Lineage-specific trisomy 21 in a neonate with resolving transient myeloproliferative syndrome.
The cellular events that lead to transient myeloproliferative syndrome (TMS) in patients with trisomy 21 mosaicism confined to the hematopoietic system are poorly understood. The authors attempt to define the event that led to the development of TMS in a single patient with clonal trisomy 21. A phenotypically normal neonate with clonal trisomy 21 is described. At the time when his TMS was resolving, fluorescent in situ hybridization analysis was performed on cell populations sorted by flow cytometry to determine what cell populations contained trisomic cells. Trisomy 21 was found in cells of the erythrocytic and monocytic lineages, but not in the stem cells, progenitor compartment, megakaryocytes, lymphocytes, or neutrophils. These results support the hypothesis that, in this neonate, trisomy 21 occurred in a multipotent hematopoietic progenitor, and a subsequent event led to the appearance of the blast population.


Dynamic simulations of colloids by core-modified dissipative particle dynamics.
We develop a core-modified dissipative particle dynamics model of colloidal systems which includes an extra term to counteract depletion forces. Results are presented covering the full range of volume fractions. Radial distribution functions for the suspending fluid are shown to change significantly as the volume fraction of colloid increases. Equilibrium results for the long-time diffusion coefficient behave as expected, but the short-time coefficient is anomalous. The form of the equilibrium stress correlation functions is discussed and the derived Green-Kubo viscosities are compared with expected semiempirical forms. For nonequilibrium shear-field simulations we find that the system temperature is not adequately controlled by the dissipative particle dynamics (DPD) thermostat alone. Results using three alternative auxiliary thermostats are compared; a naive choice leading to a string phase at high shear rate. Using a thermostat based on relative particle velocities, the model reproduced the four classical regions of colloid rheology: a first Newtonian plateau, a shear-thinning region, a second Newtonian plateau, and finally a shear-thickening region at high strain rate. The most unexpected result of this exercise is that the core-modified DPD model without auxiliary thermostat almost exactly follows the same curve despite recording a temperature increase of a factor approximately 2.5 over the range.


Prognostic Bone Metastasis-Associated Immune-Related Genes Regulated by Transcription Factors in Mesothelioma.
Mesothelioma (MESO) is a mesothelial originate neoplasm with high morbidity and mortality. Despite advancement in technology, early diagnosis still lacks effectivity and is full of pitfalls. Approaches of cancer diagnosis and therapy utilizing immune biomarkers and transcription factors (TFs) have attracted more and more attention. But the molecular mechanism of these features in MESO bone metastasis has not been thoroughly studied. Utilizing high-throughput genome sequencing data and lists of specific gene subsets, we performed several data mining algorithm. Single-sample Gene Set Enrichment Analysis (ssGSEA) was applied to identify downstream immune cells. Potential pathways involved in MESO bone metastasis were identified using Gene Oncology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, Gene Set Variation Analysis (GSVA), Gene Set Enrichment Analysis (GSEA), and Cox regression analysis. Ultimately, a model to help early diagnosis and to predict prognosis was constructed based on differentially expressed immune-related genes between bone metastatic and nonmetastatic MESO groups. In conclusion, immune-related gene SDC2, regulated by TFs TCF7L1 and POLR3D, had an important role on immune cell function and infiltration, providing novel biomarkers and therapeutic targets for metastatic MESO.


Task complexity and maximal isometric strength gains through motor learning.
This study compared the effects of a simple versus complex contraction pattern on the acquisition, retention, and transfer of maximal isometric strength gains and reductions in force variability. A control group (N = 12) performed simple isometric contractions of the wrist flexors. An experimental group (N = 12) performed complex proprioceptive neuromuscular facilitation (PNF) contractions consisting of maximal isometric wrist extension immediately reversing force direction to wrist flexion within a single trial. Ten contractions were completed on three consecutive days with a retention and transfer test 2-weeks later. For the retention test, the groups performed their assigned contraction pattern followed by a transfer test that consisted of the other contraction pattern for a cross-over design. Both groups exhibited comparable increases in strength (20.2%, P < 0.01) and reductions in mean torque variability (26.2%, P < 0.01), which were retained and transferred. There was a decrease in the coactivation ratio (antagonist/agonist muscle activity) for both groups, which was retained and transferred (35.2%, P < 0.01). The experimental group exhibited a linear decrease in variability of the torque- and sEMG-time curves, indicating transfer to the simple contraction pattern (P < 0.01). The control group underwent a decrease in variability of the torque- and sEMG-time curves from the first day of training to retention, but participants returned to baseline levels during the transfer condition (P < 0.01). However, the difference between torque RMS error versus the variability in torque- and sEMG-time curves suggests the demands of the complex task were transferred, but could not be achieved in a reproducible way.


Quasi-non-diffracting static light sheets generated by holistically optimized pupil masks.
Thin and wide light sheets are crucial for light sheet microscopy with wide field of views and near diffraction-limited resolutions. Non-diffracting light sheets feature wide span ranges but often come with strong sidelobes or increased thicknesses. We develop a computational optimization method for creating light sheets that balance the trade-offs between thickness, non-diffracting range and sidelobes. We show in theory and experiment that our optimized mask extends the static light sheet's non-diffracting range by 50 % while keeping its sidelobes below the 20 % level.


Assessing the role of genome-wide DNA methylation between smoking and risk of lung cancer using repeated measurements: the HUNT study.
It is unclear if smoking-related DNA methylation represents a causal pathway between smoking and risk of lung cancer. We sought to identify novel smoking-related DNA methylation sites in blood, with repeated measurements, and to appraise the putative role of DNA methylation in the pathway between smoking and lung cancer development. We derived a nested case-control study from the Trøndelag Health Study (HUNT), including 140 incident patients who developed lung cancer during 2009-13 and 140 controls. We profiled 850 K DNA methylation sites (Illumina Infinium EPIC array) in DNA extracted from blood that was collected in HUNT2 (1995-97) and HUNT3 (2006-08) for the same individuals. Epigenome-wide association studies (EWAS) were performed for a detailed smoking phenotype and for lung cancer. Two-step Mendelian randomization (MR) analyses were performed to assess the potential causal effect of smoking on DNA methylation as well as of DNA methylation (13 sites as putative mediators) on risk of lung cancer. The EWAS for smoking in HUNT2 identified associations at 76 DNA methylation sites (P < 5 × 10-8), including 16 novel sites. Smoking was associated with DNA hypomethylation in a dose-response relationship among 83% of the 76 sites, which was confirmed by analyses using repeated measurements from blood that was collected at 11 years apart for the same individuals. Two-step MR analyses showed evidence for a causal effect of smoking on DNA methylation but no evidence for a causal link between DNA methylation and the risk of lung cancer. DNA methylation modifications in blood did not seem to represent a causal pathway linking smoking and the lung cancer risk.


Evidence for Altered Electroencephalography Coherence in Depressed Adolescents with Suicidal Ideation and Behaviors.
Introduction: Major depressive disorder (MDD) is a primary risk factor for suicide, which is one of the leading causes of death among adolescents worldwide. Understanding the heterogeneity of suicidality in adolescents with MDD is critical for suicide prevention and intervention discovery. Quantitative electroencephalography (EEG) is a promising tool to address the knowledge gaps related to the neurophysiological characteristics of depression and suicidality. This study sought to examine resting-state EEG coherence differences in adolescents with MDD and suicidal ideation (SI)/behaviors (SB) and healthy controls (HC) to assess the utility of coherence as a biomarker of suicide. Methods: Twenty-six adolescents with MDD who were hospitalized for suicidality and 30 HC were recruited. The clinical sample was divided into SI (n = 9) and SB (n = 19) subgroups. Eyes closed resting-state EEG were recorded, and coherence was calculated. Depression severity and suicidality were assessed with the Children's Depression Rating Scale Revised and the Columbia Suicide Severity Rating Scale, respectively. Results: There were intrahemispheric differences in the right hemisphere across multiple electrode pairs. Delta, alpha, and beta coherence were higher in the SB group over the right prefrontofrontal and left parietooccipital electrode pairs, while alpha coherence was higher in the HC group over the right centroparietal electrode pair. There were no significant differences between HC and SI groups in any electrode pair. Conclusions: Patients with recent SB showed increased coherence in right frontal regions compared with patients with SI, suggesting altered cognitive states between those with SB and SI. These findings may have implications for suicide prevention in adolescents and could serve as useful biomarkers in clinical settings, but larger studies are needed to confirm the results.


The adipokine apelin-13 induces expression of prothrombotic tissue factor.
Adipocytes are cells able to produce and secrete several active substances (adipokines) with direct effects on vascular cells. Apelin, one of the most recently identified adipokines has been studied in cardiovascular system physiology in regard to vessel vasodilation and myocardial contraction, but it has not yet completely characterised for its pathophysiological role in cardiovascular disease and especially in acute coronary syndromes (ACS). Several studies have indicated that tissue factor (TF) plays a pivotal role in the pathophysiology of ACS by triggering the formation of intracoronary thrombi following endothelial injury. This study investigates the effects of apelin 12 and apelin 13 on TF in human umbilical endothelial cells (HUVECs) and monocytes. Cells were stimulated with increasing concentrations of apelin 12 or apelin 13 and then processed to evaluate TF-mRNA levels by real-time PCR as well as TF expression/activity by FACS analysis and pro-coagulant activity. Finally, a potential molecular pathway involved in modulating this phenomenon was investigated. We demonstrate that apelin 13 but not apelin 12 induces transcription of mRNA for TF. In addition, we show that this adipokine promotes surface expression of TF that is functionally active. Apelin 13 effects on TF appear modulated by the activation of the G-protein-transcription factor nuclear factor (NF)-κB axis since G-protein inhibitors suppressed NF-κB mediated TF expression. Data of the present study, although in vitro, indicate that apelin-13, induces a procoagulant phenotype in HUVECs and monocytes by promoting TF expression. These observations support the hypothesis that this adipokine might play a relevant role as an active partaker in athero-thrombotic disease.


