Evidence that two distinct crypt cell types secrete chloride and potassium in human colon.
Human colon may secrete substantial amounts of water secondary to chloride (Cl(-)) and/or potassium (K(+)) secretion in a variety of diarrhoeal diseases. Ion secretion occurs via Cl(-) and K(+) channels, which are generally assumed to be co-located in the colonocyte apical membrane, although their exact cellular sites remain unclear. To investigate the location of apical Cl(-) (CFTR) and apical K(+) (large conductance; BK) channels within human colonic epithelium. Whole-cell patch clamp recordings were obtained from intact human colonic crypts. Specific blockers of K(+) channels and CFTR identified different types of K(+) channel and CFTR under resting conditions and after stimulating intracellular cAMP with forskolin. The BK channel β3-subunit was localised by immunostaining. Two types of crypt cells were identified. One (73% of cells) had whole-cell currents dominated by intermediate conductance (IK) K(+) channels under resting conditions, which developed large CFTR-mediated currents in response to increasing intracellular cAMP. The other (27% of cells) had resting currents dominated by BK channels inhibited by the BK channel blocker penitrem A, but insensitive to both forskolin and the IK channel blocker clotrimazole. Immunostaining showed co-localisation of the BK channel β3-subunit and the goblet cell marker, MUC2. In human colon, Cl(-) secretion originates from the dominant population of colonocytes expressing apical CFTR, whereas K(+) secretion is derived from a smaller population of goblet cells expressing apical BK channels. These findings provide new insights into the pathophysiology of secretory diarrhoea and should be taken into account during the development of anti-diarrhoeal drugs.


Binding specificity of T4 DNA polymerase to RNA.
Bacteriophage T4 DNA polymerase, product of phage gene 43 (gp43), is a multifunctional DNA-binding protein and a key component of the phage DNA replicase. It is also an RNA-binding protein that selectively recognizes a site on its mRNA (the translational operator) and represses its own translation. We examined the ability of the protein to discriminate between DNA and RNA by using a gel mobility shift assay with defined RNA and DNA substrates. A higher affinity to RNA as compared with DNA (about 100-fold) was observed in assays that utilized synthetic DNA and in vitro transcribed RNA substrates bearing the T4 gene 43 translational operator sequence. The replacement of thymine with uracil in the synthetic DNA did not improve binding. The results suggest that the protein's selectivity for RNA is based in structure (intramolecular interactions) specific to the ribonucleotide sequence of the operator. Competition studies suggest that the protein determinants for RNA and DNA recognition are only partially overlapping.


Chromosomal alterations in lung adenocarcinoma from smokers and nonsmokers.
The etiology of lung tumors arising in nonsmokers remains unclear. Although mutations in the K-ras and p53 genes have been reported to be significantly higher in smoking-related lung carcinomas, in the present study we performed a more comprehensive analysis in search of additional genetic changes between lung adenocarcinoma from tobacco- and non-tobacco-exposed patients. We selected a matched cohort of 18 lifetime nonsmoking and 27 smoking patients diagnosed with primary adenocarcinoma of the lung and searched for chromosomal alterations in each tumor by testing normal and tumor tissue with 54 highly polymorphic microsatellite markers located on 28 different chromosomal arms. Allelic losses or gains at chromosomal arms 3p (37 versus 6%), 6q (46 versus 12%), 9p (65 versus 22%), 16p (28 versus 0%), 17p (45 versus 11%), and 19p (58 versus 16%) were present significantly more often in adenocarcinomas from smokers than from nonsmokers. Chromosomal arms showing allelic imbalance in lung tumors from nonsmokers were rare but occurred more often at 19q (22%), 12p (22%), and 9p (22%). The FAL (fractional allelic loss or gain) is defined as the percentage of chromosomal arm losses/gains among the total informative chromosomal arms. Tumors from smokers harbored higher levels of FAL (13 (48%) of 27 showed FAL > or = 0.3) compared with the lung tumors from the nonsmoker patients (2 (11%) of 18 showed FAL > or = 0.3; P = 0.02; odds ratio, 0.13; 95% confidence interval, 0.01-0.79). Our data demonstrate that widespread chromosomal abnormalities are frequent in lung adenocarcinoma from smokers, whereas these abnormalities are infrequent in such tumors arising in nonsmokers. These observations support the notion that lung cancers in nonsmokers arise through genetic alterations distinct from the common events observed in tumors from smokers.


Prospective Case Study of Outcome of Tibial Plateau Fractures Treated with Locking Condylar Plate.
Introduction: Tibial plateau injury involves the articular surface of the proximal tibia with diverse group of fractures that represent a wide spectrum of severity that challenge even the most experienced surgeons, but with the invent of modern diagnostic technology and the advent of locking plates, results appear to be improving over time. Method: The study was conducted on thirty patients admitted in the department of orthopaedics with diagnoses of tibial plateau fractures treated with Locking Condylar Plate. The patients were followed up for a minimum period of six months and clinico-radiological progression of fracture union with the functional outcome was studied using 100 point rating system devised by Delamarter et al. Result: Twenty-two patients showed excellent results while eight patients had good to fair and none with poor result. The average time for radiological union was 17.5 weeks. Conclusion: The results of the study concluded that while locking condylar plate seems to show excellent results in low energy tibial plateau fractures, it can probably be used to successfully treat patients with high energy fracture patterns without the need for additional medial stabilization.


[Changes in diastolic function in heart rejection: role of Doppler echocardiography].
In acute cardiac rejection, left ventricular diastolic function is altered. To study these abnormalities and their utility in cardiac allograft rejection, we studied 56 cardiac transplant recipients. All patients were assessed with endomyocardial biopsy and Doppler echocardiography done in the same day. A total of 163 Doppler studies were recollected. Cardiac transplant recipients were excluded during the early 6 weeks postoperative period. Totally, 100 biopsies were normal, 48 positive for mild rejection (Billingham Gde I-II) and 15 positive for moderate or severe rejection (Billingham Gde III-IV). Compared to negative biopsies, during acute rejection left ventricular wald thickness significantly increased (p < 0.05); isovolumic relaxation period and pressure half-time significantly decreased (p < 0.05, p < 0.001 respectively). Nevertheless, increase in peak early mitral flow velocity was only significantly associated with severe rejection (p < 0.001). Correlating only progressive shortening of isovolumic relaxation period parameter in the diagnosis of graft rejection, we forward a high sensibility (85%) and low specificity (57%). Thus, Doppler echocardiographic evaluation of left ventricular diastolic function provides a non-invasive tool for early detection of acute rejection monitoring after the early postoperative period.


Development of Site-Specific Mg(2+)-RNA Force Field Parameters: A Dream or Reality? Guidelines from Combined Molecular Dynamics and Quantum Mechanics Simulations.
The vital contribution of Mg2+ ions to RNA biology is challenging to dissect at the experimental level. This calls for the integrative support of atomistic simulations, which at the classical level are plagued by limited accuracy. Indeed, force fields intrinsically neglect nontrivial electronic effects that Mg2+ exerts on its surrounding ligands in varying RNA coordination environments. Here, we present a combined computational study based on classical molecular dynamics (MD) and Density Functional Theory (DFT) calculations, aimed at characterizing (i) the performance of five Mg2+ force field (FF) models in RNA systems and (ii) how charge transfer and polarization affect the binding of Mg2+ ions in different coordination motifs. As a result, a total of ∼2.5 μs MD simulations (100/200 ns for each run) for two prototypical Mg2+-dependent ribozymes showed remarkable differences in terms of populations of inner-sphere coordination site types. Most importantly, complementary DFT calculations unveiled that differences in charge transfer and polarization among recurrent Mg2+-RNA coordination motifs are surprisingly small. In particular, the charge of the Mg2+ ions substantially remains constant through different coordination sites, suggesting that the common philosophy of developing site-specific Mg2+ ion parameters is not in line with the physical origin of the Mg2+-RNA MD simulations inaccuracies. Overall, this study constitutes a guideline for an adept use of current Mg2+ models and provides novel insights for the rational development of next-generation Mg2+ FFs to be employed for atomistic simulations of RNA.


A review of research on the protein-bound polysaccharide (polysaccharopeptide, PSP) from the mushroom Coriolus versicolor (Basidiomycetes: Polyporaceae).
1. Protein-bound polysaccharides, designated as PSK and PSP, have been isolated from the CM-101 strain and the COV-1 strain, respectively, of the mushroom Coriolus versicolor. This article aims at summarizing existing research findings about PSP since information on PSK is well documented. 2. PSP possesses a molecular weight of approximately 100 kDa. Glutamic and aspartic acids are abundant in its polypeptide component, whereas its polysaccharide component is made up of monosaccharides with alpha-1,4 and beta-1,3 glucosidic linkages. The presence of fucose in PSK and rhamnose and arabinose in PSP distinguishes the two protein-bound polysaccharides, which are otherwise chemically similar. 3. PSP is classified as a biological response modifier. It induces, in experimental animals, increased gamma-interferon production, interleukin-2 production, and T-cell proliferation. It also counteracts the depressive effect of cyclophosphamide on white blood cell count, interleukin-2 production and delayed-type hypersensitivity reaction. Its antiproliferative activity against tumor cell lines and in vivo antitumor activity have been demonstrated. A small peptide with a molecular weight of 16-18 kDa originating from PSP has been produced with antiproliferative and antitumor activities. 4. PSP administered to patients with esophageal cancer, gastric cancer and lung cancer, and who are undergoing radiotherapy or chemotherapy, helps alleviate symptoms and prevents the decline in immune status.


