Participation of TDP1 in the repair of formaldehyde-induced DNA-protein cross-links in chicken DT40 cells.
Proteins are covalently trapped on DNA to form DNA-protein cross-links (DPCs) when cells are exposed to DNA-damaging agents. Aldehyde compounds produce common types of DPCs that contain proteins in an undisrupted DNA strand. Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs topoisomerase 1 (TOPO1) that is trapped at the 3'-end of DNA. In the present study, we examined the contribution of TDP1 to the repair of formaldehyde-induced DPCs using a reverse genetic strategy with chicken DT40 cells. The results obtained showed that cells deficient in TDP1 were sensitive to formaldehyde. The removal of formaldehyde-induced DPCs was slower in tdp1-deficient cells than in wild type cells. We also found that formaldehyde did not produce trapped TOPO1, indicating that trapped TOPO1 was not a primary cytotoxic DNA lesion that was generated by formaldehyde and repaired by TDP1. The formaldehyde treatment resulted in the accumulation of chromosomal breakages that were more prominent in tdp1-deficient cells than in wild type cells. Therefore, TDP1 plays a critical role in the repair of formaldehyde-induced DPCs that are distinct from trapped TOPO1.


Phonological similarity affects production of gestures, even in the absence of overt speech.
Highlights Does phonological similarity affect gesture production in the absence of speech?Participants produced gestures from pictures with no words presented or spoken.Same pictures and gestures but different training labels were used.Phonologically similar labels led to more errors in subsequent gestures.Thus, phonological similarity affects gesture production in the absence of speech. Are manual gestures affected by inner speech? This study tested the hypothesis that phonological form influences gesture by investigating whether phonological similarity between words that describe motion gestures creates interference for production of those gestures in the absence of overt speech. Participants learned to respond to a picture of a bottle by gesturing to open the bottle's cap, and to a picture of long hair by gesturing to twirl the hair. In one condition, the gestures were introduced with phonologically-similar labels "twist" and "twirl" (similar condition), while in the other condition, they were introduced with phonologically-dissimilar labels "unscrew" and "twirl" (dissimilar condition). During the actual experiment, labels were not produced and participants only gestured by looking at pictures. In both conditions, participants also gestured to a control pair that was used as a baseline. Participants made significantly more errors on gestures in the similar than dissimilar condition after correction for baseline differences. This finding shows the influence of phonology on gesture production in the absence of overt speech and poses new constraints on the locus of the interaction between language and gesture systems.


Human Cases of Tularemia in Armenia, 1996-2012.
A retrospective analysis was conducted of human cases and outbreaks of tularemia in the Republic of Armenia from 1996 to 2012 utilizing geographic information system software. A total of 266 human cases of tularemia were recorded in Armenia from 1996 to 2012, with yearly incidence ranging from 0 to 5.5 cases per 100,000 people. Cases predominantly affected the male population (62.8%), 11-20 year age group (37.2%), agricultural workers (49.6%), and persons residing in rural areas (93.6%). In 2003, a waterborne outbreak involving 158 cases occurred in Kotayk Marz, and in 2007, a foodborne outbreak with 17 cases occurred in Gegharkunik Marz, attributed to exposure of food products to contaminated hay. Geospatial analysis of all cases showed that the majority were associated with the steppe vegetation zone, elevations between 1,400 and 2,300 m, and the climate zone associated with dry, warm summers, and cold winters. Characterization of these environmental factors were used to develop a predictive risk model to improve surveillance and outbreak response for tularemia in Armenia.


Management of primary negative symptoms in schizophrenia: an one-year observational study.
Negative symptoms represent a separate symptom domain, with respect to depression, neurocognition, and social cognition and have a strong direct and indirect impact on real-life functioning. Furthermore, negative symptoms that do not improve following antipsychotic treatment are an important diagnostic and therapeutic challenge. We conducted a 12-month-study open-observational study to evaluate the efficacy of some atypical antipsychotics on negative symptoms, according to the following recommendations of Consensus Development Conference Attendees. In our study, we evaluated in an open-label study the efficacy of some second-generation antipsychotics (clozapine, quetiapine, olanzapine, aripiprazole, paliperidone) in 42 patients with schizophrenia or schizoaffective disorder (DSM-5 criteria) with 'persistent negative symptoms'. We used different rating scales (PANSS, CDSs, BNSS, BPRS), but mainly we focused on the new Brief Negative Symptoms Scale (BNSS) for negative symptoms. Our total data indicate an overall statistically significant reduction in all scales, although not clinically relevant.


The Skyline ecosystem: Informatics for quantitative mass spectrometry proteomics.
Skyline is a freely available, open-source Windows client application for accelerating targeted proteomics experimentation, with an emphasis on the proteomics and mass spectrometry community as users and as contributors. This review covers the informatics encompassed by the Skyline ecosystem, from computationally assisted targeted mass spectrometry method development, to raw acquisition file data processing, and quantitative analysis and results sharing.


Twenty-Five Year Survival of Children with Intellectual Disability in Western Australia.
To investigate survival up to early adulthood for children with intellectual disability and compare their risk of mortality with that of children without intellectual disability. This was a retrospective cohort study of all live births in Western Australia between January 1, 1983 and December 31, 2010. Children with an intellectual disability (n = 10 593) were identified from the Western Australian Intellectual Disability Exploring Answers Database. Vital status was determined from linkage to the Western Australian Mortality database. Kaplan-Meier product limit estimates and 95% CIs were computed by level of intellectual disability. Hazard ratios (HRs) and 95% CIs were calculated from Cox proportional hazard regression models adjusting for potential confounders. After adjusting for potential confounders, compared with those without intellectual disability, children with intellectual disability had a 6-fold increased risk of mortality at 1-5 years of age (adjusted HR [aHR] = 6.0, 95%CI: 4.8, 7.6), a 12-fold increased risk at 6-10 years of age (aHR = 12.6, 95% CI: 9.0, 17.7) and a 5-fold increased risk at 11-25 years of age (aHR = 4.9, 95% CI: 3.9, 6.1). Children with severe intellectual disability were at even greater risk. No difference in survival was observed for Aboriginal children with intellectual disability compared with non-Aboriginal children with intellectual disability. Although children with intellectual disability experience higher mortality at all ages compared with those without intellectual disability, the greatest burden is for those with severe intellectual disability. However, even children with mild to moderate intellectual disability have increased risk of death compared with unaffected children.


Gradient-mixing LEGO robots for purifying DNA origami nanostructures of multiple components by rate-zonal centrifugation.
DNA origami purification is essential for many fields, including biophysics, molecular engineering, and therapeutics. The increasing interest in DNA origami has led to the development of rate-zonal centrifugation (RZC) as a scalable, high yield, and contamination-free method for purifying DNA origami nanostructures. RZC purification uses a linear density gradient of viscous media, such as glycerol or sucrose, to separate molecules according to their mass and shape. However, many methods for creating density gradients are time-consuming because they rely on slow passive diffusion. To expedite the preparation time, we used a LEGO gradient mixer to generate rotational motion and rapidly create a quasi-continuous density gradient with a minimal layering of the viscous media. Rotating two layers of differing concentrations at an angle decreases the time needed to form the density gradient from a few hours to minutes. In this study, the density gradients created by the LEGO gradient mixer were used to purify 3 DNA origami shapes that have different aspect ratios and numbers of components, with an aspect ratio ranging from 1:1 to 1:100 and the number of components up to 2. The gradient created by our LEGO gradient mixer is sufficient to purify folded DNA origami nanostructures from excess staple strands, regardless of their aspect ratios. Moreover, the gradient was able to separate DNA origami dimers from DNA origami monomers. In light of recent advances in large-scale DNA origami production, our method provides an alternative for purifying DNA origami nanostructures in large (gram) quantities in resource-limited settings.


Community Pharmacies' Promotion of Smoking Cessation Support Services in Saudi Arabia: Examining Current Practice and Barriers.
Community pharmacists' interventions have been found to be highly effective. However, to date, there has been little information about pharmacists' potential roles and perceived barriers to providing smoking cessation. This study aimed to assess the potential role of community pharmacists in supporting their patients to quit smoking by summarizing their self-reported level of current activities, confidence, and perceived barriers; Methods: A self-administered questionnaire was used for a cross-sectional study in Saudi Arabia. As part of the questionnaire, demographic characteristics were measured, as well as confidence, perceived berries, and level of smoking cessation activities (asking, advising, assessing, assisting, and arranging, including follow-up).; Results: 370 community pharmacists practicing responded to the survey. Pharmacists indicated high activity rates about advising and assessing patients in quitting smoking, with lower rates of assisting and arranging, including following up. The rate of recording smoking status was very low. There were significant differences between gender, source of education, years practicing as a licensed pharmacist, attended an education or training program on smoking cessation, and interest in providing smoking and perceived practice of smoking cessation. Pharmacists are confident about providing smoking cessation activities. Barriers to providing smoking cessation services include unable to follow up, lack of counseling space, lack of educational materials, and lack of time.; Conclusions: Saudi Arabian community pharmacists actively offer smoking cessation services, which may reduce smoking-related health issues. It appears that pharmacists need to be empowered by team-based, systematic, comprehensive approaches to overcome barriers and enhance their confidence.


Survey and Molecular Characterization of Sarcocystidae protozoa in Wild Cricetid Rodents from Central and Southern Chile.
In Chile, studies of parasites from the family Sarcocystidae (Apicomplexa) have mostly been related to domestic animals. We aimed to assess the presence of Sarcocystidae taxa in cricetid rodents from Central and Southern Chile. We studied 207 rodents, encompassing six species, from 13 localities. We isolated DNA from tissue samples, amplified the Sarcocystidae 18S rRNA gene with polymerase chain reaction, and performed phylogenetic analyses using maximum likelihood and Bayesian inferences. In addition, we examined blood smears and performed histological studies in organs from Sarcocystidae DNA-positive animals. Three specimens were DNA-positive and three genotypes were retrieved and named: Sarcocystis sp. P61, related to Sarcocystis strixi, was detected in two Abrothrix olivacea. Toxoplasmatinae gen. sp. P99 was retrieved from those same two specimens, and was related to Toxoplasma and other genera, although it branched independently. Besnoitia sp. R34 was detected in one Abrothrix hirta, and was clustered with congeneric species associated with rodents. No protozoa were found during microscopic studies; thus, it was not possible to confirm parasitic interactions rather than accidental encounters. However, the close relatedness of the retrieved genotypes to parasites of rodents supports the hypothesis of host-parasite associations. All three genotypes are suggested as potential new taxa, including a putative new genus.


