Sporadic segmental Interstitial cell of cajal hyperplasia (microscopic GIST) with unusual diffuse longitudinal growth replacing the muscularis propria: differential diagnosis to hereditary GIST syndromes.
Gastrointestinal stromal tumors (GIST) usually form a well-circumscribed mass. However, patients with germline mutations in c-KIT, PDGFRA and NF1 may present with diffuse interstitial cell of Cajal (ICC) hyperplasia along the Auer-bach plexus without forming a discrete mass. To our knowledge, sporadic diffuse ICC hyperplasia replacing the gut wall has not been described previously. We describe herein two such cases. Case 1 was a 59-yr-old woman who presented with signs of ileus and a large mass submitted as Meckel diverticulum. The resection specimen showed a large GIST with diverticulum-like and solid areas. The diverticular component showed a diffuse proliferation of spindle cells extending for several centimetres from the solid tumor replacing the full thickness of the gut wall and lined by intact mucosa. Mutation analysis revealed a combined deletion/insertion in c-KIT exon 11 (V560delEins) in both the solid and the diffuse tumor component. Case 2 was a 66-yr-old man who underwent segmental sigmoid colon resection for adenocarcinoma in a villous adenoma. Random sections from grossly unremarkable colonic wall showed a diffuse proliferation of CD117+/CD34+ spindle cells completely replacing the muscularis propria for a length of 6 mm. Molecular analysis revealed a somatic point mutation/ deletion in exon 11 of c-KIT (Q575L; L576_W582del). Absence of multiple lesions and demonstration of a wild-type sequence for c-KIT in surrounding normal tissue ruled out the possibility of a germline mutation in both cases. This peculiar diffuse form of sporadic ICC hyperplasia results from somatic c-KIT mutations and must be distinguished from syndromic ICC hyperplasia associated with hereditary GIST syndromes.


Electrochemiluminescent aptamer-sensor for alpha synuclein oligomer based on a metal-organic framework.
The alpha synuclein (α-syn) oligomer is one of the biomarkers used for the early diagnosis of Parkinson's disease. In this paper, two electrochemiluminescent (ECL) biosensors with an aptamer as the recognition element for α-syn oligomer detection were prepared. A functionalized indium tin oxide (ITO) glass with metal-organic framework (MOF) materials provides an adequate sensing platform. Here the gold nanoparticles/metal organic frameworks (MOFs) composite (AuNPs@MOFs) using 3-aminopropyltrimethoxysilane as a binding agent, or to connect the MOFs onto the ITO directly via glutaraldehyde, both give a strong ECL emission for luminol, even under weak alkaline conditions. Thereafter, the thiolated or carboxylated aptamer was coalesced onto the MOF material functionalized electrode using an Au-S bond or amide bond via the classic 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide (EDC-NHS) coupling, respectively. Thus, the ECL emission of the sensors significantly reduced after the specific binding of the α-syn oligomer to the aptamer. The good linear relationship of the ECL sensing signals upon the logarithm of the α-syn oligomer concentration were established, from 2.43 fM to 0.486 pM or 1.39 fM to 0.243 pM, and the limit of detection reached as low as 0.42 or 0.38 fM, for these two sensors. Both of the obtained sensors have the advantages of a high sensitivity, selectivity, and reproducibility and are capable of detecting the target in human serum.


The scope of a laboratory animal program needed at a veterinary school.
The discipline of laboratory animal medicine is one of the most rapidly expanding specialties within the veterinary profession. Veterinary schools should fully accept the responsibility for introductory instruction in laboratory animal medicine in the professional curriculum. Such instruction should articulate the varied opportunities that exist for the laboratory animal veterinarian within the biomedical research community, and provide an overview of the normal biological characteristics and pathologic conditions of the common laboratory animal species. In addition, the opportunity should exist within the veterinary school for graduate and undergraduate students utilizing experimental animals to receive a comprehensive introduction to laboratory animal biology, care, and management. Instructional responsibility for such courses should be accepted by faculty veterinarians with advanced training in laboratory animal medicine. Veterinarians with advanced training in this specialty are uniquely qualified to make substantial contributions to biomedical research by promoting the health and welfare of the research animal.


Novel Compounds as TEAD Inhibitors for Treating Cancer.
Provided herein are novel compounds as TEAD inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.


Major Differences in Transcriptional Alterations in Dorsal Root Ganglia Between Spinal Cord Injury and Peripheral Neuropathic Pain Models.
Chronic, often intractable, pain is caused by neuropathic conditions such as traumatic peripheral nerve injury (PNI) and spinal cord injury (SCI). These conditions are associated with alterations in gene and protein expression correlated with functional changes in somatosensory neurons having cell bodies in dorsal root ganglia (DRGs). Most studies of DRG transcriptional alterations have utilized PNI models where axotomy-induced changes important for neural regeneration may overshadow changes that drive neuropathic pain. Both PNI and SCI produce DRG neuron hyperexcitability linked to pain, but contusive SCI produces little peripheral axotomy or peripheral nerve inflammation. Thus, comparison of transcriptional signatures of DRGs across PNI and SCI models may highlight pain-associated transcriptional alterations in sensory ganglia that do not depend on peripheral axotomy or associated effects such as peripheral Wallerian degeneration. Data from our rat thoracic SCI experiments were combined with meta-analysis of published whole-DRG RNA-seq datasets from prominent rat PNI models. Striking differences were found between transcriptional responses to PNI and SCI, especially in regeneration-associated genes (RAGs) and long noncoding RNAs (lncRNAs). Many transcriptomic changes after SCI also were found after corresponding sham surgery, indicating they were caused by injury to surrounding tissue, including bone and muscle, rather than to the spinal cord itself. Another unexpected finding was of few transcriptomic similarities between rat neuropathic pain models and the only reported transcriptional analysis of human DRGs linked to neuropathic pain. These findings show that DRGs exhibit complex transcriptional responses to central and peripheral neural injury and associated tissue damage. Although only a few genes in DRG cells exhibited similar changes in expression across all the painful conditions examined here, these genes may represent a core set whose transcription in various DRG cell types is sensitive to significant bodily injury, and which may play a fundamental role in promoting neuropathic pain.


[Tumor of the nasal cavity unusual in our region. Apropos of a case of rhinosporidiosis].
Rhinosporidiosis is an ailment of the mucous membranes provoked by a microorganism described by Seeber in 1900. It is found in Africa, South America, India, Ceylan, Phillipines and Iran. Rhinosporidium Seeberi provokes the appearance of sessile polyps, friable on the mucous membranes. The nasal mucous membrane is affected in 72% of the cases. The symptoms in otorhinolaryngology are in most cases mucous or mucopurulent rhinorrhea, chronic epistaxis and a progressive nasal obstruction. The etiologic diagnosis is based on clinic, on the examination of rhinorrhea and especially on histopathological examination. In case of lesion at nasopharynx level rhinosporidiosis must be differentiated from inflammatory or parasitic lesions, from embryonic or malignant tumour. Prognosis is generally favourable, the treatment is mainly surgical.


Epidemiology and diagnosis of tuberculous lymphadenitis in a tuberculosis low-burden country.
The aim of this article is to describe epidemiological and clinical data of patients with tuberculous lymphadenitis (TL) and evaluate the yield of the diagnostic techniques employed. Retrospective observational study was performed at the Vall d'Hebron University Hospital, Barcelona, Spain. All adult patients with confirmed TL (microbiologically) or probable TL (suspected by clinical presentation, cyto/histopathological features, and clinical improvement after specific treatment) diagnosed from January 2001 to December 2013 were included. One hundred twenty-two patients were included: 78 (63.9%) patients with confirmed diagnosis and 44 (36.1%) patients with probable TL. Seventy (57.4%) patients were nonnative residents. From 83 fine-needle aspiration (FNA) specimens, 54.8% (40/73) showed granulomatous inflammation, 62.5% (40/64) had positive mycobacterial culture, and 73.3% (11/15) tested positive with Xpert MTB/RIF (Cepheid, Sunnyvale, CA). From 62 biopsy samples, 96.8% (60/62) showed granulomatous inflammation, 64.6% (31/48) had positive mycobacterial culture, and 46.1% (6/13) tested positive with Xpert MTB/RIF. TL has increasingly been diagnosed in our setting, mostly because of cases diagnosed in nonnative residents. FNA is an easy and safe technique for the diagnosis of suspected TL, and the yield regarding mycobacterial culture seems to be similar to the obtained with biopsy. The Xpert MTB/RIF test from FNA specimens may increase the accuracy of the TL diagnosis and provides quicker results.


Wing geometric morphometrics and DNA barcoding to distinguish three closely related species of Armigeres mosquitoes (Diptera: Culicidae) in Thailand.
Armigeres subalbatus, a mosquito species widely found in Thailand and other Asian countries, serves as a vector for filarial parasites, affecting both humans and animals. However, the surveillance of this vector is complicated because of its morphological similarity to two other species, Armigeres dohami and Armigeres kesseli. To differentiate these morphologically similar species, our study employed both wing geometric morphometrics (GM) and DNA barcoding, offering a comprehensive approach to accurately identify these closely related Armigeres species in Thailand. Our GM analyses based on shape demonstrated significant accuracy in differentiating Armigeres species. Specifically, the outline-based GM method focusing on the 3rd posterior cell exhibited an accuracy rate of 82.61%, closely followed by the landmark-based GM method with 81.54%. Both these GM techniques effectively distinguished Ar. subalbatus from Ar. dohami and Ar. kesseli. Regarding DNA barcoding, our investigation of pairwise intra- and interspecific divergences revealed a "barcoding gap". Furthermore, the results of species confirmation using both species delimitation methods including the automatic barcode gap discovery method (ABGD) and the Multi-rate Poisson tree process (mPTP) were consistent with those of morphological identification, sequence comparisons with the GenBank and Barcode of Life Data System (BOLD) databases, and the neighbor-joining tree construction. These consistent results emphasize the efficacy of DNA barcoding in the precise identification of Armigeres species.


