A meta-analysis of the effects of dietary protein concentration and degradability on milk protein yield and milk N efficiency in dairy cows.
Data sets from North American (NA, 739 diets) and North European (NE, 998 diets) feeding trials with dairy cows were evaluated to investigate the effects of dietary crude protein (CP) intake and ruminal degradability on milk protein yield (MPY) and efficiency of N utilization for milk protein synthesis (MNE; milk N / N intake) in dairy cows. The NA diets were based on corn silage, alfalfa silage and hay, corn and barley grains, and soybean meal. The NE diets were based on grass silage, barley and oats grains, and soybean and rapeseed meals. Diets were evaluated for rumen-degradable and undegradable protein (RDP and RUP, respectively) concentrations according to NRC (2001). A mixed model regression analysis with random study effect was used to evaluate relationships between dietary CP concentration and degradability and MPY and MNE. In both data sets, CP intake alone predicted MPY reasonably well. Addition of CP degradability to the models slightly improved prediction. Models based on metabolizable protein (MP) intake predicted MPY better than the CP or the CP-CP degradability models. The best prediction models were based on total digestible nutrients (TDN) and CP intakes. Similar to the MPY models, inclusion of CP degradability in the CP (intake or concentration) models only slightly improved prediction of MNE in both data sets. Concentration of dietary CP was a better predictor of MNE than CP intake. Compared with the CP models, prediction of MNE was improved by inclusion of TDN intake or concentration. Milk yield alone was a poor predictor of MNE. The models developed from one data set were validated using the other data set. The MNE models based on TDN and CP intake performed well as indicated by small mean and slope bias. This meta-analysis demonstrated that CP concentration is the most important dietary factor influencing MNE. Ruminal CP degradability as predicted by NRC (2001) does not appear to be a significant factor in predicting MPY or MNE. Data also indicated that increasing milk yield will increase MNE provided that dietary CP concentration is not increased, but the effect is considerably smaller than the effect of reducing CP intake.


Cerebral hemodynamics and vascular risk factors: setting the stage for Alzheimer's disease.
Considerable information is currently available from neuroimaging, pathological, and population-based prospective studies showing that vascular risk factors are independently associated with an increased risk of Alzheimer's disease (AD). Many of these studies indicate that vascular risk factors can predict the clinical development of cognitive dysfunction and AD onset. This review examines the role of cerebral hemodynamics and vasoactive molecules that contribute to the regulation of cerebral perfusion and how three common vascular risk factors to AD, namely, hypertension, diabetes type 2, and atherosclerosis, can alter cerebral blood flow (CBF) regulation and generate perfusion pressure deficits. It is proposed that these vascular risk factors (and presumably other vascular risk factors) initiate chronic brain hypoperfusion that ultimately impair signaling from neurons, astrocytes, and endothelial cells to vascular smooth muscle controlling vessel diameter. Impaired signaling involving vascular pathways in the elderly can attenuate vessel tone and deregulate CBF. Noxious cerebral hemodynamic responses to vascular risk factors and chronic brain hypoperfusion are partly explained by Poiseuille's Law which states that miniscule changes in vessel diameter can have a dramatic effect on vessel resistance and on the rate of blood flow. Using Poiseuille's model, even minor narrowing of arteriolar diameter can lead to major reductions in CBF and in suboptimal delivery of high energy nutrients to the brain, with lethal consequences to brain cells that participate in cognitive function. Regional brain cell loss sets the stage for age-related cognitive impairment and AD onset. Keeping cerebral hemodynamic homeostasis by careful management of vascular risk factors could be a decisive therapeutic target in the prevention of AD.


Non-invasive diagnostics of blockage growth in the descending aorta-computational approach.
Atherosclerosis causes blockages to the main arteries such as the aorta preventing blood flow from delivering oxygen to the organs. Non-invasive diagnosis of these blockages is difficult, particularly in primary healthcare. In this paper, the effect of arterial blockage development and growth is investigated at the descending aorta on some possible non-invasive assessment parameters including the blood pressure waveform, wall shear stress (WSS), time-average WSS (TAWSS) and the oscillation shear index (OSI). Blockage severity growth is introduced in a simulation model as 25%, 35%, 50% and 65% stenosis at the descending aorta based on specific healthy control aorta data clinically obtained. A 3D aorta model with invasive pulsatile waveforms (blood flow and pressure) is used in the CFD simulation. Blockage severity is assessed by using blood pressure measurements at the left subclavian artery. An arterial blockage growth more than 35% of the lumen diameter significantly affects the pressure. A strong correlation is also observed between the ascending aorta pressure values, pressure at the left subclavian artery and the relative residence time (RRT). An increase of RRT downstream from the stenosis indicates a 35% stenosis at the descending aorta which results in high systolic and diastolic pressure readings. The findings of this study could be further extended by transferring the waveform reading from the left subclavian artery to the brachial artery.


The medial prefrontal cortex determines the accumbens dopamine response to stress through the opposing influences of norepinephrine and dopamine.
Although the medial prefrontal cortex (mpFC) appears to constrain stress responses, indirect evidences suggest that it might determine the stress response of the mesoaccumbens dopamine (DA) system. To test this hypothesis, we first evaluated the dynamics of norepinephrine (NE) and DA release in the mpFC and of DA release in the nucleus accumbens (NAc) of acutely stressed rats. Then, we tested the effects of selective depletion of NE or DA in the mpFC (by local 6-hydroxydopamine infusion following desipramine or 1-[2[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine(GBR 12909) on stress-induced changes in mesoaccumbens DA release. Rats experiencing restraint stress for 240 min showed an initial, short-lived increase of NE outflow in the mpFC and of DA in the NAc. These responses were followed by a sustained increase of DA in the mpFC and by a decrease to below resting levels of DA in the NAc. Moreover, selective prefrontal NE depletion eliminated the increase of NE in the mpFC and of DA in the NAc, and selective depletion of mesocortical DA eliminated the enhancement of mpFC DA as well as the inhibition of mesoaccumbens DA, without affecting basal catecholamines outflow. These results demonstrate that the opposing influences of mpFC NE and DA determine mesoaccumbens DA response to stress and suggest that alterations of this mechanism may be responsible for some major psychopathological outcomes of stress.


Infection preventionists and laboratorians: Case studies on successful collaboration.
Efforts to reduce the incidence of hospital-acquired infection (HAI) remain a significant focus for health care facilities, particularly in this era of drug-resistant organisms. With as many as 1 in every 25 hospitalized patients acquiring an infection, the need to minimize the risk of HAIs is widely recognized as critical. Advances in the fields of biomedical technology, microbiology, pharmacology, and infection control and prevention, among others, have played a tremendous role in these efforts. However, evidence suggests that a key element in this battle against HAIs is missing: collaboration and communication between these groups in health care facilities-particularly in microbiology and infection prevention. The need for collaboration between infection preventionists (IPs) and laboratorians has been addressed in the literature; however, a survey conducted by the APIC and the American Society for Microbiology demonstrated that both IPs and laboratorians feel they lack the tools to engage in this collaboration. This article addresses strategies for a working partnership between IPs and laboratorians and reports 3 case studies on successful collaborations at major medical centers.


[Characterization of the receptor population as listed and those who were submitted to pancreas and pancreas-kidney transplantation].
About 1 million cases of transplantation were registered around the world. The first Pancreas transplantation in Brazil was in 1996, proceeded by a medical team of São Paulo. The objetctive of this study was to characterize the socio- demographic and epidemiological profile of the receivers in list and those submitted to this procedure. It is an inter-relational retrospective study considereing the period from 1996 to 2004. Results demonstrated the predominance of women, from white race, and, with an average of 35 years. The origin of the patients was the states of São Paulo and Minas Gerais.


Structural Insights into the IL12:IL12 Receptor Complex Assembly by Molecular Modeling, Docking, and Molecular Dynamics Simulation.
Interleukin-12 receptor (IL12R) is a type I cytokine receptor that can promote hematopoiesis and regulate innate and adaptive immunity. It binds with the IL12 ligand, which activates the IL-12 signaling pathway that triggers hematopoietic progenitor cell proliferation and differentiation process. The structure of IL12:IL12R complex is not known. The present work describes a de novo computational method for rational protein designing to elucidate the structure of IL12:IL12R complex. Homology modeling, docking, and MD simulation methods were used to design mimics of the interaction of IL12 and IL12R. RResults: 3D structure prediction and validation confirm the accurate structure of IL12R protein that contains immunoglobin domain, fibronectin type three domain, cytokine-binding domain, and WSXWS motif. Molecular docking and MD simulation revealed that IL12R bound tightly with IL12 ligand at their interface. The estimated binding energy of the docked complex was -26.7 kcal/mol, and the interface area was 281.4 Å2. Hotspot prediction suggested that ARG34, SER58, GLU61, CYS62, LEU63, SER73, ASP142, GLN146, LYS168, THR169 ARG181, ARG183, ARG189, and TYR193 residues in IL12 ligand interacted with SER175, ALA176, CYS177, PRO178, ALA179, ALA180, GLU181, GLU182, ALA192, VAL193, HIS194, ARG208, TYR246, GLN289, ASP290, ARG291, TYR292, TYR293 and SER294 residues in IL12 receptor. The results of the study provides a simulated molecular structure of IL12:IL12R complex that could offer a promising target complex to substantiate IL12 based drug-designing approaches.


Procurement.
EAHP's position paper advocates for the involvement of hospital pharmacists in procurement. The immediate concern of any hospital pharmacist is to ensure that every patient within the hospital receives the medications needed. For this reason, hospital pharmacists have a direct stake in the efficient functioning of the medicines' supply chain. The position touches on pharmaceutical tendering which is a complex process that involves different stakeholders and steps that are regulated at national level leading to diverse solutions in the different European countries. In addition, these processes are guided by publications of other international actors such as the World Health Organisation (WHO) and the Organisation for Economic Co-operation and Development (OECD). The second part focuses on the role of hospital pharmacists in procurement which due to their knowledge and skills are specialists in the field of all medicines' procurement. Hospital pharmacists should lead in all phases of the procurement processes and practices to ensure the continuity of the supply of cost-effective and quality medicines to patients.


