Effect of social isolation stress on saliva BDNF in rat.
Salivary glands produce various compounds, including brain-derived neurotrophic factor (BDNF), which serve as biomarkers of stress-related disorders. Social isolation-induced stress models a form of chronic mild stress that induces neurodegenerative changes in the brain and behavioral alterations. This study employed a rat model to determine whether social isolation stress affects BDNF levels in saliva. Male Sprague-Dawley rats were randomly allocated to social isolation stress (1 animal/cage) or control (3-4 animals/cage) groups and reared for 8 weeks. The concentration of BDNF was quantified in specific brain regions, blood, and saliva using enzyme-linked immunosorbent assay (ELISA). The levels of expression of Bdnf and tyrosine kinase B (TrkB) mRNA were quantified using reverse transcriptase-polymerase chain reaction. Behavioral alterations were analyzed using the open-field and elevated plus maze assays. The BDNF concentration was lower in the hippocampus, prefrontal cortex, blood, and saliva of the stress group than in those of the controls. Trkb expression in the hippocampus and prefrontal cortex was decreased by social isolation stress. Moreover, the social isolation stress group showed behavioral deficits in both tests. In conclusion, these findings indicate that social isolation stress may reduce the expression of BDNF protein in blood and saliva, thus providing a potentially valuable biomarker for diagnosis of stress-related disorders.


Electrical pacing for short bowel syndrome.
In five dogs, the abroad two-thirds of the small intestine were removed, and a jejunocolostomy was performed to create the short bowel syndrome. Electrodes were affixed to the remaining proximal part of the small intestine for recording and to the distal part of the small intestine for stimulating. A comparison was made between 15 day periods in which feedings were followed by either four hours of retrograde electrical pacing or no pacing. Daily weight loss was less during the periods of pacing in each dog than during the periods of no pacing. Retrograde electrical pacing of the small intestine decreased weight loss in dogs with the short bowel syndrome.


Seq2Ref: a web server to facilitate functional interpretation.
The size of the protein sequence database has been exponentially increasing due to advances in genome sequencing. However, experimentally characterized proteins only constitute a small portion of the database, such that the majority of sequences have been annotated by computational approaches. Current automatic annotation pipelines inevitably introduce errors, making the annotations unreliable. Instead of such error-prone automatic annotations, functional interpretation should rely on annotations of 'reference proteins' that have been experimentally characterized or manually curated. The Seq2Ref server uses BLAST to detect proteins homologous to a query sequence and identifies the reference proteins among them. Seq2Ref then reports publications with experimental characterizations of the identified reference proteins that might be relevant to the query. Furthermore, a plurality-based rating system is developed to evaluate the homologous relationships and rank the reference proteins by their relevance to the query. The reference proteins detected by our server will lend insight into proteins of unknown function and provide extensive information to develop in-depth understanding of uncharacterized proteins. Seq2Ref is available at: http://prodata.swmed.edu/seq2ref.


Post partum haemorrhage in a teaching hospital in Nigeria: a 5-year experience.
The aim was to determine the incidence, causes and the maternal mortality associated with postpartum haemorrhage in a tertiary centre in Nigeria. Case records of all patients that had postpartum haemorrhage after vaginal delivery at Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife unit over a 5-year period (January 1st, 2002 to December 31st, 2006) were reviewed and analysed. Post-partum blood loss was calculated by estimating blood loses in graduated containers and in bed lines and gauze packs. 112 women had postpartum haemorrhage during the period under review. 76(67.86%) had primary postpartum haemorrhage and 36(32.14%) had secondary postpartum haemorrhage. The commonest cause of post partum haemorrhage was retained products of conception due mismanagement of the third stage of labour, this occurred in 88 women (78.57%) of cases. Other causes were uterine atony 12(10.71%), genital tract laceration 9(8.04%), disseminated intravascular coagulopathy 1(0.8%) puerperal sepsis 1(0.8%) and broken down episiotomy, 1(0.8%). The maternal mortality during the period was 90 out of which 6 were due to postpartum haemorrhage. Retained products of conception resulting from mismanagement of the third stage of labour is the most common cause of post partum haemorrhage in our centre.


Synaptic mechanisms that shape visual signaling at the inner retina.
The retina is a layered structure that processes information in two stages. The outer plexiform layer (OPL) comprises the first stage and is where photoreceptors, bipolar cells, and horizontal cells interact synaptically. This is the synaptic layer where ON and OFF responses to light are formed, as well as the site where receptive field center and surround organization is first thought to occur. The inner plexiform layer (IPL) is where the second stage of synaptic interactions occurs. This synaptic layer is where subsequent visual processing occurs that may contribute to the formation of transient responses, which may underlie motion and direction sensitivity. In addition, synaptic interactions in the IPL may also contribute to the classical ganglion cell receptive field properties. This chapter will focus on the synapse and network properties at the IPL that sculpt light-evoked ganglion cell responses. These include synaptic mechanisms that may shape ganglion cell responses like desensitizing glutamate receptors and transporters, which remove glutamate from the synapse. Recent work suggests that inhibitory signaling at the IPL contributes to the surround receptive field organization of ganglion cells. A component of this amacrine cell inhibitory signaling is mediated by GABAC receptors, which are found on bipolar cell axon terminals in the IPL. Pharmacological experiments show that a component of the ganglion cell surround signal is mediated by these receptors, indicating that the ganglion cell center and surround receptive field organization is not formed entirely in the outer plexiform layer, as earlier thought.


Cyclosporine A induces Epstein-Barr virus reactivation in tree shrew (Tupaia belangeri chinensis) model.
Epstein-Barr virus (EBV) usually exists as a latent infection in immunocompetent hosts but immunosuppressed individuals are at risk for developing EBV reactivation that leads to the uncontrolled proliferation of B lymphocytes. In this study, we have mimicked the immunosuppressed microenvironment in the tree shrew model of EBV infection by using cyclosporine A (CsA). The results showed that EBV-cocultured peripheral blood mononuclear cells (PBMCs) proliferated vigorously in response to CsA treatment in vitro. However, EBV susceptibility in vivo depended on the timing of CsA administration. Reactivation of EBV occurred in the latently EBV-infected tree shrews after treatment with 25 mg/kg/day CsA (EBV > CsA group), whereas tree shrews were no longer susceptible to infection if CsA was administered for five weeks before EBV injection (CsA > EBV group). RNA-seq analysis of both groups identified a further link between immunosuppression and EBV infection. KEGG pathway enrichment analysis revealed a significant enrichment of viral infection-related pathways in the EBV > CsA group, whereas tumor-related pathways were significantly enriched in the CsA > EBV group. A protein-protein interaction network was constructed using Cytoscape for the purpose of identifying hub genes that were then verified using qRT-PCR. In conclusion, the tree shrew model of EBV infection exhibits certain features of EBV infection in humans and serves as a valuable platform for exploring the underlying mechanisms of EBV infection.


Differential receptor usage by measles virus strains.
Recently, we demonstrated that infection of cells with all measles virus (MV) strains tested was inhibited by antibodies against CD46, although not all strains caused downregulation of the MV receptor CD46 from the surface of human cells. We now show that infection of cells with MV strain WTFb, a variant of wild-type isolate WTF which has been isolated and propagated on human BJAB cells, is not inhibited by antibodies against CD46. In contrast, infection of cells with the closely related strain WTFv, a Vero cell-adapted variant of WTF, is inhibited by antibodies against CD46. This observation led us to investigate the interaction of these viruses and the vaccine strain Edmonston (Edm) with CD46 and target cells. Cellular receptors with high affinity binding for WTFb are present on BJAB cells, but not on transfected CD46-expressing CHO cells. In contrast to the Edm strain, virus particles and solubilized envelope glycoproteins of WTFb have a very limited binding capacity to CD46. Furthermore, we show that recombinant soluble CD46 either does not bind, or binds very weakly, to WTFb glycoproteins expressed on the cell surface. Our findings indicate that wild-type MV strain WTFb and vaccine strain Edm use different binding sites on human cells. In addition, the results suggest that MV strains may alternatively use CD46 and an unknown molecule as receptors, and that the degree of usage of both receptors may be MV strain-specific.


An observational study on pedestrian and bicyclist violations at railroad grade crossings: Exploring the impact of geometrical and operational attributes.
In order to enhance the existing body of research regarding the prevalence of violations committed by pedestrians and bicyclists, this observational study utilized personal-specific, train-specific, operational, and behavioral data extracted from recorded videos at seven railroad grade crossings (RRGCs). A total of 7,332 pedestrians and 1,684 bicyclist crossing events were observed during 279 gate operation phases at seven study locations. First, two separate violation models (binary logit) for pedestrians and bicyclists were developed to determine the influence of personal-specific characteristics and other behavioral traits on probability of pedestrians' and bicyclists' violation. Later, the impact of various geometrical (railway track, distance between gates, distance between gate and nearest track, and road width) and operational (train vehicle unit) parameters on the factors that caused non-motorist violations was examined by developing distinctbinary logit models. The probability of pedestrians'and bicyclists' violationwas found to be significantly influenced by train characteristics (train speed and train occupancy time), gate operational attributes (warning time and gate blockage duration), and personal-specificcharacteristics (gender, age, crossing speed, and looking both side). Furthermore, geometrical attributes along with train vehicle unit were observed to have impact over various factors that significantly influenced the behavior of pedestrians and bicyclists to violate. The findings of this research provide essential information that could be applied in the initiatives of user awareness and enforcement program, emphasis on situational awareness and design of operational and geometricalelementsto significantlylimitthe effects of risky walking andbicycling behavior at RRGCs.


The Cross-Talk Between Gut Microbiota and Lungs in Common Lung Diseases.
Emerging findings indicate there is a vital cross-talk between gut microbiota and the lungs, which is known as gut-lung axis. The gut disturbances in lung diseases including allergy, asthma, chronic obstructive pulmonary disease, cystic fibrosis and lung cancer were observed by extensive studies. Investigating how gut microbiota impact other distant organs is of great interest in recent years. Although it has not been fully understood whether the disturbance is the cause or effect of lung diseases, alterations in the gut microbial species and metabolites have been linked to changes in immune responses and inflammation as well as the disease development in the lungs. In this article, we systemically review the role and mechanisms underlying the changes in the constituent of gut microbiota and metabolites in lung diseases. In particular, the roles of gut-lung axis in mediating immune responses and reshaping inflammation are highlighted. Furthermore, we discuss the potential of strategies to manipulate the gut microbiota and metabolites as the therapeutic approach for lung diseases.