Patient-Reported Usability of Positive Airway Pressure Equipment Is Associated With Adherence in Older Adults.
To examine the usability of positive airway pressure (PAP) devices and its association with PAP adherence among older adults with sleep-disordered breathing. We mailed questionnaires to patients aged ≥65 years prescribed PAP therapy during the prior 36 months from two large healthcare systems. Survey participants completed the Usability of Sleep Apnea Equipment-Positive Airway Pressure (USE-PAP) questionnaire, which assessed the usability of their PAP device. Other questionnaire items included demographics and self-rated health. We also abstracted adherence data (mean nightly hours of PAP use available from one site) and interface type from the electronic health record. Five hundred sixty-four patients completed the survey (response rate = 33%). The mean USE-PAP score (0 = best to 100 = worst) was 20 (SD ± 20). Mean duration of PAP use (available in 189 respondents) was 5.2 hours per night (SD ± 2.0). In a nested regression model predicting nightly hours of PAP use, a 10-point (0.5 SD) increase in USE-PAP score corresponded to a 0.37 hour/night reduction in PAP use. The model including the USE-PAP score explained a significant proportion (R2 = 15%) of the variation in nightly hours of PAP use above and beyond demographics, self-reported health, and interface type (∆R2 = 12%). Our results demonstrate that PAP usability varies among older patients and is associated with PAP adherence, above and beyond other predictors of adherence. These results support measuring and improving PAP usability to further improve PAP adherence for older patients.


Hypothalamic neurons responding to hemodynamic input and to stimulation in the pons may influence adrenocorticotropin release.
Experiments were designed to identify hemodynamically sensitive neurons in the mediodorsal hypothalamus and to determine if they were also sensitive to electrical stimulation of areas in the dorsal rostral pons that were implicated previously in the control of adrenocorticotropin (ACTH) release. Cats were anesthetized with chloralose and urethane, immobilized with gallamine, and artificially respired. Hemodynamic stimuli included constriction (CC) of the supradiaphragmatic inferior vena cava to reduce venous return and sinusoidal volume pulsation (RA) of the right atrium (1 ml peak at 1 Hz). Previously, CC was shown to facilitate and RA was shown to inhibit ACTH release. Electrical stimulation in the pons consisted of single shocks (500 microA DC, 0.05 msec, negative-to-tip) delivered on each of an array of three or four bipolar co-axial electrodes in the pons. Twenty-three neurons were tested with only RA. Of these, two were inhibited, two were facilitated, and 19 did not respond. Thirty-two neurons were tested with CC. Of these, nine were inhibited, nine were facilitated, and 14 did not respond. Seventeen neurons that responded either to RA or to CC were tested with stimulation in the pons. Of these, three were orthodromically activated and two were inhibited from a total of eight pontine sites. Six of the eight sites were within 300 microns of an area shown previously to contain neurons that responded to CC. Of 31 additional sites that were stimulated, but at which stimulation did not drive neurons that responded to hemodynamic stimuli, 26 were located more than 300 microns from this area (p less than 0.01, X2 test). The data suggest that some hypothalamic neurons involved in the hemodynamic control of ACTH release receive a projection from or through the dorsal raphe nucleus medially, and the ventral locus ceruleus, locus subceruleus, and underlying reticular formation laterally. However, other neurons may receive projections that bypass these regions.


The role of expectations and habitual emotion regulation in emotional processing: An ERP investigation.
Available evidence from separate lines of event-related potential (ERP) research has highlighted the role of expectations and emotion regulation on emotional processing by revealing that (i) expectations can alter emotional responses, and (ii) the instructed use of emotion regulation strategies may modulate emotional responses. Yet, little is known about the interplay between expectations and habitual emotion regulation strategies prior to and at the onset of an emotional event. The present study aimed to investigate this potential relationship. Participants completed an affective-cueing task consisting of cues (red squares and blue circles) signaling the likely valence of upcoming target images (negative or neutral). This task allowed us to examine the impact of expectations at 2 temporal stages, Cue Interval and Target Interval, by measuring the late positive potential (LPP) as an index of emotional processing. Habitual use of emotion regulation strategies was assessed through the Emotion Regulation Questionnaire (ERQ), which measures the use of cognitive reappraisal and expressive suppression in everyday life. In the Cue Interval, LPP amplitude was greater for negative versus neutral cues (p < .001). In the Target Interval, LPP amplitude was greater for negatively cued versus neutrally cued targets, regardless of target valence (p = .003). ERQ reappraisal, but not suppression, negatively correlated with LPP modulation as a function of cue valence during both intervals (ps < .05). These findings provide novel insights regarding the interplay between expectations and habitual emotion regulation in emotional processing both prior to and at the onset of an emotional event. (PsycINFO Database Record


The effect of salmeterol on markers of airway inflammation following segmental allergen challenge.
Inflammation is a critical component of asthma. Drugs that control asthma generally reduce the degree of airway inflammation. There is theoretical controversy surrounding the effects of beta(2)-agonists on airway inflammation, with some studies suggesting an anti-inflammatory effect, and others predicting a proinflammatory influence. We conducted a double-blind, placebo-controlled, crossover study of the effect of the long-acting beta(2)-agonist salmeterol on airway inflammation induced by segmental allergen challenge (SAC). We studied 13 allergic asthmatics controlled with as needed inhaled short-acting beta(2)-agonists alone, and used bronchoalveolar lavage 5 min and 48 h after SAC to assess airway inflammation, and the effects of salmeterol on this process. Salmeterol therapy improved FEV(1), but had no significant effect on the immediate or late cellular response to SAC. One measure of superoxide production was reduced, and interleukin-4 (IL-4) was reduced in baseline samples, but other indices of airway inflammation were unchanged by salmeterol therapy. We conclude that salmeterol therapy alone does not meaningfully reduce airway inflammation induced by SAC, but equally importantly, does not result in amplified inflammation.


Optical fiber laser induced fluorescence spectroscopy as a citrus canker diagnostic.
Citrus canker is a serious disease caused by Xanthomonas citri subsp. citri bacteria, which infects citrus plants (Citrus spp.) leading to large economic losses in citrus production worldwide. In this work, laser induced fluorescence spectroscopy (LIF) was investigated as a diagnostic technique for citrus canker disease in citrus trees at an orchard using a portable optical fiber based spectrometer. For comparison we have applied LIF to leaves contaminated with citrus canker, citrus scab, citrus variegates chlorosis, and Huanglongbing (HLB, Greening). In order to reduce the noise in the data, we collected spectra from ten leaves with visual symptoms of diseases and from five healthy leaves per plant. This procedure is carried out in order to minimize the environmental effect on the spectrum (water and nutrient supply) of each plant. Our results show that this method presents a high sensitivity (approximately 90%), however it does present a low specificity (approximately 70%) for citrus canker diagnostic. We believe that such poor performance is due to the fact that the optical fiber collects light from only a small part of the leaf. Such results may be improved using the fluorescence imaging technique on the whole leaf.


Voltage-dependent K+ currents and underlying single K+ channels in pheochromocytoma cells.
Properties of the whole-cell K+ currents and voltage-dependent activation and inactivation properties of single K+ channels in clonal pheochromocytoma (PC-12) cells were studied using the patch-clamp recording technique. Depolarizing pulses elicited slowly inactivating whole-cell K+ currents, which were blocked by external application of tetraethylammonium+, 4-aminopyridine, and quinidine. The amplitudes and time courses of these K+ currents were largely independent of the prepulse voltage. Although pharmacological agents and manipulation of the voltage-clamp pulse protocol failed to reveal any additional separable whole-cell currents in a majority of the cells examined, single-channel recordings showed that, in addition to the large Ca++-dependent K+ channels described previously in many other preparations, PC-12 cells had at least four distinct types of K+ channels activated by depolarization. These four types of K+ channels differed in the open-channel current-voltage relation, time course of activation and inactivation, and voltage dependence of activation and inactivation. These K+ channels were designated the Kw, Kz, Ky, and Kx channels. The typical chord conductances of these channels were 18, 12, 7, and 7 pS in the excised configuration using Na+-free saline solutions. These four types of K+ channels opened in the presence of low concentrations of internal Ca++ (1 nM). Their voltage-dependent gating properties can account for the properties of the whole-cell K+ currents in PC-12 cells.


Catheter sepsis in short-bowel syndrome.
Catheter sepsis with catheter removal is an important problem in patients with short-bowel syndrome. We determined the incidence of catheter sepsis and the catheter salvage rate in 20 pediatric patients with short-bowel syndrome. To evaluate the intestine as a source and translocation as the pathophysiologic mechanism for catheter sepsis, we identified the sepsis organisms, compared them with the fecal flora, and used mesenteric lymph node cultures to document translocation. The incidence of catheter sepsis was significantly higher in patients with short-bowel syndrome than in patients without short-bowel syndrome (7.8 vs 1.3 per 1000 catheter days). Overall catheter salvage was 42% and was highest in gram-negative sepsis (71%). Enteric organisms were responsible for 62% of cases of catheter sepsis in patients with short-bowel syndrome vs 12% in patients without short-bowel syndrome. Anaerobes were strikingly absent in 25 of 28 stool cultures. The sepsis organism was identified in the fecal flora in 19 of 28 cases. The dominant fecal organism or yeast was the septic organism in 12 of these 19 cases and was isolated in three of four mesenteric lymph node cultures. Our findings support translocation as a mechanism in catheter sepsis in patients with short-bowel syndrome.


Prevalence of multiple malignancies in the Netherlands in 2007.
As the number of cancer survivors increases in the Netherlands, there is a concomitant increase in patients with multiple malignancies (MMs), the prevalence of which needs to be assessed to estimate care needs. This study analyzed incidence data on all malignant cancers diagnosed between 1989 and 2006 retrieved from the population-based Netherlands Cancer Registry. The point prevalence of MMs was determined on January 1, 2007. Of all cancer survivors in 2007, 30,064 (7% of the total) were patients with MMs. Their median age was 74 (interquartile range 71-76) years. Ninety two percent (i.e., 27,660) of these patients had two cancer diagnoses. The most common subsequent cancers being squamous cell skin cancer (5,468), colorectal cancer (4,634), and breast cancer (3,959). High frequency of combinations included: (i) female breast and genital cancers (any order), (ii) urinary tract and prostate cancers (any order), (iii) Hodgkin's lymphoma and subsequent female breast cancer and (iv) non-Hodgkin's lymphoma and subsequent squamous cell skin cancer. As the number of cancer survivors continues to increase and their survival improves, MMs are becoming more important in the field of cancer surveillance.