A reconfigurable digital filterbank for hearing-aid systems with a variety of sound wave decomposition plans.
Current hearing-aid systems have fixed sound wave decomposition plans due to the use of fixed filterbanks, thus cannot provide enough flexibility for the compensation of different hearing impairment cases. In this paper, a reconfigurable filterbank that consists of a multiband-generation block and a subband-selection block is proposed. Different subbands can be produced according to the control parameters without changing the structure of the filterbank system. The use of interpolation, decimation, and frequency-response masking enables us to reduce the computational complexity by realizing the entire system with only three prototype filters. Reconfigurability of the proposed filterbank enables hearing-impaired people to customize hearing aids based on their own specific conditions to improve their hearing ability. We show, by means of examples, that the proposed filterbank can achieve a better matching to the audiogram and has smaller complexity compared with the fixed filterbank. The drawback of the proposed method is that the throughput delay is relatively long (>20 ms), which needs to be further reduced before it can be used in a real hearing-aid application.


Hepatic venous outflow reconstruction in right lobe living-donor liver graft using recipient's superficial femoral vein.
Venous congestion of a liver graft from a life donor is a disastrous complication with a high risk of graft failure. For safety reasons, the middle hepatic vein (MHV) is currently unanimously left with the donor. As this vessel provides major venous draining of the right anterior sector, reconstruction of significant MHV tributaries is controversial. We describe here successful venous outflow reconstruction in adult-to-adult right lobe living-donor liver transplantation (RL-LDLT) using the recipient's superficial femoral vein (SFV). Six months after transplantation, graft function and perfusion are excellent, and the patient is free of venous morbidity related to the harvest of the SFV.


A simple score for predicting coronary artery disease in patients with chest pain.
We have previously derived a chest pain score by comparing those with and without coronary artery disease on angiography, which was subsequently validated in patients attending coronary angiography. To test the predictive validity of the score prospectively in a more varied out-patient population, and to determine whether it had predictive validity in addition to exercise testing. Prospective clinical study. The score was applied to 405 out-patients with chest pain who subsequently underwent coronary angiography. Framingham risk analysis and exercise testing were performed in 155. The score had a sensitivity of 91.4% and specificity of 28% for coronary artery disease, which was found in 31.8%, 51%, 63%, and 82% of those with scores of 0, 1, 2, and 3, respectively. Gender (p < 0.001), age (p < 0.001), and chest pain score (p = 0.009) independently predicted coronary artery disease on multivariate Poisson regression analysis. The chest pain score had additive predictive value with Framingham risk analysis and Duke's score. This simple chest pain score can predict coronary anatomy with similar sensitivity to exercise testing, and can be used in conjunction with exercise testing and other measures. Further validation of the chest pain score in the primary care setting will be useful.


Diammonium tricadmium tris-(sulfate) dihydroxide dihydrate.
The title compound, (NH(4))(2)Cd(3)(SO(4))(3)(OH)(2)(H(2)O)(2), has been obtained serendipitously. It is isotypic with the heavier alkali analogues M(2)Cd(3)(SO(4))(3)(OH)(2)(H(2)O)(2) (M = K, Rb, Cs). The structure contains two Cd(2+) ions, one in a general position and one with site symmetry m. The former Cd(2+) ion is coordinated by three O atoms of three SO(4) groups, two hydroxide O atoms and one water O atom, the latter Cd(2+) ion by four O atoms of four SO(4) groups and two hydroxide O atoms, both in a distorted octa-hedral coordination geometry. This arrangement leads to the formation of a layered framework extending parallel to (100), with the ammonium cations situated in the voids. O-H⋯O hydrogen bonds involving the water mol-ecules, hydroxide groups and sulfate O atoms, as well as N-H⋯O hydrogen bonds between ammonium cations and sulfate O atoms consolidate the crystal packing.


Early onset atrial lesions in a patient with a novel LMNA frameshift mutation.
Genetic mutations in the lamin A/C gene (LMNA) have been linked to cardiomyopathy. Different mutational sites exhibit different clinical manifestations and prognoses. Herein, we identified a novel LMNA frameshift mutation, p.P485Tfs*67, from a patient with early-onset atrial disease. To verify the pathogenicity of this variation, a transgenic zebrafish model was constructed, which demonstrated that adult zebrafish with the LMNA mutation showed an abnormal ECG and impaired myocardial structure. Our study suggests the atrial pathogenicity of the LMNA-P485Tfs mutation, which is helpful to understand the function of the Ig-like domain of lamin A/C.


Effect of sampling time on the culturability of airborne fungi and bacteria sampled by filtration.
Air sampling of bioaerosols by filtration may be preferable for many epidemiological studies because the methods can be used to collect personal samples for a full work-shift. There is some concern, however, that the viability of fungal spores and bacterial cells might be compromised by sampling for as long as a full shift. This study was designed to determine the effect of sampling up to 6 h on the viability (measured by culture) of airborne fungi and bacteria at composting facilities. Six side-by-side samples were collected in two locations at each of three composting facilities for 1 h at 2 l/m on polycarbonate filters. Two samples in each set were then capped while clean, HEPA-filtered air was drawn across two others for an additional 2 h and across the last two for an additional 5 h. Filters were washed and the samples were analyzed for culturable bacteria and fungi, and for total bacteria and fungi by microscopic counting. Concentrations ranged from 1.7 x 10(3) to 6.2 x 10(7) c.f.u./m3 of culturable fungi and 1.17 x 10(4) to 1.0 x 10(6) c.f.u./m3 of culturable bacteria. In linear models that included duration of sampling, location, and the interaction of location and sample duration, neither sample duration nor the interaction term were significant predictors of the logs of the concentrations of culturable fungi or bacteria or of the ratio of the logs of the culturable concentrations to total concentrations for fungi or bacteria. This suggests that increased sampling time does not affect the viability of the organisms commonly found in the air at composting facilities.


Evaluation of biological potential of selected species of family Poaceae from Bahawalpur, Pakistan.
Oxidative stress as well as bacterial and fungal infections are common source of diseases while plants are source of medication for curative or protective purposes. Hence, aim of study was to compare the pharmacological potential of seven grass species in two different solvents i.e. ethanol and acetone. Preliminary phytochemical tests were done and antioxidant activities were evaluated using ELISA and their IC50 values and AAI (%) were recorded. ANOVA was used for statistical analyses. DNA damage protection assay was done using p1391Z plasmid DNA and DNA bands were analyzed. Antimicrobial activity was done via disc diffusion method and MIC and Activity Index were determined. Cytotoxic activity was carried out using the brine shrimps' assay and LC50 values were calculated using probit analysis program. Phytochemical studies confirmed the presence of secondary metabolites in most of the plant extracts. Maximum antioxidant potential was revealed in DiAEE, DiAAE (AAI- 54.54% and 43.24%) and DaAEE and DaAAE (AAI- 49.13% and 44.52%). However, PoAEE and PoAAE showed minimum antioxidant potential (AAI- 41.04% and 34.11%). SaSEE, DiAEE and ElIEE showed very little DNA damage protection activity. In antimicrobial assay, DaAEE significantly inhibited the growth of most of the microbial pathogens (nine microbes out of eleven tested microbes) among ethanol extracts while DaAAE and ImCAE showed maximum inhibition (eight microbes out of eleven tested microbes) among acetone plant extracts. However, PoAEE and PoAAE showed least antimicrobial activity. F. oxysporum and A. niger were revealed as the most resistant micro-organisms. ImCEA and ImCAE showed maximum cytotoxic potential (LC50 11.004 ppm and 7.932 ppm) as compared to the other plant extracts. Fodder grasses also contains a substantial phenols and flavonoids contents along with other secondary metabolites and, hence, possess a significant medicinal value. Ethanol extracts showed more therapeutic potential as compared to the acetone extracts. This study provides experimental evidence that the selected species contains such valuable natural compounds which can be used as medicinal drugs in future.


Obstructive sleep apnea and objective short sleep duration are independently associated with the risk of serum vitamin D deficiency.
Studies demonstrate an association between vitamin D (25(OH)D) deficiency and sleep disturbances, such as obstructive sleep apnea (OSA) and short sleep duration. However, to date, no studies have concurrently and objectively evaluated the effect of these factors on 25(OH)D. To evaluate whether OSA and objective short sleep duration are independently associated with reduced 25(OH)D in an adult population sample. A cross-sectional study included 657 individuals from the city of Sao Paulo, Brazil, as part of the ERA project. Participants fulfilled questionnaires and underwent clinical evaluation, polysomnography and blood sample collection for 25(OH)D quantification. OSA was classified into three categories (mild, moderate and severe). The risk of 25(OH)D deficiency was considered as levels<30 ng/mL. Short sleep duration was defined as total sleep time<6 hours. The risk of 25(OH)D deficiency was observed in 59.5% of the sample, affecting more individuals of the female gender, obese, with African American ethnicity, and those that were smokers, sedentary and presented hypertension and diabetes. In the final logistic model adjusted for age, gender, ethnicity, obesity, smoking, hypertension, diabetes, sedentary lifestyle, seasonality and creatinine serum levels, both OSA and short sleep duration showed significant independent associations with the risk of 25(OH)D deficiency (moderate OSA: OR for 25(OH)D<30 = 2.21, 95% CI: 1.35-3.64, p<0.01; severe OSA: OR for 25(OH)D<30 = 1.78, 95% CI: 1.06-3.00, p = 0.03; short sleep duration: OR for 25(OH)D<30 = 1.61, 95% CI: 1.15-2.26, p = 0.01). After a subgroup analysis, similar results were observed only in participants ≥50 years. OSA and short sleep duration are independently associated with the risk of 25(OH)D deficiency in an adult population. Age-related changes in vitamin D metabolism and the frequency of sleep disorders may be involved in these associations. Future studies exploring whether 25(OH)D levels may modulate OSA and sleep curtailment-related outcomes are needed.


