Seizure onset zone localization using postictal hypoperfusion detected by arterial spin labelling MRI.
Neurological dysfunction following epileptic seizures is a well-recognized phenomenon. Several potential mechanisms have been suggested to explain postictal dysfunction, with alteration in cerebral blood flow being one possibility. These vascular disturbances may be long lasting and localized to brain areas involved in seizure generation and propagation, as supported by both animal and human studies. Therefore, measuring perfusion changes in the postictal period may help localize the seizure onset zone. Arterial spin labelling is a non-invasive, rapid and reproducible magnetic resonance imaging technique that measures cerebral perfusion. To this end, we measured postictal perfusion in patients with drug resistant focal epilepsy who were admitted to our seizure-monitoring unit for presurgical evaluation. Twenty-one patients were prospectively recruited and underwent arterial spin labelling scanning within 90 min of a habitual seizure. Patients also underwent a similar scan in the interictal period, after they were seizure-free for at least 24 h. The acquired scans were subtracted to identify the areas of significant postictal hypoperfusion. The location of the maximal hypoperfusion was compared to the presumed seizure onset zone to assess for concordance. Also, the localizing value of this technique was compared to other structural and functional imaging modalities. Postictal perfusion reductions of >15 units (ml/100 g/l) were seen in 15/21 patients (71.4%). In 12/15 (80%) of these patients, the location of the hypoperfusion was partially or fully concordant with the location of the presumed seizure onset zone. This technique compared favourably to other neuroimaging modalities, being similar or superior to structural magnetic resonance imaging in 52% of cases, ictal single-photon emission computed tomography in 60% of cases and interictal positron emission tomography in 71% of cases. Better arterial spin labelling results were obtained in patients in whom the seizure onset zone was discernible based on non-invasive data. Thus, this technique is a safe, non-invasive and relatively inexpensive tool to detect postictal hypoperfusion that may provide useful data to localize the seizure onset zone. This technique may be incorporated into the battery of conventional investigations for presurgical evaluation of patients with drug resistant focal epilepsy.


[Radiofrequency ablation of resistant atrial flutter: a new anatomical approach].
Several reports have suggested that radiofrequency ablation could prevent atrial flutter resistant to antiarrhythmic therapy. The usual recommendation is to apply the radiofrequency current in a zone situated between the tricuspid valve and orifice of inferior vena cava. The aim of this study was to assess the efficacy of another site of ablation of flutter extending from the tricuspid valve to the orifice of the coronary sinus, either alone or associated with a site between the coronary sinus and the lateral wall of the right atrium. Twenty patients aged 42 to 78 years (mean : 6 +/- 11 years) were included. Atrial flutter was paroxysmal in 15 patients and chronic in 5 patients. Each patients had documented failure of 1 to 5 antiarrhythmic agents (average 3.1 +/- 1.6). The site of ablation was localised by anatomical criteria alone. During follow-up of 7 +/- 5 months (range 1 to 18 months), 13 patients had no recurrence of atrial flutter after ablation, 5 patients had recurrence and 2 patients had paroxysmal atrial fibrillation alone: the success rate was 15/20 (75%). This study suggests that the zone between the tricuspid valve and coronary sinus may be a site for radiofrequency ablation of atrial flutter. It is valuable alternative to the usually recommended technique.


Effect of Carbon Dioxide on Growth-Rates of Selected Microorganisms Isolated from Black Drum ( Pogonias cromis ).
The effect of carbon dioxide (25-100%)-enriched atmospheres on growth rates of a coryneform bacterium, Micrococcus varians , a Vibrio sp., a Moraxella sp. and Pseudomonas fluorescens growing on trypticase soy agar at 4 and 25°C was investigated. Growth rates were determined by measuring the rate of increase in the diameter of colonies on plates packed in laminated plastic pouches containing the CO2-enriched environments. Carbon dioxide caused a significant decrease in the growth rates of all the organisms and the inhibitory effect was greatly enhanced by low temperatures. At 25°C, the gram-positive organisms were more resistant to CO2 than the gram-negative organisms, while at 4°C none of the organisms grew in 25% CO2, the lowest concentration tested. When exposed to air after being incubated in CO2-enriched environments, the organisms in most instances grew at normal rates indicating limited residual effect of CO2. The effect of temperature on relative CO2 inhibition was investigated in detail for the Moraxella sp. and P. fluorescens . In an atmosphere containing 25% CO2 in air at 20°C both organisms showed approximately 25% inhibition as compared to growth in air at the same temperature, while at 10°C P. fluorescens was completely inhibited and the Moraxella sp. showed 95% inhibition.


Hepatocellular liver injury in hospitalized patients affected by COVID-19: Presence of different risk factors at different time points.
Prevalence and clinical impact of increased liver function tests in patients affected by Coronavirus disease 2019 (COVID-19) is controversial. This observational study evaluates the prevalence of transaminases elevation in hospitalized patients affected by COVID-19 and investigates the presence of factors associated with hepatocellular injury and with mortality. Data of 292 adult patients with confirmed COVID-19 admitted to the Ente Ospedaliero Cantonale (Switzerland) were retrospectively analyzed. Transaminases were increased in about one-third of patients on hospital admission and two-thirds of patients during the hospital stay. On hospital admission, transaminases were more commonly elevated in younger patients, who also reported elevated C reactive protein and a higher degree of respiratory failure. Independent factors associated with abnormal transaminases during hospitalization were drugs, in particular paracetamol (OR=2.67; 95% CI=1.38-5.18; p = 0.004) and remdesivir (OR=5.16; 95% CI=1.10-24.26; p = 0.04). Mortality was independently associated to age (OR = 1.09; 95% CI=1.05-1.13; p<0.001), admission to intensive care unit (OR=5.22; 95% CI=2.28-11.90; p<0.001) and alkaline phosphatase peak (OR=1.01; 95% CI=1.00- 1.01; p = 0.01). On hospital admission, factors associated with liver damage were linked to demographic and clinical characteristics (age, inflammation and hypoxia) while, during hospitalization, drug treatment was related to development and progression of hepatocellular damage. Mortality was associated with alkaline phosphate peak value.


Screen identifies fasudil as a radioprotector on human fibroblasts.
Radioprotectors safeguard biological system exposed to ionizing radiation (IR) by protecting normal cells from radiation damage during radiotherapy. Due to the toxicity and limited clinical utility of the present radioprotectors, it prompts us to identify novel radioprotectors that could alleviate IR-induced cytotoxicity of normal tissues. To identify new radioprotectors, we screened a chemical molecular library comprising 253 compounds in normal human fibroblasts (HFs) or 16HBE cells upon IR by CCK-8 assays and clonogenic survival assays. Fasudil was identified as a potential effective radioprotector. The results indicated that Fasudil exerts radioprotective effects on HFs against IR-induced DNA double-strand breaks (DSBs) through the regulation of DSB repair. Fasudil increased homologous recombination (HR) repair by 45.24% and decreased non-homologous end-joining (NHEJ) by 63.88% compared with untreated cells, without affecting changes to cell cycle profile. We further found that fasudil significantly facilitated the expression and foci formation of HR core proteins such as Rad51 and BRCA1 upon IR, and decreased the expression of NHEJ-associated proteins such as DNA-PKcs at 24 h post-IR. Our study identified fasudil as a novel radioprotector that exert radioprotective effects on normal cells through regulation of DSB repair by promoting HR repair.


Potential use of scrap expanded polystyrene beads for the control of Aedes triseriatus.
The potential use of expanded polystyrene (EPS) beads for control of Aedes triseriatus was tested in the laboratory and the field. Laboratory studies showed that beads present in amounts which persisted throughout a season significantly reduced the emergence of Ae. triseriatus adults by preventing normal eclosion from the pupae. In the field, tree holes containing EPS beads had significantly fewer larvae present than untreated controls. These field data suggest that EPS beads may mechanically prevent oviposition by mosquitoes.


Genome variants of adenovirus 41 (subgroup G) from children with diarrhoea in South Africa.
Fifteen strains of faecal adenovirus from 3 continents (4 from Europe, 4 from Canada, and 7 from South Africa) were typed as Ad41a by restriction enzyme analysis o the DNA using Sma I. The DNA of the strains was further compared by digestion with 9 other restriction enzymes. All strains had the same cleavage sites for enzymes Bam HI, Bg1 I, Sst I, Pvu II, and Xho I, indicating a close relationship. The Canadian and European strains also had the same cleavage sites for Hind III, Eco RI, Bst EII, and Kpn I, within the limits of resolution of the technique. Only one of the 7 South African strains had a combination of restriction sites identical to the European and Canadian strains, whereas Hind III, Eco RI, Bst EII, and Kpn I digests of the other 6 South African Ad41 DNAs showed the existence of 4 other genome types of Ad41. All 15 Ad41a strains studied were easily distinguished from Ad40 strains using any of the 10 restriction enzymes.