Ancient DNA reveals extreme egg morphology and nesting behavior in New Zealand's extinct moa.
New Zealand's extinct flightless moa radiated rapidly into a large number of morphologically diverse species, which produced an equally large range of egg morphologies. The exact number of moa species, as well as the characteristics of the eggs they laid, remains contentious. Moreover, like most extinct species, we understand little about their nesting and incubation habits. We used a modified ancient DNA extraction procedure to recover exogenous mitochondrial and nuclear DNA from the inside and outside surfaces of moa eggs. We used sequences from the inside of 69 eggshells to directly assign these remains to seven of the 10 currently recognized moa species. In addition we were able to assign, to the species level, six of the rare reconstructed "whole" eggs. These molecular results enabled us to identify two distinct lineages within the genus Euryapteryx. Members of these lineages differed in eggshell thickness, with one lineage being characterized by a relatively thin eggshell. Unexpectedly, several thin-shelled eggs were also shown to belong to the heaviest moa of the genera Dinornis, Euryapteryx and Emeus, making these, to our knowledge, the most fragile of all avian eggs measured to date. Moreover, sex-specific DNA recovered from the outer surfaces of eggshells belonging to species of Dinornis and Euryapteryx suggest that these very thin eggs were likely to have been incubated by the lighter males. The thin nature of the eggshells of these larger species of moa, even if incubated by the male, suggests that egg breakage in these species would have been common if the typical contact method of avian egg incubation was used.


Short-term socioeconomic status shift and long-term cardiovascular outcomes in China: a population-based cohort study.
Limited studies have discussed the effect of socioeconomic status (SES) shift on cardiovascular outcomes, especially in less developed regions and countries. We; therefore, explored the association between short-term SES shift and long-term cardiovascular outcomes in China. In participants who had completed China Kadoorie Biobank study resurvey, 18 672 were included in the final analysis after excluding those who had cardiovascular diseases at baseline, and those who had a cardiovascular event before the resurvey. We used education, occupation, household income and healthcare cover as measurement of SES, and generated SES class for each individual at baseline and resurvey using latent class analysis. Outcomes of interest included cardiovascular death, major coronary event (MCE) and stroke. We used accelerated failure time model to obtain survival time ratio for each level of SES shift. During a mean time gap of 2.6 years, 10 273 (55%) individuals remained stable in SES, 7763 (41.6%) shifted towards higher SES and 636 (3.4%) shifted towards lower SES. Participants were followed up for a mean of 9.8 years. After adjusting for baseline factors, sharp but not moderate SES downshift was significantly associated with shortened event-free survival time before cardiovascular deaths (p=0.02) and MCEs (p<0.001) occurred. Contrarily, moderate and sharp SES upshift was significantly associated with prolonged event-free survival time before cardiovascular deaths (p=0.0027 and p<0.001) and MCEs (p=0.0079 and p=0.009) occurred. Short-term SES improvement is associated with better long-term cardiovascular outcome in China. High baseline SES might buffer out some unfavourable impact brought by moderate SES downshift. More comprehensive strategies should be considered in policy-making for socioeconomic development.


Anti-obese action of raspberry ketone.
Raspberry ketone (4-(4-hydroxyphenyl) butan-2-one; RK) is a major aromatic compound of red raspberry (Rubus idaeus). The structure of RK is similar to the structures of capsaicin and synephrine, compounds known to exert anti-obese actions and alter the lipid metabolism. The present study was performed to clarify whether RK helps prevent obesity and activate lipid metabolism in rodents. To test the effect on obesity, our group designed the following in vivo experiments: 1) mice were fed a high-fat diet including 0.5, 1, or 2% of RK for 10 weeks; 2) mice were given a high-fat diet for 6 weeks and subsequently fed the same high-fat diet containing 1% RK for the next 5 weeks. RK prevented the high-fat-diet-induced elevations in body weight and the weights of the liver and visceral adipose tissues (epididymal, retroperitoneal, and mesenteric). RK also decreased these weights and hepatic triacylglycerol content after they had been increased by a high-fat diet. RK significantly increased norepinephrine-induced lipolysis associated with the translocation of hormone-sensitive lipase from the cytosol to lipid droplets in rat epididymal fat cells. In conclusion, RK prevents and improves obesity and fatty liver. These effects appear to stem from the action of RK in altering the lipid metabolism, or more specifically, in increasing norepinephrine-induced lipolysis in white adipocytes.


The LCR-like alpha-globin positive regulatory element functions as an enhancer in transiently transfected cells during erythroid differentiation.
A positive regulatory element (PRE) similar to the locus control region (LCR) of the human beta-globin gene cluster has recently been identified 40 kb upstream of the human zeta-globin mRNA cap site (Higgs D.R. W.G. Wood, A.P. Jarman, J. Sharpe, J. Lida, I.M. Pretorius, and H. Ayyub. 1990). We investigated the influence of the alpha PRE on human alpha-globin promoter activity in transiently transfected cells. The introduction of the alpha PRE into alpha-globin promoter/CAT expression constructs increased alpha-globin promoter activity by 15-30 fold in a human erythroid cell line (Putko) as well as in mouse erythroleukemia cells (MELCs) induced with hexamethylene bisacetamide (HMBA). When these constructs were introduced into uninduced MELCs or HeLa cells, only a 2-3 fold increase in alpha-globin promoter activity was observed. Deletion of 600 bp of alpha-globin 5' flanking sequences containing six putative SP1-binding sites had no significant effect on levels of alpha-globin promoter enhancement by the alpha PRE. We further demonstrated that the alpha PRE and HS2 of the beta-LCR could similarly enhance transcriptional activity of the SV40 early promoter in HMBA induced MELCs. Finally, we showed that alpha-globin promoter activity in the presence of the alpha PRE increased with continued HMBA exposure and was coincident with transcriptional activation of endogenous globin genes.


SubMAP: aligning metabolic pathways with subnetwork mappings.
We consider the problem of aligning two metabolic pathways. Unlike traditional approaches, we do not restrict the alignment to one-to-one mappings between the molecules (nodes) of the input pathways (graphs). We follow the observation that, in nature, different organisms can perform the same or similar functions through different sets of reactions and molecules. The number and the topology of the molecules in these alternative sets often vary from one organism to another. With the motivation that an accurate biological alignment should be able to reveal these functionally similar molecule sets across different species, we develop an algorithm that first measures the similarities between different nodes using a mixture of homology and topological similarity. We combine the two metrics by employing an eigenvalue formulation. We then search for an alignment between the two input pathways that maximizes a similarity score, evaluated as the sum of the similarities of the mapped subnetworks of size at most a given integer k, and also does not contain any conflicting mappings. Here we prove that this maximization is NP-hard by a reduction from the maximum weight independent set (MWIS) problem. We then convert our problem to an instance of MWIS and use an efficient vertex-selection strategy to extract the mappings that constitute our alignment. We name our algorithm SubMAP (Subnetwork Mappings in Alignment of Pathways). We evaluate its accuracy and performance on real datasets. Our empirical results demonstrate that SubMAP can identify biologically relevant mappings that are missed by traditional alignment methods. Furthermore, we observe that SubMAP is scalable for metabolic pathways of arbitrary topology, including searching for a query pathway of size 70 against the complete KEGG database of 1,842 pathways. Implementation in C++ is available at http://bioinformatics.cise.ufl.edu/SubMAP.html.


Association between hospitalization and discontinuity of medication therapy used in the community setting in the Netherlands.
Transitions from one healthcare setting to another often parallel transitions in health status and can be associated with intentional as well as unintentional changes in patient care. Hospitalization may put patients at increased risk of discontinuity of medication use. To assess the association between hospitalization and medication therapy discontinuities. A retrospective follow-up study was conducted using data obtained from the PHARMO Record Linkage System. We randomly selected patients who had been hospitalized (index date) between July 1, 1998, and June 30, 2000. For each hospitalized patient, one nonhospitalized patient was matched for age, sex, and geographic area, and was assigned the same index date as the corresponding hospitalized patient. The primary study outcome was the incidence of one or more medication therapy discontinuities at the index date and at several control moments during a period of 18 months before and 18 months after hospital admission. We defined 4 mutually exclusive types of discontinuities: generic-brand substitution, product substitution, therapeutic switch, and stop. The study population comprised 8681 hospitalized patients and an equal number of age/sex-matched nonhospitalized patients. Of all hospitalized patients on drug therapy at the index date (n = 5265) 3322 (63.1%) had one or more medication therapy discontinuities at the index date, compared with 1390 (33.5%) of the nonhospitalized patients taking medication at the index date (n = 4147; RR 1.82; 95% CI 1.71 to 1.94). The highest risk estimate was found for therapeutic switch (RR 5.34; 95% CI 3.93 to 7.26), followed by product substitution (RR 2.32; 95% CI 1.88 to 2.86) and stop (RR 1.98; 95% CI 1.85 to 2.13). There was no significantly increased risk for generic-brand name substitution (RR 0.87; 95% CI 0.72 to 1.06). Hospitalization is associated with discontinuity of drugs used in the community setting. Medication stops were observed most frequently. Hospital safety programs should focus attention on medication therapy discontinuities at times of transition to ensure continuity of care in relation to drug therapy.


Self-Referential Encoding on Modules of Anticodon Pairs-Roots of the Biological Flow System.
The proposal that the genetic code was formed on the basis of (proto)tRNA Dimer-Directed Protein Synthesis is reviewed and updated. The tRNAs paired through the anticodon loops are an indication on the process. Dimers are considered mimics of the ribosomes-structures that hold tRNAs together and facilitate the transferase reaction, and of the translation process-anticodons are at the same time codons for each other. The primitive protein synthesis system gets stabilized when the product peptides are stable and apt to bind the producers therewith establishing a self-stimulating production cycle. The chronology of amino acid encoding starts with Glycine and Serine, indicating the metabolic support of the Glycine-Serine C1-assimilation pathway, which is also consistent with evidence on origins of bioenergetics mechanisms. Since it is not possible to reach for substrates simpler than C1 and compounds in the identified pathway are apt for generating the other central metabolic routes, it is considered that protein synthesis is the beginning and center of a succession of sink-effective mechanisms that drive the formation and evolution of the metabolic flow system. Plasticity and diversification of proteins construct the cellular system following the orientation given by the flow and implementing it. Nucleic acid monomers participate in bioenergetics and the polymers are conservative memory systems for the synthesis of proteins. Protoplasmic fission is the final sink-effective mechanism, part of cell reproduction, guaranteeing that proteins don't accumulate to saturation, which would trigger inhibition.