Reversible dissociation and unfolding of pyruvate decarboxylase from Zymomonas mobilis.
The denaturation and renaturation process of pyruvate decarboxylase (PDC) from Zymomonas mobilis (ATCC 29191) has been investigated using guanidine hydrochloride and urea as denaturing agents. The quarternary structure of the homotetramer is strongly stabilized by the cofactors Mg2+ and thiamine diphosphate (TDP). The structural transitions were monitored by activity measurements, fluorescence spectroscopy, circular dichroism and gel-filtration chromatography. A three-step denaturation process, described as follows, is indicated by non-coincidental denaturation curves: (a) inactivation of the tetramer upon dissociation of cofactors (> 0.4 M guanidine hydrochloride, > 1 M urea); (b) dissociation of the tetramer into monomers (> 1 M guanidine hydrochloride, > 3 M urea); (c) complete unfolding of these (> 2.5 M guanidine hydrochloride, > 5 M urea). The refolding process initiated by rapid dilution of fully denatured protein in renaturation buffer involves the rapid reassociation of an inactive intermediate followed by the reconstitution of the active site.


Enzyme-linked immunosorbent assays for detection of equine antibodies specific to Sarcocystis neurona surface antigens.
Sarcocystis neurona is the primary causative agent of equine protozoal myeloencephalitis (EPM), a common neurologic disease of horses in the Americas. We have developed a set of enzyme-linked immunosorbent assays (ELISAs) based on the four major surface antigens of S. neurona (SnSAGs) to analyze the equine antibody response to S. neurona. The SnSAG ELISAs were optimized and standardized with a sample set of 36 equine sera that had been characterized by Western blotting against total S. neurona parasite antigen, the current gold standard for S. neurona serology. The recombinant SnSAG2 (rSnSAG2) ELISA showed the highest sensitivity and specificity at 95.5% and 92.9%, respectively. In contrast, only 68.2% sensitivity and 71.4% specificity were achieved with the rSnSAG1 ELISA, indicating that this antigen may not be a reliable serological marker for analyzing antibodies against S. neurona in horses. Importantly, the ELISA antigens did not show cross-reactivity with antisera to Sarcocystis fayeri or Neospora hughesi, two other equine parasites. The accuracy and reliability exhibited by the SnSAG ELISAs suggest that these assays will be valuable tools for examining the equine immune response against S. neurona infection, which may help in understanding the pathobiology of this accidental parasite-host interaction. Moreover, with modification and further investigation, the SnSAG ELISAs have potential for use as immunodiagnostic tests to aid in the identification of horses affected by EPM.


Minor pilin subunits are conserved in Vibrio cholerae type IV pili.
The nucleotide sequences of five open reading frames within the Vibrio cholerae NAGV14 type IV pilus gene cluster were determined. The genes showed high homology to the mannose-sensitive hemagglutinin (MSHA) pilus genes mshB, mshC, mshD, mshO and mshP. PCR analysis showed that a MSHA-like gene cluster is highly conserved among different V. cholerae strains, with the exception of the previously reported major pilin subunit. Recombinant MshB and MshO proteins were purified and specific antiserum was raised to each of them. Western blotting analyses showed that these antisera reacted with purified NAGV14 and MSHA pili. The results suggested that MshB and MshO are minor components of the pilus fiber. Although there was no cross-reaction between the major pilin subunits of NAGV14 and MSHA pili, minor components seemed to be highly homologous and immunologically cross-reactive.


Support groups for cancer patients.
Within the last two decades psychosocial group interventions have been developed to help cancer patients cope better with the psychosocial sequelae of cancer diagnosis and treatment. Support groups include a variety of different approaches some of which focus on behavioral aspects and symptoms (e.g. pain, fatigue) and some on the expression of emotions. Most of these support programs are structured and short-term and include elements such as delivery of information, emotional and social support, stress management strategies based on the cognitive behavioral approach and the teaching of relaxation techniques. Beyond individual therapy, group therapies can address cancer-related issues to enable patients to gain emotional support from other patients with similar experiences and to use these experiences to buffer the fear of dying and the unknown future. One of the overall therapeutic targets is the promotion of the patient's individual resources. Therefore, such groups are helpful not only for the patients, but also for their spouses and other family members, in relieving the cancer-related distress. In Germany, support groups are established in rehabilitation clinics as well as outpatient programs and play an important role in palliative and supportive care of cancer patients. Against the background of changes in the patients' role, the increasing availability of information technology (e.g. the internet) and patient advocacy in cancer treatment, support groups may be understood as a mean of empowerment of the patient. The need for group interventions such as outpatient programs for cancer patients is claimed not only by the health professionals but also by the patients themselves. There is some research emphasizing that avoidance of feelings, denial of concerns, feelings of helplessness and social isolation are correlated with poorer health outcome and poorer quality of life. Many empirical studies have provided evidence-based knowledge that structured group interventions for cancer patients improve psychological wellbeing, reduce anxiety and depression, and improve quality of life, coping and mental adjustment. Positive effects on survival have even been reported, but these effects have not yet been proven.


Effects of Mu-Opiate Receptor Gene Polymorphism rs1799971 (A118G) on the Antidepressant and Dissociation Responses in Esketamine Nasal Spray Clinical Trials.
At ketamine and esketamine doses at which antidepressant doses are achieved, these agents are relatively selective, noncompetitive, N-methyl-D-aspartate receptor antagonists. However, at substantially higher doses, ketamine has shown mu-opioid receptor (MOR-gene symbol: OPRM1) agonist effects. Preliminary clinical studies showed conflicting results on whether naltrexone, a MOR antagonist, blocks the antidepressant action of ketamine. We examined drug-induced or endogenous MOR involvement in the antidepressant and dissociative responses to esketamine by assessing the effects of a functional single nucleotide polymorphism rs1799971 (A118G) of OPRM1, which is known to alter MOR agonist-mediated responses. Participants with treatment-resistant depression from 2 phase III, double-blind, controlled trials of esketamine (or placebo) nasal spray plus an oral antidepressant were genotyped for rs1799971. Participants received the experimental agents twice weekly for 4 weeks. Antidepressant responses were rated using the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score on days 2 and 28 post-dose initiation, and dissociative side effects were assessed using the Clinician-Administered Dissociative-States Scale at 40 minutes post-dose on days 1 and 25. In the esketamine + antidepressant arm, no significant genotype effect of single nucleotide polymorphism rs1799971 (A118G) on MADRS score reductions was detected on either day 2 or 28. By contrast, in the antidepressant + placebo arm, there was a significant genotype effect on MADRS score reductions on day 2 and a nonsignificant trend on day 28 towards an improvement in depression symptoms in G-allele carriers. No significant genotype effects on dissociative responses were detected. Variation in rs1799971 (A118G) did not affect the antidepressant response to esketamine + antidepressant. Antidepressant response to antidepressant + placebo was increased in G-allele carriers, compatible with previous reports that release of endorphins/enkephalins may play a role in mediating placebo effect. NCT02417064 and NCT02418585; www.clinicaltrials.gov.


Metformin Inhibits Migration and Invasion of Cholangiocarcinoma Cells
Background: Metformin is an oral anti-diabetic agent that has been widely prescribed for treatment of type II diabetes. Anti-cancer properties of metformin have been revealed for numerous human malignancies including cholangiocarcinoma (CCA) with anti-proliferative effects in vitro. However, effects on CCA cell migration and invasion have not been fully investigated. The present study aimed to explore the inhibitory effects of metformin on motility, migration and invasion of the CCA cell line HuCCT1, and examine molecular mechanisms underlying metformin effects. Methods: HuCCT1 cells were exposed to increasing doses of metformin. Viability and growth of HuCCT1 cells were assessed by MTS and colony formation assays, respectively. Motility, migration and invasion of metformin-treated HuCCT1 cells were determined in vitro using wound healing, transwell migration and matrigel invasion assays. Expression of signaling molecules and epithelial-mesenchymal transition (EMT) markers was assessed by Western blotting. Results: It was observed that metformin significantly decreased HuCCT1 cell viability and colony formation. The agent also markedly reduced wound closure, migration and invasion of HuCCT1 cells. Furthermore, metformin exposure resulted in decreased STAT3 activation and down-regulation of anti-apoptotic protein Bcl-2 and Mcl-1 expression. In addition, it upregulated the expression of E-cadherin, while downregulating that of N-cadherin, Snail, and MMP-2. Conclusion: These results demonstrated inhibitory effects of metformin on CCA cell migration and invasion, possibly involving the STAT3 pathway and reversal of EMT markers expression. They further suggest that metformin may be useful for CCA management.


Detecting failed elements on phased array ultrasound transducers using the Edinburgh Pipe Phantom.
Imaging faults with ultrasound transducers are common. Failed elements on linear and curvilinear array transducers can usually be detected with a simple image uniformity or 'paperclip' test. However, this method is less effective for phased array transducers, commonly used in cardiac imaging. The aim of this study was to assess whether the presence of failed elements could be detected through measurement of the resolution integral (R) using the Edinburgh Pipe Phantom. A 128-element paediatric phased array transducer was studied. Failed elements were simulated using layered polyvinyl chloride (PVC) tape as an attenuator and measurements of resolution integral were carried out for several widths of attenuator. All widths of attenuator greater than 0.5 mm resulted in a significant reduction in resolution integral and low contrast penetration measurements compared to baseline (p < 0.05). Measurements of resolution integral and low contrast penetration both have the potential to be used as straightforward and inexpensive tests to detect failed elements on phased array transducers. Particularly encouraging is the result for low contrast penetration as this is a quick and simple measurement to make and can be performed with many different test objects, thus enabling 'in-the-field' checks.


Characterization of serotonin in protein and membrane mimetic environments: a spectroscopic study.
As a first step toward using the photophysical properties of serotonin to probe its interactions with biological target sites, we have examined its interactions with human serum albumin (HSA), chosen as a surrogate for the actual receptor proteins in physiological systems, and with sodium bis(2-ethylhexyl)sulfosuccinate (AOT)/heptane/water reverse micelles, chosen as a biomembrane mimetic environment for the transmembrane portion of the receptor protein. Although the emission maximum of serotonin is relatively insensitive to the polarity of the local environment, which is attributed to lack of solvent dipolar reorientation of the 5-hydroxyindole chromophore, the fluorescence anisotropy (r) served as a useful and sensitive parameter from which the binding constants (K) and Gibbs energy changes (deltaG) were estimated for serotonin-HSA and serotonin-AOT reverse micellar interactions. Fluorescence-decay studies of serotonin show double-exponential kinetics in homogeneous aqueous solvent due to the structural heterogeneity arising from different rotamers of serotonin. In contrast, upon binding to HSA, a single-exponential fluorescence-decay profile was observed indicating the occurrence of a single structural species of serotonin in the protein environment. Furthermore, far-UV-circular-dichroism (CD) spectroscopic data indicate that the secondary structural features of HSA remain essentially intact after binding to serotonin. This preliminary research can be expected to open the door to extensive future studies on interactions of serotonin with relevant target proteins and associated cell membranes involved in its diverse physiological functions.