Localization of 616 human chromosome 3-specific cosmids using a somatic cell hybrid deletion mapping panel.
A total of 5700 human chromosome 3-specific cosmid clones was isolated from a series of cosmid libraries constructed from somatic cell hybrids whose only human component was an entire chromosome 3 or a chromosome 3 containing an interstitial deletion removing 50% of long arm sequences. Several unique sequence chromosome 3-specific hybridization probes were isolated from each of 616 of these cosmids. These probes were then used to localize the cosmids by hybridization to a somatic cell hybrid deletion mapping panel capable of resolving chromosome 3 into nine distinct subregions. All 616 of the cosmids were localized to either the long or short arm of chromosome 3 and 63% of the short arm cosmids were more precisely localized. We have identified a total of 87 cosmids that contain fragments that are evolutionarily conserved. Fragments from these cosmids should prove useful in the identification of new chromosome 3-specific genes as well as in comparative mapping studies. The localized cosmids should provide excellent saturation of human chromosome 3 and facilitate the construction of physical and genetic linkage maps to identify various disease loci including Von Hippel Lindau disease and renal and small cell lung carcinoma.


Nitric oxide-mediated endothelial dysfunction--is there need to treat?
Before it gets to the development of manifest atherosclerotic lesions, all known risk factors primarily induce functional alterations in the vascular wall, namely in endothelial cells. Being termed endothelial dysfunction or endothelial activation, this condition is characterized by an altered availability of nitric oxide (NO). Under physiological conditions, NO is of unequivocal importance for the regulation of vascular homeostasis. Endothelium-derived NO released abluminally increases soluble guanylat cyclase activity in smooth muscle cells, thereby inducing relaxation and consequently vasodilatation. Intraluminally, NO inhibits the expression of adhesion molecules both on endothielial cells and neutrophils, thus preventing the adherence of cellular elements to the vascular wall. Furthermore, NO has antithrombotic effcts by inhibiting platelet aggregation and directly infuencing the synthesis of different factors involved in the coagulation cascade. Finally, in the long term, NO has been shown to exert antiproliferative properties. NO is generated intracellularly from L-arginine via NO-synthase with the help of several cofactors, including tetrahydobiopterin. Interestingly, it has recently become evident that under certain conditions, when there is a lack of tetrahydrobiopterin, NO-synthase produces reactive oxygen species instead of NO. Reactive oxygen species counteract the effects of NO and also scavenge NO resulting in the formation of peroxynitrite (ONOO). Peroxynitrite has been shown to have deleterious effects with respect to vascular function. The aim of the current review is to elucidate recent progress regarding the pathophysiological understanding of endothelial dysfunction. Furthermore, the significance of this condition for the evaluation and prognosis of patients is discussed. Finally, current therapeutical strategies in the treatment and improvement of endothelial dysfunction are highlighted.


Antiplasmodial Activity Evaluation of a Bestatin-Related Aminopeptidase Inhibitor, Phebestin.
The increasing burden and spread of resistant malaria parasites remains an immense burden to public health. These factors have driven the demand to search for a new therapeutic agent. From our screening, phebestin stood out with nanomolar efficacy against Plasmodium falciparum 3D7. Phebestin was initially identified as an aminopeptidase N inhibitor. Phebestin inhibited the in vitro multiplication of the P. falciparum 3D7 (chloroquine-sensitive) and K1 (chloroquine-resistant) strains at IC50 values of 157.90 ± 6.26 nM and 268.17 ± 67.59 nM, respectively. Furthermore, phebestin exhibited no cytotoxic against human foreskin fibroblast cells at 2.5 mM. In the stage-specific assay, phebestin inhibited all parasite stages at 100 and 10-fold its IC50 concentration. Using 72-h in vitro exposure of phebestin at concentrations of 1 μM on P. falciparum 3D7 distorted the parasite morphology, showed dying signs, shrank, and prevented reinvasion of RBCs, even after the compound was washed from the culture. An in silico study found that phebestin binds to P. falciparum M1 alanyl aminopeptidase (PfM1AAP) and M17 leucyl aminopeptidase (PfM17LAP), as observed for bestatin. In vivo evaluation using P. yoelii 17XNL-infected mice with administrations of 20 mg/kg phebestin, once daily for 7 days, resulted in significantly lower parasitemia peaks in the phebestin-treated group (19.53%) than in the untreated group (29.55%). At the same dose and treatment, P. berghei ANKA-infected mice showed reduced parasitemia levels and improved survival compared to untreated mice. These results indicate that phebestin is a promising candidate for development as a potential therapeutic agent against malaria.


Advances in skin regeneration: application of electrospun scaffolds.
The paucity of cellular and molecular signals essential for normal wound healing makes severe dermatological ulcers stubborn to heal. The novel strategies of skin regenerative treatments are focused on the development of biologically responsive scaffolds accompanied by cells and multiple biomolecules resembling structural and biochemical cues of the natural extracellular matrix (ECM). Electrospun nanofibrous scaffolds provide similar architecture to the ECM leading to enhancement of cell adhesion, proliferation, migration and neo tissue formation. This Review surveys the application of biocompatible natural, synthetic and composite polymers to fabricate electrospun scaffolds as skin substitutes and wound dressings. Furthermore, the application of biomolecules and therapeutic agents in the nanofibrous scaffolds viz growth factors, genes, antibiotics, silver nanoparticles, and natural medicines with the aim of ameliorating cellular behavior, wound healing, and skin regeneration are discussed.


The effects of prior knowledge on study-time allocation and free recall: investigating the discrepancy reduction model.
In this study, the authors examined the influence of prior knowledge activation on information processing by means of a prior knowledge activation procedure adopted from the read-generate paradigm. On the basis of cue-target pairs, participants in the experimental groups generated two different sets of items before studying a relevant list. Subsequently, participants were informed that they had to study the items in the list and that they should try to remember as many items as possible. The authors assessed the processing time allocated to the items in the list and free recall of those items. The results revealed that the experimental groups spent less time on items that had already been activated. In addition, the experimental groups outperformed the control group in overall free recall and in free recall of the activated items. Between-group comparisons did not demonstrate significant effects with respect to the processing time and free recall of nonactivated items. The authors interpreted these results in terms of the discrepancy reduction model of regulating the amount of processing time allocated to different parts of the list.


[Imaging of lipoma and liposarcoma].
The aim of this paper is to describe the two most frequent lipomatous soft tissue tumors, lipoma and liposarcoma, and to highlight the radiologic features allowing their differentiation.


Fast 3D Fluid Registration of Brain Magnetic Resonance Images.
Fluid registration is widely used in medical imaging to track anatomical changes, to correct image distortions, and to integrate multi-modality data. Fluid mappings guarantee that the template image deforms smoothly into the target, without tearing or folding, even when large deformations are required for accurate matching. Here we implemented an intensity-based fluid registration algorithm,7 accelerated by using a filter designed by Bro-Nielsen and Gramkow.3 We validated the algorithm on 2D and 3D geometric phantoms using the mean square difference between the final registered image and target as a measure of the accuracy of the registration. In tests on phantom images with different levels of overlap, varying amounts of Gaussian noise, and different intensity gradients, the fluid method outperformed a more commonly used elastic registration method, both in terms of accuracy and in avoiding topological errors during deformation. We also studied the effect of varying the viscosity coefficients in the viscous fluid equation, to optimize registration accuracy. Finally, we applied the fluid registration algorithm to a dataset of 2D binary corpus callosum images and 3D volumetric brain MRIs from 14 healthy individuals to assess its accuracy and robustness.


The blockade of immune checkpoints in cancer immunotherapy.
Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.


Opportunities for Epidemiologists in Implementation Science: A Primer.
The field of epidemiology has been defined as the study of the spread and control of disease. However, epidemiology frequently focuses on studies of etiology and distribution of disease at the cost of understanding the best ways to control disease. Moreover, only a small fraction of scientific discoveries are translated into public health practice, and the process from discovery to translation is exceedingly slow. Given the importance of translational science, the future of epidemiologic training should include competency in implementation science, whose goal is to rapidly move evidence into practice. Our purpose in this paper is to provide epidemiologists with a primer in implementation science, which includes dissemination research and implementation research as defined by the National Institutes of Health. We describe the basic principles of implementation science, highlight key components for conducting research, provide examples of implementation studies that encompass epidemiology, and offer resources and opportunities for continued learning. There is a clear need for greater speed, relevance, and application of evidence into practice, programs, and policies and an opportunity to enable epidemiologists to conduct research that not only will inform practitioners and policy-makers of risk but also will enhance the likelihood that evidence will be implemented.


Influence of beam efficiency through the patient-specific collimator on secondary neutron dose equivalent in double scattering and uniform scanning modes of proton therapy.
Conventional proton therapy facilities use double scattering nozzles, which are optimized for delivery of a few fixed field sizes. Similarly, uniform scanning nozzles are commissioned for a limited number of field sizes. However, cases invariably occur where the treatment field is significantly different from these fixed field sizes. The purpose of this work was to determine the impact of the radiation field conformity to the patient-specific collimator on the secondary neutron dose equivalent. Using a WENDI-II neutron detector, the authors experimentally investigated how the neutron dose equivalent at a particular point of interest varied with different collimator sizes, while the beam spreading was kept constant. The measurements were performed for different modes of dose delivery in proton therapy, all of which are available at the Midwest Proton Radiotherapy Institute (MPRI): Double scattering, uniform scanning delivering rectangular fields, and uniform scanning delivering circular fields. The authors also studied how the neutron dose equivalent changes when one changes the amplitudes of the scanned field for a fixed collimator size. The secondary neutron dose equivalent was found to decrease linearly with the collimator area for all methods of dose delivery. The relative values of the neutron dose equivalent for a collimator with a 5 cm diameter opening using 88 MeV protons were 1.0 for the double scattering field, 0.76 for rectangular uniform field, and 0.6 for the circular uniform field. Furthermore, when a single circle wobbling was optimized for delivery of a uniform field 5 cm in diameter, the secondary neutron dose equivalent was reduced by a factor of 6 compared to the double scattering nozzle. Additionally, when the collimator size was kept constant, the neutron dose equivalent at the given point of interest increased linearly with the area of the scanned proton beam. The results of these experiments suggest that the patient-specific collimator is a significant contributor to the secondary neutron dose equivalent to a distant organ at risk. Improving conformity of the radiation field to the patient-specific collimator can significantly reduce secondary neutron dose equivalent to the patient. Therefore, it is important to increase the number of available generic field sizes in double scattering systems as well as in uniform scanning nozzles.