Optical biosensing of nitric oxide using the metalloprotein cytochrome c'.
The metalloprotein cytochrome c' was extracted and purified from the bacterium Paracoccus denitrificans in order to develop a specific biosensing system for nitric oxide (NO). The metalloprotein was encapsulated in a porous silicate sol-gel glass to enable spectroscopic changes in the haem centre as a function of NO ligation to be quantified using absorption measurements. Spectroscopic evidence suggested that, between 2 and 4 d after encapsulation, the cytochrome c' protein changed conformation in the locality of the haem moiety, possibly from a five to a six coordinate haem centre. Such conformational changes were also observed when the cytochrome c' was stored in solution, although over a 2-3 month period. The conformational changes occurring in the protein altered the spectral characteristics of the reduced, oxidised and nitrosyl complex of the cytochrome c' and appear to change the binding affinity of the protein towards NO. However, the encapsulated (reconformed) cytochrome c' was shown to retain its selectivity towards NO with good reproducibility (seven consecutive measurements of NO produced an intensity value with a relative standard deviation of 0.28%). An NO calibration curve, using the in situ release of NO from the donor diethylamine NONOate, was obtained for the encapsulated cytochrome c' with an approximate working range of 10-400 mumol l-1.


Cell-type-specific separate regulation of the E6 and E7 promoters of human papillomavirus type 6a by the viral transcription factor E2.
Gene expression of human papillomaviruses (HPV) is tightly controlled by cellular factors and by the virally encoded E2 protein through binding to distinct sites within the regulatory noncoding region. While for the high-risk genital papillomaviruses a single promoter drives the expression of all early genes, a second promoter present in the E6 open reading frame of the low-risk HPV type 6 (HPV6) would allow an independent regulation of E6 and E7 oncogene expression. In this report, we provide the first evidence that E2 regulates both early promoters of HPV6 separately and we show that promoter usage as well as E2 regulation is cell type dependent. Among the different epithelial cell lines tested, only RTS3b cells allowed an expression pattern similar to that observed in naturally infected benign condylomas. While the E6 promoter was repressed by E2 to 50% of its basal activity, the E7 promoter was simultaneously stimulated up to fivefold. Activation of the E7 promoter was mediated predominantly by the binding of E2 to the most promoter-distal E2 binding site. Repression of the E6 promoter depended on the presence of two intact promoter-proximal binding sites. Mutation of both of these repressor binding sites reversed the effect of E2 on the E6 promoter from repression to activation. In contrast, in HT3 cells we observed an E2-mediated activation of the E6 promoter in the context of the wild-type noncoding region. This indicated that repression of the E6 promoter by binding of E2 to both promoter-proximal binding sites did not function in the cellular environment provided by HT3 cells. These data suggest that the separate regulation of the E6 and E7 promoters of HPV6 is mediated through successive occupation of binding sites with different affinities for E2 depending on the intracellular concentration of E2 and on the cellular environment provided by the infected cell.


Translating the Short-Form Headache Impact Test (HIT-6) in 27 countries: methodological and conceptual issues.
The process of translating the Short-Form Headache Impact Test (HIT-6) in 27 countries and the comparability of the content of the translations is discussed. HIT-6 translations were developed using a standard forward-backward translation process, including a cognitive debriefing step and international harmonization of the translations. Prior to translating the HIT-6, modifications were made to the English-language source form, to improve translation equivalence. In general, the HIT-6 was not difficult to translate. The most difficult items included colloquial expressions such as 'fed up' and words whose intended meaning changed in translation such as 'school' or 'lie down.' Subjects generally found the HIT-6 translations to be clear and relevant. The translation process resulted in questionnaires that are both culturally appropriate and comparable in content.


Audit of screening programme for congenital hypothyroidism in Scotland 1979-93.
To evaluate the efficiency of the screening programme for congenital hypothyroidism in Scotland and to determine the outcome in the cohort of children with positive testing for thyroid stimulating hormone (TSH). Establishment of comprehensive database for all Scottish infants with high TSH, detected on Guthrie screening. 344 infants born between August 1979 and December 1993 with TSH greater than 40 mU/l on initial Guthrie, or 15-40 mU/l on repeat Guthrie. Ages at time of: (a) Guthrie collection, (b) notification of positive result by laboratory, and (c) start of treatment; audit of late diagnosis/missed cases; categorisation of positive cases into definite and probable congenital hypothyroidism, transient TSH elevation, and uncertain status; educational status of children with definite and probable congenital hypothyroidism. 344 positive cases were categorised as having definite (224) and probable (11) congenital hypothyroidism, transient TSH elevation (88), and status uncertain (21). The overall incidence of definite/probable congenital hypothyroidism was 1 in 4400 live births. For the definite/probable groups median age of Guthrie collection was consistently between 6 and 7 days from 1983 onwards but for the whole cohort was later than 10 days in 10.5%. Median age of notification fell from 14 days in 1980 to 11 days in 1993. Median age of starting treatment ranged between 11 and 15 days from 1983 onwards. Treatment was delayed in four cases, three due to failed or late Guthrie card submission. Of 149 children with definite/ probable congenital hypothyroidism who were of school age, educational status was ascertained in 139 (93%). Only two children (1.4%) were attending special school, one of whom was known to have mild hypothyroidism. Sixteen children (11.5%) were receiving extra help in mainstream education compared with 18% of control children in the Scottish very low birth weight study. The current screening programme is working well, but efficiency could be increased by earlier and more reliable Guthrie collection. A substantial proportion of children picked up on the screening programme have a transient rise in TSH rather than true congenital hypothyroidism. The incidence of special education and learning support in Scottish children with congenital hypothyroidism appears to be no different to that of the general population.


Promotion and attenuation of FGF signaling through the Ras-MAPK pathway.
The fibroblast growth factors (FGFs) represent a large family of ligands that activate signal transduction pathways leading to diverse biological responses, including many involved in various processes during development. Here, we discuss the discovery of a subset of conserved FGF target genes that encode feedback regulators of FGF signaling itself. Members of the Sprouty, Sef, and mitogen-activated protein kinase phosphatase families are negative modulators of FGF signaling, whereas positive factors that promote FGF signaling include the ETS transcription factors ERM and PEA3 and the transmembrane protein XFLRT3. These molecules affect the FGF signaling cascade at different levels to regulate the final output of the pathway. This multilayered regulation suggests that precise adjustment of FGF signaling is critical in development.


Patient-Centered Outcomes of Microfragmented Adipose Tissue Treatments of Knee Osteoarthritis: An Observational, Intention-to-Treat Study at Twelve Months.
Microfragmented adipose tissue (MFAT) has been shown to benefit osteoarthritic patients by reducing pain and supporting tissue regeneration through a mesenchymal stem cell (MSC)-related paracrine mechanism. This observational study of 110 knees assessed patient-centered outcomes of pain, functionality, and quality of life, analyzing their variation at twelve months following one ultrasound-guided intra-articular injection of autologous MFAT for the treatment of knee osteoarthritis (KOA). Inclusion criteria were as follows: VAS >50, and the presence of KOA as diagnosed on X-ray and MRI. Exclusion criteria included the following: recent injury (<3 months) of the symptomatic knee, intra-articular steroid injections performed within the last three months, and hyaluronic acid injections prior to this treatment. Changes in VAS, OKS, and EQ-5D were scored at baseline and twelve months following a single intra-articular injection of autologous MFAT. Score variation was analyzed utilizing a nonparametric paired samples Wilcoxon test. The statistical analysis is reproducible with Open Access statistical software R (version 4.0.0 or higher). The study was carried out with full patient consent, in a private practice setting. Median VAS (pain) improved from 70 (IQR 20) to 30 (IQR 58) (p < 0.001); median OKS (function) improved from 25 (IQR 11) to 33.5 (IQR 16) (p < 0.001); and median EQ-5D (quality of life) improved from 0.62 (IQR 0.41) to 0.69 (IQR 0.28) (p < 0.001). No adverse events were reported during the intraoperative, recovery, or postoperative periods. For patients with all grades of knee osteoarthritis who were treated with intra-articular injections of MFAT, statistically significant improvements in pain, function, and quality of life were reported. Although further research is warranted, the results are encouraging and suggest a positive role for intra-articular injection of MFAT as a treatment for knee osteoarthritis.


Suppression of miR-130a-3p Attenuates Oxygen-Glucose Deprivation/Reoxygenation-Induced Dendritic Spine Loss by Promoting APP.
Cerebral stroke induces neuronal dysfunction as a consequence of neuronal morphology changes. Emerging evidence suggests that microRNAs (miRNAs) may play an important role in regulating dysfunction in stroke, yet there are still few studies examining the association between whole blood miRNAs and neuronal morphology. The present study aimed to ascertain the potential roles and mechanisms of action of miR-130a-3p in ischemic stroke. The miRNA datasets of peripheral serum in the GEO database and the mRNA datasets of the human brain after ischemia were analyzed to identify differentially expressed RNAs, and their functions were verified in cultured neurons in vitro. Furthermore, the target gene was validated by dual-luciferase reporter assay, RT-PCR, Western blot, and immunofluorescence experiments. The identified miRNA was further verified by the OGD test to restore neuronal changes after ischemia through APP. The expression of whole blood miR-130a-3p was found significantly lower in participants with ischemic stroke than in controls by analyzing expression profiling datasets of cerebral ischemia stroke obtained from the Gene Expression Omnibus (GEO) DataSets portal, which was confirmed in the MCAO model in mice. Furthermore, GO analysis showed that miR-130a-3p might directly affect neuronal function. Indeed, we demonstrated that miR-130a-3p played a central role in the inhibition of dendritic morphogenesis and in the growth of dendritic spines in vitro. We also confirmed that miR-130a-3p could regulate the expression of APP by luciferase reporter assay, RT-PCR, Western blot, and immunofluorescence experiments, which were consistent with the bioinformatic analysis. Last but not least, we also demonstrated that reducing miR-130a-3p expression partially rescued neuronal morphological changes after OGD in vitro. miR-130a-3p is a potential biomarker of cerebral stroke, can affect neuronal morphology through APP, and promote the repair of neurons by promoting APP expression after cerebral ischemia.