Association between temporal mean arterial pressure and brachial noninvasive blood pressure during shoulder surgery in the beach chair position during general anesthesia.
Estimation of cerebral perfusion pressure during elective shoulder surgery in the beach chair position is regularly performed by noninvasive brachial blood pressure (NIBP) measurements. The relationship between brachial mean arterial pressure and estimated temporal mean arterial pressure (eTMAP) is not well established and may vary with patient positioning. Establishing a ratio between eTMAP and NIBP at varying positions may provide a more accurate estimation of cerebral perfusion using noninvasive measurements. This prospective study included 57 patients undergoing elective shoulder surgery in the beach chair position. All patients received an interscalene block and general anesthesia. After the induction of general anesthesia, values for eTMAP and NIBP were recorded at 0°, 30°, and 70° of incline. A statistically significant, strong, and direct correlation between NIBP and eTMAP was found at 0° (r = 0.909, P ≤ .001), 30° (r = 0.874, P < .001), and 70° (r = 0.819, P < .001) of incline. The mean ratios of eTMAP to NIBP at 0°, 30°, and 70° of incline were 0.939 (95% confidence interval [CI], 0.915-0.964), 0.738 (95% CI, 0.704-0.771), and 0.629 (95% CI, 0.584-0.673), respectively. There was a statistically significant decrease in the eTMAP/NIBP ratio as patient incline increased from 0° to 30° (P < .001) and from 30° to 70° (P < .001). The eTMAP-to-NIBP ratio decreases as an anesthetized patient is placed into the beach chair position. Awareness of this phenomenon is important to ensure adequate cerebral perfusion and prevent hypoxic-related injuries.


Application of TAML catalysts to remove colour from pulp and paper mill effluents.
A TAML catalyst (0.5 microM, 0.23 mg/L of effluent) combined with hydrogen peroxide (6.5 mM, 0.19 g/L of effluent) were capable of permanently removing 46% of the colour from bleach plant effluent (Eop, pine-derived) in one hour at 5,000 L effluent per day. Increasing concentrations to 2 microM catalyst (0.9 mg/L of effluent) and 22 mM peroxide (0.75 g/L of effluent), resulted in removal of 78% of the colour. In addition, 29% of the chlorinated organic material (AOX) was also removed. A laboratory investigation indicated that the oxidative process predominantly removed phenolic structures. The low aromatic content of the effluent meant that the majority of the organic material was not substantially altered during treatment. Thus chemical oxygen demand was essentially unchanged. This technology was able to remediate colour from effluents derived from both softwood (pine) and hardwood (eucalypt). Laboratory studies on catalyst life-time during effluent treatment, demonstrated that activity was maintained for a sufficient period to eliminate all the chromophore available to the active species, but that the catalyst did not survive long enough to be discharged into the receiving environment. Microtox tests showed that catalyst degradation products were not toxic to the receiving environment.


Identification and characterization of cells with cancer stem cell properties in human primary lung cancer cell lines.
Lung cancer (LC) with its different subtypes is generally known as a therapy resistant cancer with the highest morbidity rate worldwide. Therapy resistance of a tumor is thought to be related to cancer stem cells (CSCs) within the tumors. There have been indications that the lung cancer is propagated and maintained by a small population of CSCs. To study this question we established a panel of 15 primary lung cancer cell lines (PLCCLs) from 20 fresh primary tumors using a robust serum-free culture system. We subsequently focused on identification of lung CSCs by studying these cell lines derived from 4 representative lung cancer subtypes such as small cell lung cancer (SCLC), large cell carcinoma (LCC), squamous cell carcinoma (SCC) and adenocarcinoma (AC). We identified a small population of cells strongly positive for CD44 (CD44(high)) and a main population which was either weakly positive or negative for CD44 (CD44(low/-)). Co-expression of CD90 further narrowed down the putative stem cell population in PLCCLs from SCLC and LCC as spheroid-forming cells were mainly found within the CD44(high)CD90(+) sub-population. Moreover, these CD44(high)CD90(+) cells revealed mesenchymal morphology, increased expression of mesenchymal markers N-Cadherin and Vimentin, increased mRNA levels of the embryonic stem cell related genes Nanog and Oct4 and increased resistance to irradiation compared to other sub-populations studied, suggesting the CD44(high)CD90(+) population a good candidate for the lung CSCs. Both CD44(high)CD90(+) and CD44(high)CD90(-) cells in the PLCCL derived from SCC formed spheroids, whereas the CD44(low/-) cells were lacking this potential. These results indicate that CD44(high)CD90(+) sub-population may represent CSCs in SCLC and LCC, whereas in SCC lung cancer subtype, CSC potentials were found within the CD44(high) sub-population.


Is it Possible to Obtain Immunofluorescence Data in Formalin-Fixed Paraffin-Embedded Skin Samples for the Diagnosis of Pemphigus Vulgaris and Bullous Pemphigoid.
The gold-standard method for assessment of autoimmune bullous disease is direct/indirect immunofluorescence (IF) examination applied to fresh frozen tissue. Since the sensitivity of IF is greatly reduced in formalin-fixed paraffin-embedded (FFPE) tissues, IF cannot be relied upon in these samples. However, immunohistochemistry with the C4d antibody is a promising marker used as a surrogate for immune complex deposition, in nephropathology practice, and the paraffin IF method is also used as a "salvage" technique when fresh frozen tissue is not available or lacks glomeruli. We aimed to investigate whether it is possible to obtain immunofluorescence data from FFPE tissues diagnosed with bullous pemphigoid (BP) and pemphigus vulgaris (PV) and its relationship with inflammatory parameters in the skin. Eighty-nine in-house cases with both IgG and C3 positivity by routine immunofluorescence examination were included in the study. Inflammation parameters were evaluated in hematoxylin-eosin sections. Immunofluorescence study with IgG protease digestion and C4d immunohistochemistry were performed. Results of 83 biopsies were obtained by paraffin immunofluorescence with IgG. There were positive reactions in 28 (34%) of these 83 biopsies. Five of the 28 positive results belonged to BP (18%), and 23 were PV (82%). Ten positive results were on lesional skin (36%), and 18 (64%) were on non-lesional skin. In the immunohistochemical study with C4d, 84 biopsy results were obtained. There were positive reactions in 34 (40.4%) of 84 biopsies. Of the 34 positive results, 12 belonged to BP (35.3%) and 22 to PV (64.7%). Again, 22 (64.7%) of 34 positive results belonged to lesional skin, and 12 (35.3%) belonged to non-lesional skin. When both techniques were used together, 44 (54%) of 81 biopsies yielded positive results for at least one of the two studies, while in 37 (46%), both tests showed negative results. The sensitivity of both IgG and C4d was less than in the literature, especially in BP-diagnosed biopsies. Positive samples were mostly PV. In conclusion, obtaining immunofluorescence data in FFPE samples is possible and is independent of the related skin being lesional or not, however, negative results should not be relied upon.


Atherosclerosis and malignant tumours.
Aortic and coronary atherosclerosis were studied in subjects with a malignant disease and compared with those in the three atherosclerosis reference groups. In general, subjects with a malignant disease had little atherosclerosis, except for men with lung or prostatic cancer; in particular, men with lung cancer tended to have more extensive aortic atherosclerosis. Atherosclerosis was less extensive in subjects with tumours specific to females. The ratios between the different types of lesions was preserved and the change was therefore quantitative rather than qualitative. No proof of a real negative influence on atherosclerosis by malignant diseases was found but wasting could be one factor influencing the development of atherosclerosis in tumour subjects. Such subjects, except those with lung and prostatic cancer, could have been included in the low atherosclerosis group which was an index of the mean basic level of atherosclerosis in the populations studied.


Basic principles of developmental caregiving.
Providing a developmental care approach does not mean you must have all the latest positioning aids and the best technology for reducing light and noise in your nursery. Providing a developmental care approach means realizing that you are going to communicate with the baby and that the baby will communicate with you as you care for him. As you observe the baby and watch what he tells you, you can adjust your care to those messages. You will feel different about your care, and you will be enriched beyond your expectations.


Effect of endotoxin on the hypothalamic-pituitary-adrenal axis in sheep.
Endotoxin has been shown to stimulate ACTH and cortisol secretion through an action at the hypothalamic level. However, the nature of hypothalamic neurohormones, corticotropin-releasing hormone (CRH) and especially arginine vasopressin (AVP), involved in that regulation is still controversial. The purpose of this study was to determine the effects of an acute i.v. endotoxin administration on CRH and AVP secretion into hypophysial portal blood (HPB). The experiment has been performed in sheep since it is possible to collect HPB and quantify CRH and AVP secretion in this animal under physiological conditions. The release of both peptides into HPB was stimulated by endotoxin injection, the increase in portal AVP being more pronounced than that of CRH. An initial, transient, increase in jugular AVP concentrations was observed, probably due to the activation of magnocellular AVP neurons. In conclusion, our data indicate that the activation of the pituitary-adrenal axis after endotoxin injection is associated with an increased release of both CRH and AVP into HPB. Magnocellular AVP neurons are initially stimulated while parvocellular CRH and AVP neurons are stimulated throughout the experiment.


The Mediterranean diet contributes to the preservation of left ventricular systolic function and to the long-term favorable prognosis of patients who have had an acute coronary event.
The effect of the cardioprotective Mediterranean diet on the development of cardiac abnormalities and prognosis of cardiac patients has rarely been investigated. We sought to evaluate the relation between the Mediterranean diet, the development of left ventricular systolic dysfunction (LVSD) at hospitalization, and the 2-y prognosis of patients who have had an acute coronary syndrome (ACS). During 2006-2009, 1000 consecutive patients with ACS were enrolled; of these patients, 459 had LVSD (ejection fraction <40%) at hospitalization [367 men with a mean (+/-SD) age of 64 +/- 14 y, and 92 women aged 71 +/- 12 y], whereas 541 had preserved left ventricular systolic function (421 men aged 62 +/- 12 y, and 120 women aged 67 +/- 12 y). Adherence to the Mediterranean diet was assessed by the validated Mediterranean Diet Score (MedDietScore; theoretical range: 0-55). The MedDietScore was associated with less likelihood of developing LVSD at hospitalization [odds ratio (OR) per 1/55 unit: 0.93; 95% CI: 0.88, 0.99; P = 0.04], less likelihood of remodeling (ie, ejection fraction <50% at 3 mo follow-up; OR: 0.90; 95% CI: 0.78, 1.03: P = 0.06), and less likelihood of recurrent cardiovascular disease events during the 2 y of follow-up (OR: 0.88; 95% CI: 0.80, 0.98; P = 0.04), after adjustment for various confounders. Greater adherence to the Mediterranean diet seems to preserve left ventricular systolic function and is associated with better long-term prognosis of patients who have had an ACS.