What is the benefit of coarse wheat bran in patients with irritable bowel syndrome?
The effect of open treatment with coarse wheat bran was compared with response to placebo, given in the form of a double blind, cross over drug trial, in patients with irritable bowel syndrome. Both bran and placebo significantly reduced the severity of most of the symptoms. Constipation was the only symptom that improved significantly with bran, but not with placebo, and was the only symptom that predicted a successful outcome with bran. Diarrhoea did not improve with bran. In fact, stools became less formed in patients presenting with this symptom. The incidence of pain and urgency was significantly more frequent on bran compared with placebo. Compared with a baseline period, bran treatment resulted in an acceleration of whole gut transit time (p less than 0.05) increases in daily stool weight (p less than 0.01) and the proportion of unformed stools (p less than 0.01) but no change in stool frequency. Coarse wheat bran was no better than placebo for most symptoms in irritable bowel syndrome, although its efficacy in constipation was confirmed.


Effects of selective cardiac denervation on collateral blood flow after coronary artery occlusion in conscious dogs.
The extent to which cardiac nerves regulate responses to myocardial ischemia remains controversial. Our data in conscious dogs indicate that neither selective posterior left ventricular (LV) wall denervation nor selective ventricular denervation, leaving the atria intact, modifies the effects of coronary artery occlusion (for 24 h) on regional myocardial function and infarct size as compared to normally innervated dogs. Since hemodynamic changes were similar among the three groups after coronary artery occlusion, it is possible to speculate that responses of collateral blood flow to the ischemic zone were also not modified by chronic selective cardiac denervation. To address this, individual samples were selected and included in either the infarcted (TTC negative) or salvaged (TTC positive) group. The infarcted and salvaged samples were paired according to blood flow levels of 0.1-0.2, 0.2-0.3, or 0.3-0.4 ml/min/g at either 5 min, 1 h, 3 h, or 6 h after coronary artery occlusion. The results demonstrated similar patterns of myocardial blood flow in tissue samples within the area at risk after coronary artery occlusion in the animals, regardless of whether the ischemic zone was innervated or denervated. While blood flow rose in ischemic tissue that ultimately was salvaged, and tended not to rise over the 24 h monitoring period in tissue samples that became necrotic, no differences could be discerned on the basis of intact or absent innervation of the ischemic zone. Thus, chronic absence of cardiac nerves does not affect regulation of ischemic zone blood flow following coronary artery occlusion in conscious dogs.


Increased sensitivity to K+ deprivation in colonic H,K-ATPase-deficient mice.
Previous studies using isolated tissues suggest that the colonic H, K-ATPase (cHKA), expressed in the colon and kidney, plays an important role in K+ conservation. To test the role of this pump in K+ homeostasis in vivo, we generated a cHKA-deficient mouse and analyzed its ability to retain K+ when fed a control or K+-free diet. When maintained on a control diet, homozygous mutant (cHKA-/-) mice exhibited no deficit in K+ homeostasis compared to wild-type (cHKA+/+ greater, similar mice. Although fecal K+ excretion in cHKA-/- mice was double that of cHKA+/+ mice, fecal K+ losses were low compared with urinary K+ excretion, which was similar in both groups. When maintained on a K+-free diet for 18 d, urinary K+ excretion dropped over 100-fold, and to similar levels, in both cHKA-/- and cHKA+/+ mice; fecal K+ excretion was reduced in both groups, but losses were fourfold greater in cHKA-/- than in cHKA+/+ mice. Because of the excess loss of K+ in the colon, cHKA-/- mice exhibited lower plasma and muscle K+ than cHKA+/+ mice. In addition, cHKA-/- mice lost twice as much body weight as cHKA+/+ mice. These results demonstrate that, during K+ deprivation, cHKA plays a critical role in the maintenance of K+ homeostasis in vivo.


Tobacco smoke exposure recruits inflammatory airspace monocytes that establish permissive lung niches for Mycobacterium tuberculosis.
Tobacco smoking doubles the risk of active tuberculosis (TB) and accounts for up to 20% of all active TB cases globally. How smoking promotes lung microenvironments permissive to Mycobacterium tuberculosis (Mtb) growth remains incompletely understood. We investigated primary bronchoalveolar lavage cells from current and never smokers by performing single-cell RNA sequencing (scRNA-seq), flow cytometry, and functional assays. We observed the enrichment of immature inflammatory monocytes in the lungs of smokers compared with nonsmokers. These monocytes exhibited phenotypes consistent with recent recruitment from blood, ongoing differentiation, increased activation, and states similar to those with chronic obstructive pulmonary disease. Using integrative scRNA-seq and flow cytometry, we identified CD93 as a marker for a subset of these newly recruited smoking-associated lung monocytes and further provided evidence that the recruitment of monocytes into the lung was mediated by CCR2-binding chemokines, including CCL11. We also show that these cells exhibit elevated inflammatory responses upon exposure to Mtb and accelerated intracellular growth of Mtb compared with mature macrophages. This elevated Mtb growth could be inhibited by anti-inflammatory small molecules, providing a connection between smoking-induced pro-inflammatory states and permissiveness to Mtb growth. Our findings suggest a model in which smoking leads to the recruitment of immature inflammatory monocytes from the periphery to the lung, which results in the accumulation of these Mtb-permissive cells in the airway. This work defines how smoking may lead to increased susceptibility to Mtb and identifies host-directed therapies to reduce the burden of TB among those who smoke.


Patient interaction in homecare systems to treat cardiovascular diseases in the long term.
The rapid aging of the population worldwide will dramatically increase the number of people affected by chronic diseases in the next years. This social situation makes it necessary a paradigm shift from reactive care to preventive care. New technological paradigms, like Ambient Intelligence and Ubiquitous Computing, allow the development of Personal Health Systems (PHS) that guarantee the continuity of care and a better use of health resources. Therefore, patients should become the centre of the health care process, and PHS should be designed to fulfill the patient's goals and needs. User-centred methodologies provide a good framework for designing general use applications, but they do not usually take into account factors like the context where the interaction is taking place or the medical, social and business contexts that surround the patient. This paper presents a model for designing user's interaction in medical applications. The final goal is to develop highly usable user interfaces and to improve the user experience, aiming to guarantee the patient's adherence to the medical protocols and recommendations.


The reliability of measuring pain distribution and location using body pain diagrams in patients with acute whiplash-associated disorders.
The objective of this study was to measure the interexaminer reliability of scoring pain distribution using paper and electronic body pain diagrams in patients with acute whiplash-associated disorder and to assess the intermethod reliability of measuring pain distribution and location using paper and electronic diagrams. We conducted an interexaminer reliability study on 80 participants recruited from a randomized controlled trial on the conservative management of acute grade I/II whiplash-associated disorder. Participants were assessed for inclusion/exclusion criteria by an experienced clinician. As part of the baseline assessment, participants independently completed paper and electronic pain diagrams. Diagrams were scored independently by 2 examiners using the body region method. Interexaminer and intermethod reliability was computed using intraclass correlation coefficients (ICCs) for pain distribution and κ coefficient for pain location. We used Bland-Altman plots to compute limits of agreement. The interexaminer reliability was ICC = 0.925 for paper and ICC = 0.997 for the electronic body pain diagram. The intermethod reliability for measuring pain distribution ranged from ICC = 0.63 to ICC = 0.93. For pain location, the intermethod reliability varied from κ = 0.23 (posterior neck) to κ = 0.90 (right side of the face). We found good to excellent interexaminer reliability for scoring 2 versions of the body pain diagram. Pain distribution and pain location were reliably and consistently measured on body pain diagrams using paper and electronic methods; therefore, clinicians and researchers may choose either medium when using body pain diagrams.


Ultrafast Spectroscopy Reveals Slow Water Dynamics in Biocondensates.
Cells achieve high spatiotemporal control over biochemical processes through compartmentalization to membrane-bound as well as membraneless organelles that assemble by liquid-liquid phase separation. Characterizing the balance of forces within these environments is essential to understanding their stability and function, and water is an integral part of the condensate, playing an important role in mediating electrostatic and hydrogen-bonding interactions. Here, we investigate the ultrafast, picosecond hydrogen-bond dynamics of a model biocondensate consisting of a peptide poly-l-arginine (Poly-R) and the nucleic acid adenosine monophosphate (AMP) using coherent two-dimensional infrared (2D IR) spectroscopy. We investigated three vibrational modes: the arginine side-chain C═N stretches, an AMP ring mode, and the amide backbone carbonyl stretching modes. Dynamics slow considerably between the dilute phase and the condensate phase for each vibrational probe. For example, the arginine side-chain C═N modes slow from 0.38 to 2.26 ps due to strong electrostatic interactions. All-atom molecular dynamics simulations provide an atomistic interpretation of the H-bond network disruption resulting from electrostatic contributions as well as collapse within the condensate. Simulations predict that a fraction of water molecules are highly constrained within the condensate, explaining the observed slowdown in the H-bond dynamics.


White matter developmental trajectories associated with persistence and recovery of childhood stuttering.
Stuttering affects the fundamental human ability of fluent speech production, and can have a significant negative impact on an individual's psychosocial development. While the disorder affects about 5% of all preschool children, approximately 80% of them recover naturally within a few years of stuttering onset. The pathophysiology and neuroanatomical development trajectories associated with persistence and recovery of stuttering are still largely unknown. Here, the first mixed longitudinal diffusion tensor imaging (DTI) study of childhood stuttering has been reported. A total of 195 high quality DTI scans from 35 children who stutter (CWS) and 43 controls between 3 and 12 years of age were acquired, with an average of three scans per child, each collected approximately a year apart. Fractional anisotropy (FA), a measure reflecting white matter structural coherence, was analyzed voxel-wise to examine group and age-related differences using a linear mixed-effects (LME) model. Results showed that CWS exhibited decreased FA relative to controls in the left arcuate fasciculus, underlying the inferior parietal and posterior temporal areas, and the mid body of corpus callosum. Further, white matter developmental trajectories reflecting growth rate of these tract regions differentiated children with persistent stuttering from those who recovered from stuttering. Specifically, a reduction in FA growth rate (i.e., slower FA growth with age) in persistent children relative to fluent controls in the left arcuate fasciculus and corpus callosum was found, which was not evident in recovered children. These findings provide first glimpses into the possible neural mechanisms of onset, persistence, and recovery of childhood stuttering. Hum Brain Mapp 38:3345-3359, 2017. © 2017 Wiley Periodicals, Inc.


