Variations in the virulence, for pregnant guinea pigs, of campylobacters isolated from man.
Pregnant guinea pigs were used to compare the virulence of four human isolates of Campylobacter fetus ss. fetus and four of C. jejuni on the basis of their ability to cause abortion and bacteraemia. Of the four strains of C. fetus ss. fetus two produced abortion readily after intramuscular injection. The four C. jejuni isolates were, however, of comparatively low virulence and no differences between them were demonstrated. Some of the isolates differed in their ability to survive in vitro in human and guinea-pig serum. It is suggested that campylobacters vary in their virulence for man and that this may influence the outcome of infections. Guinea pigs may prove useful in studying the pathogenesis of systemic campylobacter infections.


The intrinsic value of visual information affects saccade velocities.
Let us assume that the purpose of any movement is to position our body in a more advantageous or rewarding state. For example, we might make a saccade to foveate an image because our brain assigns an intrinsic value to the information that it expects to acquire at the endpoint of that saccade. Different images might have different intrinsic values. Optimal control theory predicts that the intrinsic value that the brain assigns to targets of saccades should be reflected in the trajectory of the saccade. That is, in anticipation of foveating a highly valued image, our brain should produce a saccade with a higher velocity and shorter duration. Here, we considered four types of images: faces, objects, inverted faces, and meaningless visual noise. Indeed, we found that reflexive saccades that were made to a laser light in anticipation of viewing an image of a face had the highest velocities and shortest durations. The intrinsic value of visual information appears to have a small but significant influence on the motor commands that guide saccades.


Disposition of soy isoflavones in normal human breast tissue.
Despite decades of research on the relation between soy and breast cancer, questions regarding the absorption, metabolism, and distribution of isoflavones in breast tissue largely remain unanswered. We evaluated the potential health effects of isoflavone consumption on normal breast tissue; isoflavone concentrations, metabolites, and biodistribution were investigated and compared with 17beta-estradiol exposure. In this dietary intervention study, healthy women were randomly allocated to a soy milk (n = 11; 16.98-mg genistein and 5.40-mg daidzein aglycone equivalents per dose), soy supplement (n = 10; 5.27-mg genistein and 17.56-mg daidzein aglycone equivalents per dose), or control (n = 10) group. After a run-in period > or = 4 d, 3 doses of soy milk or soy supplements were taken daily for 5 d before an esthetic breast reduction. Blood and breast biopsies were collected during surgery and analyzed with liquid chromatography-tandem mass spectrometry. After soy administration, genistein and total daidzein concentrations, which were expressed as aglycone equivalents, ranged from 135.1 to 2831 nmol/L and 105.1 to 1397 nmol/L, respectively, in hydrolyzed serum and from 92.33 to 493.8 pmol/g and 22.15 to 770.8 pmol/g, respectively, in hydrolyzed breast tissue. The major metabolites identified in nonhydrolyzed samples were genistein-7-O-glucuronide and daidzein-7-O-glucuronide, with an overall glucuronidation of 98%. Total isoflavones showed a breast adipose/glandular tissue distribution of 40:60, and their mean (+/-SEM) derived 17beta-estradiol equivalents toward estrogen receptor beta were 21 +/- 4-fold and 40 +/- 10-fold higher than the 17beta-estradiol concentrations in adipose (0.283 +/- 0.089 pmol/g, P < 0.001) and glandular (0.246 +/- 0.091 pmol/g, P = 0.001) fractions, respectively. After intake of soy milk and soy supplements, isoflavones reach exposure levels in breast tissue at which potential health effects may occur.


Telomeres and telomerase in the fetal origins of cardiovascular disease: a review.
Telomeres are noncoding functional DNA repeat sequences at the ends of chromosomes that decrease in length by a predictable amount at each cell division. When the telomeres become critically short, the cell is no longer able to replicate and enters cellular senescence. Recent work has shown that within individuals, telomere length tracks with cardiovascular health and aging and is also affected by growth variation, both prenatally and postnatally. Therefore telomere length can be a marker of both growth history (cell division) and tissue function (senescence). Relationships between early growth and later health have emerged as a research focus in the epidemiology of chronic diseases of aging, such as heart disease and diabetes. The "fetal origins" literature has demonstrated that hormonal and nutritional aspects of the intrauterine environment not only affect fetal growth but also can permanently alter the metabolic program of the individual. Smaller infants tend to have a higher risk of developing cardiovascular disease. Much less attention has been paid to possible genetic links between the processes of early growth and later disease. Our aim in this review is to summarize evidence for one such genetic mechanism, telomere attrition, that may underlie the fetal origins of cardiovascular disease and to discuss this mechanism in light of the evolution of senescence.


Autophagy is essential to suppress cell stress and to allow BCR-Abl-mediated leukemogenesis.
Hematopoietic cells normally require cell extrinsic signals to maintain metabolism and survival. In contrast, cancer cells can express constitutively active oncogenic kinases such as BCR-Abl that promote these processes independent of extrinsic growth factors. When cells receive insufficient growth signals or when oncogenic kinases are inhibited, glucose metabolism decreases and the self-digestive process of autophagy is elevated to degrade bulk cytoplasm and organelles. Although autophagy has been proposed to provide a cell-intrinsic nutrient supply for mitochondrial oxidative metabolism and to maintain cellular homeostasis through degradation of damaged organelles or protein aggregates, its acute role in growth factor deprivation or inhibition of oncogenic kinases remains poorly understood. We therefore developed a growth factor-dependent hematopoietic cell culture model in which autophagy can be acutely disrupted through conditional Cre-mediated excision of the autophagy-essential gene Atg3. Treated cells rapidly lost their ability to perform autophagy and underwent cell cycle arrest and apoptosis. Although Atg3 was essential for optimal upregulation of mitochondrial oxidative pathways in growth factor withdrawal, this metabolic contribution of autophagy did not appear critical for cell survival, as provision of exogenous pyruvate or lipids could not completely rescue Atg3 deficiency. Instead, autophagy suppressed a stress response that otherwise led to p53 phosphorylation and upregulation of p21 and the pro-apoptotic Bcl-2 family protein Puma. Importantly, BCR-Abl-expressing cells had low basal levels of autophagy, but were highly dependent on this process, and rapidly underwent apoptosis upon disruption of autophagy through Atg3 deletion or treatment with chemical autophagy inhibitors. This dependence on autophagy extended in vivo, as Atg3 deletion also prevented BCR-Abl-mediated leukemogenesis in a cell transfer model. Together these data demonstrate a critical role for autophagy to mitigate cell stress, and that cells expressing the oncogenic kinase BCR-Abl appear particularly dependent on autophagy for cell survival and leukemogenesis.


Neuroprotective Activity of Grape Seed and Skin Extract Against Lithium Exposure Using Proteomic Research.
Lithium (Li) has raised scientific concern because it represents a serious problem threatening human health. This study aimed firstly at analyzing and potentially quantifying the impact of Li and grape seed and skin extract (GSSE) separately and, secondly, describing the possible neuroprotective activity of GSSE against Li toxicity. To this end, rats were exposed for 30 days to different Li concentrations (0, 2, and 100 mg/kg bw), to GSSE (4000 mg/kg bw), and to binary mixture of Li and GSSE. Liquid chromatography (HPLC-MS/MS) analysis used for GSSE showed that 15 phenolic compounds are present in the extract. Significant modifications of proteins were detected in the brain using proteomics research after treatment. Proteins were successfully identified by a linear ion trap-Orbitrap mass spectrometer. These proteins can be roughly related to oxidative stress, glycolysis, signaling pathway, and inflammation. Additionally, proteins involved in cell junction such as myosin, spectrin, tubulin, ERM-binding phosphoprotein, and dynein were also affected by Li exposure. Dose response was detected for most expressed proteins after Li treatment. In contrast, GSSE induced the expression and/or the stabilization of some proteins changed after Li treatment in the brain showing its neuroprotective activity. These data demonstrate that proteomic analysis is a powerful tool to provide valuable insights into mechanisms of toxicity of Li in the nervous system of Wistar rats. To our knowledge, this is the first evidence of using GSSE as neuroprotective model against Li toxicity. These findings provide impetus for future investigation on GSSE against other toxic chemicals.


Modulation of eicosanoid production due to mast cell-macrophage interaction.
The experiments discussed above demonstrate that macrophages and possibly PMN modulate and contribute to immediate hypersensitivity reactions. Antigen stimulation of sensitized mast cells in vitro in the presence of macrophages showed that the latter contribute prostaglandins and modulate the 5-lipoxygenase products. Early in the time course, 5-lipoxygenase products, including leukotrienes, were enhanced and later decreased. The decrease appeared to be due to active oxygen species and may serve as a negative feedback mechanism to maintain relative homeostasis.


Interprofessional training: Start with the youngest! A program for undergraduate healthcare students in Geneva, Switzerland.
Demography of patients and complexity in the management of multimorbid conditions has made collaborative practice a necessity for the future, also in Switzerland. Since 2012, the University of Applied Sciences (UAS) and its Healthcare School as well as the University of Geneva (UG) with its Medical Faculty have joined forces to implement a training program in collaborative practice, using simulation as one of the main learning/teaching process. The actual program consists of three sequential modules and totalizes 300 h of teaching and learning for approximately 1400-1500 students from six tracks (nutritionists, physiotherapists, midwives, nurses, technologists in medical radiology, physicians); in 2019 another hundred pharmacists will also be included. The main issues addressed by the modules are Module 1: the Swiss healthcare system and collaborative tools. Module 2: roles and responsibilities of the different health professionals, basic tools acquisition in team working (situation monitoring, mutual support, communication). Module 3: the axis of quality and safety of care through different contexts and cases. A very first evaluation of the teaching and learning and particularly on the aspects of acquisition of collaborative tools shows positive attitudes of students towards the implementation of this new training program. Furthermore, a pre-post questionnaire on teamwork aspects reveals significant modifications.


