Laparoendoscopic single site surgery in urology: A single centre experience.
To analyze our experience of 87 cases with single port surgery, which is also known as laparoendoscopic single site surgery (LESS). Case records of all LESS procedures performed between December 2007 and June 2010 were analysed. The procedures performed were donor nephrectomy (n=45), simple nephrectomy (n=27), radical nephrectomy (n=5), pyeloplasty (n=9), and ureteroneocystostomy (n=1). Parameters analysed were operating room (OR) time, estimated blood loss (EBL), visual analogue score (VAS), and complications in all patients undergoing LESS procedure and additionally, warm ischaemia time (WIT) and graft outcome in patients undergoing LESS donor nephrectomy. In reconstructive procedures, the functional assessment was performed with a diuretic renogram at 6 months. In LESS donor nephrectomy, the mean WIT was 6.9 ± 1.9 min. Mean serum creatinine in recipients at 1 month was 0.96 ± 0.21 mg%. We encountered one instance each of renal artery injury, renal vein injury, large bowel injury, minor cortical laceration at the upper pole and two instances of diaphragmatic injury. In LESS simple nephrectomy, the average OR time was 148.7 ± 52.2 min and hospital stay was 3.7 ± 1.2 days. There was one instance of large bowel injury during specimen retrieval. In LESS radical nephrectomy, the average OR time was 202.5 ± 35.7 min and average hospital stay was 4.2 ± 1.3 days. 6 patients of LESS pyeloplasty completed follow up with a diuretic renogram showing a good drainage. LESS ureteroneocystostomy could also be performed successfully without any complications. LESS surgery can be accomplished safely in nephrectomy and reconstructive procedures such as pyeloplasty and ureteroneocystostomy with equivalent outcomes as standard laparoscopy and with added benefits of cosmesis and quicker convalescence. LESS donor nephrectomy is a technically feasible procedure; current status of procedure needs to be proved with randomised controlled studies.


The wheat SnRK1α family and its contribution to Fusarium toxin tolerance.
Deoxynivalenol (DON) is a mycotoxin produced by phytopathogenic Fusarium fungi in cereal grain and plays a role as a disease virulence factor. TaFROG (Triticum aestivum Fusarium Resistance Orphan Gene) enhances wheat resistance to DON and it interacts with a sucrose non-fermenting-1 (SNF1)-related protein kinase 1 catalytic subunit α (SnRK1α). This protein kinase family is central integrator of stress and energy signalling, regulating plant metabolism and growth. Little is known regarding the role of SnRK1α in the biotic stress response, especially in wheat. In this study, 15 wheat (Triticum aestivum) SnRK1α genes (TaSnRK1αs) belonging to four homoeologous groups were identified in the wheat genome. TaSnRK1αs are expressed ubiquitously in all organs and developmental stages apart from two members predominantly detected in grain. While DON treatment had either no effect or downregulated the transcription of TaSnRK1αs, it increased both the kinase activity associated with SnRK1α and the level of active (phosphorylated) SnRK1α. Down-regulation of two TaSnRK1αs homoeolog groups using virus induced gene silencing (VIGS) increased the DON-induced damage of wheat spikelets. Thus, we demonstrate that TaSnRK1αs contribute positively to wheat tolerance of DON and conclude that this gene family may provide useful tools for the improvement of crop biotic stress resistance.


Aerosol deposition in the nose as a function of body size.
The effect of body size on nasal doses from inhaled aerosols has not been measured directly in people. Two basic types of computational models are used to calculate inhaled particle deposition in adults. One type uses an impaction parameter that incorporates particle aerodynamic diameter and the average airflow rate. The second type uses the nasal pressure drop and particle aerodynamic diameter. Although both types of models have been adjusted to give reasonably accurate deposition efficiencies for adults, they predict very different deposition efficiencies when they are applied to young children. This is not surprising because the airflow-type model has no body-size-dependent parameters, unlike the pressure-drop-type model. The objective of our studies was to test these two types of computational models using idealized hollow nasal models of two sizes, representing the adult and young child. The results indicate that a pressure-drop relationship fits the aerosol deposition data very well. When the properly scaled physiological air flows and minute ventilations are used in a nasal dose calculation, the young child is seen to have potentially larger nasal doses than those of an adult.


[Monoclonal antibodies of the ICO series against differentiation antigens of human lymphocytes].
The principal characteristics of monoclonal antibodies (MCA) ICO have been presented. The MCA ICO panel includes MCA against differentiating antigens of T- and B-lymphocytes, myelomonocytes, human leukemia-associated antigens. The following MCA have been described: MCA ICO-87 against common T-cell antigen CD7, ICO-33 and ICO-80 against common T-cell antigen CD5, MCA ICO-10 against Thy-1 antigen of early thymocytes, ICO-44 against CD1c antigen of cortical thymocytes, MCA ICO-90 against CD3 antigen of mature T-lymphocytes, MCA ICO-86 against CD4 antigen of T-helper/inductor cells, MCA ICO-31 against CD8 antigen of T-suppressor/cytotoxic cells, MCA ICO-1 against nonpolymorphic antigens of HLA II class, MCA ICO-12 against CD22 antigen of B-lymphocytes, MCA ICO-30 against mu-chain of human IgGM, MCA ICO-66 against CD37 antigen of B-lymphocytes, MCA ICO-88 against antigen of activated T- and B-cells, MCA ICO-35 against lymphoblasts, MCA ICO-88 against CD38 antigen of thymocytes and activated cells.


Home front: post-deployment mental health and divorces.
Since 2003, about 14 % of U.S. Army soldiers have reported symptoms of posttraumatic stress disorder (PTSD) following deployments. In this article, we examine how post-deployment symptoms of PTSD and of other mental health conditions are related to the probability of divorce among married active-duty U.S. Army soldiers. For this purpose, we combine Army administrative individual-level longitudinal data on soldiers' deployments, marital history, and sociodemographic characteristics with their self-reported post-deployment health information. Our estimates indicate that time spent in deployment increases the divorce risk among Army enlisted personnel and that PTSD symptoms are associated with further increases in the odds of divorce. Although officers are generally less likely to screen positive for PTSD than enlisted personnel, we find a stronger relationship between PTSD symptoms and divorces among Army officers who are PTSD-symptomatic than among enlisted personnel. We estimate a larger impact of deployments on the divorce risk among female soldiers, but we do not find a differential impact of PTSD symptoms by gender. Also, we find that most of the effect of PTSD symptoms occurs early in the career of soldiers who deploy multiple times.


Tropism and innate host responses of the 2009 pandemic H1N1 influenza virus in ex vivo and in vitro cultures of human conjunctiva and respiratory tract.
The novel pandemic influenza H1N1 (H1N1pdm) virus of swine origin causes mild disease but occasionally leads to acute respiratory distress syndrome and death. It is important to understand the pathogenesis of this new disease in humans. We compared the virus tropism and host-responses elicited by pandemic H1N1pdm and seasonal H1N1 influenza viruses in ex vivo cultures of human conjunctiva, nasopharynx, bronchus, and lung, as well as in vitro cultures of human nasopharyngeal, bronchial, and alveolar epithelial cells. We found comparable replication and host-responses in seasonal and pandemic H1N1 viruses. However, pandemic H1N1pdm virus differs from seasonal H1N1 influenza virus in its ability to replicate in human conjunctiva, suggesting subtle differences in its receptor-binding profile and highlighting the potential role of the conjunctiva as an additional route of infection with H1N1pdm. A greater viral replication competence in bronchial epithelium at 33 degrees C may also contribute to the slight increase in virulence of the pandemic influenza virus. In contrast with highly pathogenic influenza H5N1 virus, pandemic H1N1pdm does not differ from seasonal influenza virus in its intrinsic capacity for cytokine dysregulation. Collectively, these results suggest that pandemic H1N1pdm virus differs in modest but subtle ways from seasonal H1N1 virus in its intrinsic virulence for humans, which is in accord with the epidemiology of the pandemic to date. These findings are therefore relevant for understanding transmission and therapy.


A large region (approximately equal to 95 kDa) of human factor VIII is dispensable for in vitro procoagulant activity.
Factor VIII (antihemophilic factor) is a high molecular weight plasma glycoprotein that participates in the blood clotting cascade. The recent cloning and sequence analysis of the cDNA encoding human factor VIII revealed an obvious domain structure for the protein, which can be represented as A1-A2-B-A3-C1-C2. We now report the DNA sequence analysis of porcine exons encoding the entire B domain and part of the A2 and A3 domains. We found an unusually high degree of porcine-human amino acid sequence divergence in the B region compared with the limited sequence available for other regions of the porcine factor VIII molecule. In addition to sequence divergence, there are numerous gaps in the porcine B domain totalling over 200 amino acids. Recombinant DNA techniques were used to effect the removal of large segments of DNA encoding the B domain from the full-length human factor VIII cDNA. These constructs directed the synthesis of biologically active factor VIII when introduced into mammalian cells despite the deletion of up to 38% of the factor VIII molecule.


HD iPSC-derived neural progenitors accumulate in culture and are susceptible to BDNF withdrawal due to glutamate toxicity.
Huntington's disease (HD) is a fatal neurodegenerative disease, caused by expansion of polyglutamine repeats in the Huntingtin gene, with longer expansions leading to earlier ages of onset. The HD iPSC Consortium has recently reported a new in vitro model of HD based on the generation of induced pluripotent stem cells (iPSCs) from HD patients and controls. The current study has furthered the disease in a dish model of HD by generating new non-integrating HD and control iPSC lines. Both HD and control iPSC lines can be efficiently differentiated into neurons/glia; however, the HD-derived cells maintained a significantly greater number of nestin-expressing neural progenitor cells compared with control cells. This cell population showed enhanced vulnerability to brain-derived neurotrophic factor (BDNF) withdrawal in the juvenile-onset HD (JHD) lines, which appeared to be CAG repeat-dependent and mediated by the loss of signaling from the TrkB receptor. It was postulated that this increased death following BDNF withdrawal may be due to glutamate toxicity, as the N-methyl-d-aspartate (NMDA) receptor subunit NR2B was up-regulated in the cultures. Indeed, blocking glutamate signaling, not just through the NMDA but also mGlu and AMPA/Kainate receptors, completely reversed the cell death phenotype. This study suggests that the pathogenesis of JHD may involve in part a population of 'persistent' neural progenitors that are selectively vulnerable to BDNF withdrawal. Similar results were seen in adult hippocampal-derived neural progenitors isolated from the BACHD model mouse. Together, these results provide important insight into HD mechanisms at early developmental time points, which may suggest novel approaches to HD therapeutics.