Wnt/beta-catenin signaling is involved in the induction and maintenance of primitive hematopoiesis in the vertebrate embryo.
The formation of primitive (embryonic) blood in vertebrates is mediated by spatio-temporally restricted signaling between different tissue layers. In Xenopus, in which primitive blood originates in the ventral blood island, this involves the secretion of bone morphogenetic protein (BMP) ligands by the ectoderm that signal to the underlying mesoderm during gastrulation. Using novel transgenic reporter lines, we report that the canonical Wnt/β-catenin pathway is also activated in the blood islands in Xenopus. Furthermore, Wnt-reporter activity was also detected in the blood islands of the mouse yolk sac. By using morpholino-mediated depletion in Xenopus, we identified Wnt4 as the ligand that is expressed in the mesoderm of the ventral blood island and is essential for the expression of hematopoietic and erythroid marker genes. Injection of an inducible Wnt-interfering construct further showed that, during gastrulation, Wnt/β-catenin signaling is required both in the mesoderm and in the overlying ectoderm for the formation of the ventral blood island. Using recombination assays with embryonic explants, we document that ectodermal BMP4 expression is dependent on Wnt4 signals from the mesoderm. Our results thus reveal a unique role for Wnt4-mediated canonical signaling in the formation and maintenance of the ventral blood island in Xenopus.


Effect of ischemia and reperfusion on enzymes of carbohydrate metabolism in rat kidney.
Ischemia results in rapid decline in mitochondrial electron transfer, resulting in decreased ATP levels, and fall in intracellular pH. The purpose of the study was to examine the effects of ischemia and reperfusion on the activities of enzymes of carbohydrate metabolism in rat kidney. Ischemia was induced by occlusion of the left renal artery for specified times. The activities of Na-K ATPase, lactate dehydrogenase (LDH), Malate dehydrogenase (MDH), glucose-6-phosphate dehydrogenase (G6PDH), malic enzyme (ME), glucose-6-phosphatase (G6Pase), and fructose-1, 6-bisphosphatase (FBPase) were studied in the homogenates of whole (WC), superficial (SCH), and juxtamedullary (JMCH) cortices and medulla (MH). The activities of LDH, G6Pase, FBPase, and ME rapidly increased whereas those of MDH and G6PDH decreased by brief ischemia of 5 min both in the cortex and medulla. Prolonged ischemia (15-60 min) caused progressive decrease in the enzyme activities. Reperfusion for 60 min caused complete recovery of the enzyme activities studied. The results demonstrate that activities of carbohydrate metabolism enzymes are restored by short-term reperfusion following 30 min ischemia.


Interaction between PAR-3 and the aPKC-PAR-6 complex is indispensable for apical domain development of epithelial cells.
The evolutionarily conserved polarity proteins PAR-3, atypical protein kinase C (aPKC) and PAR-6 critically regulate the apical membrane development required for epithelial organ development. However, the molecular mechanisms underlying their roles remain to be clarified. We demonstrate that PAR-3 knockdown in MDCK cells retards apical protein delivery to the plasma membrane, and eventually leads to mislocalized apical domain formation at intercellular regions in both two-dimensional and three-dimensional culture systems. The defects in PAR-3 knockdown cells are efficiently rescued by wild-type PAR-3, but not by a point mutant (S827/829A) that lacks the ability to interact with aPKC, indicating that formation of the PAR-3-aPKC-PAR-6 complex is essential for apical membrane development. This is in sharp contrast with tight junction maturation, which does not necessarily depend on the aPKC-PAR-3 interaction, and indicates that the two fundamental processes essential for epithelial polarity are differentially regulated by these polarity proteins. Importantly, highly depolarized cells accumulate aPKC and PAR-6, but not PAR-3, on apical protein-containing vacuoles, which become targeted to PAR-3-positive primordial cell-cell contact sites during the initial stage of the repolarization process. Therefore, formation of the PAR-3-aPKC-PAR-6 complex might be required for targeting of not only the aPKC-PAR-6 complex but also of apical protein carrier vesicles to primordial junction structures.


Plasma-fibroblast gel as scaffold for islet transplantation.
The transplant of pancreatic islets into the liver can restore normal blood glucose levels in patients with type I diabetes. However, long-term results have indicated that the site and method of transplantation still need to be optimized to improve islet engraftment. This study was designed to assess the efficiency of the use of clotted blood plasma containing fibroblasts ("plasma-fibroblast gel") as a scaffold for subcutaneous islet transplantation in diabetic athymic mice. Islets embedded in the plasma-fibroblast gel were able to resolve hyperglycemia in transplanted mice, restoring normoglycemia over a 60-day period and allowing gradual body weight recovery. Glucose clearances were significantly improved when compared to those recorded in diabetic animals and similar to those observed in the control group (free islets transplanted beneath the kidney capsule). Histological evaluation revealed functional islets within a subcutaneous tissue rich in collagen fibers that was well vascularized, with blood vessels observed around and inside the islets. These findings suggest that this approach could be used as an alternative option for the treatment of type I diabetes in human clinical practice.


Duplications and functional divergence of ADP-glucose pyrophosphorylase genes in plants.
ADP-glucose pyrophosphorylase (AGPase), which catalyses a rate limiting step in starch synthesis, is a heterotetramer comprised of two identical large and two identical small subunits in plants. Although the large and small subunits are equally sensitive to activity-altering amino acid changes when expressed in a bacterial system, the overall rate of non-synonymous evolution is approximately 2.7-fold greater for the large subunit than for the small subunit. Herein, we examine the basis for their different rates of evolution, the number of duplications in both large and small subunit genes and document changes in the patterns of AGPase evolution over time. We found that the first duplication in the AGPase large subunit family occurred early in the history of land plants, while the earliest small subunit duplication occurred after the divergence of monocots and eudicots. The large subunit also had a larger number of gene duplications than did the small subunit. The ancient duplications in the large subunit family raise concern about the saturation of synonymous substitutions, but estimates of the absolute rate of AGPase evolution were highly correlated with estimates of omega (the non-synonymous to synonymous rate ratio). Both subunits showed evidence for positive selection and relaxation of purifying selection after duplication, but these phenomena could not explain the different evolutionary rates of the two subunits. Instead, evolutionary constraints appear to be permanently relaxed for the large subunit relative to the small subunit. Both subunits exhibit branch-specific patterns of rate variation among sites. These analyses indicate that the higher evolutionary rate of the plant AGPase large subunit reflects permanent relaxation of constraints relative to the small subunit and they show that the large subunit genes have undergone more gene duplications than small subunit genes. Candidate sites potentially responsible for functional divergence within each of the AGPase subunits were investigated by examining branch-specific patterns of rate variation. We discuss the phenotypes of mutants that alter some candidate sites and strategies for examining candidate sites of presently unknown function.


Characteristics of non-O1 Vibrio cholerae isolated from the effluents of a treatment plant.
We report the results of a study concerning the characteristics of 19 Non-O1 Vibrio cholerae strains isolated from the incoming sewage and the effluents of the treatment plant in Bologna (Italy). These strains were compared to those of a strain of Vibrio cholerae biotype El Tor. The behaviour of the Non-O1 Vibrios was seen to be quite similar to those of the El Tor biotype in all aspects studied and antigenic correlations were found by means of immunoblotting and cytotoxin production on VERO cells. Since these bacterial strains may be pathogenic in humans, we believe it useful to describe some of their characteristics.


Height Variation Depending on the Source of Antenna Phase Centre Corrections: LEIAR25.R3 Case Study.
In this study, we compared two sets of antenna phase center corrections for groups of the same type of antenna mounted at the continuously operating global navigation satellite system (GNSS) reference stations. The first set involved type mean models provided by the International GNSS Service (release igs08), while the second set involved individual models developed by Geo++. Our goal was to check which set gave better results in the case of height estimation. The paper presents the differences between models and their impact on resulting height. Analyses showed that, in terms of the stability of the determined height, as well as its variability caused by increasing the facade mask, both models gave very similar results. Finally, we present a method for how to estimate the impact of differences in phase center corrections on height changes.


Investigation of Fluorination on Donor Moiety of Donor-Acceptor 4,7-Dithienylbenzothiadiazole-Based Conjugated Polymers toward Enhanced Photovoltaic Efficiency.
It is known that fluorination on π-conjugated donor-acceptor (D-A) polymers can significantly affect the optoelectronic properties and fluorination on A moiety has been well established for design of efficient photovoltaic materials. For example, polymers based on 4,7-dithienyl-5,6-difluorobenzothiadiazole (DTffBT) have been intensively investigated and exhibited excellent performance, but the corresponding DTBT-based polymers without fluorine often display an unfavorable efficiency. With the purpose of improving photovoltaic efficiency of DTBT-based D-A polymers, we design three polymers PDTBT-TxfBT (x = 0, 1, 2) with fluorination on D moiety (TxfBT) and systematically investigate fluorination on the photophysical/electrochemical and photovoltaic properties. The results show that polymer solar cells (PSCs) based on PDTBT-TBT exhibit moderate power conversion efficiency (PCE) of 5.84%. However, the bis-fluorination on TffBT moiety (PDTBT-TffBT) can greatly enhance the molecular planarity and intermolecular interaction, improve the charge transport and heterojunction morphology, and further suppress the charge recombination losses. PSCs based on PDTBT-TffBT demonstrate obviously improved photovoltaic efficiency with the best PCE up to 7.53% without any processing additives, which ranks among the top DTBT-based PSCs. However, it should be noted that unsymmetrical fluorination on TfBT moiety (PDTBT-TfBT) impairs the regularity of polymer backbone and intermolecular interaction, increases the recombination losses, and seriously reduces the short-circuit current density and efficiency (5.44%). The results exhibit that fluorination on D moiety is a helpful strategy for design high-performance photovoltaic materials and the regularity of fluorination is crucial to improving efficiencies.