Neutrophil depletion protects against liver injury from bacterial endotoxin.
Neutrophil (PMN) infiltration is an early occurrence in the liver after exposure to hepatotoxic doses of endotoxin lipopolysaccharide (LPS). The purpose of this study was to test the hypothesis that PMNs contribute to the pathogenesis of LPS hepatotoxicity. The immunoglobulin fraction from serum of rabbits immunized with rat PMNs (anti-PMN Ig) was administered intravenously to rats 18 and 6 hours before exposure to an hepatotoxic dose of LPS (Escherichia coli 0128:B12). This protocol caused a greater than 95% reduction in circulating PMNs, which was maintained for the duration of the study. The immunoglobulin fraction from nonimmunized rabbits was used as a control (control Ig). Rats pretreated with control Ig exhibited a marked increase in the number of PMNs in the liver 1.5 hours after LPS exposure. This increase in hepatic PMNs was significantly reduced by pretreatment with anti-PMN Ig. Marked elevations in both alanine and aspartate aminotransferase activities (1086 +/- 311 and 880 +/- 183 SF units/ml, respectively) were observed in plasma from control Ig-treated rats 6 hours after intravenous administration of LPS (3.0 mg/kg). The response to LPS was greatly attenuated in animals receiving anti-PMN Ig (145 +/- 111 and 224 +/- 49 SF units/ml alanine and aspartate aminotransferase activities, respectively). Pretreatment of rats with immunoglobulins to rat lymphocytes reduced numbers of circulating lymphocytes but did not afford protection against the hepatotoxic effects of LPS. These results suggest that PMNs contribute to the pathogenesis of LPS hepatotoxicity.


Aberration correction for improving the image quality in STED microscopy using the genetic algorithm.
With a purely optical modulation of fluorescent behaviors, stimulated emission depletion (STED) microscopy allows for far-field imaging with a diffraction-unlimited resolution in theory. The performance of STED microscopy is affected by many factors, of which aberrations induced by the optical system and biological samples can distort the wave front of the depletion beam at the focal plane to greatly deteriorate the spatial resolution and the image contrast. Therefore, aberration correction is imperative for STED imaging, especially for imaging thick specimens. Here, we present a wave front compensation approach based on the genetic algorithm (GA) to restore the distorted laser wave front for improving the quality of STED images. After performing aberration correction on two types of zebrafish samples, the signal intensity and the imaging resolution of STED images were both improved, where the thicknesses were 24 μm and 100 μm in the zebrafish retina sample and the zebrafish embryo sample, respectively. The results showed that the GA-based wave front compensation approach has the capability of correction for both system-induced and sample-induced aberrations. The elimination of aberrations can prompt STED imaging in deep tissues; therefore, STED microscopy can be expected to play an increasingly important role in super-resolution imaging related to the scientific research in biological fields.


Effects of carbon dioxide inhalation on psychomotor and mental performance during exercise and recovery.
On separate days, 6 highly trained participants performed psychomotor tests while breathing for 60 min 3 carbon dioxide (CO(2)) mixtures (room air, 3% CO(2), or 4% CO(2)) prior to, between, and following two 15-min treadmill exercise bouts (70% VO(2)(max)). Each individual was extensively practiced (at least 4 days) before testing began, and both gas conditions and order of tasks were counterbalanced. Results showed physiological reactions and work-related psychomotor effects, but no effects of gas concentration on addition, multiplication, grammatical reasoning, or dynamic postural balance. These findings help define behavioral toxicity levels and support a re-evaluation of existing standards for the maximum allowable concentrations (also emergency and continuous exposure guidance levels) of CO(2). This research explored the selection of psychometric instruments of sufficient sensitivity and reliability to detect subtle changes in performance caused by exposure to low levels of environmental stress, in this case differential levels of CO(2) in the inspired air.


A single amino acid change in the glycoprotein of lymphocytic choriomeningitis virus is associated with the ability to cause growth hormone deficiency syndrome.
Persistent infection of C3H/St mice with certain strains of lymphocytic choriomeningitis virus (LCMV) causes a growth hormone (GH) deficiency syndrome (GHDS) manifested as growth retardation and hypoglycemia. Infected mice show high levels of viral replication in the GH-producing cells in the anterior pituitary leading to decreased synthesis of GH mRNA and protein despite the absence of detectable virus-induced cell structural damage. Virus clones isolated from the GHDS-negative LCMV WE strain can cause the disease, while others cannot. The genetic basis of this phenotypic difference is a nucleotide substitution resulting in a single amino acid difference in the viral glycoprotein. Reassortant studies indicate that the single amino acid substitution (Ser-153 to Phe) is sufficient to allow infection of the GH-producing cells and cause GHDS. These results show that a single change in the genome can affect viral pathogenicity by altering the tropism of the virus.


Cost-effectiveness analysis of 3-D computerized tomography colonography versus optical colonoscopy for imaging symptomatic gastroenterology patients.
When symptomatic gastroenterology patients have an indication for colonic imaging, clinicians have a choice between optical colonoscopy (OC) and computerized tomography colonography with three-dimensional reconstruction (3-D CTC). 3-D CTC provides a minimally invasive and rapid evaluation of the entire colon, and it can be an efficient modality for diagnosing symptoms. It allows for a more targeted use of OC, which is associated with a higher risk of major adverse events and higher procedural costs. A case can be made for 3-D CTC as a primary test for colonic imaging followed if necessary by targeted therapeutic OC; however, the relative long-term costs and benefits of introducing 3-D CTC as a first-line investigation are unknown. The aim of this study was to assess the cost effectiveness of 3-D CTC versus OC for colonic imaging of symptomatic gastroenterology patients in the UK NHS. We used a Markov model to follow a cohort of 100,000 symptomatic gastroenterology patients, aged 50 years or older, and estimate the expected lifetime outcomes, life years (LYs) and quality-adjusted life years (QALYs), and costs (£, 2010-2011) associated with 3-D CTC and OC. Sensitivity analyses were performed to assess the robustness of the base-case cost-effectiveness results to variation in input parameters and methodological assumptions. 3D-CTC provided a similar number of LYs (7.737 vs 7.739) and QALYs (7.013 vs 7.018) per individual compared with OC, and it was associated with substantially lower mean costs per patient (£467 vs £583), leading to a positive incremental net benefit. After accounting for the overall uncertainty, the probability of 3-D CTC being cost effective was around 60 %, at typical willingness-to-pay values of £20,000-£30,000 per QALY gained. 3-D CTC is a cost-saving and cost-effective option for colonic imaging of symptomatic gastroenterology patients compared with OC.


Knowledge, attitudes and behaviour of hospital health-care workers regarding influenza A/H1N1: a cross sectional survey.
To assess the knowledge, the attitudes, and the behaviour towards influenza A/H1N1 and the vaccination among health-care workers (HCWs). A sample of HCWs was selected from a random sample of non-teaching public hospitals, located in the cities of Naples and Avellino (Italy), received a self-administered anonymous questionnaire including questions about socio-demographic characteristics, knowledge on modes of transmission and preventative measures, attitudes and behaviour relating to influenza A/H1N1. Only 36.1% correctly knew the main modes of transmission, and that HCWs are a risk category and this level of knowledge was significantly higher in HCWs having received information through scientific journals. A higher perceived risk of contracting influenza A/H1N1 has been observed in the HCWs more knowledgeable, in those considering influenza A/H1N1 a serious disease, and in those working in surgical wards. Only 16.7% have received the influenza A/H1N1 vaccination and HCWs with more fear of contracting influenza A/H1N1, those considering vaccine more useful and less dangerous were more likely to receive vaccine. Education and communication strategies for improving the level of knowledge and for the immunization uptake regarding influenza A/H1N1 HCWs are strongly needed.


Exposure to dust, endotoxin and airborne microorganisms in wastewater sludge thermal drying units.
The objective of this study was to assess workers' exposure to bioaerosols in sludge drying units. Simultaneous collection of inhalable dust and airborne biological agents was carried out using rotating cup samplers (CIP 10, Arelco). Sixteen stationary and 30 personal measurements were performed in three drying plants, during summer and winter. Microbial content of air was characterized by high amounts of Gram-negative bacteria, endotoxin, and thermophilic actinomycetes. High differences between exposure levels were observed with regard to workplaces and tasks. Dryers and conveyors in operation were closed, and the monitoring task in the dryer room was associated with low levels of personal exposure, close to background levels. Conversely, cleaning and maintenance of the dryer and conveyors required the equipment to be opened, giving significantly higher task-based personal exposure levels. The fall of dried sludge into indoor containers resulted in high emission and spreading of dust. Mean personal exposure levels to fungi were moderate or low for all tasks. Based on the results of this study, appropriate means of operational control and personal protection are being developed and implemented on sites.


Integrating Screening, Brief Intervention and Referral to Treatment (SBIRT) for Substance Use into Prenatal Care.
Universal screening for substance use during pregnancy, brief intervention, and referral to treatment (SBIRT) is recommended by ACOG and the USPSTF. Here we present the implementation of SBIRT into the electronic health record (EHR) to inform clinical intervention and collect data on the prevalence of substance use during pregnancy at three prenatal clinics. A literature-based SBIRT instrument was developed. The tool was integrated into the EHR of a resident Ob/Gyn clinic, an MFM practice, and an Ob/Gyn generalist practice at our institution, an academic, tertiary care medical center in an urban area, and automated reports of aggregate retrospective EHR data were used to monitor patient responses to SBIRT over time. Data reports included patient responses to screening for substance use, brief intervention, and referral to treatment from January to December 2018 RESULTS: An interprofessional team of health care providers and systems analysts guided the SBIRT implementation process. As of December 2018, overall SBIRT performance during prenatal care encounters was 1797/2619 (69%), 432/1350 (32%), and 1290/1518 (85%) in the resident clinic, MFM practice, and generalist practice, respectively. Eighty (5.1%) women in the resident clinic, 2 (0.5%) in the MFM practice and 14 (1%) in the generalist practice reported past or present substance use. Integrating universal SBIRT into prenatal care using the EHR requires a multi-disciplinary approach. The SBIRT tool facilitates reportable substance use screening, brief intervention, and referral to treatment during prenatal care. Future reports will further characterize substance use in our prenatal practices and inform intervention strategies in this population.


The effect of HI-6 on cholinesterases and on the cholinergic system of the rat bladder.
The current standard treatment of organophosphate poisoning consists of an administration of anticholinergic drugs and cholinesterase reactivators (oximes). Oximes can react - except their reactivating effect on cholinesterases - directly with cholinoreceptors. HI-6 is an oxime that may have an inhibitory effect on the muscarinic receptors, too. In our work, we have investigated an influence of HI-6 on the acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and on the muscarinic receptors in vitro. The study was conducted using biosensor technique and on the rat bladder using in vitro test (tissue bath; methacholine as muscarinic agonist). IC50 for BChE from human serum was determined to be 1.01x10-6 M and for human erythrocytes AChE 3.31x10-6 M, respectively. We assume that the demonstrated contractile response can be attributed to the inhibition of the AChE at the lower concentration and to a predominant inhibition of muscarinic receptor at higher concentration of compound tested.


