, we demonstrated that combinatorial inhibition of COX-2 and DNMT using Celecoxib and Decitabine synergistically inhibited GC growth in vitro and in vivo. Conclusion: This study suggested that PGE2 promotes DNA methylation in GC, and that co-targeting of PGE2 and DNMT inhibits GC.


Specific molecular and cellular events induced by irradiated X-ray photoactivatable drugs raise the problem of co-toxicities: particular consequences for anti-cancer synchrotron therapy.
Synchrotrons are capable of producing intense low-energy X-rays that enable the photoactivation of high-Z elements. Photoactivation therapy (PAT) consists of loading tumors with photoactivatable drugs and thereafter irradiating them at an energy, generally close to the K-edge of the element, that enhances the photoelectric effect. To date, three major photoactivatable elements are used in PAT: platinum (cisplatin and carboplatin), iodine (iodinated contrast agents and iododeoxyuridine) and gadolinium (motexafin gadolinium). However, the molecular and cellular events specific to PAT and the radiobiological properties of these photoactivatable drugs are still misknown. Here, it is examined how standard and synchrotron X-rays combined with photoactivatable drugs impact on the cellular response of human endothelial cells. These findings suggest that the radiolysis products of the photoactivatable drugs may participate in the synergetic effects of PAT by increasing the severity of radiation-induced DNA double-strand breaks. Interestingly, subpopulation of highly damaged cells was found to be a cellular pattern specific to PAT. The data show that the efficiency of emerging anti-cancer modalities involving synchrotron photoactivation strongly depends on the choice of photoactivatable drugs, and important series of experiments are required to secure their clinical transfer before applying to humans.


Chromosomal mutations that increase the production of a plasmid-encoded haemolysin in Escherichia coli.
Transposon mutagenesis was used to isolate two Escherichia coli mutants which express very large amounts of haemolysin when carrying the multicopy plasmid pANN202-312. E. coli strain Hha-2 was isolated by Mud1 mutagenesis, and strain Hha-3 by Tn5 mutagenesis. The transposon insertion was chromosomal in both mutants and could be demonstrated to be unrelated to the haemolytic region of the plasmid. The substantial increase in both extracellular and intracellular haemolysin production was dependent upon plasmid copy number and was drastically reduced when either mutant carried the low-copy-number haemolytic plasmid pHly152. In both mutants, the marked increase in extracellular production was dependent upon the specific haemolysin transport genes, hlyB and hlyD. The lack of either gene function resulted in no external haemolysin production. SDS-PAGE analysis showed no change in the pattern of outer-membrane proteins of the mutants, although changes (differing between the two mutants) were seen in their periplasmic proteins. The mutations of both strains (termed hha-2 and hha-3) were mapped at minute 10.5 of the E. coli chromosome. No relation to any known gene affecting gene regulation in E. coli could be found.


Dietary compound ellagic acid alleviates skin wrinkle and inflammation induced by UV-B irradiation.
Ellagic acid, a polyphenol compound present in berries and pomegranate, has received attention as an agent that may have potential bioactivities preventing chronic diseases. This study examined photoprotective effects of ellagic acid on collagen breakdown and inflammatory responses in UV (ultraviolet)-B irradiated human skin cells and hairless mice. Ellagic acid attenuated the UV-B-induced toxicity of HaCaT keratinocytes and human dermal fibroblasts. Non-toxic ellagic acid markedly prevented collagen degradation by blocking matrix metalloproteinase production in UV-B-exposed fibroblasts. Anti-wrinkle activity of ellagic acid was further investigated in hairless mice exposed to UV-B, in which it attenuated UV-B-triggered skin wrinkle formation and epidermal thickening. Topical application of 10 micromol/l ellagic acid diminished production of pro-inflammatory cytokines IL-1beta and IL-6, and blocked infiltration of inflammatory macrophages in the integuments of SKH-1 hairless mice exposed to UV-B for 8 weeks. In addition, this compound mitigated inflammatory intracellular cell adhesion molecule-1 expression in UV-B-irradiated keratinocytes and photoaged mouse epidermis. These results demonstrate that ellagic acid prevented collagen destruction and inflammatory responses caused by UV-B. Therefore, dietary and pharmacological interventions with berries rich in ellagic acid may be promising treatment strategies interrupting skin wrinkle and inflammation associated with chronic UV exposure leading to photoageing.