5-Azacytidine (5Az) induces apoptosis in PC12 cells: a model for 5Az-induced apoptosis in developing neuronal cells.
Our previous in vivo and in vitro studies showed that 5-azacytidine (5Az), a cytidine analog, induced apoptosis in developing neuronal cells in mice. To develop a system in which the precise molecular mechanism of 5Az-induced apoptosis in developing neuronal cells could be elucidated, we carried out the present study with PC12 cells. These cells are derived from a rat pheochromocytoma and extrude neurites in response to nerve growth factor (NGF). Light microscopy showed dose-dependent pyknotic and karyorrhectic changes in undifferentiated PC12 cells. Although they were less sensitive to 5Az, NGF-treated differentiated cells showed the same changes. Analysis by the TUNEL method (an in situ method for the detection of apoptosis) showed positive signals in the pyknotic and fragmented nuclei of these cells. Transmission electron microscopy revealed margination, segmentation, and condensation of nuclear chromatin, cell body shrinkage, and cytoplasmic vacuolization. Scanning electron microscopy demonstrated bleb formation on the cell surface. These pathomorphological changes are typical of apoptosis. 5Az seemed to affect cells that were in the proliferative stage; when the cells were terminally differentiated, their sensitivity to 5Az appeared to decline. PC12 cells could be used as a pathomorphological and biochemical model for studies of 5Az-induced neuronal cell apoptosis at the molecular and genetic level.


Transposable elements and tumor progression.
Although the concept that transposable elements (TEs) have the potential to enhance their host genomic evolution is widely accepted, it is still generally assumed that TEs primarily owe their prosperity to replicative advantage because the immediate effects on their hosts are generally harmful. To mitigate deleterious impact, hosts employ a cosuppression strategy to tame these perilous elements. The peculiarity of this strategy, however, is that TEs, as targets of suppression, also serve as primary components of this 'TE immune system'. Based on this view, we propose a possible mechanism whereby TEs are involved in tumor progression.


[Gillies and McLaughlin's dynamic muscle support in irreversible facial palsy].
The goals in surgical treatment of unilateral long-standing facial paralysis are individual concepts restoring mimetic function, aesthetic facial symmetry at rest and protection of the eye by complete eyelid closure. Facial reanimation with free neuromuscular flaps is the actual standard treatment. The reanimation of the paralysed eyelid is still a major problem. Gillies described in 1934 his technique using the transposition of the temporal muscle with two strips of its own fascia performing a dynamic support of the upper and lower eyelid. McLaughlin was using the temporal muscle in combination with fascia lata for the reanimation of the oral muscle sling (1953). There are still some indications for these procedures. The long-term follow-up of 93 patients with Gillies procedure and 180 patients with McLaughlin's muscle support gives a sound base for decision making in facial reanimation.


NY-BR-1 Antigen Expression and anti-NY-BR-1 IgG in Egyptian Breast Cancer Patients: Clinicopathological and Prognostic Significance.
Breast cancer is the most common gynecological malignancy in the world. In Egypt, it ranks the first among female malignancies with incidence of 37.7%. Over the last decades, the integration of prognostic and predictive markers in treatment decisions has led to more individualized and optimized therapy. NY-BR-1 antigen has been shown to be frequently expressed in breast cancers. The study aimed to assess the tissue expression of NY-BR-1 antigen and serum IgG antibody to this antigen in Egyptian breast cancer females. The study was conducted on 60 females (10 healthy, 10 having benign breast lesions, 40 with malignant breast cancer). NY-BR-1 Ag expression was evaluated by immunohistochemistry and anti-NY-BR-1 IgG was assessed by ELISA. Results revealed a significant difference in NY-BR-1 Ag expression between benign and malignant breast cancer patients. There was a significant correlation between NY-BR-1 antigen expression and estrogen receptor's status (P = 0.019), stage of the disease (P = 0.008), menopausal status (P = 0.008), lymph node involvement (P = 0.022) and anti-NY-BR-1 IgG (P = 0.032) among the studied individuals. In addition, there was a statistically significant increase in anti-NY-BR-1 IgG O.D. results among malignant breast cancer group. It is correlated with tumor type (P < 0.001) and progesterone receptor status (P = 0.038). In conclusion, our work may represent a step towards identification of a new prognostic marker specific for breast cancer.


Central action of 6-hydroxytryptamine in rats.
The effects of 6-hydroxytryptamine (6-HT), an analogue of 5-hydroxytryptamine (5-HT) injected into a lateral brain ventricle of rats (i.c.v.) on the behaviour of animals spontaneous and exploratory activity as well as amphetamine and chlorpromazine influenced motor activity were studied. Moreover, 6-HT i.c.v. effect was investigated on rectal body temperature, duration and hexobarbital induced sleep, blood pressure and heart rate. In a separate series of experiments the effect of 6-HT after i.c.v. administration of 200 microgram was studied on the level of 5-HT, 5-hydroxyindoleacetic acid, noradrenaline, dopamine and acetylcholine as well as on the activity of acetylcholine esterase and acetyltransferase in the whole brain and in its various parts. It was demonstrated that 6-HT had a short-lasting inhibitory effect on the behaviour of animals and on the concentrations of biogenic amines in the brain. Although the effects of 6-HT in certain pharmacological tests used here resembled the known effects of 5-HT, it seems that the action of 6-HT on the central nervous system is of low specificity.


Lipid biomarkers recording marine microbial community structure changes through the Frasnian-Famennian mass extinction event.
Studying the response and recovery of marine microbial communities during mass extinction events provides an evolutionary window through which to understand the adaptation and resilience of the marine ecosystem in the face of significant environmental disturbances. The goal of this study is to reconstruct changes in the marine microbial community structure through the Late Devonian Frasnian-Famennian (F-F) transition. We performed a multiproxy investigation on a drill core of the Upper Devonian New Albany Shale from the Illinois Basin (western Kentucky, USA). Aryl isoprenoids show green sulfur bacteria expansion and associated photic zone euxinia (PZE) enhancement during the F-F interval. These changes can be attributed to augmented terrigenous influxes, as recorded collectively by the long-chain/short-chain normal alkane ratio, carbon preference index, C30 moretane/C30 hopane, and diahopane index. Hopane/sterane ratios reveal a more pronounced dominance of eukaryotic over prokaryotic production during the mass extinction interval. Sterane distributions indicate that the microalgal community was primarily composed of green algae clades, and their dominance became more pronounced during the F-F interval and continued to rise in the subsequent periods. The 2α-methylhopane index values do not show an evident shift during the mass extinction interval, whereas the 3β-methylhopane index values record a greater abundance of methanotrophic bacteria during the extinction interval, suggesting enhanced methane cycling due to intensified oxygen depletion. Overall, the Illinois Basin during the F-F extinction experienced heightened algal productivity due to intensified terrigenous influxes, exhibiting similarities to contemporary coastal oceans that are currently undergoing globalized cultural eutrophication. The observed microbial community shifts associated with the F-F environmental disturbances were largely restricted to the extinction interval, which suggests a relatively stable, resilient marine microbial ecosystem during the Late Devonian.


Quinidine and procainamide inhibit murine macrophage uptake of apoptotic and necrotic cells: a novel contributing mechanism of drug-induced-lupus.
A number of mechanisms have been proposed to explain the etiology of drug-induced lupus (DIL) but the effect of apoptotic and necrotic cell handling has not been previously examined. To evaluate the effect of quinidine and procainamide at therapeutic range concentrations, on the uptake of apoptotic and necrotic thymocytes by murine peritoneal macrophages and on macrophage survival, as a novel mechanism for DIL. Thymocytes were stained and induced to undergo apoptosis by serum withdrawal. Apoptosis was evaluated using annexin V and propidum iodide (PI) and PI staining. Necrosis was induced by heating. Peritoneal macrophages were treated with quinidine or procainamide at a range of therapeutic concentrations and incubated with stained apoptotic and necrotic thymocytes. Apoptotic and necrotic cell uptake was evaluated by flow cytometry using double staining of thymocytes and macrophages and by confocal microscopy. Green fluorescent latex beads were used as controls for phagocytosis. Significantly decreased uptake of apoptotic and necrotic cells was seen in the presence of quinidine and procainamide. The documented effect was mainly on the number of apoptotic/necrotic cells per macrophage. Uptake of fluorescent latex beads offered to resident macrophages was not significantly affected by quinidine or procainamide. No pro-apoptotic effect of quinidine or procainamide on macrophages was seen. Quinidine and procainamide at therapeutic range concentrations specifically inhibit clearance of apoptotic and necrotic cells by peritoneal macrophages. Altered handling of apoptotic and necrotic cells may represent a contributing mechanism for DIL.


PhosphaBase: an ontology-driven database resource for protein phosphatases.
PhosphaBase is an ontology-driven database resource containing information on the protein phosphatase family. It is the first public resource dedicated to protein phosphatases, which are enzymes that perform dephosphorylation reactions. In conjunction with the phosphorylation action of protein kinases, phosphatases are involved in important control and communication mechanisms in the cell. They have also been implicated in many human diseases, including diabetes and obesity, cancers, and neurodegenerative conditions. PhosphaBase aims to centralize the growing base of knowledge in the phosphatase research domain. The resource is built around a formal, domain-specific DAML+OIL ontology, and the data are collected from heterogeneous biological sources using Gene Ontology terms as a means of data extraction. The overall ontology-driven architecture provides a robust structure with distinct advantages for sustainability and provides the potential for the development of diagnostic tools, as well as a data repository.