A modelling study of long term green roof retention performance.
This paper outlines the development of a conceptual hydrological flux model for the long term continuous simulation of runoff and drought risk for green roof systems. A green roof's retention capacity depends upon its physical configuration, but it is also strongly influenced by local climatic controls, including the rainfall characteristics and the restoration of retention capacity associated with evapotranspiration during dry weather periods. The model includes a function that links evapotranspiration rates to substrate moisture content, and is validated against observed runoff data. The model's application to typical extensive green roof configurations is demonstrated with reference to four UK locations characterised by contrasting climatic regimes, using 30-year rainfall time-series inputs at hourly simulation time steps. It is shown that retention performance is dependent upon local climatic conditions. Volumetric retention ranges from 0.19 (cool, wet climate) to 0.59 (warm, dry climate). Per event retention is also considered, and it is demonstrated that retention performance decreases significantly when high return period events are considered in isolation. For example, in Sheffield the median per-event retention is 1.00 (many small events), but the median retention for events exceeding a 1 in 1 yr return period threshold is only 0.10. The simulation tool also provides useful information about the likelihood of drought periods, for which irrigation may be required. A sensitivity study suggests that green roofs with reduced moisture-holding capacity and/or low evapotranspiration rates will tend to offer reduced levels of retention, whilst high moisture-holding capacity and low evapotranspiration rates offer the strongest drought resistance.


Pluripotent Stem Cell-Based Therapeutics for Muscular Dystrophies.
Pluripotent stem cells (PSCs) represent an attractive cell source for treating muscular dystrophies (MDs) since they easily allow for the generation of large numbers of highly regenerative myogenic progenitors. Using reprogramming technology, patient-specific PSCs have been derived for several types of MDs, and genome editing has allowed correction of mutations, opening the opportunity for their therapeutic application in an autologous transplantation setting. However, there has been limited progress on preclinical studies that validate the therapeutic potential of these gene corrected PSC-derived myogenic progenitors. In this review, we highlight the major research advances, challenges, and future prospects towards the development of PSC-based therapeutics for MDs.


A randomized clinical trial comparing prompt photodynamic therapy with 3 months observation in patients with acute central serous chorioretinopathy with central macular leakage.
The purpose of the study was to demonstrate whether photodynamic therapy in patients with acute central serous chorioretinopathy, with the leakage point within one optic disk diameter from the fovea, can be safely deferred. A single-center, randomized, controlled trial was conducted. Patients were randomized to photodynamic therapy within a week after presentation (Group I, 26 patients) or observation during 3 months (Group II, 26 patients). If leakage or subretinal fluid was observed during any control visit, photodynamic therapy was performed (again) within a week. Primary outcome was change of visual acuity (Early Treatment Diabetic Retinopathy Study) after 12 months. Secondary outcomes were visual acuity, central foveal thickness, metamorphopsia, and color discrimination. Photodynamic therapy procedures: group I, 26 at baseline, 2 retreatments at 3 months; group II, 10 at 3 months, 1 at 6 months (2 subjects refusing treatment), 2 retreatments at 6 months. At 12 months, mean visual acuity of all patients had improved by 6.5 letters (P < 0.001), mean central foveal thickness was 172 µm less (P < 0.001). After photodynamic therapy, visual acuity recovered faster and metamorphopsia significantly improved (3 months, P < 0.001). Differences between groups at 12 months were not significant. The (intended) number of photodynamic therapy (re)treatments in group II (n = 15) was 46% less than in group I (n = 28). Visual acuity and central foveal thickness at 12 months were similar. Therefore, the preferred management of acute central serous chorioretinopathy at presentation appears to be observation for 3 months.


Early diagenetic processes generate iron and manganese oxide layers in the sediments of Lake Baikal, Siberia.
Distinct layers of iron(III) and manganese(IV) (Fe/Mn) oxides are found buried within the reducing part of the sediments in Lake Baikal and cause considerable complexity and steep vertical gradients with respect to the redox sequence. For the on-site investigation of the responsible biogeochemical processes, we applied filter tube samplers for the extraction of sediment porewater combined with a portable capillary electrophoresis instrument for the analyses of inorganic cations and anions. On the basis of the new results, the sequence of diagenetic processes leading to the formation, transformation, and dissolution of the Fe/Mn layers was investigated. With two exemplary cores we demonstrate that the dissolution of particulate Fe and Mn is coupled to the anaerobic oxidation of CH₄ (AOM) either via the reduction of sulphate (SO₄(2-)) and the subsequent generation of Fe(II) by S(-II) oxidation, or directly coupled to Fe reduction. Dissolved Fe(II) diffuses upwards to reduce particulate Mn(IV) thus forming a sharp mineral boundary. An alternative dissolution pathway is indicated by the occurrence of anaerobic nitrification of NH₄(+) observed at locations with Mn(IV). Furthermore, the reasons and consequences of the non-steady-state sediment pattern and the resulting redox discontinuities are discussed and a suggestion for the burial of active Fe/Mn layers is presented.


The effects of cash transfers and vouchers on the use and quality of maternity care services: A systematic review.
Cash transfers and vouchers are forms of 'demand-side financing' that have been widely used to promote maternal and newborn health in low- and middle-income countries during the last 15 years. This systematic review consolidates evidence from seven published systematic reviews on the effects of different types of cash transfers and vouchers on the use and quality of maternity care services, and updates the systematic searches to June 2015 using the Joanna Briggs Institute approach for systematic reviewing. The review protocol for this update was registered with PROSPERO (CRD42015020637). Data from 51 studies (15 more than previous reviews) and 22 cash transfer and voucher programmes suggest that approaches tied to service use (either via payment conditionalities or vouchers for selected services) can increase use of antenatal care, use of a skilled attendant at birth and in the case of vouchers, postnatal care too. The strongest evidence of positive effect was for conditional cash transfers and uptake of antenatal care, and for vouchers for maternity care services and birth with a skilled birth attendant. However, effects appear to be shaped by a complex set of social and healthcare system barriers and facilitators. Studies have typically focused on an initial programme period, usually two or three years after initiation, and many lack a counterfactual comparison with supply-side investment. There are few studies to indicate that programmes have led to improvements in quality of maternity care or maternal and newborn health outcomes. Future research should use multiple intervention arms to compare cost-effectiveness with similar investment in public services, and should look beyond short- to medium-term service utilisation by examining programme costs, longer-term effects on service utilisation and health outcomes, and the equity of those effects.


Binding of AP-1 Golgi adaptors to membranes requires phosphorylated cytoplasmic domains of the mannose 6-phosphate/insulin-like growth factor II receptor.
In mammalian cells, clathrin-coated vesicles mediate transport of the lysosomal enzyme receptors from the trans-Golgi network to the endocytic pathway. A critical step of this process is the recruitment of Golgi-specific adaptors onto Golgi membranes for efficient clathrin polymerization. An in vitro assay was used here to quantitate this event in streptolysin-O-permeabilized NRK cells. At 37 degrees C, these interactions are cytosol- and energy-dependent, sensitive to GTP gamma S (guanosine 5'-O-(thiotriphosphate)) and brefeldin A. We report that Golgi-specific adaptor binding is enhanced in mannose 6-phosphate/insulin-like growth factor II (IGF II) receptor-overexpressing cells and reduced in mannose 6-phosphate receptor-deficient cells. Furthermore, adaptor binding is partially inhibited after addition of soluble cytoplasmic domains of the mannose 6-phosphate/IGF II receptor. Almost complete inhibition is only observed when this domain is phosphorylated on serines 2421 and 2492, a major modification acquired during exit of the receptor from the Golgi. These results show that the mannose 6-phosphate/IGF II receptor is part of the components that recruit the Golgi-specific adaptors and that its phosphorylation is an important feature for high affinity interactions with sorting components.


Epidemiological risk factors associated with high global frequency of inapparent dengue virus infections.
Dengue is a major international public health concern, and the number of outbreaks has escalated greatly. Human migration and international trade and travel are constantly introducing new vectors and pathogens into novel geographic areas. Of particular interest is the extent to which dengue virus (DENV) infections are subclinical or inapparent. Not only may such infections contribute to the global spread of DENV by human migration, but also seroprevalence rates in naïve populations may be initially high despite minimal numbers of detectable clinical cases. As the probability of severe disease is increased in secondary infections, populations may thus be primed, with serious public health consequences following introduction of a new serotype. In addition, pre-existing immunity from inapparent infections may affect vaccine uptake, and the ratio of clinically apparent to inapparent infection could affect the interpretation of vaccine trials. We performed a literature search for inapparent DENV infections and provide an analytical review of their frequency and associated risk factors. Inapparent rates were highly variable, but "inapparent" was the major outcome of infection in all prospective studies. Differences in the epidemiological context and type of surveillance account for much of the variability in inapparent infection rates. However, one particular epidemiological pattern was shared by four longitudinal cohort studies: the rate of inapparent DENV infections was positively correlated with the incidence of disease the previous year, strongly supporting an important role for short-term heterotypic immunity in determining the outcome of infection. Primary and secondary infections were equally likely to be inapparent. Knowledge of the extent to which viruses from inapparent infections are transmissible to mosquitoes is urgently needed. Inapparent infections need to be considered for their impact on disease severity, transmission dynamics, and vaccine efficacy and uptake.


Height-growth response to climatic changes differs among populations of Douglas-fir: a novel analysis of historic data.
Projected climate change will affect existing forests, as substantial changes are predicted to occur during their life spans. Species that have ample intraspecific genetic differentiation, such as Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco), are expected to display population-specific growth responses to climate change. Using a mixed-effects modeling approach, we describe three-year height (HT) growth response to changes in climate of interior Douglas-fir populations. We incorporate climate information at the population level, yielding a model that is specific to both species and population. We use data from provenance tests from previous studies that comprised 236 populations from Idaho, Montana, and eastern Washington, USA. The most sensitive indicator of climate was the mean temperature of the coldest month. Population maximum HT and HT growth response to changes in climate were dependent on seed source climate. All populations had optimum HT growth when transferred to climates with warmer winters; those originating in sites with the warmest winters were taller across sites and had highest HT growth at transfer distances closest to zero; those from colder climates were shortest and had optimum HT growth when transferred the farthest. Although this differential response damped the height growth differences among populations, cold-climate populations still achieved their maximum growth at lower temperatures than warm-climate populations. The results highlight the relevance of understanding climate change impacts at the population level, particularly in a species with ample genetic variation among populations.