The Ornithodolite as a tool to quantify animal space use and habitat selection: a case study with birds diving in tidal waters.
Animal-attached technologies can be powerful means to quantify space use and behavior; however, there are also ethical implications associated with capturing and instrumenting animals. Furthermore, tagging approaches are not necessarily well-suited for examining the movements of multiple individuals within specific, local areas of interest. Here, we assess a method of quantifying animal space use based on a modified theodolite with an inbuilt laser rangefinder. Using a database of >4200 tracks of migrating birds, we show that detection distance increases with bird body mass (range 5 g to >10 kg). The maximum distance recorded to a bird was 5500 m and measurement error was ≤5 m for targets within this distance range: a level comparable to methods such as GPS tagging. We go on to present a case study where this method was used to assess habitat selection in seabirds operating in dynamic coastal waters close to a tidal turbine. Combining positional data with outputs from a hydrographic model revealed that great cormorants (Phalacrocorax carbo) appeared to be highly selective of current characteristics in space and time, exploiting areas where mean current speeds were <0.8 m·s-1 and diving at times when turbulent energy levels were low. These birds also oriented into tidal currents during dives. Taken together, this suggests that collision risks are low for cormorants at this site, as the 2 conditions avoided by cormorants (high mean current speeds and turbulence levels) are associated with operational tidal turbines. Overall, we suggest that this modified theodolite system is well-suited to the quantification of movement in small areas associated with particular development strategies, including sustainable energy devices.


Associated factors to the consumption of non-nutritive sweeteners in the Mexican adult population.
To identify the associated factors to the consumption of non-nutritive sweeteners (NNS) in the Mexican adult population since its consumption has increased exponentially worldwide. An online survey was applied to 5 038 Mexican adults to evaluate the frequency of NNS consumption and classify the population in tertiles. The sociodemographic, lifestyle and health status characteristics of the participants were compared by gradient of NNS consumption, and a multiple linear regression analysis was performed to determine the associated factors to the NNS consumption. The variables that showed a positive association (p≤0.01) with the consumption of NNS were economic income, BMI, smoking, physical activity, diet quality, the presence of chronic diseases (diabetes, hypertension, or dyslipidemias), and the consumption of fruit. The age and the consumption of confectionery and sugar-sweetened beverages were negatively associated (p<0.01) with the consumption of NNS. The results of this study help to characterize the target population that is a consumer of NNS since it is recommended not encourage the preference for sweet taste and to promote a decrease in the consumption of both caloric and NNS, preferring the natural flavor of food.


Prevalence of ischemic heart disease and management of coronary risk in daily clinical practice: results from a Mediterranean cohort of HIV-infected patients.
There are conflicting data on the prevalence of coronary events and the quality of the management of modifiable cardiovascular risk factors (CVRF) in HIV-infected patients. We performed a retrospective descriptive study to determine the prevalence of coronary events and to evaluate the management of CVRF in a Mediterranean cohort of 3760 HIV-1-infected patients from April 1983 through June 2011. We identified 81 patients with a history of a coronary event (prevalence 2.15%); 83% of them suffered an acute myocardial infarction. At the time of the coronary event, CVRF were highly prevalent (60.5% hypertension, 48% dyslipidemia, and 16% diabetes mellitus). Other CVRF, such as smoking, hypertension, lack of exercise, and body mass index, were not routinely assessed. After the coronary event, a significant decrease in total cholesterol (P = 0.025) and LDL-cholesterol (P = 0.004) was observed. However, the percentage of patients who maintained LDL-cholesterol > 100 mg/dL remained stable (from 46% to 41%, P = 0.103). Patients using protease inhibitors associated with a favorable lipid profile increased over time (P = 0.028). The prevalence of coronary events in our cohort is low. CVRF prevalence is high and their management is far from optimal. More aggressive interventions should be implemented to diminish cardiovascular risk in HIV-infected patients.


Actin dynamics and the Bmp pathway drive apical extrusion of proepicardial cells.
The epicardium, the outer mesothelial layer enclosing the myocardium, plays key roles in heart development and regeneration. During embryogenesis, the epicardium arises from the proepicardium (PE), a cell cluster that appears in the dorsal pericardium (DP) close to the venous pole of the heart. Little is known about how the PE emerges from the pericardial mesothelium. Using a zebrafish model and a combination of genetic tools, pharmacological agents and quantitative in vivo imaging, we reveal that a coordinated collective movement of DP cells drives PE formation. We found that Bmp signaling and the actomyosin cytoskeleton promote constriction of the DP, which enables PE cells to extrude apically. We provide evidence that cell extrusion, which has been described in the elimination of unfit cells from epithelia and the emergence of hematopoietic stem cells, is also a mechanism for PE cells to exit an organized mesothelium and fulfil their developmental fate to form a new tissue layer, the epicardium.


Simulation of the resonance Raman spectrum for uracil.
The resonance Raman spectrum of uracil is simulated using the Herzberg-Teller short-time dynamics formalism. The ground-state geometry is optimized at the levels of PBE0/aug-cc-pVTZ and B3LYP/aug-cc-pVTZ, respectively. The gradient of the bright excited state is computed using time-dependent density functional theory and spin-flip time-dependent density functional theory. The excited-state calculations are carried out in both the gas phase and implicit water using the conductor-like polarizable continuum model. The ground-state equilibrium structure is found to impact the resulting resonance Raman spectrum significantly. The simulated resonance Raman spectrum using the long-range corrected functionals, that is, CAMB3LYP and LC-BLYP, and based on the PBE0/aug-cc-pVTZ optimized ground-state structure shows better agreement with the experimental spectrum than using standard hybrid functionals, that is, PBE0 and B3LYP. The solvation effect leads to a change in the energetic order of the n → π* and π → π* excited states, and it improves the agreement with the experimental spectrum, especially with regard to the relative intensities of the peaks with frequencies greater than 1600 cm(-1).


Programmable on-chip and off-chip network architecture on demand for flexible optical intra-datacenters.
The paper presents a novel network architecture on demand approach using on-chip and-off chip implementations, enabling programmable, highly efficient and transparent networking, well suited for intra-datacenter communications. The implemented FPGA-based adaptable line-card with on-chip design along with an architecture on demand (AoD) based off-chip flexible switching node, deliver single chip dual L2-Packet/L1-time shared optical network (TSON) server Network Interface Cards (NIC) interconnected through transparent AoD based switch. It enables hitless adaptation between Ethernet over wavelength switched network (EoWSON), and TSON based sub-wavelength switching, providing flexible bitrates, while meeting strict bandwidth, QoS requirements. The on and off-chip performance results show high throughput (9.86Ethernet, 8.68Gbps TSON), high QoS, as well as hitless switch-over.


Metabolic and Proliferative State of Vascular Adventitial Fibroblasts in Pulmonary Hypertension Is Regulated Through a MicroRNA-124/PTBP1 (Polypyrimidine Tract Binding Protein 1)/Pyruvate Kinase Muscle Axis.
An emerging metabolic theory of pulmonary hypertension (PH) suggests that cellular and mitochondrial metabolic dysfunction underlies the pathology of this disease. We and others have previously demonstrated the existence of hyperproliferative, apoptosis-resistant, proinflammatory adventitial fibroblasts from human and bovine hypertensive pulmonary arterial walls (PH-Fibs) that exhibit constitutive reprogramming of glycolytic and mitochondrial metabolism, accompanied by an increased ratio of glucose catabolism through glycolysis versus the tricarboxylic acid cycle. However, the mechanisms responsible for these metabolic alterations in PH-Fibs remain unknown. We hypothesized that in PH-Fibs microRNA-124 (miR-124) regulates PTBP1 (polypyrimidine tract binding protein 1) expression to control alternative splicing of pyruvate kinase muscle (PKM) isoforms 1 and 2, resulting in an increased PKM2/PKM1 ratio, which promotes glycolysis and proliferation even in aerobic environments. Pulmonary adventitial fibroblasts were isolated from calves and humans with severe PH (PH-Fibs) and from normal subjects. PTBP1 gene knockdown was achieved via PTBP1-siRNA; restoration of miR-124 was performed with miR-124 mimic. TEPP-46 and shikonin were used to manipulate PKM2 glycolytic function. Histone deacetylase inhibitors were used to treat cells. Metabolic products were determined by mass spectrometry-based metabolomics analyses, and mitochondrial function was analyzed by confocal microscopy and spectrofluorometry. We detected an increased PKM2/PKM1 ratio in PH-Fibs compared with normal subjects. PKM2 inhibition reversed the glycolytic status of PH-Fibs, decreased their cell proliferation, and attenuated macrophage interleukin-1β expression. Furthermore, normalizing the PKM2/PKM1 ratio in PH-Fibs by miR-124 overexpression or PTBP1 knockdown reversed the glycolytic phenotype (decreased the production of glycolytic intermediates and byproducts, ie, lactate), rescued mitochondrial reprogramming, and decreased cell proliferation. Pharmacological manipulation of PKM2 activity with TEPP-46 and shikonin or treatment with histone deacetylase inhibitors produced similar results. In PH, miR-124, through the alternative splicing factor PTBP1, regulates the PKM2/PKM1 ratio, the overall metabolic, proliferative, and inflammatory state of cells. This PH phenotype can be rescued with interventions at various levels of the metabolic cascade. These findings suggest a more integrated view of vascular cell metabolism, which may open unique therapeutic prospects in targeting the dynamic glycolytic and mitochondrial interactions and between mesenchymal inflammatory cells in PH.