Helminth community structure of sympatric eastern American toad, Bufo americanus americanus, northern leopard frog, Rana pipiens, and blue-spotted salamander, Ambystoma laterale, from southeastern Wisconsin.
One-hundred twelve amphibians, including 51 blue-spotted salamanders, Ambystoma laterale, 30 eastern American toads, Bufo americanus americanus, and 31 northern leopard frogs, Rana pipiens, were collected during April-October 1996 from Waukesha County, Wisconsin and examined for helminth parasites. The helminth compound community of this amphibian assemblage consisted of at least 10 species: 9 in American toads, 8 in leopard frogs, and 3 in blue-spotted salamanders. American toads shared 7 species with leopard frogs, and 2 species occurred in all 3 host species. Although there was a high degree of helminth species overlap among these sympatric amphibians, statistically significant differences were found among host species and percent of indirect or direct-life cycle parasites of amphibian species individual component communities (chi2 = 1,015, P < 0.001). American toads had a higher relative abundance of nematodes, 59%, than larval cestodes, 31%, and larval and adult trematodes, 10%, whereas leopard frogs had a higher relative abundance of larval cestodes, 71.3%, and larval and adult trematodes, 25.3%, than nematodes 3.4%. This is related to ecological differences in habitat and dietary preferences between these 2 anuran species. Helminth communities of blue-spotted salamanders were depauperate and were dominated by larval trematodes, 94%, and few nematodes, 6%. Low helminth species richness in this host species is related to this salamander's relatively small host body size, smaller gape size, lower vagility, and more fossorial habitat preference than the other 2 anuran species. Adult leopard frogs and toads had significantly higher mean helminth species richness than metamorphs, but there was no significant difference in mean helminth species richness among adult and metamorph blue-spotted salamanders. Considering adult helminths, the low species richness and low vagility of caudatans as compared with anurans suggest that local factors may be more important in structuring caudatan helminth communities of salamanders than of anuran hosts. Helminth species infecting salamanders may be more clumped in their geographic distribution as compared with anurans, and the role of other hosts and their parasites at the compound community level may be important in structuring helminth communities of salamanders.


Progressive derangement of the T cell compartment in a case of Evans syndrome.
Evans syndrome (ES) is a rare disorder characterized by combined autoimmune thrombocytopenia and autoimmune hemolytic anemia. Several studies have documented a number of B cell defects, whereas only limited information is currently available about the T cell subset. A wide panel of immunological analyses aiming specifically at a quantitative and qualitative evaluation of the T cell compartment was performed in an unusual case of ES. The peripheral distribution of the T cell subsets, the diversity of the T cell receptor (TCR) repertoires, the cytokine profile and the T cell apoptosis have been longitudinally evaluated. On first investigation, flow-cytometric immunophenotyping showed a remarkable alteration of T cell homeostasis with deeply reduced CD4+ naive T cells and recent thymic emigrants. This was seen in association with increased levels of T cell activation and apoptosis. Consistently with these data the cytokine profile was characterized by high interferon-gamma and low interleukin-2 levels. Staining for CD4 and CD25 molecules showed decreased percentages of circulating regulatory T cells according to the autoimmune nature of ES. Finally, restricted TCR repertoires were demonstrated by a skewed TCR beta chain variable (TCRBV) gene usage as well as oligoclonal third complementarity-determining region (CDR3) profiles. A deterioration of the above-mentioned parameters and a worsening of the clinical condition were observed during the follow-up requiring more intensive treatments. The demonstration of multiple T cell defects, in addition to providing pathogenetic information, is likely to alter both acute treatment and outcome of ES.


The 'methodic' exploration of the ethical and pastoral dimension in interaction: the cycle of encounter.
Social competence can be understood as the capacity to interact with each other. As such, it is the acquisition and optimization of an interior attitude that transcends technique; it is a way of loving and doing justice to one another. A scheme is presented to explore the ethical and spiritual dimensions of the pastoral counseling process. Ethics is both an objective discipline and a relationship. Relationships are built during qualitative encounters that build respect and construct religious meanings. All encounters share this process. This article explores the logic of ethical dynamics with particular focus on pastoral counseling encounters.


Control, Suppression, and Monitoring of Infectious Laryngotracheitis in a Multiage Commercial Layer Pullet Farm in Canada.
A multiage commercial layer pullet operation with a history of chicken embryo-origin (CEO) modified live infectious laryngotracheitis (ILT) virus vaccination suffered severe ILT outbreaks in 2017. The initial sequencing revealed that the circulating virus was of vaccine origin. Changes to the timing and dosage of CEO ILT vaccine failed to control the outbreak. The clinical resolution of the outbreak occurred with the transition to a turkey herpesvirus vector vaccine given in-hatchery, followed by a tissue culture-origin vaccine given on the farm. The circulating ILT viruses were monitored periodically by next-generation sequencing. This site became free of ILT virus within 1 yr after implementing the new vaccination program.


Risk scores for diabetes and impaired glycaemia in the Middle East and North Africa.
To develop risk scores for diabetes and diabetes or impaired glycaemia for individuals living in the Middle East and North Africa region. In addition, to derive national risk scores for Algeria, Saudi Arabia and the United Arab Emirates and to compare the performance of the regional risk scores with the national risk scores. An opportunistic sample of 6588 individuals aged 30-75 years was screened. Screening consisted of a questionnaire and a clinical examination including measurement of HbA(1c). Two regional risk scores and national risk scores for each of the three countries were derived separately by stepwise backwards multiple logistic regression with diabetes [HbA(1c) ≥ 48 mmol/mol (≥ 6.5%)] and diabetes or impaired glycaemia [HbA(1c) ≥ 42 mmol/mol (≥ 6.0%)] as outcome. The performance of the regional and national risk scores was compared in data from each country by receiver operating characteristic analysis. The eight risk scores all included age and BMI, while additional variables differed between the scores. The areas under the receiver operating characteristic curves were between 0.67 and 0.70, and for sensitivities approximately 75%; specificities varied between 50% and 57%. The regional and the national risk scores performed equally well in the three national samples. Two regional risk scores for diabetes and diabetes or impaired glycaemia applicable to the Middle East and North Africa region were identified. The regional risk scores performed as well as the national risk scores derived in the same manner.


Cold-reactive alloantibodies and allograft malfunction occurring immediately posttransplant.
Certain kidney allografts function promptly, whereas others subjected to similarly optimal procurement and preservation methods do not. Previous reports have indicated that such unexplained allograft malfunction (AM) could be due to the presence of cold-reactive IgM alloantibodies (i.e., lymphocytotoxins and agglutinins) present in renal transplant recipients. These investigations were undertaken to determine whether the presence of such alloantibodies was associated with any histological abnormalities. Pretransplant and 1-hr posttransplant biopsies were analyzed from 49 cadaveric renal allografts that came from ideal donors and were subjected to "optimal" preservation. First, no correlation could be made between AM and the severity of renal tubular cell disruption. However, glomerular lesions in the posttransplant biopsy correlated significantly with the development of AM. Segmental glomerular intracapillary red blood cell aggregates and fibrin deposition were present in 71% of biopsies in the 21 allografts with AM, whereas such lesions were present in 29% of biopsies in the 28 allografts with immediate function (P less than 0.005). Development of glomerular lesions correlated significantly with the presence of cold-reactive lymphocytotoxins (CRL) in the recipient (60% vs. 9%). Sera containing CRL were found to also have IgM antiendothelial cell antibody. These observations suggest that another possible mechanism for lack of prompt allograft function is a self-limiting vascular injury, that occurs in the cold and is immune-mediated.


Making Sense of the Growth Behavior of Ultra-High Magnetic Gd2-Doped Silicon Clusters.
The growth behavior, stability, electronic and magnetic properties of the Gd2Sin- (n = 3-12) clusters are reported, which are investigated using density functional theory calculations combined with the Saunders 'Kick' and the Artificial Bee Colony algorithm. The lowest-lying structures of Gd2Sin- (n = 3-12) are all exohedral structures with two Gd atoms face-capping the Sin frameworks. Results show that the pentagonal bipyramid (PB) shape is the basic framework for the nascent growth process of the present clusters, and forming the PB structure begins with n = 5. The Gd2Si5- is the potential magic cluster due to significantly higher average binding energies and second order difference energies, which can also be further verified by localized orbital locator and adaptive natural density partitioning methods. Moreover, the localized f-electron can be observed by natural atomic orbital analysis, implying that these electrons are not affected by the pure silicon atoms and scarcely participate in bonding. Hence, the implantation of these elements into a silicon substrate could present a potential alternative strategy for designing and synthesizing rare earth magnetic silicon-based materials.


Prematurity is related to high placental cortisol in preeclampsia.
Fetal growth is compromised in animal models with high cortisol availability. In healthy pregnancies, the fetus is protected from high circulating cortisol levels by the placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which is reduced in preeclampsia. We hypothesized increased placental cortisol availability in preeclampsia as missing link to fetal growth restriction and prematurity. Placental tissue was obtained from 39 pregnant women dichotomized normotensive (n = 16) or preeclamptic (n = 23). Placental steroid hormone metabolites were analyzed by gas chromatography-mass spectrometry. Apparent 11beta-HSD2 enzyme activity was calculated as substrate to product ratio. Estradiol and pregnandiol positively correlated with gestational age. Cortisol was virtually absent in 93.8% of controls, yet detectable in 79.3% of preeclamptic samples resulting in an odds ratio (OR) of 0.019 (95% CI 0.002-0.185) for the presence of placental cortisol. Apparent 11beta-HSD2 activity directly correlated with birth weight (R2 = 0.16; p < 0.02) and gestational age (R2 = 0.11; p < 0.04) ensuing a reduced risk of premature delivery (OR 0.12; 95% CI 0.02-0.58). We conclude that normotensive pregnancies are characterized by an almost completely inactivated placental cortisol. In line with our hypothesis, reduced 11beta-HSD2 activity in preeclampsia is unable to abolish placental cortisol, a finding clearly associated with prematurity and low birth weight.


Insensitivity of tryptophan fluorescence to local charge mutations.
The steady state fluorescence spectral maximum (λmax) for tryptophan 140 of Staphylococcal nuclease remains virtually unchanged when nearby charged groups are removed by mutation, even though large electrostatic effects on λmax might be expected. To help understand the underlying mechanism of this curious result, we have modeled λmax with three sets of 50-ns molecular dynamics simulations in explicit water, equilibrated with excited state and with ground state charges. Semiempirical quantum mechanics and independent electrostatic analysis for the wild-type protein and four charge-altering mutants were performed on the chromophore using the coordinates from the simulations. Electrostatic contributions from the nearby charged lysines by themselves contribute 30-90 nm red shifts relative to the gas phase, but in each case, contributions from water create compensating blue shifts that bring the predicted λmax within 2 nm of the experimental value, 332 ± 0.5 nm for all five proteins. Although long-range collective interactions from ordered water make large blue shifts, crucial for determining the steady state λmax for absorption and fluorescence, such blue shifts do not contribute to the amplitude of the time dependent Stokes shift following excitation, which comes from nearby charges and only ∼6 waters tightly networked with those charges. We therefore conclude that for STNase, water and protein effects on the Stokes shift are not separable.