Creatine kinase-MB isoenzyme adaptations in stressed human skeletal muscle of marathon runners.
The creatine kinase (CK) isoenzyme composition was determined in serial gastrocnemius muscle biopsies obtained from 12 male marathon runners. The mean muscle CK-MB composition significantly increased after chronic exercise (training) from 5.3% (pretraining) to 7.7% (premarathon) as well as after acute exercise (postmarathon) to 10.5% of the total CK activity (P less than 0.05). However, no significant differences in total CK activities were detected. Additionally, mitochondrial CK and CK-BB isoenzymes were present in muscle homogenates. A significant correlation was observed in the increase in mean serum total CK (3,322 U/l) and CK-MB (174 U/l) activities 24 h after the race (r = 0.98, P less than 0.05). These results show that gastrocnemius muscle adapts to long-distance training and racing with increased CK-MB activities and imply that skeletal muscle is the major source of elevated serum CK-MB activities in marathon runners.


Cyclic nucleotide phosphodiesterases: important signaling modulators and therapeutic targets.
By catalyzing hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), cyclic nucleotide phosphodiesterases are critical regulators of their intracellular concentrations and their biological effects. As these intracellular second messengers control many cellular homeostatic processes, dysregulation of their signals and signaling pathways initiate or modulate pathophysiological pathways related to various disease states, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication, chronic obstructive pulmonary disease, and psoriasis. Alterations in expression of PDEs and PDE-gene mutations (especially mutations in PDE6, PDE8B, PDE11A, and PDE4) have been implicated in various diseases and cancer pathologies. PDEs also play important role in formation and function of multimolecular signaling/regulatory complexes, called signalosomes. At specific intracellular locations, individual PDEs, together with pathway-specific signaling molecules, regulators, and effectors, are incorporated into specific signalosomes, where they facilitate and regulate compartmentalization of cyclic nucleotide signaling pathways and specific cellular functions. Currently, only a limited number of PDE inhibitors (PDE3, PDE4, PDE5 inhibitors) are used in clinical practice. Future paths to novel drug discovery include the crystal structure-based design approach, which has resulted in generation of more effective family-selective inhibitors, as well as burgeoning development of strategies to alter compartmentalized cyclic nucleotide signaling pathways by selectively targeting individual PDEs and their signalosome partners.


Second moment method for evaluating human health risks from groundwater contaminated by trichloroethylene.
Pollutants in groundwater aquifers may constitute a significant human health risk. A large variation in response may result among human populations experiencing the same level and duration of exposure to pollutants. Variability in response, as a result of exposure to a carcinogenic contaminant such as trichloroethylene (TCE), can be represented by a distribution function of safe doses. Spatial variability in aquifer characteristics and contaminant transport parameters requires the use of stochastic transport models to quantify variability in exposure concentrations. A second moment method is used to evaluate the probability of exceeding safe dose levels for a contaminated aquifer. The name of this method stems from the fact that the formulation is based on the first and second moments of the random variables. With this method, the probability is a function of the variability of contaminant concentration (which incorporates variability in hydrogeologic parameters such as hydraulic conductivity) and the variability in response in the human population. In this manner, the severity of the health risk posed by a contaminated aquifer and the evaluation of appropriate strategies and technologies for aquifer remediation are a function of contaminant concentrations and human health risks. The applicability and limitations of this method are demonstrated with data on groundwater contaminated by TCE at Hill Air Force Base, Utah.


Sickle cell anemia: an i.v. nursing challenge.
Patients with sickle cell anemia present a true challenge to an I.V. nurse's skill, but what is the reason for their difficult venous access? Is it the disease, its treatment, or both? The author will attempt to arrive at an answer to this perplexing situation. A review of the disease itself, the genetics involved, the pathophysiology, treatment modalities in the most frequently seen manifestations, and some possible answers to the problem are addressed.


Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte-Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn's Disease.
Granulocyte-macrophage colony-stimulating factor auto-antibodies (GMAbs) suppress neutrophil-extrinsic GM-CSF signaling and increase risk for stricturing behavior in Crohn's disease (CD). We aimed to define clinical, genomic, and functional associations with neutrophil-intrinsic GM-CSF signaling. Missense mutations in CSF2RA, CSF2RB, JAK2, STAT5A, and STAT5B were identified using whole-exome sequencing in 543 pediatric inflammatory bowel disease (IBD) patients. Neutrophil-intrinsic GM-CSF signaling was defined using the GM-CSF-induced STAT5 stimulation index (GMSI) in 180 pediatric IBD patients and 26 non-IBD controls. Reduced GM-CSF signaling (GMSI-Lo) was defined as the 20th percentile within the control group. Variation in neutrophil phospho-protein abundance, bacterial killing, and the global pattern of gene expression with the GMSI was determined. We validated 18 potentially damaging missense mutations in CSF2RA and CSF2RB. CSF2RA A17G carriage increased from 10% in those with intact neutrophil GMSI to 32% in those with low GMSI (P = 0.02). The frequency of reduced Staphylococcus aureus killing increased from 17% in those with intact neutrophil GMSI to 35% in GMSI-Lo neutrophils (P = 0.043). Crohn's disease neutrophils with low GMSI exhibited specific alterations in phospho-protein networks and genes regulating cytokine production, wound healing, and cell survival and proliferation. Stricturing behavior increased from 7% in patients with both low GMAb and intact GMSI to 64% in patients with both elevated GMAb and low GMSI (P < 0.0001). Low/normal neutrophil-intrinsic GM-CSF signaling is associated with CSF2RA missense mutations, alterations in gene expression networks, and higher rates of disease complications in pediatric CD.


BarleyVarDB: a database of barley genomic variation.
Barley (Hordeum vulgare L.) is one of the first domesticated grain crops and represents the fourth most important cereal source for human and animal consumption. BarleyVarDB is a database of barley genomic variation. It can be publicly accessible through the website at http://220.127.116.11/BarleyVar. This database mainly provides three sets of information. First, there are 57 754 224 single nuclear polymorphisms (SNPs) and 3 600 663 insertions or deletions (InDels) included in BarleyVarDB, which were identified from high-coverage whole genome sequencing of 21 barley germplasm, including 8 wild barley accessions from 3 barley evolutionary original centers and 13 barley landraces from different continents. Second, it uses the latest barley genome reference and its annotation information publicly accessible, which has been achieved by the International Barley Genome Sequencing Consortium (IBSC). Third, 522 212 whole genome-wide microsatellites/simple sequence repeats (SSRs) were also included in this database, which were identified in the reference barley pseudo-molecular genome sequence. Additionally, several useful web-based applications are provided including JBrowse, BLAST and Primer3. Users can design PCR primers to asses polymorphic variants deposited in this database and use a user-friendly interface for accessing the barley reference genome. We envisage that the BarleyVarDB will benefit the barley genetic research community by providing access to all publicly available barley genomic variation information and barley reference genome as well as providing them with an ultra-high density of SNP and InDel markers for molecular breeding and identification of functional genes with important agronomic traits in barley. Database URL: http://188.8.131.52/BarleyVar.


Artificial nutrition after major abdominal surgery: impact of route of administration and composition of the diet.
To evaluate the impact of the route of administration of artificial nutrition and the composition of the diet on outcome. Prospective, randomized, clinical trial. Department of surgery, university hospital. One hundred sixty-six consecutive patients undergoing curative surgery for gastric or pancreatic cancer. At operation, the patients were randomized into three groups to receive: a) a standard enteral formula (control group; n = 55); b) the same enteral formula enriched with arginine, RNA, and omega-3 fatty acids (enriched group; n = 55); and c) total parenteral nutrition (TPN group; n = 56). The three regimens were isocaloric and isonitrogenous. Enteral nutrition was started within 12 hrs following surgery. The infusion rate was progressively increased to reach the nutritional goal (25 kcal/kg/day) on postoperative day 4. Tolerance of enteral feeding, rate and severity of postoperative complications, and length of hospital stay were recorded. Early enteral infusion was well tolerated. Side effects were recorded in 22.7% of the patients, but only 6.3% did not reach the nutritional goal. The enriched group had a lower severity of infection than the parenteral group (4.0 vs. 8.6; p < .05). In subgroups of malnourished (n = 78) and homologous transfused patients (n = 42), the administration of the enriched formula significantly reduced both severity of infection and length of stay compared with the parenteral group (p < .05). Moreover, in transfused patients, the rate of septic complications was 20.0% in the enriched group, 38.4% in the control group, and 42.8% in the TPN group. Early enteral feeding is a suitable alternative to TPN after major abdominal surgery. The use of the enriched diet appears to be more beneficial in malnourished and transfused patients.


Type 2 Diabetes Mellitus is Associated with Carotid Artery Plaques in Patients with Premature Coronary Heart Disease.
In subjects without a history of coronary heart disease (CHD), type 2 diabetes mellitus (T2DM) is associated with carotid artery plaques (CAP), which is a better marker than high carotid intima-media thickness (hCIMT) for predicting first or recurrent cardiovascular events. The objective of this study is to analyze the association of T2DM with CAP and hCIMT in premature CHD patients. Premature CHD was considered before the age of 55 years in men and before 65 in women. T2DM was defined according to the American Diabetes Association criteria. CAP was defined as a focal structure encroaching the arterial lumen by at least 50% of the surrounding IMT value or with a thickness > 1.5 mm. Among 1196 patients (CHD duration 1.5 years [interquartile range: 0.4-5.6]), 37.2% had T2DM, and 97.8% were on antihypertensive, 94.4% on lipid-lowering, and 97.3% on anti-aggregate treatment. hCIMT prevalence was similar in patients with or without T2DM, whereas CAP prevalence was higher among T2DM patients (17.7% vs. 30.9%; p < 0.001). T2DM showed association with CAP, independently of CHD evolution and glycemic control (odds ratio: 1.57; 95% confidence interval: 1.09-2.26). T2DM has an independent association with CAP. Early detection of recurrent cardiovascular events, with CAP identification, could be useful to prevent complications in patients with CHD.