Mild or moderate renal insufficiency does not increase circulating levels of cobalt and chromium in patients with metal-on-metal hip arthroplasty.
To determine whether there is any association between glomerular filtration rate (GFR) and blood cobalt (Co) and chromium (Cr) levels in patients with metal-on-metal (MoM) hip arthroplasty. We identified 179 patients with a unilateral 36 mm diameter head as part of a stemmed Summit-Pinnacle MoM hip arthroplasty. GFR was calculated using the Modification of Diet in Renal Disease formula. Normal renal function (GFR ≥ 90 ml/min/1.73 m2) was seen in 74 patients. Mild renal insufficiency (GFR 60 to 89 ml/min/1.73 m2) was seen in 90 patients and moderate renal insufficiency (GFR 30 to 59 ml/min/1.73 m2) in 15. There was no statistical difference in Co and Cr levels between patients with normal renal function and those with mild or moderate renal insufficiency. No correlation was seen between creatinine and blood metal ion levels or between GFR and blood metal ion levels. Linear regression analysis did not show any association between Co and Cr levels and GFR. We did not find any association between GFR and blood metal ion levels. Consequently, the accumulation of Co and Cr in blood due to renal insufficiency does not seem to be a major risk in patients with mild or moderate renal insufficiency. Cite this article Bone Joint J 2017;99-B:1147-52.


A novel human artificial chromosome gene expression system using herpes simplex virus type 1 vectors.
Human artificial chromosome (HAC) vectors are an important gene transfer system for expression and complementation studies. We describe a significant advance in HAC technology using infectious herpes simplex virus type 1 (HSV-1) amplicon vectors for delivery. This highly efficient method has allowed gene-expressing HACs to be established in glioma-, kidney- and lung-derived cells. We also developed an HSV-1 hypoxanthine phosphoribosyltransferase (HPRT) HAC vector, which generated functional HPRT-expressing HACs that complemented the genetic deficiency in human cells. The transduction efficiency of the HSV-1 HAC amplicons is several orders of magnitude higher than lipofection-mediated delivery. Studies on HAC stability between cell types showed important differences that have implications for HAC development and gene expression in human cells. This is the first report of establishing gene-expressing HACs in human cells by using an efficient, high-capacity viral vector and by identifying factors that are involved in cell-type-specific HAC instability. The work is a significant advance for HAC technology and the development of HAC gene expression systems in human cells.


Auditory delta event-related oscillatory responses are decreased in Alzheimer's disease.
Visual delta event-related (ERO) and evoked oscillations (EO) of Alzheimer patients (AD) are different than healthy. In the present study, the analysis is extented to include auditory ERO and EO in AD. The rationale is to reveal whether the auditory ERO delta responses are also reduced, and whether this is a general phenomenon in Alzheimer patients upon applying stimuli with cognitive load. Thirty-four mild AD subjects [17 de-novo and 17 medicated (cholinergic)] and seventeen healthy controls were included. Auditory oddball paradigm and sensory auditory stimuli were applied to the subjects. Oscillatory responses were analyzed by measuring maximum amplitudes in delta frequency range (0.5-3.5 Hz). Auditory delta ERO (0.5-3.5 Hz) responses of healthy controls were higher than either de-novo AD or medicated AD group, without a difference between two AD subgroups. Furthermore, the auditory EO after presentation of tone bursts yielded no group difference. Our findings imply that delta ERO is highly unstable in AD patients in comparison to age-matched healthy controls only during the cognitive paradigm. Our results favor the hypothesis that neural delta networks are activated during cognitive tasks and that the reduced delta response is a general phenomenon in AD, due to cognitive impairment.


On the Margins of Pharmaceutical Citizenship: Not Taking HIV Medication in the "Treatment Revolution" Era.
With the expanding pharmaceuticalization of public health, anthropologists have begun to examine how biomedicine's promissory discourses of normalization and demarginalization give rise to new practices of and criteria for citizenship. Much of this work focuses on the biomedicine-citizenship nexus in less-developed, resource-poor contexts. But how do we understand this relationship in resource-rich settings where medicines are readily available, often affordable, and a highly commonplace response to illness? In particular, what does it mean to not use pharmaceuticals for a treatable infectious disease in this context? We are interested in these questions in relation to the recent push for early and universal treatment for HIV infection in Australia for the twin purposes of individual and community health. Drawing on Ecks's concept of pharmaceutical citizenship, we examine the implications for citizenship among people with HIV who refuse or delay recommended medication. We find that moral and normative expectations emerging in the new HIV "treatment revolution" have the capacity to both demarginalize and marginalize people with HIV.


Racial/ethnic discrimination and well-being during adolescence: A meta-analytic review.
This meta-analytic study systematically investigates the relations between perceived racial/ethnic discrimination and socioemotional distress, academics, and risky health behaviors during adolescence, and potential variation in these relations. The study included 214 peer-reviewed articles, theses, and dissertations, with 489 unique effect sizes on 91,338 unique adolescents. Random-effects meta-analyses across 11 separate indicators of well-being identified significant detrimental effects. Greater perceptions of racial/ethnic discrimination were linked to more depressive and internalizing symptoms; greater psychological distress; poorer self-esteem; lower academic achievement and engagement; less academic motivation; greater engagement in externalizing behaviors, risky sexual behaviors, and substance use; and more associations with deviant peers. Metaregression and subgroup analyses indicated differences by race/ethnicity, Gender × Race/Ethnicity interactions, developmental stage, timing of retrospective measurement of discrimination, and country. Overall, this study highlights the pernicious effects of racial/ethnic discrimination for adolescents across developmental domains and suggests who is potentially at greater risk. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Improving the outcome of umbilical cord blood transplantation through ex vivo expansion or graft manipulation.
The outcome of umbilical cord blood transplantation for adult patients with hematologic malignancies now rivals that of matched unrelated donor transplantation. However, relatively low lymphocyte and hematopoietic stem and progenitor cell dose is a source of significant morbidity and mortality. Multiple strategies are now being studied to overcome these limitations. One strategy involves ex vivo expansion of the umbilical cord blood unit before transplantation. Ex vivo expansion has the potential to increase the number of lymphocytes, committed progenitors and long-term repopulating hematopoietic stem cells. Increasing the numbers of lymphocytes and committed progenitor cells will address the issue of delayed hematopoietic recovery after umbilical cord blood transplantation. Increasing the hematopoietic stem cell content will improve the availability of adequately sized and matched cord blood units for transplantation. It may also eliminate the need for dual umbilical cord blood transplantation for those without an adequately sized single umbilical cord blood graft. The second strategy involves exposure of the umbilical cord blood graft to compounds aimed at improving homing and engraftment following transplantation. Such a strategy may also address the problem of slow hematopoietic recovery as well as the increased risk of graft failure. Many of these strategies are now being tested in late-phase multi-center clinical trials. If proven cost-effective and efficacious, they may alter the landscape of donor options for allogeneic stem cell transplantation.


Socioeconomic and behavioral determinants of tooth brushing frequency: results from the representative French 2010 HBSC cross-sectional study.
To describe tooth brushing frequency and its association with a wide range of socioeconomic and behavioral characteristics, using a nationally representative sample of school-aged children in France. Our sample included 11,337 students aged from 10 to 16 years, who answered the HBSC questionnaire. Some variables were grouped into composite variables, thus generating scores for: eating habits, health and body, relationships with parents, socioeconomic status (SES) of family, and school life. Multivariate logistic regression analyses were used to study the relationship between these variables and tooth brushing frequency. Girls were more likely to brush twice a day than boys [adjusted Odds Ratio: aOR 2.47, 95 percent confidence interval CI95% (1.97; 3.11), aOR 1.89, CI95% (1.56; 2.29), aOR 1.45, CI95% (1.25; 1.68) for low, mid, and high school life score, respectively]. Students were more likely to brush twice a day when they had high (versus low) scores for healthy eating habits [aOR = 1.60; 95 percent CI: (1.40; 1.83)], well-being concerning health and body [aOR = 1.61; 95 percent CI: (1.40; 1.86)] and SES [aOR = 1.25; 95 percent CI: (1.09; 1.43)]. We believe that preventive health campaigns should target school and family environments more specifically to reach the most disadvantaged sections of the population and include promotion of whole health. The messages should be designed to efficiently reach adolescents, e.g., by appealing to their maturity, self-esteem, and emotional factors. Through the incorporation of qualitative research elements, identifying the reasons for not brushing twice a day would also help to develop new prevention programs.


Electro-mechano responsive properties of gelatin methacrylate (GelMA) hydrogel on conducting polymer electrodes quantified using atomic force microscopy.
Electrical stimulation of hydrogels has been performed to enable micro-actuation or controlled movement of ions and biomolecules such as in drug release applications. Hydrogels are also increasingly used as low modulus, biocompatible coatings on electrode devices and thus are exposed to the effects of electrical stimulation. As such, there is growing interest in the latter, especially on the dynamic and nanoscale physical properties of hydrogels. Here, we report on the electro-mechano properties of photocrosslinkable gelatin methacrylate (GelMA) hydrogel applied as coatings on conducting polymer polypyrrole-dodecylbenze sulfonate (PPy-DBSA) electrodes. In particular, Electrochemical-Atomic Force Microscopy (EC-AFM) was used to quantify the nanoscale actuation and dynamic changes in Young's modulus as the GelMA coating was electrically stimulated via the underlying PPy-DBSA electrode. Pulsed electrical stimulation was shown to induce dynamic expansion and contraction, or nanoscale actuation, of the GelMA hydrogel due to the reversible ingress of electrolyte ions and associated changes in osmotic pressure during oxidation and reduction of the PPy-DBSA film. In addition, dynamic changes in the Young's modulus of up to 50% were observed in the hydrogel and correlated with the actuation process and ion diffusion during oxidation and reduction of the underlying PPy-DBSA film. These dynamic properties were investigated for hydrogels with varying degrees of cross-linking, porosity and modulus, the latter ranging from ≈0.2-1 kPa. The study demonstrates an AFM-based approach to quantify the dynamic physical properties of hydrogels, which are shown to be modulated via electrical stimulation. This can enable a better understanding of the electro-mechano mechanisms that are important for the controlled release of drugs or controlling cell interactions at the hydrogel-cell interface.