Traumatic brain injury among U.S. active duty military personnel and negative drinking-related consequences.
This study used the 2008 Department of Defense Survey of Health Related Behaviors among Active Duty Military Personnel to determine whether traumatic brain injury (TBI) is associated with past year drinking-related consequences. The study sample included currently drinking personnel who had a combat deployment in the past year and were home for ≥6 months (N = 3,350). Negative binomial regression models were used to assess the incidence rate ratios of consequences, by TBI-level. Experiencing a TBI with a loss of consciousness for more than 20 minutes was significantly associated with consequences independent of demographics, combat exposure, posttraumatic stress disorder, and binge drinking. The study's limitations are noted.


The effect of submarine groundwater discharge on the ocean.
The exchange of groundwater between land and sea is a major component of the hydrological cycle. This exchange, called submarine groundwater discharge (SGD), is comprised of terrestrial water mixed with sea water that has infiltrated coastal aquifers. The composition of SGD differs from that predicted by simple mixing because biogeochemical reactions in the aquifer modify its chemistry. To emphasize the importance of mixing and chemical reaction, these coastal aquifers are called subterranean estuaries. Geologists recognize this mixing zone as a site of carbonate diagenesis and dolomite formation. Biologists have recognized that terrestrial inputs of nutrients to the coastal ocean may occur through subterranean processes. Further evidence of SGD comes from the distribution of chemical tracers in the coastal ocean. These tracers originate within coastal aquifers and reach the ocean through SGD. Tracer studies reveal that SGD provides globally important fluxes of nutrients, carbon, and metals to coastal waters.


Molecular cloning of cDNA for SPase, a monkey cathepsin L orthologue.
SPase is a cysteine protease isolated from an African green monkey kidney cell line, CV-1, and has selective cleavage activity toward transcription factor SP-1 and retinoblastoma susceptibility gene product RB. In this study, a cDNA encoding SPase was cloned from a cDNA library prepared from CV-1 cells. The cDNA clone encodes 333 amino acids and is 96.5% identical to human cathepsin L at the nucleotide and amino acid sequence levels. SPase appears to be translated as a preproenzyme based on the comparison between the deduced amino acid sequence and the N-terminal sequence of the purified enzyme. Northern blot analysis exhibited the considerably higher expression of SPase in CV-1 cells compared with COS-1 cells, showing a good correlation with enzymatic activity in these cell lines. Bacterially expressed SPase protein exhibited proteolytic activity toward SP-1 and RB proteins. These observations suggest that SPase is a monkey cathepsin L orthologue.


Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels.
The human ether-a-go-go-related gene (HERG) encodes a K+ channel with biophysical properties nearly identical to the rapid component of the cardiac-delayed rectifier K+ current (I(Kr)). HERG channels are one primary target for the pharmacological management of arrhythmias. In this study, we investigated the acute effects of the class III antiarrhythmic drug amiodarone on HERG channels expressed heterologously in Xenopus oocytes by use of the two-microelectrode voltage clamp technique. Amiodarone blocked HERG channels with an IC50 of 9.8 microM with a maximum outward tail current reduction of 62.8%. The block consisted of two main components, a closed channel block that could not be reversed within the time of experiments and an open channel block with a slow unblock, having a recovery time constant of 73 s at -80 mV. Inactivation of the HERG channel at very positive potentials could not prevent amiodarone block. These results indicate that HERG channels can be blocked by amiodarone in closed, open and inactivated states. The block of open channels was cumulative, use-dependent and voltage-dependent. In summary, our data suggest that the strong class III antiarrhythmic action of amiodarone is at least partially based upon its acute inhibitory effects on HERG potassium channels.


Can a single dose of human papillomavirus (HPV) vaccine prevent cervical cancer? Early findings from an Indian study.
Human papillomavirus (HPV) vaccination is a major strategy for preventing cervical and other ano-genital cancers. Worldwide HPV vaccination introduction and coverage will be facilitated if a single dose of vaccine is as effective as two or three doses or demonstrates significant protective effect compared to 'no vaccination'. In a multi-centre cluster randomized trial of two vs three doses of quadrivalent HPV vaccination (Gardasil™) in India, suspension of the vaccination due to events unrelated to the study led to per protocol and partial vaccination of unmarried 10-18 year old girls leading to four study groups, two by design and two by default. They were followed up for the primary outcomes of immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity for the vaccine-targeted HPV types and HPV infections. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov, number NCT00923702. Of the 17,729 vaccinated girls, 4348 (25%) received three doses on days 1, 60, 180 or later, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses on days 1 and 60, and 4950 (28%) received one dose. One dose recipients demonstrated a robust and sustained immune response against HPV 16 and 18, albeit inferior to that of 3- or 2-doses and the antibody levels were stable over a 4 year period. The frequencies of cumulative incident and persistent HPV 16 and 18 infections up to 7 years of follow-up were similar and uniformly low in all the vaccinated study groups; the frequency of HPV 16 and 18 infections were significantly higher in unvaccinated age-matched control women than among vaccine recipients. The frequency of vaccine non-targeted HPV types was similar in the vaccinated groups but higher in the unvaccinated control women. Our results indicate that a single dose of quadrivalent HPV vaccine is immunogenic and provides lasting protection against HPV 16 and 18 infections similar to the three- and two-dose vaccine schedules, although the study suffer from some limitations. Data on long term protection beyond 7 years against HPV infection and cervical precancerous lesions are needed before policy guidelines regarding a single dose can be formulated and implemented. Significant and long-lasting protective effect of a single dose can be a strong argument to introduce one dose of the HPV vaccine in many low income countries where the current standard of care for cervical cancer prevention is 'no intervention'.


Treatment-free remission in patients with chronic myeloid leukemia following the discontinuation of tyrosine kinase inhibitors.
Tyrosine kinase inhibitors (TKIs) discontinuation in patients with Philadelphia-chromosome-positive chronic myeloid leukemia (Ph-positive CML) is increasingly considered. We aim to evaluate the outcome of patients with CML who discontinued TKIs, and determine the factors associated with differences in the success rates of treatment-free remission (TFR). Patients with Ph-positive CML treated between October 1999 and February 2017 who discontinued therapy were analyzed. A major molecular response (MMR) was defined as BCR-ABL1/ABL1 ratio on the International Scale ≤0.1%. TFR failure was defined as the loss of MMR on any single test. We analyzed TFR rates according to duration and depth of response, and conducted a multivariate analysis for factors associated with loss of MMR. Two-hundred and eighty-four patients were analyzed; 199 patients (70%) electively discontinued TKIs. At a median follow-up of 36 months (95% confidence interval, 32-40) after TKI discontinuation, 53 patients (19%) lost MMR. The estimated 5-year TFR rate was 79%. All but one patient regained MMR after resuming therapy. The estimated 5-year TFR rates were higher with MR4 and MR4.5 ≥5 years, compared with MR4 <5 years (87% vs. 92% vs. 64%; p < .0001). By multivariate analysis, only the duration of MR4 or MR4.5 ≥5 years before stopping treatment was associated with a lower risk of loss of MMR. In summary, TFR is safe and feasible in patients with Ph-positive CML on TKI therapy. Achieving MR4 or MR4.5 for at least 5 years is correlated with a better outcome.


Curable or treatable? The implications of different definitions of illness when treating patients suffering from amyotrophic lateral sclerosis.
People suffering from amyotrophic lateral sclerosis (ALS) have complex health and care needs. The purpose of this study was to gain insight into the gaps in the health and community service care provided to ALS patients. In order to ensure continuity of care, specialist centres have to build effective relationships with local primary health care services and community services, health managers, physicians, patients, families and the surrounding support networks. We undertook a qualitative study that examined the specialist centres in hospitals, communities and primary care services. In 2010 we carried out 47 semi-structured interviews and one group interview in Italy, targeting all those involved in ALS care, on all levels. We used purposive sampling to obtain maximum variation across professions, sectors and services. Participants reported gaps arising when local health managers have to assess patient eligibility for certain services. The need to set priorities when allocating resources means that professionals 'categorize' patients without considering the multidimensional nature of their needs. For instance, rehabilitation is generally guaranteed for people with temporary or non-progressive functional limitations, yet it is not granted to degenerative patients. Patients with similar physical conditions, with perceived differences of other kinds (i.e. curable vs. treatable), may experience differential access to care.


Notes from the field: fatal rat-bite fever in a child - San Diego County, California, 2013.
In August 2013, the County of San Diego Health and Human Services Agency was notified of a fatal case of rat-bite fever (RBF) in a previously healthy male, aged 10 years, who owned pet rats. Two days before his death, the patient experienced rigors, fevers, vomiting, headaches, and leg pains. His physician noted a fever of 102.6°F (39.2ºC), documented a normal examination, diagnosed viral gastroenteritis, and prescribed anti-nausea medication. During the next 24 hours, the patient experienced vomiting and persistent fever. He was confused and weak before collapsing at home. Paramedics reported the patient was unresponsive and had dilated pupils; resuscitation was initiated in the field and was continued for >1 hour after arrival at the emergency department but was unsuccessful. A complete blood count performed during resuscitation revealed anemia (hemoglobin 10.0 g/dL [normal = 13.5-18.0 g/dL], thrombocytopenia (platelets 40,000/µL [normal = 140,000-440,000/µL]), leukocytosis (white blood cells 17,900 cells/µL [normal = 4,000-10,500/µL]) with 16% band neutrophils; the patient also had evidence of disseminated intravascular coagulation. No rash or skin breakdown was noted. Lung, liver, and epiglottis tissue collected postmortem was positive for Streptobacillus moniliformis DNA by polymerase chain reaction.