[Method of estimation of lysozyme activity in serum with chitin azure as substrate].
The method of estimation of lysozyme activity in serum when chitin azure is used as substrate is described. The basis of incubation medium is 0.1 M acetate buffer, pH 5.0. It was judged about activity of lysozyme by fluorescence of azure in incubation medium at the end of three hour incubation at 37 degrees C after separation on non-reacted chitin azure by short time centrifugation. It was shown that development of wound infection is accompanied by increasing of chitinase activity of lysozyme in serum.


Graph embedding and unsupervised learning predict genomic sub-compartments from HiC chromatin interaction data.
Chromatin interaction studies can reveal how the genome is organized into spatially confined sub-compartments in the nucleus. However, accurately identifying sub-compartments from chromatin interaction data remains a challenge in computational biology. Here, we present Sub-Compartment Identifier (SCI), an algorithm that uses graph embedding followed by unsupervised learning to predict sub-compartments using Hi-C chromatin interaction data. We find that the network topological centrality and clustering performance of SCI sub-compartment predictions are superior to those of hidden Markov model (HMM) sub-compartment predictions. Moreover, using orthogonal Chromatin Interaction Analysis by in-situ Paired-End Tag Sequencing (ChIA-PET) data, we confirmed that SCI sub-compartment prediction outperforms HMM. We show that SCI-predicted sub-compartments have distinct epigenetic marks, transcriptional activities, and transcription factor enrichment. Moreover, we present a deep neural network to predict sub-compartments using epigenome, replication timing, and sequence data. Our neural network predicts more accurate sub-compartment predictions when SCI-determined sub-compartments are used as labels for training.


Management of acute ischaemic stroke.
Ischaemic strokes comprise the majority of strokes in clinical medicine. With the widespread use of thrombolytic therapy within 3 hours of presentation the long-term disability as a result of ischaemic stroke has improved markedly. This article summarizes the clinical management of ischaemic strokes including recent advances.


[Outcome and cognitive changes of mild cognitive impairment in the elderly: a follow-up study of 47 cases].
To examine the cognitive changes and outcome of mild cognitive impairment (MCI) in the elderly and to explore the predictive factors of development from MCI into dementia. A cross-sectional and longitudinal parallel cohort study design was conducted among 47 patients with MCI (MCI group), aged 72.4 +/- 7.1, and 50 sex, marital status, and professional structure-matched normal controls (NC group), aged 67.9 +/- 5.3, using the Neuropsychological Battery of Cognitive Assessment Instruments developed by World Health Organization (WHO-BCAI) and the Wechsler Memory Scale (WMS) to assess the cognitive function. Follow-up was conducted for 34.0 +/- 1.8 months. The diagnosis of dementia was based on the criteria in the Diagnostic and Statistical Manual-IV. Dementia was diagnosed in 13 of the 47 MCI patients with a prevalence rate of 27.7%, significantly higher than that in the NC group (2.0%, 1/50, P < 0.01). The mean total score of mini-mental status examination (MMSE) of the MCI group decreased by 2.2 +/- 3.7, significantly more than that of the NC group (1.0 +/- 1.9, P < 0.01). The mean total mental quotient (MQ) of the MCI group decreased by 12.6 +/- 17.3, significantly more than that of the NC group (3.9 +/- 8.4, P < 0.01). The values of MMSE and MQ of the 13 cases in the MCI group who developed into dementia patients decreased by 5.5 +/- 2.8 and 30.0 +/- 18.0 respectively. The WHO-BCAI assessment demonstrated that the scores of performance of verbal learning, verbal fluency, visual reasoning, trail making, sorting and spatial construct tests of the cases in the MCI group who developed into dementia patients were significantly poorer than those of the NC group (P < 0.01). Logistic analysis based on the baseline assessment suggested that the total score of MMSE and its subtest of orientation, score of orientation memory of WMS, and the scores of performance of trail making, attention, and delayed recall tested by WHO-BCAI were all statistically significant predictive factors for MCI converting into dementia (P < 0.01 or 0.05). The predictive accuracy rates of MMSE, WMS, and WHO-BCAI were 70.3%, 78.4% and 90.7% respectively. MCI diagnosed based on the criteria of pure MCI modified by the authors is indeed a transitional state from normal aging to dementia, especially Alzheimer's type of dementia. The cognitive change for MCI converting into dementia is characterized in the areas of orientation, attention, speech and executive function. These predictive factors for MCI to develop dementia are valuable in early detection and prevention of dementia in the elderly.


Impact of acute rejection episodes on long-term graft survival following simultaneous kidney-pancreas transplantation.
Although it is well established that acute rejection is one of the major risk factors for chronic graft loss following kidney transplantation, its effect on long-term graft survival following simultaneous kidney-pancreas transplants (SKPTs) is less well known. We analyzed a large cohort of SKPTs and cadaver kidney transplants reported to the United Network for Organ Sharing database during 1988-97, to determine the impact of acute rejection episodes on long-term kidney and pancreas graft survival. Only patients whose kidney and pancreas grafts had survived for at least 1 year were included. Other potential risk factors influencing long-term graft survival were included in the analysis. Of the 4251 SKPTs, 45% had no acute rejection, 36% had kidney only rejection, 3% had pancreas only rejection, and 16% had both kidney and pancreas rejection within the 1st year post transplant. The 5-year kidney and pancreas graft survival rates adjusted for other risk factors were 91% and 85%, respectively; for those with no acute rejection episodes, 88% and 84%, respectively; for those with kidney only rejection, 94% and 83%, respectively; for those with pancreas only rejection; and 86% and 78%, respectively, for those with both kidney and pancreas rejection. The relative risk (RR) of kidney graft failure was 1.32 when acute rejection involved the kidney graft only, while the RR was 1.53 when the rejection involved both organs. We conclude that acute rejection episodes have a negative impact on the long-term kidney graft survival in the SKPT population similar to that in the cadaver kidney transplant population. Patients who had acute rejection episodes of both kidney and pancreas have the worst long-term graft survival.


High and low pressure irrigation in contaminated wounds with exposed bone.
Irrigation and debridement are essential in the initial management of traumatic wounds. The relative efficicacy of low pressure irrigation compared with high pressure irrigation remains unclear. The purpose of this study was to examine the time dependent efficacy of both high and low pressure lavage in removing adherent bacteria from traumatic wounds with exposed bone. Using an in-vivo model, we created bilateral Staphylococcus aureus contaminated femoral wounds in 30 mice. The wounds were incubated for 1 to 10 hours and lavaged with either high (70 psi) or low pressure lavage (1-2 psi). The mean colony forming units of bacteria were compared between groups at each time point. High and low pressure lavage were effective in removing adherent bacteria from contaminated wounds up to 8 hours and 4 hours, respectively. High pressure lavage was more effective than low pressure at every time point. The efficacy of low pressure lavage in wounds with exposed bone is questionable when irrigation is delayed beyond 4 hours.


Hepatitis E virus infection remodels the mature tRNAome in macrophages to orchestrate NLRP3 inflammasome response.
Hepatitis E virus (HEV) infection has been shown to activate NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in macrophages, a key mechanism of causing pathological inflammation, but the mechanisms regulating this response remain poorly understood. Here, we report that the mature tRNAome dynamically responds to HEV infection in macrophages. This directs IL-1β expression, the hallmark of NLRP3 inflammasome activation, at mRNA and protein levels. Conversely, pharmacological inhibition of inflammasome activation abrogates HEV-provoked tRNAome remodeling, revealing a reciprocal interaction between the mature tRNAome and the NLRP3 inflammasome response. Remodeling the tRNAome results in improved decoding of codons directing leucine- and proline synthesis, which are the major amino acid constituents of IL-1β protein, whereas genetic or functional interference with tRNAome-mediated leucine decoding impairs inflammasome activation. Finally, we demonstrated that the mature tRNAome also actively responds to lipopolysaccharide (a key component of gram-negative bacteria)-triggered inflammasome activation, but the response dynamics and mode of actions are distinct from that induced by HEV infection. Our findings thus reveal the mature tRNAome as a previously unrecognized but essential mediator of host response to pathogens and represent a unique target for developing anti-inflammatory therapeutics.


Clinical, diagnostic, and pathologic features and surgical outcomes of combined hepatocellular-cholangiocarcinoma in dogs: 14 cases (2009-2021).
To describe the clinical, diagnostic, and pathological features and postoperative prognosis of canine combined hepatocellular-cholangiocarcinoma (cHCC-CCA). 14 privately owned dogs that underwent surgical treatment. The medical records, including signalment, clinical signs, blood test, urine analysis, computed tomography (CT) findings, intraoperative findings, and pathological findings, were retrospectively reviewed in the dogs with cHCC-CCA. Of 306 dogs that underwent surgical removal of hepatic masses, 14 dogs (4.6%) were pathologically confirmed to have cHCC-CCA. Median age and body weight were 11.3 years and 7.3 kg, respectively. There were no specific clinicopathological findings for cHCC-CCA. CT revealed a massive hepatic mass in all dogs and the inclusion of cyst-like lesions within the mass in 13 dogs. Intrahepatic metastases were found at time of surgery in 2 dogs (14.3%). Of the residual 12 dogs, 1 dog showed postoperative formation of intrahepatic nodules suggestive of metastases and another had intrahepatic and pulmonary nodules and a forelimb skin mass, suggesting postoperative metastases. The median survival time of the patients with cHCC-CCA was 700 days (range, 10 to 869 days) after surgery. To the authors' knowledge, this is the first study to describe the clinical, diagnostic, and pathological features and postoperative prognosis of canine cHCC-CCA. The clinical and diagnostic features of canine cHCC-CCA might be more similar to those of HCC rather than to those of CCA, but the preoperative diagnosis differentiating between HCC and cHCC-CCA was challenging. Our study suggests that the postoperative prognosis of canine patients with cHCC-CCA is similar to that of dogs with HCC.