Epidemiological Analysis of the First 1389 Cases of COVID-19 in Poland: A Preliminary Report.
BACKGROUND The World Health Organization has declared COVID-19 a global pandemic. This paper presents an epidemiological analysis of the first phase of the COVID-19 epidemic in Poland. MATERIAL AND METHODS This cross-sectional study was carried out between 3 and 27 March 2020 on a sample of 1389 laboratory-confirmed COVID-19 cases in Poland. Data were obtained from epidemiological reports collected by the Chief Sanitary Inspectorate. Analysis includes the number of COVID-19 cases, number of deaths, number of hospitalizations, number of people quarantined, and number of laboratory tests performed. RESULTS The first case was confirmed on 4 March 2020. Over 24 days after the first case, the total number of confirmed infections rose to 1389 (34,000 laboratory tests were performed). The highest incidence rates (over 5 per 100,000) were observed in the 2 central administrative regions (Mazowieckie and Łódzkie) and in the south-western region of Dolnośląskie, which borders the Czech Republic and Germany. Based on available data about age and sex, a clearly higher incidence was observed in the 20-29 years (4.0 per 100,000), 40-49 years (4.1 per 100,000), and 50-59 years (4.3 per 100,000) age groups. In the period analyzed (24 days), there were 16 confirmed deaths (average age 65.5 years; 81.2% males). CONCLUSIONS The proportion of women and men with confirmed COVID-19 infection was similar to the sex ratio in the general population. Infections were relatively less common in those aged under 20 years. The largest numbers of confirmed cases were detected in 3 of the 4 largest cities, each of which has an international airport.


Percutaneous endoscopic gastrostomy versus nasogastric tube feeding for adults with swallowing disturbances.
A number of conditions compromise the passage of food along the digestive tract. Nasogastric tube (NGT) feeding is a classic, time-proven technique, although its prolonged use can lead to complications such as lesions to the nasal wing, chronic sinusitis, gastro-oesophageal reflux, and aspiration pneumonia. Another method of infusion, percutaneous endoscopy gastrostomy (PEG), is generally used when there is a need for enteral nutrition for a longer time period. There is a high demand for PEG in patients with swallowing disorders, although there is no consistent evidence about its effectiveness and safety as compared to NGT. To evaluate the effectiveness and safety of PEG compared with NGT for adults with swallowing disturbances. We searched The Cochrane Library, MEDLINE, EMBASE, and LILACS from inception to January 2014, and contacted the main authors in the subject area. There was no language restriction in the search. We planned to include randomised controlled trials comparing PEG versus NGT for adults with swallowing disturbances or dysphagia and indications for nutritional support, with any underlying diseases. The primary outcome was intervention failure (e.g. feeding interruption, blocking or leakage of the tube, no adherence to treatment). We used standard methodological procedures expected by The Cochrane Collaboration. For dichotomous and continuous variables, we used risk ratio (RR) and mean difference (MD), respectively with the random-effects statistical model and 95% confidence interval (CI). We assumed statistical heterogeneity when I² > 50%. We included 11 randomised controlled studies with 735 participants which produced 16 meta-analyses of outcome data. Meta-analysis indicated that the primary outcome of intervention failure, occurred in lower proportion of participants with PEG compared to NGT (RR 0.18, 95% CI 0.05 to 0.59, eight studies, 408 participants, low quality evidence) and this difference was statistically significant. For this outcome, we also subgrouped the studies by endoscopic gastrostomy technique into pull, and push and not reported. We observed a significant difference favouring PEG in the pull subgroup (RR 0.07, 95% CI 0.01 to 0.35, three studies, 90 participants). Thepush subgroup contained only one clinical trial and the result favoured PEG (RR 0.05, 95% CI 0.00 to 0.74, one study, 33 participants) techniques. We found no statistically significant difference in cases where the technique was not reported (RR 0.43, 95% CI 0.13 to 1.44, four studies, 285 participants).There was no statistically significant difference between the groups for meta-analyses of the secondary outcomes of mortality (RR 0.86, 95% CI 0.58 to 1.28, 644 participants, nine studies, very low quality evidence), overall reports of any adverse event at any follow-up time point (ITT analysis, RR 0.83, 95% CI 0.51 to 1.34), 597 participants, 6 studies, moderate quality evidence), specific adverse events including pneumonia (aspiration) (RR 0.70, 95% CI 0.46 to 1.06, 645 participants, seven studies, low quality evidence), or for the meta- analyses of the secondary outcome of nutritional status including weight change from baseline, and mid-arm circumference at endpoint, although there was evidence in favour of PEG for meta-analyses of mid-arm circumference change from baseline (MD 1.16, 95% CI 1.01 to 1.31, 115 participants, two studies), and levels of serum albumin were higher in the PEG group (MD 6.03, 95% CI 2.31 to 9.74, 107 participants).For meta-analyses of the secondary outcomes of time on enteral nutrition, there was no statistically significant difference (MD 14.48, 95% CI -2.74 to 31.71; 119 participants, two studies). For meta-analyses of quality of life measures (EuroQol) outcomes in two studies with 133 participants, for inconvenience (RR 0.03, 95% CI 0.00 to 0.29), discomfort (RR 0.03, 95% CI 0.00 to 0.29), altered body image (RR 0.01, 95% CI 0.00 to 0.18; P = 0.001) and social activities (RR 0.01, 95% CI 0.00 to 0.18) the intervention favoured PEG, that is, fewer participants found the intervention of PEG to be inconvenient, uncomfortable or interfered with social activities. However, there were no significant differences between the groups for pain, ease of learning to use, or the secondary outcome of length of hospital stay (two studies, 381 participants). PEG was associated with a lower probability of intervention failure, suggesting the endoscopic procedure may be more effective and safe compared with NGT. There is no significant difference in mortality rates between comparison groups, or in adverse events, including pneumonia related to aspiration. Future studies should include details of participant demographics including underlying disease, age and gender, and the gastrostomy technique.


Understanding vaccine hesitancy around vaccines and vaccination from a global perspective: a systematic review of published literature, 2007-2012.
Vaccine "hesitancy" is an emerging term in the literature and discourse on vaccine decision-making and determinants of vaccine acceptance. It recognizes a continuum between the domains of vaccine acceptance and vaccine refusal and de-polarizes previous characterization of individuals and groups as either anti-vaccine or pro-vaccine. The primary aims of this systematic review are to: 1) identify research on vaccine hesitancy; 2) identify determinants of vaccine hesitancy in different settings including its context-specific causes, its expression and its impact; and 3) inform the development of a model for assessing determinants of vaccine hesitancy in different settings as proposed by the Strategic Advisory Group of Experts Working Group (SAGE WG) for dealing with vaccine hesitancy. A broad search strategy, built to capture multiple dimensions of public trust, confidence and hesitancy around vaccines, was applied across multiple databases. Peer-reviewed studies were selected for inclusion if they focused on childhood vaccines [≤ 7 years of age], used multivariate analyses, and were published between January 2007 and November 2012. Our results show a variety of factors as being associated with vaccine hesitancy but they do not allow for a complete classification and confirmation of their independent and relative strength of influence. Determinants of vaccine hesitancy are complex and context-specific - varying across time, place and vaccines.


Leadership Training in Graduate Medical Education: A Systematic Review.
Leadership is a critical component of physician competence, yet the best approaches for developing leadership skills for physicians in training remain undefined. We systematically reviewed the literature on existing leadership curricula in graduate medical education (GME) to inform leadership program development. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, we searched MEDLINE, ERIC, EMBASE, and MedEdPORTAL through October 2015 using search terms to capture GME leadership curricula. Abstracts were reviewed for relevance, and included studies were retrieved for full-text analysis. Article quality was assessed using the Best Evidence in Medical Education (BEME) index. A total of 3413 articles met the search criteria, and 52 were included in the analysis. Article quality was low, with 21% (11 of 52) having a BEME score of 4 or 5. Primary care specialties were the most represented (58%, 30 of 52). The majority of programs were open to all residents (81%, 42 of 52). Projects and use of mentors or coaches were components of 46% and 48% of curricula, respectively. Only 40% (21 of 52) were longitudinal throughout training. The most frequent pedagogic methods were lectures, small group activities, and cases. Common topics included teamwork, leadership models, and change management. Evaluation focused on learner satisfaction and self-assessed knowledge. Longitudinal programs were more likely to be successful. GME leadership curricula are heterogeneous and limited in effectiveness. Small group teaching, project-based learning, mentoring, and coaching were more frequently used in higher-quality studies.


Handgrip Strength, but Not 5-Meter Walk, Adds Value to a Clinical Nutrition Assessment.
Decreased physical functioning is associated with malnutrition and common in acute care patients; determining loss of function is often considered part of a comprehensive nutrition assessment. Handgrip strength (HGS) and 5-meter timed walk (5m) are functional measures used in a variety of settings. This analysis sought to determine which functional measure could be added to a hospital nutrition assessment, based on its feasibility and capacity to discriminate patient subgroups. Eligible medical patients (no delirium/dementia, admitted from community; n = 1250), recruited from 5 hospitals that participated in a previous multisite action research study, provided data on demographics, HGS, 5m, nutrition status, perceived disability, and other characteristics. Significantly more patients (z = 17.39, P < .00001) were able to complete HGS than 5m (92% versus 43%, respectively). Median HGS was 28.0 kg for men and 14.7 kg for women. Of patients who completed the 5m, mean completion time was 8.98 seconds (median, 6.79 seconds, SD = 6.59). 5m and HGS scores were significantly worse with patient-perceived disability (z = -9.56, t = 10.69, respectively; P < .0001; 95% confidence interval [CI], [7.33, 10.63]; [1.76, 3.18]). HGS was associated with nutrition status (t = 4.13, P < .001; 95% CI [2.02, 5.67]), although it showed poor validity as a single nutrition indicator. These data indicate that HGS is a more useful functional measure than 5m when added to a hospital nutrition assessment. Determination of HGS cutpoints to identify low strength in acute care patients will promote its use.