[Some aspects of the pathogenesis of trophic venous ulcers].
This paper deals with essentials of trophic venous ulcer pathogenesis, their criticism as well as with the treatment of some phenomena which should be taken into account when creating any new theory of the pathogenesis and essentials of the treatment of trophic ulcers. Basically, this concerns inflammation as a general biological reaction. Chronic venous insufficiency (CVI) changes capillary permeability. The paravasal space is invaded by red blood cells. On break down they secrete hemosiderin, protein molecules and lipid complexes. All this is denatured to form substances liable to resorption. According to the biological laws resorption may be brought about only by means of inflammatory reaction, more exactly, through its cellular phases--acute (leucocytic) and chronic (macrophagal). It is assumed that the main signal for activation of leucocytes is accumulation of the above-indicated decomposition products rather than hypertension which, in non-occlusive CVI forms, cannot be proven numerically. The basic cause of trophic ulcers lies in the permanent cellular phase of the common defence inflammatory reaction because of the presence of the non-transient injurious factor. The permanently repeated cycles of the inflammatory trio (vascular, cellular and reparative phases), being in different correlation, form in the ulcer itself an unusual system which is not governed by the regularities of wound process. Bacterial contamination and colonization of trophic ulcer occur without fail but this process bears secondary character after impairment of barrier skin function and emergence of skin defects. At the same time different processes may take place in trophic ulcer such as exudation in the form of serous and seropurulent discharge, formation of the fibrinonecrotic deposit, formation of granulation tissue, and appearance of islets of unstable epithelialization. From the conceptual viewpoint such a state can be regarded as a system marked by closed pseudochaotic activity. To start up healing, this self-reproducing system must be destroyed while ulcer must transform to a wound with the linear sequence of processes.


Complications Associated With Anesthesia Services in Endoscopic Procedures Among Patients With Cirrhosis.
Anesthesia services for endoscopic procedures have proliferated with the promise of increased comfort and safety. Cirrhosis patients are higher risk for sedation, yet limited data are available describing anesthesia complications in this population. This cross-sectional study utilized the National Anesthesia Clinical Outcomes Registry, a multicenter quality-improvement database from 2010 to 2015. Patients with cirrhosis undergoing an endoscopy were identified by International Classification of Diseases, Ninth Revision (ICD-9)/Current Procedures Terminology (CPT) codes. The outcome of interest was serious anesthesia-related complication defined as cardiovascular, respiratory, neurological, drug related, patient injury, death, or unexpected admission. A mixed-effects multivariate logistic regression model determined odds ratios (ORs) between variables and serious complications, adjusting for potential confounders. In total, 9,007 endoscopic procedures were performed among patients with cirrhosis; 92% were esophagogastroduodenoscopies. The majority (81%) were American Society of Anesthesiologists (ASA) class ≥3, and 72% had a history of hepatic encephalopathy, ascites, varices, hepatorenal syndrome, or spontaneous bacterial peritonitis identified by ICD-9/CPT codes. In total, 87 complications were reported, 33 of which were serious. Frequency of serious complications was 0.4% or 378.6 per 100,000 procedures (95% confidence interval [CI], 260.8, 531.3). The majority of serious complications were cardiovascular (21 of 33), including 15 cardiac arrests. Serious complications were significantly associated with ASA 4/5 (OR, 3.84; 95% CI, 1.09, 13.57) and general anesthesia (OR, 4.71; 95% CI, 1.20, 18.50), adjusting for age, sex, ASA class, anesthesia type, inpatient status, portal hypertension history, and variable complication reporting practices. Anesthesia complications among endoscopic procedures in cirrhosis are rare overall. Serious complications were predominantly cardiac and associated with sicker patients undergoing general anesthesia. The complexity of end-stage liver disease may warrant more intensive care during endoscopic procedures, including anesthesia monitoring.


Proactively location-based suppression elicited by statistical learning.
Recently, Wang and Theeuwes used the additional singleton task and showed that attentional capture was reduced for the location that was likely to contain a distractor [1]. It is argued that due to statistical learning, the location that was likely to contain a distractor was suppressed relative to all other locations. The current study replicated these findings and by adding a search-probe condition, we were able to determine the initial distribution of attentional resources across the visual field. Consistent with a space-based resource allocation ("biased competition") model, it was shown that the representation of a probe presented at the location that was likely to contain a distractor was suppressed relative to other locations. Critically, the suppression of this location resulted in more attention being allocated to the target location relative to a condition in which the distractor was not suppressed. This suggests that less capture by the distractor results in more attention being allocated to the target. The results are consistent with the view that the location that is likely to contain a distractor is suppressed before display onset, modulating the first feed-forward sweep of information input into the spatial priority map.


Reversing pathology in a preclinical model of Alzheimer's disease by hacking cerebrovascular neoangiogenesis with advanced cancer therapeutics.
Cognitive decline leading to dementia, accompanied by the accumulation of amyloid-beta (Aβ) in neuritic plaques together with the appearance of neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein (tau), are previously noted hallmarks of Alzheimer's disease (AD). We previously discovered hypervascularity in brain specimens from AD patients and consistent with this observation, we demonstrated that overexpression of Aβ drives cerebrovascular neoangiogenesis leading to hypervascularity and coincident tight-junction disruption and blood-brain barrier (BBB) leakiness in animal models of AD. We subsequently demonstrated that amyloid plaque burden and cerebrovascular pathogenesis subside when pro-angiogenic Aβ levels are reduced. Based on these data, we propose a paradigm of AD etiology where, as a compensatory response to impaired cerebral blood flow (CBF), Aβ triggers pathogenic cerebrovascular neoangiogenesis that underlies the conventional hallmarks of AD. Consequently, here we present evidence that repurposing anti-cancer drugs to modulate cerebrovascular neoangiogenesis, rather than directly targeting the amyloid cascade, may provide an effective treatment for AD and related vascular diseases of the brain. We explored whether the anti-cancer drug, Axitinib, a small molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR) can inhibit aberrant cerebrovascular neoangiogenic changes, reduce Aβ deposits and reverse cognitive decline in an animal model of AD. One month post-treatment with Axitinib, we employed a battery of tests to assess cognition and memory in aged Tg2576 AD mice and used molecular analysis to demonstrate reduction of amyloid plaques, BBB leakage, hypervascularity and associated disease pathology. Targeting the pro-angiogenic pathway in AD using the cancer drug, Axitinib, dramatically reduced cerebrovascular neoangiogenesis, restored BBB integrity, resolved tight-junction pathogenesis, diminishes Aβ depositions in plaques and effectively restores memory and cognitive performance in a preclinical mouse model of AD. Modulation of neoangiogenesis, in an analogous approach to those used to treat aberrant vascularization in cancer and also in the wet form of age-related macular degeneration (AMD), provides an alternative therapeutic strategy for intervention in AD that warrants clinical investigation. None.


Macromolecular crowding potently stimulates DNA supercoiling activity of Mycobacterium tuberculosis DNA gyrase.
Macromolecular crowding, manifested by high concentrations of proteins and nucleic acids in living cells, significantly influences biological processes such as enzymatic reactions. Studying these reactions in vitro, using agents such as polyetthylene glycols (PEGs) and polyvinyl alcohols (PVAs) to mimic intracellular crowding conditions, is essential due to the notable differences from enzyme behaviors observed in diluted aqueous solutions. In this article, we studied Mycobacterium tuberculosis (Mtb) DNA gyrase under macromolecular crowding conditions by incorporating PEGs and PVAs into the DNA supercoiling reactions. We discovered that high concentrations of potassium glutamate, glycine betaine, PEGs, and PVA substantially stimulated the DNA supercoiling activity of Mtb DNA gyrase. Steady-state kinetic studies showed that glycine betaine and PEG400 significantly reduced the KM of Mtb DNA gyrase and simultaneously increased the Vmax or kcat of Mtb DNA gyrase for ATP and the plasmid DNA molecule. Molecular dynamics simulation studies demonstrated that PEG molecules kept the ATP lid of DNA gyrase subunit B in a closed or semiclosed conformation, which prevented ATP molecules from leaving the ATP-binding pocket of DNA gyrase subunit B. The stimulation of the DNA supercoiling activity of Mtb DNA gyrase by these molecular crowding agents likely results from a decrease in water activity and an increase in excluded volume.


Effects of endopeptidase inhibition on the contraction-relaxation response of isolated human vaginal tissue.
INTRODUCTION.: Vasoactive peptides, such as bradykinin, C-type natriuretic peptide (CNP), vasoactive intestinal polypeptide (VIP), and endothelin 1 (ET-1), are assumed to be involved in the control of female genital vascular and nonvascular smooth muscle. Tissue levels of said peptides are controlled by the activity of endopeptidase enzymes. Theoretically, in female genital tissues, inhibiting the degradation of bradykinin, CNP, and VIP, or the conversion of Big ET-1 into ET-1 should result in an enhancement in smooth muscle relaxation and, thus, an improvement in sexual response. AIM.: Elucidate the effects of the endopeptidase inhibitor KC 12615 on the contraction/relaxation response of isolated human vaginal smooth muscle to Big ET-1, bradykinin, CNP, or VIP. METHODS.: Tissue bath experiments were carried out to ascertain the responses of human vaginal tissue challenged by ET-1 (0.1 μM) to increasing concentrations of bradykinin, CNP, and VIP (0.01 μM, 0.1 μM, and 1 μM, respectively). The effects were also evaluated following preexposure to KC 12615 (10 μM, for 20 minutes). MAIN OUTCOME MEASURES.: Measure the effects of KC 12615 on the relaxation of isolated human vaginal smooth muscle brought about by bradykinin, CNP, or VIP and the contraction mediated by Big ET-1. RESULTS.: The tension induced by ET-1 was reversed by bradykinin, CNP, or VIP (-25 ± 6.6%, -13.3 ± 2.2%, and -17.6 ± 10%, respectively). Big ET-1 induced contraction of the vaginal tissue. Preexposure of the tissue to KC 12615 increased the relaxation exerted by bradykinin, CNP, or VIP (to -39.2 ± 5.8%, -40.7 ± 7.3%, and -44.6 ± 19%, respectively). The contraction induced by Big ET-1 was attenuated in the presence of KC 12615 (to approximately 25% of the initial response). CONCLUSION.: Inhibition of endopeptidase activity can antagonize the contraction of human vaginal tissue induced by Big ET-1 and increase the relaxation induced by vasoactive endogenous peptides.