Frequency-specific adaptation in human auditory cortex depends on the spectral variance in the acoustic stimulation.
In auditory cortex, activation and subsequent adaptation is strongest for regions responding best to a stimulated tone frequency and less for regions responding best to other frequencies. Previous attempts to characterize the spread of neural adaptation in humans investigated the auditory cortex N1 component of the event-related potentials. Importantly, however, more recent studies in animals show that neural response properties are not independent of the stimulation context. To link these findings in animals to human scalp potentials, we investigated whether contextual factors of the acoustic stimulation, namely, spectral variance, affect the spread of neural adaptation. Electroencephalograms were recorded while human participants listened to random tone sequences varying in spectral variance (narrow vs. wide). Spread of adaptation was investigated by modeling single-trial neural adaptation and subsequent recovery based on the spectro-temporal stimulation history. Frequency-specific neural responses were largest on the N1 component, and the modeled neural adaptation indices were strongly predictive of trial-by-trial amplitude variations. Yet the spread of adaption varied depending on the spectral variance in the stimulation, such that adaptation spread was broadened for tone sequences with wide spectral variance. Thus the present findings reveal context-dependent auditory cortex adaptation and point toward a flexibly adjusting auditory system that changes its response properties with the spectral requirements of the acoustic environment.


Relation of mild idiopathic polyhydramnios to perinatal outcome.
The relation between clinically obvious polyhydramnios and poor perinatal outcome has been described. Much less is known about mild, unexplained polyhydramnios, which usually is initially suggested by sonographic examination late in gestation. The purpose of the present investigation was to relate mild idiopathic polyhydramnios to perinatal outcome. Mild polyhydramnios was defined sonographically as an amniotic fluid index of 24.1-39.9 during fetal biophysical testing. All subjects had singleton gestations not complicated by conditions known to predispose to polyhydramnios. We diagnosed mild polyhydramnios in 97 of 1177 patients (8.2%) undergoing fetal testing at 26-42 gestational weeks. Premature delivery, intrapartum complications, and neonatal depression were no more frequent in the pregnancies complicated by mild, unexplained polyhydramnios than in a comparable control group with normal fluid volume. The mild polyhydramnios group showed a significantly higher incidence of birth weight greater than 4000 g than did the control group (18.6 versus 8.6%; P less than .05). We conclude that mild idiopathic polyhydramnios in late gestation is relatively common. Except for a higher incidence of large for gestational age fetuses, this condition by itself is not associated with an increased risk of adverse perinatal outcomes.


Collegial decision making based on social amplification leads to optimal group formation.
Group-living animals are often faced with choosing between one or more alternative resource sites. A central question in such collective decision making includes determining which individuals induce the decision and when. This experimental and theoretical study of shelter selection by cockroach groups demonstrates that choices can emerge through nonlinear interaction dynamics between equal individuals without perfect knowledge or leadership. We identify a simple mechanism whereby a decision is taken on the move with limited information and signaling and without comparison of available opportunities. This mechanism leads to optimal mean benefit for group individuals. Our model points to a generic self-organized collective decision-making process independent of animal species.


Golgi localized β1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLCε to regulate cardiac hypertrophy.
Increased adrenergic tone resulting from cardiovascular stress leads to development of heart failure, in part, through chronic stimulation of β1 adrenergic receptors (βARs) on cardiac myocytes. Blocking these receptors is part of the basis for β-blocker therapy for heart failure. Recent data demonstrate that G protein-coupled receptors (GPCRs), including βARs, are activated intracellularly, although the biological significance is unclear. Here we investigated the functional role of Golgi βARs in rat cardiac myocytes and found they activate Golgi localized, prohypertrophic, phosphoinositide hydrolysis, that is not accessed by cell surface βAR stimulation. This pathway is accessed by the physiological neurotransmitter norepinephrine (NE) via an Oct3 organic cation transporter. Blockade of Oct3 or specific blockade of Golgi resident β1ARs prevents NE dependent cardiac myocyte hypertrophy. This clearly defines a pathway activated by internal GPCRs in a biologically relevant cell type and has implications for development of more efficacious β-blocker therapies.


Radiation and immunotherapy: emerging mechanisms of synergy.
Immunotherapy (IO) has become a standard treatment in patients with metastatic and locally advanced non-small cell lung cancer (NSCLC), and is now being tested in patients with early stage disease. IO agents currently in use for lung cancer target PD-1, PD-L1, and CTLA-4. While survival and tumor control have improved with IO, many patients have limited or short responses to IO. Therefore, methods to improve the systemic response to IO are needed. Radiation therapy (RT) is an integral component of lung cancer treatment, and may improve systemic response to IO by increasing antigen presentation, increasing co-stimulatory signaling, increasing T-cells recruitment, upregulating PD-L1, increasing tumor stromal lymphocyte infiltration, and altering the microenvironment. IO after definitive chemoradiation is now standard treatment in unresectable stage III NSCLC following publication of the PACIFIC clinical trial. For early stage NSCLC, IO is being investigated in conjunction with stereotactic body radiotherapy (SBRT). The benefit of adding RT to IO in patients with metastatic disease may be especially pronounced in patients with low baseline PD-L1 expression, potentially when delivered as a short course of SBRT, as supported by the PEMBRO-RT clinical trial. Current and ongoing clinical trials are evaluating the optimal radiation dose, timing, and sequencing of RT with IO.


Spatial information transfer in hippocampal place cells depends on trial-to-trial variability, symmetry of place-field firing, and biophysical heterogeneities.
The relationship between the feature-tuning curve and information transfer profile of individual neurons provides vital insights about neural encoding. However, the relationship between the spatial tuning curve and spatial information transfer of hippocampal place cells remains unexplored. Here, employing a stochastic search procedure spanning thousands of models, we arrived at 127 conductance-based place-cell models that exhibited signature electrophysiological characteristics and sharp spatial tuning, with parametric values that exhibited neither clustering nor strong pairwise correlations. We introduced trial-to-trial variability in responses and computed model tuning curves and information transfer profiles, using stimulus-specific (SSI) and mutual (MI) information metrics, across locations within the place field. We found spatial information transfer to be heterogeneous across models, but to reduce consistently with increasing levels of variability. Importantly, whereas reliable low-variability responses implied that maximal information transfer occurred at high-slope regions of the tuning curve, increase in variability resulted in maximal transfer occurring at the peak-firing location in a subset of models. Moreover, experience-dependent asymmetry in place-field firing introduced asymmetries in the information transfer computed through MI, but not SSI, and the impact of activity-dependent variability on information transfer was minimal compared to activity-independent variability. We unveiled ion-channel degeneracy in the regulation of spatial information transfer, and demonstrated critical roles for N-methyl-d-aspartate receptors, transient potassium and dendritic sodium channels in regulating information transfer. Our results demonstrate that trial-to-trial variability, tuning-curve shape and biological heterogeneities critically regulate the relationship between the spatial tuning curve and spatial information transfer in hippocampal place cells.


Lack of Heterologous Cross-reactivity toward HLA-A*02:01 Restricted Viral Epitopes Is Underpinned by Distinct αβT Cell Receptor Signatures.
αβT cell receptor (TCR) genetic diversity is outnumbered by the quantity of pathogenic epitopes to be recognized. To provide efficient protective anti-viral immunity, a single TCR ideally needs to cross-react with a multitude of pathogenic epitopes. However, the frequency, extent, and mechanisms of TCR cross-reactivity remain unclear, with conflicting results on anti-viral T cell cross-reactivity observed in humans. Namely, both the presence and lack of T cell cross-reactivity have been reported with HLA-A*02:01-restricted epitopes from the Epstein-Barr and influenza viruses (BMLF-1 and M158, respectively) or with the hepatitis C and influenza viruses (NS31073 and NA231, respectively). Given the high sequence similarity of these paired viral epitopes (56 and 88%, respectively), the ubiquitous nature of the three viruses, and the high frequency of the HLA-A*02:01 allele, we selected these epitopes to establish the extent of T cell cross-reactivity. We combined ex vivo and in vitro functional assays, single-cell αβTCR repertoire sequencing, and structural analysis of these four epitopes in complex with HLA-A*02:01 to determine whether they could lead to heterologous T cell cross-reactivity. Our data show that sequence similarity does not translate to structural mimicry of the paired epitopes in complexes with HLA-A*02:01, resulting in induction of distinct αβTCR repertoires. The differences in epitope architecture might be an obstacle for TCR recognition, explaining the lack of T cell cross-reactivity observed. In conclusion, sequence similarity does not necessarily result in structural mimicry, and despite the need for cross-reactivity, antigen-specific TCR repertoires can remain highly specific.


Effect of protein, polysaccharide, and oxygen concentration profiles on biofilm cohesiveness.
It is important to control biofilm cohesiveness to optimize process performance. In this study, a membrane-aerated biofilm reactor inoculated with activated sludge was used to grow mixed-culture biofilms of different ages and thicknesses. The cohesions, or cohesive energy levels per unit volume of biofilm, based on a reproducible method using atomic force microscopy (F. Ahimou, M. J. Semmens, P. J. Novak, and G. Haugstad, Appl. Environ. Microbiol. 73:2897-2904, 2007), were determined at different locations within the depths of the biofilms. In addition, the protein and polysaccharide concentrations within the biofilm depths, as well as the dissolved oxygen (DO) concentration profiles within the biofilms, were measured. It was found that biofilm cohesion increased with depth but not with age. Level of biofilm cohesive energy per unit volume was strongly correlated with biofilm polysaccharide concentration, which increased with depth in the membrane-aerated biofilm. In a 12-day-old biofilm, DO also increased with depth and may therefore be linked to polysaccharide production. In contrast, protein concentration was relatively constant within the biofilm and did not appear to influence cohesion.