Controlled fragmentation of multimaterial fibres and films via polymer cold-drawing.
Polymer cold-drawing is a process in which tensile stress reduces the diameter of a drawn fibre (or thickness of a drawn film) and orients the polymeric chains. Cold-drawing has long been used in industrial applications, including the production of flexible fibres with high tensile strength such as polyester and nylon. However, cold-drawing of a composite structure has been less studied. Here we show that in a multimaterial fibre composed of a brittle core embedded in a ductile polymer cladding, cold-drawing results in a surprising phenomenon: controllable and sequential fragmentation of the core to produce uniformly sized rods along metres of fibre, rather than the expected random or chaotic fragmentation. These embedded structures arise from mechanical-geometric instabilities associated with 'neck' propagation. Embedded, structured multimaterial threads with complex transverse geometry are thus fragmented into a periodic train of rods held stationary in the polymer cladding. These rods can then be easily extracted via selective dissolution of the cladding, or can self-heal by thermal restoration to re-form the brittle thread. Our method is also applicable to composites with flat rather than cylindrical geometries, in which case cold-drawing leads to the break-up of an embedded or coated brittle film into narrow parallel strips that are aligned normally to the drawing axis. A range of materials was explored to establish the universality of this effect, including silicon, germanium, gold, glasses, silk, polystyrene, biodegradable polymers and ice. We observe, and verify through nonlinear finite-element simulations, a linear relationship between the smallest transverse scale and the longitudinal break-up period. These results may lead to the development of dynamical and thermoreversible camouflaging via a nanoscale Venetian-blind effect, and the fabrication of large-area structured surfaces that facilitate high-sensitivity bio-detection.


Differential Effects of Retinoic Acid Concentrations in Regulating Blood-Brain Barrier Properties.
The blood-brain barrier (BBB) is a multifaceted property of the brain vasculature that protects the brain and maintains homeostasis by tightly regulating the flux of ions, molecules, and cells across the vasculature. Blood vessels in the brain are formed by endothelial cells that acquire barrier properties, such as tight and adherens junctions, soon after the brain vasculature is formed. Endothelial WNT signaling is crucial to induce these BBB properties by regulating their expression and stabilization. Recent studies have implicated retinoic acid (RA) signaling in BBB development and shown that pharmacological concentrations of RA (≥5 µm) can induce BBB properties in cultured brain endothelial cells. However, a recent study demonstrated that RA inhibits endothelial WNT signaling during brain development, suggesting that RA does not promote BBB properties. We therefore investigated whether RA plays a physiological role in BBB development. We found that BBB function and junctional protein expression was unaffected in mouse mutants that have a reduced capacity to synthesize RA (Rdh10 mutants). Furthermore, embryos exposed to a RA-enriched diet did not enhance BBB protein expression. Together, our data indicate that RA is not capable of inducing, nor is it required for, BBB protein expression in vivo. Like other studies, we found that pharmacological concentrations of RA induce BBB genes in cultured murine brain endothelial cells, and this may involve activation of the LXR/RXR signaling pathway. Our data do not support a role for RA in BBB development, but confirm reports that pharmacological RA is a robust tool to induce BBB properties in culture.


Still more to learn about late-life cognitive development: How personality and health predict 20-year cognitive trajectories.
We examined the role of personality and health as time-invariant and time-varying predictors of changes in different cognitive domains based on data from the Interdisciplinary Longitudinal Study on Adult Development. Our sample consisted of 500 individuals born between 1930 and 1932 (baseline age: M = 62.87 years, SD = 0.89 years) who were assessed up to 4 times over an interval of up to 20 years. Cognitive abilities were measured by multiple well-established tests representing crystallized intelligence, fluid intelligence, and information processing speed. Because of poor psychometric properties of openness in our sample, only 4 of the Big Five personality traits (neuroticism, extraversion, agreeableness, and conscientiousness) were used. Based on in-depth medical examinations, physicians rated study participants' health. When considered as time-invariant predictors, lower baseline neuroticism and extraversion scores were associated with better baseline performance on the crystallized and fluid ability tests. Higher initial extraversion was associated with less steep decline in information processing speed. Worse baseline physician health was associated with lower baseline scores on fluid abilities and information processing speed. Moreover, worse initial health was associated with steeper decline in crystallized and fluid abilities. From a time-varying perspective, crystallized abilities were lower on measurement occasions when individuals revealed poorer health. Our findings suggest that late-life cognitive abilities are differentially related with personality and health. Overall, personality characteristics are associated with late-life cognitive abilities, but less so from a time-varying perspective. They also seem to be of limited importance for the prediction of long-term change in cognitive abilities. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


NMR analysis of the alphaIIb beta3 cytoplasmic interaction suggests a mechanism for integrin regulation.
The integrin αIIbβ3 is a transmembrane (TM) heterodimeric adhesion receptor that exists in equilibrium between resting and active ligand binding conformations. In resting αIIbβ3, the TM and cytoplasmic domains of αIIb and β3 form a heterodimer that constrains αIIbβ3 in its resting conformation. To study the structure and dynamics of the cytoplasmic domain heterodimer, we prepared a disulfide-stabilized complex consisting of portions of the TM domains and the full cytoplasmic domains. NMR and hydrogen-deuterium exchange of this complex in micelles showed that the αIIb cytoplasmic domain is largely disordered, but it interacts with and influences the conformation of the β3 cytoplasmic domain. The β3 cytoplasmic domain consists of a stable proximal helix contiguous with the TM helix and two distal amphiphilic helices. To confirm the NMR structure in a membrane-like environment, we studied the β3 cytoplasmic domain tethered to phospholipid bilayers. Hydrogen-deuterium exchange mass spectrometry, as well as circular dichroism spectroscopy, demonstrated that the β3 cytoplasmic domain becomes more ordered and helical under these conditions, consistent with our NMR results. Further, these experiments suggest that the two distal helices associate with lipid bilayers but undergo fluctuations that would allow rapid binding of cytoplasmic proteins regulating integrin activation, such as talin and kindlin-3. Thus, these results provide a framework for understanding the kinetics and thermodynamics of protein interactions involving integrin cytoplasmic domains and suggest that such interactions act in a concerted fashion to influence integrin stalk separation and exposure of extracellular ligand binding sites.


Extrication Times During Avalanche Companion Rescue: A Randomized Single-Blinded Manikin Study.
Aims: This study aimed to determine the time needed for one or two companion rescuers to access, extricate, and deliver cardiopulmonary resuscitation (CPR) to a fully buried manikin during a simulated avalanche burial scenario. Materials and Methods: In this randomized, single-blinded study, 18 medical students were required to extricate a manikin manually from a simulated avalanche burial of 1 m in depth, either alone or in teams of two. Each participant performed three consecutive tests with the manikin in three different positions in random order. Results: Median time to first manikin contact was 2.5 minutes, median time to airway access 7.2 minutes, and median time to standard position for CPR 10.1 minutes. Overall, the number of rescuers (one compared to two rescuers, 10.5 minutes vs. 9.3 minutes; p = 0.686) and the burial position of the manikin (10.8 minutes vs. 10.6 minutes vs. 8.8 minutes; p = 0.428) had no influence on extrication times. Preexisting training (6.1 minutes vs. 11.0 minutes p = 0.006) and a learning effect obtained during the experiments (12.4 minutes the first test vs. 9.3 in the third test; p = 0.017) improved all extrication times. Conclusion: It takes an average of 7 minutes after location of a simulated avalanche victim, buried at a depth of 1 m, to free the airway, plus a further 3 minutes to initiate CPR in standard supine position. This is more than two-thirds of the 15 minutes considered necessary for successful companion avalanche rescue. Even minimal training significantly reduced extrication times. These findings emphasize the importance of regular practice in specific extrication techniques that should be part of any training in avalanche companion rescue.


Different sensing modes of fluoride and acetate based on a calix[4]arene with 25,27-bistriazolylmethylpyrenylacetamides.
25,27-Bis{1'-N-(1-pyrenyl)-aminocarbonylmethyl-1H-[1',2',3']tri-azolyl-4'-methoxy}-26,28-dihydroxycalix[4]arene, 4, is synthesized as a fluorescent chemosensor for the selective detection of both anions and ion pairs in MeCN. Sensor 4 uses bis-triazoles as ligands to bind a metal ion, bis-amides and bis-triazoles as the sites to recognize anions, and pyrenes as fluorophores. Among eight anions screened, chemosensor 4 showed a marked fluorescence change toward F(-), H2PO4(-) and AcO(-), but 4 responded to each anion in a distinct way. In the presence of F(-) at low concentrations, the dynamic excimer emission of compound 4 at λ(max) 482 nm was quenched, but an emission at λ(max) 472 nm appeared at large doses of F(-). A control compound 6 showed very similar red shifts in the UV-vis and excitation spectra as 4 did, and its 472 nm emission band grew as the fluoride doses increased. Thus, the growth of the 472 nm emission of 4 and 6 in the presence of excess F(-) may be because strong H-bonding interactions of amido protons with F(-) favoured the formation of pyrene dimers in the ground state with charge transfer characteristics. The addition of H2PO4(-), unlike F(-), to a solution of 4 showed an enhanced monomer emission but a decreased excimer emission (λ(max) 482 nm). Adding AcO(-) to 4 produced a systematic change from a dynamic excimer (λ(max) 482 nm) to λ(max) 472 nm but with very little change in the UV-vis spectrum. Time-resolved fluorescence measurements on compound 6 with F(-) and AcO(-) confirmed that the 472 nm emission band mainly came from static excimers for the former, but was partly from a dynamic excimer for the latter because it contained a growth component in the fluorescence decay traces. Without pre-treatment with an anion, chemosensor 4 showed recognition of only metal ions Cu(2+), Hg(2+) and Cr(3+), but it became sensitive to Ag(+) when it was pretreated with fluoride.


Resolution of primary murine listeriosis and acquired resistance to lethal secondary infection can be mediated predominantly by Thy-1+ CD4- CD8- cells.
Mice depleted of CD4+, CD8+, Thy-1+ CD4- CD8-, or all three types of cells by appropriate monoclonal antibody treatment were tested for their ability to express resistance against a primary and secondary Listeria monocytogenes infection. It was found that mice depleted of CD8+, CD4+, or both of these subsets of T cells remained capable of controlling and then resolving both a primary infection and a secondary infection lethal for normal animals. In contrast, depleting mice of a population of Thy-1+ CD8- CD4- cells that remain after CD4+ and CD8+ T cells had been removed, rendered them incapable of resolving a sublethal primary infection or of expressing acquired immunity to a lethal secondary infection. The results point to the possibilities that Thy1+ CD4- CD8- alpha beta T cells, Thy1+ CD4- CD8- gamma delta T cells, Thy-1+ NK cells, or all three types of these host cells are involved in anti-L. monocytogenes resistance.