Global and site-specific detection of human integrin alpha 5 beta 1 glycosylation using tandem mass spectrometry and the StrOligo algorithm.
Glycans are oligosaccharides associated with proteins, and are known to confer specific functions and conformations on glycoproteins. As protein tridimensional structures are related to function, the study of glycans and their impact on protein folding can provide important information to the field of proteomics. The subdiscipline of glycomics (or glycoproteomics) is rapidly growing in importance as glycans in proteins have shown to be involved in protein-protein or protein-(drug, virus, antibody) interactions. Glycomics studies most often aim at identifying glycosylation sites, and thus are performed on deglycosylated proteins resulting in loss of site-specific details concerning the glycosylation. In order to obtain such details by mass spectrometry (MS), either whole glycoproteins must be digested and analyzed as mixtures of peptides and glycopeptides, or glycans must be isolated from glycopeptide fractions and analyzed as pools. This article describes parallel experiments involving both approaches, designed to take advantage of the StrOligo algorithm functionalities with the aim of characterizing glycosylation microheterogeneity on a specific site. A hybrid quadrupole-quadrupole-time-of-flight (QqTOF) instrument equipped with a matrix-assisted laser desorption/ionization (MALDI) source was used. Glycosylation of alpha 5 beta 1 subunits of human integrin was studied to test the methodology. The sample was divided in two aliquots, and glycans from the first aliquot were released enzymatically, labelled with 2-aminobenzamide, and identified using tandem mass spectrometry (MS/MS) and the StrOligo program. The other aliquot was digested with trypsin and the resulting peptides separated by reversed-phase high-performance liquid chromatography (HPLC). A specific collected fraction was then analyzed by MS before and after glycan release. These spectra allowed, by comparison, detection of a glycopeptide (several glycoforms) and elucidation of peptide sequence. Compositions of glycans present were proposed, and identification of possible glycan structures was conducted using MS/MS and StrOligo.


Reflux esophagitis. Diagnosis, pathophysiology, and management.
Reflux esophagitis is a common disorder in which esophageal inflammation is caused by the reflux of gastric contents. The diagnostic approach includes documentation that reflux is present, that the patient's symptoms are caused by the reflux, and that esophageal mucosal damage has occurred. Therapy is guided by the current multifactorial pathophysiology model, which includes efficacy of the antireflux mechanism, volume of gastric fluid, potency of refluxed material, esophageal clearance, and tissue resistance factors. Although recurrences are common, treatment with life style changes supplemented with combinations of liquid antacids, H2 blockers, sucralfate, bethanechol, and metoclopramide is usually effective.


Blood oxygen level-dependent measurement of acute intra-renal ischemia.
Ischemic nephropathy is a common cause of end-stage renal disease. Exploration of the mechanisms of deterioration of renal function is limited due to lack of noninvasive techniques available to study the single kidney. The Blood Oxygen Level-Dependent (BOLD) MRI method can measure deoxyhemoglobin and therefore indirectly estimates renal oxygen content, but has never been evaluated in renal artery stenosis (RAS). This study was therefore designed to test if BOLD can detect the characteristic of renal hypoxia induced by RAS. RAS was induced in 8 pigs using an occluder placed around the right renal artery. Renal blood flow (RBF) was measured continuously with an ultrasound probe. BOLD signal was measured bilaterally in the cortex and medulla (as the slope of the logarithm of MR signal) at baseline and at the lower limit of RBF autoregulation. The measurements were then repeated during six sequential graded decreases in RBF (80 to 0% of baseline) and during recovery. During the control period, BOLD signals were not significantly different between the right and the left kidneys. In the occluded kidney, BOLD signal of the cortex (19.3 +/- 1.9/s) and the medulla (17.3 +/- 2.0/s) increased during occlusion gradually and significantly (P < 0.0001) to a maximum (at total occlusion) of 33.8 +/- 2.0/s (+79%) and 29.8 +/- 2.3/s (+78%), respectively, and returned to baseline values during recovery. This study shows that the BOLD technique can noninvasively detect change in intra-renal oxygenation during an acute reduction of RBF. This study provides a strong rationale for developing the BOLD method for the detection and evaluation of renal hypoxia induced by RAS, which may be potentially applicable in humans.


Collection of buccal cell DNA using treated cards.
We devised a simple, noninvasive, cost-efficient technique for collecting buccal cell DNA for molecular epidemiology studies. Subjects (n = 52) brushed their oral mucosa and expectorated the fluid in their mouths, which was applied to "Guthrie" cards pretreated to retard bacterial growth and inhibit nuclease activity (IsoCode, Schleicher and Schuell, Keene, NH). The cards are well-suited for transport and storage because they dry quickly, need no processing, and are compact and lightweight. We stored the samples at room temperature for 5 days to mimic a field situation and then divided them into portions from which DNA was extracted either immediately or after storage for 9 months at room temperature, -20 degrees C, or -70 degrees C. The fresh samples had a median yield of 2.3 microg of human DNA (range, 0.2-53.8 microg), which was adequate for at least 550 PCR reactions. More than 90% of the samples were amplified in all three beta-globin gene fragment assays attempted. DNA extract frozen for 1 week at -20 degrees C also performed well. Stored samples had reduced DNA yields, which achieved statistical significance for room temperature and -70 degrees C, but not -20 degrees C, storage. However, because all of the stored samples tested were successfully amplified, the observed reduction may represent tighter DNA fixation to the card over time rather than loss of genetic material. We conclude that treated cards are an alternative to brushes/swabs and mouth rinses for the collection of buccal cell DNA and offer some advantages over these methods, particularly for large-scale or large-scale or long-term studies involving stored samples and studies in which samples are collected off-site and transported. Future studies that enable direct comparisons of the various buccal cell collection methods are needed.


[A principle of maximum topological similarity in molecular systematics].
The paper deals with the problem of phylogenetic reconstruction on the basis of comparative analysis of features. Main attention is paid to comparison and classification of the biopolymer sequences. Different approaches to this task are critically reviewed. The novel principle of construction of tree-like classification schemes permitting subsequent evolutionary analysis is proposed. It concentrates on reconstruction of the tree with a topologic structure that is most close to topologic features, imprinted in the source distance matrix. Realization of this approach was made possible by development of the special formalism, enabling evaluation and comparison of topologic features of distance matrices and trees.


Pituitary adenoma volumetry with 3D Slicer.
In this study, we present pituitary adenoma volumetry using the free and open source medical image computing platform for biomedical research: (3D) Slicer. Volumetric changes in cerebral pathologies like pituitary adenomas are a critical factor in treatment decisions by physicians and in general the volume is acquired manually. Therefore, manual slice-by-slice segmentations in magnetic resonance imaging (MRI) data, which have been obtained at regular intervals, are performed. In contrast to this manual time consuming slice-by-slice segmentation process Slicer is an alternative which can be significantly faster and less user intensive. In this contribution, we compare pure manual segmentations of ten pituitary adenomas with semi-automatic segmentations under Slicer. Thus, physicians drew the boundaries completely manually on a slice-by-slice basis and performed a Slicer-enhanced segmentation using the competitive region-growing based module of Slicer named GrowCut. Results showed that the time and user effort required for GrowCut-based segmentations were on average about thirty percent less than the pure manual segmentations. Furthermore, we calculated the Dice Similarity Coefficient (DSC) between the manual and the Slicer-based segmentations to proof that the two are comparable yielding an average DSC of 81.97±3.39%.


[Transduction of various mammalian bone marrow-derived mesenchymal stem cells by baculovirus].
The use of stem cells will lead to novel treatments for a wide range of diseases due to their properties of self-renewing, pluripotent, and undifferentiated state, and the stem cells are usually genetically modified for cell and gene therapy. If the baculovirus, as a new gene vector, can be effectively transduced into various mammalian bone marrow-derived mesenchymal stem cells (BMSCs) in vitro, it will be a better gene vector to genetically modify the stem cells. The aim of the present study is to investigate the transduction efficiency of recombinant baculovirus (BacV-CMV-EGFP), which expressed a reporter gene encoding enhanced green fluorescent protein (EGFP) under a cytomegalovirus immediate early (CMV-IE) promoter, into various mammalian BMSCs. The BMSCs of mouse, rat, porcine, rhesus, and human were cultured primarily in vitro. After more than three passages, the mammalian BMSCs were seeded into dishes and cultured in a humidified incubator at 37 °C with 5% CO(2). When the cells reached about 80% confluence, the complete medium was removed by aspiration. The cells were transduced with recombinant baculovirus at a multiplicity of infection (MOI) of 200 vector genomes/cell with 500 μL PBS at 25 °C for 4 h. At the end of baculovirus transduction, cells were washed and incubated with 2 mL complete medium, and baculovirus-transduced mammalian BMSCs were cultured in a humidified incubator for 2 d. Then, the inverted fluorescent microscope was used to observe GFP expressions in different mammalian BMSCs, and flow cytometry was used to detect the transduction efficiency of baculovirus in various mammalian BMSCs. After more than three passages, the BMSCs of mouse, rat, porcine, rhesus, and human showed a homogeneous spindle-shaped morphology. Compared with the BMSCs of mouse, rat and porcine, the inverted fluorescent microscope observations showed that there were more BMSCs expressing GFP and greater mean fluorescence intensity in rhesus and human transduced with baculovirus. The baculovirus could efficiently transduce into the BMSCs of mouse, rat, porcine, rhesus and human, and the transduction efficiency was (20.21±3.02)%, (22.51±4.48)%, (39.13±5.79)%, (71.16±5.36)% and (70.67±3.74)%, respectively. In conclusion, baculovirus displays different transduction efficiency into various mammalian BMSCs. Due to the high transduction efficiency for primate and human BMSCs, baculovirus is possibly a more suitable gene vector to genetically modify BMSCs of human and primates.


Epidural analgesia and anticoagulant therapy. Experience with one thousand cases of continuous epidurals.
One thousand lumbar epidural blocks in 950 patients undergoing vascular surgery are reported. All patients were receiving oral anticoagulants pre-operatively. Mean thrombotest (TT) was 19.3% (normal range 70-130%). During surgery intravascular heparin was administered. At the end of surgery, the kaolin cephalin clotting time (KCCT) was 68 (+/- 0.8) seconds (normal range 35-60 seconds), and partial thromboplastin time (PTT) was 536 (77.9%, normal control of 100%). Despite the anticoagulant therapy, no side effects were observed in any patient which could be related to haemorrhage or haematoma formation in the epidural space. It is concluded that, provided adequate precautions are taken, epidural analgesia can be safely used in patients receiving anticoagulant therapy.


Adreno-medullary hypertension: a review of syndromes, pathophysiology, diagnosis, and treatment.
Hypertension may be attributable to various disorders involving the central or peripheral adrenergic (catecholamine) pathways. Pheochromocytoma is the best known of these disorders, but many syndromes mimic the clinical features of this tumor. In adreno-medullary hypertension, cardiovascular tissues are stimulated by activation of alpha or beta adrenergic receptors, or both. Specific diagnosis of adreno-medullary hypertension depends on careful clinical assessment and selection of sensitive and specific biochemical tests for measuring the catecholamines and their principal metabolites in urine or plasma. If such tests indicate the presence of a chromaffin cell neoplasm, accurate localization (imaging) is provided by computed axial tomography (CAT) or magnetic resonance imaging (MRI). Adreno-medullary hypertension is effectively controlled, pharmacologically, by alpha and beta receptor antagonists, which may be given intravenously for emergencies. Excess catecholamine synthesis by pheochromocytomas can be reduced by methyltyrosine. Surgical cure of pheochromocytomas can be expected in most instances, but long-term surveillance for recurrent tumors, some of which may be malignant, is needed. Chemotherapy can reduce the tumor bulk of a malignant pheochromocytoma. Recent use of molecular biology techniques may be helpful in early detection of malignant transformation.