A perceptually efficient VBR rate control algorithm.
This paper describes a rate control algorithm for a variable bit-rate (VBR) video coder. The algorithm described varies the quantizer step size of the coder according to properties of an image sequence that affect the perception of errors. The algorithm also limits the output bit-rate of the coder without the use of buffers to more efficiently use network bandwidth. It is shown that a VBR encoder using this algorithm will provide decoded image sequences with a consistent perceived quality that is comparable with, or better than, the perceived quality of images coded with a CBR encoder.


Chronic gastritis may predict risk of cerebral small vessel disease.
Chronic gastritis, especially that caused by helicobacter pylori (HP) infection, has been associated with increased risk of ischemic stroke. But the relationship between chronic gastritis and cerebral small vessel disease (CSVD) remains largely undetermined. This study aimed to determine the potential predictors for CSVD, with chronic gastritis and its proxies as alternatives. Patients aged 18 years or older with indications for electronic gastroscopy were enrolled. Presence of CSVD was evaluated with brain magnetic resonance imaging (MRI) results. Degree of CSVD was scored according to established criteria. Logistic regression analysis was used for identifying possible risk factors for CSVD. Of the 1191 enrolled patients, 757 (63.6%) were identified as with, and 434 (36.4%) as without CSVD. Multivariate analysis indicated that patients with chronic atrophic gastritis had an increased risk for CSVD than those without (adjusted odds ratio = 1.58; 95% CI, 1.08-2.32; P < 0.05). Chronic atrophic gastritis is associated with the presence of CSVD. We should routinely screen the presence of CSVD for patients with chronic atrophic gastritis.


Review article: heart rate and blood pressure control in vasovagal syncope.
Vasovagal syncope is characterized by transient failure of usually reliable physiologic mechanisms responsible for maintaining both systemic arterial pressure and cerebral blood flow. Two circulatory phenomena are almost universally present: systemic arterial vasodilation and bradycardia. A third phenomenon, cerebrovascular constriction, has also been described but its contribution to the faint is less well established. The neural reflex pathways responsible for triggering the circulatory changes in the vasovagal faint are incompletely understood, but have recently been the subject of renewed interest. In part, this interest probably stems from the frequency with which vasovagal symptoms are now recognized to be the cause of fainting spells. Additionally, however, there is an increasingly recognized need to develop treatment strategies for those affected patients in whom recurrent vasovagal symptoms are particularly troublesome. It is the goal of this discussion to focus on those aspects of circulatory control, and in particular on potential interactions among certain neural and humoral systems, which may contribute to the inappropriate physiologic responses associated with the vasovagal faint.


A novel family of Ca2+/calmodulin-binding proteins involved in transcriptional regulation: interaction with fsh/Ring3 class transcription activators.
A novel CaM-binding protein was isolated through protein-protein interaction based screening of an Arabidopsis cDNA expression library using a 35S calmodulin (CaM) probe. There are four additional homologs in the Arabidopsis genome with similar structures: a BTB domain in the N-terminus and a Zf-TAZ domain in the C-terminus. Hence, they were designated as AtBT1-5 (Arabidopsis thaliana BTB and TAZ domain protein). CaM-binding experiments revealed that all five AtBTs are CaM-binding proteins, and their CaM-binding domains were mapped to the C-terminus. AtBT homologs are also present in rice, but are not present in human, animal, yeast or other organisms, suggesting that the BTB and TAZ domain proteins are plant-specific. The AtBT1-smGFP fusion protein expressed in tobacco BY-2 cells showed that AtBT1 targets the nucleus. Yeast two-hybrid screening using an AtBT1 fragment as bait identified two interacting proteins (AtBET10 and AtBET9) belonging to the family of fsh/Ring3 class transcription regulators. The BTB domain of the AtBTs is required for the interaction, and this protein-protein interaction was confirmed by GST pull-down. AtBET10 also interacts with AtBT2 and AtBT4, and exhibited a transcriptional activation function in yeast cells. AtBTs exhibit varying responses to different stress stimuli, but all five genes responded rapidly to H2O2 and salicylic acid (SA) treatments. These results suggest that AtBTs play a role in transcriptional regulation, and signal molecules such as Ca2+, H2O2, and SA affect transcriptional machinery by altering the expression and conformation of AtBTs which interact with transcriptional activators such as AtBET10.


Pet-1 is required across different stages of life to regulate serotonergic function.
Transcriptional cascades are required for the specification of serotonin (5-HT) neurons and behaviors modulated by 5-HT. Several cascade factors are expressed throughout the lifespan, which suggests that their control of behavior might not be temporally restricted to programming normal numbers of 5-HT neurons. We used new mouse conditional targeting approaches to investigate the ongoing requirements for Pet-1 (also called Fev), a cascade factor that is required for the initiation of 5-HT synthesis, but whose expression persists into adulthood. We found that Pet-1 was required after the generation of 5-HT neurons for multiple steps in 5-HT neuron maturation, including axonal innervation of the somatosensory cortex, expression of appropriate firing properties, and the expression of the Htr1a and Htr1b autoreceptors. Pet-1 was still required in adult 5-HT neurons to preserve normal anxiety-related behaviors through direct autoregulated control of serotonergic gene expression. These findings indicate that Pet-1 is required across the lifespan of the mouse and that behavioral pathogenesis can result from both developmental and adult-onset alterations in serotonergic transcription.


A large community outbreak of gastroenteritis associated with consumption of drinking water contaminated by river water, Belgium, 2010.
SUMMARY On 6 December 2010 a fire in Hemiksem, Belgium, was extinguished by the fire brigade with both river water and tap water. Local physicians were asked to report all cases of gastroenteritis. We conducted a retrospective cohort study among 1000 randomly selected households. We performed a statistical and geospatial analysis. Human stool samples, tap water and river water were tested for pathogens. Of the 1185 persons living in the 528 responding households, 222 (18·7%) reported symptoms of gastroenteritis during the time period 6-13 December. Drinking tap water was significantly associated with an increased risk for gastroenteritis (relative risk 3·67, 95% confidence interval 2·86-4·70) as was place of residence. Campylobacter sp. (2/56), norovirus GI and GII (11/56), rotavirus (1/56) and Giardia lamblia (3/56) were detected in stool samples. Tap water samples tested positive for faecal indicator bacteria and protozoa. The results support the hypothesis that a point-source contamination of the tap water with river water was the cause of the multi-pathogen waterborne outbreak.


[Yeast associations with mosquitoes of the genus Aedes Mg. (Diptera, Culicidae) in the Tom-Ob river region].
The inner microflora of blood-sucking mosquitoes genus Aedes inhabiting different biotops of aspen-birch woods of the Tomsc Priob region has been investigated. 120 strains of yeasts genera Pichia, Hansenula, Saccharomyces, Torulaspora, Metschnicowia, Rhodotorula, Cryptococcus, Candida and Aueobasidium have been isolated, the most number of species belong to the genus Pichia. Yeasts P. guilliermondii, A. pullulans and M. pulcherrima have been found during all periods of insects collection. The most number of yeasts species has been found in mosquitos of mass species--A. diantaeus, A. excrucians. A. punctor and A. communis. It is supposed that isolated yeasts are collected by mosquitoes off natural substrates in the course of their development.


Randomized Study of the Effects of Zinc, Vitamin A, and Magnesium Co-supplementation on Thyroid Function, Oxidative Stress, and hs-CRP in Patients with Hypothyroidism.
Hypothyroidism can occur due to deficiencies in micronutrients such as zinc, magnesium, and vitamin A. The aim of this study was to determine the effects of supplementation with these micronutrients on thyroid function, oxidative stress, and hs-CRP levels in patients with hypothyroidism. In a randomized double-blind, placebo-controlled trial with two parallel groups, 86 hypothyroid patients aged 20-65 were allocated to receive daily supplementation with either: (intervention group, n = 43) one 30 mg zinc gluconate capsule per day, one 250 mg magnesium oxide tablet per day, and one 25,000 IU vitamin A capsule twice/week for 10 weeks or (placebo group, n = 43) placebo capsules and tablets as above for 10 weeks. Neither of the groups changed their diet or physical activity. Thyroid hormones (free and total thyroxine (FT4 and TT4), free tri-iodothyronine (FT3), and thyroid-stimulating hormone (TSH)), oxidative markers (malondialdehyde (MDA) and total antioxidant capacity (TAC)), serum hs-CRP, and anthropometric indices (height and weight) were assessed at the baseline and at the end of the study. In the intervention group, we found a significant increase in serum FT4, decreased anthropometric indices, and lower levels of serum hs-CRP by the end of the 10 week protocol (P < 0.05). In the placebo group, serum TAC was decreased and hs-CRP increased (P < 0.05), with no significant changes in serum TSH, FT3, TT4, and MDA after the intervention. Zinc, vitamin A, and magnesium supplementation may have beneficial effects in patients with hypothyroidism and in diseases associated with hyperthyroidism.


Influence of Ligand Structure on Excited State Surface Chemistry of Lead Sulfide Quantum Dots.
The ligand-nanocrystal boundaries of colloidal quantum dots (QDs) mediate the primary energy and electron transfer processes that underpin photochemical and photocatalytic transformations at their surfaces. We use mid-infrared transient absorption spectroscopy to reveal the influence that ligand structure and bonding to nanocrystal surfaces have on the changes of the excited state surface chemistry of this boundary in PbS QDs and the corresponding impact on charge transfer processes between nanocrystals. We demonstrate that oleate ligands undergo marked changes in their bonding to surfaces in the excitonic excited states of the nanocrystals, indicating that oleate passivated PbS surfaces undergo significant structural changes following photoexcitation. These changes can impact the surface mobility of the ligands and the ability of redox shuttles to approach the nanocrystal surfaces to undergo charge transfer in photocatalytic reactions. In contrast, markedly different transient vibrational features are observed in iodide/mercaptoproprionic acid passivated PbS QD films that result from charge transfer between neighboring nanocrystals and localization of holes at the nanocrystal surfaces near MPA ligands. This ability to distinguish the influence that excitonic excited states vs charge transfer processes have on the surface chemistry of the ligand-nanocrystal boundary lays the groundwork for exploration of how this boundary can be understood and controlled for the design of nanocrystalline materials tailored for specific applications in solar energy harvesting and photocatalytic reactions.