Effects of phosphoramidon and pepstatin A on the secretion of endothelin-1 and big endothelin-1 by human umbilical vein endothelial cells: measurement by two-site enzyme-linked immunosorbent assays.
1. Two-site enzyme-linked immunosorbent assays have been developed for the rapid, sensitive and non-isotopic measurement of endothelin-1 and big endothelin-1. The sensitivities of detection were 0.5 and 0.3 fmol/well, with ED50 values of 13 and 12 fmol/well for the endothelin-1 and big endothelin-1 assays, respectively. Each assay is highly selective for its corresponding antigen. The ET-1 assay showed no detectable cross-reactivity with ET-1-(1-20), indicating that the assay only recognizes the 21-amino acid biologically active peptide. 2. The two assays were used to measure the effects of two classes of protease inhibitor on the basal release of enothelin-1 and big endothelin-1 from cultured first-passage human umbilical vein endothelial cells. 3. The secretion of both peptides was time-dependent over 12 h. The metalloprotease inhibitor phosphoramidon (1 x 10(-4) mol/l) significantly reduced the amount of endothelin-1 secreted into the medium (P < 0.05), with a concomitant increase in the secreted levels of big endothelin-1 (P < 0.01). The aspartyl protease inhibitor, pepstatin A, also caused a significant decrease in the secretion of endothelin (P < 0.05). However, unlike phosphoramidon, there was no increase in the levels of big ET-1 compared with the controls. At these concentrations, neither inhibitor affected the viability of the cells as indicated by Trypan Blue exclusion. 4. The two assays permit the direct measurement of endothelin-1 and its precursor, and will be of use in the elucidation of the putative human endothelin-converting enzyme(s).(ABSTRACT TRUNCATED AT 250 WORDS)


Shock tube and chemical kinetic modeling study of the oxidation of 2,5-dimethylfuran.
A detailed kinetic model describing the oxidation of 2,5-dimethylfuran (DMF), a potential second-generation biofuel, is proposed. The kinetic model is based upon quantum chemical calculations for the initial DMF consumption reactions and important reactions of intermediates. The model is validated by comparison to new DMF shock tube ignition delay time measurements (over the temperature range 1300-1831 K and at nominal pressures of 1 and 4 bar) and the DMF pyrolysis speciation measurements of Lifshitz et al. [ J. Phys. Chem. A 1998 , 102 ( 52 ), 10655 - 10670 ]. Globally, modeling predictions are in good agreement with the considered experimental targets. In particular, ignition delay times are predicted well by the new model, with model-experiment deviations of at most a factor of 2, and DMF pyrolysis conversion is predicted well, to within experimental scatter of the Lifshitz et al. data. Additionally, comparisons of measured and model predicted pyrolysis speciation provides validation of theoretically calculated channels for the oxidation of DMF. Sensitivity and reaction flux analyses highlight important reactions as well as the primary reaction pathways responsible for the decomposition of DMF and formation and destruction of key intermediate and product species.


The natural history of non-Hodgkin's lymphomata stages I and II.
Progress in the management of non-Hodgkin's lymphomata has been impeded by lack of information on the natural history of these diseases. Confusion about the significance of histopathology, extranodal presentations and routes of spread renders much of previously published data relatively uninterpretable. To evaluate the relative prognostic significance of presentation, histopathology and lymphography, a retrospective study was undertaken on 226 patients with Stage I and II disease, who were treated with intensive irradiation to the involve regions. The slides on these patients were reviewed and reclassified in terms of the Rappaport system. The results of this study demonstrated that a nodular histopathological pattern was the most important prognostic factor. The significance of this finding and other factors are discussed in terms of possible new approaches to treatment.


Anti-inflammatory and Anti-oxidative Activities of Paeonol and Its Metabolites Through Blocking MAPK/ERK/p38 Signaling Pathway.
The possible protective and curative effects of paeonol on carrageenan-induced acute hind paw edema in rats and dextran sulfate sodium (DSS)-induced colitis in mice have been evaluated. After oral administration, paeonol (20 and 40 mg/kg) reduced the edema increase in paw volumes and also the development of DSS-induced murine colitis. Furthermore, anti-inflammatory and anti-oxidant activities of paeonol (1) together with its 10 metabolites (M2~M11) were investigated by using in vitro anti-inflammatory and anti-oxidant assays. M3 and M11 exhibited significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities (with EC50 values of 93.44 and 23.24 μM, respectively). All the metabolites except M8 showed hydroxyl radical scavenging activities, and M3 and M11 were the most potent agents (with EC50 values of 336.02 and 124.05 μM, respectively). Inhibitory effects of paeonol, M2~M11 on the overproduction of nitric oxide (NO), and the release of TNF-α were also tested. M3 and M11 potently inhibited lipopolysaccharide (LPS)-induced overproduction of NO in macrophage RAW 264.7. Western blot results demonstrated that paeonol, M3, and M11 downregulated the high expression of inducible nitric oxide synthase (iNOS) and COX-2 proteins, and the effects of M3 and M11 were more potent when compared with paeonol. These findings indicated that paeonol may play anti-inflammatory and anti-oxidant roles by changing to its active metabolites after absorption. In addition, further investigations on the mechanism showed that paeonol, M3, and M11 blocked the phosphorylation of MAPK/ERK 1/2 and p38, whereas they showed no effect on the phosphorylation of JNK. The above results suggested that pre-treatment with paeonol might be an effective therapeutic intervention against inflammatory diseases including colitis.


Complete nucleotide sequence of cfr-carrying IncX4 plasmid pSD11 from Escherichia coli.
We report the complete nucleotide sequence of a plasmid carrying the multiresistance gene cfr. This plasmid was isolated from an Escherichia coli strain of swine origin in 2011. This 37,672-bp plasmid, pSD11, had an IncX4 backbone similar to those of the IncX4 plasmids obtained from the United States and Australia, in which the cfr gene was flanked by two copies of IS26 and a truncated Tn1331 was inserted.


Hyaluronic acid gel-core liposomes (hyaluosomes) enhance skin permeation of ketoprofen.
Since FDA approval of the first transdermal patch in 1979, the utilizing of skin as a route of systemic drug administration has attracted the attention of the formulation scientists. The liposomes research in the area of transdermal drug delivery has been around for decades. This study aimed at comparing the latest gel-core liposomes (hyaluosomes) with nonconventional liposomal systems such as propylene glycol (PG)-liposomes, ethosomes, transferosomes and conventional liposomes loaded with ketoprofen. The modified thin-film hydration method was used to prepare these liposomal systems; size, zeta potential, EE%, TEM, rheological properties, in vitro release and ex vivo permeation studies were performed. Vesicle size and PDI ranged from 160 nm to 700 nm and 0.15 to 0.5, respectively. More interestingly, thermal gelation and shear-thinning characteristics were only recorded with hyaluosomes; while Newtonian behavior and low viscosity values (2 mPas.s to 6 mPa.s) were shown with all other liposomal systems. Hyaluosomes recorded superior (3-fold increases) transdermal permeation characteristics (flux and permeability coefficient), compared with other liposomal systems. With the advancement in liposomal sciences, this study warrants hyaluosomes as a promising transdermal liposomal system for favorable rheological characteristics as well as superior transdermal permeation that proved greater capacity than conventional and other non-conventional liposomal systems.


Public health nursing practice change and recommendations for improvement.
This paper reports the characteristics of recent public health nursing (PHN) practice change experienced by staff-level public health nurses. Recommendations for improving PHN practice offered by study participants are reported and discussed. A cross-sectional written survey was used to collect data from 424 public health nurses in 76 local health departments (LHDs) in Wisconsin (68% response rate) in 2003. Characteristics of practice change were identified using a 15-item-scaled response set. Recommendations on improving practice were made through responses to an open-ended survey question. Content analysis was conducted to identify major themes among the responses. PHN practice has become more population focused. Major themes emerging from the recommendations for practice improvement included increasing system and organizational resources, expanding visibility of public health, and strengthening collaboration. Implications for practice include the need for continuing education in concepts and skills required for population-focused PHN practice, advocacy for more public health resources, and collaboration with academic partners for education and research.


A soluble form of the triggering receptor expressed on myeloid cells-1 modulates the inflammatory response in murine sepsis.
The triggering receptor expressed on myeloid cells (TREM)-1 is a recently discovered receptor expressed on the surface of neutrophils and a subset of monocytes. Engagement of TREM-1 has been reported to trigger the synthesis of proinflammatory cytokines in the presence of microbial products. Previously, we have identified a soluble form of TREM-1 (sTREM-1) and observed significant levels in serum samples from septic shock patients but not controls. Here, we investigated its putative role in the modulation of inflammation during sepsis. We observed that sTREM-1 was secreted by monocytes activated in vitro by LPS and in the serum of animals involved in an experimental model of septic shock. Both in vitro and in vivo, a synthetic peptide mimicking a short highly conserved domain of sTREM-1 appeared to attenuate cytokine production by human monocytes and protect septic animals from hyper-responsiveness and death. This peptide seemed to be efficient not only in preventing but also in down-modulating the deleterious effects of proinflammatory cytokines. These data suggest that in vivo modulation of TREM-1 by sTREM peptide might be a suitable therapeutic tool for the treatment of sepsis.


Pure uterine lipoma.
Pure fatty tumors of the uterus are extremely rare and usually develop in postmenopausal women. We present the first reported Japanese case of a pure uterine lipoma, in which a preoperative diagnosis was made by magnetic resonance imaging (MRI) and was pathologically confirmed postoperatively. As in our case, MRI is currently the best modality for determining the internal architecture of a tumor and the presence of fat. Because of the benign nature of a uterine lipoma, such an approach can avoid unnecessary surgery in asymptomatic patients.


Systemic lupus erythematosus and neutropaenia: a hallmark of haematological manifestations.
Systemic lupus is a chronic autoimmune disease characterised by its phenotypic heterogeneity. Neutropaenia is a frequent event in SLE occurring in 20%-40% of patients depending on the threshold value of neutrophil count. On a daily basis, the management of neutropaenia in SLE is difficult with several possible causes. Moreover, the infectious consequences of neutropaenia in SLE remain not well defined. 998 patients from the Lupus BioBank of the upper Rhein (LBBR), a large German and French cohort of patients with SLE, mostly of Caucasian origin (83%), were included in this study. Neutropaenia was considered when neutrophil count was below 1800×106/L. An additional analysis of detailed medical records was done for 65 LBBR patients with neutropaenia. 208 patients with neutropaenia (21%) were compared with 779 SLE patients without neutropaenia. Neutropaenia in SLE was significantly associated with thrombocytopaenia (OR 4.11 (2.57-10.3)), lymphopaenia (OR 4.41 (2.51-11.5)) and low C3 (OR 1.91 (1.03-4.37)) in multivariate analysis. 65 representative patients with neutropaenia were analysed. Neutropaenia was moderate to severe in 38%, chronic in 31%, and both severe and chronic in 23% of cases. Moderate to severe and chronic neutropaenia were both associated with lymphopaenia and thrombopaenia. Chronic neutropaenia was also associated anti-Ro/SSA antibodies and moderate to severe neutropaenia with oral ulcers. This study is to date the largest cohort to describe neutropaenia in SLE. Neutropaenia displays a strong association with other cytopaenias, suggesting a common mechanism. Chronic neutropaenia is associated with anti-Ro/SSA antibodies with or without identified Sjögren's disease.