Components of the Reovirus Capsid Differentially Contribute to Stability.
The mammalian orthoreovirus (reovirus) outer capsid is composed of 200 μ1-σ3 heterohexamers and a maximum of 12 σ1 trimers. During cell entry, σ3 is degraded by luminal or intracellular proteases to generate the infectious subviral particle (ISVP). When ISVP formation is prevented, reovirus fails to establish a productive infection, suggesting proteolytic priming is required for entry. ISVPs are then converted to ISVP*s, which is accompanied by μ1 rearrangements. The μ1 and σ3 proteins confer resistance to inactivating agents; however, neither the impact on capsid properties nor the mechanism (or basis) of inactivation is fully understood. Here, we utilized T1L/T3D M2 and T3D/T1L S4 to investigate the determinants of reovirus stability. Both reassortants encode mismatched subunits. When μ1-σ3 were derived from different strains, virions resembled wild-type particles in structure and protease sensitivity. T1L/T3D M2 and T3D/T1L S4 ISVPs were less thermostable than wild-type ISVPs. In contrast, virions were equally susceptible to heating. Virion associated μ1 adopted an ISVP*-like conformation concurrent with inactivation; σ3 preserves infectivity by preventing μ1 rearrangements. Moreover, thermostability was enhanced by a hyperstable variant of μ1. Unlike the outer capsid, the inner capsid (core) was highly resistant to elevated temperatures. The dual layered architecture allowed for differential sensitivity to inactivating agents.IMPORTANCE Nonenveloped and enveloped viruses are exposed to the environment during transmission to a new host. Protein-protein and/or protein-lipid interactions stabilize the particle and protect the viral genome. Mammalian orthoreovirus (reovirus) is composed of two concentric, protein shells. The μ1 and σ3 proteins form the outer capsid; contacts between neighboring subunits are thought to confer resistance to inactivating agents. We further investigated the determinants of reovirus stability. The outer capsid was disrupted concurrent with the loss of infectivity; virion associated μ1 rearranged into an altered conformation. Heat sensitivity was controlled by σ3; however, particle integrity was enhanced by a single μ1 mutation. In contrast, the inner capsid (core) displayed superior resistance to heating. These findings reveal structural components that differentially contribute to reovirus stability.


[Determination of metal ions in tobacco and application of clustering analysis].
The contents of potassium, magnesium, sodium, manganese, ferrum and zinc were determined by flame spectrometry and atomic absorption spectrometry respectively. The dataset was clustered by fuzzy c-means (FCM) clustering analysis and hierarchical clustering analysis. It is shown that the results of the FCM clustering analysis are more accurate than those of the hierarchical cluster analysis, and it is with positive meaning to apply FCM clustering analysis to estimating the producing area of tobaccos.


Human-facilitated metapopulation dynamics in an emerging pest species, Cimex lectularius.
The number and demographic history of colonists can have dramatic consequences for the way in which genetic diversity is distributed and maintained in a metapopulation. The bed bug (Cimex lectularius) is a re-emerging pest species whose close association with humans has led to frequent local extinction and colonization, that is, to metapopulation dynamics. Pest control limits the lifespan of subpopulations, causing frequent local extinctions, and human-facilitated dispersal allows the colonization of empty patches. Founder events often result in drastic reductions in diversity and an increased influence of genetic drift. Coupled with restricted migration, this can lead to rapid population differentiation. We therefore predicted strong population structuring. Here, using 21 newly characterized microsatellite markers and approximate Bayesian computation (ABC), we investigate simplified versions of two classical models of metapopulation dynamics, in a coalescent framework, to estimate the number and genetic composition of founders in the common bed bug. We found very limited diversity within infestations but high degrees of structuring across the city of London, with extreme levels of genetic differentiation between infestations (FST = 0.59). ABC results suggest a common origin of all founders of a given subpopulation and that the numbers of colonists were low, implying that even a single mated female is enough to found a new infestation successfully. These patterns of colonization are close to the predictions of the propagule pool model, where all founders originate from the same parental infestation. These results show that aspects of metapopulation dynamics can be captured in simple models and provide insights that are valuable for the future targeted control of bed bug infestations.


Tobacco control practices in 25 schools of West Bengal.
Information about tobacco use prevalence, knowledge and attitude was assessed among school personnel in schools of West Bengal. Statistical analysis was done using SUDAAN and the C-sample procedure in Epi-Info. The school response rate was 100%. Current any smoking and smokeless tobacco use was reported by 30.9% and 13.1% school personnel, respectively. Current daily smoking, and smokeless tobacco use reported by 20.4%, and 5.8% school personnel respectively. Men reported significantly more for all kinds of daily tobacco use as compared to women. School tobacco control policy on three scales was reported poor (17.7-30%). However most of the school personnel felt need for such policies (82.7-93.6%). Teaching and training on tobacco was reported low (29.9%-50.4%). However most of the school personnel (79.1-93.6%) were supportive on different measures of tobacco control. Training of school personnel may provide students with essential tools to help them adopt and maintain a smoke free lifestyle.


Detection and analysis of transitional activity in manifold space.
Activity monitoring is important for assessing daily living conditions for elderly patients and those with chronic diseases. Transitions between activities can present characteristic patterns that may be indicative of quality of movement. To detect and analyze transitional activities, a manifold-based approach is proposed in this paper. The proposed method uses a recursive spectral graph-partitioning algorithm to segment transitions in activity. These segments are subsequently mapped to a reference manifold space. Categorization of transitions is performed with the corresponding features in the manifold space. The practical value of the work is demonstrated through data collected under laboratory conditions, as well as patients recovering from total knee replacement operations, demonstrating specific transitions and motion impairment compared to normal subjects.


Beneficial effects of catalase or pyruvate in a most-probable-number technique for the detection of Staphylococcus aureus.
The effects of the addition of catalase (EC 18.104.22.168) or pyruvate on the enumeration of Staphylococcus aureus in Trypticase soy broth with 10% NaCl were examined using a most-probable-number technique. Addition of catalase or pyruvate to the broth increased enumeration of all heat-stressed S. aureus strains tested. Increases were also observed with nonstressed cells. Catalase and pyruvate were similarly effective when added to Trypticase soy broth-10% NaCl in enumerating staphylococci naturally present in low-temperature-rendered ground-beef samples.


Risky single-occasion drinking amongst young people--definition, correlates, policy, and intervention: a broad overview of research findings.
Risky single-occasion drinking (RSOD) has dire consequences upon health and well-being including unplanned pregnancies, sexually transmitted diseases such as HIV/AIDS, crime, and car accidents. The prevalence of RSOD among young people is alarming. Despite this, as yet, a review of existing literature on RSOD amongst young people is lacking. This article will provide an overview of this area of research focusing on the definition of RSOD, its prevalence among young people, health and behavioural effects of RSOD, the perceived risk of RSOD among young people, and interventions to reduce RSOD in young people. In addition, recommendations are made for health educators interested in reducing the incidence of RSOD in young people.


Multimodality Imaging of Transposition of the Great Arteries.
Transposition of the great arteries (TGA) is a congenital conotruncal abnormality characterized by discordant connections between the ventricles and great arteries, with the aorta originating from the right ventricle (RV), and the pulmonary artery (PA) originating from the left ventricle (LV). The two main types of TGA are complete transposition or dextro-transposition of the great arteries (D-TGA), commonly referred to as d-loop, and congenitally corrected transposition (CCTGA), commonly referred to as l-loop or L-TGA. In D-TGA, the connections between the ventricles and atria are concordant, whereas in CCTGA they are discordant, with the left atrium connected to the RV, and the right atrium connected to the LV. D-TGA manifests during the neonatal period and can be surgically managed by atrial switch operation (AtrSO), arterial switch operation (ASO), Rastelli procedure, or Nikaidoh procedure. Arrhythmia, systemic ventricular dysfunction, baffle stenosis, and baffle leak are the common complications of AtrSO, whereas supravalvular pulmonary or branch PA stenosis, neoaortic dilatation, and coronary artery narrowing are the common complications of ASO. CCTGA may manifest late in life, even in adulthood. Surgeries for associated lesions such as tricuspid regurgitation, subpulmonic stenosis, and ventricular septal defect may be performed. A double-switch operation that includes both the atrial and arterial switch operations constitutes anatomic correction for CCTGA. Imaging plays an important role in the evaluation of TGA, both before and after surgery, for helping define the anatomy, quantify hemodynamics, and evaluate complications. Transthoracic echocardiography is the first-line imaging modality for presurgical planning in children with TGA. MRI provides comprehensive morphologic and functional information, particularly in adults after surgery. CT is performed when MRI is contraindicated or expected to generate artifacts. The authors review the imaging appearances of TGA, with a focus on pre- and postsurgical imaging. Online supplemental material is available for this article. ©RSNA, 2021.


Expression of SSX2 tumor antigen in baculovirus expression system and its application for screening of blood serum of melanoma patients.
To clone, express in baculovirus expression system and purify SSX2 tumor antigen and to use it for screening of blood serum of melanoma patients. Cloning and expression of SSX2 antigen in Bac-to-Bac baculovirus expression system as His-tag fusion protein, expression of recombinant SSX2 in insect cells with following purification by affinity chromatography on Ni-NTA agarose, ELISA of blood serum of melanoma patients (n = 29) and healthy donors (n = 27) were used. SSX2 was cloned in baculovirus expression system, expressed, purified using affinity chromatography and used in ELISA as antigen. Comparative analysis of blood serum of melanoma patients and healthy donors revealed higher level of SSX2-positivity of blood serum from the patients with cancer. SSX2 antigen expressed in baculovirus expression system can be used for serological analysis of blood serum of oncological patients.


Thermally managed eclipse Z-scan.
We report a new variation of the conventional Z-scan method to characterize the third-order optical nonlinearity of photonic materials. By exploiting the combination of the eclipse Z-scan with a thermal nonlinearity management technique, we demonstrate an improvement in sensitivity and flexibility of the method to simultaneously characterize the thermal and nonthermal nonlinearity of optical materials. The method is demonstrated by measuring the nonlinear refractive index in CS(2), SiO(2) and H(2)O, standard materials, and also in a biomaterial, the amino acid Tryptophan in water solution, using a femtosecond Ti-Sapphire laser operating at 76MHz repetition rate.