Functional crosstalk between exon enhancers, polypyrimidine tracts and branchpoint sequences.
We recently identified enhancer elements that activate the weak 3' splice site of alpha-tropomyosin exon 2 as well as a variety of heterologous weak 3' splice sites. To understand their mechanism of action, we devised an iterative selection strategy to identify functional pyrimidine tracts and branchpoint sequences in the presence or absence of enhancer elements. Surprisingly, we found that strong pyrimidine tracts were selected regardless of the presence of enhancer elements. However, the presence of enhancer elements resulted in the selection of multiple, non-consensus branchpoint sequences. Thus, enhancer elements apparently activate weak 3' splice sites primarily by increasing the efficiency of splicing of introns containing branchpoint sequences with less than optimal U2-branchpoint pairing arrangements. Comparison of consensus sequences from both our selection strategy and compilations of published intron sequences suggests that exon enhancer elements could be widespread and play an important role in the selection of 3' splice sites.


Mental Health Literacy Affects Mental Health Attitude: Is There a Gender Difference?
Objectives: In the current study, we aimed to compare the levels of and factors associated with mental health attitude between males and females. Of particular interest was ascertaining the degree to which mental health literacy was related to mental health attitude and whether this relationship would vary by gender. Methods: A total of 732 participants aged 18 years or more were recruited from attendees at the 2016 Minnesota State Fair. We used the Mental Health Literacy Scale (MHLS) to measure attitude toward and literacy of mental health. Results: Our multivariate analysis reported that males' mental health attitude was significantly lower than females. Some factors associated with mental health attitude differed by gender as well. Among men, receiving more social support, experiencing higher levels of depression, and being married predicted greater mental health attitude. Among women, older age was associated with lower mental health attitude levels. However, mental health literacy was the strongest factor regardless of gender. Men and women with greater mental health literacy had a more positive mental health attitude. Conclusions: Provision of tailored mental health literacy education both for males and females could potentially improve the public's mental health attitude toward mental illness.


A 5-yr change in Norwegian 9-yr-olds' objectively assessed physical activity level.
To describe changes in objectively assessed physical activity by socioeconomic status (SES) between 1999-2000 and 2005 in 9-yr-old children living in Oslo, Norway. Two cross-sectional studies were conducted in 1999-2000 and 2005. The participation rate was 70.9% in 1999-2000 and 91.4% in 2005. Participants were identified by SES based on whether the school they attended was in an area designated as high, middle, or low mean income. Physical activity was assessed objectively by accelerometers. A total of 718 children (1999-2000, n = 340; 2005, n = 378) provided valid physical activity assessments that met all inclusion criteria. General linear models were used to assess the changes in physical activity between 1999-2000 and 2005. A significant increase in mean physical activity level and physical activity during weekends was observed between the two study periods (P = 0.02 and <0.001, respectively), with the patterns being similar for girls and boys. Interactions were found between change in physical activity and SES. Although the mean physical activity level and moderate-to-vigorous physical activity (MVPA) among children from low-SES groups showed no change over time, an increase was seen among children from middle-SES groups. Moreover, in high-SES groups, an increase was observed for mean physical activity level (girls only) between study periods, whereas no change was seen for MVPA participation. Nine-year-old children living in Oslo, Norway, have increased both their mean and weekend physical activity level between 1999-2000 and 2005. However, because these opportunities are not equal across SES groups, interventions are required to focus on the needs of children from low-SES groups.


A common frameshift mutation and other variants in GJB4 (connexin 30.3): Analysis of hearing impairment families.
Mutations in GJB1, GJB2, GJB3 and GJB6 are involved in hearing impairment. GJB2, GJB3 and GJB6 are also mutated in patients with hyperproliferative skin disorders. The human GJB4 gene has been deduced in silico and a mutation in a family with erythrokeratodermia variabilis has been reported. We describe here the analysis of the GJB4 gene in hearing impairment patients and control subjects. We have identified a common (4%) frameshift mutation (154del4) in GJB4 in both affected and hearing subjects, one patient being homozygous for the mutation. We have also detected five amino acid variants (R103C, R124Q, R160C, C169W and E204A) in individuals that have not skin disorders. While mutation 154del4 is not associated with hearing impairment the involvement of some of the amino acid variants detected here is uncertain. These GJB4 variants should help to define the putative role of connexin 30.3 in both skin disorders and hearing impairment.


Tai Chi as a Body-Mind Exercise for Promotion of Healthy Aging in Nursing Home Residents: Appropriateness, Feasibility, and Effectiveness.
The lack of activity, opportunity for providing input and participation in activities, and interaction with other people are the features of institutional living which reinforces dependency among nursing home residents. Residents are usually frustrated with paternalistic-type care. Arranging health-oriented meaningful activities for residents contributes to health promotion and enhancement of healthy aging. Moreover, it contributes to the cultivation of a positive meaning of life which is particularly important as residents reach the late geriatric stages of their lives. With exercise being seen as generally beneficial for health, Tai Chi as a Chinese-based exercise with a body-mind emphasis and unique characteristics becomes a particularly suitable exercise in aiding the residents in this major shift of lifestyle. This paper analyzes the appropriateness, feasibility, and effectiveness of Tai Chi in promoting healthy aging for residents. Theoretical considerations and scientific evaluations lend it appropriate, feasible, and effective in providing physiological and psychosocial health benefits to the residents. This paper recommends the use of Tai Chi to promote healthy aging in nursing home residents. With a rapidly aging population and mounting demand for residential geriatric care worldwide, this paper's timely findings should provide important implications for adopting Tai Chi to advance the quality of care delivered by nursing homes worldwide.


Murine susceptibility to two-stage skin carcinogenesis is influenced by the agent used for promotion.
Several approaches were employed to investigate whether murine stock and strain differences in susceptibility to two-stage skin carcinogenesis are due to differences in the metabolism of the initiating aromatic hydrocarbons, or the consequences of the agents used for promotion. A cell-mediated mutagenesis assay was used to quantitatively compare the abilities of cultured newborn SENCAR, DBA/2, C57BL/6 and BALB/c keratinocytes to metabolize dimethylbenz[a]anthracene (DMBA) to mutagenic and cytotoxic metabolites. At equivalent concentrations of DMBA, throughout a 25-fold range in promutagen concentration, C57BL/6, BALB/c and SENCAR keratinocyte-dependent mutant frequencies were very similar and approximately twice DBA/2 keratinocyte-dependent mutant frequencies. In in vivo tumor studies, C57BL/6 mice were more sensitive than SENCAR mice to complete skin carcinogenesis protocols employing repetitive weekly treatments with DMBA and benzo[a]pyrene (BP). At equivalent concentrations of either DMBA or BP, C57BL/6 mice developed carcinomas sooner, and had a greater number of carcinomas per animal. SENCAR mice were very sensitive to two-stage skin carcinogenesis protocols employing BP and DMBA as initiators and benzoyl peroxide and 12-O-tetradecanoylphorbol-13-acetate (TPA) as promoters. C57BL/6 mice were relatively refractory to TPA promotion but sensitive to promotion with benzoyl peroxide. These findings suggest that murine stock and strain-dependent differences in sensitivity to two-stage skin carcinogenesis may not be due to major differences in the metabolism of the initiating hydrocarbons, but are partially the consequences of the agents used for promotion.


[Study of the contractile function of the myocardium with the aid of echocardiography].
The problems of studying the contractile function of the myocardium were investigated in patients with acquired heart diseases and varying stages of circulation insufficiency. Echocardiography was used to examine 92 patients, aged 17 to 38 years. The results of the examination permitted to obtain a clear understanding of the degree of changes in the myocardium contractile function. The most valuable parameters of echocardiogrammes which permit to record the early signs of cardiac insufficiency include the myocardium excursions rate, the ejection fraction, the contraction rate of the circular fibers of the myocardium, the percentage of shortening the anterior-posterior dimensions of the left ventricle.


Reduced risk of heart failure with intensified multifactorial intervention in individuals with type 2 diabetes and microalbuminuria: 21 years of follow-up in the randomised Steno-2 study.
In type 2 diabetes mellitus, heart failure is a frequent, potentially fatal and often forgotten complication. Glucose-lowering agents and adjuvant therapies modify the risk of heart failure. We recently reported that 7.8 years of intensified compared with conventional multifactorial intervention in individuals with type 2 diabetes and microalbuminuria in the Steno-2 study reduced the risk of cardiovascular disease and prolonged life over 21.2 years of follow-up. In this post hoc analysis, we examine the impact of intensified multifactorial intervention on the risk of hospitalisation for heart failure. One hundred and sixty individuals were randomised to conventional or intensified multifactorial intervention, using sealed envelopes. The trial was conducted using the Prospective, Randomised, Open, Blinded Endpoints (PROBE) design. After 7.8 years, all individuals were offered intensified therapy and the study continued as an observational follow-up study for an additional 13.4 years. Heart-failure hospitalisations were adjudicated from patient records by an external expert committee blinded for treatment allocation. Event rates were compared using a Cox regression model adjusted for age and sex. Eighty patients were assigned to each treatment group. Ten patients undergoing intensive therapy vs 24 undergoing conventional therapy were hospitalised for heart failure during follow-up. The HR (95% CI) was 0.30 (0.14, 0.64), p = 0.002 in the intensive-therapy group compared with the conventional-therapy group. Including death in the endpoint did not lead to an alternate overall outcome; HR 0.51 (0.34, 0.76), p = 0.001. In a pooled cohort analysis, an increase in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) during the first two years of the trial was associated with incident heart failure. Intensified, multifactorial intervention for 7.8 years in type 2 diabetic individuals with microalbuminuria reduced the risk of hospitalisation for heart failure by 70% during a total of 21.2 years of observation. ClinicalTrials.gov NCT00320008.