Revision anterior cruciate ligament reconstruction: etiology of failures and clinical results.
A retrospective study was performed to determine the etiology of failed primary anterior cruciate ligament (ACL) reconstruction and evaluate the clinical results of revision ACL surgery. From January 1989 to January 1996, 90 patients with failed ACL reconstructions underwent revision ACL surgery. The etiology of failed ACL reconstruction included 47 surgical technical errors, 22 traumatic reinjuries, 7 lack of graft incorporation, 3 loss of motion, 3 related to synthetic grafts, and 8 alignment or combined ligamentous instability patterns not addressed. Of 52 revision ACL patients with minimum 2-year follow-up, 43 responded to a questionnaire and underwent a comprehensive physical examination. The Hospital for Special Surgery knee ligament evaluation revealed 63% good/excellent results. Objective laxity test revealed 77% of all patients had 0/+1 grade on Lachman and a mean 2.86-mm KT 1000. The overall results of revision ACL surgery are encouraging in providing symptomatic relief and restoring stability; however, they are significantly lower than primary ACL surgery.


Extrathymic CD4/CD8 double positive T cells.
Mature T lymphocytes expressing the alphabeta T cell receptor are generally classified as either CD4+ or CD8+, based on the mutually exclusive expression of these two lymphocyte coreceptors. Contrary to this conventional division, there is considerable evidence that significant numbers of CD4/CD8 double positive (DP) lymphocytes exist in the peripheral blood and secondary lymphoid tissues of swine, chickens and monkeys. Although CD4/CD8 DP T cells are rarely present in human peripheral blood the relative percentage of this lymphocyte population can increase spontaneously in healthy individuals and in persons suffering from certain disease conditions. DP can also be found among those T cells infiltrating arthritic joints, rejected kidney grafts and certain tumors. In humans, and rats, CD4/CD8 DP T cells appear transiently following activation of their progenitors. Murine DP cells have been described as a subset of intraepithelial lymphocytes (IELs). However, the relationship of IELs to DP cells in the peripheral blood of other species is unknown. Because of their unconventional phenotype and rarity in human and mice, most immunologists have ignored extrathymic CD4/CD8 DP lymphocytes. Nevertheless, their abundance in the peripheral blood of swine, monkeys and chickens makes it impossible to dismiss this lymphocyte population. Here are reports that have described extrathymic lymphocytes exhibiting a CD4+CD8dim phenotype in several species reviewed. Swine and monkey lymphocytes with this phenotype are represented by small resting cells that simultaneously express CD4 and CD8alpha molecules. The available evidence favors the notion that such DP T cells in swine are comprised predominantly of MHC class II restricted memory CD4+ helper T cells that after activation have acquired the ability to express the CD8alpha chain and then to maintain this DP phenotype. Moreover, porcine CD4/CD8 DP T cells appear to be comprised of memory cells due to their ability to respond to recall antigen, resilience to thymectomy, increase in proportion with age, expression of memory T cell markers, production of interferon-gamma and localization to inflammatory sites. Some of these characteristics are also descriptive of human and monkey CD4/CD8 DP T cells. Thus, in swine, humans and monkeys, these phenotypically distinct lymphocytes appear to represent a primed T cell subset. The possible functional significance of the simultaneous expression of the CD4 and CD8 co-receptors on mature T cells is discussed.


Features of nuclear architecture that influence gene expression in higher eukaryotes: confronting the enigma of epigenetics.
Complex mechanisms that influence gene expression in mammalian cells have been studied intensively over recent years. Genetic elements that control both the tissue specific patterns and levels of gene expression together with the proteins they bind have been characterised in detail and are clearly pivotal in activating pathways of gene expression. But it is also clear that the behaviour of these genetic elements is complicated by epigenetic factors, so that their introduction into cells with the necessary developmental history-and hence appropriate global concentrations of essential transcription factors-will not guarantee the desired levels of transcription. Recent experiments have reinforced this view and confirmed that apparently critical functions performed by defined genetic elements at certain chromosomal sites are not inevitably recapitulated at other chromosomal locations. Hence, a re-evaluation of the function of critical control elements is required using experimental systems that simplify the range of factors arising from local chromatin organisation. In this way, it should be possible to reveal the intricacies of gene expression that might eventually allow us to reproduce natural levels of expression from artificial gene constructs in human cells. J. Cell. Biochem. Suppl. 35:69-77, 2000.


Ovarian cancer: staging with CT and MR imaging.
To evaluate ovarian cancer staging and tumor resectability with computed tomography (CT) or magnetic resonance (MR) imaging. Eighty-two women underwent CT (n = 43) or MR imaging (n = 50); eleven of these 82 underwent both. Imaging was performed within 4 weeks of surgical staging. Radiologic, surgical, and histopathologic findings were compared. Overall staging accuracy was similar for CT and MR imaging (77% [33 of 43] vs 78% [39 of 50]). Evaluation of pelvic cancer extent was better with MR imaging than with CT. There was no difference in detection of abdominal disease. Most mesenteric and small-bowel implants were not detected with either CT or MR imaging. For CT, the positive predictive value for cancer nonresectability was 100% (three of three patients); the negative predictive value was 92% (37 of 40 patients). The positive and negative predictive values for MR imaging were 91% (10 of 11 patients) and 97% (38 of 39 patients). While the staging accuracy of both CT and MR imaging is only moderate, prediction of tumor resectability is excellent.


[Feasibility and effectiveness study of a simplified mobile self-education and self-monitoring application for patients with severe chronic obstructive pulmonary disease].
Chronic obstructive pulmonary disease (COPD) and its exacerbations cause a deterioration in quality of life and a significant consumption of medical resources. Patient empowerment supported by education and self-monitoring practices can improve quality of life and reduce the number of hospital admissions. With the development of telemedicine, a lot of digital applications have been studied. Many are considered too complicated to use. So, we partnered with an IT company in Liège named «COMUNICARE» to develop a simplified application that is managed autonomously, without the support of a health professional. In addition, we conducted a prospective pilot study including patients with severe COPD with exacerbations. We observed an excellent rate of use despite low comfort with a smartphone. The primary objective of reducing the number of hospitalizations was not achieved. Nevertheless, we observed interesting results concerning the symptomatology, overall satisfaction and help with therapeutic compliance.


Exploiting bi-directional global transition patterns and personal preferences for missing POI category identification.
Recent years have witnessed the increasing popularity of Location-based Social Network (LBSN) services, which provides unparalleled opportunities to build personalized Point-of-Interest (POI) recommender systems. Existing POI recommendation and location prediction tasks utilize past information for future recommendation or prediction from a single direction perspective, while the missing POI category identification task needs to utilize the check-in information both before and after the missing category. Therefore, a long-standing challenge is how to effectively identify the missing POI categories at any time in the real-world check-in data of mobile users. To this end, in this paper, we propose a novel neural network approach to identify the missing POI categories by integrating both bi-directional global non-personal transition patterns and personal preferences of users. Specifically, we delicately design an attention matching cell to model how well the check-in category information matches their non-personal transition patterns and personal preferences. Finally, we evaluate our model on two real-world datasets, which clearly validate its effectiveness compared with the state-of-the-art baselines. Furthermore, our model can be naturally extended to address next POI category recommendation and prediction tasks with competitive performance.


Generalized eczematous reaction after fractional carbon dioxide laser therapy for tattoo allergy.
Allergic tattoo reactions form a therapeutically difficult entity. Treatment with conventional quality-switched lasers does not completely remove the allergenic particles and may lead to generalized hypersensitivity reactions. Recently, ablative fractional laser therapy was introduced as a treatment for allergic tattoo removal. We present two cases of allergic reactions to red tattoo ink treated with 10,600-nm fractional CO2 laser. At the end of treatment, almost complete removal of red ink accompanied by a significant reduction of symptoms was observed in the first patient, whereas the second patient developed an acute generalized eczematous reaction after five treatments. These findings confirm that ablative fractional laser therapy is capable of significant removal of tattoo ink in an allergic tattoo reaction. However, it implies a risk of generalized hypersensitivity reactions. To our knowledge, this is the first case of a generalized hypersensitivity reaction following treatment of tattoo allergy with the fractional CO2 laser.