Evaluation of Antigen-Specific IgM and IgG Production during an In Vitro Peripheral Blood Mononuclear Cell Culture Assay.
The recent attention given to diseases associated with memory B-cell (mBC)-produced antibodies (Abs) suggests the need for a similar in vitro assay to evaluate the functions of mBCs. Here, we cultured peripheral blood mononuclear cells (PBMCs) with the intent to collect mBC-derived Abs in vitro and maintain their cell-cell contact-dependent interactions with helper T-cells. PBMCs were cultured with interleukin (IL)-21, CpG-oligodeoxynucleotides (ODN), phorbol myristate acetate (PMA), and phytohemagglutinin/leucoagglutinin (PHA-L) in 24-well flat-bottom plates (5 × 105 cells/well). A culture supernatant analysis of PBMCs from healthy donors (n = 10) indicated that antigen-specific IgM Ab levels in a PBMC culture supernatant might be better able to demonstrate the antigen sensitization status in a smaller peripheral blood sample, compared to IgG because Epstein-Barr virus-specific IgM mBCs circulate peripherally at a significantly higher frequency once antiviral humoral immunity has stabilized. Thus, our in vitro assay demonstrated the potential significance of antigen-specific IgM Ab production in the culture supernatants. Furthermore, an analysis of cultured PBMCs from allograft kidney recipients (n = 16) sensitized with de novo donor-specific human leukocyte antigen (HLA)-specific Abs (DSAs) showed that IgM-type HLA-specific Abs were detected mainly from the culture supernatants from PBMCs of patients with stable graft function, whereas IgG isotype HLA Abs were detectable only from patients with biopsy-proven antibody-mediated rejection. In other words, these IgG isotype Abs also represented an activated humoral immune response in vivo. Additionally, IgM- and IgG-expressing mBCs from healthy donors (n = 5) were cultured with IL-21, CpG-ODN, and a supernatant produced by stimulating CD19+ B-cell-depleted PBMCs with PHA-L and PMA in 24-well flat-bottom plates (1 × 105 cells/well), and the resulting in vitro analysis provided some information regarding the biological processes of IgG and IgM mBCs in peripheral blood. Taken together, our findings suggest that antigen-specific Ab subtype analyses of supernatants from cultured PBMCs might more effectively and accurately reflect a patient's Ab-associated pathological condition vs. than serum IgG and IgM levels.


Robotic-Assisted Spine Surgery Using the Mazor XTM System: 2-Dimensional Operative Video.
We demonstrate the setup and workflow of performing robotic spine surgery using the Mazor XTM system (MAZOR Robotics Inc, Orlando, Florida) in this video. An illustrative case was presented, including detailed steps for S2AI screw and lumbar pedicle screw placement using robotic assistance. A step-by-step narration is provided along with discussion of surgical nuances. Robotic spine surgery can be a safe and efficient method for screw placement, which can potentially reduce the risk of screw malposition. Spine surgeons should be familiar with this technology and keep this technique in their armamentarium. There is no identifying information in this video. A patient consent was obtained for publishing of the material included in the video.


Cost-analysis of teledentistry in residential aged care facilities.
The purpose of this research was to conduct a cost-analysis, from a public healthcare perspective, comparing the cost and benefits of face-to-face patient examination assessments conducted by a dentist at a residential aged care facility (RACF) situated in rural areas of the Australian state of Victoria, with two teledentistry approaches utilizing virtual oral examination. The costs associated with implementing and operating the teledentistry approach were identified and measured using 2014 prices in Australian dollars. Costs were measured as direct intervention costs and programme costs. A population of 100 RACF residents was used as a basis to estimate the cost of oral examination and treatment plan development for the traditional face-to-face model vs. two teledentistry models: an asynchronous review and treatment plan preparation; and real-time communication with a remotely located oral health professional. It was estimated that if 100 residents received an asynchronous oral health assessment and treatment plan, the net cost from a healthcare perspective would be AU$32.35 (AU$27.19-AU$38.49) per resident. The total cost of the conventional face-to-face examinations by a dentist would be AU$36.59 ($30.67-AU$42.98) per resident using realistic assumptions. Meanwhile, the total cost of real-time remote oral examination would be AU$41.28 (AU$34.30-AU$48.87) per resident. Teledental asynchronous patient assessments were the lowest cost service model. Access to oral health professionals is generally low in RACFs; however, the real-time consultation could potentially achieve better outcomes due to two-way communication between the nurse and a remote oral health professional via health promotion/disease prevention delivered in conjunction with the oral examination.


Cerebral radiofrequency exposures during adolescence: Impact on astrocytes and brain functions in healthy and pathologic rat models.
The widespread use of mobile phones by adolescents raises concerns about possible health effects of radiofrequency electromagnetic fields (RF EMF 900 MHz) on the immature brain. Neuro-development is a period of particular sensitivity to repeated environmental challenges such as pro-inflammatory insults. Here, we used rats to assess whether astrocyte reactivity, perception, and emotionality were affected by RF EMF exposures during adolescence. We also investigated if adolescent brains were more sensitive to RF EMF exposures after neurodevelopmental inflammation. To do so, we either performed 80 μg/kg intra-peritoneal injections of lipopolysaccharides during gestation or 1.25 μg/h intra-cerebro-ventricular infusions during adolescence. From postnatal day (P)32 to 62, rats were subjected to 45 min RF EMF exposures to the brain (specific absorption rates: 0, 1.5, or 6 W/kg, 5 days/week). From P56, they were tested for perception of novelty, anxiety-like behaviors, and emotional memory. To assess astrocytic reactivity, Glial Fibrillary Acidic Protein was measured at P64. Our results did not show any neurobiological impairment in healthy and vulnerable RF EMF-exposed rats compared to their sham-exposed controls. These data did not support the hypothesis of a specific cerebral sensitivity to RF EMF of adolescents, even after a neurodevelopmental inflammation. Bioelectromagnetics. 37:338-350, 2016. © 2016 Wiley Periodicals, Inc.


The Impact of Biologic Treatment on PD-1/PD-L1 Pathway Disturbances in Psoriasis.
The programmed death-1 (PD-1) receptor plays a major physiological role in the maintenance of immune tolerance and, by interaction with its ligands (PD-L1 and PD-L2), prevents the development of multiple immune-mediated diseases. There is growing evidence of the PD-1/PD-L1 pathway playing an important role in the pathogenesis of psoriasis. In total, 84 subjects with psoriasis were included in this study, together with 29 healthy subjects as a control group. Twenty-eight of the psoriatic patients were treated with biologic therapy (TNF-alpha, interleukin (IL)-12/23, or IL-17 inhibitors). The amounts of PD-1- and PD-L1-positive T-cells in peripheral blood were evaluated using flow cytometry. Significantly lower levels of peripheral blood mononuclear cells (PBMCs) with the expression of PD-1 and PD-L1 were found in psoriatic patients compared to healthy individuals, i.e., CD3/PD-1-, CD3/PD-L1-, CD4/PD-1-, CD4/PD-L1-, CD8/PD-L1-, CD19/PD-1-, and CD19/PD-L1-positive cells. Biologic treatment resulted in the elevation of CD3/PD-L1- and CD8/PD-L1- and a decrease in CD8/PD-1-positive PBMCs. Our results confirm previous observations of the PD-1/PD-L1 pathway being disrupted in psoriasis, and that these disturbances may play an important role in development of the disease. Biologic drugs may reverse several abnormalities observed within this pathway, which may explain their excellent efficacy in the treatment of psoriasis. Further research should be conducted to fully explain the results obtained.


Rare earth elements (REE) for the removal and recovery of phosphorus: A review.
There is little doubt that 'rock phosphate' reserves are decreasing, with phosphorus (P) peak to be reached in the coming decades. Hence, removal and recovery of phosphorus (P) from alternative nutrient-rich waste streams is critical and of great importance owing to its essential role in agricultural productivity. Adsorption technique is efficient, cost-effective, and sustainable for P recovery from waste streams which otherwise can cause eutrophication in receiving waters. As selective P sorption using rare earth elements (REE) are gaining considerable attention, this review extensively focuses on P recovery by utilising a range of REE-incorporated adsorbents. The review briefly provides existing knowledge of P in various waste streams, and examines the chemistry and behaviour of REE in soil and water in detail. The impact of interfering ions on P removal using REE, adsorbent regeneration for reuse, and life cycle assessment of REE are further explored. While it is clear that REE-sorbents have excellent potential to recover P from wastewaters and to be used as fertilisers, there are gaps to be addressed. Future studies should target recovery and reuse of REE as P fertilisers using real wastewaters. More field trials of synthesized REE-sorbents are highly recommended before practical application.


A complicated infection by cutaneous Nocardia wallacei and pulmonary Mycobacterium abscessus in a Chinese immunocompetent patient: a case report.
Nocardiosis is an infectious disease caused by Nocardia that primarily affects immunocompromised hosts. Mycobacterium abscessus is a common opportunistic pathogen that causes disease in humans, including pulmonary and extrapulmonary infection. Nocardia spp. infection is uncommon, and infection with Nocardia wallacei and Mycobacterium abscessus is even rarer. A 59-year-old immunocompetent woman with risk factors for environmental exposure developed nocardiosis and presented to the hospital with a cough, shortness of breath, hemoptysis, and a back abscess. An enhanced computed tomography (CT) of the chest revealed partial destruction of the right lung, as well as consolidation of the right upper lobe. Rare pathogens N. wallacei and Mycobacterium abscessus were detected by metagenomic next-generation sequencing (mNGS) from abscess on the back and lung puncture tissue, respectively. She was treated with a combination of antibiotics and was finally discharged with a good prognosis. In this case, we present a patient who was successfully diagnosed with N. wallacei and Mycobacterium abscessus infection using mNGS. This importance of using mNGS in pathogen detection and the effective use of antibiotics in treating patients with long-term rare infections is highlighted in this report.


Insights into conceptus elongation and establishment of pregnancy in ruminants.
This review integrates established and new information on the factors and pathways regulating conceptus-endometrial interactions, conceptus elongation and establishment of pregnancy in sheep and cattle. Establishment of pregnancy in domestic ruminants begins at the conceptus stage (embryo or fetus and associated extra-embryonic membranes) and includes pregnancy recognition signalling, implantation and the onset of placentation. Survival and growth of the preimplantation blastocyst and elongating conceptus require embryotrophic factors (amino acids, carbohydrates, proteins, lipids and other substances) provided by the uterus. The coordinated and interactive actions of ovarian progesterone and conceptus-derived factors (interferon-τ and prostaglandins) regulate expression of elongation- and implantation-related genes in the endometrial epithelia that alter the uterine luminal milieu and affect trophectoderm proliferation, migration, attachment, differentiation and function. A comparison of sheep and cattle finds both conserved and non-conserved embryotrophic factors in the uterus; however, the overall biological pathways governing conceptus elongation and establishment of pregnancy are likely conserved. Given that most pregnancy losses in ruminants occur during the first month of pregnancy, increased knowledge is necessary to understand why and provide a basis for new strategies to improve pregnancy outcome and reproductive efficiency.