Impact of Early Life Factors on Metabolic Phenotypes of Obesity in Preschool Children.
To investigate the impact of factors in the first 1,000 days of life on metabolic phenotypes of obesity in preschool children in a cohort study. We recruited 3-year-old children for the study. Early life factors included maternal age at delivery, maternal education, prepregnancy BMI, gestational weight gain, gravidity, history of gestational diabetes mellitus, delivery mode, gestational age, family history of metabolic disorders, paternal education, annual family income, child sex, birth weight, and breastfeeding duration. According to BMI and metabolic status, children were classified as metabolically healthy (no metabolic risk factors) with normal weight (MHNW), metabolically unhealthy (one or more metabolic risk factors) with normal weight (MUNW), metabolically healthy with overweight or obesity (MHO), and metabolically unhealthy with overweight or obesity (MUO). We recruited 3,822 children for the study, with 3,015 analyzed. Accelerated BMI z score growth rate between 6 and 24 months was associated with MHO (β = 0.022; 95% CI 0.009, 0.036) and MUO (β = 0.037; 95% CI 0.018, 0.056). Maternal overweight (odds ratio [OR] 3.16; 95% CI 1.55, 6.42) and obesity (OR 8.14; 95% CI 3.73, 17.76) before pregnancy and macrosomia (OR 2.47; 95% CI 1.32, 4.59) were associated with MHO, and maternal obesity before pregnancy (OR 6.35; 95% CI 2.17, 18.52) increased the risk of MUO. Early life factors, such as maternal obesity and accelerated BMI growth rate between 6 and 24 months, were related not only to MHO but also to MUO. Children with these early life factors should be given interventions for weight control to prevent metabolic abnormalities.


Cellular plasticity: 1712 to the present day.
Cell identity is a fundamental feature of cells. Tissues are often organized into cellular hierarchies characterized by progressive differentiation and developmental commitment. However, it is been historically evident that the cells of many organisms of various phyla, especially in the context of injury, exhibit remarkable plasticity in terms of their ability to convert into other cell types. Recent modern studies, using genetic lineage tracing, have demonstrated that many mature functional cells retain a potential to undergo lineage reversion (dedifferentiation) or to convert into cells of other more distant lineages (transdifferentiation) following injury. Similarly, mimicking progenitor cell transdetermination, stem cells can interconvert. These forms of plasticity may be essential for organismal survival, and are likely part and parcel of regeneration.


Functional variants of the melanocortin-4 receptor associated with the Odontoceti and Mysticeti suborders of cetaceans.
Cetaceans, a group of mammals adapted to the aquatic environment that descended from terrestrial artiodactyls, exhibit tremendous interspecific differences in a number of phenotypes, including feeding behavior, such as filter feeding in the Mysticeti vs prey-hunting Odontoceti, and size, with the smallest cetacean, the vaquita, at 1.4 meters and the largest, the blue whale, reaching 33 meters. The Melanocortin-4 receptor (MC4R) regulates food intake, energy balance, and somatic growth in both mammals and teleosts. In this study, we examined allelic variants of the MC4R in cetaceans. We sequenced the MC4R from 20 cetaceans, and pharmacologically characterized 17 of these protein products. Results identified a single variation at amino acid 156 in the MC4R from representative species of major cetacean lineages uniquely associated with the toothed whales or Odontoceti (arginine at 156) and baleen whales or Mysticeti (glutamine at 156). The Q156 receptor variant found in the larger baleen whales was functionally less responsive to its endogenous anorexigenic ligand, α-MSH. Furthermore, the R156 receptor variant showed greater constitutive activity and a higher affinity for ligand. These data suggest that the MC4R may be one gene involved in the evolution of feeding ecology, energy balance, and body size in cetaceans.


[A case of ectopic vas deferens opening into the bladder].
A case of epididymitis in a two years old boy owing to an ectopic vas deferens opening into the bladder is reported. Only a very few similar cases have been recorded in the world literature.


Multilocus sequence typing of Neisseria meningitidis directly from cerebrospinal fluid.
MLST typing of Neisseria meningitidis directly from clinical material was introduced in the National Reference Laboratory for Meningococcal Infections in Prague. Four cerebrospinal fluid samples were obtained from patients with suspected meningococcal invasive disease. In all samples, all classical laboratory methods gave negative results and the only positive method was PCR, which revealed Neisseria meningitidis group C (two specimens) and group B (two specimens), respectively. MLST performed directly from cerebrospinal fluid revealed that the strains causing the two group C infections were of sequence type (ST) 11, while the two group B infections were characterized as ST-32 and ST-33 respectively. Multi-locus sequence typing of meningococci directly from clinical material offers the opportunity to improve further the surveillance of meningococcal disease and has now been introduced into the routine portfolio of tests employed at the national reference laboratory of the Czech Republic.


Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement.
Since their introduction in clinical practice in the 1950's, Sulfonylureas (SUs) have remained the main-stay of pharmacotherapy in the management of type 2 diabetes. Despite their well-established benefits, their place in therapy is inappropriately being overshadowed by newer therapies. Many of the clinical issues associated with the use of SUs are agent-specific, and do not pertain to the class as such. Modern SUs (glimepiride, gliclazide MR) are backed by a large body of evidence, experience, and most importantly, outcome data, which supports their role in managing patients with diabetes. Person-centred care, i.e., careful choice of SU, appropriate dosage, timing of administration, and adequate patient counseling, will ensure that deserving patients are not deprived of the advantages of this well-established class of anti-diabetic agents. Considering their efficacy, safety, pleiotropic benefits, and low cost of therapy, SUs should be considered as recommended therapy for the treatment of diabetes in South Asia. This initiative by SAFES aims to encourage rational, safe and smart prescription of SUs, and includes appropriate medication counseling.


Prognostic value of contrast-enhanced cardiac magnetic resonance imaging in patients with newly diagnosed non-ischemic cardiomyopathy: cohort study.
Owing to its variable course from asymptomatic cases to sudden death risk stratification is of paramount importance in newly diagnosed non-ischemic cardiomyopathy. We tested whether late gadolinium enhancement (LGE) assessed by cardiac magnetic resonance (CMR) imaging is a prognostic marker in consecutive patients with newly diagnosed non-ischemic cardiomyopathy. We enrolled 185 patients who presented for evaluation of newly diagnosed non-ischemic cardiomyopathy. Coronary artery disease was excluded by coronary angiography. Following risk markers were additionally assessed: NYHA functional class (≥II), brain natriuretic peptide (>100 ng/l), troponin I (TnI, ≥0.03 µg/l), left ventricular ejection fraction (LVEF, ≤40%), left ventricular enddiastolic diameter (>55 mm) and QRS duration (>98 ms). Endpoint of the study was the composite of all-cause mortality, heart transplantation, aborted sudden death, sustained ventricular tachycardia or hospitalization due to decompensated heart failure within three years of follow-up. During median follow-up of 21 months, 54 patients (29.2%) reached the composite endpoint. Ninety-four of the 185 patients (50.8%) were judged LGE-positive. Prognosis of LGE-positive patients was significantly worse than that of LGE-negative patients (cumulative 3-year event rates of 67.4% in LGE-positive and 27.2% in LGE-negative patients, respectively; p = 0.021). However, in multivariable analysis, presence of LGE was not an independent predictor of outcome. Only LVEF ≤40% and TnI ≥0.03 µg/l were independent risk predictors of the composite endpoint yielding relative risks of 3.9 (95% CI 1.9-8.1; p<0.0001) and 2.2 (95% CI 1.2-4.0; p = 0.014), respectively. In consecutive patients presenting with newly diagnosed non-ischemic cardiomyopathy, LGE-positive patients had worse prognosis. However, only traditional risk parameters like left ventricular performance and cardiac biomarkers but not presence of LGE were independent risk predictors.


Lithobezoar--an unusual cause of dyspepsia.
Bezoar is the accumulation of exogenous undigested materials in the gastrointestinal tract. Various names have been used to describe bezoars based on the accumulated material. Commonly seen types are phytobezoar (composed of vegetable matter and seeds of fruits), tricobezoar (hair) lactobezoar (milk cuds). Lithobezoar (composed of stones and rocks) is uncommon and only limited reports are available in the English literature. The authors report a case of gastrointestinal lithobezoar presenting with ulcer-like abdominal pain. Some of the stones were removed endoscopically and some got expelled out after the use of promotility drugs. Invariably, there are predisposing factors for such behaviour. This case emphasises a meticulous psychiatric evaluation in a given patient, in order to prevent recurrence of symptoms.


Biocompatibility and permeability of dialyzer membranes do not affect anemia, erythropoietin dosage or mortality in japanese patients on chronic non-reuse hemodialysis: a prospective cohort study from the J-DOPPS II study.
Considerable controversy exists over the impact of the biocompatibility and flux characteristics of dialyzer membranes on anemia in chronic hemodialysis patients. A subset of 1,207 subjects from the Japanese arm of DOPPS phase II was analyzed. Patient characteristics included mean age 59 years, male sex 60%, BMI 20.6, time on dialysis therapy 7.8 years, and diabetes rate 27%. Dialysis parameters were Kt/V 1.33, and normalized protein catabolic rate 1.05 g/kg/day. Initial hemoglobin level was 10.1 g/dl. 79% were treated by intravenous erythropoietin with mean weekly doses of 4,500 IU. Hemoglobin levels and erythropoietin doses during 2-year study period were not affected by dialysis membrane biocompatibility (unmodified cellulose or biocompatible) or flux (standard or high performance). The 2-year survival rate was 90.9% and was influenced by older age, presence of cardiovascular diseases and amyloidosis, lower levels of BMI and serum albumin, but not by other variables, including dialysis membranes. Use of biocompatible membranes was associated with a lower all-cause mortality (8.3 vs. 13.0% for bioincompatible, p = 0.037), but this difference was not significant in multivariate analyses (hazard ratio 0.70, p = 0.17 by Cox multivariate analysis). The biocompatibility and permeability of dialyzer membranes had no effect on anemia, erythropoietin dosage or all-cause mortality in Japanese chronic hemodialysis patients treated by non-reuse dialysis.