Chloride intracellular channels as novel biomarkers for digestive system tumors (Review).
Digestive system malignant tumors are common tumors, and the traditional treatment methods for these tumors include surgical resection, radiotherapy, chemotherapy, and molecularly targeted drugs. However, diagnosis remains challenging, and the early detection of postoperative recurrence is complicated. Therefore, it is necessary to explore novel biomarkers to facilitate clinical diagnosis and treatment. Accumulating evidence supports the crucial role of chloride channels in the development of multiple types of cancers. Given that chloride channels are widely expressed and involved in cell proliferation, apoptosis and cell cycle, among other processes, they may serve as a promising diagnostic and therapeutic target. Chloride intracellular channels (CLICs) are a class of chloride channels that are upregulated or downregulated in certain types of cancer. Furthermore, in certain cases, during cell cycle progression, the localization and function of the cytosolic form of the transmembrane proteins of CLICs are also altered, which may provide a key target for cancer therapy. The aim of the present review was to focus on CLICs as biomarkers for digestive system tumors.


Solar light active silver/iron oxide/zinc oxide heterostructure for photodegradation of ciprofloxacin, transformation products and antibacterial activity.
This paper reports on the multitasking potential of a silver/iron oxide/zinc oxide (Ag/Fe2O3/ZnO) heterostructure, which was used for the photocatalytic decomposition of ciprofloxacin (CPX) and bacterial disinfection. The Ag/Fe2O3/ZnO heterostructure was successfully prepared using a facile precipitation method, and characterization results showed interesting structural, morphological, compositional and luminescent properties. The morphological results of the prepared heterostructure confirmed the deposition of Ag nanoparticles onto the surface of ZnO nanoplates and Fe2O3 nanorods. Treatment studies showed that the Ag/Fe2O3/ZnO heterostructure had superior solar light driven photocatalytic activity towards CPX degradation (76.4%) compared to bare Fe2O3 nanorods (43.2%) and ZnO nanoplates (63.1%), Ag/Fe2O3 (28.2%) and Ag/ZnO (64.5%) under optimized conditions (initial CPX concentration: 10 mg/L; pH 4; catalyst loading: 0.3 g/L). Reactive species study confirmed the roles of e-, h+, OH and O2- in the photocatalytic degradation process. This photocatalytic behaviour of the Ag/Fe2O3/ZnO heterostructure could be attributed to the improved full solar spectrum harvesting capacity, separation of charge carriers and migration of e-/h+ across the heterostructure interface. In addition, the Ag/Fe2O3/ZnO heterostructure also showed good antibacterial activity against Escherichia coli (E. coli) under both dark and visible light conditions. This might be due to generation of reactive oxygen species during the reaction. To the best of our knowledge, this is the first study till date on the utilization of Ag/Fe2O3/ZnO heterostructure for the photocatalytic degradation of CPX and E. coli bacteria disinfection. Therefore, this work offers an attractive path to design ZnO-based ternary heterostructures for solar-driven applications in wastewater remediation.


The period of susceptibility to the physiological effects of unilateral eye closure in kittens.
1. Kittens were visually deprived by suturing the lids of the right eye for various periods of time at different ages. Recordings were subsequently made from the striate cortex, and responses from the two eyes compared. As previously reported, monocular eye closure during the first few months of life causes a sharp decline in the number of cells that can be influenced by the previously closed eye.2. Susceptibility to the effects of eye closure begins suddenly near the start of the fourth week, remains high until some time between the sixth and eighth weeks, and then declines, disappearing finally around the end of the third month. Monocular closure for over a year in an adult cat produces no detectable effects.3. During the period of high susceptibility in the fourth and fifth weeks eye closure for as little as 3-4 days leads to a sharp decline in the number of cells that can be driven from both eyes, as well as an over-all decline in the relative influence of the previously closed eye. A 6-day closure is enough to give a reduction in the number of cells that can be driven by the closed eye to a fraction of the normal. The physiological picture is similar to that following a 3-month monocular deprivation from birth, in which the proportion of cells the eye can influence drops from 85 to about 7%.4. Cells of the lateral geniculate receiving input from a deprived eye are noticeably smaller and paler to Nissl stain following 3 or 6 days' deprivation during the fourth week.5. Following 3 months of monocular deprivation, opening the eye for up to 5 yr produces only a very limited recovery in the cortical physiology, and no obvious recovery of the geniculate atrophy, even though behaviourally there is some return of vision in the deprived eye. Closing the normal eye, though necessary for behavioural recovery, has no detectable effect on the cortical physiology. The amount of possible recovery in the striate cortex is probably no greater if the period of eye closure is limited to weeks, but after a 5-week closure there is a definite enhancement of the recovery, even though it is far from complete.


Interneurons and proprioneurons in the adult human spinal grey matter and in the general somatic and visceral afferent cranial nerve nuclei.
Using the classification of Abdel-Maguid & Bowsher (1984), interneurons of the dorsal horn of the grey matter of the human spinal cord and medulla oblongata were found to belong to only three 'families' of neurons, out of a possible thirteen. This is in itself one of the justifications for the method of classification. Functional identification of these human neurons has been made on the basis of topological, morphological and projectional comparison with known cells in other mammalian species. Among the cells identified are gelatinosal interneurons and Renshaw cells of laminae VII and VIII. Neurons belonging to the same 'family' as Waldeyer cells of lamina I continue around the outer edge of the grey matter, their dendrites forming a part of the boundary between grey and white matter. Interneurons with small and very small dendrite fields lie on interlaminar boundaries and have mediolaterally oriented dendrites, in contrast to the craniocaudally oriented dendritic field of most dorsal horn neurons. If such dendrites lying along interlaminar boundaries are also found to exist in other species, it may explain the abrupt change in physiological characteristics which is found on passing an electrode from one lamina to another.


Amoebic liver abscess: a comparative study of needle aspiration versus conservative treatment.
Amoebic liver abscess is a serious problem in Pakistan. Its management includes antimicrobial drugs, needle aspiration and surgical drainage. This study was done to see the therapeutic efficacy, safety and outcome of ultrasound guided needle aspiration of amoebic liver abscess combined with antiamoebic drugs. This was a prospective study with a minimum follow up of six months comparing the results of needle aspiration plus antiamoebic drugs with drug treatment alone in Amoebic Liver Abscess. It was carried in Surgical 'B' Unit of Ayub Teaching Hospital from July 1998 to June 2001. The patients were divided into two groups. Group A with abscess < 300 cm3 were treated with drugs alone. Group B patients with abscess > 300 cm3 or smaller abscesses which failed to respond to medical treatment were treated with both needle aspiration and drugs. Main outcome measures were abdominal pain, fever, anorexia, hepatomegaly, resolution of amoebic liver abscess on ultrasound, length of hospital stay and any complications. There were 46 patients in the study group. 21 (45.5%) patients were in Group A and 25 (54.5%) in Group B. The ages ranged from 15-70 years. 38 patients were male and 8 were females. The right lobe was involved in 44 (95.5%) patients and left lobe in 2 (4.5%) patients. Mean volume of abscess in Group A was 225 cm3 and in Group B was 560 cm3. Needle aspiration was successful in 24 (96.3%) patients and failed in 1 (3.7%) patient. The mean time of clinical improvement was 7 and 3 days respectively in Groups A and B. The mean hospital stay was shorter in Group B (3.5 day) than Group A (7.5 days). The resolution of abscess seen on ultrasound was rapid in Group B. Complications occurred in only one patient in Group B. No mortality was seen in any group. Needle aspiration combined with antiamoebic drugs is more effective than drug treatment alone in the management of amoebic liver abscess.


Production of Vitamin D3 Enriched Biomass of Saccharomyces Cerevisiae as A Potential Food Supplement: Evaluation and Optimization of Culture Conditions Using Plackett-Burman and Response Surface Methodological Approaches.
Vitamin D deficiency causes osteoporosis, osteopenia, fractures, rickets, and more recently is linked with some chronic illnesses such as cancer. Because of the safety and probiotic properties of the yeast Saccharomyces cerevisiae, we hypothesized that yeast cells enriched with cholecalciferol (vitamin D3) could represent a solution for prevention or treatment of vitamin D deficiency. In this study S. cerevisiae was used as a vitamin D3 accumulator for the first time and the optimal conditions for enrichment of S. cerevisiae were determined. The Plackett-Burman screening studies were used for selection of the most important factors affecting cholecalciferol entrapment. Response surface methodology was employed for optimization of cholecalciferol accumulation in S. cerevisiae cells by using Box-Behnken design. A modified quadratic polynomial model fit the data appropriately. The optimal points of variables to maximize the response were cholecalciferol initial concentration of 358021.16 IU/mL, tryptone concentration of 1.82 g/L, sucrose concentration of 7.13 % (w/v), and shaking speed of 140.46 rpm. The maximum amount of cholecalciferol in dry cell weight of S. cerevisiae was 4428.11 IU/g. The cholecalciferol entrapment in yeast biomass increased about two-folds in optimized condition which indicates efficiency of optimization.