Immunoglobulin G dimers and immune complexes are dispensable for the therapeutic efficacy of intravenous immune globulin in murine immune thrombocytopenia.
Several mechanisms have been proposed to explain the therapeutic effects of intravenous immunoglobulin (IVIG) in immune thrombocytopenia (ITP). Noteworthy, a major role has been attributed to immunoglobulin (Ig)G dimers present in IVIG. It has also been suggested that immune complexes formed between IVIG and the patient's proteins after infusion could contribute to the therapeutic effect of IVIG in several autoimmune disorders. We recently observed that in-house preparations of polyclonal human IgG derived from small pools of plasma and devoid of IgG dimers were as efficient as IVIG in a mouse model of thrombocytopenia. In this work, we revisited the role of IgG dimers in the therapeutic effects of IVIG in ITP. We used the passive mouse model of ITP to determine the therapeutic efficacy of human IgG preparations devoid of IgG dimers and of dimer-enriched and -depleted commercial IVIG. Immune complex formation between IVIG and mouse plasma proteins was evaluated using a combination of chromatography and immunoprecipitation procedures. All preparations tested showed the same efficacy to alleviate ITP, regardless of their dimer contents. Significant amounts of immune complexes formed between IVIG and mouse plasma proteins were detected. However, the amount of immune complexes detected using the in-house preparation of human polyclonal IgG and mouse plasma was significantly lower, although the in-house preparation exhibited the same therapeutic efficacy as commercial IVIG. IgG dimers and immune complexes are dispensable to prevent thrombocytopenia in a mouse model of the disease.


Randomized controlled pilot study testing use of smartphone technology for obesity treatment.
The established interventions for weight loss are resource intensive which can create barriers for full participation and ultimate translation. The major goal of this pilot study was to evaluate the feasibility, acceptability, and preliminary efficacy of theoretically based behavioral interventions delivered by smartphone technology. The study randomized 68 obese adults to receive one of four interventions for six months: (1) intensive counseling intervention, (2) intensive counseling plus smartphone intervention, (3) a less intensive counseling plus smartphone intervention, and (4) smartphone intervention only. The outcome measures of weight, BMI, waist circumference, and self-reported dietary intake and physical activity were assessed at baseline and six months. The sample was 78% female and 49% African American, with an average age of 45 years, and average BMI of 34.3 kg/m(2). There were trends for differences in weight loss among the four intervention groups. Participants in the intensive counseling plus self-monitoring smartphone group and less intensive counseling plus self-monitoring smartphone group tended to lose more weight than other groups (5.4 kg and 3.3 kg, resp.). The results of this pilot trial of a weight loss intervention provide preliminary support for using a smartphone application for self-monitoring as an adjunct to behavioral counseling.


Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2.
The canonical role of the bone-derived fibroblast growth factor 23 (Fgf23) is to regulate the serum inorganic phosphate (Pi) level. As part of a feedback loop, serum Pi levels control Fgf23 secretion through undefined mechanisms. We recently showed in vitro that the two high-affinity Na+-Pi co-transporters PiT1/Slc20a1 and PiT2/Slc20a2 were required for mediating Pi-dependent signaling. Here, we addressed the contribution of PiT1 and PiT2 to the regulation of Fgf23 secretion. To this aim, we used PiT2 KO and DMP1Cre; PiT1lox/lox fed Pi-modified diets, as well as ex vivo isolated long bone shafts. Fgf23 secretion and expression of Pi homeostasis-related genes were assessed. In vivo, PiT2 KO mice responded inappropriately to low-Pi diets, displaying abnormally normal serum levels of intact Fgf23. Despite the high iFgf23 level, serum Pi levels remained unaffected, an effect that may relate to lower αKlotho expression in the kidney. Moreover, consistent with a role of PiT2 as a possible endocrine Pi sensor, the iFGF23/cFGF23 ratios were suppressed in PiT2 KO mice, irrespective of the Pi loads. While deletion of PiT1 in osteocytes using the DMP1-Cre mice was inefficient, adenovirus-mediated deletion of PiT1 in isolated long bone shafts suggested that PiT1 does not contribute to Pi-dependent regulation of Fgf23 secretion. In contrast, using isolated bone shafts from PiT2 KO mice, we showed that PiT2 was necessary for the appropriate Pi-dependent secretion of Fgf23, independently from possible endocrine regulatory loops. Our data provide initial mechanistic insights underlying the Pi-dependent regulation of Fgf23 secretion in identifying PiT2 as a potential player in this process, at least in high Pi conditions. Targeting PiT2, therefore, could improve excess FGF23 in hyperphosphatemic conditions such as chronic kidney disease.


Surgical treatment of non-penetrating injury to the aorta.
During a 17-year period, eight cases of blunt traumatic injury to the aorta were surgically treated at our hospital. The locations of the lesions were the descending thoracic aorta in four cases, abdominal aorta in two cases, and traumatic DeBakey type IIIb dissection in two cases. Surgical repairs were carried out during the acute or subacute period in four cases and others were electively treated during the chronic period. One patient suffering from acute traumatic dissection of the aorta died of acute renal failure following acute ischemia in the lower extremities 10 days after surgery. Accordingly, the overall mortality rate was 12.5% in this series. We believe that elective operations should be carefully considered if they are possible.


Increased complications of chronic erythrocytapheresis compared with manual exchange transfusions in children and adolescents with sickle cell disease.
Children and adolescents with sickle cell disease (SCD) are at high risk of strokes and are frequently treated with red blood cell (RBC) transfusions. The goal is to suppress hemoglobin (Hb) S while minimizing transfusion-induced iron overload. RBCs may be given via simple transfusion, manual exchange transfusion (MET), or erythrocytapheresis (aRBCX). Chronic transfusion practices vary among institutions. This single-institution, retrospective cohort study compares Hb S control and therapy complication rates between MET and aRBCX in a cohort of children and adolescents with SCD and stroke during a 5-year period from 2008 through 2012. Duration and mode of transfusion therapy, achievement of Hb S suppression goal, iron burden by ferritin levels, and catheter complications were evaluated. Thirty-seven children were included in analysis. The prevalence of catheter complications was 75% in aRBCX recipients compared with 0% in MET recipients (P < 0.001). There was no significant difference between modalities in achieving Hb S suppression or ferritin goals, but those receiving aRBCX had a greater likelihood of discontinuing chelation therapy. Among aRBCX recipients, adherence to >90% of transfusion appointments was associated with achieving Hb S suppression goals. aRBCX may have increased complication risks compared with MET for chronic transfusion therapy in SCD. Risks and benefits of aRBCX and MET should be considered when selecting a chronic transfusion modality. Transfusion therapy modalities should be compared in prospective studies for stroke prevention in children with SCD.


Sample preparation method for isolation of single-cell types from mouse liver for proteomic studies.
It becomes increasingly clear that separation of pure cell populations provides a uniquely sensitive and accurate approach to protein profiling in biological systems and opens up a new area for proteomic analysis. The method we described could simultaneously isolate population of hepatocytes (HCs), hepatic stellate cells (HSCs), Kupffer cells (KCs) and liver sinusoidal endothelial cells (LSECs) by a combination of collagenase-based density gradient centrifugation and magnetic activated cell sorting with high purity and yield for the first time. More than 98% of the isolated HCs were positive for cytokeratin 18, with a viability of 91%. Approximately 97% of the isolated HSCs expressed glial fibrillary acidic protein with a viability of 95%. Nearly 98% of isolated KCs expressed F4/80 with a viability of 94%. And the purity of LSECs reached up to 91% with a viability of 94%. And yield for HCs, HSCs, LSECs and KCs were 6.3, 1.3, 2.6 and 5.0 million per mouse. This systematic isolation method enables us to study the proteome profiling of different types of liver cells with high purity and yield, which is especially useful for sample preparation of Human Liver Proteome Project.


Effects of d-galactose-induced ageing on the heart and its potential interventions.
Ageing is a strong independent risk factor for disability, morbidity and mortality. Post-mitotic cells including those in the heart are a particular risk to age-related deterioration. As the occurrence of heart disease is increasing rapidly with an ageing population, knowledge regarding the mechanisms of age-related cardiac susceptibility and possible therapeutic interventions needs to be acquired to prevent advancing levels of heart disease. To understand more about the ageing heart, numerous aged animal models are being used to explore the underlying mechanisms. Due to time-consuming for investigations involving naturally aged animals, mimetic ageing models are being utilized to assess the related effects of ageing on disease occurrence. d-galactose is one of the substances used to instigate ageing in various models, and techniques involving this have been widely used since 1991. However, the mechanism through which d-galactose induces ageing in the heart remains unclear. The aim of this review was to comprehensively summarize the current findings from in vitro and in vivo studies on the effects of d-galactose-induced ageing on the heart, and possible therapeutic interventions against ageing heart models. From this review, we hope to provide invaluable information for future studies and based on the findings from experiments involving animals, we can inform possible therapeutic strategies for the prevention of age-related heart diseases in clinical settings.


Partial characterization of gamma (immune) interferon mRNA extracted from human lymphocytes.
gamma (immune) interferon (IFN-gamma) was induced in cultures of fresh human lymphocytes by combined treatment with a phorbol ester (12-O-tetradecanoylphorbol 13-acetate, TPA) and the T cell mitogen phytohemagglutinin (PHA). Compared to the IFN-gamma yields obtained with PHA induction alone, the inclusion of TPA caused a significant enhancement of IFN-gamma production. Poly(A)-containing mRNA was isolated from mononuclear cells induced with TPA and PHA. Injected into Xenopus laevis oocytes, this mRNA preparation gave rise to IFN activity with characteristic properties of human IFN-gamma. Sucrose density gradient centrifugation analysis showed that IFN-gamma mRNA sedimented at 15 S, suggesting that it contains a total of about 1400 nucleotides.


Chorioangiomas.
Six cases of chorioangioma of the placenta and a review of relevant leterature are presented. The incidence of chorioangiomas is higher than generally realized because many small chorioangiomas are missed in routine examination of placentas. A case of chorioangioma with foci resembling hemangiopericytoma is presented. Cases of large chorioangiomas seem to occur when the placenta is large. Hydramnios is commonly found with large chiorangiomas, and both of these conditions may be conducive to premature births. There is an increased incidence of toxemia in pregnant patients with chorioangiomas, and the condition is unrelated to the size of the tumor. Diligent examination of infants associated with chorioangioma of the placenta is suggested, as these infants may have unsuspected congenital anomalies.