A photonic crystal based sensing scheme for acetylcholine and acetylcholinesterase inhibitors.
We present a new scheme for sensing biomolecules by combining an enzyme hydrogel with a photonic crystal hydrogel layer that responds to ionic strength and pH changes. We demonstrate this unique combination by successfully detecting acetylcholine (ACh) and acetylcholinesterase (AChE) inhibitors. Specifically, the sandwich assembly is composed of layers of photonic crystals and a polyacrylamide hydrogel functionalized with AChE. The photonic crystal film has a red color and turns dark purple within 2-6 minutes of the enzymatic reaction upon analyte addition. This 3D photonic crystal sensor responds to acetylcholine in the 1 nM to 10 μM concentration range (which includes the relevant range of ACh concentrations in human body fluids). Michaelis-Menten kinetics of the enzyme were determined which correlated well with literature data demonstrating the uninhibited reactivity of the immobilized enzyme. Furthermore, the presence of the acetylcholinesterase inhibitor neostigmine at concentrations as low as 1 fM was demonstrated, which is even below the necessary detection limit for clinical diagnostics. We suggest that this novel concept will find its application in clinical diagnostics, for pesticide and nerve agent detection.


Effect of nosocomial bloodstream infections on mortality, length of stay, and hospital costs in older adults.
To quantify the effect of nosocomial bloodstream infection (BSI) on older adults, including mortality, length of stay (LOS), and costs attributed to BSI. Retrospective cohort study. Eight acute care hospitals (7 community hospitals and 1 tertiary university-affiliated facility) belonging to the Duke Infection Control Outreach Network (DICON) from the states of North Carolina and Virginia. Elderly patients over 65 years of age. A multistate, multicenter, matched, retrospective cohort study was conducted from January 1994 through June 2002 in eight hospitals from the Southern-Central United States. Patients aged >65 years with nosocomial BSI were enrolled. Controls without bloodstream infection were matched to cases. Outcomes during the 90-day period following hospital discharge were evaluated to determine the association between BSI and mortality, hospital costs, and LOS. Eight-hundred thirty cases and 830 matched controls were identified, all with a mean age of 74.4 years. Among cases, 81% of BSIs were central line-associated and Staphylococcus aureus was the most common pathogen accounting for 34.6% of infections (2/3 were methicillin resistant). The mortality rate of cases was 49.4%, compared to 33.2% for controls (OR = 2.1, P < .001), LOS was 29.2 days for cases and 20.2 days for controls (P < .001), and hospital charges were $102,276 for cases compared to $69,690 for controls (P < .001). The mean LOS and mean costs attributable to BSI were 10 days and $43,208, respectively. Nosocomial BSI in older adults was significantly associated with increases in 90-day mortality, increased LOS, and increased costs of care. Preventive interventions to eliminate nosocomial BSIs in older adults would likely be cost effective.


Molecular determinants of the factor VIII/von Willebrand factor complex revealed by BIVV001 cryo-electron microscopy.
Interaction of factor VIII (FVIII) with von Willebrand factor (VWF) is mediated by the VWF D'D3 domains and thrombin-mediated release is essential for hemostasis after vascular injury. VWF-D'D3 mutations resulting in loss of FVIII binding are the underlying cause of von Willebrand disease (VWD) type 2N. Furthermore, the FVIII-VWF interaction has significant implications for the development of therapeutics for bleeding disorders, particularly hemophilia A, in which endogenous VWF clearance imposes a half-life ceiling on replacement FVIII therapy. To understand the structural basis of FVIII engagement by VWF, we solved the structure of BIVV001 by cryo-electron microscopy to 2.9 Å resolution. BIVV001 is a bioengineered clinical-stage FVIII molecule for the treatment of hemophilia A. In BIVV001, VWF-D'D3 is covalently linked to an Fc domain of a B domain-deleted recombinant FVIII (rFVIII) Fc fusion protein, resulting in a stabilized rFVIII/VWF-D'D3 complex. Our rFVIII/VWF structure resolves BIVV001 architecture and provides a detailed spatial understanding of previous biochemical and clinical observations related to FVIII-VWF engagement. Notably, the FVIII acidic a3 peptide region (FVIII-a3), established as a critical determinant of FVIII/VWF complex formation, inserts into a basic groove formed at the VWF-D'/rFVIII interface. Our structure shows direct interaction of sulfated Y1680 in FVIII-a3 and VWF-R816 that, when mutated, leads to severe hemophilia A or VWD type 2N, respectively. These results provide insight on this key coagulation complex, explain the structural basis of many hemophilia A and VWD type 2N mutations, and inform studies to further elucidate how VWF dissociates rapidly from FVIII upon activation.