Defining the potential of aglycone modifications for affinity/selectivity enhancement against medically relevant lectins: synthesis, activity screening, and HSQC-based NMR analysis.
The emerging significance of lectins for pathophysiological processes provides incentive for the design of potent inhibitors. To this end, systematic assessment of contributions to affinity and selectivity by distinct types of synthetic tailoring of glycosides is a salient step, here taken for the aglyconic modifications of two disaccharide core structures. Firstly we report the synthesis of seven N-linked-lactosides and of eight O-linked N-acetyllactosamines, each substituted with a 1,2,3-triazole unit, prepared by copper-catalyzed azide-alkyne cycloaddition (CuAAC). The totally regioselective β-D-(1 → 4) galactosylation of a 6-O-TBDPSi-protected N-acetylglucosamine acceptor provided efficient access to the N-acetyllactosamine precursor. The resulting compounds were then systematically tested for lectin reactivity in two binding assays of increasing biorelevance (inhibition of lectin binding to a surface-presented glycoprotein and to cell surfaces). As well as a plant toxin, we also screened the relative inhibitory potential with adhesion/growth-regulatory galectins (total of eight proteins). This type of modification yielded up to 2.5-fold enhancement for prototype proteins, with further increases for galectins-3 and -4. Moreover, the availability of (15)N-labeled proteins and full assignments enabled (1)H, (15)N HSQC-based measurements for hu- man galectins-1, -3, and -7 against p-nitrophenyl lactopyranoside, a frequently tested standard inhibitor containing an aromatic aglycone. The measurements confirmed the highest affinity against galectin-3 and detected chemical shift differences in its hydrophobic core upon ligand binding, besides common alterations around the canonical contact site for the lactoside residue. What can be accomplished in terms of affinity/selectivity by this type of core extension having been determined, the applied combined strategy should be instrumental for proceeding with defining structure-activity correlations at other bioinspired sites in glycans and beyond the tested lectin types.


A behavioral perspective on conduct disorders.
THIS paper provides a selective overview of behavioral approaches for conduct-disordered behavior. Although no definitive statement can be made regarding etiology, some empirical support exists for behavioral strategies. Assessment approaches discussed include the behavioral interview, behavioral observations, and behavioral checklists. Decisions regarding types of behavioral interventions to be employed directly follow from assessment data. Assessment information can be formulated in terms of a behavioral excess/skill deficit model. Hence, conduct-disordered behavior can be a function of excessive disruptive behavior and/or a lack of requisite skills necessary to obtain satisfaction. Parental training strategies in contingency management and contingency contracting are discussed regarding behavioral excesses. Relative to skill deficits, contingency procedures along with skills training in communication, problem-solving and self-control are reviewed, using parental training and cognitive-behavioral frameworks. In general, these interventions have empirically demonstrated efficacy. However, future research is required to identify specific factors that account for successful treatment, and attention should be directed toward preventive issues. Important data could be obtained from the identification of high-risk environmental situations. A predictive understanding of high-risk populations could result in the development of early intervention programs, which might to some extent obviate the occurrence of conduct disorders.


Detection of imprinting effects for hypertension based on general pedigrees utilizing all affected and unaffected individuals.
Imprinting effects can lead to parent-of-origin patterns in many complex human diseases. For hypertension, previous studies revealed the possible involvement of imprinted genes. Genetic Analysis Workshop 18 real data, with hypertensive phenotype and genotype of more than 1000 individuals from 20 pedigrees, provided us an opportunity to further substantiate such findings. To test for imprinting effects, we developed a pedigree-parental-asymmetry test taking both affected and unaffected offspring into consideration (PPATu). We carried out a simulation study based on the Genetic Analysis Workshop 18 pedigrees to show that PPATu has well-controlled type I error and is indeed more powerful than the pedigree-parental-asymmetry test (PPAT), an existing method that does not utilize information from unaffected offspring. We then applied PPATu to Genetic Analysis Workshop 18 genome-wide association study data from 20 pedigrees. We identified a number of single-nucleotide polymorphisms showing significant imprinting effects that are within genomic regions that have been previously implicated to be associated with hypertension.


Possible radical scavenging properties of cicletanine and renal protection in Dahl salt sensitive rats.
Much interest in cicletanine, a novel antihypertensive drug, has grown because it uniquely stimulates prostacyclin (PGI2) production and may, thereby, provide further cardiovascular protection. We postulated that cicletanine may be an antioxidant, and assessed its ability to protect the kidney in Dahl salt-sensitive (Dahl S) rats on a high salt diet. Cicletanine eradicated in vitro a stable radical, DPPH, and decreased the lipid peroxidation both in rat brain homogenate and in a xanthine-xanthine oxidase (X-XOD) superoxide generating system. Furthermore, cicletanine attenuated the inhibition of PGI2 synthase activity by 15HPETE. However, cicletanine did not exhibit superoxide dismutase-like activity in X-XOD system, suggesting that it behaves primarily as a hydroxy radical scavenger. A 6 week cicletanine treatment reduced blood pressure in Dahl S rats fed a high salt diet, and ameliorated functional and morphological injury to the kidney. This attenuation of glomerular sclerosis correlated with the attenuation of lipid peroxidation in the kidney homogenate. These data indicate that cicletanine is an antioxidant that protects the kidney from salt-induced hypertension in Dahl salt-sensitive strain rats.


Is Psychology Headed in the Right Direction?
Is psychology headed in the right direction? In this essay, I share my views on the answer to this question. I begin by describing how recent advances in technology, heightened levels of interdisciplinary collaboration, a renewed emphasis on considering the broader implications of basic psychological research, and field-wide efforts to encourage optimal research practices have combined to tilt psychology's trajectory upward. I then offer three suggestions for how to maintain the field's upward slanting course: (a) collaborate more to build cumulative knowledge, (b) improve the way we communicate contextual factors in psychological research, and (c) examine the psychological effects of technology. I conclude by offering a single piece of advice for new researchers and a few closing comments.


Deciphering the genetic basis of root morphology, nutrient uptake, yield, and yield-related traits in rice under dry direct-seeded cultivation systems.
In the face of global water scarcity, a successful transition of rice cultivation from puddled to dry direct-seeded rice (DDSR) is a future need. A genome-wide association study was performed on a complex mapping population for 39 traits: 9 seedling-establishment traits, 14 root and nutrient-uptake traits, 5 plant morphological traits, 4 lodging resistance traits, and 7 yield and yield-contributing traits. A total of 10 significant marker-trait associations (MTAs) were found along with 25 QTLs associated with 25 traits. The percent phenotypic variance explained by SNPs ranged from 8% to 84%. Grain yield was found to be significantly and positively correlated with seedling-establishment traits, root morphological traits, nutrient uptake-related traits, and grain yield-contributing traits. The genomic colocation of different root morphological traits, nutrient uptake-related traits, and grain-yield-contributing traits further supports the role of root morphological traits in improving nutrient uptake and grain yield under DDSR. The QTLs/candidate genes underlying the significant MTAs were identified. The identified promising progenies carrying these QTLs may serve as potential donors to be exploited in genomics-assisted breeding programs for improving grain yield and adaptability under DDSR.


A remarkable autosomal heteromorphism in Pseudoryzomys simplex 2n = 56; FN = 54-55 (Rodentia, Sigmodontinae).
Pseudoryzomys simplex, the false rice rat, is a monotypic genus of the Oryzomyini tribe (Sigmodontinae) distributed in part of Bolivia, Paraguay, Argentina and Brazil. Its diploid number has been described as 56 acrocentric chromosomes decreasing in size and no karyotype figure has been depicted. Herein, we present karyotypic data on P. simplex, including chromosome banding and molecular fluorescent in situ hybridization using telomeric sequences and the whole X-chromosome of its sister clade Holochilus brasiliensis (HBR) as probes. A case of remarkable autosomal heteromorphism due to the presence of a whole heterochromatic arm leading to the variability of FN is reported, as well as the occurrence of regions of homology between the X and Y chromosomes (pseudoautosomal regions) after chromosome painting with the HBR X probe on P. simplex metaphases.


Ligand effects in the syntheses and structures of novel heteroleptic and homoleptic bismuth(III) formamidinate complexes.
Metathesis reactions of the alkali metal formamidinates M(RNC(H)NR), M = Li or K; R = C(6)H(3)-2,6-Pr(i)(2) (L(1)), C(6)H(3)-2,6-Et(2) (L(2)); C(6)H(2)-2,4,6-Me(3) (L(3)), C(6)H(3)-2,6-Me(2) (L(4)) or C(6)H(4)-2-Ph (L(5)), with BiX(3) (X = Cl or Br) gave a range of bismuth(iii) formamidinate complexes [Bi(L)Br(micro-Br)(thf)](2) (L = L(1), L(4)), [{Bi(L(1))Cl(2)(thf)}(2)Bi(L(1))Cl(2)], [Bi(L)(2)X] (L = L(2), L(5), X = Br; L = L(1), X = Cl), and [Bi(L)(3)] (L = L(2), L(3)). An analogous organometallic complex Bi(L(1))(2)Bu(n) was also isolated as a side product in one instance. Structural characterisation of the di-halide complexes show symmetrical dimers for X = Br, with two bromide bridges, and a coordinated thf molecule on each Bi atom, whereas for X = Cl a thf deficient species was crystallised, and has a weakly associated trinuclear array with two coordinated thf molecules per three Bi atoms. Complexes of the form Bi(L)(2)X (X = Br, Cl, Bu(n)) and Bi(L)(3) all have monomeric structures but the Bi(L)(3) species show marked asymmetry of the formamidinate binding, suggesting that they have reached coordination saturation.


Case report: eosinophilic colitis with high antibody titre against Ascaris suum.
Eosinophilic gastroenteritis (EGE) is an inflammatory disease characterized by eosinophilic infiltration of the gastrointestinal tract accompanied by varying abdominal symptoms and usually by peripheral blood eosinophilia. Although the precise aetiology of EGE remains to be determined, contribution of allergic process to certain allergens, such as foods, drugs and parasites, has been repeatedly proposed as the pathogenesis of the disease. Here we report on a rare case of a woman who had extensive eosinophilic infiltration in the descending and rectal colon with a high titre of IgG antibody against Ascaris suum. The patient was successfully treated with prednisolone.