Clinical relevance of brain volume measures in multiple sclerosis.
Multiple sclerosis (MS) is a chronic disease with an inflammatory and neurodegenerative pathology. Axonal loss and neurodegeneration occurs early in the disease course and may lead to irreversible neurological impairment. Changes in brain volume, observed from the earliest stage of MS and proceeding throughout the disease course, may be an accurate measure of neurodegeneration and tissue damage. There are a number of magnetic resonance imaging-based methods for determining global or regional brain volume, including cross-sectional (e.g. brain parenchymal fraction) and longitudinal techniques (e.g. SIENA [Structural Image Evaluation using Normalization of Atrophy]). Although these methods are sensitive and reproducible, caution must be exercised when interpreting brain volume data, as numerous factors (e.g. pseudoatrophy) may have a confounding effect on measurements, especially in a disease with complex pathological substrates such as MS. Brain volume loss has been correlated with disability progression and cognitive impairment in MS, with the loss of grey matter volume more closely correlated with clinical measures than loss of white matter volume. Preventing brain volume loss may therefore have important clinical implications affecting treatment decisions, with several clinical trials now demonstrating an effect of disease-modifying treatments (DMTs) on reducing brain volume loss. In clinical practice, it may therefore be important to consider the potential impact of a therapy on reducing the rate of brain volume loss. This article reviews the measurement of brain volume in clinical trials and practice, the effect of DMTs on brain volume change across trials and the clinical relevance of brain volume loss in MS.


Isolation and antimicrobial susceptibility of Brachy -spira species from feces of layer chickens in Germany.
Anaerobic spirochetes of the genus Brachyspira are important pathogens causing swine dysentery (Brachyspira [B.] hyodysenteriae) and porcine intestinal spirochetosis (B. pilosicoli, PIS). In addition, avian intestinal spirochetosis (AIS) is caused by B. pilosicoli, B. intermedia and B. alvinipulli. Despite the economic impact of AIS, the disease has not received appropriate attention in Germany. This study was aimed at identifying Brachyspira spp. in Germany and determining their antimicrobial susceptibility. From 2009 to 2013, a total of 71 fecal swabs were obtained from clinically healthy layer hens from eight different commercial flocks. Brachyspira spp. culture was performed in trypticase soybean agar added with 5% sheep blood. Species determination was conducted by PCRs targeting the NADH-gen and the 16S rDNA or by nox-gene sequencing. Antimicrobial susceptibility to macrolides, lincosamides and pleuromutilins was tested by a microdilution assay. Brachyspira spp. were isolated from 40 (56.3%) swabs distributed over all eight flocks. In 26 cases, the following species were determined by PCR: B. pilosicoli (n = 16), B. intermedia (2), B. innocens (3), B. murdochii (1), mixtures of B. pilosicoli/B. intermedia (2), B. innocens/B. intermedia (1), B. innocens/B. murdochii (1). Remaining isolates were characterized by noxgene sequencing as B. "pulli" (n = 9), B. alvinipulli (3), B. intermedia (1) and as not identifiable (1). Antimicrobial susceptibility testing of 37 isolates revealed minimal inhibitory concentrations 90 (MIC90) of > 128 mg/l (tylosin), 64 mg/l (lincomycin), 8 mg/l (tiamulin) and 4 mg/l (valnemulin), respectively. Comparing to breakpoints applied to pigs, these values lie within the range of resistance. The demonstration of different Brachyspira spp., particularly B. pilosicoli, intermedia and alvinipulli in commercial layers, indicates the need of further research to assess their potential role in causing AIS in German poultry flocks. The increased antimicrobial resistance of Brachyspira spp. isolates to tylosin and pleuromutilins is likely associated with extensive use of these drugs in poultry medicine.


Suggested rationale for prevention and treatment of glucocorticoid-induced bone loss in dermatologic patients.
Glucocorticoid-induced bone loss is the most predictable and debilitating complication of prolonged administration of systemic corticosteroids. It has been shown that patients treated with glucocorticoids have an increased risk of osteoporotic fractures, resulting in marked morbidity, particularly in elderly individuals. Studies on the effect of glucocorticoids on bone density and the efficacy of treatment regimens (namely, bisphosphonates and calcitonin) for preventing bone loss have been mainly on patients with asthma and rheumatologic diseases. However, no long-term studies have been done on the impact of prolonged corticosteroid treatment in dermatologic patients. The purpose of this review is to raise awareness about osteoporosis and new preventive measures among the dermatologists treating patients with glucocorticoids at high doses and for long periods. We summarize the assessment methods used to evaluate this condition, examine the results of clinical trials of drugs, and suggest a practical approach to managing corticosteroid osteoporosis in dermatologic patients based on data collected from published articles.


Do individual characteristics influence the beta-elliptic modeling errors during ellipse drawing movements?
This paper investigates whether age, gender, and degree of familiarity with writing have an influence on the Beta-elliptic model errors during hand-drawing on a graphical tablet. A database of elliptical hand drawing movements was built within a sample of 99 participants aged between 19 and 85 years. Using the Beta-elliptic model, the velocity profile was modeled by overlapped Beta functions and the drawing trajectory was segmented between velocity extrema and each segment geometry was modeled by elliptic arcs. Average absolute and relative geometric, curvature and curvilinear velocity errors were 0.27 mm, 0.68%, 4.54 mm, 0.48%, 4.68 mm/s, and 8.79% respectively. Statistical analyses revealed not significant or low correlation between modeling errors and age and movement velocity, and no significant or low error differences according to gender or degree of familiarity with writing.


Health care networks implementation and regional governance challenges in the Legal Amazon Region: an analysis of the QualiSUS-Rede Project.
This paper aims to analyze the potential, limits and challenges of regional governance in the implementation process of health care networks in three Brazilian regions: Alto Solimões (Amazonas), Belém (Pará) and an interstate region comprising Tocantins, Pará and Maranhão states (Topama). The study is based on the evaluation study on the implementation of the Quality Health Care Network Development and Improvement Project (QualiSUS-Rede). This is a qualitative multiple case study with the analysis of official documents and use of semi-structured interviews with key stakeholders conducted from July to December 2014. Governance review encompassed three components: stakeholders involved, especially local steering groups and their regional coordination capacity; strategies used for strengthening regional governance, anchored on the intervention's modeling; and implementation of local health care networks. Results point that the regional managing commissions were the main governance strategy and that the QualiSUS-Rede Project strengthened regional governance and integration differently in every case, depending on stakeholders' administration and consensus capacity on regional and political priorities.


Structural elements responsible for conversion of streptavidin to a pseudoenzyme.
Avidin enhances the hydrolysis of biotinyl p-nitrophenyl ester (BNP) under mild alkaline conditions, whereas streptavidin prevents hydrolysis of BNP up to pH 12. Recently, we imposed hydrolytic activity on streptavidin by rational mutagenesis, based on the molecular elements responsible for the hydrolysis by avidin. Three mutants were designed, whereby the desired features, the distinctive L124R point mutation (M1), the L3,4 loop replacement (M2), and the combined mutation (M3), were transferred from avidin to streptavidin. The crystal structures of the mutants, in complex with biotinyl p-nitroanilide (BNA), the stable amide analogue of BNP, were determined. The results demonstrate that the point mutation alone has little effect on hydrolysis, and BNA exhibits a conformation similar to that of streptavidin. Substitution of a lengthier L3,4 loop (from avidin to streptavidin), resulted in an open conformation, thus exposing the ligand to solvent. Moreover, the amide bond of BNA was flipped relative to that of the streptavidin and M1 complexes, thus deflecting the nitro group toward Lys-121. Consequently, the leaving group potential of the nitrophenyl group of BNP is increased, and M2 hydrolyzes BNP at pH values >8.5. To better emulate the hydrolytic potential of avidin, M3 was required. The combination of loop replacement and point mutation served to further increase the leaving group potential by interaction of the nitro group with Arg-124 and Lys-121. The information derived from this study may provide insight into the design of enzymes and transfer of desired properties among homologous proteins.


[Pharma-clinics. The drug of the month. Rofecoxib (Vioxx)].
Rofecoxib (Vioxx, Merck Sharp & Dohme) is a potent and selective inhibitor of the COX-2 isoform of cyclooxygenase which is used as a nonsteroidal anti-inflammatory drug (NSAID). It is indicated in the symptomatic relief of pain due to osteoarthritis. The initial oral dosage of rofecoxib is 12.5 mg once daily in adults, and this dose may be increased up to a maximal dosage of 25 mg once daily if necessary. Its clinical efficacy seems to be similar to that of other NSAIDs at maximal recommended dosages, but its safety profile, especially gastrointestinal tolerance, is much better because of the COX-2 selectivity. Ongoing clinical trials are performed in patients with rheumatoid arthritis.


The chemokine decoy receptor D6 prevents excessive inflammation and adverse ventricular remodeling after myocardial infarction.
Leukocyte infiltration in ischemic areas is a hallmark of myocardial infarction, and overwhelming infiltration of innate immune cells has been shown to promote adverse remodeling and cardiac rupture. Recruitment of inflammatory cells in the ischemic heart depends highly on the family of CC-chemokines and their receptors. Here, we hypothesized that the chemokine decoy receptor D6, which specifically binds and scavenges inflammatory CC-chemokines, might limit inflammation and adverse cardiac remodeling after infarction. D6 was expressed in human and murine infarcted myocardium. In a murine model of myocardial infarction, D6 deficiency led to increased chemokine (C-C motif) ligand 2 and chemokine (C-C motif) ligand 3 levels in the ischemic heart. D6-deficient (D6(-/-)) infarcts displayed increased infiltration of pathogenic neutrophils and Ly6Chi monocytes, associated with strong matrix metalloproteinase-9 and matrix metalloproteinase-2 activities in the ischemic heart. D6(-/-) mice were cardiac rupture prone after myocardial infarction, and functional analysis revealed that D6(-/-) hearts had features of adverse remodeling with left ventricle dilation and reduced ejection fraction. Bone marrow chimera experiments showed that leukocyte-borne D6 had no role in this setting, and that leukocyte-specific chemokine (C-C motif) receptor 2 deficiency rescued the adverse phenotype observed in D6(-/-) mice. We show for the first time that the chemokine decoy receptor D6 limits CC-chemokine-dependent pathogenic inflammation and is required for adequate cardiac remodeling after myocardial infarction.