Resilience of Octocoral Forests to Catastrophic Storms.
After centuries of human-mediated disturbances, Caribbean reef communities are vastly different from those described in the 1950s. Many are functionally dominated by macroalgae, but this community state represents only one of several possibilities into which present-day coral reefs can transition. Octocorals have always been abundant on Caribbean reefs, but increases in their abundance over the last few decades suggest that arborescent octocorals have the potential to expand their populations on reefs that hitherto had been dominated by scleractinians. Here we show that octocoral-dominated communities at three sites on the fringing reefs of St. John, US Virgin Islands, were resilient to the effects of two Category 5 hurricanes in 2017. We describe the dynamics of octocoral communities over five years at three sites on shallow reefs (~9-m depth), and test for the effects of Hurricanes Irma and Maria. The hurricanes depressed the densities of juvenile and adult octocoral colonies as much as 47%. However, there were only weak effects on species richness and the relative abundances of the octocoral species. The hurricanes did not alter patterns of spatial variability in octocoral community structure that existed among sites prior to the storms. The density of octocoral recruits (individuals ≤ 5 cm high) was reduced in the year following the hurricanes, mainly due to a decline in abundance of recruits <0.5 cm, but returned to pre-storm densities in 2019. Persistently high octocoral recruitment provides a mechanism supporting ecological resilience of these communities. Continuing environmental degradation is a threat to all tropical marine communities, but the reefs of St. John illustrate how "octocoral forests" can persist as the structurally dominant community on Caribbean reefs.


Immunologic cross-reactions among mammalian acute phase proteins.
Crystalline rabbit Cx-reactive protein has been compared immunologically with the analogous crystalline C-reactive protein of man. Immunologic cross-reactivity has been demonstrated between the acute phase proteins of man, rabbit, and monkey. Double-diffusion reactions in agar and passive cutaneous anaphylaxis reactions in vivo both indicate that these acute phase proteins are antigenically closely similar but not identical. Guinea pigs with delayed hypersensitivity to C-reactive protein exhibit delayed skin reactions when tested with Cx-reactive protein and vice versa.


Development of B lymphocytes-1,2.
A rough outline of the development pathway of stem cells to B lymphocytes in mammals is beginning to emerge. The stem cell is most probably either identical to or closely related to the spleen colony-forming unit or hemopoietic stem cell. The stem cell appears not to be specificity-restricted and to lack Ig surface receptors. Whether part of B-cell development in mammals takes place in a specialized lymphoid environment, analogous to the bursa of Fabricius in birds, is still unresolved. The bone marrow does not form such an environment. The bone marrow and spleen, but not the lymph nodes, of mice contain a nondividing B-cell precursor population at an intermediate stage of development between the stem cell and B cell. This population has Ig surface receptors and is specificity-restricted. It cannot be initiated into differentiating into antibody-producing cells. However, under appropriate conditions it can give rise to functional B cells within 3 days. Newly-formed B cells (designated B1) are physically different from mature B cells (designated B2) and appear to be a dividing population of cells differentiating from the B-cell precursor to B2 nondividing cell populations.


Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia.
A number of vitamins and minerals have been shown to influence carcinogenesis in experimental animals. In humans, epidemiologic evidence suggests that intake of fruits and vegetables may reduce risk of esophageal and other cancers. Vitamins and minerals in these foods may contribute to the reduced cancer risk. The people of Linxian, China, have persistently low intake of multiple nutrients and exhibit one of the world's highest rates of esophageal/gastric cardia cancer, with an exceptionally high risk of esophageal dysplasia. To determine whether supplementation with multiple vitamins and minerals may reduce esophageal/gastric cardia cancer among persons with esophageal dysplasia, we conducted a 6-year prospective intervention trial in Linxian. Mortality and cancer incidence were ascertained from May 1985 through May 1991 for 3318 persons with cytologic evidence of esophageal dysplasia who were randomly assigned to receive, throughout that period, daily supplementation with 14 vitamins and 12 minerals or placebo. Doses were typically two to three times U.S. Recommended Daily Allowances. Compliance was assessed by counting unused pills monthly for all trial participants and by assaying nutrient levels in blood collected from samples of individuals randomly selected without replacement every 3 months throughout the trial. Cancers were identified through routine surveillance and by special cytology and endoscopy screenings after 2 1/2 years and 6 years. A total of 324 deaths occurred during the 6-year intervention period; 167 occurred in the control (placebo) group and 157 occurred in the supplement group. Cancer was the leading cause of death (54% of all deaths); 18% were due to cerebrovascular diseases and 29% to other causes. Cumulative esophageal/gastric cardia death rates were 8% lower (relative risk [RR] = 0.92; 95% confidence interval [CI] = 0.67-1.28) among individuals receiving supplements rather than placebo, a nonsignificant (P > .10) difference. Risk of total mortality was 7% lower (RR = 0.93; 95% CI = 0.75-1.16; P > .10), total cancer 4% lower (RR = 0.96; 95% CI = 0.71-1.29; P > .10), cerebrovascular disease 38% lower (RR = 0.62; 95% CI = 0.37-1.06; P = .08), and other diseases 12% higher (RR = 1.12; 95% CI = 0.74-1.69; P > .10) among the treated group. Cumulative cancer incidence rates were nearly the same in the two groups. No substantial short-term beneficial effect on incidence or mortality for this type of cancer occurred following daily supplementation with multiple vitamins and minerals among adults with precancerous lesions of the esophagus. Although no statistically significant short-term benefits were observed, longer follow-up should be more informative about the effectiveness of this 6-year supplementation on cancer and other diseases among individuals with esophageal dysplasia.


Nonendoscopic placement and use of percutaneous gastrostomy tubes in pigs (Sus scrofa domestica).
Swine have supplanted dogs and other large animal species in many biomedical applications and have become the model of choice for numerous areas of research. Anatomic, behavioral, and handling concerns often require pigs to be surgically instrumented for many procedures. Oral dosing in pigs can be accomplished by feeding substances in a palatable substrate, temporarily placing an oral or nasal gastric tube, or permanent surgical placement of an esophagostomy or gastrostomy tube. Oral and nasal gastric tube placement is difficult in conscious, unrestrained animals and is suitable only for short-term enteral access. Placing esophagostomy and gastrostomy tubes is suitable for long-term enteral access and allows easy and rapid administration of substances directly into the stomach. However, these methods frequently require major surgical manipulation for placement. Nonendoscopic percutaneous gastrostomy tube placement is used in companion animals to establish permanent or temporary enteral access. We successfully have adapted this procedure in swine as a method for short-term enteral access. This technique has several advantages over the traditional surgical method for gastrostomy tube placement. It is minimally invasive, results in less animal pain and distress, requires less procedural and recovery time, and is inexpensive. Disadvantages include the potential for splenic entrapment, splenic penetration, perforation of the esophagus, and other complications related to misplacement of the tube or applicator. This paper describes the equipment, technique, and potential complications for placing a nonendoscopic percutaneous gastrostomy tube in swine.


BioMet Toolbox: genome-wide analysis of metabolism.
The rapid progress of molecular biology tools for directed genetic modifications, accurate quantitative experimental approaches, high-throughput measurements, together with development of genome sequencing has made the foundation for a new area of metabolic engineering that is driven by metabolic models. Systematic analysis of biological processes by means of modelling and simulations has made the identification of metabolic networks and prediction of metabolic capabilities under different conditions possible. For facilitating such systemic analysis, we have developed the BioMet Toolbox, a web-based resource for stoichiometric analysis and for integration of transcriptome and interactome data, thereby exploiting the capabilities of genome-scale metabolic models. The BioMet Toolbox provides an effective user-friendly way to perform linear programming simulations towards maximized or minimized growth rates, substrate uptake rates and metabolic production rates by detecting relevant fluxes, simulate single and double gene deletions or detect metabolites around which major transcriptional changes are concentrated. These tools can be used for high-throughput in silico screening and allows fully standardized simulations. Model files for various model organisms (fungi and bacteria) are included. Overall, the BioMet Toolbox serves as a valuable resource for exploring the capabilities of these metabolic networks. BioMet Toolbox is freely available at www.sysbio.se/BioMet/.


Fuel Cell Measurements with Cathode Catalysts of Sputtered Pt3 Y Thin Films.
Fuel cells are foreseen to have an important role in sustainable energy systems, provided that catalysts with higher activity and stability are developed. In this study, highly active sputtered thin films of platinum alloyed with yttrium (Pt3 Y) are deposited on commercial gas diffusion layers and their performance in a proton exchange membrane fuel cell is measured. After acid pretreatment, the alloy is found to have up to 2.5 times higher specific activity than pure platinum. The performance of Pt3 Y is much higher than that of pure Pt, even if all of the alloying element was leached out from parts of the thin metal film on the porous support. This indicates that an even higher performance is expected if the structure of the Pt3 Y catalyst or the support could be further improved. The results show that platinum alloyed with rare earth metals can be used as highly active cathode catalyst materials, and significantly reduce the amount of platinum needed, in real fuel cells.


Extreme resilience and dissipation in heterogeneous elasto-plastomeric crystals.
We present a microstructure-topology-based approach for designing macroscopic, heterogeneous soft materials that exhibit outstanding mechanical resilience and energy dissipation. We investigate a variety of geometric configurations of resilient yet dissipative heterogeneous elasto-plastomeric materials that possess long-range order whose microstructural features are inspired by crystalline metals and block copolymers. We combine experiments and numerical simulations on 3D-printed prototypes to study the extreme mechanics of these heterogeneous soft materials under cyclic deformation conditions up to an extreme strain of >200% with strain rates ranging from quasi-static (5.0 × 10-3 s-1) to high levels of >6.0 × 101 s-1. Moreover, we investigate the complexity of elastic and inelastic "unloading" mechanisms crucial for the understanding of shape recovery and energy dissipation in extreme loading situations. Furthermore, we propose a simple but physically intuitive approach for designing microstructures that exhibit a nearly isotropic behavior in both elasticity and inelasticity across different crystallographic orientations from small to large strains. Overall, our study sets a significant step toward the development of sustainable, heterogeneous soft material architectures at macroscopic scales that can withstand harsh mechanical environments.