Interaction of blood plasma with antifouling surfaces.
Nonspecific adsorption of proteins is a crucial problem in the detection of analytes in complex biological media by affinity sensors operating with label-free detection. We modified the gold surface of surface plasmon resonance (SPR) sensors with three types of promising antifouling coatings: self-assembled monolayers (SAM)s of alkanethiolates terminated with diethylene glycol and carboxylic groups, poly(ethylene glycol) (PEG) grafted onto the SAMs, and zwitterionic polymer brushes of poly(carboxybetaine methacrylate), poly(sulfobetaine methacrylate), and poly(phosphorylcholine methacrylate). Using SPR, we compared the efficacy of the coatings to reduce nonspecific adsorption from human blood plasma and from single-protein solutions of human serum albumin, immunoglobulin G, fibrinogen, and lysozyme. There was no direct relationship between values of water contact angles and plasma deposition on the coated surfaces. A rather high plasma deposition on SAMs was decreased by grafting PEG chains. Fouling on PEG was observed only from plasma fractions containing proteins with molecular mass higher than 350 000 Da. The adsorption kinetics from plasma collected from different healthy donors differed. Poly(carboxybetaine methacrylate) completely prevented the deposition from plasma, but the other more hydrophilic zwitterionic polymers prevented single-protein adsorption but did not prevent plasma deposition. The results suggest that neither wettability nor adsorption of the main plasma proteins was the main indicator of deposition from blood plasma.


Enterovirus in sudden unexpected deaths in infants.
Conventional approaches to virus detection failed to provide convincing evidence of a viral etiology in sudden unexplained deaths in infants (SUDI). Many viruses may not have been detected by the routinely used methods; among them enteroviruses (EV) have seldom been found in SUDI. In this study EV were sought directly in stools, in pharyngeal and tracheal samples and in myocardial and lung tissues, by using a nested PCR; they were also sought indirectly by detecting IgM antibodies with a new capture immunoassay. Twenty-four SUDI cases were divided into two groups: Group I, certainly associated with; or Group II, not associated with clinical, biologic or histologic signs of viral infection. EV were found in stools but their prevalence was not significantly different between Group I and Group II (20 and 22.2%, respectively). On the contrary EV were detected in respiratory tract and/or lung samples in 53.8% of infants of Group I and in none of Group II. Anti-EV IgM antibodies were detected in 55.5% of infants of Group I and in none of Group II. These results indicate that EV infection may be specifically associated with the subgroup of SUDI with viral signs, raising the question of its role in this condition.


The momentary relationship between stress and headaches in adolescent girls.
The objective of this study was to compare the relationship between repeated momentary reports of stress and headaches in female adolescents with varying degrees of headache frequency. Headaches are the most common form of pain reported by adolescents affecting more than a third of all adolescents. High levels of stress during adolescence may predispose an adolescent to experience headaches in adulthood. Randomized, momentary data collection of stress and headaches provides the most accurate data regarding the adolescent experience of these variables. The research methodology, ecological momentary assessment, is a valid approach to better understand the relationship between stress and headaches in adolescence. Data were obtained by each participant's use of an electronic diary (ED), which captured repeated momentary reports of perceived stress, head pain, and stress-related symptoms in female adolescents with varying degrees of recurrent headache. Seven times per day for the 21-day study period, teen girls responded to ED questions about their current stress levels, head pain, and stress-related symptoms. Based on participants' momentary reports of headaches, Low Headache, Moderate Headache, and Chronic Headache groups were created. General estimating equation models were used to analyze the relationship between momentary variables as well as the lag effect between stress and head pain. Thirty-one participants, aged 14-18 years, completed 2841 randomized ED reports and reported 674 occurrences of headache. The Chronic Headache and Moderate Headache groups reported significantly increased levels of stress, head pain, and headaches. The relationship between momentary stress and head pain was significantly strong both within and across participants. The strength of this relationship increased with increased headache activity. A significant lag effect was found between stress and headaches; however, the effect of depression as a moderator of the stress and headache relationship remains unclear. Perceived stress and head pain was highly correlated in these female adolescents. Given the large population of teens affected by headaches, a plausible next step would be to validate these results in other samples and to determine methods with which to identify teens who may be at risk for a pattern of increasing stress and headaches.


Effect of light quality on the organization of photosynthetic electron transport chain of pea seedlings.
The activity of NADP and O(2) photoreduction by water is essentially higher in chloroplasts isolated from pea seedlings (Pisum sativum L.) grown under blue light as compared with that from plants grown under red light. In contrast, the photoreduction of NADP and O(2) with photosystem I only is practically the same or even lower in chloroplasts isolated from plants grown under blue light. The addition of plastocyanin does not affect the rate or the extent of NADP photoreduction by water in the chloroplasts isolated from plants grown under blue light, whereas it sharply activates NADP reduction in the chloroplasts isolated from plants grown under red light. The extent of the light-induced oxidation of cytochrome f is appreciably higher in chloroplasts isolated from plants grown under blue light. Cytochrome b(559) plays the predominant role in the oxidoreductive reactions of these chloroplasts. Furthermore, the fluorescence measurements indicate more effective transfer of excitation energy from chlorophyll to the photosystem II reaction center in chloroplasts isolated from plants grown under blue light.The data reported are interpreted in terms of differential rates of electron transport from water in the two chloroplast preparations.


Ultra-low luminescence of humid air and its possible role in negative air ion therapy.
One of the unresolved questions related to the mechanism of action of light negative air ions (reactive oxygen species) produced by air ionizers upon humans and animals is transmission of these short-living chemical species upon long distances from the place of their origin. We discovered the phenomenon which may probably resolve this problem. When a thin layer of water hydrating a hygroscopic surface absorbs rare UV-photons capable to split water molecules a flash of photon emission in UV- and visible regions of spectrum is observed. This flash (or oxygen-dependent oxidative processes underlying it) initiate reactions accompanied with generation of electronic excitation in the air contacting water film. Excitation propagates through the air at macroscopic distances, and the level of propagating excitation increases with elevation of air humidity. When air humidity exceeds 50% air excitation gains oscillatory-wave character. This phenomenon may endow into the mechanism of action of air ions generated artificially, and also into some natural processes where ordered water films may form and the latter may serve targets for energy impulses initiating oxygen-dependent oxidative processes in these films.


Knee joint forces during downhill walking with hiking poles.
The aim of this study was to determine external and internal loads on the knee joint during downhill walking with and without hiking poles. Kinematic, kinetic and electromyographic data were collected from eight males during downhill walking on a ramp declined at 25 degrees. Planar knee joint moments and forces were calculated using a quasi-static knee model. The results were analysed for an entire pole-cycle as well as differentiated between single and double support phases and between each step of a pole-cycle. Significant differences between downhill walking with and without hiking poles were observed for peak and average magnitudes of ground reaction force, knee joint moment, and tibiofemoral compressive and shear forces (12-25%). Similar reductions were found in patellofemoral compressive force, the quadriceps tendon force and the activity of the vastus lateralis; however, because of a high variability, these differences were not significant. The reductions seen during downhill walking with hiking poles compared with unsupported downhill walking were caused primarily by the forces applied to the hiking poles and by a change in posture to a more forward leaning position of the upper body, with the effect of reducing the knee moment arm.


Defining the blood plasma protein repertoire of seven day old dairy calves - a preliminary study.
During the early postnatal period in calves various adaptational changes occur. These functional, morphological and also metabolic alteration are reflected by blood plasma protein changes as they are secreted and shed from many cells and tissues. Blood plasma protein pattern of an adult cattle differs in some respect when compared with neonatal calves. There exist a very few data concerning 2-D maps of neonatal calves blood plasma. The above prompted us to establish protein pattern of this biological fluid characteristic of healthy, 7 day old, Polish Black-and-White (Polish Friesian) breed calves. Blood plasma proteins of the isoelectric point ranging from 4.0 to 7.0 were analyzed by the aid of high resolution two-dimensional electrophoresis (2-DE). Subsequently, 79 excised protein spots corresponding to 23 different gene products were identified using matrix-assisted laser desorption/ionisation mass spectrometer (MALDI-TOF MS). Protein map obtained in the present study may be useful in assessing the changes in the calves blood plasma protein profiles occurring in response to different physiological and/or pathophysiological factors.


Electrophysiologic evidence for involvement of the pituitary region in opiate analgesia.
In the past, various reports have discussed the relationship between the pituitary and analgesia. The purpose of the present study was to explore the possible role of the pituitary region in the mediation of pain by opioids. Tooth pulp evoked potentials recorded from primary somatosensory cortex and from the pituitary region of rabbits were recorded before and after an injection of opiates. Tooth pulp evoked potentials recorded from the primary somatosensory cortex were markedly inhibited after admission of fentanyl, while the tooth pulp evoked potentials recorded from the pituitary region were facilitated. It is concluded that the pituitary region plays a role in the mediation of pain and that this area is involved in the mechanism of opiate analgesia.