A monoclonal antibody inhibitory to human P450 2D6: a paradigm for use in combinatorial determination of individual P450 role in specific drug tissue metabolism.
Human cytochrome P450 2D6 metabolizes more than 50 common drugs and is polymorphically expressed, with 5-10% of the population lacking expression caused by mutant genes. This may result in a defective and toxic response in deficient individuals treated with 2D6 drug substrates. Baculovirus-expressed 2D6 was used to immunize mice for hybridoma production and two clones yielded monoclonal antibodies, that were positive against 2D6 by ELISA and inhibited 2D6 catalysed metabolism of bufuralol, dextromethorphan and phenanthrene by more than 90%. The inhibitory activity was highly specific to 2D6 and the monoclonal antibodies did not bind to 11 other P450s, nor inhibit seven human P450s tested. Analysis of eight human liver microsome samples showed that their basal bufuralol 1'-hydroxylase activity varied from 6.7-83.5 pmol min-1 nmol-1 P450. The monoclonal antibody 512-1-8 inhibited 2D6-dependent bufuralol 1'-hydroxylase in these samples by 10-70% indicating a widely variable role for 2D6 in human liver bufuralol 1'-hydroxylase activity and a role for other P450s in bufuralol metabolism. Independent analysis of several recombinant human P450s showed that 2D6, 2C8, 2C9, 2C19 and 1A2 exhibited bufuralol 1'-hydroxylase activity with 2D6 and 2C19 being the most active. Further analysis of three liver samples was made with individual inhibitory monoclonal antibodies. Inhibitory antibodies to 2D6, 2B6, 2E1, 2C8/9/19, 3A4 and 1A2 were added to the microsomes either singly or additively. Inhibitory activity of bufuralol 1'-hydroxylase was observed with antibodies to 2D6 (14-76%), 2C8/9/19 (24-69%) and 1A2 (2-25%) indicating a variable and different role for each of these P450s in the bufuralol 1'-hydroxylase of human liver. The monoclonal antibodies to 2B6, 2E1 and 3A4 were not inhibitory, indicating that these enzymes play no role in bufuralol 1'-hydroxylase metabolism. When the three antibodies to 2D6, 2C8/9/19 and 1A2, respectively, were all added, the total bufuralol 1'-hydroxylase of the liver samples was inhibited by more than 90%, indicating that the latter P450s catalyse all of liver bufuralol 1'-hydroxylase metabolism. These studies demonstrate that inhibitory monoclonal antibodies offer a simple and precise method for assessing the quantitative role of each P450 in the metabolism of a P450 substrate in a tissue, which include drugs, carcinogens, mutagens, toxic chemicals and endobiotics.


[Effect of daily blood sampling on creatine phosphokinase, SGOT, and SGPT activity in the serum of monkeys].
Activities of aspartate aminotransferase and creatine phosphokinase were distinctly altered within the first 6-7 days of daily blood-sampling in 4 Macaca rhesus. As the subsequent adaptation to the procedure conditions developed and the defensive excitement was decreased the following enzymatic activities were found: aspartate aminotransferase -14.04 +/- 0.58 UN/ml, alanine aminotransferase -19.45 +/- 0.79 UN/ml, creatine phosphokinase -1.88 +/- 0.14 UN/ml.


The combined positive impact of Lean methodology and Ventana Symphony autostainer on histology lab workflow.
Histologic samples all funnel through the H&E microtomy staining area. Here manual processes intersect with semi-automated processes creating a bottleneck. We compare alternate work processes in anatomic pathology primarily in the H&E staining work cell. We established a baseline measure of H&E process impact on personnel, information management and sample flow from historical workload and production data and direct observation. We compared this to performance after implementing initial Lean process modifications, including workstation reorganization, equipment relocation and workflow levelling, and the Ventana Symphony stainer to assess the impact on productivity in the H&E staining work cell. Average time from gross station to assembled case decreased by 2.9 hours (12%). Total process turnaround time (TAT) exclusive of processor schedule changes decreased 48 minutes/case (4%). Mean quarterly productivity increased 8.5% with the new methods. Process redesign reduced the number of manual steps from 219 to 182, a 17% reduction. Specimen travel distance was reduced from 773 ft/case to 395 ft/case (49%) overall, and from 92 to 53 ft/case in the H&E cell (42% improvement). Implementation of Lean methods in the H&E work cell of histology can result in improved productivity, improved through-put and case availability parameters including TAT.


Involvement of calcium, calmodulin and protein phosphorylation in morphogenesis of Candida albicans.
N-Acetyl-D-glucosamine-induced germ tube formation in Candida albicans at 37 degrees C was accompanied by an increase in the rate of protein phosphorylation. The calmodulin antagonist trifluoperazine and the Ca2+ ionophore A23187, which inhibited germ tube formation, also reduced the rate of phosphorylation. The rate of phosphorylation was also reduced when cells were incubated at 25 degrees C, which favoured yeast-phase growth. Two-dimensional SDS-PAGE analysis of phosphoproteins from germ-tube-forming and yeast cells revealed two germ-tube-specific and three yeast-specific phosphoproteins. Germ tubes and hyphae had more calmodulin activity than yeast cells, irrespective of the germ-tube-inducing condition used. As a first step towards understanding the inhibitory effect of trifluoperazine on germ tube formation, calmodulin from C. albicans was purified to homogeneity. It was heat stable, and displayed a pronounced Ca2(+)-induced shift in electrophoretic mobility.


Polar motion measurements: subdecimeter accuracy verified by intercomparison.
An important bound on the accuracy of modern techniques for monitoring polar motion is established by intercomparison of measurement series from two different observing techniques, very long baseline interferometry and satellite laser ranging. The root-mean-square differences between the estimates of the pole position from both techniques are shown to be only 2 milliseconds of arc (about 6 centimeters at one Earth radius). In the absence of common systematic errors, these differences bound the total errors in both sets of estimates. An initial investigation did not reveal any clear signature in the pole position that seems to be associated with major earthquakes. Continued measurements at this level of accuracy hold promise for resolving long-standing arguments over such questions as the nature of the excitation mechanism required to maintain the motion of the pole.


Gene therapy: future therapy for erectile dysfunction.
Advances in molecular biological techniques, completion of the Human Genome Project, and the ensuing age of molecular medicine, in conjuction with the sum of a decades-long accumulation of knowledge of the physiology of erection and the pathophysiology of erectile dysfunction have converged to make gene therapy for erectile dysfunction a distinct possibility. In short, both the intrinsic complexities of mechanisms responsible for ensuring normal erection and the multifactorial nature of erectile dysfunction ensure that there is a relatively vast number of physiologically relevant molecular targets for gene therapy. As such, perhaps it is not surprising that virtually every preclinical gene therapy strategy/target examined thus far has been largely successful in ameliorating conditions associated with compromised erectile function in vivo and/or in vitro. This report highlights the goals and strategies of gene therapy for erectile dysfunction and reviews the strategies that initially have been employed. In short, the preclinical data, while still quite preliminary in many regards, are nonetheless quite impressive and encouraging. If similar success is obtained in clinical trials, gene therapy for erectile dysfunction may provide the first concrete "proof of concept" for using gene therapy in the treatment of human smooth muscle disorders.


A double-blind placebo-controlled trial of fluoxetine for repetitive behaviors and global severity in adult autism spectrum disorders.
The effects of fluoxetine and placebo on repetitive behaviors and global severity were compared in adults with autism spectrum disorders (ASDs). Adults with ASDs were enrolled in a 12-week double-blind placebo-controlled fluoxetine trial. Thirty-seven were randomly assigned to fluoxetine (N=22) or placebo (N=15). Dosage followed a fixed schedule, starting at 10 mg/day and increasing as tolerated up to 80 mg/day. Repetitive behaviors were measured with the compulsion subscale of the Yale-Brown Obsessive Compulsive Scale; the Clinical Global Impression (CGI) improvement scale was used to rate improvement in obsessive-compulsive symptoms and overall severity. There was a significant treatment-by-time interaction indicating a significantly greater reduction in repetitive behaviors across time for fluoxetine than for placebo. With overall response defined as a CGI global improvement score of 2 or less, there were significantly more responders at week 12 in the fluoxetine group than in the placebo group. The risk ratio was 1.5 for CGI global improvement (responders: fluoxetine, 35%; placebo, 0%) and 1.8 for CGI-rated improvement in obsessive-compulsive symptoms (responders: fluoxetine, 50%; placebo, 8%). Only mild and moderate side effects were observed. Fluoxetine treatment, compared to placebo, resulted in significantly greater improvement in repetitive behaviors, according to both the Yale-Brown compulsion subscale and CGI rating of obsessive-compulsive symptoms, as well as on the CGI overall improvement rating. Fluoxetine appeared to be well tolerated. These findings stand in contrast to findings in a trial of citalopram for childhood autism.


Hospitalizations during infancy in three population-based studies in Southern Brazil: trends and differentials.
Three cohort studies of children born in the urban area of Pelotas, Southern Brazil, were carried out in 1982, 1993, and 2004. The aim of these studies was to measure the occurrence of hospitalization in the first year of life and to examine the association between hospitalization and the cause of admission and sex, birth weight, and family income. Cause of admission was categorized as "diarrhea" and "all other causes". The frequency of children hospitalized at least once during their first year of life was 19.6% in 1982, 18.1% in 1993, and 19.2% in 2004. There was a marked reduction in hospitalizations due to diarrhea, but the frequency of hospitalization for all causes remained constant. In all three cohorts, infants from poorer families and those born weighing under 2,000g showed the highest frequencies of hospitalization due to diarrhea and all other causes, and the latter also showed a marked increase in hospitalizations due to all causes. These findings could be explained by an epidemic of preterm births in the study population.


Meta-analysis of Exercise Training on Left Ventricular Ejection Fraction in Heart Failure with Reduced Ejection Fraction: A 10-year Update.
The role of exercise training modality to attenuate left ventricular (LV) remodeling in heart failure patients with reduced ejection fraction (HFrEF) remains uncertain. The authors performed a systematic review and meta-analysis of published reports on exercise training (moderate-intensity continuous aerobic, high-intensity interval aerobic, and resistance exercise) and LV remodeling in clinically stable HFrEF patients. We searched MEDLINE, Cochrane Central Registry of Controlled Trials, CINAHL, and PubMed (2007 to 2017) for randomized controlled trials of exercise training on resting LV ejection fraction (EF) and end-diastolic and end-systolic volumes in HFrEF patients. 18 trials reported LV ejection fraction (LVEF) data, while 8 and 7 trials reported LV end-diastolic and LV end-systolic volumes, respectively. Overall, moderate-intensity continuous training (MICT) significantly increased LVEF (weighted mean difference, WMD = 3.79%; 95% confidence interval, CI, 2.08 to 5.50%) with no change in LV volumes versus control. In trials ≥6 months duration, MICT significantly improved LVEF (WMD = 6.26%; 95% CI 4.39 to 8.13%) while shorter duration (<6 months) trials modestly increased LVEF (WMD = 2.33%; 95% CI 0.84 to 3.82%). High-intensity interval training (HIIT) significantly increased LVEF compared to control (WMD = 3.70%; 95% CI 1.63 to 5.77%) but was not different than MICT (WMD = 3.17%; 95% CI -0.87 to 7.22%). Resistance training performed alone or combined with aerobic training (MICT or HIIT) did not significantly change LVEF. In clinically stable HFrEF patients, MICT is an effective therapy to attenuate LV remodeling with the greatest benefits occurring with long-term (≥6 months) training. HIIT performed for 2 to 3 months is superior to control, but not MICT, for improvement of LVEF.