Transient Central Sleep Apnea Runs Triggered by Disorder of Arousal in a Child.
We report the case of a 5-year-old girl with frequent nocturnal episodes of disorder of arousal (confusional arousals, sleep terrors, and sleep walking), occurring at the end of periods of slow wave sleep, followed by return to sleep accompanied by the occurrence of periodic breathing with a run of approximately 10 to 20 central events. The duration of the central events and oxyhemoglobin desaturation were both maximum at the beginning of each run and became progressively less prominent with the development of the sequences. Night episodes disappeared with bedtime clonazepam but behavioral problems occurred as a paradoxical response; thus, clonazepam was stopped. Sleep extension and melatonin were then started, which were followed by a reduction of night episode frequency and intensity. This observation appears to be the first report of central sleep apnea sequences triggered by parasomnia and, if confirmed by additional reports, it might be considered to be a possible new classification of "complex parasomnia."


Stabilization of DNA triple helices by a series of mono- and disubstituted amidoanthraquinones.
We have used quantitative DNase I footprinting to measure the relative affinities of four disubstituted and two monosubstituted amidoanthraquinone compounds for intermolecular DNA triplexes, and have examined how the position of the attached base-functionalized substituents affects their ability to stabilize DNA triplexes. All four isomeric disubstituted derivatives examined stabilize DNA triplexes at micromolar or lower concentrations. Of the compounds studied the 2,7-disubstituted amidoanthraquinone displayed the greatest triplex affinity. The order of triplex affinity for the other disubstituted ligands decreases in the order 2,7 > 1,8 = 1,5 > 2,6, with the equivalent monosubstituted compounds being at least an order of magnitude less efficient. The 1,5-disubstituted derivative also shows some interaction with duplex DNA. These results have been confirmed by molecular modelling studies, which provide a rational basis for the structure-activity relationships. These suggest that, although all of the compounds bind through an intercalative mode, the 2,6, 2,7 and 1,5 disubstituted isomers bind with their two side groups occupying adjacent triplex grooves, in contrast with the 1,8 isomer which is positioned with both side groups in the same triplex groove.


The suppressive effect of resveratrol on HIF-1α and VEGF expression after warm ischemia and reperfusion in rat liver.
Hypoxia-inducible factor-1α (HIF-1α) is overexpressed in many human tumors and their metastases, and is closely associated with a more aggressive tumor phenotype. The aim of the present study was to investigate the effect of resveratrol (RES) on the expression of ischemic-induced HIF-1α and vascular endothelial growth factor (VEGF) in rat liver. Twenty-four rats were randomized into Sham, ischemia/reperfusion (I/R), and RES preconditioning groups. I/R was induced by portal pedicle clamping for 60 minutes followed by reperfusion for 60 minutes. The rats in RES group underwent the same surgical procedure as I/R group, and received 20 mg/kg resveratrol intravenously 30 min prior to ischemia. Blood and liver tissue samples were collected and subjected to biochemical assays, RT-PCR, and Western blot assays. I/R resulted in a significant (P<0.05) increase in liver HIF-1α and VEGF at both mRNA and protein levels 60 minutes after reperfusion. The mRNA and protein expressions of HIF-1α and VEGF decreased significantly in RES group when compared to I/R group (P<0.05). The inhibiting effect of RES on the expressions of HIF-1α and VEGF induced by I/R in rat liver suggested that HIF-1α/VEGF could be a promising drug target for RES in the development of an effective anticancer therapy for the prevention of hepatic tumor growth and metastasis.


Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma.
Mutations of the p53 gene are associated with a poor prognosis in several types of cancer. We investigated the prognostic importance of p53 mutations in patients with aggressive B-cell lymphoma. We examined the relation between the presence or absence of a detectable p53 mutation in lymphoma cells and the response to chemotherapy and overall survival in 102 previously untreated patients with aggressive B-cell lymphoma. Mutations of the p53 gene were identified by polymerase-chain-reaction-mediated analysis of single-strand conformation polymorphisms and by direct sequencing. Of 102 cases of aggressive B-cell lymphoma, 22 (22 percent) involved p53 mutations. The rate of complete remission was significantly lower in patients with a tumor carrying a p53 mutation (6 of 22 patients, 27 percent) than in those with the wild-type p53 gene (61 of 80 patients, 76 percent) (P<0.001). Overall survival was significantly lower among patients with p53 mutations than among those with the wild-type p53 gene; the Kaplan-Meier estimates of survival at five years were 16 percent and 64 percent, respectively (P<0.001). Multivariate analysis incorporating prognostic factors from the international prognostic index demonstrated that p53 mutations had independent effects on the rates of complete remission and survival. When we categorized patients according to the international prognostic index, we found no effect of p53 mutations in patients in the groups at high-intermediate and high risk. However, these mutations were significantly associated (P< 0.001) with low rates of complete remission (33 percent vs. 91 percent) and survival (27 percent vs. 81 percent at five years) in the groups at low and low-intermediate risk. Mutations of the p53 gene are associated with a poor prognosis in patients with aggressive B-cell lymphoma.


Tafenoquine: A Step toward Malaria Elimination.
There is a pressing need for compounds with broad-spectrum activity against malaria parasites at various life cycle stages to achieve malaria elimination. However, this goal cannot be accomplished without targeting the tenacious dormant liver-stage hypnozoite that causes multiple relapses after the first episode of illness. In the search for the magic bullet to radically cure Plasmodium vivax malaria, tafenoquine outperformed other candidate drugs and was approved by the U.S. Food and Drug Administration in 2018. Tafenoquine is an 8-aminoquinoline that inhibits multiple life stages of various Plasmodium species. Additionally, its much longer half-life allows for single-dose treatment, which will improve the compliance rate. Despite its approval and the long-time use of other 8-aminoquinolines, the mechanisms behind tafenoquine's activity and adverse effects are still largely unknown. In this Perspective, we discuss the plausible underlying mechanisms of tafenoquine's antiparasitic activity and highlight its role as a cellular stressor. We also discuss potential drug combinations and the development of next-generation 8-aminoquinolines to further improve the therapeutic index of tafenoquine for malaria treatment and prevention.


[Effect of hypokinesia and varying microclimate on vestibular function].
The functional state of the vestibular system of the bed rested man is characterized by a decrease of the nystagmic parameters, increase of autonomic reactions and elongation of illusory sensations. This may reduce the static and kinetic stability of man to acceleration. The bed rest induced vestibular changes can be attributed to the functional changes in higher compartments of the central nervous system. The influence of an altered atmosphere on the vestibular function is insignificant.


Modulation of neurotransmitter action: control of the gamma-aminobutyric acid response through the benzodiazepine receptor.
The ability of several homologous benzodiazepine and heterologous nonbenzodiazepine ligands to alter the conductance increase induced in spinal cord neurons by gamma-aminobutyric acid (GABA) was determined. Complete dose-response curves were carried out on individual neurons, reducing error introduced by cell-to-cell variability. The efficacies of modulation differ for "classical" benzodiazepines and novel nonbenzodiazepine drugs in a manner consistent with a model of control of GABA receptor action through a common receptor. There was no apparent correlation between efficacy and potency. CL 218,872, a triazolopyridazine, gave the lowest efficacy of the tranquilizers tested. Ro 15-1788 (an imidazobenzodiazepine) potentiated g GABA with high potency and low efficacy, consistent with an action as a partial agonist and an "antagonist" of classical benzodiazepine action. In order of increasing efficacy, Ro 15-1788, CL 218,872, and flurazepam are partial agonists, whereas clonazepam, chlordiazepoxide, diazepam, and flunitrazepam are full agonists. The beta-carboline drugs methyl-beta-carboline-3-carboxylate (beta-CCM) and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) are "anxiogenics" and convulsants that were found to exert through the benzodiazepine receptor-inhibitory and apparently insurmountable control of g GABA . beta-CCM and DMCM display large negative efficacies and act like effectors at a site distinct from the picrotoxin-sensitive chloride ionophore and coincident with the benzodiazepine site. The actions of these different benzodiazepine receptor ligands in vivo range from anxiolytic and anticonvulsant to anxiogenic and convulsant. Efficacy rather than potency almost certainly determines the qualitative nature of the pharmacological actions of these drugs.


Linc00511 acts as a competing endogenous RNA to regulate VEGFA expression through sponging hsa-miR-29b-3p in pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Long non-coding RNAs (lncRNAs) are important regulators in pathological processes, yet their potential roles in PDAC are poorly understood. Here, we identify a fundamental role for a novel lincRNA, linc00511, in the progression of PDAC. Linc00511 levels in PDAC tissue specimens and cell lines were examined by quantitative real-time PCR. Corresponding adjacent non-neoplastic tissues were used as controls. The function of linc00511 in PDAC cell lines was determined by RNA interference approach in vitro and in vivo. Fluorescence in situ hybridization (FISH) was used to characterize linc00511 expression in PDAC cells. Insights of the mechanism of competitive endogenous RNAs (ceRNAs) were obtained from bioinformatic analysis, luciferase assays and RIP assays. The association between the linc00511/hsa-miR29b-3p axis and VEGFA was verified by Western blotting assay. Immunohistochemistry was performed to evaluate the expression of VEGFA in PDAC samples. The aberrant up-regulation of linc00511 was detected in PDAC cell lines and patient specimens compared with controls. An increase in linc00511 expression indicates the adverse clinical pathological characteristics and poor prognosis. Functionally, linc00511 depletion in PDAC cells decreased proliferation, migration, invasion and endothelial tube formation. Mechanistically, linc00511 could up-regulate VEGFA via its competing endogenous RNA (ceRNA) activity on hsa-miR-29b-3p. In summary, our results define an important axis controlling proliferation, invasion and tumour angiogenesis in PDAC. Linc00511 is a novel lncRNA that plays a significant regulatory role in the pathogenesis and progression of PDAC. Thus, Linc00511 represents a new prognostic biomarker to predict clinical outcome of PDAC patients after surgery and may serve as a potential therapeutic target for PDAC treatment.