The social gradient in life expectancy: the contrary case of Okinawa in Japan.
This paper examines the social gradient theory of health and life expectancy presented by Evans and his colleagues [Evans, R.G., Barer, M.L. and Marmor, T.R. (Eds.), 1994. Why are some People Healthy and others not? The Determinants of Health of Populations. Aldine de Gruyter, New York]. They maintain that social hierarchy is the determining factor in the health of large populations largely because it promotes differences in stress or the ability to cope with stress. For example, as Japan has risen to the top ranks of the economic hierarchy of nations in the late 20th century, Japanese life expectancy improved dramatically. Evans [Evans, R.G., 1994. Introduction. In: Evans, R., Barer, M., Marmor T. (Eds.), Why are some People Healthy and others not? The Determinants of Health of Populations. Aldine de Gruyter, New York, pp. 3-26.] notes that something lies behind this rapid increase in longevity and the major change was the hierarchical position of Japan relative to the rest of the world. However, we reviewed life expectancy data within Japan and found that Okinawans traditionally rank at the top in health and life expectancy and at the bottom in socioeconomic indicators. We find that the social gradient thesis does not apply in Japan and suggest that what is more important for health are health lifestyles, especially diet and social support. More research is needed to assess the validity of the social gradient thesis if it is to be used on a cross-national basis.


COX-2/5-LOX dual acting anti-inflammatory drugs in cancer chemotherapy.
Emerging reports now indicate alterations of arachidonic acid metabolism with carcinogenesis and many COX and LOX inhibitors (used for the treatment of inflammatory diseases) are being investigated as potential anticancer drugs. Results from clinical trials seem to be encouraging but a better knowledge of the dynamic balance that shifts toward lipoxygenases (and different isoforms of LOXs) and cyclooxygenase-2 are essential to progress in the design of new drugs more specially directed on chemoprevention or chemotherapy of human cancers. So, on the basis of these results, it seemed useful to study the advantages of combination of COX inhibitor with LOX inhibitor and a next step will be the conception of dual inhibitors able to induce the anticarcinogenic and/or to inhibit the procarcinogenic enzymes responsible for polyunsaturated fatty acid metabolism. After a rapid summary of some recent reviews published on the involvement of different COX and LOX isoforms present in human cells, we will discuss on cross-talk reported between the downstream pathways which contribute to the development and progression of human cancers. This will lead us to evoke and to justify alternative strategies to develop agents that modulate multiple targets simultaneously with the aim of enhancing efficacy or improving safety relative to drugs that address only a single enzyme.


Better visual outcome associated with early vitrectomy in the management of endophthalmitis.
To examine the role of early vitrectomy in the management of endophthalmitis from all causes. Retrospective study of 290 consecutive subjects diagnosed with endophthalmitis at Auckland District Health Board between 1 January 2006 and 31 July 2019. Main outcome measure was visual acuity at 9-month follow-up and proportion of subjects with severe vision loss (≤20/200). Median age at presentation was 70.4 years and 151 subjects (52.1%) were women. Cataract surgery was the most common cause of endophthalmitis in 92 subjects (31.7%) followed by intravitreal injection in 57 (19.7%), endogenous endophthalmitis in 48 subjects (16.6%), non-surgical trauma in 42 subjects (14.5%), glaucoma surgery in 24 subjects (8.3%), vitrectomy in 22 subjects (7.6%) and corneal in 5 subjects (1.7%). Culture was positive in 136 (46.9%) with gram-positive organisms most common (76.5%). Early vitrectomy was performed in 82 subjects (28.3%). Median visual acuity at 9 months was 20/100 (IQR 20/30 to light perception), and severe vision loss occurred in 100 (43.5%). Retinal detachment occurred in 35 eyes (12.1%) and 26 eyes were enucleated. On multivariate analysis, younger age, poor presenting visual acuity and culture-positive endophthalmitis were associated with worse outcomes, and early vitrectomy was associated with better outcomes. Early vitrectomy (within 24 hours) is associated with better visual outcomes at 9 months, while younger age, poor presenting visual acuity and culture-positive endophthalmitis are associated with poorer visual acuity outcomes.


MAEA is an E3 ubiquitin ligase promoting autophagy and maintenance of haematopoietic stem cells.
Haematopoietic stem cells (HSCs) tightly regulate their quiescence, proliferation, and differentiation to generate blood cells during the entire lifetime. The mechanisms by which these critical activities are balanced are still unclear. Here, we report that Macrophage-Erythroblast Attacher (MAEA, also known as EMP), a receptor thus far only identified in erythroblastic island, is a membrane-associated E3 ubiquitin ligase subunit essential for HSC maintenance and lymphoid potential. Maea is highly expressed in HSCs and its deletion in mice severely impairs HSC quiescence and leads to a lethal myeloproliferative syndrome. Mechanistically, we have found that the surface expression of several haematopoietic cytokine receptors (e.g. MPL, FLT3) is stabilised in the absence of Maea, thereby prolonging their intracellular signalling. This is associated with impaired autophagy flux in HSCs but not in mature haematopoietic cells. Administration of receptor kinase inhibitor or autophagy-inducing compounds rescues the functional defects of Maea-deficient HSCs. Our results suggest that MAEA provides E3 ubiquitin ligase activity, guarding HSC function by restricting cytokine receptor signalling via autophagy.


Effect of flash release and pectinolytic enzyme treatments on wine polysaccharide composition.
Various treatments, including flash release and addition of pectic enzymes, have been proposed to enhance degradation of grape berry cell walls and extraction of aroma and phenolic compounds into the wines. The effect of flash release and enzyme treatment used separately or in combination on wine polysaccharide composition was studied. The flash release process increased extraction of polysaccharides originating from grape berry cell walls, that is, polysaccharides rich in arabinose and galactose (PRAGs) and type II rhamnogalacturonan (RG-II), thus yielding enriched wines. Increasing the duration of high-temperature exposure before the flash release treatment further increased extraction of polysaccharides. However, the wine obtained by pressing immediately after flash release and fermenting in the liquid phase contained lower amounts of grape polysaccharides, indicating that their extraction required skin maceration. The use of enzymes without or with flash release modified the composition and the structure of pectic polysaccharides. In particular, it induced the loss of PRAG terminal arabinose residues.


Amino acid digestibility and metabolizable energy of genetically selected soybean products.
To determine the ME and amino acid digestibility of 5 soybean meal (SBM) samples, a precision-fed rooster assay and a chick assay were conducted. The 5 samples were cold-pressed (extruded) soybean meals or solvent-extracted (defatted) soybean meal. Of the cold-pressed varieties (unheated), there was an ultra-low trypsin SBM, a low-trypsin SBM, and a heated and unheated commodity SBM. The solvent-extracted SBM was a heated commodity blend. The TME and AME values were compared between each category: cold-pressed and defatted, as well as between the 2 assays. Semipurified diets containing dextrose as the main energy source were formulated to meet the bird's nutrient requirements, with each diet containing a different SBM product. The TME rooster assay was a precision-fed rooster assay in which 5 birds per diet were fasted for 24 h, crop intubated with 35 g of the test diet containing 46.58% cold-pressed or defatted SBM, and excreta was then collected for 48 h. The total aromatic amino acids rooster assay followed the same protocol, but cecectomized birds were used. For the chick assay, 480 one-day-old chicks were fed a standard corn-SBM starter diet until 17 d of age, and on d 18, the chicks were allowed ad libitum access to the SB-dextrose diets. Excreta were collected on d 22, dried, ground, and analyzed for gross energy and CP to determine ME. The SBM samples that were genetically selected to have lower trypsin inhibitor levels and higher protein had higher ME values and increased amino acid digestibility than the commodity cold-pressed SBM samples. Genetic selection of soybeans for certain traits can have positive effects on the ME value and amino acid digestibility for roosters and chicks.


Associations of Glucometabolic Indices with Aortic Stiffness in Patients Undergoing Peritoneal Dialysis with and without Diabetes Mellitus.
Disruptions in glucose metabolism are frequently observed among patients undergoing peritoneal dialysis (PD) who utilize glucose-containing dialysis solutions. We aimed to investigate the relationship between glucometabolic indices, including fasting glucose, insulin resistance, advanced glycation end products (AGEs), PD-related glucose load, and icodextrin usage, and aortic stiffness in PD patients with and without diabetic mellitus (DM). This study involved 172 PD patients (mean age 58.3 ± 13.5 years), consisting of 110 patients without DM and 62 patients with DM. Aortic stiffness was assessed using the carotid-femoral pulse wave velocity (cfPWV). Impaired fasting glucose was defined as a fasting glucose level ≥ 100 mg/dL. Homeostatic model assessment for insulin resistance (HOMA-IR) scores, serum AGEs, dialysate glucose load, and icodextrin usage were assessed. Patients with DM exhibited the highest cfPWV (9.9 ± 1.9 m/s), followed by those with impaired fasting glucose (9.1 ± 1.4 m/s), whereas patients with normal fasting glucose had the lowest cfPWV (8.3 ± 1.3 m/s), which demonstrated a significant trend. In non-DM patients, impaired fasting glucose (β = 0.52, 95% confidence interval [CI] = 0.01-1.03, p = 0.046), high HOMA-IR (β = 0.60, 95% CI = 0.12-1.08, p = 0.015), and a high PD glucose load (β = 0.58, 95% CI = 0.08-1.08, p = 0.023) were independently associated with increased cfPWV. In contrast, none of the glucometabolic factors contributed to differences in cfPWV in DM patients. In conclusion, among PD patients without DM, impaired fasting glucose, insulin resistance, and PD glucose load were closely associated with aortic stiffness.