Vibrotactile Thresholds on the Mastoid and Forehead Position of Deaf Patients Using Radioear B71 and B81.
The main objective of this study was to measure the vibrotactile thresholds on the mastoid process and forehead positions using patients with bilateral deafness and to compare the results from the two bone conduction vibrators Radioear B71 and B81. There is a possibility that the vibrotactile sensation on the skin makes it difficult to discriminate between sound and vibration. The risk is highest for patients who have bone conduction hearing thresholds in proximity to or worse than their vibrotactile thresholds. All measurements were performed similar to regular bone conduction threshold testing using an audiometer-driven bone conduction vibrator and pulsed warble tones, but the patients were instructed to respond only when feeling vibrations of the bone conduction vibrator instead of when hearing sound. Both the posterior forehead position and the mastoid process position on the temporal bone were tested for comparative reasons. In total, 16 patients participated in the study, 31% females and 69% males of age 29 to 77 years. All subjects were cochlear implant recipients, either uni- or bilaterally implanted. They were selected based on their audiogram data showing unmeasurable unaided hearing. The force level at which the vibrotactile thresholds were reached, increased with frequency from 125 up to 500 Hz, but remained constant for higher frequencies up to 2 kHz. A statistically significant difference was found between the 2 devices at 125 Hz at both the mastoid process and forehead position, where the vibrotactile threshold seem to be more sensitive for B71, possibly due to contribution of distortion components. There was no statistically significant difference in vibrotactile thresholds between the mastoid process and forehead position in absolute values (force level in dB re 1 µN), but in terms of hearing levels (dB HL) there was an average difference of 10 and 9 dB for B71 and B81, respectively. The results indicate that the vibrotactile thresholds can be confounded with bone conduction hearing thresholds measurements up to 500 Hz when using a standard audiometer and in particular when measuring on the forehead position.


Investigation of the piroplasm diversity circulating in wildlife and cattle of the greater Kafue ecosystem, Zambia.
Piroplasms are vector-borne intracellular hemoprotozoan parasites that infect wildlife and livestock. Wildlife species are reservoir hosts to a diversity of piroplasms and play an important role in the circulation, maintenance and evolution of these parasites. The potential for likely spillover of both pathogenic and non-pathogenic piroplasm parasites from wildlife to livestock is underlined when a common ecological niche is shared in the presence of a competent vector. To investigate piroplasm diversity in wildlife and the cattle population of the greater Kafue ecosystem, we utilized PCR to amplify the 18S rRNA V4 hyper-variable region and meta-barcoding strategy using the Illumina MiSeq sequencing platform and amplicon sequence variant (ASV)-based bioinformatics pipeline to generate high-resolution data that discriminate sequences down to a single nucleotide difference. A parasite community of 45 ASVs corresponding to 23 species consisting of 4 genera of Babesia, Theileria, Hepatozoon and Colpodella, were identified in wildlife and the cattle population from the study area. Theileria species were detected in buffalo, impala, hartebeest, sable antelope, sitatunga, wild dog and cattle. In contrast, Babesia species were only observed in cattle and wild dog. Our results demonstrate possible spillover of these hemoprotozoan parasites from wildlife, especially buffalo, to the cattle population in the wildlife-livestock interface. We demonstrated that the deep amplicon sequencing of the 18S rRNA V4 hyper-variable region for wildlife was informative. Our results illustrated the diversity of piroplasma and the specificity of their hosts. They led us to speculate a possible ecological cycle including transmission from wildlife to domestic animals in the greater Kafue ecosystem. Thus, this approach may contribute to the establishment of appropriate disease control strategies in wildlife-livestock interface areas.


Effect of the cannabinoid CB1 receptor antagonist, SR141716, on nociceptive response and nerve demyelination in rodents with chronic constriction injury of the sciatic nerve.
Many reports have shown the efficacy of cannabinoid agonists in chronic pain, whereas no report exists concerning the potential effect of cannabinoid antagonists following prolonged treatment. We tested the effects of repeated administration of the selective cannabinoid receptor type 1 (CB1) antagonist, SR141716 (rimonabant), in rats with chronic constriction injury of the sciatic nerve (CCI), an animal model of neuropathic pain. The repeated oral administration of SR141716 (1, 3 and 10 mg/kg, once a day for 1 week, from day 7 after the injury) dose dependently attenuated both thermal and mechanical hyperalgesia. A similar effect was observed in CCI wild-type mice, whereas SR141716 was unable to elicit pain relief in CB1 knockout mice, suggesting CB1 receptors involvement in the SR141716-induced antihyperalgesia. The antihyperalgesic activity of SR141716 was associated with a significant reduction of several pro-inflammatory and pro-nociceptive mediators such as tumor necrosis factor alpha (TNFalpha), prostaglandin-E2 (PGE2), lipoperoxide and nitric oxide (NO) levels. The histological analysis of sciatic nerve sections showed a marked degeneration of myelinated fibers in CCI rats, which was substantially reduced after repeated administration of SR141716. This suggests that the compound may favour myelin repair and consequently promote long-lasting functional recovery. This was confirmed by the maintenance of recovery for at least four weeks after treatment discontinuation. In conclusion, the present findings suggest that SR141716 is effective not only in alleviating neuropathic pain but also in favouring the nerve myelin repair.


Hunting-related shooting incidents in Pennsylvania, 1987-1999.
Characteristics and rates of shooting injuries associated with hunting various game species are unreported. For the 1,345 hunting-related shooting incidents in Pennsylvania from 1987 to 1999, age-adjusted hunter injury rates and case-fatality ratios were calculated for each of seven species hunted. Differences in the incidents and injuries were tested (p < 0.05). Fall turkey hunters had the highest (7.5 per 100,000 hunters) and grouse hunters the lowest (1.9 per 100,000) injury rate. The case-fatality ratio was highest for deer hunters (10.3%) and lowest for pheasant hunters (1.3%). Poor skill was the leading cause of deer hunting injuries, and poor judgment the leading cause for injuries during the hunting of other species. Coinciding with changes in regulations requiring orange clothing for hunters, the injury rates for fall turkey hunters initially decreased (rate ratio, 4.1), then increased (rate ratio, 0.5). Hunters younger than 20 years had the highest injury rates. The rates and characteristics of hunting-related shooting injuries varied by hunted species. Hunter orange clothing regulations appeared to reduce fall turkey hunting injury rates.


[Considering family commitments in the process of psycho-social rehabilitation].
The current transformation of psychiatric assistance has focused on the family as an important factor. This exploratory study had the objective to identify the family's overload produced by the relationship with the person who has mental problems. Thirteen families of hospitalized patients were interviewed. We have identified in their reports the overload of commitments that they experienced while treating the patient before/after the hospitalization, added to the lack of support given by the health system. The nursing professional has an opportunity of working with the family of the patient, helping to solve the problems and revealing the importance of reestablishing the patient's social network along the rehabilitation process.


[Chronic inflammatory bowel disease in elderly people].
Inflammatory bowel disease is mainly diagnosed in younger patients. However, the number of elderly patients (age > 60 years) affected by Crohn's disease or ulcerative colitis is increasing. In the elderly, symptoms often differ from the younger population. Older patients generally present a milder clinical course and are less often affected by extraintestinal disease activity. Treatment options are similar to the ones in younger patients. Due to the higher risk of drug interactions and side effects, comorbidities and comedication of the older patients play a pivotal role in the selection of the specific treatment agent. In therapy refractory disease, surgical treatment is also a valuable option for patients > 60 years. Furthermore, vaccination, prevention of infections and regular cancer screening is mandatory in this vulnerable population.


Polo-like kinase is necessary for flagellum inheritance in Trypanosoma brucei.
Polo-like kinases play an important role in a variety of mitotic events in mammalian cells, ranging from centriole separation and chromosome congression to abscission. To fulfill these roles, Polo-like kinase homologs move to different cellular locations as the cell cycle progresses, starting at the centrosome, progressing to the spindle poles and then the midbody. In the protist parasite Trypanosoma brucei, the single polo-like kinase homolog T. brucei PLK (TbPLK) is essential for cytokinesis and is necessary for the correct duplication of a centrin-containing cytoskeletal structure known as the bilobe. We show that TbPLK has a dynamic localization pattern during the cell cycle. The kinase localizes to the basal body, which nucleates the flagellum, and then successively localizes to a series of cytoskeletal structures that regulate the position and attachment of the flagellum to the cell body. The kinase localizes to each of these structures as they are duplicating. TbPLK associates with a specialized set of microtubules, known as the microtubule quartet, which might transport the kinase during its migration. Depletion of TbPLK causes defects in basal body segregation and blocks the duplication of the regulators that position the flagellum, suggesting that its presence on these structures might be necessary for their proper biogenesis. TbPLK migrates throughout the cell in T. brucei, but the specific locations to which it targets and its functions are geared towards the inheritance of a properly positioned and attached flagellum.


Scanpath modeling and classification with hidden Markov models.
How people look at visual information reveals fundamental information about them; their interests and their states of mind. Previous studies showed that scanpath, i.e., the sequence of eye movements made by an observer exploring a visual stimulus, can be used to infer observer-related (e.g., task at hand) and stimuli-related (e.g., image semantic category) information. However, eye movements are complex signals and many of these studies rely on limited gaze descriptors and bespoke datasets. Here, we provide a turnkey method for scanpath modeling and classification. This method relies on variational hidden Markov models (HMMs) and discriminant analysis (DA). HMMs encapsulate the dynamic and individualistic dimensions of gaze behavior, allowing DA to capture systematic patterns diagnostic of a given class of observers and/or stimuli. We test our approach on two very different datasets. Firstly, we use fixations recorded while viewing 800 static natural scene images, and infer an observer-related characteristic: the task at hand. We achieve an average of 55.9% correct classification rate (chance = 33%). We show that correct classification rates positively correlate with the number of salient regions present in the stimuli. Secondly, we use eye positions recorded while viewing 15 conversational videos, and infer a stimulus-related characteristic: the presence or absence of original soundtrack. We achieve an average 81.2% correct classification rate (chance = 50%). HMMs allow to integrate bottom-up, top-down, and oculomotor influences into a single model of gaze behavior. This synergistic approach between behavior and machine learning will open new avenues for simple quantification of gazing behavior. We release SMAC with HMM, a Matlab toolbox freely available to the community under an open-source license agreement.