Concentration gradient driven molecular dynamics: a new method for simulations of membrane permeation and separation.
In this study, we introduce a new non-equilibrium molecular dynamics simulation method to perform simulations of concentration driven membrane permeation processes. The methodology is based on the application of a non-conservative bias force controlling the concentration of species at the inlet and outlet of a membrane. We demonstrate our method for pure methane, ethane and ethylene permeation and for ethane/ethylene separation through a flexible ZIF-8 membrane. Results show that a stationary concentration gradient is maintained across the membrane, realistically simulating an out-of-equilibrium diffusive process, and the computed permeabilities and selectivity are in good agreement with experimental results.


Identification of a human orthologue of Sec34p as a component of the cis-Golgi vesicle tethering machinery.
The roles of the components of the Sec34p protein complex in intracellular membrane trafficking, first identified in the yeast Saccharomyces cerevisiae, have yet to be characterized in higher eukaryotes. We cloned a human cDNA whose predicted amino acid sequence showed 41% similarity to yeast Sec34p with homology throughout the entire coding region. Affinity-purified antibodies raised against the human SEC34 protein (hSec34p) recognized a cellular protein of 94 kDa in both soluble and membrane fractions. Like yeast Sec34p, cytosolic hSec34p migrated with an apparent molecular mass of 300 kDa on a glycerol velocity gradient, suggesting that it is part of a protein complex. Immunofluorescence microscopy localized hSec34p to the Golgi compartment in cells of all species examined, where it co-localized well with the cis/medial Golgi marker membrin and partially co-localized with cis-Golgi network marker p115 and trans-Golgi marker TGN38. The co-localization with membrin was maintained at 15 degrees C and after microtubule depolymerization with nocodazole. During transport of the tsO45 vesicular stomatitis virus G protein through the Golgi, there was significant overlap with the hSec34p compartment. Green fluorescent protein-hSec34 expressed in HeLa cells was restricted to Golgi cisternae, and its membrane association was sensitive to brefeldin A treatment. Taken together, our findings indicate that hSec34p is part of a peripheral membrane protein complex localized on cis/medial Golgi cisternae where it may participate in tethering intra-Golgi transport vesicles.


Impact of Intravenous Fluid Therapy on Survival Among Patients With Ebola Virus Disease: An International Multisite Retrospective Cohort Study.
Intravenous fluid (IVF) is a frequently recommended intervention in Ebola virus disease (EVD), yet its impact on patient outcomes remains unclear. This retrospective cohort study evaluated patients with EVD admitted to 5 Ebola treatment units (ETUs) in West Africa. The primary outcome was the difference in 28-day survival between cases treated and not treated with IVF. To control for demographic and clinical factors related to both IVF exposure and survival, cases were compared using propensity score matching. To control for time-varying patient and treatment factors over the course of ETU care, a marginal structural proportional hazards model (MSPHM) with inverse probability weighting was used to assess for 28-day survival differences. Among 424 EVD-positive cases with data for analysis, 354 (83.5%) were treated with IVF at some point during their ETU admission. Overall, 146 (41.3%) cases treated with IVF survived, whereas 31 (44.9%) cases not treated with any IVF survived (P = .583). Matched propensity score analysis found no significant difference in 28-day survival between cases treated and not treated with IVF during their first 24 and 48 hours of care. Adjusted MSPHM survival analyses also found no significant difference in 28-day survival for cases treated with IVF (27.3%) compared to those not treated with IVF (26.9%) during their entire ETU admission (P = .893). After adjustment for patient- and treatment-specific time-varying factors, there was no significant difference in survival among patients with EVD treated with IVF as compared to those not treated with IVF.


Enhancement of TNF receptor p60-mediated cytotoxicity by TNF receptor p80: requirement of the TNF receptor-associated factor-2 binding site.
TNFR p60 (TNFR60) is the main mediator of TNF-induced apoptosis, although in some cells TNFR80 is also involved. TNFR80-dependent induction or enhancement of cytotoxicity has been explained by intracellular signaling, "ligand passing," or induction of endogenous TNF. Using HeLa transfectants expressing wild-type TNFR80 and deletion mutants derived from them, we have investigated the mechanism of TNFR80-mediated cytotoxicity. TNFR80 induces no cytotoxicity on its own, but is functional in these transfectants, as selective stimulation activates nuclear factor-kappaB (NF-kappaB) and induces NF-kappaB-dependent cellular responses (IL-6 and manganese superoxide dismutase). TNFR60-induced cytotoxicity, however, is enhanced about 1000-fold by costimulation of TNFR80, whereas only additive responses are observed with regard to NF-kappaB-dependent responses. Ligand passing is not critically involved, because a similar potentiation of TNFR60-mediated cytotoxicity was observed when agonistic Abs were used for stimulation of both receptors. In addition, in HeLa cells overexpressing a truncated form of TNFR80 lacking the cytoplasmic domain, no TNFR80-dependent potentiation of TNFR60-mediated cytotoxicity was detectable, emphasizing that intracellular signaling of TNFR80 is required for synergistic activity. The involvement of endogenously produced TNF can be ruled out by the use of TNF-neutralizing Abs. The ability of TNFR80 to cooperate with TNFR60 could be mapped to the binding site for the TNF receptor-associated factor-2. These results are in agreement with a differential cooperation of both TNFR; an additive effect is obtained in those responses that are initiated by both receptors via identical pathways, i.e., activation of NF-kappaB, whereas induction of cytotoxicity is most likely mediated by distinct signaling pathways, allowing positive cooperativity.


[Diagnostic significance of gastrointestinal hormones].
Determination of gastrointestinal hormones by radioimmunoassay in plasma is important for detection of endocrine-active tumours in the gut. Since in most cases multiple endocrine tumours occur, a variety of hormones such as gastrin, vasoactive intestinal polypeptide, glucagon, somatostatin, pancreatic polypeptide and neurotensin should be measured. Gastrin is helpful as a diagnostic tool in differentiating between Zollinger-Ellison syndrome and antral G-cell hyperplasia or hyperfunction. Autonomic neuropathy of the gut (as in diabetics) can be detected by measurements of plasma pancreatic polypeptide. The diagnostic value of measurements of plasma cholecystokinin, secretin and other gut peptide hormones is not yet defined.


Interventions to Promote Fundamental Movement Skills in Childcare and Kindergarten: A Systematic Review and Meta-Analysis.
Proficiency in fundamental movement skills (FMS) lays the foundation for being physically active and developing more complex motor skills. Improving these motor skills may provide enhanced opportunities for the development of a variety of perceptual, social, and cognitive skills. The objective of this systematic review and meta-analysis was to assess the effects of FMS interventions on actual FMS, targeting typically developing young children. Searches in seven databases (CINAHL, Embase, MEDLINE, PsycINFO, PubMed, Scopus, Web of Science) up to August 2015 were completed. Trials with children (aged 2-6 years) in childcare or kindergarten settings that applied FMS-enhancing intervention programs of at least 4 weeks and meeting the inclusion criteria were included. Standardized data extraction forms were used. Risk of bias was assessed using a standard scoring scheme (Effective Public Health Practice Project-Quality Assessment Tool for Quantitative Studies [EPHPP]). We calculated effects on overall FMS, object control and locomotor subscales (OCS and LMS) by weighted standardized mean differences (SMDbetween) using random-effects models. Certainty in training effects was evaluated using GRADE (Grading of Recommendations Assessment, Development, and Evaluation System). Thirty trials (15 randomized controlled trials and 15 controlled trials) involving 6126 preschoolers (aged 3.3-5.5 years) revealed significant differences among groups in favor of the intervention group (INT) with small-to-large effects on overall FMS (SMDbetween 0.46), OCS (SMDbetween 1.36), and LMS (SMDbetween 0.94). Our certainty in the treatment estimates based on GRADE is very low. Although there is relevant effectiveness of programs to improve FMS proficiency in healthy young children, they need to be interpreted with care as they are based on low-quality evidence and immediate post-intervention effects without long-term follow-up.


Serum concentrations of primidone and its metabolites, phenylethylmalonamide and phenobarbital, in the dog.
The elimination of primidone, phenylethylmalonamide, and phenobarbital (administered IV) was studied in dogs. The elimination half-lives were primidone, 1.85 +/- 0.3 (SEM) hours; phenylethylmalonamide, 7.1 +/- 1.45 hours; and phenobarbital, 40.9 +/- 4.96 hours. Dogs given repeated oral doses of primidone for 14 or 21 days had smaller primidone serum concentrations after each dosing. Dogs given 1.0 g of primidone orally (59.2 decreasing to 50.5 mg/kg of body weight) for 21 days accumulated the phenobarbital metabolite with apparent steady-state concentrations of 10 to 20 micrograms/ml and phenylethylmalonamide in concentrations of 2 to 5 micrograms/ml. Serum primidone concentrations decreased after repeated dosing and were measurable in only 1 dog 24 hours after the 21st dose and peak concentrations of 4 to 7 micrograms/ml were measured at 4 hours after the 22nd dose.


Evaluation of a comprehensive school-based AIDS education programme in rural Masaka, Uganda.
A 19 activity extracurricular school-based AIDS education programme lasting 1 year was conducted in rural southwestern Uganda using specially trained teachers, and was evaluated using mutually supportive quantitative and qualitative methods. In total, 1274 students from 20 intervention schools and 803 students from 11 control schools completed questionnaires at baseline, and their classes were followed up. In addition, 93 students from five of the intervention schools participated in 12 focus group discussions. The programme had very little effect--seven of the nine key questionnaire variables showed no significant increase in score after the intervention. Data from the focus group discussions suggest that the programme was incompletely implemented, and that key activities such as condoms and the role-play exercises were covered only very superficially. The main reasons for this were a shortage of classroom time, as well as teachers' fear of controversy and the unfamiliar. We conclude that large-scale comprehensive school-based AIDS education programmes in sub-Saharan Africa may be more completely implemented if they are fully incorporated into national curricula and examined as part of life-skills education. This would require teachers to be trained in participatory teaching methods while still at training college.