Breast conservation therapy--surgical aspects.
Breast conservation therapy is now accepted as an alternative to mastectomy for early stage breast cancer. In 1991 the NIH recommended a regime consisting of the excision of a primary tumour with a 1 cm-margin of breast tissue around and an axillary node dissection followed by postoperative administration of 45-50 Gy irradiation. Although this regime is popular in most centres, several issues remain controversial. These are (1) selection of cases, (2) surgical technique, (3) histopathology and radiology, and (4) adjutant therapy. In this presentation I shall deal mainly with the surgical aspects of breast conservation.


Self-association during heterogeneous nucleation onto well-defined templates.
We investigated the interplay between self-associates in solution and surface templating by studying the crystallization behavior of isonicotinamide (INA) and 2,6-dihydroxybenzoic acid (DHB) in the presence of self-assembled monolayers (SAM). The end group of the SAM as well as the hydrogen-bonding capabilities of the solvent and self-association of INA and DHB were found to be important in polymorph crystallization on SAMs. In the case of INA in ethanol, both chain and dimer self-associates are present in the solution. In the absence of SAMs the polymorph form II (dimer structure) is the crystallization outcome. In ethanol the 4-mercaptopyridine and 4-mercaptobenzoic acid SAMs organize INA chain associates at the template surface and enable the crystallization of form I while the 16-mercaptohexadecanoic acid SAM results in the crystallization of form II. Raman spectroscopy suggests that molecular interactions between INA and the SAM are responsible for the formation of specific polymorphs. XRPD results in the identification of the orientation of the crystal on the surface that further verified the results obtained by Raman spectroscopy. In nitrobenzene and nitromethane INA associates in solution only as chains and crystallization results in the formation of form IV and form I, respectively (both chain forms). The crystals formed in the bulk solution and on SAMs were the same, which seems to indicate that the self-association in nitrobenzene and nitromethane is not influenced by the presence of templates. In the case of DHB in toluene and chloroform, all three SAMs nucleated only one type of polymorph (stable form 2). In the case of toluene the polymorphic outcome was stable form 2 instead of metastable form 1, which is favored in toluene in the absence of the SAMs. Again, Raman spectroscopy and XRPD suggest that DHB-SAM molecular interactions may be responsible for the formation of form 2.


[Antiplatelet agents and older patients: which drugs and what evidence?].
Antiplatelet drugs are a cornerstone for the management of all atherosclerosis-related conditions, increasingly frequent with advanced age. Associations of antiplatelet drugs increase the bleeding risk and the overall net clinical benefit should be carefully assessed. In the absence of recommendations made specifically for the elderly practical suggestions can be inferred from subgroup analyses of large trials. The association of two antiplatelet agents should be limited to acute coronary syndromes for a maximum of one year, avoiding prasugrel in 75 years and older patients, and to coronary angioplasties for a minimum duration depending on the type of stent. In elderly patients with atrial fibrillation and ischemic heart disease more than one year after coronary stenting, a vitamin K antagonist alone is usually sufficient.


Expression of the chloroplast thioredoxins f and m is linked to short-term changes in the sugar and thiol status in leaves of Pisum sativum.
Thioredoxins (TRXs) f and m are key components in the light regulation of photosynthetic metabolism via thiol-dithiol modulation in chloroplasts of leaves; however, little is known about the factors modulating the expression of these proteins. To investigate the effect of sugars as photosynthetic products on the expression of PsTRX f and m1 genes, sucrose and glucose were externally supplied to pea plants during the day. There was an increase in the mRNA levels of PsTRX f and m1 genes in response mainly to glucose. When leaf discs were incubated for up to 4h in the dark, glucose also led to an increase in both mRNA and protein levels of TRXs f and m, while sucrose had no substantial effect. Expression of PsDOF7, a carbon metabolism-related transcription factor gene, was also induced by glucose. Protein-DNA interaction showed that PsDOF7 binds specifically to the DOF core located in PsTRX f and m1 gene promoters. Transient expression in agroinfiltrated pea leaves demonstrated that PsDOF7 activated transcription of both promoters. The incubation of leaf discs in dithiotreitol (DTT) to increase the redox status led to a marked increase in the mRNA and protein levels of both TRXs within 4h. The increase in TRX protein levels occurred after 1h DTT feeding, implying a rapid effect of the thiol status on TRX f and m1 protein turnover rates, while transcriptional regulation took 3h to proceed. These results show that the protein levels of both TRXs are under short-term control of the sugar and thiol status in plants.


Modulating the morphology and electrical properties of GaAs nanowires via catalyst stabilization by oxygen.
Nowadays, III-V compound semiconductor nanowires (NWs) have attracted extensive research interest because of their high carrier mobility favorable for next-generation electronics. However, it is still a great challenge for the large-scale synthesis of III-V NWs with well-controlled and uniform morphology as well as reliable electrical properties, especially on the low-cost noncrystalline substrates for practical utilization. In this study, high-density GaAs NWs with lengths >10 μm and uniform diameter distribution (relative standard deviation σ ∼ 20%) have been successfully prepared by annealing the Au catalyst films (4-12 nm) in air right before GaAs NW growth, which is in distinct contrast to the ones of 2-3 μm length and widely distributed of σ ∼ 20-60% of the conventional NWs grown by the H2-annealed film. This air-annealing process is found to stabilize the Au nanoparticle seeds and to minimize Ostwald ripening during NW growth. Importantly, the obtained GaAs NWs exhibit uniform p-type conductivity when fabricated into NW-arrayed thin-film field-effect transistors (FETs). Moreover, they can be integrated with an n-type InP NW FET into effective complementary metal oxide semiconductor inverters, capable of working at low voltages of 0.5-1.5 V. All of these results explicitly demonstrate the promise of these NW morphology and electrical property controls through the catalyst engineering for next-generation electronics.


Collaborative Evaluation of the Healthy Habits Program: An Effective Community Intervention to Improve Mobility and Cognition of Chinese Older Adults Living in the U.S.
There is a growing demand to reduce ethnic health disparities. The Healthy Habits Program (HHP) was implemented to provide a community-based physical activity and education intervention for Chinese older adults living in Boston, Massachusetts. This study evaluated the HHP by assessing outcomes that are critical for maintaining independence of older persons. Quantitative evaluation was performed on 50 Chinese older adults enrolled in the HHP. The community members were trained in data collection and management. Cognition (Mini Mental State Examination (MMSE), Trail Making Test and Complex Walking Task), mobility (Short Physical Performance Battery (SPPB) and maximal gait speed), depressive symptoms (Patient Health Questionnaire-9), perceived disability (World Health Organization Disability Assessment 2.0), nutritional status (Mini Nutrition Assessment®), and strength (grip and leg strength) were assessed at baseline and at 6 months. All tests were translated into Chinese. Of the 50 participants (mean age 68.4 years; 68% female), 78% achieved the goal of performing exercise ≥3 times/week. After 6 months, clinically meaningful improvements were observed in mobility (mean SPPB score changed from 10.3 to 11.1 points; p=0.01) and cognition (mean MMSE score changed from 26.0 to 27.8 points; p=0.001). There were also statistically significant improvements in executive function, depressive symptoms and perceived disability (p<0.05). Culturally sensitive community interventions, such as the HHP, are effective for improving mobility and cognition of Chinese older adults. This reveals the potential of promoting successful aging in minority populations through community settings, and should be advocated to reduce ethnic health disparities in the U.S.


[Preservation of hearing and facial nerve function in surgery for acoustic neuroma].
The results concerning the preservation of hearing and facial nerve function in 71 patients with 74 acoustic neuromas operated on from 1979 to 1990 are presented. All patients have been operated on in half-sitting position by one surgeon using the suboccipital-transmeatal approach. Postoperative facial nerve function was good (House degree I or degrees II) in 42/73 patients (58%), moderate (House degrees III or degrees IV) in 13/37 (18%), and poor (House degrees V or degrees VI) in 18/73 (24%). Preservation of useful hearing was achieved in 17%. The smaller the tumour and the easier the preparation the better was the functional result. Beside anatomic integrity of nerves and endolymphatic system the internal auditory artery as the most important vessel for the inner ear blood supply should be respected. The cochlear nerve intact in 47 patients we only found one case with recurrent tumour in a patient with neurofibromatosis 2. Preservation of the cochlear nerve did not have an increased risk of tumour recurrence in our group of patients.


Distinctly different behavioral responses of a copepod, Temora longicornis, to different strains of toxic dinoflagellates, Alexandrium spp.
Zooplankton responses to toxic algae are highly variable, even towards taxonomically closely related species or different strains of the same species. Here, the individual level feeding behavior of a copepod, Temora longicornis, was examined which offered 4 similarly sized strains of toxic dinoflagellate Alexandrium spp. and a non-toxic control strain of the dinoflagellate Protoceratium reticulatum. The strains varied in their cellular toxin concentration and composition and in lytic activity. High-speed video observations revealed four distinctly different strain-specific feeding responses of the copepod during 4h incubations: (i) the 'normal' feeding behavior, in which the feeding appendages were beating almost constantly to produce a feeding current and most (90%) of the captured algae were ingested; (ii) the beating activity of the feeding appendages was reduced by ca. 80% during the initial 60min of exposure, after which very few algae were captured and ingested; (iii) capture and ingestion rates remained high, but ingested cells were regurgitated; and (iv) the copepod continued beating its appendages and captured cells at a high rate, but after 60min, most captured cells were rejected. The various prey aversion responses observed may have very different implications to the prey and their ability to form blooms: consumed but regurgitated cells are dead, captured but rejected cells survive and may give the prey a competitive advantage, while reduced feeding activity of the grazer may be equally beneficial to the prey and its competitors. These behaviors were not related to lytic activity or overall paralytic shellfish toxins (PSTs) content and composition and suggest that other cues are responsible for the responses.