Eliminating genes for a two-component system increases PHB productivity in Cupriavidus basilensis 4G11 under PHB suppressing, nonstress conditions.
Species of bacteria from the genus Cupriavidus are known, in part, for their ability to produce high amounts of poly-hydroxybutyrate (PHB) making them attractive candidates for bioplastic production. The native synthesis of PHB occurs during periods of metabolic stress, and the process regulating the initiation of PHB accumulation in these organisms is not fully understood. Screening an RB-TnSeq transposon library of Cupriavidus basilensis 4G11 allowed us to identify two genes of an apparent, uncharacterized two-component system, which when omitted from the genome enable increased PHB productivity in balanced, nonstress growth conditions. We observe average increases in PHB productivity of 56% and 41% relative to the wildtype parent strain upon deleting each gene individually from the genome. The increased PHB phenotype disappears, however, in nitrogen-free unbalanced growth conditions suggesting the phenotype is specific to fast-growing, replete, nonstress growth. Bioproduction modeling suggests this phenotype could be due to a decreased reliance on metabolic stress induced by nitrogen limitation to initiate PHB production in the mutant strains. Due to uncertainty in the two-component system's input signal and regulon, the mechanism by which these genes impart this phenotype remains unclear. Such strains may allow for the use of single-stage, continuous bioreactor systems, which are far simpler than many PHB bioproduction schemes used previously, given a similar product yield to batch systems in such a configuration. Bioproductivity modeling suggests that omitting this regulation in the cells may increase PHB productivity up to 24% relative to the wildtype organism when using single-stage continuous systems. This work expands our understanding of the regulation of PHB accumulation in Cupriavidus, in particular the initiation of this process upon transition into unbalanced growth regimes.


Elucidating the survival and response of carbapenem resistant Klebsiella pneumoniae after exposure to imipenem at sub-lethal concentrations.
The increasing prevalence of antibiotic resistant pathogens poses a serious threat to global health. However, less emphasis has been placed to co-relate the gene expression and metabolism of antibiotic resistant pathogens. This study aims to elucidate gene expression and variations in metabolism of multidrug resistant Klebsiella pneumoniae after exposure to antibiotics. Phenotypic responses of three genotypically distinct carbapenem resistant Klebsiella pneumoniae (CRKP) strains untreated and treated with sub-lethal concentrations of imipenem were investigated via phenotype microarrays (PM). The gene expression and metabolism of the strain harboring blaNDM-1 before and after exposure to sub-lethal concentration of imipenem were further investigated by RNA-sequencing (RNA-Seq) and 1H NMR spectroscopy respectively. Most genes related to cell division, central carbon metabolism and nucleotide metabolism were downregulated after imipenem treatment. Similarly, 1H NMR spectra obtained from treated CRKP showed decrease in levels of bacterial end products (acetate, pyruvate, succinate, formate) and metabolites involved in nucleotide metabolism (uracil, xanthine, hypoxanthine) but elevated levels of glycerophosphocholine. The presence of anserine was also observed for the treated CRKP while FAPγ-adenine and methyladenine were only present in untreated bacterial cells. As a conclusion, the studied CRKP strain exhibited decrease in central carbon metabolism, cell division and nucleotide metabolism after exposure to sub-lethal concentrations of imipenem. The understanding of the complex biological system of this multidrug resistant bacterium may help in the development of novel strategies and potential targets for the management of the infections.


Clomipramine in the prevention of migraine.
Clomipramine was compared with placebo in the prevention of migraine headache. Both treatments reduced the frequency of attack markedly but there was no significant difference between the two. The severity of the attack was reduced in both cases but not significantly. The duration of attack was not affected. Significantly more side-effects were seen in the clomipramine group.


Clinical and genetic associations of renal function and diabetic kidney disease in the United Arab Emirates: a cross-sectional study.
Within the Emirati population, risk factors and genetic predisposition to diabetic kidney disease (DKD) have not yet been investigated. The aim of this research was to determine potential clinical, laboratory and reported genetic loci as risk factors for DKD. Four hundred and ninety unrelated Emirati nationals with type 2 diabetes mellitus (T2DM) were recruited with and without DKD, and clinical and laboratory data were obtained. Following adjustments for possible confounders, a logistic regression model was developed to test the associations of 63 single nucleotide polymorphisms (SNPs) in 43 genetic loci with DKD (145 patients with DKD and 265 without DKD). Linear regression models, adjusted for age and gender, were then used to study the genetic associations of five renal function traits, including 83 SNPs with albumin-to-creatinine ratio, 92 SNPs with vitamin D (25-OH cholecalciferol), 288 SNPs with estimated glomerular filtration rate (eGFR), 363 SNPs with serum creatinine and 73 SNPs with blood urea. Patients with DKD, as compared with those without the disease, were mostly men (52%vs38% for controls), older (67vs59 years) and had significant rates of hypertension and dyslipidaemia. Furthermore, patients with DKD had T2DM for a longer duration of time (16vs10 years), which in an additive manner was the single factor that significantly contributed to the development of DKD (p=0.02, OR=3.12, 95% CI 1.21 to 8.02). Among the replicated associations of the genetic loci with different renal function traits, the most notable included SHROOM3 with levels of serum creatinine, eGFR and DKD (Padjusted=0.04, OR=1.46); CASR, GC and CYP2R1 with vitamin D levels; as well as WDR72 with serum creatinine and eGFR levels. Associations were found between several genetic loci and risk markers for DKD, which may influence kidney function traits and DKD in a population of Arab ancestry.


Real-Space, in Situ Maps of Hydrogel Pores.
We characterize the porosity of hydrogels by imaging the displacement trajectories of embedded tracer particles. This offers the possibility of characterizing the size and projected shape of individual pores as well as direct, real-space maps of heterogeneous porosity and its distribution. The scheme shows that when fluorescent spherical particles treated to avoid specific adsorption are loaded into the gel, their displacement trajectories from Brownian motion report on the size and projected shape in which the pore resides, convoluted by the particle size. Of special interest is how pores and their distribution respond to stimuli. These ideas are validated in agarose gels loaded with latex particles stabilized by adsorbed bovine serum albumin. Gels heated from room temperature produced an increasingly more monodisperse pore size distribution because increasing temperature preferentially enlarges smaller pores, but this was irreversible upon cooling, and shearing agarose gels beyond the yield point destroyed larger pores preferably. The method is considered to be generalizable beyond the agarose system presented here as proof of concept.


First Case of Lethal Encephalitis in Western Europe Due to European Bat Lyssavirus Type 1.
Inaccurate diagnosis of encephalitis is a major issue as immunosuppressive treatments can be deleterious in case of viral infection. The European bat lyssavirus type 1 (EBLV-1), a virus related to rabies virus, is endemic in European bats. No human case has yet been reported in Western Europe. A 59-year-old patient without specific past medical history died from encephalitis. A colony of bats lived in an outbuilding of his house. No diagnosis was made using standard procedures. We used a next generation sequencing (NGS) based transcriptomic protocol to search for pathogens in autopsy samples (meninges and brain frontal lobe). Results were confirmed by polymerase chain reaction (PCR) and by antibody testing in serum. Immunochemistry was used to characterize inflammatory cells and viral antigens in brain lesions. Cells and mice were inoculated with brain extracts for virus isolation. The patient's brain lesions were severe and diffuse in white and gray matter. Perivascular inflammatory infiltrates were abundant and rich in plasma cells. NGS identified European bat lyssavirus type 1a in brain, which was confirmed by PCR. A high titer of neutralizing antibodies was found in serum. No viral antigen was detected, and the virus could not be isolated by cell culture or by mouse inoculation. The patient died from European bat lyssavirus type 1a infection. NGS was key to identifying this unexpected viral etiology in an epidemiological context that did not suggest rabies. People exposed to bats should be strongly advised to be vaccinated with rabies vaccines, which are effective against EBLV-1.


Psychometrics of the AAN Caregiver Driving Safety Questionnaire and contributors to caregiver concern about driving safety in older adults.
ABSTRACTBackground:The American Academy of Neurology (AAN) updated their practice parameters in the evaluation of driving risk in dementia and developed a Caregiver Driving Safety Questionnaire, detailed in their original manuscript (Iverson Gronseth, Reger, Classen, Dubinsky, & Rizzo, 2010). They described four factors associated with decreased driving ability in dementia patients: history of crashes or citations, informant-reported concerns, reduced mileage, and aggressive driving. An informant-reported AAN Caregiver Driving Safety Questionnaire was designed with these elements, and the current study was the first to explore the factor structure of this questionnaire. Additionally, we examined associations between these factors and cognitive and behavioral measures in patients with mild cognitive impairment or early Alzheimer's disease and their informants. Exploratory factor analysis revealed a four-component structure, consistent with the theory behind the AAN scale composition. These four factor scores also were significantly associated with performance on cognitive screening instruments and informant reported behavioral dysfunction. Regressions revealed that behavioral dysfunction predicted caregiver concerns about driving safety beyond objective patient cognitive dysfunction. In this first known quantitative exploration of the scale, our results support continued use of this scale in office driving safety assessments. Additionally, patient behavioral changes predicted caregiver concerns about driving safety over and above cognitive status, which suggests that caregivers may benefit from psychoeducation about cognitive factors that may negatively impact driving safety.


Low-carbon yak cheese: transition to biogas in a Himalayan socio-technical niche.
This study looks at how potential for resilient low-carbon solutions can be understood and enhanced in the diverse environmental, economic and socio-political contexts in which actual scenarios of energy needs and diverse development pathways take shape. It discusses socio-technical transition approaches to assist implementation of a biogas digester system. This will replace fuelwood use in the high forests of Central Nepal, where yak cheese production provides livelihood income but is under threat from the Langtang National Park, which is concerned to protect biodiversity. Alternatives for digester design are discussed, and the consultative issues for deliberative processes among stakeholders' varied agendas raised.


The Effect of Type D Personality on Quality of Life in Patients with Multiple Sclerosis.
The Type D personality was reported as an important indicator of adverse clinical outcomes and quality of life in various diseases. The objective of this study was to investigate the relationships between the Type D personality and clinical features and the effect of Type D personality on quality of life in patients with multiple sclerosis (MS). Seventy-four patients with MS participated in this study. Clinical parameters of the patients were recorded and disability was assessed using the Expanded Disability Status Scale (EDSS). Patients were examined with the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Type D Scale (DS14), and 36-Item Short-Form Health Survey (SF-36). BDI and BAI scores were significantly higher and mental subscale of the SF-36 scores were significantly lower in Type D compared to nonType D (p<0.001, p=0.001, and p<0.001, respectively). The total DS14 scores were found to be positively correlated with EDSS, BDI, and BAI and negatively correlated with SF-36 mental subscale (p=0.02, p<0.001, p<0.001, and p<0.001, respectively). Multivariate linear regression analysis indicated that the total DS14 score was independently associated with the mental component of SF-36 (p<0.001). The Type D personality traits may worsen the quality of life, particularly the mental component, in patients with MS. Consequently, the assessment of MS patients by brief and valid DS14 may be valuable for clinical practice.