Comparative evaluation of methods for estimating potential human exposure to ozone: photochemical modeling and ambient monitoring.
Photochemical modeling and ambient monitoring of ground-level ozone concentrations provide two alternative/complementary methods for calculating potential population exposure estimates. A comparative evaluation of these methods was undertaken over a study area comprised of the entire state of New Jersey and neighboring parts of Delaware, Maryland, Pennsylvania, and New York. Kriging, a geostatistical interpolation technique, was used for the interpolation of hourly ozone data from 38 air quality monitoring stations operating within the study area, to derive concentration fields for the entire domain. The Urban Airshed Model (UAM-IV), a comprehensive photochemical grid-based model, was then used to calculate the same concentrations from emissions and meteorology inputs. Concentration fields, thus developed, were linked with corresponding population data to calculate potential population exposure estimates to outdoor ozone (Ep.o). The adequacy of kriging as an interpolation technique was evaluated by comparing Ep.o estimates derived via photochemical UAM modeling with those calculated by using concentrations obtained from kriging UAM-calculated values at the locations of the monitoring stations. In general, UAM was found to predict higher Ep.o compared to those derived by kriging observations. In order to test the robustness of the interpolation methodology with respect to assumptions of statistical correlation, two different semivariogram models, spherical and exponential, were used for kriging. Application of the different semivariograms yielded almost identical Ep.o patterns.


A comparison of medical drainage (needle aspiration) and surgical drainage (arthrotomy or arthroscopy) in the initial treatment of infected joints.
Acute infectious arthritis remains a clinical emergency where early diagnosis and appropriate therapy are essential to a successful outcome. The therapeutic requirements for a successful outcome include early diagnosis, appropriate antibiotics, joint mobilization and adequate drainage. The method of drainage can be medical with needle aspiration or surgical with arthroscopic or open surgical debridement. The literature review presented in this chapter supports the value of the initial use of medical therapy in the management of the acutely infected joint, with surgical drainage reserved for failure of medical management or for initial drainage of hip infections where needle aspiration is difficult.


Water protection after tympanostomy (Shepard) tubes does not decrease otorrhea incidence - retrospective cohort study.
Myringotomy for tube insertion is the most common otologic surgery. Otorrhea is a frequent complication of this procedure and, to prevent it, most surgeons strongly recommend avoiding contact with water as this is thought to adversely impact on post-operative quality of life. To understand the benefit of this recommendation. Observational study - retrospective cohort study comparing the incidence of post-operative otorrhea and its impact on patients' quality of life, in two groups of patients comprising children under 10 years of age who underwent bilateral myringotomy and tube placement for chronic otitis media with effusion between May 2011 and May 2012. One group received water protection care after surgery, the other did not. Data was collected through telephonic interview, after one year of follow up (one year after the procedure). Water exposure without protection was considered the exposure event. Incidence of otorrhea and perceived impact on quality of life were the outcome measures. Results were compared after logistic regression. We included 143 children: 116 were not exposed to water without protection and 27 were exposed. In the not exposed group 36.2% had at least one episode of otorrhea, compared to 40.0% of the exposed group. Odds ratio for otorrhea on exposed was 1.21 (95% CI 0.51-2.85, p=0.6). Negative impact on quality of life was reported by parents of 48.2% on the not exposed children, compared to 40.7% on the exposed group. This difference was not significant (p=0.5). We found that recommending water protection did not have beneficial effect on the incidence of otorrhea after myringotomy with tubes on chronic otitis media with effusion. However, such measures did not appear to have a negative impact on quality of life. This is a populational observational study with few cases (143 cases); these final statements would be better stated by a very large populational study with another large control group.


Abdominal Adiposity and Physical Inactivity Are Positively Associated with Breast Cancer: A Case-Control Study.
To examine whether breast cancer is associated with body composition and level of physical activity, considering the menstrual status. This was a case-control study with 116 women recently diagnosed with breast cancer and 226 controls. Body composition was assessed by dual-energy X-ray absorptiometry, and cardiometabolic risk was assessed by conicity index and waist-to-height ratio. The short version of the International Physical Activity Questionnaire was used to estimate the level of physical activity. All analyses were adjusted for age and BMI. The total body fat percentage, android body fat, android-gynoid ratio, and waist circumference were positively associated (p < 0.05), whereas the percentage of lean body mass (p <0.05) and the level of physical activity (p < 0.01) were inversely associated with breast cancer in premenopausal women. Among postmenopausal women, physical activity decreased the chance of developing breast cancer by 49% (95% CI = 0.29 to 0.92, p = 0.02). A low percentage of lean body mass and high abdominal adiposity in the premenopausal period increase the chances of developing breast cancer. Regular physical activity is inversely associated with breast cancer in pre- and postmenopausal women.


[The determination of the volume of circulating plasma using the indicator T-1824].
A method for measuring circulating plasma volume (CPV) by diluting T-1824 indicator is described, making allowance for the exponential pattern of labeled serum albumin elimination from the vascular bed. The method consists in double collection of blood samples after intravenous injection of the indicator, computation of the constant of its extravasation rate, and extrapolation to the zero time. Analysis of the results obtained by this method and CPV values derived from the hematocrit and circulating blood volume--(CBV) estimated with the help of Albert table (1971), as well as with CPV value derived from the hematocrit and CBV measured by impedance method in 22 patients with slight uncomplicated ventral and diaphragmal hernias has demonstrated high linear correlation coefficients, +0.77 and +0.78 (p less than 0.01), respectively.


Combination Therapy of Radiotherapy and Anti-PD-1/PD-L1 Treatment in Non-Small-cell Lung Cancer: A Mini-review.
Immune checkpoint inhibitors against programmed cell death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) are a standard pharmacologic therapy for patients with non-small-cell lung cancer (NSCLC). Substantial data have accumulated in recent years showing that radiotherapy combined with immunotherapy is more effective than monotherapy alone. Preclinical studies have shown that PD-L1 expression is upregulated on tumor cells after radiotherapy, resulting in the synergistically enhanced antitumor effect of irradiation and PD-L1 blockade. In the clinical setting, patients receiving radiotherapy before anti-PD-1 treatment have had a significantly better prognosis than those who have not undergone radiotherapy. In the present report, we reviewed previous studies of the combination of radiotherapy and anti-PD-1/PD-L1 treatment for NSCLC. In addition, we report our case of a patient whose PD-L1 expression gradually increased in brain metastases from NSCLC after repeated radiotherapy. In the perspectives portion, we focused on the questions of how to integrate radiotherapy into anti-PD-1/PD-L1 agent regimens and described several ongoing clinical trials.


Administering a Behavioral Test Battery in Rodents.
Although animal models cannot broadly represent uniquely human psychiatric or psychological syndromes such as anxiety, depression, or schizophrenia, behavioral testing in rodents can be extremely helpful to investigate specific disease aspects and symptoms. Animal behavioral test batteries allow researchers to reveal specific behavioral changes in genetically modified mice or following targeted treatments or in response to environmental interventions. Examples of types of behaviors that can be combined in a test battery include anxiety-like behavior, learning and memory, depression-relevant behavior, social interaction, and locomotor hyperactivity. Here, we describe several commonly used and relatively simple behavioral tests which can be combined in the same cohort of animals.


Enzyme Mechanism and Slow-Onset Inhibition of Plasmodium falciparum Enoyl-Acyl Carrier Protein Reductase by an Inorganic Complex.
Malaria continues to be a major cause of children's morbidity and mortality worldwide, causing nearly one million deaths annually. The human malaria parasite, Plasmodium falciparum, synthesizes fatty acids employing the Type II fatty acid biosynthesis system (FAS II), unlike humans that rely on the Type I (FAS I) pathway. The FAS II system elongates acyl fatty acid precursors of the cell membrane in Plasmodium. Enoyl reductase (ENR) enzyme is a member of the FAS II system. Here we present steady-state kinetics, pre-steady-state kinetics, and equilibrium fluorescence spectroscopy data that allowed proposal of P. falciparum ENR (PfENR) enzyme mechanism. Moreover, building on previous results, the present study also evaluates the PfENR inhibition by the pentacyano(isoniazid)ferrateII compound. This inorganic complex represents a new class of lead compounds for the development of antimalarial agents focused on the inhibition of PfENR.


Odours of cancerous mouse congeners: detection and attractiveness.
Chemical communication plays a major role in social interactions. Cancer, by inducing changes in body odours, may alter interactions between individuals. In the framework of research targeting non-invasive methods to detect early stages of cancer development, this study asked whether untrained mice could detect odour changes in cancerous congeners. If yes, were they able to detect cancer at an early developmental stage? Did it influence female preference? Did variations in volatile organic components of the odour source paralleled mice behavioural responses? We used transgenic mice strains developing or not lung cancer upon antibiotic ingestion. We sampled soiled bedding of cancerous mice (CC) and not cancerous mice (NC), at three experimental conditions: before (T0), early stage (T2) and late stage (T12) of cancer development. Habituation/generalisation and two-way preference tests were performed where soiled beddings of CC and NC mice were presented to wild-derived mice. The composition and relative concentration of volatile organic components (VOC) in the two stimuli types were analysed. Females did not show directional preference at any of the experimental conditions, suggesting that cancer did not influence their choice behaviour. Males did not discriminate between CC and NC stimuli at T0 but did so at T2 and T12, indicating that wild-derived mice could detect cancer at an early stage of development. Finally, although the VOC bouquet differed between CC and NC it did not seem to parallel the observed behavioural response suggesting that other types of odorant components might be involved in behavioural discrimination between CC and NC mice.


Functional delivery of synthetic naked siRNA to the human trabecular meshwork in perfused organ cultures.
To investigate whether naked short-interfering RNA (siRNA) molecules could be directly delivered to perfused intact human trabecular meshwork (TM) tissue, whether this siRNA could silence a trabecular meshwork preferred gene, and whether it could counteract the downstream effect of a deleterious agent (dexamethasone, DEX) by silencing its receptor. Anterior segments from post-mortem normal human donors were perfused at 3.4+/-0.3 microl/min-constant flow or 15 mmHg-constant pressure to stable baseline (outflow facility, C=0.22+/-0.19 microl/min/mmHg; n=14). Commercial siRNAs were diluted in DMEM (Dulbecco's Modified Eagle's Medium) perfusion medium and used without coupling to transfection reagents ("naked"). Perfusion of Cy3-labeled siRNA was performed at 100 nM for 48 h followed by 24 h with DMEM medium (two pairs). Perfusions of Matrix GLA protein (MGP) siRNA (100 nM; right eye [Oculus Dexter]; OD) and scramble-siRNA (control; left eye [Oculus Sinster]; OS) were performed for 48 h (two pairs). Perfusions of glucocorticoid receptor (GR)-siRNA (OD) and scramble-control (OS) were performed for 48 h and continued by adding 100 nM DEX to the perfusion media for an additional 24 h (two pairs). Frozen sections of labeled anterior segments were analyzed by confocal fluorescence microscopy. Differential expression of GR, MGP, myocilin (MYOC), cornea-derived transcript 6 (CDT6), and 18S genes was determined by reverse-transcriptase TaqMan polymerase chain reacion (RT-TaqMan PCR) on RNA extracted from dissected trabecular meshwork. Primary human trabecular meshwork cells were generated from single individuals and transfected using the nucleofector electroporator with program T-23. Levels of secreted MYOC in the effluents were analyzed by western blot. Histological evaluation of anterior segments perfused with Cy3 labeled siRNA followed by unlabeled medium showed intense fluorescence in the trabecular meshwork region. MGP gene expression was silenced in the trabecular meshwork perfused with naked MGP siRNA. MGP transcripts were reduced 94.7% +/- 0.62 (individual 3) and 93.6% +/- 0.13 (individual 4) from those present in the contralateral eye perfused with the scramble control. Pretreatment of GR siRNA followed by DEX treatment caused a reduction of the MYOC and CDT6 gene expressions when compared with eyes pretreated with scramble-control (percent silencing: 99.3% +/- 0.005 and 97.3% +/- 0.25, respectively, for individual 5 and 98.2% +/- 0.06 and 85.6% +/- 0.88, respectively, for individual 6). Western blots revealed the decrease of MYOC secreted by GR siRNA-treated cell and organ cultures. Readily available siRNA can be delivered to the intact human trabecular meshwork by intracameral perfusion. The delivered naked siRNA is functional, inhibiting not only the targeted gene but also their downstream effectors. This functional intracameral delivery might be of use to protect the trabecular meshwork from unwanted insults and could have important therapeutic applications.