Synthesis of arylacetates from benzylic alcohols and oxalate esters through decarboxylative coupling.
Follow that dream: By combining a reversible transesterification between benzylic alcohols and dialkyl oxalates with catalytic decarboxylation of the resulting esters, a regiospecific C-C-bond-forming reaction to give α-arylacetates was achieved. In the overall process, CO2 and a volatile alcohol are the only byproducts. Various α-arylacetates were thus synthesized in high yields from easily accessible starting materials in the presence of catalytic amounts of Pd(OAc)2, dppp, and DABCO (see scheme).


Seminiferous tubule degeneration in human cryptorchid testes.
Two types of degenerating seminiferous tubules were found in cryptorchid testes with Sertoli cell hyperplasia of children and adults: 1) tubules with central degeneration, and 2) tubules with total degeneration. Central degeneration begins with degenerative changes in germ cells that accumulate in the lumen of the seminiferous tubule. Some Sertoli cells may also be affected. Degenerated cells finally disappear, and the remaining tubule is composed of only a cuboidal epithelium, which consists mainly of Sertoli cells and occasional germ cells surrounding a wide lumen. Total degeneration is principally seen in tubules with severe germinal hypoplasia. All the seminiferous epithelium cells degenerate and lose their characteristic distribution, forming a disorganized Sertoli cell nodule surrounded by a thickened basement membrane. Lastly, Sertoli cells disintegrate, and the seminiferous epithelium disappears. Tubular degeneration might be related to the thickening of the basement membrane, which hinders metabolic interchange between the seminiferous epithelium and the interstitium.


Gamma and Decay Energy Spectroscopy Measurements of Trinitite.
We report gamma ray spectroscopy measurements of trinitite samples and analogous samples obtained from detonation sites in Nevada and Semipalatinsk, as well as in situ measurements of topsoil at the Trinity site. We also report the first isotopic composition measurements of trinitite using the novel forensics technique of decay energy spectroscopy (DES) as a complement to traditional forensics techniques. Our gamma spectroscopy and DES measurements are compared to other published results.


Short communication: transmission of hepatitis B viruses with lamivudine resistance mutations in newly diagnosed HIV individuals.
From 1519 newly diagnosed HIV individuals seen in Madrid between the years 2000 and 2008, 65 (4.3%) were HBsAg(+). Two HIV/HBV-coinfected patients showed the lamivudine resistance mutation M204V in HBV while no drug resistance mutations were recognized in HIV. None of them admitted prior exposure to antiretroviral drugs. Thus, HIV/HBV-coinfected patients might benefit from baseline drug resistance testing for both HIV and HBV to optimize the selection of anti-HBV active antiviral therapy.


Two derivatives of 1,5-disubstituted tetrazoles: 1-(4-nitrophenyl)-1H-tetrazol-5-amine and {(E)-[1-(4-ethoxyphenyl)-1H-tetrazol-5-yl]iminomethyl}dimethylamine.
The geometric features of 1-(4-nitrophenyl)-1H-tetrazol-5-amine, C(7)H(6)N(6)O(2), correspond to the presence of the essential interaction of the 5-amino group lone pair with the pi system of the tetrazole ring. Intermolecular N-H...N and N-H...O hydrogen bonds result in the formation of infinite chains running along the [110] direction and involve centrosymmetric ring structures with motifs R(2)(2)(8) and R(2)(2)(20). Molecules of {(E)-[1-(4-ethoxyphenyl)-1H-tetrazol-5-yl]iminomethyl}dimethylamine, C(12)H(16)N(6)O, are essentially flattened, which facilitates the formation of a conjugated system spanning the whole molecule. Conjugation in the azomethine N=C-N fragment results in practically the same length for the formal double and single bonds.


[Innovative bipolar radiofrequency volumetric reduction with "ORL-Set" for treatment of habitual snorers].
The present study was undertaken in an effort to assess the use and the efficacy of an innovative radiofrequency system (RaVoR, Select-Sutter, Freiburg i. Br.) and the bipolar electrodes conceived by the author for the treatment of habitual, disruptive snoring. The author's own surgical method takes into account a number of published retrospective studies on radiofrequency application in the treatment of snoring and is based on important anatomical, physiopathological and histological knowledge. Thirty-one patients diagnosed with primary snoring and five patients with associated sleep apnea syndrome (SAS) were treated according to the method and with the RaVoR system in the past three years. The intensity as well as the snoring density was assessed on a numeric analogue scale (NAS; ranging from 0 = "patient doesn't snore anymore" to 4 = "patient continues to snore as before"), which was filled out by the partner preoperatively and postoperatively after 6 months and 2 years. Snoring was reduced in 31 (86 %) patients (NAS </= 2). Ten of them (28 %) stopped snoring altogether, according to their sleeping partners. The bipolar radiofrequency method with the ORL-Set (RaVoR) has proven to be a safe and effective means for the treatment of snoring and some cases of SAS.


Classification of Data from Electronic Nose Using Gradient Tree Boosting Algorithm.
In this paper, an approach that can fast classify the data from the electronic nose is presented. In this approach the gradient tree boosting algorithm is used to classify the gas data and the experiment results show that the proposed gradient tree boosting algorithm achieved high performance on this classification problem, outperforming other algorithms as comparison. In addition, electronic nose we used only requires a few seconds of data after the gas reaction begins. Therefore, the proposed approach can realize a fast recognition of gas, as it does not need to wait for the gas reaction to reach steady state.


Glomerular mRNA expression of prothrombotic and antithrombotic factors in renal transplants with thrombotic microangiopathy.
Thrombotic microangiopathy (TMA) in renal transplants (rTx-TMA) is a serious complication and is usually either recurrent TMA (RecTMA) due to humoral rejection (HR-TMA) or due to calcineurin inhibitor toxicity (CNI-TMA). Although the triggers are known, our knowledge about the thrombogenic transcriptome changes in the microvessels is rudimentary. We examined the expression of several prothrombotic and antithrombotic genes in 25 biopsies with rTx-TMA (6 RecTMA, 9 HR-TMA, and 10 CNI-TMA) and 8 controls. RNA from microdissected glomeruli of paraffin-embedded tissue was isolated and mRNA transcripts were quantified with real-time polymerase chain reaction after preamplification. Results were correlated with clinicopathologic parameters. Glomerular mRNA expression of KLF2, KLF4, and tPA was lower and that of PAI-1 was higher in rTx-TMA than in the controls. Glomerular mRNA expression of KLF2 and KLF4 correlated with that of tPA and inversely with that of PAI-1 in rTx-TMA. The mRNA expression of complement regulators CD46 and CD59 were higher in rTx-TMA than in the controls. Only in HR-TMA were glomerular ADAMTS13 and CD55 down-regulated. The glomerular capillary bed seems to contribute to all subtypes of rTx-TMA by down-regulation of the endothelial transcription factors KLF2 and KLF4, indicating dedifferentiation with subsequent up-regulation of PAI-1 and down-regulation of tPA, resulting in inhibition of local fibrinolysis. Decreased glomerular expression of ADAMTS13 and CD55 could be an additional pathway toward microthrombosis exclusively in HR-TMA.


Psychometric properties of the Child Anxiety Life Interference Scale - Preschool Version.
Despite growing recognition of childhood anxiety as a common and often debilitating clinical concern, we have limited knowledge of the particular ways in which anxiety interferes with daily life for young children who have not yet entered formal schooling. The present study evaluated the psychometric properties of the Child Anxiety Life Interference Scale - Preschool Version (CALIS-PV). The CALIS-PV is a brief (18 item) parent-report measure of the impacts of a young child's anxiety on their own life and that of her or his parent. Participants were 784 parents of a child aged 3-7 years, who completed the CALIS-PV as a part of the follow-up assessment battery for two anxiety prevention trials targeted at preschool children with temperamental inhibition. Confirmatory factor analysis supported three CALIS-PV factors reflecting anxiety-related life interference at home, outside home and on parent life. The three factors showed good internal consistency and good convergent and divergent validity, and successfully differentiated children with and without an anxiety diagnosis. Findings provide initial support for the CALIS-PV as a reliable and valid measure of the daily life impacts of childhood anxiety for preschool-aged children and their parents.


Emerging role of a phosphatonin in mineral homeostasis and its derangements.
The study of a distinct group of renal phosphate wasting disorders with bone disease which comprise X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR) and tumour-induced osteomalacia (TIO) gave rise to the identification of different hormone-like peptides, also known as phosphatonins. These factors are responsible for the major disease features that characterize XLH, ADHR and TIO. Recent reports on one of these phosphatonins, fibroblast growth factor-23 (FGF-23), point to a general role of this factor in mineral ion metabolism. The main focus regards recent evidence implicating FGF-23 in normal and disordered mineral homeostasis with special emphasis on chronic kidney disease. The interactions of FGF-23 with phosphate, parathyroid hormone and vitamin D are discussed in detail. The FGF-23 has been shown to increase urinary phosphate excretion, inhibit bone mineralization and suppress 1,25-dihydroxy vitamin D(3)[1,25(OH)(2)D(3)], the main characteristics that XLH, ADHR and TIO have in common. Apart from its role in these phosphate wasting disorders serum FGF-23 is elevated in hypoparathyroidism and humoral hypercalcaemia of malignancy and responds to altered dietary phosphate and calcium supply in healthy subjects. The FGF-23 is also variably elevated in chronic kidney disease and associated secondary hyperparathyroidism where it correlates positively with serum phosphate and parathyroid hormone and negatively with 1,25(OH)(2)D(3). Such relationships, along with data from experimental studies, raise the question of whether FGF-23 contributes to the pathophysiology of chronic kidney disease.