The convergence properties of a clipped Hopfield network and its application in the design of keystream generator.
We first present a modified Hopfield network, the clipped Hopfield network, with synaptic weights assigned to three values {-1,0,+1}. We give the necessary conditions under which a set of 2n binary vectors can be stored as stable points of the network. We show that in the parallel updating mode, for most of the state vectors, the network will always converge to these 2n stable points. We further demonstrate that these 2n stable points can be divided into two groups, the alpha group and the beta group, each with n stable points. It is shown that the basins of attraction of the stable points in the alpha group are evenly distributed, and the basins of attraction of the stable points in the beta group are also evenly distributed. By ways of application, we show that this class of Hopfield network can be used to build a cryptographically secure keystream generator.


Effect of Hemodynamics on Stroke Risk in Symptomatic Atherosclerotic Vertebrobasilar Occlusive Disease.
Atherosclerotic vertebrobasilar (VB) occlusive disease is a significant etiology of posterior circulation stroke, with regional hypoperfusion as an important potential contributor to stroke risk. To test the hypothesis that, among patients with symptomatic VB stenosis or occlusion, those with distal blood flow compromise as measured by large-vessel quantitative magnetic resonance angiography (QMRA) are at higher risk of subsequent posterior circulation stroke. A prospective, blinded, longitudinal cohort study was conducted at 5 academic hospital-based centers in the United States and Canada; 82 patients from inpatient and outpatient settings were enrolled. Participants with recent VB transient ischemic attack or stroke and 50% or more atherosclerotic stenosis or occlusion in vertebral and/or basilar arteries underwent large-vessel flow measurement in the VB territory using QMRA. Physicians performing follow-up assessments were blinded to QMRA flow status. Follow-up included monthly telephone calls for 12 months and biannual clinical visits (for a minimum of 12 months, and up to 24 months or the final visit). Enrollment took place from July 1, 2008, to July 31, 2013, with study completion on June 30, 2014; data analysis was performed from October 1, 2014, to April 10, 2015. Standard medical management of stroke risk factors. The primary outcome was VB-territory stroke. Of the 82 enrolled patients, 72 remained eligible after central review of their angiograms. Sixty-nine of 72 patients completed the minimum 12-month follow-up; median follow-up was 23 (interquartile range, 14-25) months. Distal flow status was low in 18 of the 72 participants (25%) included in the analysis and was significantly associated with risk for a subsequent VB stroke (P = .04), with 12- and 24-month event-free survival rates of 78% and 70%, respectively, in the low-flow group vs 96% and 87%, respectively, in the normal-flow group. The hazard ratio, adjusted for age and stroke risk factors, in the low distal flow status group was 11.55 (95% CI, 1.88-71.00; P = .008). Medical risk factor management at 6-month intervals was similar between patients with low and normal distal flow. Distal flow status remained significantly associated with risk even when controlling for the degree of stenosis and location. Distal flow status determined using a noninvasive and practical imaging tool is robustly associated with risk for subsequent stroke in patients with symptomatic atherosclerotic VB occlusive disease. Identification of high-risk patients has important implications for future investigation of more aggressive interventional or medical therapies.


A prospective clinical study with one year follow up of deep caries management using a novel biomaterial.
The objectives of this study was to check the outcome of the direct and indirect pulp capping procedure using MTA (Mineral Trioxide Aggregate) by comparing the pre-and post-operative pain by using VAS scale, associating the pre- and post- operative changes in intraoral periapical radiograph and clinical symptoms. In this prospective clinical study 10 cases (5 for direct and 5 for indirect) with deep carious lesions (symptomatic) with no periapical changes were selected for the trial. The participants were subjected to deep caries management procedure under rubber dam where MTA is placed as pulp capping material followed by immediate restoration with sandwich technique using composite resin. The participants were followed up at recall visits of 1 month, 3 months, 6 months and 1 year intervals for clinical and radiographic evaluation. The results of the study, analyzing the VAS, clinical symptoms and radiographic changes did not show any signs of pain, clinical and radiographic symptoms at 1 month, 3 months, 6 months and 1 year intervals. It was concluded that MTA can be used for deep caries management as a pulp capping material which being equivalent to calcium hydroxide.


[GRADE guidelines: 13. Preparing Summary of Findings tables and evidence profiles - continuous outcomes].
Presenting continuous outcomes in Summary of Findings tables presents particular challenges to interpretation. When each study uses the same outcome measure, and the units of that measure are intuitively interpretable (e.g., duration of hospitalisation, duration of symptoms), presenting differences in means is usually desirable. When the natural units of the outcome measure are not easily interpretable, choosing a threshold to create a binary outcome and presenting relative and absolute effects become a more attractive alternative. When studies use different measures of the same construct, calculating summary measures requires converting to the same units of measurement for each study. The longest standing and most widely used approach is to divide the difference in means in each study by its standard deviation and present pooled results in standard deviation units (standardised mean difference). Disadvantages of this approach include vulnerability to varying degrees of heterogeneity in the underlying populations and difficulties in interpretation. Alternatives include presenting results in the units of the most popular or interpretable measure, converting to dichotomous measures and presenting relative and absolute effects, presenting the ratio of the means of intervention and control groups, and presenting the results in minimally important difference units. We outline the merits and limitations of each alternative and provide guidance for meta-analysts and guideline developers. Summary of Findings tables provide succinct presentations of evidence quality and magnitude of effects. Summarising the findings of continuous outcomes presents special challenges to interpretation that become daunting when individual trials use different measures for the same construct. The most commonly used approach to providing pooled estimates for different measures, presenting results in standard deviation units, has limitations related to both statistical properties and interpretability. Potentially preferable alternatives include presenting results in the natural units of the most popular measure, transforming into a binary outcome and presenting relative and absolute effects, presenting the ratio of the means of intervention and control groups, and presenting results in preestablished minimally important difference units.


Synthesis of disulfide-bonded outer membrane proteins during the developmental cycle of Chlamydia psittaci and Chlamydia trachomatis.
The disulfide bond cross-linked major outer membrane protein (MOMP) of the extracellular elementary bodies (EBs) of Chlamydia psittaci was reduced to its monomeric form within 1 h of entry of EBs into host cells by a process which was inhibited by chloramphenicol, while monomeric forms of three cross-linked cysteine-rich proteins could not be detected in Sarkosyl outer membrane complexes at any time in either extracellular or intracellular forms of C. psittaci. Synthesis and incorporation of the MOMP into outer membrane complexes were detected early in the infection cycle (12 h postinfection), while synthesis and incorporation of the cysteine-rich proteins were not observed until reticulate bodies had begun to reorganize into EBs at 20 to 22 h postinfection. By 46 h postinfection, the intracellular population of C. psittaci consisted mainly of EBs, the outer membrane complexes of which were replete with monomeric MOMP and cross-linked cysteine-rich proteins. Upon lysis of infected cells at 46 h, the MOMP was rapidly cross-linked, and infectious EBs were released. The status of the MOMP of intracellular Chlamydia trachomatis was similar to the status of the MOMP of C. psittaci in that the MOMP was largely uncross-linked at 24 and 48 h postinfection, but formed interpeptide disulfide bonds when it was exposed to an extracellular environment late in the developmental cycle. In contrast to C. psittaci, only a fraction of the cross-linked MOMP of infecting EBs of C. trachomatis was reduced by 4 h postinfection, and reduction of the MOMP was not inhibited by chloramphenicol. Exposure of extracellular EBs of C. trachomatis and C. psittaci to dithiothreitol reduced the MOMP but failed to stimulate metabolic activities normally associated with reticulate bodies.


Clinically relevant breast cancer reporting: using process measures to improve anatomic pathology reporting.
Breast cancer reports form an important part of the basis of clinical decision making for patients. Our objectives were to improve breast cancer reporting in the Urban Central Region in Utah of Intermountain Health Care in a clinically relevant manner and to show that the method chosen actually improved information transfer among physicians of breast cancer patients and led to durable changes in pathologist behavior. METHODS/INTERVENTION: Pathologists designed a synoptic report based on interviews with oncologists about what data were meaningful. The report format was piloted with one hospital pathology group, modified, and implemented in three hospitals. A report evaluation of missing information was done before, immediately after, and 2 years after the intervention. Oncologists were surveyed after 2 years to evaluate satisfaction with report format. Changing breast cancer reporting to a synoptic format significantly decreased information missing from pathology reports. Prior to implementation, 32 of 365 reports lacked some item(s) of pathology information desirable to clinicians; after the intervention, 8 of 250 reports contained missing information. After 2 years, 1 in 190 reports contained missing data elements. Synoptic breast cancer reports continued to be used by pathologists throughout the reporting period. Oncologists responding to a survey reported uniform satisfaction with the new reporting format. Pathologists are important members of the clinical oncology team. They provide patient-specific information crucial to patient care. Activities designed to improve the quality of reporting processes should use clinically relevant indicators of process improvement, such as measurement of missing information and satisfaction of clinical colleagues with format/quality of information.


Unintended pregnancy. Consequences and solutions for a worldwide problem.
Unintended pregnancy is a worldwide problem that affects women, their families, and society. Unintended pregnancy can result from contraceptive failure, non-use of contraceptive services, and, less commonly, rape. Abortion is a frequent consequence of unintended pregnancy and, in the developing world, can result in serious, long-term negative health effects including infertility and maternal death. In many developing countries, poverty, malnutrition, and lack of sanitation and education contribute to serious health consequences for women and their families experiencing an unintended pregnancy. Regardless of the cause, unintended pregnancy and its negative consequences can be prevented by access to contraceptive services including emergency contraception, safe and legal abortion services, and a society that allows women to determine their own reproductive choices. Addressing unintended pregnancy and its substantial human and dollar costs should be a priority in every country. The availability of reliable contraception for all, regardless of age or ability to pay, is an essential first step. Women and adolescents require access to age-appropriate and culturally sensitive reproductive health care services, including emergency contraception. Access to safe, legal abortion services is necessary to impact the staggering maternal mortality rates worldwide. Midwives throughout the world provide the majority of care for women of reproductive age. It is essential to identify those at risk for unintended pregnancy, provide the services they require, and remain diligent to ensure that those women and their families have safe options to consider when faced with an unintended pregnancy. In 1920, Magaret Sanger said, "No women can call herself free who does not control her own body." Although great strides have been made to improve the health and status of women since Ms. Sanger spoke those words, there remains much work to be done.