Measurement of the silver ion concentration in wound fluids after implantation of silver-coated megaprostheses: correlation with the clinical outcome.
Tumor patients and patients after traumas are endangered by a reduced immune defense, and a silver coating on their megaprostheses may reduce their risks of infection. The aim of this study was to determine the silver ion concentration directly measured from the periprosthetic tissue and the influence on the clinical outcome. Silver ions were evaluated in 5 mL wound fluids two days postoperatively and in blood patients 7 and 14 days after surgery using inductively coupled plasma emission spectrometry in 18 patients who underwent total joint replacement with a silver-coated megaendoprosthesis. The concentration of silver ions averaged 0.08 parts per million. Patients who showed an increased silver concentration in the blood postoperatively presented a lower silver concentration in the wound fluids and a delayed decrease in C-reactive protein levels. There were significantly fewer reinfections and shorter hospitalization in comparison with a group that did not receive a silver-coated megaprosthesis. An increased concentration of silver in the immediate surroundings of silver-coated prostheses was demonstrated for the first time in cohorts of patients with trauma or tumors. An elevated concentration of silver ions in the direct periprosthetic tissue may have reduced the infection rate.


Patterns of cortical thickness associated with impulse control disorders in Parkinson's disease.
Previous functional neuroimaging studies in Parkinson's disease (PD) patients with impulse control disorders (ICDs) demonstrated dysfunction of the reward network, although the extent of anatomical changes is unclear. The aim of this study was to measure brain cortical thickness and subcortical volumes, and to assess their relationship with presence and severity of symptoms, in PD patients with and without ICDs. We studied 110 PD patients (N=58 with ICDs) and 33 healthy controls (all negative for ICDs) who underwent an extensive neurological, neuropsychological, and behavioral assessment as well as structural 1.5 Tesla magnetic resonance imaging (MRI). Between-group differences in brain cortical thickness and subcortical volumes, assessed with the FreeSurfer 5.1 tool, were analyzed. In patients with ICDs, we found significant cortical thinning in fronto-striatal circuitry, specifically in the right superior orbitofrontal, left rostral middle frontal, bilateral caudal middle frontal region, and corpus callosum, as well as volume reduction in the right accumbens and increase in the left amygdala. Finally, we observed a positive association relationship between severity of impulsive symptoms and left rostral middle frontal, inferior parietal, and supramarginal areas. These results support the involvement of both reward and response inhibition networks in PD patients with ICDs. Moreover, their severity is associated with alterations in brain regions linked with reward and top-down control networks. Increased understanding of the mechanisms underlying impulsive and compulsive behaviors might help improve therapeutic strategies for these important disorders.


Mechanical spectral hole burning of an entangled polymer solution in the stress-controlled domain.
Nonresonant spectral hole burning has proven to be a versatile method to characterize the dynamics of complex fluids, including polymers. Early work focused on dielectric susceptibility measurements in glass forming liquids, while recent work from our lab used mechanical viscoelastic measurements to investigate polymer melts and solutions. While the observed results were similar, the interpretations were different, with the former being interpreted by attributing the "holes" in the response as being due to dynamic heterogeneity in the system that is related to the glass or other transition, while the latter was interpreted in a way that suggested that the observed holes depend on the type of dynamics (Rouse, terminal, etc.) rather than an identifiable spatial heterogeneity. In this work, we have expanded mechanical spectral hole burning (MSHB) into the stress-controlled domain and carried out experiments in the rubbery regime of a polystyrene solution, similar to one which was tested previously with strain-controlled MSHB. The effects of pump stress amplitude, pump frequency, and waiting time were investigated. The mechanical holes in both directions (vertical and horizontal) were successfully burned, unlike the strain-controlled MSHB experiments on the same polystyrene solution, in which vertical holes were at best incomplete. The hole intensity exhibits a linear relationship with the amount of energy dissipated in the system during the large mechanical pump modification. The results suggest that the stress-controlled MSHB can be combined with strain-controlled MSHB to build a more complete framework to investigate the dynamics of polymeric materials and is consistent with the dynamic heterogeneity being related to the type of dynamics rather than to localized heating effects.


Evaluation of a psychoeducational intervention for adolescents with inflammatory bowel disease.
Inflammatory bowel disease (IBD), comprising Crohn's disease, ulcerative colitis, and indeterminate colitis, often has its onset in adolescence. The aim of this study was to evaluate whether a psychoeducational group intervention (aiming to enhance information seeking and giving about the disease, relaxation, social competence, and positive thinking) can strengthen the coping efforts of adolescents with IBD and have a positive effect on their Health-Related Quality of Life (HRQoL). Adolescent IBD patients from the Emma Children's Hospital AMC and adolescent members of the Crohn and Ulcerative Colitis Association in The Netherlands, were invited to participate in The intervention study. Using reliable and valid self-report instruments the adolescent's coping styles, feelings of competence, and HRQoL were assessed before and 6-8 months after the intervention. The parents were asked to fill in the Child Behavior Check List. Linear regression analyses were performed to test whether group participation was predictive of the outcome measures while correcting for the first measurement occasion and sex. Forty patients responded positively to invitation to the intervention. Eighteen adolescents, however, lived too far away to attend and served as a control group. Twenty-two children were enrolled and attended in groups of four to six children in six group sessions, supervised by two psychologists. The intervention seemed to have a positive effect on: coping (predictive control, P<0.01), feelings of competence (global self-worth, P<0.05 and physical appearance, P<0.01), and HRQoL (body image, P<0.05). These results give good reason to continue this intervention study with a larger population.


Isolation of the gene encoding an immunodominant membrane protein of the apple proliferation phytoplasma, and expression and characterization of the gene product.
An immunodominant membrane protein (IMP) of the apple proliferation (AP) phytoplasma was detected in preparations from AP-diseased periwinkle plants using monoclonal and polyclonal antibodies to the AP agent. Following isolation from Western blots and partial sequencing, degenerate oligonucleotides derived from the IMP sequence were used as probes to identify a DNA fragment containing the ORF encoding the IMP. Complete sequencing and subsequent analysis of the cloned DNA fragment revealed the presence of two ORFs, predicted to encode proteins with molecular masses of 25 kDa (P-318A) and 19 kDa (P-318B). Whilst database searches failed to assign a possible function to P-318A, analysis of P-318B predicted an amphiphilic membrane protein with a positively charged N-terminal portion, followed by a hydrophobic segment forming an alpha-helix, and a hydrophilic C-terminal part located outside of the cell. The amphiphilic nature of P-318B was confirmed by its solubility in Triton X-114. The gene encoding P-318B was expressed in Escherichia coli and the resulting protein was used to immunize rabbits. The antiserum obtained reacted specifically with P-318B. The same protein was also detected by an antiserum raised against antigen preparations from AP-diseased plants. The P-318B antiserum did not react with antigen preparations from plants infected with the closely related pear decline phytoplasma. However, in Southern hybridization studies, the gene encoding the IMP hybridized to genomic fragments of the pear decline and European stone fruit yellows phytoplasmas. It also showed significant sequence similarity to a gene encoding an antigenic membrane protein of the sweet potato witches' broom phytoplasma, but not to a gene encoding a major immunogenic membrane protein of an aster yellows group phytoplasma. Since it appears that most phytoplasmas possess a major immunogenic membrane protein which may have a function in pathogenesis, this work may be a basis for further studies on fundamental aspects of host-pathogen interactions. It also describes a new approach to obtain suitable immunogens to produce specific antibodies for detection and characterization of the non-culturable phytoplasmas.


[Hyperprolactinemia in chronic renal insufficiency: an interesting model of hypothalamo-hypophyseal dysfunction].
It is note that hyperprolactinemia is frequently associated to chronic renal failure (CRF). The etiopathogenesis of this endocrine disorder is not clearly understood, trying to evaluate the possible hypothalamic-pituitary cause we have evaluated the Prl levels under some pharmacological tests: TRH (200 mcg i.v.),Domperidone (DOM)(10 mg i.v.),Nomifensine (NOM)(200 mg p.o.)and Bromocriptine (BRC)(2.5 mg p.o.) in 3 groups of patients: CRF(8 cases), dysfunctional (8 cases) and tumoral (9 cases) hyperPrl. Prl plasma levels have been evaluated by RIA (kits,Biodata,Roma). In patients affected by CRF either direct (BRC) than indirect (NOM) agonist acting dopaminergic drugs failed to induce a reduction in Prl plasma levels, like to tumoral patients for NOM, and in contrast to the significant decrease after BRC (-70%) in tumoral and (-74%) in dysfunctional and NOM (-50%) observed in dysfunctional patients. CRF and dysfunctional patients showed significant response to TRH and DOM, being prolactinoma bearing patients unresponsive to these tests. These results show an hyporesponsivity of pituitary Prl secreting cells to dopaminergic control suggesting the existence of central etiopathological factor in inducing hyperprolactinemia in CRF patients.