Hypersensitivity pneumonitis--pathology and pathogenesis.
Early reports of hypersensitivity pneumonitis postulated that the disease was infectious or resulted from the toxic properties of the inhaled organic dusts. The finding of precipitating antibodies to moldy hay in farmers afflicted with farmer's lung suggested a role for antibody in pathogenesis, and a type III (antigen-antibody complex-mediated or Arthus) hypersensitivity reaction based on the classification of allergic reactions by Gell and Coombs was postulated. Subsequent studies have indicated the importance of cell-mediated (delayed) hypersensitivity (type IV). It must be recognized that hypersensitivity mechanisms are quite complicated and that the classification of Gell and Coombs is an oversimplification; interreacting humoral and cellular responses are typical of most hypersensitivity reactions of whatever classic type as originally defined. The prime importance of T-cell- and macrophage-mediated inflammation in HP, however, is indicated by histopathology, animal models, and in vitro correlates in humans. Major difficulties in defining completely the exact effector mechanisms involved in the pathogenesis of HP include the absence of a reliable in vitro correlate of antigen-specific effector T cells (the so called TDH cell) and the overwhelming versatility of the macrophage. There is no direct evidence to support contributions by precipitins, complement, or genetic host factors in the pathogenesis of hypersensitivity pneumonitis, nor are there studies as yet of cellular cytotoxicity contributions. Cellular and antibody interactions may lead to immunosuppressive processes modulating inflammatory responses and preventing disease despite immunogenesis. Animal models are helpful in dissecting mechanisms and defining effector functions. The eventual goal in studies of pathogenesis is to provide better tools for definitive diagnosis and methods of disease prevention, modulation, and cure.


[Cerebral vasospasm: clinical and biochemical aspects and treatment (author's transl)].
Cerebral vasospasm is caused by many factors. Primarily it is caused by Noradrenalin (NA) localised in the vessel walls and by platelet aggregation, with raising of the concentration of 5-HT in the intima. Its prolongation is based on blood breakdown products and or biochemical disturbances of brain metabolism. The most potent vasoconstrictors are acting through the vessel's own receptors (Serotonin, NE, Histamin), so the most effective therapy is based on the contractile system of the vessel. By blocking the alpha-receptors by Phenoxybenzamine, blockade of the Phosphodiesterase by Papaverin, Euphyllin to raise the concentration of cAMP and stimulation of Adenyl-Cyclase-System by beta-stimulation, it is possible to get good results in the treatment of cerebral arterial vasospasm.


Somatotopic organization of the human periventricular gray matter.
The periventricular gray (PVG) matter is an established anatomical target for chronic deep brain stimulation (DBS) in the treatment of certain intractable pain syndromes. Data relating to the representation of pain and other somatosensory modalities within the PVG in humans are negligible. We examined the character and location of somatosensory responses elicited by electrical stimulation along the length of the PVG in a patient who underwent unilateral DBS for intractable nociceptive head pain. Consistent responses were obtained and indicated the presence of a somatotopic representation in this region. The contralateral lower limb was represented cranially, followed by the upper limb and trunk, with the face area located caudally, near the level of the superior colliculi. Bilateral representation was only observed in the forehead and scalp.


Transcription Factor Hepatocyte Nuclear Factor-1β Regulates Renal Cholesterol Metabolism.
HNF-1β is a tissue-specific transcription factor that is expressed in the kidney and other epithelial organs. Humans with mutations in HNF-1β develop kidney cysts, and HNF-1β regulates the transcription of several cystic disease genes. However, the complete spectrum of HNF-1β-regulated genes and pathways is not known. Here, using chromatin immunoprecipitation/next generation sequencing and gene expression profiling, we identified 1545 protein-coding genes that are directly regulated by HNF-1β in murine kidney epithelial cells. Pathway analysis predicted that HNF-1β regulates cholesterol metabolism. Expression of dominant negative mutant HNF-1β or kidney-specific inactivation of HNF-1β decreased the expression of genes that are essential for cholesterol synthesis, including sterol regulatory element binding factor 2 (Srebf2) and 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr). HNF-1β mutant cells also expressed lower levels of cholesterol biosynthetic intermediates and had a lower rate of cholesterol synthesis than control cells. Additionally, depletion of cholesterol in the culture medium mitigated the inhibitory effects of mutant HNF-1β on the proteins encoded by Srebf2 and Hmgcr, and HNF-1β directly controlled the renal epithelial expression of proprotein convertase subtilisin-like kexin type 9, a key regulator of cholesterol uptake. These findings reveal a novel role of HNF-1β in a transcriptional network that regulates intrarenal cholesterol metabolism.


[Chloroderivatives of phenoxyacetic acid as antagonists of thyroid hormones].
A 24-hour stay of the Rana temporaria tadpoles in solutions of the sodium and diethylamine salts of 2,4-dichlorophenoxyacitic acid (with 1 and 2 mg/l, respectively) significantly inhibits their metamorphosis. An addition of these salts to a solution containing thyroidin in a concentration of 1--5 mg/l hinders the action of hormone stimulating metamorphosis. The effect of the sodium salt of 2,4-dichlorophenoxyacetic acid prevents the destruction of some tadpoles by toxic concentrations of thyroidin. The above data justify referring the chloroderivatives of the phenoxyacetic acid to antagonists of the thyroid hormones.


Outcome in severe acute renal failure associated with malaria.
Malaria, a common health problem in certain parts of the world, has a considerable morbidity and mortality. This study reports its occurrence with a serious complication, acute renal failure (ARF), at a Third World tertiary care centre. All registered patients with ARF who had history and clinical findings suggestive of malaria and had malarial parasites on peripheral blood smears were included in this study. The data on their modes of presentation, management and outcome have been analysed. Between January 1990 and December 1999, a total of 2098 patients with ARF were seen at the centre. Of these, 124 (5.9%) developed ARF due to malaria (falciparum in 121 and vivax in three). The male:female ratio was 4:1 and 84 (68%) patients were oligo- or anuric on presentation. Mean serum creatinine on admission was 9.43 +/- 5.39 mg/dl and 99 (79.8%) patients required renal replacement therapy. Of the cohort, 32 (25.8%) died, most within 48 h of admission. Age, oliguria, central nervous system involvement and presence of disseminated intravascular coagulopathy emerged as bad prognostic factors in simple univariate analysis. Of the survivors, 77 (62%) had complete recovery of renal function, while 15 (12%) were progressing towards recovery when lost to follow-up. The number of dialysis sessions did not differ significantly between the oliguric and non-oliguric groups. In patients who do not succumb early to ARF of severe malaria, treatment with antimalarials and dialysis brings about recovery of renal function.


Depression underdiagnosis and the effects on quality of life in outpatients with HIV at a Nigerian university teaching hospital.
The study aimed to determine the frequency of depressive disorder in a sample of patients with HIV and its level of underdiagnosis by attending physicians. The study also explored the effect of depressive disorder on the quality of life (QOL) of patients with HIV. A sociodemographic questionnaire was administered to patients with HIV attending a medical out-patient clinic at Ahmadu Bello University Teaching Hospital, central northern Nigeria. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to screen for depressive symptoms, and the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) was used to confirm the diagnosis of depressive disorder. The patients' medical records were screened for documentation of depressive symptoms or previous treatment with antidepressants by an attending physician. The World Health Organization Quality of Life assessment short version (WHOQOL-BREF) was used to measure six domains of QOL. A total of 310 patients with HIV participated in the study; of these, 14.2% (n = 44) met the diagnostic criteria for depressive disorder, according to the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10). All of these cases of depressive disorder had not been previously recognised by any attending physician. Of the 310 participants, 58 (18.7%) had a 'poor' score and 252 (81.3%) had an 'average or above' score for overall QOL. Of the 44 with depressive disorder, 28 (63.6%) were among those with a poor score for overall QOL. A fairly similar pattern was observed for all the other domains, with patients with depressive disorder accounting for greater proportions of the participants with poor domain scores. Thus, the authors found that depression is common but seldom clinically recognised in people with HIV, and that it is associated with a reduction in quality of life. Identifying and treating depression in patients with HIV will improve functioning and general wellbeing.


Peripheral blood lymphocyte receptors for B-lymphoblastoid cell lines (B-LCL).
Because interactions between B cells and T lymphoyctes are of fundamental importance in the generation of the immune response to most antigens, we attempted to identify the cells capable of binding B-lymphoblastoid cell lines (B-LCL), their tissue distribution, and their presence in other species. Cells bearing a surface receptor for B-LCL were found in human peripheral blood, tonsil, and bone marrow, as well as mouse and rat spleen. Binding cells were phenotypically heterogeneous. The majority are T cells as defined by their ability to bind sheep red blood cells (E-rosettes). However, a subpopulation of non-T-lymphocytes were capable of binding B-LCL. This was demonstrated by depleting T cells with an E-rosette centrifugation technique and then performing a double rosette assay. The wide distribution of T lymphocytes with receptors for B-lymphoblastoid cells within peripheral lymphoid organs and their presence in several species suggest that these surface molecules may represent one of the means by which T cells and B cells interact in the induction of the immune response to T-dependent antigens.


Loss of the Prader-Willi syndrome protein necdin causes defective migration, axonal outgrowth, and survival of embryonic sympathetic neurons.
Prader-Willi syndrome is a neurodevelopmental disorder marked by abnormalities in feeding, drinking, thermoregulation, intestinal motility, and reproduction, suggesting disruption of the autonomic nervous system. Necdin, one of several proteins genetically inactivated in individuals with Prader-Willi syndrome, is important for the differentiation of central and sensory neurons. We now show that formation, migration, and survival of sympathetic superior cervical ganglion neurons are impaired in Ndn-null embryos. We observed reduced innervation of superior cervical ganglion target organs, including the submandibular gland, parotid gland, and nasal mucosa. While the formation of other sympathetic chain ganglia is unaffected, axonal extension is impaired throughout the sympathetic nervous system. These results demonstrate a novel role for necdin in cellular migration, in addition to its roles in survival and axon outgrowth. Furthermore, reduced sympathetic function provides a plausible explanation for deficiencies of salivary gland function in individuals with congenital necdin deficiency consequent to Prader-Willi syndrome.