Implications of a Decentralized Postpartum Unit Design and Clinical Operations.
This postoccupancy study sought to understand whether a decentralized unit design supported a postpartum care delivery model by evaluating nurses' efficiency, staff perception, acoustical conditions, and patient satisfaction. Today, standardization and decentralization design concepts are being applied to all types of inpatient unit. There have been many studies that investigated how these concepts influence care delivery on medical-surgical units, but no study has evaluated a postpartum unit. This study utilized a mixed-method approach that involved unobtrusive shadowing (roughly 25 hr) and surveying (n = 19) of nursing staff, physical acoustic readings (eight, 24-hr readings), and comparison of patient satisfaction pre- and postmove. On average, nurses spent roughly 36.90% of their time at charting stations. Nurses were observed mostly using the central charting station located at the entry of the unit and adjacent to the well-baby nursery rather than the five decentralized chart stations. This was due to nurses operating with old workflow habits, not fully integrating electronic medical records, and needing to be near the nursery and other nurses. Nurses were satisfied with their ability to interact and their proximity to supplies, patients, and team members while in the central charting station. Additionally, patient satisfaction significantly increased postmove, particularly with the overall hospital's quietness and cleanliness. This study highlights the importance of aligning administrative operations of the unit with the design intent. Although standardization and decentralization design concepts aimed to improve nurses' workflow, misalignment with the operations may not deliver the most optimal outcomes.


Intravenous Tissue Plasminogen Activator Improves the Outcome in Very Elderly Korean Patients with Acute Ischemic Stroke.
In a recent pooled analysis of randomized clinical trials (RCTs), intravenous tissue plasminogen activator (TPA) improves the outcome in patients aged ≥80 years. However, it is uncertain whether the findings are applicable to clinical practice in Asian populations. From a multicenter stroke registry database of Korea, we identified patients with acute ischemic stroke who were aged ≥ 80 years. Using multivariable analysis and propensity score (PS)-matched analyses, we assessed the effectiveness and safety of intravenous TPA within 4.5 hours. Among 2,334 patients who met the eligible criteria, 236 were treated with intravenous TPA (mean age, 83±5; median NIHSS, 13 [IQR, 8-17]). At discharge, the TPA group compared to the no-TPA group had a favorable shift on the modified Rankin Scale (mRS) score (multivariable analysis, OR [95% CI], 1.51 [1.17-1.96], P=0.002; PS-matched analysis, 1.54 [1.17-2.04], P=0.002) and was more likely to achieve mRS 0-1 outcome (multivariable analysis, 2.00 [1.32-3.03], P=0.001; PS-matched analysis, 1.59 [1.04-2.42], P=0.032). TPA treatment was associated with an increased risk of symptomatic intracranial hemorrhage (multivariable analysis, 5.45 [2.80-10.59], P<0.001; PS-matched analysis, 4.52 [2.24-9.13], P<0.001), but did not increase the in-hospital mortality (multivariable analysis, 0.86 [0.50-1.48], P=0.58; PS-matched analysis, 0.88 [0.52-1.47], P=0.61). In the setting of clinical practice, intravenous TPA within 4.5 hours improved the functional outcome despite an increased risk of symptomatic intracranial hemorrhage in very elderly Korean patients. The findings, consistent with those from pooled analysis of RCTs, strongly support the use of TPA for this population.


Delayed matrix metalloproteinase inhibition reduces intracerebral hemorrhage after embolic stroke in rats.
Hemorrhagic transformation (HT) and brain edema are life-threatening complications of recombinant tissue plasminogen activator (rt-PA)-induced reperfusion after ischemic stroke. The risk of HT limits the therapeutic window for reperfusion to 3 h after stroke onset. Pre-treatment with matrix metalloproteinase (MMP) inhibitors reduces HT and cerebral edema in experimental stroke. However, whether a delayed therapeutic intervention would be beneficial is unknown. In this study, 215 male Sprague-Dawley rats were subjected to embolic stroke and 75 rats were included in the final analysis. The animals were treated with the MMP inhibitor p-aminobenzoyl-gly-pro-D-leu-D-ala-hydroxamate before or after 3 or 6 h of ischemia. Animals were monitored for reperfusion and received rt-PA 6 h after ischemia onset. The results at 24 h showed that MMP inhibition 3 h after ischemia significantly decreased the degree of brain edema (17% of hemispheric enlargement in the treated group versus 24% in controls, P=0.018), reduced the risk (OR=0.163; 95% CI: 0.029 to 0.953) and gravity (0.09 versus 0.19 mg of parenchymal hemoglobin, P=0.02) of intracerebral hemorrhage, and improved neurological outcome (20% of the treated animals had a slight deficit; all of the controls had a bad outcome, P<0.05). Delaying MMP inhibition to 6 h after ischemia restricted the beneficial role of the treatment to a reduction in the risk of parenchymal hemorrhage (OR=0.242; 95% CI: 0.060 to 0.989). Our results confirm the involvement of MMPs in HT and support the possibility of extending the therapeutic window for thrombolysis in stroke by administering a broad-spectrum MMP inhibitor after the onset of ischemia.


Coronary Artery Fistula.
Coronary artery fistulae are rare abnormalities of the coronary arteries that are usually discovered incidentally on coronary angiogram. Most patients remain asymptomatic, and significant hemodynamic consequences are rarely observed. The following report describes the case of a patient presenting with symptoms of congestive cardiac failure due to multiple coronary artery fistulae.


The orderly splicing of the first three leaders of the adenovirus-2 major late transcript.
A strategy based on the hybridization of labeled nucleoplasmic RNA to a short cloned cDNA probe was devised to study the ligation of the three first leader sequences (Le1, Le2, Le3) of the major late adenovirus-2 transcript. The hybridized RNA was subsequently fractionated by electrophoresis and identified with the aid of restriction fragments of the DNA probe. The ligations were shown to occur stepwise and in an orderly fashion. Le1 and Le2 were first ligated without detectable lag time. The tripartite leader was formed after a lag time of 10-15 min probably due, for a large part, to the stepwise excision of the intervening sequence between Le2 and Le3. The possible processing intermediate Le2-Le3 was not detected.


Efficacy and Safety of Anti-Tumor Necrosis Factor Alpha in Very Early Onset Inflammatory Bowel Disease.
Very early onset inflammatory bowel disease (VEOIBD) is defined as disease onset in patients younger than 6 years. Challenges in treatment of VEOIBD include lack of approved therapies and increased incidence of monogenic immunodeficiencies. We report on patterns of anti-TNF use, efficacy, and safety in a large cohort of patients with VEOIBD. Very early onset inflammatory bowel disease patients receiving care at a single center were prospectively enrolled in a data registry and biorepository starting in 2012. Whole exome sequencing was available to all patients. Clinical data including IBD medication use and response were extracted from the medical record. We examined antitumor necrosis factor (anti-TNF) cumulative exposure and time to failure and evaluated the effect of covariates on anti-TNF failure using Cox proportional hazard regression. In this cohort of 216 VEOIBD patients with median 5.8-year follow-up, 116 (53.7%) were TNF-exposed. Sixty-two TNF-exposed patients (53.4%) received their first dose at younger than 6 years. Cumulative exposure to anti-TNF was 23.6% at 1 year, 38.4% at 3 years, and 43.4% at 5 years after diagnosis. Cumulative exposure was greater in patients with Crohn's disease (P = .0004) and in those diagnosed in 2012 or later (P < .0001). Tumor necrosis factor failure occurred in 50.9% of those exposed. Features predictive of anti-TNF failure included ulcerative colitis/IBD-unclassified (hazard ratio, 1.94; P = .03), stricturing (hazard ratio, 2.20; P = .04), and younger age at diagnosis (hazard ratio, 1.25; P = .01). Adverse events occurred in 22.6% of infliximab-exposed and 14.3% of adalimumab-exposed. Efficacy and safety of anti-TNFs in VEOIBD is comparable to what has previously been reported in older patients.


Significance of Some Proliferation Markers and Some Prognostic Factors in Patients with Multiple Myeloma and their Impact on the Patients' Survival.
Multiple myeloma (MM) is influenced by genetic and micro-environmental changes. Malignant plasma cells produce an abnormal monoclonal immunoglobulin, as well as cytokines, such as IL-10 and IL-6 which stimulate cells of the bone marrow microenvironment (BMM) and cause dysfunction and failure of many organs. B cell activating factor (BAFF), IL6, IL10 are known to influence the growth and survival of the malignant clone. The objectives of the present study were to investigate the circulating levels of BAFF , IL-10 and IL-6 , correlate them with well-known parameters of disease activity in patients with MM, and to detect their impact on the patients' survival. This study was conducted on 89 newly diagnosed MM patients and seventy apparently healthy volunteers as a normal control group. BAFF, IL6, IL10 were measured by ELISA for both groups. Survival analysis was performed for all patients. Studied markers were higher in the MM patients compared to the normal control subjects. Patients' survival was improved by high serum BAFF levels. High levels of BAFF were found to improve patients' survival. BAFF and IL-6 can be considered probable diagnostic markers for MM.


Trend, prevalence and predictors of successful vaginal birth after caesarean section in Ethiopia: a systematic review and meta-analysis.
Vaginal birth after caesarean section (VBAC) is an alternative to a caesarean section (CS) in the absence of repeat or new indications for primary CS. There is a knowledge gap regarding the trend and successful VBAC in Ethiopia. Therefore this systematic review and meta-analysis aimed to assess the trend, pooled prevalence of successful VBAC and its predictors in Ethiopia. Electronic databases (SCOPUS, CINAHL, Embase, PubMed and Web of Science), Google Scholar and lists of references were used to search works of literature in Ethiopia. Stata version 14 was used for analysis and the odds ratios of the outcome variable were determined using the random effects model. Heterogeneity among the studies was assessed by computing values for I2 and p-values. Also, sensitivity analyses and funnel plots were done to assess the stability of pooled values to outliers and publication bias, respectively. A total of 12 studies with a sample size of 2080 were included in this study. The overall success rate of VBAC was 52% (95% confidence interval 42 to 65). Cervical dilatation ≥4 cm at admission, having a prior successful vaginal delivery and VBAC were the predictors of successful VBAC. Meta-analyses and sensitivity analyses showed the stability of the pooled odds ratios and the funnel plots did not show publication bias. The pooled prevalence of successful VBAC was relatively low compared with existing evidence. However, the rate was increasing over the last 3 decades, which implies it needs more strengthening and focus to decrease maternal morbidity and mortality by CS complications. Promoting VBAC by emphasizing factors favourable for its success during counselling mothers who previously delivered by CS to enhance the prevalence of VBAC.