Gene expression profiling of Sinapis alba leaves under drought stress and rewatering growth conditions with Illumina deep sequencing.
Sinapis alba has many desirable agronomic traits including tolerance to drought. In this investigation, we performed the genome-wide transcriptional profiling of S. alba leaves under drought stress and rewatering growth conditions in an attempt to identify candidate genes involved in drought tolerance, using the Illumina deep sequencing technology. The comparative analysis revealed numerous changes in gene expression level attributable to the drought stress, which resulted in the down-regulation of 309 genes and the up-regulation of 248 genes. Gene ontology analysis revealed that the differentially expressed genes were mainly involved in cell division and catalytic and metabolic processes. Our results provide useful information for further analyses of the drought stress tolerance in Sinapis, and will facilitate molecular breeding for Brassica crop plants.


Effect of type 2 diabetes mellitus on efficacy and safety of therapeutic apheresis for severe hypertriglyceridemia.
The efficacy and safety of triglyceride (TG) apheresis in patients with type 2 diabetes mellitus (DM) is unclear. Diabetic complications may predispose patients to adverse events (AEs) associated with the apheresis procedure, and diabetic dyslipidemia may negatively affect the efficacy of therapeutic apheresis (TA). We investigated the effect of DM on the efficacy and complications of TA. Patients with severe hypertriglyceridemia who underwent apheresis for treatment or for the prevention of acute pancreatitis were included in this retrospective study. Epidemiological data, lipid parameters, and AEs were recorded before and after each therapeutic session. A total of 166 procedures were performed in 27 patients. Group 1 included 17 patients with type 2 DM, and Group 2 included 10 patients without DM. The mean percentage decrease in TG levels (TG%) was higher in Group 1 (71.9% vs 60.6%, P < .001). The TG% was negatively correlated with the duration of DM in Group 1 (r = -.49, P < .001). The total number of TA sessions was 142 in patients who underwent double filtration plasmapheresis and 24 in patients who underwent therapeutic plasma exchange. We observed 9 (5.4%) mild-to-moderate AEs. No intergroup difference was observed in the total number of AEs (P = .06). TA is safe and effective in patients with type 2 DM with severe hypertriglyceridemia.


Standardizing Radiation Exposure during Cardiac Catheterization in Children with Congenital Heart Disease: Data from a Multicenter Brazilian Registry.
In recent years the increasing number of interventional procedures has resulted in growing concerns regarding radiation exposure for patients and staff. The evaluation of radiation exposure in children is difficult due to the great variability in body weight. Therefore, reference levels of radiation are not well defined for this population. To study and validate the ratio of dose-area product (DAP) to patient weight as a reference measurement of radiation for hemodynamic congenital heart disease procedures in children. This observational multicenter study uses data obtained from a Brazilian registry of cardiac catheterization for congenital heart disease from March 2013 to June 2014. Inclusion criteria were all patients aged <18 years old undergoing hemodynamic procedures for congenital heart disease, with recorded DAP doses. P-value < 0.05 was considered as statistically significant. This study evaluated 429 patients with median age and weight of 50 (10, 103) months and 15 (7, 28) kg, respectively. Median DAP was 742.2 (288.8, 1,791.5) μGy.m2. There was a good correlation between DAP and weight-fluoroscopic time product(rs=0.66). No statistically significant difference was observed in DAP/weight ratio between therapeutic and diagnostic procedures. There was a wide variation in the DAP/weight ratio among the therapeutic procedures (p<0.001). The DAP/weight ratio is the simplest and most applicable measurement to evaluate radiation exposure in a pediatric population. Although there is limited literature available, the doses obtained in the present study were similar to those previously found. Ongoing research is important to evaluate the impact of strategies to reduce radiation exposure in this population (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0).


Salivary α-amylase copy number is not associated with weight trajectories and glycemic improvements following clinical weight loss: results from a 2-phase dietary intervention study.
Several studies recently reported contradicting results regarding the link between amylase 1 (AMY1) copy numbers (CNs), obesity, and type 2 diabetes. The aim of this study was to assess the impact of AMY1 CN on anthropometrics and glycemic outcomes in obese individuals following a 2-phase dietary weight loss intervention. Using the paralog ratio test, AMY1 CNs were accurately measured in 761 obese individuals from the DiOGenes study. Subjects first underwent an 8-wk low-calorie diet (LCD, at 800 kcal/d) and then were randomly assigned to a 6-mo weight maintenance dietary (WMD) intervention with arms having different glycemic loads. At baseline, a modest association between AMY1 CN and BMI (P = 0.04) was observed. AMY1 CN was not associated with baseline glycemic variables. In addition, AMY1 CN was not associated with anthropometric or glycemic outcomes following either LCD or WMD. Interaction analyses between AMY1 CN and nutrient intake did not reveal any significant association with clinical parameters (at baseline and following LCD or WMD) or when testing gene × WMD interactions during the WMD phase. In the absence of association with weight trajectories or glycemic improvements, the AMY1 CN cannot be considered as an important biomarker for response to a clinical weight loss and weight maintenance programs in overweight/obese subjects. This trial was registered at www.clinicaltrials.gov as NCT00390637.


Neuronal Presentation of Antigen and Its Possible Role in Parkinson's Disease.
Patients with Parkinson's disease (PD) and other synucleinopathies often exhibit autoimmune features, including CD4+ and some CD8+ T lymphocytes that recognize epitopes derived from alpha-synuclein. While neurons have long been considered to not present antigens, recent data indicate that they can be induced to do so, particularly in response to interferons and other forms of stress. Here, we review literature on neuronal antigen presentation and its potential role in PD. Although direct evidence for CD8+ T cell-mediated neuronal death is lacking in PD, neuronal antigen presentation appears central to the pathology of Rasmussen's encephalitis, a pediatric neurological disorder driven by cytotoxic T cell infiltration and neuroinflammation. Emerging data suggest that T cells enter the brain in PD and other synucleinopathies, where the majority of neuromelanin-containing substantia nigra and locus coeruleus neurons express MHC Class I molecules. In cell culture, CD8+ T cell recognition of antigen:MHC Class I complexes on neuronal membranes leads to cytotoxic responses and neuronal cell death. Recent animal models suggest the possibility of T cell autoreactivity to mitochondrial antigens in PD. It remains unclear if neuronal antigen presentation plays a role in PD or other neurodegenerative disorders, and efforts are underway to better elucidate the potential impact of autoimmune responses on neurodegeneration.


THE FINE STRUCTURE OF HYMENOMONAS (CRICOSPHAERA) CARTERAE. II. OBSERVATIONS ON SCALE AND COCCOLITH PRODUCTION.
The fine structure of the marine coccolithophorid Hymenomonas (Cricosphaera) carterae (Braarud & Fagerland) Manton & Peterfi is reported. Details of the formation of the circular organic body scales are presented. Their formation is shown to be closely linked with the presence of tubules found within the Golgi cisternae. The details of coccolith production are also discussed. The formation of the organic matrix scale appears to be associated with a densely staining organelle, the intracellular coccolith pre-cursor. The precise mechanisms involved in the mineralization of the organic matrix scale is not known but 2 possibilities are discussed. The production of coccoliths in H. carterae is compared with coccolith production in other coccolithophorids that have been investigated finestructurally.


Key Stakeholder Perspectives on Introducing a Front-of-Pack Labelling Scheme on Packaged Foods in China: A Qualitative Study.
Front-of-pack (FoP) labelling on foods is recommended by the World Health Organization (WHO) to address the growing global burden of diet-related noncommunicable diseases (NCDs), but this policy has not yet been implemented in China. The aim of this study was to ascertain key stakeholders' views on barriers and facilitators to developing a feasible and acceptable FoP labelling policy in the Chinese context. Semistructured interviews were used to elicit opinions from diverse representatives in roles of FoP labelling policy influence. Participants were identified by purposive and snowball sampling. The Consolidated Framework for Implementation Research (CFIR) was adopted to facilitate data collection and analysis. Themes and subthemes were generated using deductive and inductive approaches. Thirty participants were interviewed. The major barriers were the absence of national contextual analysis, perceived complexity of the process of policy development, disagreement on a preferred FoP labelling format, cost for the food industry, low priority compared to food safety policies, lack of existing regulatory framework or authorised nutrient profiling system, limited knowledge of FoP labelling, and the lack of planning and engagement with stakeholders. Facilitators included existing prerequisites, experiences and lessons from the pilot, policy coherence with Healthy China 2030, and support from external agents (e.g., WHO). Further efforts are required to develop and collate evidence to demonstrate the scientific, legal, and political feasibility of introducing effective FoP labelling.