Health-related quality of life of children with a positive carrier status for inherited cardiovascular diseases.
Familial hypercholesterolemia, hypertrophic cardiomyopathy, and long QT Syndrome are genetic cardiovascular conditions which may lead to sudden cardiac death at a young age. Preventive measures include lifestyle modifications, medications, and/or cardiac devices. Hence, identification of carrier children can protect them for the potentially life threatening consequences at a young age. Yet, informing children about their genetic risk status and subjecting them to treatment may have negative consequences. This preliminary study aimed to explore (1) how the health-related quality of life of carrier children compares to the quality of life of Dutch children in general; and (2) to what extent the carrier children's quality of life and their parents' perception thereof concur. Our method involved carrier children (n = 35), aged between 8 and 18 years, and their parents (n = 37) who completed a self-report questionnaire. Children's health-related quality of life was assessed with a children and parent version of the KIDSCREEN. Dutch reference data were available from a representative national sample. Our results show no statistically significant differences in scores between carrier children and the reference group. Also, no differences were found between carrier children and their parents' ratings, with the exception of the scale "psychological well being". Parents rated their child's psychological well being significantly lower. We identified no problems with the well-being of carrier children as compared to a representative sample of peers. This may offer some initial reassurance to those who have concerns about the implications of genetically testing children for one of these cardiovascular conditions. Yet, attention to possible problems in these children remains warranted.


Long-term exposure to ambient air pollution and risk of leukemia and lymphoma in a pooled European cohort.
Leukemia and lymphoma are the two most common forms of hematologic malignancy, and their etiology is largely unknown. Pathophysiological mechanisms suggest a possible association with air pollution, but little empirical evidence is available. We aimed to investigate the association between long-term residential exposure to outdoor air pollution and risk of leukemia and lymphoma. We pooled data from four cohorts from three European countries as part of the "Effects of Low-level Air Pollution: a Study in Europe" (ELAPSE) collaboration. We used Europe-wide land use regression models to assess annual mean concentrations of fine particulate matter (PM2.5), nitrogen dioxide (NO2), black carbon (BC) and ozone (O3) at residences. We also estimated concentrations of PM2.5 elemental components: copper (Cu), iron (Fe), zinc (Zn); sulfur (S); nickel (Ni), vanadium (V), silicon (Si) and potassium (K). We applied Cox proportional hazards models to investigate the associations. Among the study population of 247,436 individuals, 760 leukemia and 1122 lymphoma cases were diagnosed during 4,656,140 person-years of follow-up. The results showed a leukemia hazard ratio (HR) of 1.13 (95% confidence intervals [CI]: 1.01-1.26) per 10 μg/m3 NO2, which was robust in two-pollutant models and consistent across the four cohorts and according to smoking status. Sex-specific analyses suggested that this association was confined to the male population. Further, the results showed increased lymphoma HRs for PM2.5 (HR = 1.16; 95% CI: 1.02-1.34) and potassium content of PM2.5, which were consistent in two-pollutant models and according to sex. Our results suggest that air pollution at the residence may be associated with adult leukemia and lymphoma.


Control of Mycobacterium avium subsp. paratuberculosis infection in agricultural species.
Paratuberculosis or Johne's disease is a chronic intestinal disease caused by Mycobacterium avium subsp. paratuberculosis, which continues to spread in agricultural species. Control of paratuberculosis is challenging and should not be underestimated. Due to the long incubation period of the infection, disease is largely subclinical in domesticated livestock. Hence, direct effects on animal productivity and welfare are often masked and may appear insufficient to justify large investments in control programmes by individual farmers, livestock industries or governments. Furthermore, in some countries the main effects of the disease are indirect, resulting from the impact of market discrimination against herds and flocks known to be infected, or from the control measures enforced to reduce transmission. In such circumstances, producers may be unwilling to co-operate with surveillance that may detect infection in herds or flocks. As control programmes are rarely successful in eliminating the infection from a herd or flock in the short term without an aggressive and costly programme, financial and community support assists producers to deal with the challenge. Successful prevention and control depends on animal health authorities and livestock industries acquiring a good understanding of the nature and epidemiology of infection, and of the application of tools for diagnosis and control. Building support for control programmes under the leadership of the affected livestock industries is critical, as programmes are unlikely to be successful without ongoing political will, supported by funding for research, surveillance and control.


Experimental analysis of adherence counseling: implications for hypertension management.
A time series "reversal" design demonstrated that behavioral counseling increased medication adherence from about 60 to 100% for a black, hypertensive patient. However, inadequate pharmacological treatment yielded no clinically important blood pressure decrease. The combination of improved compliance and minimal blood pressure reduction led the patient's physician to explore higher doses and alternate medications to achieve blood pressure control. The physician's aggressive medical treatment was initiated only after the patient's compliance had been improved. Thus, this study suggests that paraprofessional counseling can increase compliance and illustrates the need for both behavioral and physiological data in clinical management to avoid blaming patients for poorly controlled blood pressure.


New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab.
Overview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression. Results: Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case. Conclusions: In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.


Statistical characterization and classification of edge-localized plasma instabilities.
The statistics of edge-localized plasma instabilities (ELMs) in toroidal magnetically confined fusion plasmas are considered. From first principles, standard experimentally motivated assumptions are shown to determine a specific probability distribution for the waiting times between ELMs: the Weibull distribution. This is confirmed empirically by a statistically rigorous comparison with a large data set from the Joint European Torus. The successful characterization of ELM waiting times enables future work to progress in various ways. Here we present a quantitative classification of ELM types, complementary to phenomenological approaches. It also informs us about the nature of ELM processes, such as whether they are random or deterministic. The methods are extremely general and can be applied to numerous other quasiperiodic intermittent phenomena.


The effects and interactions of GABAergic and dopaminergic agents in the prevention of form deprivation myopia by brief periods of normal vision.
Intravitreal injections of GABA antagonists, dopamine agonists and brief periods of normal vision have been shown separately to inhibit form-deprivation myopia (FDM). Our study had three aims: (i) establish whether GABAergic agents modify the myopia protective effect of normal vision, (ii) investigate the receptor sub-type specificity of any observed effect, and (iii) consider an interaction with the dopamine (DA) system. Prior to the period of normal vision GABAergic agents were applied either (i) individually, (ii) in combination with other GABAergic agents (an agonist with an antagonist), or (iii) in combination with DA agonists and antagonists. Water injections were given to groups not receiving drug treatments so that all experimental eyes received intravitreal injections. As shown previously, constant form-deprivation resulted in high myopia and when diffusers were removed for 2 h per day the period of normal vision greatly reduced the FDM that developed. GABA agonists inhibited the protective effect of normal vision whereas antagonists had the opposite effect. GABAA/C agonists and D2 DA antagonists when used in combination were additive in suppressing the protective effect of normal vision. A D2 DA agonist restored some of the protective effect of normal vision that was inhibited by a GABA agonist (muscimol). The protective effect of normal vision against form-deprivation is modifiable by both the GABAergic and DAergic pathways.


Tunable terahertz generation in the picosecond regime from the stimulated polariton scattering in a LiNbO3 crystal.
We demonstrate narrowband tunable terahertz generation from a picosecond LiNbO3 polariton laser, pumped by a CW mode-locked Nd:YVO4 picosecond laser. We generated up to 5.4 μW of terahertz output in untuned mode. We tuned the terahertz output, using etalons in the cavity, from 0.51 to 2.12 THz. Terahertz output powers of 3.7 μW and 2.4 μW were achieved at terahertz frequencies of 1.6 THz and 0.9 THz, respectively.


Risk analysis of use of different classes of antidepressants on subsequent dementia: A nationwide cohort study in Taiwan.
Depression and dementia are common mental health problems and are associated in several ways. Early-life depression is associated with increased risk of later life dementia, and depression can present as a preclinical symptom or consequence of dementia. Despite the plausible relationship between these two clinical entities, the potential association between antidepressant medication and dementia has rarely been investigated. We conducted a 9-year retrospective analysis of Taiwan's National Health Insurance Research Database (NHIRD), enrolling 5819 cases who had received prescriptions of antidepressants between 2003 and 2006, and 23,276 (with ratio of 1:4) age, sex, and index date-matched controls. The hazard ratio (HR) of dementia among antidepressant users with depression was 2.42 (95% confidence interval (CI): 1.15-5.10), for those without depression was 4.05 (95% CI: 3.19-5.15), compared to antidepressant non-users respectively. Among the 6 classes of common antidepressants used in Taiwan, the adjusted HRs were 3.66 (95% CI: 2.62-5.09) for SSRIs, 4.73 (95% CI: 2.54-8.80) for SNRI, 3.26 (95% CI: 2.30-4.63) for TCAs, 6.62 (95% CI: 3.34-13.13) for TeCA, 4.94 (95% CI: 2.17-11.24) for MAOI, and 4.48 (95% CI: 3.13-6.40) for SARI. Furthermore, the multivariate analysis result showed that the adjusted HRs of cumulative defined daily doses (cDDDs) were 3.74 (95% CI: 2.91-4.82), 3.73 (95% CI: 2.39-5.80) and 5.22 (95% CI: 3.35-8.14) for those who had cDDDs of <90, 90-180 and >180 compared to those who had taken no antidepressant medication. This is a retrospective study based on secondary data, hence, we could not claim causality between antidepressant medication and dementia. However, a potential association between antidepressant and occurrence of dementia after controlling for the status of depression was observed. Lack of patients' data about smoking status and body mass index in NHIRD, which are considered related to dementia, was also a limitation in this study. In this study, we concluded that antidepressant medication is a potential risk factor for dementia, independent from any effect of depression itself.


Regional blood flow responses to stimulation of the subthalamic locomotor region.
Recent studies have suggested that descending central command from an area in the diencephalon (subthalamic locomotor region - STLR) is involved in the control of ventilation, arterial pressure and heart rate during exercise. The purpose of this study was to determine if electrical activation of the STLR in anesthetized cats elicits changes in regional blood flow and vascular resistances similar to those evoked by exercise. Therefore, organ blood flows (radioactive microsphere technique), arterial pressure (AP), heart rate (HR), and respiratory output (quantified from phrenic nerve activity) were recorded during resting conditions and during STLR stimulation. Stimulation of the subthalamic locomotor region produced increases in AP, HR and respiratory output similar to those reported previously. These changes were accompanied by increased blood flow to the heart, diaphragm and limb skeletal muscles. A concomitant decrease occurred in blood flow to the kidneys. In addition, the vascular resistances of the intestines, gallbladder and stomach increased. These vascular and respiratory responses are similar to those occurring during static exercise in conscious cats.