Estrogen Effects on Wound Healing.
Wound healing is a physiological process, involving three successive and overlapping phases-hemostasis/inflammation, proliferation, and remodeling-to maintain the integrity of skin after trauma, either by accident or by procedure. Any disruption or unbalanced distribution of these processes might result in abnormal wound healing. Many molecular and clinical data support the effects of estrogen on normal skin homeostasis and wound healing. Estrogen deficiency, for example in postmenopausal women, is detrimental to wound healing processes, notably inflammation and re-granulation, while exogenous estrogen treatment may reverse these effects. Understanding the role of estrogen on skin might provide further opportunities to develop estrogen-related therapy for assistance in wound healing.


The role of microtubules in cell shape and pigment distribution in spreading erythrophores.
In order to investigate the role of microtubules in determining overall shape of the cell and distribution of pigment granules, a correlative whole cell electron microscopic and immunofluorescence light microscopic study was done of microtubule distribution during spreading of cultured erythrophores from scales of the squirrel fish, Holocentrus. After dissociation from the scale and immediately after attachment, erythrophores are round with long thin processes containing bundles of microtubules with associated pigment granules. In time these processes attach, and elongate, and cytoplasmic ground substance fills areas between microtubule bundles, preceding the appearance of microtubules in these areas of the cell. By 8 h cells are fully spread (star-shaped), prominent microtubule bundles have disappeared, and microtubules (along with pigment granules) are more evenly dispersed throughout the cell. After 24 h cells have increased in size, in number of microtubules, and in the length of preexisting tubules. The sequence of events in normal spreading is altered if cytochalasin D, cycloheximide, or nocodazole is included in the culture medium. Cytochalasin D, a microfilament-disrupting drug, prevents attachment and spreading, but allows elongation to occur. Cycloheximide, a protein synthesis inhibitor, allows for attachment and elongation, but no spreading. Nocodazole, a microtubule-disrupting drug, allows for attachment and spreading, but an irregular cell outline is the result. Even though spreading can occur without them, it is concluded that a normal number and distribution of microtubules are required for the development of normal cell shape and pigment distribution.


[Virus exchange between feeding ticks in the absence of viremia in a vertebrate host (distant transmission)].
The data obtained with tick-borne encephalitis virus did not confirm the conclusion made by L. D. Jones et al. (1987, 1989) on the possibility of distant virus transmission from infected to non-infected ticks feeding at some distance on the host unable to produce suprathreshold viremia level and on the role of saliva gland substrate as the enhancer of the process. The property discovered by L. D. Jones et al. may be intrinsic not to all arboviruses but only to Orthomyxoviridae with which they worked. Therefore, we don't see any reasons for a complete revision of WHO definition of arboviruses. However, the possibility of arbovirus exchange during joint feeding of ticks of different sexes and species on aviremic animals has been confirmed. In these cases due to sexual and other pheromones and virus release with saliva during blood-sucking Flaviviridae and Orthomyxoviridae virus exchange is possible between infected and non-infected ticks: tick-borne encephalitis virus is exchanged in 33-100% of cases between sexes and in up to 30% of cases between species, while Orthomyxoviridae virus is exchanged in 54-88% of cases between male and female individuals of the same species.


Computational pharmaceutics - A new paradigm of drug delivery.
In recent decades pharmaceutics and drug delivery have become increasingly critical in the pharmaceutical industry due to longer time, higher cost, and less productivity of new molecular entities (NMEs). However, current formulation development still relies on traditional trial-and-error experiments, which are time-consuming, costly, and unpredictable. With the exponential growth of computing capability and algorithms, in recent ten years, a new discipline named "computational pharmaceutics" integrates with big data, artificial intelligence, and multi-scale modeling techniques into pharmaceutics, which offered great potential to shift the paradigm of drug delivery. Computational pharmaceutics can provide multi-scale lenses to pharmaceutical scientists, revealing physical, chemical, mathematical, and data-driven details ranging across pre-formulation studies, formulation screening, in vivo prediction in the human body, and precision medicine in the clinic. The present paper provides a comprehensive and detailed review in all areas of computational pharmaceutics and "Pharma 4.0", including artificial intelligence and machine learning algorithms, molecular modeling, mathematical modeling, process simulation, and physiologically based pharmacokinetic (PBPK) modeling. We not only summarized the theories and progress of these technologies but also discussed the regulatory requirements, current challenges, and future perspectives in the area, such as talent training and a culture change in the future pharmaceutical industry.


Phase separation modulates the functional amyloid assembly of human CPEB3.
How functional amyloids are regulated to restrict their activity is poorly understood. The cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is an RNA-binding protein that adopts an amyloid state key for memory persistence. Its monomer represses the translation of synaptic target mRNAs while phase separated, whereas its aggregated state acts as a translational activator. Here, we have explored the sequence-driven molecular determinants behind the functional aggregation of human CPEB3 (hCPEB3). We found that the intrinsically disordered region (IDR) of hCPEB3 encodes both an amyloidogenic and a phase separation domain, separated by a poly-A-rich region. The hCPEB3 amyloid core is composed by a hydrophobic region instead of the Q-rich stretch found in the Drosophila orthologue. The hCPEB3 phase separation domain relies on hydrophobic interactions with ionic strength dependence, and its droplet ageing process leads to a liquid-to-solid transition with the formation of a non-fibril-based hydrogel surrounded by starburst droplets. Furthermore, we demonstrate the differential behavior of the protein depending on its environment. Under physiological-like conditions, hCPEB3 can establish additional electrostatic interactions with ions, increasing the stability of its liquid droplets and driving a condensation-based amyloid pathway.


Recent advances in DAPYs and related analogues as HIV-1 NNRTIs.
HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent most promising anti-AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). They have a unique antiviral potency, high specificity and low cytotoxicity. However, to a great extent, the efficacy of HIV-1 NNRTIs is compounded by rapid emergence of drug resistant virus strains, which calls for continuous efforts to develop novel HIV-1 NNRTIs. Diarylpyrimidine (DAPY) derivatives, one family of NNRTIs with superior activity profiles against wild-type HIV-1 and mutant strains, have attracted considerable attention over the past few years. Among the potent lead DAPY compounds, etravirine was approved by FDA in January 2008, and its analogue rilpivirine (TMC278) has advanced to phase III clinical trials. The successful development of DAPYs results from a multidisciplinary approach involving traditional medicinal chemistry, structural biology, crystallography and computational chemistry. Recently, a number of novel characteristics of DAPYs including conformational flexibility, positional adaptability, key hydrogen bonds and specifically targeting conserved residues of RT, have been identified, providing valuable avenues for further optimization and development of new DAPY analogues as promising anti-HIV drug candidates. In this review, we first present a brief historical account of the medicinal chemistry of the DAPY NNRTIs, then focus on the extensive structural modifications, SAR studies, and binding mode analysis based on crystallographic and molecular modeling. Other structural related NNRTI scaffolds will also be reviewed.


Guessing versus misremembering in recognition: A comparison of continuous, two-high-threshold, and low-threshold models.
The two-high-threshold (2HT) model of recognition memory assumes that people make memory errors because they fail to retrieve information from memory and make a guess, whereas the continuous unequal-variance (UV) model and the low-threshold (LT) model assume that people make memory errors because they retrieve misleading information from memory. We explored the nature of memory errors by comparing guessing and memory performance. In 2 experiments, participants studied lists of words followed by a test in which each trial was preceded by a cue indicating the probability that the trial would have a studied word. Participants first guessed whether or not the word would be studied, and then they saw the word and responded again. When the response that was more likely according to the cue was the correct response, participants made more errors after attempting to remember the word than in their initial guesses. This suggests that participants made errors because they retrieved misleading information even when they could guess the correct response on the basis of the probability cue. We also compared the models in terms of their ability to fit ROC functions using parametric bootstrap procedures to correct for model mimicry. These analyses supported both the UV and LT models over the 2HT model. (PsycINFO Database Record


Plastid-bearing sea slugs fix CO2 in the light but do not require photosynthesis to survive.
Several sacoglossan sea slugs (Plakobranchoidea) feed upon plastids of large unicellular algae. Four species--called long-term retention (LtR) species--are known to sequester ingested plastids within specialized cells of the digestive gland. There, the stolen plastids (kleptoplasts) remain photosynthetically active for several months, during which time LtR species can survive without additional food uptake. Kleptoplast longevity has long been puzzling, because the slugs do not sequester algal nuclei that could support photosystem maintenance. It is widely assumed that the slugs survive starvation by means of kleptoplast photosynthesis, yet direct evidence to support that view is lacking. We show that two LtR plakobranchids, Elysia timida and Plakobranchus ocellatus, incorporate (14)CO2 into acid-stable products 60- and 64-fold more rapidly in the light than in the dark, respectively. Despite this light-dependent CO2 fixation ability, light is, surprisingly, not essential for the slugs to survive starvation. LtR animals survived several months of starvation (i) in complete darkness and (ii) in the light in the presence of the photosynthesis inhibitor monolinuron, all while not losing weight faster than the control animals. Contrary to current views, sacoglossan kleptoplasts seem to be slowly digested food reserves, not a source of solar power.


The rhodopsin-arrestin-1 interaction in bicelles.
G-protein-coupled receptors (GPCRs) are essential mediators of information transfer in eukaryotic cells. Interactions between GPCRs and their binding partners modulate the signaling process. For example, the interaction between GPCR and cognate G protein initiates the signal, while the interaction with cognate arrestin terminates G-protein-mediated signaling. In visual signal transduction, arrestin-1 selectively binds to the phosphorylated light-activated GPCR rhodopsin to terminate rhodopsin signaling. Under physiological conditions, the rhodopsin-arrestin-1 interaction occurs in highly specialized disk membrane in which rhodopsin resides. This membrane is replaced with mimetics when working with purified proteins. While detergents are commonly used as membrane mimetics, most detergents denature arrestin-1, preventing biochemical studies of this interaction. In contrast, bicelles provide a suitable alternative medium. An advantage of bicelles is that they contain lipids, which have been shown to be necessary for normal rhodopsin-arrestin-1 interaction. Here we describe how to reconstitute rhodopsin into bicelles, and how bicelle properties affect the rhodopsin-arrestin-1 interaction.