Results of streamlined regional ambulance transport and subsequent treatment of acute abdominal aortic aneurysms.
To describe the triage of patients operated for non-ruptured and ruptured abdominal aortic aneurysms (AAAs) before the endovascular era. Retrospective single-centre cohort study. All patients treated for an acute AAA between 1998 and 2001 and admitted to our hospital were evaluated in the emergency department for urgent AAA surgery. All time intervals, from the telephone call from the patient to the ambulance department, to the arrival of the patient in the operating theatre, were analysed. Intraoperative, hospital and 1-year survival were determined. 160 patients with an acute AAA were transported to our hospital. Mean (SD) age was 71 (8) years, and 138 (86%) were men. 34 (21%) of these patients had symptomatic, non-ruptured AAA (sAAA) and 126 patients had ruptured AAA (rAAA). All patients with sAAA and 98% of patients with rAAA were operated upon. For the patients with rAAA, median time from telephone call to arrival at the hospital was 43 min (interquartile range 33-53 min) and median time from arrival at the hospital to arrival at the operating room was 25 min (interquartile range 11-50 min). Intraoperative mortality was 0% for sAAA and 11% for rAAA (p = 0.042), and hospital mortality was 12% and 33%, respectively (p = 0.014). A multidisciplinary unified strategy resulted in a rapid throughput of patients with acute AAA. Rapid transport, diagnosis and surgery resulted in favourable hospital mortality. Despite the fact that nearly all the patients were operated upon, survival was favourable compared with published data.


Cyclo-oxygenase (COX) inhibitors for treating preterm labour.
Preterm birth is a major cause of perinatal mortality and morbidity. Cyclo-oxygenase (COX) inhibitors inhibit uterine contractions, are easily administered and appear to have few maternal side effects. However, adverse effects have been reported in the fetus and newborn as a result of exposure to COX inhibitors. To assess the effects on maternal and neonatal outcomes of COX inhibitors administered as a tocolytic agent to women in preterm labour when compared with (i) placebo or no intervention and (ii) other tocolytics. In addition, to compare the effects of non-selective COX inhibitors with COX-2 selective inhibitors. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (24 August 2014). We also contacted recognised experts and searched reference lists of retrieved studies. All published and unpublished randomised trials in which COX inhibitors were used for tocolysis for women in labour between 20 and 36 completed weeks' gestation. Two review authors independently evaluated methodological quality and extracted data. We sought additional information from study authors. Results are presented using risk ratio (RR; dichotomous data) and mean difference (MD; continuous data) with 95% confidence interval (CI). The number needed to treat for benefit (NNTB) and the number needed to treat for harm (NNTH) were calculated for statistically different categorical outcomes. With the addition of seven studies with a total of 684 women, this review now includes outcome data from 20 studies including 1509 women. The non-selective COX inhibitor indomethacin was used in 15 studies. The overall quality of the included studies was considered moderate to low.Three small studies (102 women), two of which were conducted in the 1980's, compared COX inhibition (indomethacin only) with placebo. No difference was shown in birth less than 48 hours after trial entry (average RR 0.20, 95% CI 0.03 to 1.28; two studies with 70 women). Indomethacin resulted in a reduction in preterm birth (before completion of 37 weeks of gestation) in one small study (36 women) (RR 0.21, 95% CI 0.07 to 0.62; NNTB 2, 95% CI 2 to 4); and an increase in gestational age at birth (average MD 3.59 weeks, 95% CI 0.65 to 6.52; two studies with 66 women) and birthweight (MD 716.34 g, 95% CI 425.52 to 1007.16; two studies with 67 infants). No difference was shown in measures of neonatal morbidity or neonatal mortality.Compared with betamimetics, COX inhibitors resulted in a reduction in birth less than 48 hours after trial entry (RR 0.27, 95% CI 0.08 to 0.96; NNTB 7, 95% CI 6 to 120; two studies with 100 women) and preterm birth (before completion of 37 weeks of gestation) (RR 0.53, 95% CI 0.28 to 0.99; NNTB 6, 95% CI 4 to 236; two studies with 80 women) although no benefit was shown in terms of neonatal morbidity or mortality. COX inhibition was also associated with fewer maternal adverse affects compared with betamimetics (RR 0.19, 95% CI 0.11 to 0.31; NNTB 3, 95% CI 2 to 3; five studies with 248 women) and maternal adverse effects requiring cessation of treatment (average RR 0.09, 95% CI 0.02 to 0.49; NNTB 5, CI 95% 5 to 9; three studies with 166 women).No differences were shown when comparing COX inhibitors with magnesium sulphate (MgSO4) (seven studies with 792 women) or calcium channel blockers (CCBs) (two studies with 230 women) in terms of prolonging pregnancy or for any fetal/neonatal outcomes. There were also no differences in very preterm birth (before completion of 34 weeks of gestation) and no maternal deaths occurred in the one study that reported on this outcome. However COX inhibitors resulted in fewer maternal adverse affects when compared with MgSO4 (RR 0.39, 95% CI 0.25 to 0.62; NNTB 11, 95% CI 9 to 17; five studies with 635 women).A comparison of non-selective COX inhibitors versus any COX-2 inhibitor (two studies with 54 women) did not demonstrate any differences in maternal, fetal or neonatal outcomes.No data were available to assess COX inhibitors compared with oxytocin receptor antagonists (ORAs). Further, no data were available on extremely preterm birth (before 28 weeks of gestation), longer-term infant outcomes or costs. In this review, no clear benefit for COX inhibitors was shown over placebo or any other tocolytic agents. While some benefit was demonstrated in terms of postponement of birth for COX inhibitors over placebo and betamimetics and also maternal adverse effects over betamimetics and MgSO4, due to the limitations of small numbers, minimal data on safety, lack of longer-term outcomes and generally low quality of the studies included in this review, we conclude that there is insufficient evidence on which to base decisions about the role of COX inhibition for women in preterm labour. Further well-designed tocolytic studies are required to determine short- and longer-term infant benefit of COX inhibitors over placebo and other tocolytics, particularly CCBs and ORAs. Another important focus for future studies is identifying whether COX-2 inhibitors are superior to non-selective COX inhibitors. All future studies on tocolytics for women in preterm labour should assess longer-term effects into early childhood and also costs.


Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase.
Reverse transcriptase (RT) from the human immunodeficiency virus continues to be an attractive drug target for antiretroviral therapy. June 2022 will commemorate the 30th anniversary of the first Human Immunodeficiency Virus (HIV) RT crystal structure complex that was solved with non-nucleoside reverse transcriptase inhibitor nevirapine. The release of this structure opened opportunities for designing many families of non-nucleoside reverse transcriptase inhibitors (NNRTIs). In paying tribute to the first RT-nevirapine structure, we have developed several compound classes targeting the non-nucleoside inhibitor binding pocket of HIV RT. Extensive analysis of crystal structures of RT in complex with the compounds informed iterations of structure-based drug design. Structures of seven additional complexes were determined and analyzed to summarize key interactions with residues in the non-nucleoside inhibitor binding pocket (NNIBP) of RT. Additional insights comparing structures with antiviral data and results from molecular dynamics simulations elucidate key interactions and dynamics between the nucleotide and non-nucleoside binding sites.


Long-term results of total hip arthroplasty with a cemented custom-designed swan-neck femoral component for congenital dislocation or severe dysplasia: a follow-up note.
This follow-up study updates the results in a consecutive series of nineteen cemented total hip replacements with a swan-neck femoral component in patients with congenital dislocation or severe hip dysplasia. The series was previously reported on in 1993. The patients were petite, with an average height of 152 cm and an average weight of 50 kg, and the femoral canals could not accommodate an off-the-shelf femoral component. Sixteen of the nineteen hips were available for follow-up at an average of 13.3 years (range, eleven to twenty years). Fourteen hips had up-to-date clinical and radiographic examinations. At the time of the latest follow-up, thirteen hips were rated as excellent; two, as good; and one, as a failure because of loosening of both components requiring revision eleven years after the index operation. Another hip required acetabular revision because of loosening fifteen years after the index operation. The rates of femoral and acetabular component revision were 6% and 12.5%, respectively. Radiographic analysis demonstrated that no femoral component was loose. One cup was definitely loose at 19.5 years, and three cups were possibly loose at an average of fourteen years. The radiographic rate of acetabular loosening was 33%. The total rate of cup failure (radiographic loosening and revision) was 43%. The excellent clinical and radiographic results associated with the swan-neck femoral component, and the 94% rate of survival, at an average of 13.3 years (range, eleven to twenty years) indicate that the biomechanical objectives of this custom-designed prosthesis for patients with congenital dislocation or severe hip dysplasia were met. On the basis of this favorable long-term experience, we still use this prosthesis when the anatomic abnormality cannot be adequately addressed by use of a commercially available prosthetic component.


Dutch translation and cross-cultural adaptation of the PROMIS® physical function item bank and cognitive pre-test in Dutch arthritis patients.
Patient-reported physical function is an established outcome domain in clinical studies in rheumatology. To overcome the limitations of the current generation of questionnaires, the Patient-Reported Outcomes Measurement Information System (PROMIS®) project in the USA has developed calibrated item banks for measuring several domains of health status in people with a wide range of chronic diseases. The aim of this study was to translate and cross-culturally adapt the PROMIS physical function item bank to the Dutch language and to pretest it in a sample of patients with arthritis. The items of the PROMIS physical function item bank were translated using rigorous forward-backward protocols and the translated version was subsequently cognitively pretested in a sample of Dutch patients with rheumatoid arthritis. Few issues were encountered in the forward-backward translation. Only 5 of the 124 items to be translated had to be rewritten because of culturally inappropriate content. Subsequent pretesting showed that overall, questions of the Dutch version were understood as they were intended, while only one item required rewriting. Results suggest that the translated version of the PROMIS physical function item bank is semantically and conceptually equivalent to the original. Future work will be directed at creating a Dutch-Flemish final version of the item bank to be used in research with Dutch speaking populations.


Direct identification of dyes in textiles by direct analysis in real time-time of flight mass spectrometry.
We present here a method requiring no sample preparation for direct identification of the organic dye compounds quercetin, indigotin, and alizarin in reference materials, in solution, and also in situ in dyed fibers by use of direct analysis in real time (DART) ionization and high-resolution time-of-flight mass spectrometry. Exact mass determinations on small samples of dyed textiles were completed in less than 1 min. With the ability to identify flavonoid, indigoid, and anthraquinone classes of dyes, this technique shows early promise as an additional analytical tool in the challenging analysis of organic dyes in rare cultural heritage materials and possesses the unique advantages of sensitivity and simplicity without the preparatory procedures required by other methods.