A norepinephrine-dependent mechanism in the preoptic/anterior hypothalamic area but not in the mediobasal hypothalamus is involved in the regulation of the gonadotropin-releasing hormone pulse generator in ovariectomized rats.
Pulsatile gonadotropin secretion from the pituitary is dependent upon the gonadotropin-releasing hormone (Gn-RH) pulse generator producing intermittent release of the neuropeptide into the portal vessels. Various neurotransmitters seem to be involved in the regulation of pulsatile Gn-RH release. The present study was an attempt to determine in vivo the temporal relation of preoptic/anterior hypothalamic area (PO/AH) norepinephrine (NE) release and pulsatile luteinizing hormone (LH) secretion in ovariectomized rats. To assess whether NE acts in the PO/AH to maintain pulsatile Gn-RH release, we applied locally an alpha 1-receptor antagonist into this structure. Push-pull cannulae (PPC) were implanted into the PO/AH of ovariectomized rats. The contralateral, not PPC-implanted PO/AH was lesioned electrochemically. Another group of ovariectomized rats was implanted with a PPC into the mediobasal hypothalamus. Two experiments were performed: (1) To determine whether the PO/AH or the mediobasal hypothalamus is the site where NE exerts its stimulatory effect on LH secretion, we applied doxazosine, a new specific alpha 1-receptor antagonist, locally into these structures by means of PPC. The effect of this adrenergic drug on the Gn-RH pulse generator was examined by measuring blood LH levels. (2) To study the temporal relation between in vivo release rates of NE and amine metabolites in the preoptic area and pulsatile pituitary LH secretion, preoptic perfusates and blood samples were collected at 5-min intervals. Brain perfusates were subjected to high-performance liquid chromatography-electrochemical analysis. In blood samples LH concentrations were determined.(ABSTRACT TRUNCATED AT 250 WORDS)


Development and validation of a production process of platelet lysate for autologous use.
Growth factors (GF) contained in platelets are a potential source to improve wound healing by the stimulation and acceleration of soft tissue and bone healing. This resulted in the idea that autologous platelet-rich plasma or platelet lysate (PL) containing high levels of GF might improve healing processes. Today platelet products are already applied in bone and maxillofacial surgery. In recent years, cosmetic surgery and facial rejuvenation procedures are growing steadily. New methods including platelet products aiming to induce non-surgical reduction of wrinkles upon topical injection and to minimize surgical risks in general are developed. Several point-of-care devices are already available on the market. However, the amount of PL obtained by these kits is far too high for certain applications in cosmetic surgery and they offer no possibility of storing the remaining material in a sterile manner. Therefore we developed a procedure for the sterile production of smaller amounts of PL in a closed system that can also be split into several products for repeated administration. The closed system was determined to be a bag system designed for an autologous blood donation of 100 ml whole blood. We set a special focus on the validation of the production procedure, mainly regarding sterility and platelet recovery. For validation 22 healthy volunteers were asked for a blood donation, which was centrifuged twice to obtain concentrated platelets (CP). A freeze-thaw cycle caused lysis of the CP to get approximately 8.48 ± 1.36 ml PL. We yielded satisfying results of 100% sterility and a platelet recovery of 36.92% ± 18.71%. We therefore conclude that the PL obtained is ready for studies comparing it with traditional treatments.


Impact in stability during sequential CDR grafting to construct camelid VHH antibodies against zinc oxide and gold.
Biomolecules which recognize inorganic materials and metal surfaces gain much attention for creating new type of nanomaterials and sensors. 4F2, a camelid VHH antibody, recognizes ZnO surface and has been applied for sensor applications. 4F2 was constructed sequential complementarity determining region (CDR) replacement on the parental VHH antibody, termed the Construction of Antibody by Integrating Grafting and Evolution Technology; CAnIGET procedure. Here, we evaluate the influence of CDR replacements during 4F2 generation using calorimetric technique. We found that the initial peptide grafting at CDR1 results in the stability reduction and subsequent CDR3 randomize and selection restore the stability during the construction of 4F2. Further examination using anti-gold VHH, AuE32, revealed that the final CDR3 randomize and selection step has little effect in stability while the initial CDR1 grafting reduces the stability as same as the case for 4F2. Our results showing here provide the detailed view of the stability alteration during the CAnIGET procedure.


Consent and the individual detained in custody.
It has been acknowledged that autonomy is one of the prima facie principles in modern medical practice and integral to the interchange between doctor and patient even if that meeting does not fulfil the normal criteria for a consultation. The lead having been taken by other jurisdictions, the General Medical Council, the UK national regulatory body for doctors, has now acknowledged the concept of informed consent that was first espoused in cases such as Rogers v. Whitaker. In regard to the concept of informed consent, there are three pertinent issues that the Forensic Physician should consider in deciding upon the adequacy of this: Did that person have capacity in the eyes of the law? The Forensic Physician may be asked to examine individuals whose age span ranges from the newly born to the elderly and there will be potential conflict of interest between parent and child or elderly people and their carers. Even if adequate information was imparted, did a person under the (significant) influence of alcohol or drugs understand the likely implications that would flow from their decision? Was the individual concerned given appropriate information beforehand--in other words, was the consent truly informed? Was the consent given voluntarily? Voluntariness is probably the most significant ethical worry likely to confront the doctor, particularly when examining an individual for fitness to be detained or fitness to be interviewed, both categories of which make up the main work load in this sub-specialty. The thorny ethical dilemmas faced in this specialty are considered and how the professional standard originally defined in Hunter v Hanley and re-iterated in the Bolam test (with subsequent modification in Bolitho) affect the way in which the clinician deals with the problems is likely to face.


Effect of Nomega-nitro-L-arginine methyl ester-induced intrauterine growth restriction on postnatal lung growth in rats.
Infants with intrauterine growth restriction (IUGR) are at high risk for morbidity and mortality. Preeclampsia, one of the leading causes of IUGR, begins during the canalicular phase of lung development. The aim of our study was to determine whether induced IUGR was responsible for abnormal lung development in rat pups. We randomized pregnant Sprague-Dawley rats to daily gavage with either the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME; n = 5, 50 mg . kg(-1) . d(-1)) or pure water (n = 6). The pups were weighed at birth and on postnatal days 7 and 14. At each of these time points, pups were killed and their lung growth was assessed on the basis of lung volume and light-microscopy morphometric data. At birth, body weight, total alveolar surface area, and alveolar surface density were significantly decreased and alveolar size was significantly increased in the L-NAME group, compared with the control group. On day 7, body weight was similar in the two groups, and the only significant difference was smaller total alveolar surface area in the L-NAME group. On day 14, neither body weight nor lung morphometric parameters were significantly different between the L-NAME group and the controls. These results suggest that postnatal catch-up growth may completely correct the lung development disorders present at birth in IUGR pups, in parallel with the catch-up body weight gain.


Reduction in Lesion Incidence in Pork Carcass Using Transdermal Needle-free Injection of Foot-and-Mouth Disease Vaccine.
Foot-and-mouth disease (FMD) is an infectious disease affecting pigs. The control of FMD in swine husbandry is very important because its outbreak results in a vast economic loss. FMD vaccination has effectively controlled FMD; however, it results in economic loss associated with the incidence of lesions in the pork meat at the injection site. The objective of this study was to investigate the effects of transdermal needle-free injection (NFI) of the FMD vaccine on the incidence of lesions at the injection site. Pigs (n=493) in the control group were vaccinated with the FMD vaccine using a commercial syringe needle, while 492 pigs in the transdermal NFI group received the FMD vaccine using a needle-free gas-powered jet injector. After the slaughter of the pigs, the incidence of lesions at the injection site of all pigs was checked by plant workers. The result of this study showed that the incidence of lesions in the pork ham from pigs vaccinated with NFI was 14.82% lower than that in control pigs (p<0.01). In addition, lesions generated in the NFI group were found just in the subcutaneous tissue. Therefore, the incidence of lesions at the injection site in pork from pigs vaccinated with the FMD vaccine can be effectively reduced by using transdermal NFI rather than a conventional syringe needle.


Reduced Risk of Corporal Tumors in Patients With Head and Neck Paragangliomas With p.Pro81Leu Mutations.
Patients with head and neck paragangliomas who are positive for the SDHD p.Pro81Leu (P81L) mutation are thought to have a distinct phenotype from other SDHx mutations, but few studies have focused on this mutation. The objective of this study was to determine the hazard of developing a second primary, metastatic, or recurrent paraganglioma in SDHx patients with or without P81L. Retrospective chart review of 60 patients with head and neck paragangliomas and genetic testing, followed for a median of 9 years. Single academic medical center. Univariable Cox proportional hazards regression evaluated second primary and recurrent paragangliomas in patients with SDHD P81L, SDHx non-P81L, and nonhereditary paraganglioma. This series comprised 31 patients without SDHx, 14 with SDHD P81L, and 15 with other SDHx mutations. At a median 9 years of follow-up, corporal (not head and neck) second primary paragangliomas occurred in 31% of patients with SDHx non-P81L mutations, compared with 0% and 4% of patients with SDHD P81L and without SDHx mutations, respectively. Second corporal paragangliomas were more likely in patients with SDHx non-P81L mutations than in those without a mutation (hazard ratio = 5.461, 95% confidence interval: 0.596-50.030, p = .13). This is the first study to report a lower likelihood of corporal tumors for patients with head and neck paragangliomas with SDH mutations positive for P81L. Larger studies are needed to determine if head and neck paraganglioma patients with P81L qualify for less intensive imaging surveillance to screen for second primary paragangliomas outside the head and neck.


Hydrogen cyanide production due to mid-size impacts in a redox-neutral N2-rich atmosphere.
Cyanide compounds are amongst the most important molecules of the origin of life. Here, we demonstrate the importance of mid-size (0.1-1 km in diameter) hence frequent meteoritic impacts to the cyanide inventory on the early Earth. Subsequent aerodynamic ablation and chemical reactions with the ambient atmosphere after oblique impacts were investigated by both impact and laser experiments. A polycarbonate projectile and graphite were used as laboratory analogs of meteoritic organic matter. Spectroscopic observations of impact-generated ablation vapors show that laser irradiation to graphite within an N2-rich gas can produce a thermodynamic environment similar to that produced by oblique impacts. Thus, laser ablation was used to investigate the final chemical products after this aerodynamic process. We found that a significant fraction (>0.1 mol%) of the vaporized carbon is converted to HCN and cyanide condensates, even when the ambient gas contains as much as a few hundred mbar of CO2. As such, the column density of cyanides after carbon-rich meteoritic impacts with diameters of 600 m would reach ~10 mol/m(2) over ~10(2) km(2) under early Earth conditions. Such a temporally and spatially concentrated supply of cyanides may have played an important role in the origin of life.