[Portuguese (Brazil) cross-cultural adaptation of the Hwalek-Sengstock Elder Abuse Screening Test (H-S/EAST) used to identify risk of violence against the elderly].
This article describes the cross-cultural adaptation, for use in Brazil, of the Hwalek-Sengstock Elder Abuse Screening Test (H-S/EAST), used to identify risk of domestic violence against the elderly. Evaluating the conceptual and item equivalences, the article concludes that they are pertinent in the Brazilian context. Semantic equivalence covered the terms' correspondence in referential/denotative meaning and the items' general/connotative correspondence per se. Measurement equivalence was investigated by means of psychometric properties. As with the original instrument in English, the factor analysis revealed three dimensions. Six of the seven items loaded satisfactorily in factor 1 ("situation of potential abuse" scale). Internal consistency proved reasonable, with discreet intra-observer reproducibility. The second factor representing the dimension of "violation of personal rights or direct abuse" showed similar performance. Even so, the study identified an exchange of items between these scales and crossed loads. A third scale that was supposed to encompass the "characteristics of vulnerability" did not show the same performance. The conclusion was that even without demonstrating complete equivalence, the H-S/EAST could already be recommended, at least in part, in the Brazilian context.


Extensive global movement of multidrug-resistantM. tuberculosis strains revealed by whole-genome analysis.
While the international spread of multidrug-resistant (MDR) Mycobacterium tuberculosis strains is an acknowledged public health threat, a broad and more comprehensive examination of the global spread of MDR-tuberculosis (TB) using whole-genome sequencing has not yet been performed. In a global dataset of 5310 M. tuberculosis whole-genome sequences isolated from five continents, we performed a phylogenetic analysis to identify and characterise clades of MDR-TB with respect to geographic dispersion. Extensive international dissemination of MDR-TB was observed, with identification of 32 migrant MDR-TB clades with descendants isolated in 17 unique countries. Relatively recent movement of strains from both Beijing and non-Beijing lineages indicated successful global spread of varied genetic backgrounds. Migrant MDR-TB clade members shared relatively recent common ancestry, with a median estimate of divergence of 13-27 years. Migrant extensively drug-resistant (XDR)-TB clades were not observed, although development of XDR-TB within migratory MDR-TB clades was common. Application of genomic techniques to investigate global MDR migration patterns revealed extensive global spread of MDR clades between countries of varying TB burden. Further expansion of genomic studies to incorporate isolates from diverse global settings into a single analysis, as well as data sharing platforms that facilitate genomic data sharing across country lines, may allow for future epidemiological analyses to monitor for international transmission of MDR-TB. In addition, efforts to perform routine whole-genome sequencing on all newly identified M. tuberculosis, like in England, will serve to better our understanding of the transmission dynamics of MDR-TB globally.


Rude color glasses: The contaminating effects of witnessed morning rudeness on perceptions and behaviors throughout the workday.
Using an experimental experience sampling design, we investigate how witnessing morning rudeness influences workers' subsequent perceptions and behaviors throughout the workday. We posit that a single exposure to rudeness in the morning can contaminate employees' perceptions of subsequent social interactions leading them to perceive greater workplace rudeness throughout their workday. We expect that these contaminated perceptions will have important ramifications for employees' work behaviors. In a 10-day study of 81 professional and managerial employees, we find that witnessed morning rudeness leads to greater perceptions of workplace rudeness throughout the workday and that those perceptions, in turn, predict lower task performance and goal progress and greater interaction avoidance and psychological withdrawal. We also find that the contaminating effect of morning rudeness depends on core self-evaluations (CSE)-employees high (vs. low) in CSE are affected less by exposure to morning rudeness. We discuss implications for practice and theory. (PsycINFO Database Record


Gene(s) and individual feeding behavior: Exploring eco-evolutionary dynamics underlying left-right asymmetry in the scale-eating cichlid fish Perissodus microlepis.
The scale-eating cichlid fish Perissodus microlepis is a textbook example of bilateral asymmetry due to its left or right-bending heads and of negative frequency-dependent selection, which is proposed to maintain this stable polymorphism. The mechanisms that underlie this asymmetry remain elusive. Several studies had initially postulated a simple genetic basis for this trait, but this explanation has been questioned, particularly by reports observing a unimodal distribution of mouth shapes. We hypothesize that this unimodal distribution might be due to a combination of genetic and phenotypically plastic components. Here, we expanded on previous work by investigating a formerly identified candidate SNP associated to mouth laterality, documenting inter-individual variation in feeding preference using stable isotope analyses, and testing their association with mouth asymmetry. Our results suggest that this polymorphism is influenced by both a polygenic basis and inter-individual non-genetic variation, possibly due to feeding experience, individual specialization, and intraspecific competition. We introduce a hypothesis potentially explaining the simultaneous maintenance of left, right, asymmetric and symmetric mouth phenotypes due to the interaction between diverse eco-evolutionary dynamics including niche construction and balancing selection. Future studies will have to further tease apart the relative contribution of genetic and environmental factors and their interactions in an integrated fashion.


Isoelectric-focusing patterns of cyclic nucleotide phosphodiesterase from rat heart.
1. Isoelectric focusing on a flat gel bed of the rat heart cytosolic fraction resolved cyclic nucleotide phosphodiesterase activity into several forms, characterized by their substrate specificity, kinetic constants and dependence towards Ca2+ and calmodulin. A peak of pI 4.9 displayed 20 times more affinity for cyclic GMP than for cyclic AMP and was markedly inhibited by EGTA. A less substrate-specific form, only slightly sensitive to EGTA inhibition, focused at pH 5.45. Several overlapping peaks detected between pH 5.55 and pH6 specifically hydrolysed cyclic AMP, with non-Michaelian kinetics; these peaks were insensitive to Ca2+ chelation. 2. Isoelectric focusing did not dissociate enzyme-calmodulin complexes, as none of the resulting peaks was activatable by calmodulin plus Ca2+. 3. Some new information on rat cardiac phosphodiesterase is obtained with this technique, which is convenient for routine analytical studies of phosphodiesterase, as well as for preparative purposes.


Interstrand cross-linking by bizelesin produces a Watson-Crick to Hoogsteen base-pairing transition region in d(CGTAATTACG)2.
1H NMR analysis of the bizelesin adduct of d(CGTAATTACG)2 indicates that adenines six base pairs apart on opposite DNA strands are cross-linked, yielding two major adduct conformations differing in the central duplex region (5'AATT-3'): one (major product) contains an AT step wherein both adenines are syn-oriented and Hoogsteen base paired to thymines (5HG model); the other contains anti-oriented AT-step adenines that show no evidence of hydrogen bonding with pairing thymines (5OP model). The 5OP model consists of three conformers undergoing exchange and differing in the orientation of the AT-step thymines. Bizelesin's size, rigidity, and cross-linking properties restrict the DNA adduct's range of motion and freeze out DNA conformation(s) adopted during the cross-linking process. This most reactive DNA sequence, 5'-TAATTA-3', yields an adduct conformation (5HG) containing a stable region of Watson-Crick (WC) to Hoogsteen (HG) to Watson-Crick base-pairing transitions. While bizelesin exercises a selective effect on DNA conformation, it intrudes into regions of base stacking less than other Hoogsteen pairing-inducing drugs (e.g., echinomycin). Because of this capacity to induce stable Hoogsteen base pairing with only minimal distortion of base-base stacking, bizelesin affords an opportunity to explore this unusual DNA conformation.


Chronic microfiber exposure in adult Japanese medaka (Oryzias latipes).
Microplastic fibers (MFs) pollute aquatic habitats globally via sewage release, stormwater runoff, or atmospheric deposition. Of the synthetic MFs, polyester (PES) and polypropylene (PP) are the most common. Field studies show that fish ingest large quantities of MFs. However, few laboratory studies have addressed host responses, particularly at the organ and tissue levels. Adult Japanese medaka (Oryzias latipes), a laboratory model fish, were exposed to aqueous concentrations of PES or PP MFs (10,000 MFs/L) for 21 days. Medaka egested 1,367 ± 819 PES MFs (0.1 ± 0.04 mg) and 157 ± 105 PP MFs (1.4 ± 0.06 mg) per 24 hrs, with PP egestion increasing over time. Exposure did not result in changes in body condition, gonadosomatic- or hepatosomatic indices. PES exposure resulted in no reproductive changes, but females exposed to PP MFs produced more eggs over time. MF exposure did not affect embryonic mortality, development, or hatching. Scanning electron microscopy (SEM) of gills revealed denuding of epithelium on arches, fusion of primary lamellae, and increased mucus. Histologic sections revealed aneurysms in secondary lamellae, epithelial lifting, and swellings of inner opercular membrane that altered morphology of rostral most gill lamellae. SEM and histochemical analyses showed increased mucous cells and secretions on epithelium of foregut; however, overt abrasions with sloughing of cells were absent. For these reasons, increased focus at the tissue and cell levels proved necessary to appreciate toxicity associated with MFs.


[Computer modeling of the three-dimensional structure of full-length cytochrome B5].
The computer-aided reconstruction of 3D structure of full-length cytochrome b5 was done. Software Sybyl 6.4 from Tripos running on workstation Silicon Graphics Indigo2 (R4400, XZ) was used. The reconstruction was carried out by computer modelling of membrane part of cytochrom b5 with subsequent linking with known structure of water-soluble b5 part (fragment 5-91 of amino acid residues-file 3B5C in the protein data bank, PDB). The obtained structure of full-length cytochrome b5 was refined in the mixture of polar and nonpolar solvents by molecular dynamics simulation and deterministic minimization. Molecular dynamics simulation was performed in periodic box of binary system of solvents with a step of 1 fs during 550 ps at constant number of particles, pressure and temperature. The balance of system was achieved after 400 ps. With period in 5 ps the potential energy was minimized without molecular dynamics interruption. As a result 100 conformations of full-length cytochrome b5 were obtained. Distribution of potential energy was from -2.7 x 10(4) to -4.2 x 10(4) kcal/mol. Conformation of cytochrome b5 with minimal value of potential energy was accepted as the final. Analysis of lipophilic surface of obtained model have shown that membrane bounded part is more hydrophobic and forms a loop structure. This model corresponds to some known experimental data about cytochrome b5 structure.