[Induction of post-partum ovulation in creole cows by using a Norgestomet implant and temporary removal of the calf].
Two treatments were used to attempt to induce ovulation in anoestrous post-partum creole cows. The use of a Norgestomet implant for 7 days followed by removal of the calf for 48 h induced ovulation in 91, 83 and 71% of anoestrous creole cows treated respectively at 37, 48 and 51 days post partum (implant insertion). In the same time, the cycling rates of the control groups were 30, 35 and 35%, respectively. But calf removal for 48 h at 60 and 80 days without progestagen priming failed to increase the number of cycling cows compared to the control group. Whatever the treatment and the post-partum day, calf growth was not different between the treated and the control groups at 30, 60 and 90 days post-partum, and there was no mastitis.


[Phosphorus-calcium metabolism in children under prolonged treatment with anticonvulsants. (II)].
Comparative assessments were made regarding the effects of prolonged administration of anticonvulsant drugs (phenobarbital, carbamazepine, valproate and polytherapy) on the different biochemical parameters related to phosphocalcium metabolism, in 98 children between 1 and 14 years. The most patent effect was on the levels of 25-Hydroxycholecalciferol which went down significantly (p = 0.0001) in children treated with phenobarbital (34.5 +/- 17 ng/ml) or polytherapy (28.4 +/- 18 ng/ml) in relation to those treated with carbamazepine (49.2 +/- 15 ng/ml) or valproate (43.1 +/- 15 ng/ml) and to control group (45.9 +/- 13 ng/ml). The alkaline phosphatase has been found significantly higher among those treated with phenobarbital, carbamazepine and polytherapy, evidencing significant differences in relation to those treated with valproate and to control group (p less than 0.05). For calcium, parathyroid hormone and osteocalcine levels no differences were found in the different drugs, nor with control group. Depending on the duration of treatment there was a significant reduction (p = 0.02) in the levels of 25-Hydroxycholecalciferol in children treated over 3 years, but no difference for calcium, phosphorous, alkaline phosphatase and PTH under this parameter.


Influence of the noise model on level set active contour segmentation.
We analyze level set implementation of region snakes based on the maximum likelihood method for different noise models that belong to the exponential family. We show that this approach can improve segmentation results in noisy images and we demonstrate that the regularization term can be efficiently determined using an information theory-based approach, i.e., the minimum description length principle. The criterion to be optimized has no free parameter to be tuned by the user and the obtained segmentation technique is adapted to nonsimply connected objects.


Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial.
Preeclampsia complicates approximately 3-5% of pregnancies and remains a major cause of maternal and neonatal morbidity and mortality. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Pravastatin, a hydrophilic, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, has been shown in preclinical studies to reverse various pathophysiological pathways associated with preeclampsia, providing biological plausibility for its use for preeclampsia prevention. However, human trials are lacking. As an initial step in evaluating the utility of pravastatin in preventing preeclampsia and after consultation with the US Food and Drug Administration, we undertook a pilot randomized controlled trial with the objective to determine pravastatin safety and pharmacokinetic parameters when used in pregnant women at high risk of preeclampsia. We conducted a pilot, multicenter, double-blind, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12(0/7) and 16(6/7) weeks' gestation were assigned to daily pravastatin 10 mg or placebo orally until delivery. Primary outcomes were maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included rates of preeclampsia and preterm delivery, gestational age at delivery, birthweight, and maternal and cord blood lipid profile (clinicaltrials.gov identifier NCT01717586). Ten women assigned to pravastatin and 10 to placebo completed the trial. There were no differences between the 2 groups in rates of study drug side effects, congenital anomalies, or other adverse or serious adverse events. There was no maternal, fetal, or neonatal death. Pravastatin renal clearance was significantly higher in pregnancy compared with postpartum. Four subjects in the placebo group developed preeclampsia compared with none in the pravastatin group. Although pravastatin reduced maternal cholesterol concentrations, umbilical cord cholesterol concentrations and infant birthweight were not different between the groups. The majority of umbilical cord and maternal pravastatin plasma concentrations at the time of delivery were below the lower limit of quantification of the assay. Pravastatin use was associated with a more favorable pregnancy angiogenic profile. This study provides preliminary safety and pharmacokinetic data regarding the use of pravastatin for preventing preeclampsia in high-risk pregnant women. Although the data are preliminary, no identifiable safety risks were associated with pravastatin use in this cohort. This favorable risk-benefit analysis justifies using pravastatin in a larger clinical trial with dose escalation.


Investigating acupuncture using brain imaging techniques: the current state of play.
We have systematically researched and reviewed the literature looking at the effect of acupuncture on brain activation as measured by functional magnetic resonance imaging and positron emission tomography. These studies show that specific and largely predictable areas of brain activation and deactivation occur when considering the traditional Chinese functions attributable to certain specific acupuncture points. For example, points associated with hearing and vision stimulates the visual and auditory cerebral areas respectively. Pain, however, is a complex matrix that is intimately intertwined with expectation. Acupuncture clearly affects this matrix in both specific and non-specific manner that is consistent with its specific clinical effects, as well as the effects of expectation on pain relief. This article summarizes the current imaging literature.


Phylogeographic structure and cryptic speciation in the trans-Antarctic moss Pyrrhobryum mnioides.
Many bryophyte species have distributions that span multiple continents. The hypotheses historically advanced to explain such distributions rely on either long-distance spore dispersal or slow rates of morphological evolution following ancient continental vicariance events. We use phylogenetic analyses of DNA sequence variation at three chloroplast loci (atpB-rbcL spacer, rps4 gene, and trnL intron and 3' spacer) to examine these two hypotheses in the trans-Antarctic moss Pyrrhobryum mnioides. We find: (1) reciprocal monophyly of Australasian and South American populations, indicating a lack of intercontinental dispersal; (2) shared haplotypes between Australia and New Zealand, suggesting recent or ongoing migration across the Tasman Sea; and (3) reciprocal monophyly among Patagonian and neotropical populations, suggesting no recent migration along the Andes. These results corroborate experimental work suggesting that spore features may be critical determinants of species range. We use the mid-Miocene development of the Atacama Desert, 14 million years ago, to calibrate a molecular clock for the tree. The age of the trans-Antarctic disjunction is estimated to be 80 million years ago, consistent with Gondwanan vicariance, making it among the most ancient documented cases of cryptic speciation. These data are in accord with niche conservatism, but whether the morphological stasis is a product of stabilizing selection or phylogenetic constraint is unknown.


Bias due to lack of patient blinding in clinical trials. A systematic review of trials randomizing patients to blind and nonblind sub-studies.
Blinding patients in clinical trials is a key methodological procedure, but the expected degree of bias due to nonblinded patients on estimated treatment effects is unknown. Systematic review of randomized clinical trials with one sub-study (i.e. experimental vs control) involving blinded patients and another, otherwise identical, sub-study involving nonblinded patients. Within each trial, we compared the difference in effect sizes (i.e. standardized mean differences) between the sub-studies. A difference <0 indicates that nonblinded patients generated a more optimistic effect estimate. We pooled the differences with random-effects inverse variance meta-analysis, and explored reasons for heterogeneity. Our main analysis included 12 trials (3869 patients). The average difference in effect size for patient-reported outcomes was -0.56 (95% confidence interval -0.71 to -0.41), (I(2)=60%, P=0.004), i.e. nonblinded patients exaggerated the effect size by an average of 0.56 standard deviation, but with considerable variation. Two of the 12 trials also used observer-reported outcomes, showing no indication of exaggerated effects due lack of patient blinding. There was a larger effect size difference in 10 acupuncture trials [-0.63 (-0.77 to -0.49)], than in the two non-acupuncture trials [-0.17 (-0.41 to 0.07)]. Lack of patient blinding also increased attrition and use of co-interventions: ratio of control group attrition risk 1.79 (1.18 to 2.70), and ratio of control group co-intervention risk 1.55 (0.99 to 2.43). This study provides empirical evidence of pronounced bias due to lack of patient blinding in complementary/alternative randomized clinical trials with patient-reported outcomes.


[Postpartum hysterectomy performed as a consequence of chronic myometritis].
As a diffuse chronic inflammation, myometritis is very rare and usually follows after postpartal placenta remains or postabortion infections, but it can be also associated with endometrial or ascendent infection. Chronic myometritis is often followed by profuse bleeding, though in most cases it cannot be recognized as it is asymptomatic. Histologically, that chronic process is characterized by the presence of fibriosis within the muscles and mononuclear cells (lymphoplasmocytic and histiocytic) infiltration. A 24 old woman's second child was delivered per vias naturalis but the next day the profuse bleeding occured which would not stop even after repeated curretages and suspecting a case of placenta accreta and uterus atony, subtotal hysterectomy was performed. Histologically, the disappearance of the regular arrangement of the smooth muscles and stroma could be seen with the devastation of myometrium due to the diffuse reduction of its smooth muscle bundles and cells, as well as their atrophy, necrobiosis and apoptosis with the minimal preservation of the muscle bundles and little cell groups of the myometrium, an abundant presence of the fibrocollagene and myxoid transformed connective tissue, group cells similar to the mesenchymal tissue and adipocytes. It was not possible to find this variant of the changes on the myometrium in the available literature. The present case is about the clinically unknown asymptomatic myometritis, possibly developed in the postpartal period of the previous pregnancy. It is our opinion that it is most probably an autoagressive process directed towards the smooth muscle cells of the myometrium, as shown by their reduction and inflammatory cells composition, which plays an important role in the immune reactions (lymphocytes, plasma cells, eosinophilis, histocytes). A subtotal hysterectomy was performed on a woman, 24 years old, who gave birth to her second child and had profuse postpartal bleeding in sprite of repeated curettages. On the basis of this uterus atony, there is the clinically non-manifested chronic myometritis. The chronic inflammation resulted in a subtotal reduction of myometrium muscle mass, its replacement sclerosis, the multiplication of adipocytes, mesenchymal cells, histiocytes, lymphomonocytes and dissection of muscle fascicles.