Emergency obstetric referrals at a university teaching hospital, Nigeria.
To identify factors in our unbooked obstetric emergency cases that contribute to the increase in maternal mortality. A retrospective study. Maternity Ward, University of Nigeria Teaching Hospital, Enugu, Nigeria, between January 1966 and December 1999. Four hundred and thirty five cases of emergency obstetric referrals treated during the review period. The incidence of unbooked obstetric emergencies is 9.5% and the high risk obstetric group, the primigravida and grand multiparous women constituted 63% of it. Majority (80%) of the patients belonged to the lower socio-economic class and prolonged and obstructed labour were the commonest mode of presentation. Sources of referrals were hospital/clinics (46%), maternity homes (23%), traditional birth attendants (TBAs)(16%) and prayer houses (2.3%). There were obvious delays at the referral sources and most of the patients presented in poor clinical states. Forty per cent of total maternal mortality in the hospital were attributed to unbooked cases with haemorrhage and sepsis being the major causes. Also perinatal mortality of 40.2% was recorded. Lack of basic education and poverty are the major identifiable risk factors. Improving health care facilities, female education, regular training courses for medical personnel and elimination of quacks are advocated.


Difficult Consent Scale: An Assessment Scale for Anticipated Difficulty in Obtaining Consent for Organ Donation.
Seeking consent for organ procurement from a brain-dead patient 's family is challenging, especially in developing countries. In the Middle East, legislation necessitates an opt-in system that engages all first-degree relatives. To improve our success rate in the Masih Daneshvari Organ Procurement Unit in Tehran, Iran, we invented a scale for the consent process to predict the degree of difficulty of each family interview before venturing into it. We reviewed the records of brain-dead patients treated in our unit over the previous 10 years. Focusing on cases where families refused to donate organs, we searched for determinants that played a role in the final results. We extracted minor and major determinants, then ascribed a 3-level scale to each determinant (from 1, easiest, to 3, most difficult). We thereby obtained a clear assessment of each consent-taking session based on determinants from real encounters. We analyzed 150 brain-dead patients and extracted 17 determinants: 2 major and 15 minor. We grouped these into 3 distinct categories: A, patient-related; B, family-related; C, hospital-related. Inspired by the Glasgow Coma Scale, we named our scale the "Difficulty Consent Scale, " in which a score of 15, using the minor determinants, indicates the easiest scenario for obtaining consent and 45 indicates the most difficult scenario. The 2 major factors function as coefficients to either double or halve the degree of difficulty. This speculative model may help the managers of organ procurement units choose the best-suited person for any family interview, and it may help clinicians attempting to obtain consent to compare their results over time. Our model must be tested in a real context to discover its predictive power.


Improved intestinal absorption of water-soluble drugs by acetylation of G2 PAMAM dendrimer nanocomplexes in rat.
In search of an effective and less toxic absorption enhancer, we synthesized primary amine acetylation of generation 2 polyamidoamine (G2 PAMAM) dendrimer (Ac-G2) by the reaction of G2 PAMAM dendrimer with acetic anhydride, and evaluated the effects of Ac-G2 on the intestinal absorption of poorly absorbable water-soluble drugs using an in situ closed-loop method in rats. The results indicated that Ac50-G2 had a greatest absorption enhancing effect for 5(6)-carboxyfluorescein (CF) in various acetylation levels of G2 PAMAM dendrimers. Ac50-G2 with various concentrations (0.1-1.0%, w/v) could significantly improve the intestinal absorption of alendronate, CF, and fluorescein isothiocyanate-labeled dextrans (FD4), although they did not enhance the absorption of macromolecular drug of FD10, and the absorption enhancement effect of Ac50-G2 was concentration-dependent. Furthermore, we examined the intestinal membrane damage with or without Ac50-G2. The results displayed Ac50-G2 at lower concentrations (0.1-0.5%, w/v) did not cause any observed toxic effect to the intestinal membranes. These findings suggested Ac50-G2 at lower concentrations (below 0.5%, w/v) might be promising as an effective and safe absorption enhancers to promote the intestinal absorption of poorly absorbable drugs.


High-performance acute care hospitals: Excelling across multiple emergency general surgery operations in the geriatric patient.
As the geriatric population grows, the need for hospitals performing high quality emergency general surgery (EGS) on older patients will increase. Identifying clusters of high-performing geriatric emergency general surgery hospitals would substantiate the need for in-depth analyses of hospital-specific structures and practices that benefit older EGS patients. The objectives of this study were therefore to identify clusters of hospitals based on mortality performance for geriatric patients undergoing common EGS operations and to determine if hospital performance was similar for all operation types. Hospitals in the California State Inpatient Database were included if they performed a range of eight common EGS operations in patients 65 years or older, with a minimum requirement of three of each operation performed over 2 years. Multivariable beta regression models were created to define hospital-level risk-adjusted mortality. Centroid cluster analysis was used to identify groups of hospitals based on mortality and to determine if mortality-performance differed by operation. One hundred seven hospitals were included, performing a total of 24,279 operations in older patients. Hospitals separated into three distinct clusters: high, average, and low performers. The high-performing hospitals had survival rates 1 to 2 standard deviations better than the low-performers (p < 0.001). For each cluster, high performance in any one EGS operation consistently translated into high performance across all EGS operations. Hospitals conducting EGS operations in the geriatric patient population cluster into three distinct groups based on their survival performance. High-performing hospitals significantly outperform the average and low performers across every operation. The high-performers achieve reliable, high-quality results regardless of operation type. Further qualitative research is needed to investigate the perioperative drivers of hospital performance in the geriatric EGS population. Study Type Prognostic, level III.


Discovery, biological evaluation, and structure-activity and -selectivity relationships of 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-methylacetamides, a novel class of potent and selective monoamine oxidase inhibitors.
The use of selective inhibitors of monoamine oxidase A (MAO-A) and B (MAO-B) holds a therapeutic relevance in the treatment of depressive disorders and Parkinson's disease (PD), respectively. Here, the discovery of a new class of compounds acting as monoamine oxidase inhibitors (MAO-Is) and bearing a 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-alkylacetamide skeleton is reported. 6'-Sulfonyloxy derivatives exhibited outstanding affinities to MAO-A (7.0 nM < IC50 < 49 nM, much higher than moclobemide) and a pronounced MAO-A/B selectivity. The corresponding 6'-benzyloxy derivatives showed potent MAO-B inhibition and inverted selectivity profile. The rigid E-geometry of the exocyclic double bond allowed a more efficient binding conformation compared to more flexible and less active 2-(1-benzofuran-3-yl)-N-methylacetamide isomers and 4-N-methylcarboxamidomethylcoumarin analogues. Focused structural modifications and docking simulations enabled the identification of key molecular determinants for high affinity toward both MAO isoforms. These novel MAO-Is may represent promising hits for the development of safer therapeutic agents with a potential against depression, PD, and other age-related neurodegenerative pathologies.


High secondary resistance to quinolones in German Helicobacter pylori clinical isolates.
The aim of this study was to update data on levofloxacin/ciprofloxacin and triple resistance (resistance to metronidazole, clarithromycin and levofloxacin/ciprofloxacin) in Helicobacter pylori clinical isolates and to identify the impact of prior eradication therapies on their development. We tested the antimicrobial susceptibility to amoxicillin, metronidazole, clarithromycin, levofloxacin/ciprofloxacin, tetracycline and rifampicin of 5296 clinical H. pylori strains isolated between 2006 and 2011. Information on prior eradication therapies was gathered and their impact on the development of antimicrobial resistance, in particular to levofloxacin/ciprofloxacin and triple resistance, was analysed. From 2006 onwards, both levofloxacin/ciprofloxacin and triple resistance have steadily increased and peaked in 2011 with 29.1% and 18.6%, respectively. Unsuccessful prior eradication attempts proved a major risk factor for resistance development. Patients who had undergone unsuccessful eradication attempts harboured levofloxacin/ciprofloxacin- and triple-resistant isolates significantly more often than untreated individuals (26.7% and 18.1% versus 10.6% and 1.6%). Levofloxacin/ciprofloxacin and triple resistance occurred significantly more often in patients who had received quinolones when compared with patients who had not (44.5% versus 23.1% and 28.7% versus 15.6%). We did not observe any significant differences in resistance rates in the different German federal states. Resistance to levofloxacin/ciprofloxacin and triple resistance have continuously risen and reached worrying numbers. Hence we strongly advise against the use of quinolones in empirical second-line therapies for H. pylori without prior susceptibility testing and/or a carefully taken patient medical history.


Citizenship as practice: Handling communication problems in encounters between persons with dementia and social workers.
The overall aim of the study was to investigate if and how persons with dementia were able to take part in negotiations for formal support, as cases of citizenship as practice The transcripts used for analysis were from 11 assessment meetings conducted in Sweden, in which the formal applicant was a person with dementia. The findings suggest that the actual participation of persons with dementia in assessment meetings varies. Communication problems were found in the meetings to different degrees and were dealt with differently and with various consequences. For those persons with dementia contributing at the same levels as the other participants, there was an attempt at mutual understanding. For those making fewer contributions, the other interlocutors took over the initiative and thus affected the practice of citizenship by persons with dementia in a negative way. The practice of citizenship is situation based and varies depending on all participants. When the person with dementia is able to participate in the conversation, social workers can facilitate for them to overcome communication problems by giving them more time and signaling acceptance. If the person with dementia has great problems in participating, the other participants can find different strategies to at least involve her or him in the conversation.


Effect of the average number of reference speckles in speckle imaging using off-axis speckle holography.
The propagation of a coherent beam of light through a random scattering medium results in the generation of a speckle pattern. Although the intensity distribution of the speckle pattern is random in nature, the information of the object hidden behind a scattering medium is scrambled into it. The scrambled object information can be retrieved using the off-axis speckle holographic technique, where the object retrieval is made from a recorded interferogram, formed by the superposition of the object speckles and a tilted reference speckle pattern. In the present paper, the effect of the average number of reference speckles on the signal-to-noise ratio of the retrieved object is investigated in two different random domains of the reference speckles, which are defined from the study of the Shannon entropy of the reference speckle patterns. The observed results can be useful in tuning the visibility and sharpness of the object, retrieved by employing the off-axis speckle holographic technique.