Neuropathic Pain Causes Memory Deficits and Dendrite Tree Morphology Changes in Mouse Hippocampus.
Neuropathic pain manifests in a diverse combination of sensory symptoms and disorders of higher nervous activity, such as memory deficiency, anxiety, depression, anhedonia, etc. This suggests the participation of brain structures, including the hippocampus, in the pathogenesis of neuropathic pain. The elucidation of central sensitization mechanisms underlying neuropathic pain cognitive and affective symptoms may be useful in the development of new and effective treatments for these common disorders. The study aims to elucidate the effect of chronic neuropathic pain on cognitive function and underlying neuronal plasticity in the hippocampus. Chronic constriction injury of mouse right hind limb sciatic nerve was used as a model of neuropathic pain. The presence of neuropathic pain was confirmed by the thermal and mechanical allodynia. The morphology of the CA1 pyramidal neurons and the dentate gyrus (DG) granule neurons were studied using Golgi-Cox staining. The hippocampal proteins concentration was determined by immunohistochemistry and ELISA. Behavioral testing revealed reduced locomotor activity as well as impaired working and long-term memory in mice with a ligated nerve. We revealed changes in the dendritic tree morphology in CA1 and the dentate gyrus hippocampal subregions. We found the atrophy of the CA1 pyramidal neurons and an increase in the dendritic tree complexity in DG. Moreover, changes in the density of dendritic spines were observed in these regions. In addition, we revealed increased expression of the Arc protein in DG granule neurons and decreased surface expression of AMPA receptors within the hippocampus. Decreased AMPA receptors expression underlies observed altered dendrite arborization and dendritic spines morphology. We found that pain information entering the hippocampus causes neuronal plasticity changes. The changes in neurite arborization, dendritic length and dendritic spines morphology as well as protein expression are observed within the hippocampal regions involved in the processing of pain information. Moreover, changes in the dendrite morphology in hippocampal subregions are different due to the anatomical and functional heterogeneity of the hippocampus. Apparently, the detected morphological and biochemical changes can underlie the observed hippocampus-dependent behavioral and cognitive impairment in animals with neuropathic pain.


Restoration and conservation of anatomic pieces.
In this study, a restoration process was developed with potassium hydroxide (KOH), in order to improve each of the structures for their posterior fixation, through the use of new methods such as the Chilean conservative fixative solution (SFCCh), with exceptional results. Restore anatomical pieces corresponding to corpse and organs, being these last set with the SFCCh. In this work dealt with processes of restoration with potassium hydroxide, sodium chloride, and sodium hypochlorite, the process began with the cleanliness and suture of the structures for subsequent fixing in Chilean conservative fixative solution, making use of a corpse and different anatomical parts. Work based on items found in the database, Elsevier, Science Direct, ProQuest, and MEDLINE. At the end of the process of restoration and conservation of the anatomical pieces, was observed an improvement in muscle pigment with decrease of rigidity in the specimen, additionally a recovery of appearance in the vascular-nervous elements was achieved. The organs were much more malleable and the structures facilitate the identification of specific details, its subsequent immersion in SFCCh allows the longer preservation of the obtained results. The restoration with potassium hydroxide allows the improvement in the appearance of the different anatomical structures and simultaneously to facilitate its study. The SFCCh is an alternative that replaces partially the use of formaldehyde. In addition, it presents toxicity reduction.


[Euthanasia in advanced dementia: a moral impossibility].
Advance directives containing a request for euthanasia in cases of severely debilitating dementia are of no use. In such an advanced stage of the disease, the doctor would have to administer lethal medication to a patient who does not realise what is happening to him/her. The Dutch Euthanasia Act is ambivalent about this possibility.


Comparison of various treatments for sleep bruxism using determinants of number needed to treat and effect size.
Sleep bruxism (SB) is associated with temporomandibular pain, headaches, tooth wear, and disruption of the bed partner's sleep. The aim of this report was to compare SB treatments from various experimental studies to guide the selection of a treatment for a large sample size study. After a literature search, randomized controlled studies of 7 pharmacologic treatments and 3 oral devices were included. The number needed to treat (NNT) was calculated from raw data from the sleep laboratory at the Hôpital du Sacré-Coeur, Montréal or from published articles when sufficient data were available. The effect size (ES) was calculated for all included studies. In the most effective treatments, the NNT ranged from 1 to 4, while a high ES was above 0.8. The treatments with the best NNT and ES results were the mandibular advancement device (MAD) and clonidine. The NNT (+/-95% CI) and ES were 2.2 (1.4 to 5.3) and 1.5 for the MAD, and 3.2 (1.7 to 37.3) and 0.9 for clonidine, respectively. An NNT of 3.8 (1.9 to -69.4) and an ES of 0.6 were observed with the occlusal splint, with a reduction of 42% in the SB index. NNT could not be calculated for clonazepam, although the ES was 0.9. Although the NNT and ES results seem to indicate that the MAD and clonidine are the most promising experimental treatments, both treatments were associated with side effects (ie, discomfort for the MAD; REM suppression and morning hypotension for clonidine). The occlusal splint and clonazepam seem to be acceptable short-term alternatives, although further longitudinal, large sample size randomized controlled trials in SB management are needed.


The importance of a satisfactory biopsy for the diagnosis of lung cancer in the era of personalized treatment.
Advances in molecular biology are improving the understanding of lung cancer and changing the approach to treatment. A satisfactory biopsy that allows for histologic characterization and mutation analysis is becoming increasingly important. Most patients with lung cancer are diagnosed at an advanced stage, and diagnosis is often based on a small biopsy or cytology specimen. Here, we review the techniques available for making a diagnosis of lung cancer, including bronchoscopy, ultrasound-guided bronchoscopy, mediastinoscopy, transthoracic needle aspiration, thoracentesis, and medical thoracoscopy. We also discuss the indications, complications, and tissue yields of those techniques, especially as they pertain to testing for molecular markers.


Simultaneous motion estimation and image reconstruction (SMEIR) for 4D cone-beam CT.
Image reconstruction and motion model estimation in four-dimensional cone-beam CT (4D-CBCT) are conventionally handled as two sequential steps. Due to the limited number of projections at each phase, the image quality of 4D-CBCT is degraded by view aliasing artifacts, and the accuracy of subsequent motion modeling is decreased by the inferior 4D-CBCT. The objective of this work is to enhance both the image quality of 4D-CBCT and the accuracy of motion model estimation with a novel strategy enabling simultaneous motion estimation and image reconstruction (SMEIR). The proposed SMEIR algorithm consists of two alternating steps: (1) model-based iterative image reconstruction to obtain a motion-compensated primary CBCT (m-pCBCT) and (2) motion model estimation to obtain an optimal set of deformation vector fields (DVFs) between the m-pCBCT and other 4D-CBCT phases. The motion-compensated image reconstruction is based on the simultaneous algebraic reconstruction technique (SART) coupled with total variation minimization. During the forward- and backprojection of SART, measured projections from an entire set of 4D-CBCT are used for reconstruction of the m-pCBCT by utilizing the updated DVF. The DVF is estimated by matching the forward projection of the deformed m-pCBCT and measured projections of other phases of 4D-CBCT. The performance of the SMEIR algorithm is quantitatively evaluated on a 4D NCAT phantom. The quality of reconstructed 4D images and the accuracy of tumor motion trajectory are assessed by comparing with those resulting from conventional sequential 4D-CBCT reconstructions (FDK and total variation minimization) and motion estimation (demons algorithm). The performance of the SMEIR algorithm is further evaluated by reconstructing a lung cancer patient 4D-CBCT. Image quality of 4D-CBCT is greatly improved by the SMEIR algorithm in both phantom and patient studies. When all projections are used to reconstruct a 3D-CBCT by FDK, motion-blurring artifacts are present, leading to a 24.4% relative reconstruction error in the NACT phantom. View aliasing artifacts are present in 4D-CBCT reconstructed by FDK from 20 projections, with a relative error of 32.1%. When total variation minimization is used to reconstruct 4D-CBCT, the relative error is 18.9%. Image quality of 4D-CBCT is substantially improved by using the SMEIR algorithm and relative error is reduced to 7.6%. The maximum error (MaxE) of tumor motion determined from the DVF obtained by demons registration on a FDK-reconstructed 4D-CBCT is 3.0, 2.3, and 7.1 mm along left-right (L-R), anterior-posterior (A-P), and superior-inferior (S-I) directions, respectively. From the DVF obtained by demons registration on 4D-CBCT reconstructed by total variation minimization, the MaxE of tumor motion is reduced to 1.5, 0.5, and 5.5 mm along L-R, A-P, and S-I directions. From the DVF estimated by SMEIR algorithm, the MaxE of tumor motion is further reduced to 0.8, 0.4, and 1.5 mm along L-R, A-P, and S-I directions, respectively. The proposed SMEIR algorithm is able to estimate a motion model and reconstruct motion-compensated 4D-CBCT. The SMEIR algorithm improves image reconstruction accuracy of 4D-CBCT and tumor motion trajectory estimation accuracy as compared to conventional sequential 4D-CBCT reconstruction and motion estimation.


Effect of metaphit on dopaminergic neurotransmission in rat striatal slices: involvement of the dopamine transporter and voltage-dependent sodium channel.
Metaphit, an isothiocyanate analog of phencyclidine (PCP), increased the basal release of radioactivity (outflow) from perfused rat striatal slices preloaded with [3H]dopamine above levels observed with the dopamine uptake blocker nomifensin. Preperfusing the slices with metaphit, followed by its removal, attenuated the amphetamine- or dopamine-induced outflow. In slices prepared from reserpine-pretreated rats, the metaphit (100 microM)-induced outflow was reduced to that observed with 10 microM nomifensin, suggesting a vesicular releasing effect of metaphit in addition to dopamine uptake blockade. Electrically induced overflow of radioactivity from normal slices was stimulated by nomifensin and PCP, and by metaphit at 3 microM; it was unaffected by metaphit at 10 and 25 microM, and inhibited by higher concentrations of metaphit. Evidence that the latter effect is due to blockade of voltage-dependent sodium channels is as follows. First, metaphit, as did PCP, inhibited the binding of [3H]batrachotoxinin A 20-alpha benzoate to rat striatal synaptoneurosomes by increasing its dissociation rate; the effect of PCP, but not that of metaphit, was reversible by washing. Second, metaphit, as did PCP, inhibited veratridine (5 microM)-induced influx of [14C]guanidinium ion into synaptoneurosomes. Third, metaphit inhibited overflow of radioactivity from [3H]dopamine-preloaded slices induced by 2.5 microM veratridine, as did the sodium channel blocker tetrodotoxin.