Thinking through the multimodal treatment of localized oesophageal cancer: the point of view of the surgeon.
This review examines current developments and controversies in the multimodal management of oesophageal cancer, with an emphasis on surgical dilemmas and outcomes from the surgeon's perspective. Despite the advancement of oncological neoadjuvant treatments, there is still no consensus on what regimen is superior. The majority of patients may still fail to respond to neoadjuvant therapy and suffer potential harm without any survival advantage as a result. In patients who do not respond, adjuvant therapy is still often recommended after surgery despite any evidence for its benefit. We examine the implications of different regimens and treatment approaches for both squamous cell cancer and adenocarcinoma of the oesophagus. The efficacy of neoadjuvant treatment is highly variable and likely relates to variability of tumour biology. Ongoing work to identify responders, or optimize treatment on an individual patient, should increase the efficacy of multimodal therapy and improve patient outcomes.


[Discrete phenotypical variability of electrophoretic specters of one of myogen systems in the Acipenseridae family].
Analysis of electrophoregrams of water-soluble proteins of white skeletal muscle of 10 fish species belonging to three genera of the Acipenseridae family has allowed revealing an earlier not described system that can serve as a biochemical marker. This protein system represents a set of five fractions (A, B, C, D, E). A part of the studied species is monomorphous for one of these fractions (sterlet, starred sturgeon, great sturgeon, and big shovelnose had phenotype A, barbel sturgeon--phenotype C, great Siberian sturgeon--phenotype D). In all individuals of the Amur sturgeon the identical three-component specter (phenotype ACE) was revealed. In the Sakhalin, Siberian, and Russian sturgeons a clearly expressed polymorphism was observed. Among the studied species the Russian sturgeon was characterized by the highest degree of heterogeneity and polymorphism. In the studied sample of this species all five protein variants are found, whereas in other species--only a part of this set.


[Sputum drainage by ultrasonic nebulization and the diagnosis of pulmonary carcinoma].
From June 1984 to June 1989, the sputum drain age by ultrasonic nebulization was done in 1155 cases of suspected lung cancer. From 286 positive cases, 157 (54.9%) were confirmed to be pulmonary cancer histologically. The general cytological and histological identification coincidence rate is 86%.


Genetic diversity and population structure of Capitulum mitella (Linnaeus, 1767) in Fujian (China) revealed by mtDNA COI sequences.
Background: Capitulum mitella is a widely distributed and ecologically important stalked barnacle that settles extensively on rocky shores. This species contributes to the structural complexity of intertidal habitats and plays a critical role in the marine ecosystem. This study aimed to reveal the genetic diversity and population structure of C. mitella by analyzing the mitochondrial cytochrome oxidase I (COI) gene. Methods: A 683bp fragment of the COI gene was sequenced from 390 individuals sampled from six localities in Fujian, China. Results: A total of 84 distinct haplotypes were identified through the analysis of 82 polymorphic sites, resulting in an average haplotype diversity (h) of 0.660 and nucleotide diversity (π) of 0.00182. Analysis of molecular variance (AMOVA) and pairwise F ST statistics showed no significant population structure. Neutrality tests and mismatch distributions provided evidence of recent population expansion for the species. Conclusions: We suggest that the species' high dispersal ability, and ocean currents coupled with limited physical barriers in the region, contribute to its current phylogeographic structure. These findings enhance our comprehension of the genetic diversity and population structure of C. mitella, providing valuable insights for future conservation efforts.


Age-related changes in dermal collagen physical properties in human skin.
Collagen is the major structural protein in the skin. Fragmentation and disorganization of the collagen fibrils are the hallmarks of the aged human skin dermis. These age-related alterations of collagen fibrils impair skin structural integrity and make the tissue microenvironment more prone to skin disorders. As the biological function of collagen lies predominantly in its physical properties, we applied atomic force microscopy (AFM) and nanoindentation to evaluate the physical properties (surface roughness, stiffness, and hardness) of dermal collagen in young (25±5 years, N = 6) and aged (75±6 years, N = 6) healthy sun-protected hip skin. We observed that in the aged dermis, the surface of collagen fibrils was rougher, and fiber bundles were stiffer and harder, compared to young dermal collagen. Mechanistically, the age-related elevation of matrix metalloproteinase-1 (MMP-1) and advanced glycation end products (AGEs) are responsible for rougher and stiffer/harder dermal collagen, respectively. Analyzing the physical properties of dermal collagen as a function of age revealed that alterations of the physical properties of collagen fibrils changed with age (22-89 years, N = 18). We also observed that the reticular dermis is rougher and mechanically stiffer and harder compared to the papillary dermis in human skin. These data extend the current understanding of collagen beyond biological entities to include biophysical properties.


A double-blind comparative study of prophylactic antibiotic therapy in open heart surgery: penicillin G versus vancomycin.
A double-blind clinical study was carried out comparing the prophylactic effectivity of penicillin G with vancomycin in 113 adult patients undergoing open heart surgery. Eighty of these underwent valve replacement. A total of 14 of 52 penicillin-treated patients (26.9%) and 5 of 61 vancomycin-treated patients (8.2%) suffered from postoperative infection (0.005 less than p less than 0.02). Five patients in the penicillin group and none in the vancomycin group developed postoperative wound infection (0.01 less than p less than 0.02). No significant differences in blood culture and sepsis, tracheal culture and clinical respiratory tract infection, urine culture and clinical urinary tract infection, and colonization rate were found between the 2 groups. No cases of prosthetic valve endocarditis were diagnosed. Bacteriologic culture and resistance studies did not reveal significant changes concerning the resistance patterns; in particular, the emergence of a vancomycin-resistant strain of Staphylococcus albus was not seen. A decrease in the colonization rate with Staphylococcus albus from 53% in 1975 to 1977 to 34.6% and 31.1% in the penicillin and vancomycin groups, respectively, was found in the following 2 years.


Molecular Phylogeny and Dating Reveal a Terrestrial Origin in the Early Carboniferous for Ascaridoid Nematodes.
Ascaridoids are among the commonest groups of zooparasitic nematodes (roundworms) and occur in the alimentary canal of all major vertebrate groups, including humans. They have an extremely high diversity and are of major socio-economic importance. However, their evolutionary history remains poorly known. Herein, we performed a comprehensive phylogenetic analysis of the Ascaridoidea. Our results divided the Ascaridoidea into six monophyletic major clades, i.e., the Heterocheilidae, Acanthocheilidae, Anisakidae, Ascarididae, Toxocaridae, and Raphidascarididae, among which the Heterocheilidae, rather than the Acanthocheilidae, represents the sister clade to the remaining ascaridoids. The phylogeny was calibrated using an approach that involves time priors from fossils of the co-evolving hosts, and dates the common ancestor of the Ascaridoidea back to the Early Carboniferous (approximately 360.47-325.27 Ma). The divergence dates and ancestral host types indicated by our study suggest that members of the Ascaridoidea first parasitized terrestrial tetrapods, and subsequently, extended their host range to elasmobranchs and teleosts. We also propose that the fundamental terrestrial-aquatic switches of these nematodes were affected by changes in sea-level during the Triassic to the Early Cretaceous.


Transesterification of Lactic Acid Oligomers with Ethanol, a Way to Anhydrous Ethyl Lactate: A Kinetic Study.
A new method for the preparation of anhydrous ethyl ester of lactic acid was studied. The selected method is based on catalytic transesterification of lactic acid oligomers, which were prepared for this purpose by autocatalytic oligomerization of lactic acid. In this work, a kinetic model for the case of catalytic alcoholysis of oligoesters was derived assuming a first-order reaction and equimolar content of reactants in the reaction mixture. The model makes it possible to obtain the values of the reaction rate and equilibrium constants and the equilibrium alcohol concentration by regression analysis at one time. The model was verified by measuring the rate of consumption of ethanol over the time at various reaction temperatures with anhydrous FeCl₃ as the catalyst. The reaction was studied at overpressure under autogenous conditions in the temperature range of 100⁻180 °C. For the catalyst concentration of 1 mol %, the activation energy value was 64.35 kJ·mol-1. The dependence of equilibrium composition and rate constant on the temperature was obtained. The derived model is generally applicable to all first-order equilibrium reactions. The presumption is that the forward and reverse reactions are of the same order and have the same stoichiometry and equivalent amounts of reactants at the beginning of the reaction.


[Orthopedic examination techniques of the knee joint--basis for diagnosis and indications].
The work up of indication is the aim of each thorough examination. Using the example of the knee joint, we subdivide into five group of diagnosis: anterior knee pain (femoropatellar syndrome), intraarticular derangement, osteoarthritis, infectious and rheumatoid arthritis, forms of bursitis and tendinitis. Clinical signs, diagnosis and natural history are listed, which present the basis of indication.


Improved Training and Semen Collection Outcomes Using the Closed Box Chair for Macaques.
Collaborative semen collection in monkeys is a valuable tool in research, animal collection management, and conservation efforts. To obtain samples, monkeys are often restrained in open restraint chairs (ORC) with the "pole and collar" technique. While commonly used, this restraint is not tolerated by all individuals; some become anxious or aggressive towards the poles and people. In an effort to refine this procedure and improve welfare of the monkeys, we examined the use of a "closed box chair" (CBC), a clear, plexiglass box in which the monkey is trained to sit for sperm collection. The CBC does not require pole and collar, and although legs are secured, the arms and neck are not restrained. The use of CBCs has increased in recent years; however, there are few studies demonstrating its effects on scientific outcomes. We used positive reinforcement techniques to train 34 adult male rhesus macaques (Macaca mulatta) to provide semen samples using either the ORC or the CBC. While all CBC monkeys (n = 14) were reliably trained for this procedure, only 75% of ORC (n = 20) males completed the training (p = 0.04). It took significantly less time to train animals in the CBC than the ORC (201.0 vs. 412.4 min; p <0.001). In a controlled subset, males restrained with ORC (n = 7) produced a significantly lower ejaculatory volume than those collected by CBC (n = 10) (297.6 µL vs. 522.1 µL respectively; p = 0.04) and had a lower concentration of sperm (186.0 × 106/mL vs. 367.5 × 106/mL respectively; p = 0.017), although there were no differences with respect to sperm motility (p = 0.15). Our data suggest the closed box chair technique reduces stress on the animals while enhancing semen quality, supporting the use of the CBC as an important refinement.