Toward beta cell replacement for diabetes.
The discovery of insulin more than 90 years ago introduced a life-saving treatment for patients with type 1 diabetes, and since then, significant progress has been made in clinical care for all forms of diabetes. However, no method of insulin delivery matches the ability of the human pancreas to reliably and automatically maintain glucose levels within a tight range. Transplantation of human islets or of an intact pancreas can in principle cure diabetes, but this approach is generally reserved for cases with simultaneous transplantation of a kidney, where immunosuppression is already a requirement. Recent advances in cell reprogramming and beta cell differentiation now allow the generation of personalized stem cells, providing an unlimited source of beta cells for research and for developing autologous cell therapies. In this review, we will discuss the utility of stem cell-derived beta cells to investigate the mechanisms of beta cell failure in diabetes, and the challenges to develop beta cell replacement therapies. These challenges include appropriate quality controls of the cells being used, the ability to generate beta cell grafts of stable cellular composition, and in the case of type 1 diabetes, protecting implanted cells from autoimmune destruction without compromising other aspects of the immune system or the functionality of the graft. Such novel treatments will need to match or exceed the relative safety and efficacy of available care for diabetes.


Prevalence and burden of illness of migraine in managed care patients.
To determine the 3-month prevalence rate of migraine in a health maintenance organization (HMO) population, using a 2-stage screening process and neurologist exam, and to examine the burden of illness associated with both previously diagnosed and previously undiagnosed migraine in this population A migraine assessment was sent to a random sample of 1,000 HMO patients between April 1999 and January 2000. Those screening positive and a random sample of those screening negative for migraine were evaluated by neurologists using a structured diagnostic assessment. Then, those diagnosed to have migraines by the study's neurologists completed a battery of 3 questionnaires, evaluating severity, distress, and impairment Of 1,000 questionnaires sent, 753 (75.3%) were returned. The estimate of prevalence of migraine in this population ranged from 21.4% (adjusted for response bias) to 27.8% (unadjusted for selection bias). Only 48% of respondents had been previously diagnosed with migraine. The typical migraine caused moderate-to-severe distress in 69%, and 66% had definite or extreme interference in their social or occupational functioning. The average migraineur missed 7.6 hours of work due to migraine in the past 3 months. Previously undiagnosed migraine was associated with substantial impairment, with 58% of responders reporting interference with daily activities and 54% reporting moderate or greater distress. There was no significant difference between previously diagnosed and undiagnosed migraineurs on 3 outcome measures: pain, interference, or days of missed work. A higher proportion of previously diagnosed migraineurs (84%) reported moderate or greater distress compared with undiagnosed migraineurs (54%, P=0.002). Using a neurologist exam, the researchers found that the prevalence of migraine headaches was higher than previously reported. About one half of migraineurs had been previously undiagnosed. Undiagnosed migraine is associated with significant pain, distress, and dysfunction and is similar in these respects to diagnosed migraine. Increased public education and physician education on migraine are warranted.


Unexpected increases in soil carbon eventually fell in low rainfall farming systems.
Understanding the drivers of soil organic carbon (SOC) change over time and confidence to predict changes in SOC are essential to the development and long-term viability of SOC trading schemes. This study investigated temporal changes in total SOC, total nitrogen (N), and carbon (C) fractions (particulate organic carbon - POC, resistant organic carbon - ROC and humus organic carbon - HOC) over a 16-year period for four contrasting farming systems in a low rainfall environment (424 mm) at Condobolin, Australia. The farming systems were 1) conventional tillage mixed farming (CT); 2) reduced tillage mixed farming (RT); 3) continuous cropping (CC); and 4) perennial pasture (PP). The SOC dynamics were also modelled using APSIM C and N modules, to determine the accuracy of this model. Results are presented in the context of land managers participating in Australian climate change mitigation schemes. There was an increase in SOC for all farming systems over the first 12 years (total organic C, TOC% at 0-10 cm increased from 1.33% to 1.77%), which was predominately in the POC% fraction (POC% at 0-10 cm increased from 0.14% to 0.5%). Between 2012 and 2015, there was a decrease in SOC back to starting levels (TOC = 1.22% POC = 0.12% at 0-10 cm) in all systems. The PP system had higher TOC%, POC% and HOC% levels on average and higher SOC stocks to 30 cm depth at the final measurement in 2015 (PP = 30.43 t C ha-1; cropping systems = 23.71 t C ha-1), compared to the other farming systems. There was a decrease in TN% over time in all farming systems except PP. The average C:N increased from 14.1 in 1999 to 19.7 in 2012, after which time the SOC levels decreased and C:N dropped back to 15.8. The temporal change in SOC was not able to be represented by the AusFarm model. There are three important conclusions for policy development: 1) monitoring temporal changes in SOC over 12 years did not indicate long-term sequestration, required to assure "permanence" in SOC trading (i.e. 25-100 years) due to the susceptibility of POC to degradation; 2) without monitoring SOC in reference land uses (e.g. CT cropping system as a control in this experiment) it is not possible to determine the net carbon sequestration, and therefore the true climate change mitigation value; and 3) modelling SOC using AusFarm/APSIM, does not fully represent the temporal dynamics of SOC in this low rainfall environment.


Case series of Bartonella quintana blood culture-negative endocarditis in Washington, DC.
Prior studies (predominantly from Europe) have demonstrated blood culture-negative endocarditis due to Bartonella. Our objective was to describe three cases of Bartonella quintana endocarditis identified within one year at a large hospital in Washington, DC, USA. We constructed a descriptive case series from a retrospective review of medical records from April to December 2013 at an 800-bed urban hospital. All three patients (ages: 52, 55 and 57 years) were undomiciled/homeless men with a history of alcoholism. Although they had negative blood cultures, echocardiography demonstrated aortic/mitral valve perforation and regurgitation in one patient, aortic/mitral valve vegetation with mitral regurgitation in the second patient, and aortic valve vegetation with regurgitation in the third patient. The patients had positive Bartonella quintana serum immunoglobulin G (IgG) with negative immunoglobulin M (IgM). PCR on DNA extracted from cardiac valves was positive for Bartonella, and DNA sequencing of PCR amplicons identified Bartonella quintana. Patients received treatment with doxycycline/rifampin or doxycycline/gentamicin. Clinicians should consider Bartonella endocarditis as a differential diagnosis in patients who fit elements of the Duke Criteria, as well as having a history of homelessness and alcoholism.


Exposure to Stressors Facilitates Long-Term Synaptic Potentiation in the Lateral Habenula.
The lateral habenula (LHb) is a small part of the epithalamus that projects to monoamine centers in the brain. Previously, neurotransmission onto the LHb was shown to be abnormally potentiated in animal models of depression. However, synaptic plasticity in this brain area and the effect of stressor exposure on synaptic plasticity of the LHb have not been investigated. Thus, we explored whether the LHb undergoes dynamic changes in synaptic efficacy or not. First, we observed that a moderate LTP occurs in a fraction of LHb neurons obtained from naive Sprague Dawley rats. Interestingly, a single exposure to acute stressors, such as inescapable foot shock or restraint plus tail shock (RTS), significantly enhances the magnitude of LTP in the LHb. We also observed an increased number of LHb neurons expressing phosphorylated cAMP response element-binding protein (pCREB) after exposure to stressors, which may contribute to determine the threshold for LTP induction. LTP induction in the LHb resulted in an additional increase in the number of pCREB-expressing neurons in stress-exposed animals but not in naive control animals. Together, we showed that LHb neurons have heterogeneous propensity for synaptic potentiation at rest; however, a single exposure to stressors greatly facilitates LTP induction in the LHb, suggesting that fundamental alterations in synaptic plasticity in the LHb may occur in animal models of depression or post-traumatic stress disorder.SIGNIFICANCE STATEMENT Stress exposure is known to cause depression in human patients and animal models, although explanations at the cellular level remain to be elaborated. Here, we show that the lateral habenula (LHb) exhibits LTP after a pattern of brief strong stimulation. In addition, we show that stress exposure facilitates LTP in the LHb by lowering the threshold for LTP induction. We observed a selective increase in the number of neurons expressing pCREB in the LHb of animal models of depression. LTP induction results in a further increase in the density of pCREB-expressing neurons only after stress exposure. Our study provides the first evidence that animal models of depression exhibit altered synaptic plasticity of the LHb.


Rhodolith primary and carbonate production in a changing ocean: The interplay of warming and nutrients.
Rhodolith beds, like many other marine ecosystems, are affected by climate change that is causing an increase in the magnitude and frequency of extreme high temperature events (heat waves). Unfortunately, this does not represent the sole peril for these communities, as coastal urbanization in conjunction with altered precipitation patterns can increase terrestrial-derived nutrient input. In Brazil, rhodolith beds are among the most extensive coastal benthic ecosystems, but despite their vast distribution and great ecological and economic importance, studies on the productivity of these communities and the impact of changing environmental conditions are almost non-existent. This study addressed the individual and combined effects of increases in temperature and nutrient concentration on the physiological performance of two widely distributed rhodolith species, Lithothamnion crispatum and Melyvonnea erubescens. The results showed species-specific responses in net photosynthetic performance, with no response in L. crispatum, while M. erubescens responded negatively to both increase in temperature and nutrients. In contrast, calcification in both species showed a significant decline at high temperature. No interactive effects were found between temperature and nutrients, yet their combined negative effects were additive, resulting in negative daily-integrated net productivity and a large decline in daily carbonate production in both species. This has strong implications for rhodolith bed primary productivity and carbonate production, as heat waves may potentially cause a strong decline in carbonate production (ca. 50% loss), accompanied by a severe drop in primary productivity that will be even more pronounced under high-nutrient conditions. Also, the species-specific responses to changes in temperature and nutrient concentration suggest that the magnitude of impact of these factors on rhodolith bed productivity will depend on the species dominating the community and may finally result in changes in rhodolith community composition.


Diagnosis and management of relapsing pancreatitis associated with cystic neoplasms of the pancreas.
One of the most important causes of relapsing pancreatitis is a cystic neoplasm of the pancreas. These low grade malignancies may cause pancreatitis by obstructing or communicating with a pancreatic duct. Patients with relapsing pancreatitis and a focal fluid fluid collection should be investigated for the possibility of a mucinous cystic neoplasm. Cross sectional imaging can provide a diagnosis with the imaging findings of a low attenuation cystic lesion containing mural calcification (CT scanning) or a lobular T2 enhancing lesion (MRCP). Endoscopic ultrasound can provide more detailed imaging with the ability to guide fine needle aspiration of the cyst fluid. Cyst fluid analysis can provide a diagnosis of a mucinous cystic lesion with the combination of cytology (mucinous epithelium), elevated carcinoembryonic antigen (CEA), and the presence of DNA mutations. Management of these patients consists of surgical resection and monitoring in patients not able to withstand surgery.