Reduction of CAII Expression in Gastric Cancer: Correlation with Invasion and Metastasis.
Human carbonic anhydrases II (CAII) gene plays an important role in different cancer. However, its relevance to gastric cancer (GC) remains unclear. In the present study, we aimed to investigate the expression of CAII in GC and explore its correlation with some clinicopathologic characteristics of GC. The expression of CAII in 20 specimens of normal gastric mucosa, 38 specimens of intraepithelial neoplasia and 112 specimens of gastric carcinoma were detected by immunohistochemical techniques. Survival in GC with CAII expression was studied. The positive rate of CAII protein in normal gastric mucosa was significantly higher than that in intraepithelial neoplasia and gastric carcinoma (100% vs. 63.16% and 28.57%, P<0.001). The positive rate of CAII protein was significantly higher in gastric carcinoma at early stages than that at advanced stages (70.0% vs. 19.57%, P<0.001). The positive rate of CAII protein was significantly lower in gastric carcinoma with lymph node metastases than that without lymph node metastases (10.81% vs. 37.33%, P<0.05). Furthermore, the positive rate of CAII protein was significantly lower in poorly-differentiated gastric carcinoma than in moderately- or well-differentiated gastric carcinoma (15.94% vs. 31.03% or 60.00%, P<0.05). Moreover, CAII expression was not related with sex, age and tumor size. The patients with CAII-positive tumors showed a better survival rate than those with CAII-negative tumors (P=0.024, log-rank test). CAII expression was related with stages and lymph node metastases in gastric carcinoma. The reduction of CAII expression in GC might promote tumor cell motility and contribute to tumor growth and metastasis.


"That's too stereotypical … I don't want that to be how I identify": Identity and body-related sport experiences of racialized young women athletes in Canada.
There is minimal research on the sport experiences of racialized young women athletes in Canada. When studying racialized groups, an inclusive and meaningful approach to research is necessary because ethnicity and race are integral to understanding identity, diversity, discrimination, and overall experiences in sport. The purpose of this qualitative description study was to explore the identities and body-related sport experiences of racialized young women athletes in a variety of sports in Canada. Eight racialized young women athletes (ages 14-18 years; Mage = 16.63, SD = 1.19) participated in multiple semi-structured one-on-one interviews and reflexive photography. A reflexive thematic analysis was conducted, and three overarching themes were generated that describe the athletes' identities and body-related sport experiences: (a) Who I am vs who they say I am; (b) My unique body in sport; and (c) The importance of representation. From these findings, three critical factors - intersectionality, discrimination, and diversity - are examined that influence the quality of sport experiences for racialized young women athletes in Canada.


Pleiotropic effects of the mioC mutation on the physiology of Pseudomonas aeruginosa PAO1.
Flavodoxin (Fld) is a bacterial electron-transfer protein that possesses flavin mononucleotide as a prosthetic group. In the genomes of the Pseudomonas species, the mioC gene is the sole gene, annotated Fld, but its function remains unclear. In this study, phenotype microarray analysis was performed using the wild-type and mioC mutant of pathogenic Pseudomonas aeruginosa PAO1. Our results showed that the mioC mutant is very resistant to oxidative stress. Different antibiotics and metals worked differently on the sensitivity of the mutant. Other pleiotropic effects of mutation in the mioC gene, such as biofilm formation, aggregation ability, motility and colony morphology, were observed under iron stress conditions. Most of the phenotypic and physiological changes could be recovered in the wild type by complementation. Mutation of the mioC gene also influenced the production of pigments. The mioC mutant and mioC over-expressed complementation cells, over-produced pyocyanin and pyoverdine, respectively. Various secreted chemicals were also changed in the mutant, which was confirmed by (1) H NMR analysis. Interestingly, physiological alterations of the mutant strain were restored by the cell-free supernatant of the wild type. The present study demonstrates that the mioC gene plays an important role in the physiology of P. aeruginosa and might be considered as a suitable drug target candidate in pathogenic P. aeruginosa.


School-based oral health education increases caries inequalities.
To evaluate the effect of one and half years of an oral health promotion program in primary schools. A cluster-randomized controlled trial. 740 students aged 9-12 years (48% female) recruited from the fifth grade of 18 different primary schools in West Pomerania, Germany. General and oral health education was provided to the teachers in the intervention schools, which they conveyed to their students. No additional measures were conducted in the control schools. Medical and dental school examinations, as well as questionnaires for the students and their parents were conducted at baseline and follow-up. Data were analysed using Poisson regression models. A significant incident rate ratio between caries increment was found, with a 35% higher risk in the control group. However, parents' socioeconomic characteristics modified the effect of the program on their children, as high socio-economic status in the intervention group was associated with 94% reduction in the incidence risk ratio (p ⟨ 0.001). The program was effective in improving dental health among students with higher socio-economic status. No preventive effect could be found in low socio-economic status groups.