Downward social mobility and major depressive episodes among Latino and Asian-American immigrants to the United States.
The authors analyzed the association between downward social mobility in subjective social status among 3,056 immigrants to the United States and the odds of a major depressive episode. Using data from the National Latino and Asian American Study (2002-2003), the authors examined downward mobility by comparing immigrants' subjective social status in their country of origin with their subjective social status in the United States. The dependent variable was the occurrence of a past-year episode of major depression defined according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. Logistic regression models were used to control for a variety of sociodemographic and immigration-related characteristics. Analyses suggested that a loss of at least 3 steps in subjective social status is associated with increased risk of a depressive episode (odds ratio = 3.0, 95% confidence interval: 1.3, 6.6). Other factors independently associated with greater odds of depression included Latino ethnicity, female sex, having resided for a longer time in the United States, and being a US citizen. The findings suggest that immigrants who experience downward social mobility are at elevated risk of major depression. Policies or interventions focused only on immigrants of low social status may miss another group at risk: those who experience downward mobility from a higher social status.


Fetal brain genomic reprogramming following asphyctic preconditioning.
Fetal asphyctic (FA) preconditioning is effective in attenuating brain damage incurred by a subsequent perinatal asphyctic insult. Unraveling mechanisms of this endogenous neuroprotection, activated by FA preconditioning, is an important step towards new clinical strategies for asphyctic neonates. Genomic reprogramming is thought to be, at least in part, responsible for the protective effect of preconditioning. Therefore we investigated whole genome differential gene expression in the preconditioned rat brain. FA preconditioning was induced on embryonic day 17 by reversibly clamping uterine circulation. Male control and FA offspring were sacrificed 96 h after FA preconditioning. Whole genome transcription was investigated with Affymetrix Gene1.0ST chip. Data were analyzed with the Bioconductor Limma package, which showed 53 down-regulated and 35 up-regulated transcripts in the FA-group. We validated these findings with RT-qPCR for adh1, edn1, leptin, rdh2, and smad6. Moreover, we investigated differences in gene expression across different brain regions. In addition, we performed Gene Set Enrichment Analysis (GSEA) which revealed 19 significantly down-regulated gene sets, mainly involved in neurotransmission and ion transport. 10 Gene sets were significantly up-regulated, these are mainly involved in nucleosomal structure and transcription, including genes such as mecp2. Here we identify for the first time differential gene expression after asphyctic preconditioning in fetal brain tissue, with the majority of differentially expressed transcripts being down-regulated. The observed down-regulation of cellular processes such as neurotransmission and ion transport could represent a restriction in energy turnover which could prevent energy failure and subsequent neuronal damage in an asphyctic event. Up-regulated transcripts seem to exert their function mainly within the cell nucleus, and subsequent Gene Set Enrichment Analysis suggests that epigenetic mechanisms play an important role in preconditioning induced neuroprotection.


Growth and nutrient removal efficiency of duckweed (lemna minor) from synthetic and dumpsite leachate under artificial and natural conditions.
Sustainable management of leachate produced from the dumpsite is one of the major concerns in developing countries Aquatic plants such as duckweed have the potential to remove pollutants from wastewater which can also be cost-effective and feasible options for leachate treatment. Therefore, the objective of our present study was to examine the growth and nutrient removal efficiency of duckweed (Lemna minor) on leachate. Three tests were performed each by growing lemna minor on synthetic leachate under controlled conditions and on dumpsite leachate under natural conditions. During each test, duckweed was grown in 300 ml plastic containers with a surface area of 25.8 cm2. About 60 mg of fresh mass of duckweed was grown on 250 ml leachate at an internal depth of 9.5 cm. Results revealed that, in comparison to synthetic leachate, duckweed removed Chemical Oxygen Demand (COD), nitrogen (N), and phosphorous (P) more efficiently from dumpsite leachate under natural climatic conditions. However, the amounts of N and P absorbed into duckweed body mass were about 16% and 35% respectively more at synthetic leachate under controlled conditions. Maximum growth rate of duckweed (7.03 g m-2 day-1) was also observed for synthetic leachate in comparison to the growth rate of 4.87 g m-2 day-1 at dumpsite leachate. Results of this study provide a useful interpretation of duckweed growth and nutrient removal dynamics from leachate under natural and laboratory conditions.


Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis.
Primate studies and some observational human data have raised concern regarding an association of first-trimester efavirenz exposure with central nervous system congenital anomalies. The objective of this review is to update evidence on efavirenz safety in HIV-infected pregnant women to inform revision of the 2013 WHO guidelines for antiretroviral therapy in low and middle-income countries. A systematic review and meta-analysis. We searched for studies reporting birth outcomes among women exposed to efavirenz during the first trimester of pregnancy up to 10 January 2014. Relative risks of congenital anomalies comparing women exposed to efavirenz and nonefavirenz-based antiretroviral regimens were pooled using random effects meta-analysis. Twenty-three studies were included in this review, among which 21 reported the birth outcomes of 2026 live births among women exposed to efavirenz during the first trimester of pregnancy. Forty-four congenital anomalies were reported, giving a pooled proportion of 1.63% [95% confidence interval (95% CI) 0.78-2.48], with only one neural tube defect. Twelve studies reported birth outcomes of women exposed to efavirenz or nonefavirenz-containing regimens during the first trimester of pregnancy. Pooled analysis found no differences in overall risks congenital anomalies between these two groups (relative risk 0.78, 95% CI 0.56-1.08). The incidence of neural tube defects was low, 0.05% (95% CI <0.01-0.28), and similar to incidence in the general population. This updated analysis found no evidence of an increased risk of overall or central nervous system congenital anomalies associated with first-trimester exposure to efavirenz, similar to previous systematic reviews. This review contributed to the evidence base for the revised 2013 WHO guidelines on antiretroviral therapy, which recommend that efavirenz can be included as part of first-line therapy in adults regardless of sex, and that it can be used throughout pregnancy, including during the first trimester. However, because of the low incidence of central nervous system anomalies in the overall population and relatively small number of exposures in the current literature, continued birth outcomes prospective surveillance is warranted.


Experimental Study of Nonclassical Teleportation Beyond Average Fidelity.
Quantum teleportation establishes a correspondence between an entangled state shared by two separate parties that can communicate classically and the presence of a quantum channel connecting the two parties. The standard benchmark for quantum teleportation, based on the average fidelity between the input and output states, indicates that some entangled states do not lead to channels which can be certified to be quantum. It was recently shown that if one considers a finer-grained witness, then all entangled states can be certified to produce a nonclassical teleportation channel. Here we experimentally demonstrate a complete characterization of a new family of such witnesses, of the type proposed in Phys. Rev. Lett. 119, 110501 (2017)PRLTAO0031-900710.1103/PhysRevLett.119.110501 under different conditions of noise. We report nonclassical teleportation using quantum states that cannot achieve average fidelity of teleportation above the classical limit. We further use the violation of these witnesses to estimate the negativity of the shared state. Our results have fundamental implications in quantum information protocols and may also lead to new applications and quality certification of quantum technologies.


T cell receptor repertoire for a viral epitope in humans is diversified by tolerance to a background major histocompatibility complex antigen.
Two unusual characteristics of the memory response to the immunodominant Epstein-Barr virus (EBV) epitope FLRGRAYGL, which associates with HLA B8, have provided an unique opportunity to investigate self tolerance and T cell receptor (TCR) plasticity in humans. First, the response is exceptionally restricted, dominated by cytotoxic T lymphocytes (CTL) with identical TCR protein sequences (Argaet, V. P., C. W. Schmidt, S. R. Burrows, S. L. Silins, M. G. Kurilla, D. L. Doolan, A. Suhrbier, D. J. Moss, E. Kieff, T. B. Sculley, and I. S. Misko. 1994. J. Exp. Med. 180:2335-2340). Second, CTL expressing this receptor are cross-reactive with the alloantigen HLA B* 4402 on uninfected cells (Burrows, S. R., R. Khanna, J. M. Burrows, and D. J. Moss. 1994. J. Exp. Med. 179:1155-1161). No CTL using this conserved public TCR could be reactivated from the peripheral blood of EBV exposed individuals expressing both HLA B8 and B*4402, demonstrating the clonal inactivation of potentially self-reactive T cells in humans. A significant FLRGRAYGL-specific response was still apparent, however, and TCR sequence analysis of multiple CTL clones revealed an oligoclonal TCR repertoire for this determinant within these individuals, using diverse V and J gene segments and CDR3 regions. In addition, a significant public TCR component was identified in which several distinct alpha/beta rearrangements are shared by CTL clones from a number of unrelated HLA B8+, B*4402+ donors. The striking dominance of public TCR in the response to this EBV epitope suggests a strong genetic bias in TCR gene recombination. Fine specificity analysis using peptide analogues showed that, of six different antigen receptors for FLRGRAYGL/HLA B8, none associate closely with the peptide's full array of potential TCR contact residues. Whereas the HLA B*4402-cross-reactive receptor binds amino acids toward the COOH terminus of the peptide, others preferentially favor an NH2-terminal determinant, presumably evading an area that mimics a structure presented on HLA B*4402. Thus, tolerance to a background major histocompatibility antigen can effectively diversify the TCR repertoire for a foreign epitope by deflecting the response away from an immunodominant combination of TCR-binding residues.


Accurate computation of the Briot-Sellmeier and Briot-Cauchy chromatic dispersion coefficients from the transmittance spectrum of thin films of arbitrary absorptance.
An exact formalism devoted to the determination of dispersion coefficients is described. The method takes into account two frequent experimental configurations: a solid thin layer on a substrate and a fluid, or solid, layer between a substrate and a superstrate. Introducing the concepts of reduction and reduced finesse, this method is based entirely on the fringes' spectral position of the maxima in the transmittance spectrum. It is found that the chromatic dispersion does not affect the spectral position of the minima in the same way as it does for the maxima. There is no need to get the refractive-index curve, n(lambda), to determine the dispersion coefficients nor to work at multiple incidence angles. Bringing together the possible nonrestrictive approximations, the method becomes easy and simple to implement from a spectrophotometer in tandem with a computer. In addition, the spectrometer does not require ordinate-axis calibration, and knowledge of the substrate's and superstrate's refractive index is not required. Alternatively, the method can be easily used to accurately determine the thickness of thin layers. A numerical example using a thin layer of 2-methyl-4-nitroaniline (MNA) is given.


Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs.
Microglia are the resident macrophage-like population in the CNS. Microglia remain quiescent until injury or infection activates the cells to perform effector inflammatory and APC functions. Our previous studies have shown that microglia infected with a neurotropic strain of Theiler's murine encephalomyelitis virus secreted innate immune cytokines and up-regulated costimulatory molecules and MHC class II, enabling the cells to present viral and myelin Ags to CD4+ T cells. Recently, TLRs have been shown to recognize pathogen-associated molecular patterns and initiate innate immune responses upon interaction with infectious agents. We examined TLR expression on brain microglia and their functional responses upon stimulation with various TLR agonists. We report that mouse microglia express mRNA for all of the recently identified TLRs, TLR1-9, used for recognition of bacterial and viral molecular patterns. Furthermore, stimulation of quiescent microglia with various TLR agonists, including LPS (TLR4), peptidoglycan (TLR2), polyinosinic-polycytidylic acid (TLR3), CpG DNA (TLR9), and infection with viable Theiler's murine encephalomyelitis virus, activated the cells to up-regulate unique patterns of innate and effector immune cytokines and chemokines at the mRNA and protein levels. In addition, TLR stimulation activated up-regulation of MHC class II and costimulatory molecules, enabling the microglia to efficiently present myelin Ags to CD4+ T cells. Thus, microglia appear to be a unique and important component of both the innate and adaptive immune response, providing the CNS with a means to rapidly and efficiently respond to a wide variety of pathogens.


Interactions between the microtubule-associated tau proteins and S100b regulate tau phosphorylation by the Ca2+/calmodulin-dependent protein kinase II.
Binding between the microtubule-associated tau protein and S100b protein was demonstrated by affinity chromatography and cross-linking experiments and was manifested in the effect of S100b on tau protein phosphorylation by protein kinase II. All three expressions of the binding showed that S100b discriminates among the four species of tau, revealing for the first time that the different kinds of tau may differ functionally. Noncovalent interaction between tau and S100b depended on the presence of Ca2+ or Zn2+ and resulted in total inhibition of tau phosphorylation by protein kinase II. In the absence of reducing agent, covalent binding studies between Cys84 beta in the carboxyl-terminal region of the S100b-beta subunit and tau proteins confirmed interactions between the two proteins. It is suggested that the homologous calcium-binding domain that characterizes the carboxyl terminus of S100 and the tubulin subunit may be responsible for the common interaction of both proteins with tau proteins. The physicochemical relationship between S100 subunits and p11, the subunit of a substrate for tyrosine kinase, and their similarity in interaction with protein kinase substrates are discussed.


Aortic ejection velocity in healthy Boxers with soft cardiac murmurs and Boxers without cardiac murmurs: 201 cases (1997-2001).
To determine aortic ejection velocity in healthy adult Boxers with soft ejection murmurs without overt structural evidence of left ventricular outflow tract obstruction and in healthy Boxers without cardiac murmurs. Retrospective study. 201 Boxers. Dogs were examined independently by 2 individuals for evidence of a cardiac murmur, and a murmur grade was assigned. Maximal instantaneous (peak) aortic ejection velocity was measured by means of continuous-wave Doppler echocardiography from a subcostal location. Forty-eight dogs were reexamined approximately 1 year later. A soft (grade 1, 2, or 3) left-basilar ejection murmur was detected in 113 (56%) dogs. Overall median aortic ejection velocity was 1.91 m/s (range, 1.31 to 4.02 m/s). Dogs with murmurs had significantly higher aortic ejection velocities than did those without murmurs (median, 2.11 and 1.72 m/s, respectively). Auscultation of a murmur was 87% sensitive and 66% specific for the identification of aortic ejection velocity > 2.0 m/s. An ejection murmur and aortic ejection velocity > 2.0 m/s were identified in 73 (36%) dogs. For most dogs, observed changes in murmur grade and aortic ejection velocity during a follow-up examination 1 year later were not clinically important. Results suggested that ejection murmurs were common among healthy adult Boxers and that Boxers with murmurs were likely to have high (> 2.0 m/s) aortic ejection velocities. The cause of the murmurs in these dogs is unknown.


Addressing intersections in HIV/AIDS and mental health: the role of organizations for d/Deaf and hard of hearing individuals in South Africa.
Like south africans generally, d/Deaf and hard of hearing South Africans are at risk of HIV/AIDS and mental disorders resulting from barriers to communication and care. In interviews and a focus group, members of South African organizations for d/Deaf and hard of hearing individuals all gave priority to HIV/AIDS education and prevention, citing risks resulting from language and communication barriers, inadequate schooling, and insufficient information in South African Sign Language. Participants gave varied descriptions of HIV/AIDS programs in schools for d/Deaf and hard of hearing students and described school initiatives they had directed. Some participants gave mental health problems lesser priority; others said susceptibility to mental disorders may result from communication difficulties and therefore warrants specialized services. Others, seeing a need to address mental health in HIV/AIDS prevention, had designed programs accordingly. Such prevention efforts merit support, as do activities to reduce communication barriers.


Central nervous system infections in immunocompromised patients.
Although rare, central nervous system (CNS) infections are increasingly being recognized in immunocompromised patients. The goal of the present review is to provide a practical diagnostic approach for the intensivist, and to briefly discuss some of the most prevalent conditions. Immunocompromised patients presenting with new neurological symptoms should always be suspected of a CNS infection. These infections carry a poor prognosis, especially if intracranial hypertension, severely altered mental status or seizures are present. Clinical examination and serum blood tests should be followed by brain imaging, and when no contra-indications are present, a lumbar puncture including cerebrospinal fluid PCR to identify causative organisms. Empirical therapy depends on the type of immunodeficiency. In HIV-infected patients, the most common CNS infection is cerebral toxoplasmosis, whereas in other immunocompromised patients, aspergillosis, cryptococcal meningitis and tuberculous meningitis are more prevalent. Multiple pathogens can be detected in up to 15% of patients. The diagnostic value of fast multiplex PCR has yet to be evaluated in this setting. CNS infections represent a rare but severe complication in immunocompromised patients. A systematic approach including early diagnosis, appropriate antimicrobial treatment, early ICU admission and aggressive measures to reduce intracranial pressure may improve outcome.


The effect of protein complexation on the mechanical stability of Im9.
Force mode microscopy can be used to examine the effect of mechanical manipulation on the noncovalent interactions that stabilize proteins and their complexes. Here we describe the effect of complexation by the high affinity protein ligand E9 on the mechanical resistance of the simple four-helical protein, Im9. When concatenated into a construct of alternating I27 domains, Im9 unfolded below the thermal noise limit of the instrument ( approximately 20 pN). Complexation of E9 had little effect on the mechanical resistance of Im9 (unfolding force approximately 30 pN) despite the high avidity of this complex (K(d) approximately 10 fM).


Functional network analysis of obese and lean Göttingen minipigs elucidates changes in oxidative and inflammatory networks in obese pigs.
The Göttingen minipig model of obesity is used in pre-clinical research to predict clinical outcome of new treatments for metabolic diseases. However, treatment effects often remain unnoticed when using single parameter statistical comparisons due to the small numbers of animals giving rise to large variation and insufficient statistical power. The purpose of this study was to perform a correlation matrix analysis of multiple multi-scale parameters describing co-segregation of traits in order to identify differences between lean and obese minipigs. More than 40 parameters, ranging from physical, cardiovascular, inflammatory and metabolic markers were measured in lean and obese animals. Correlation matrix analysis was performed using permutation test and bootstrapping at different levels of significance. Single parameter comparisons yielded significant differences between lean and obese animals mainly for known physical traits. On the other hand, functional network analysis revealed new co-segregations, particularly in the domain of inflammatory and oxidative stress markers in the obese animals that were not present in the lean. Functional networks of lean or obese minipigs could be utilised to assess drug effects and predict changes in parameters with a certain degree of precision, on the basis of the networks confidence intervals. Comparison of functional networks in minipigs with those of human clinical data may be used to identify common parameters or co-segregations related to obesity between animal models and man.


Clinical features and outcomes of patients with type 2 myocardial infarction: Insights from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial.
Type 2 myocardial infarction (MI) is characterized by an imbalance between myocardial blood supply and demand, leading to myocardial ischemia without coronary plaque rupture, but its diagnosis is challenging. In the TRACER trial, patients with non-ST-segment elevation acute coronary syndromes were included. We aimed to describe provoking factors, cardiac biomarker profiles, treatment patterns, and clinical outcomes of patients with type 2 MIs. MI events during trial follow-up were adjudicated by an independent clinical events classification committee (CEC) and were classified according to the Third Universal Definition of MI. Using available source documents retrieved as part of the CEC process, we performed a retrospective chart abstraction to collect details on the type 2 MIs. Cox regression models were used to explore the association between MI type (type 1 or type 2) and cardiovascular death. Overall, 10.3% (n=1327) of TRACER participants had a total of 1579 adjudicated MIs during a median follow-up of 502 days (25th and 75th percentiles [IQR] 349-667). Of all MIs, 5.2% (n=82) were CEC-adjudicated type 2 MIs, occurring in 76 patients. The incidence of type 2 MI was higher in the first month following randomization, after which the distribution became more scattered. The most frequent potential provoking factors for type 2 MIs were tachyarrhythmias (38.2%), anemia/bleeding (21.1%), hypotension/shock (14.5%), and hypertensive emergencies (11.8%). Overall, 36.3% had a troponin increase >10× the upper limit of normal. Coronary angiography was performed in 22.4% (n=17) of patients during hospitalizations due to type 2 MIs. The hazard of cardiovascular death was numerically higher following type 2 MI (vs. no MI, adj. HR 11.82, 95% CI 5.71-24.46; P<.0001) than that of type 1 MI (vs. no MI, adj. HR 8.90, 95% CI 6.93-11.43; P<.0001). Type 2 MIs were more prevalent in the first month after ACS, were characterized by the presence of triggers and infrequent use of an invasive strategy, and were associated with a high risk of death. Further efforts are needed to better define the role and implications of type 2 MI in both clinical practice and research.