Role of prolonged intravenous heparin in unstable angina patients prior to coronary angioplasty.
The optimal timing of coronary angioplasty in unstable angina patients is controversial. Early reports suggested using 3-5 days of intravenous heparin and aspirin for plaque stabilization before angioplasty. There is no clearcut data in this regard from the published literature. The purpose of this study was to evaluate whether delaying the angioplasty in order to stabilize the plaque affected the outcome. We reviewed the hospital course of patients who were admitted with unstable angina through the emergency room and ruled out for myocardial infarction, and who required angioplasty during the index hospitalization. To diminish the influence of coronary stenting and glycoprotein IIb/IIIa receptor blockade, we reviewed all patients admitted during 1994. Of the 305 patients, 166 patients received < or = 48 hours and 139 patients received > 48 hours of intravenous heparin infusion before angioplasty. Both groups were well-matched. The procedural success was similar in both the groups (98% vs 97%, P = 0.72). The complication rate was similar in both groups, including abrupt closure, emergency bypass surgery, myocardial infarction and death. Length of hospital stay was significantly prolonged in the group with > 48 hours of heparin infusion (4.4 +/- 3.0 vs 7.4 +/- 3.6 days; P < 0.001). In patients with unstable angina undergoing angioplasty, prolonged duration of heparin infusion influenced the procedural outcome or postprocedural complications, but prolonged the hospital stay. These data suggest that early angioplasty of unstable angina patients is safe and may be cost-effective, even in the absence of stenting and potent antiplatelet agents. However, prospective, randomized trials are needed to clarify the need for and duration of heparin infusion prior to angioplasty in unstable angina patients.


Epidrugs in the Immunotherapy of Cutaneous and Uveal Melanoma.
Epigenetic modifications can affect numerous mechanisms used by neoplastic cells to evade immune control. In melanoma epigenetic defects, caused by dysregulations in the expression of genome writers, erasers, or readers, play a significant role in the reduced expression of molecules required for efficient immune recognition as well as antigen presentation and processing. Alterations in gene expression were identified in tumor-associated antigens (TAAs), human leukocyte antigen (HLA) complex, co-stimulatory/accessory molecules, antigen processing machinery (APM), and NKG2D ligands that have shown to be silenced or down-regulated in melanoma. In agreement with the inherent reversibility of epigenetic silencing, epigenetic drugs such as inhibitors of DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone methyltransferase enhancer of Zeste homolog 2 (EZH2), and modifiers of microRNA (miRNA) dysregulation or antagomirs can restore the expression of these molecules, favouring the recognition of cancer cells by immune responses, reducing the resistance to Natural Killer (NK) and cytotoxic T cells (CTL), and enhancing the functions of antigen presenting cells. Moreover, inhibitors of reader proteins seem to preferentially affect the NF-kB-induced activation of pro-inflammatory cytokine genes. At present an increasing interest is shown toward new combined therapeutic approaches employing epidrugs or new molecular inhibitors and in vivo immunotherapies, such as vaccines and adoptive T-cell transfer (ACT). This review summarizes the current understanding of the role of epidrugs in the modulation of molecules involved in the melanoma immune response and focuses on their future clinical use in new therapeutic combinations for melanoma treatment.


Analysis of a Chinese hamster ovary cell mutant with defective mobilization of cholesterol from the plasma membrane to the endoplasmic reticulum.
The factors involved in shuttling cholesterol among cellular membranes have not been defined. Using amphotericin B selection, we previously isolated Chinese hamster ovary cell mutants expressing defects in intracellular cholesterol transport. Complementation analysis among seven mutants identified one cell line, mutant 3-6, with a unique defect. The present analysis revealed three key features of mutant 3-6. First, the movement of cholesterol both from the endoplasmic reticulum and through lysosomes to the plasma membrane was normal. However, when intact 3-6 cells were treated with sphingomyelinase, movement of plasma membrane cholesterol to acyl CoA:cholesterol acyltransferase in the endoplasmic reticulum was defective. Cellular cholesterol was mobilized to this enzyme upon activation by 25-hydroxycholesterol. Second, mutant 3-6 did not utilize endogenously synthesized sterol or low density lipoprotein-derived cholesterol for growth as effectively as parental Chinese hamster ovary cells. Finally, despite normal movement of cholesterol to the plasma membrane, mutant 3-6 was amphotericin B resistant. The plasma membrane cholesterol content was normal as assessed by cholesterol oxidase treatment and Semliki Forest virus fusion, which suggests that the 3-6 mutation alters the organization of cholesterol in the plasma membrane. Our characterization of this mutant cell line should facilitate the identification of gene(s) required for this transport pathway.


Multi-step aberrant CpG island hyper-methylation is associated with the progression of adult T-cell leukemia/lymphoma.
Aberrant CpG island methylation contributes to the pathogenesis of various malignancies. However, little is known about the association of epigenetic abnormalities with multistep tumorigenic events in adult T cell leukemia/lymphoma (ATLL). To determine whether epigenetic abnormalities induce the progression of ATLL, we analyzed the methylation profiles of the SHP1, p15, p16, p73, HCAD, DAPK, hMLH-1, and MGMT genes by methylation specific PCR assay in 65 cases with ATLL patients. The number of CpG island methylated genes increased with disease progression and aberrant hypermethylation in specific genes was detected even in HTLV-1 carriers and correlated with progression to ATLL. The CpG island methylator phenotype (CIMP) was observed most frequently in lymphoma type ATLL and was also closely associated with the progression and crisis of ATLL. The high number of methylated genes and increase of CIMP incidence were shown to be unfavorable prognostic factors and correlated with a shorter overall survival by Kaplan-Meyer analysis. The present findings strongly suggest that the multistep accumulation of aberrant CpG methylation in specific target genes and the presence of CIMP are deeply involved in the crisis, progression, and prognosis of ATLL, as well as indicate the value of CpG methylation and CIMP for new diagnostic and prognostic biomarkers.


Profiling the cytokines in gingival crevicular fluid using a cytokine antibody array.
Various compounds have been detected in gingival crevicular fluid (GCF) as indicators of periodontal disease activity. Therefore, the analysis of GCF may be especially beneficial for diagnosing current periodontal status and addressing the effects of treatment. Moreover, the identification of new markers in GCF may also contribute to elucidating novel mechanisms involved in periodontal disease. This study sought novel marker proteins specific to chronic periodontitis by profiling cytokines in GCF using a cytokine antibody array system. Human cytokine array V, which detects 79 cytokines on one membrane, was used to determine the profile of cytokines in GCF from seven subjects with chronic periodontitis and seven subjects with healthy periodontia. The profile was exposed to x-ray film and quantified using image analysis software. Healthy and diseased sites were compared statistically. We detected 10 cytokines in periodontally healthy sites and 36 cytokines in periodontally diseased sites. Interleukin-8 (IL-8) and transforming growth factor-beta 2 (TGF-beta2) were detected at high levels in healthy and diseased subjects. There were significant differences between healthy and diseased subjects in the levels of tissue inhibitor of metalloproteinases-2 (TIMP-2), tumor necrosis factor-beta (TNF-beta), growth-related oncogene (GRO), interferon-inducible protein-10 (IP-10), angiogenin (Ang), vascular endothelial growth factor (VEGF), insulin-like growth factor binding protein-3 (IGFBP-3), osteoprotegerin (OPG), epidermal growth factor (EGF), glial-derived neurotrophic factor (GDNF), pulmonary and activation-regulated chemokine (PARC), oncostatin M (OSM), fibroblast growth factor-4 (FGF-4), IL-16, homologous to lymphotoxins (LIGHT), and placenta growth factor (PlGF). Of these, the newly detected cytokines were GRO, Ang, IGFBP-3, GDNF, PARC, OSM, FGF-4, IL-16, LIGHT, and PlGF. In this study, we detected several cytokines in GCF using a cytokine antibody array system, including both inflammatory cytokines and various growth factors. Therefore, periodontal disease may participate in the wound healing process and in tissue destruction via the inflammatory process. Our results suggest that the quantification of these cytokines in GCF provides useful information for the diagnosis of periodontal disease status.


Aorta coarctation presenting with intracranial aneurysm rupture.
Most vascular diseases have a tendency to affect both heart and the brain. Intracranial aneurysms are more often found in patients with aorta coarctation than in general population, and aneurysm rupture occurs much earlier in these patients. Here, we report a case of aorta coarctation which was diagnosed with its cerebrovascular complications. Before presenting with cerebrovascular complications, the disease can easily be diagnosed with physical examination and non-invasive radiological investigations like echocardiography or cardiac magnetic resonance imaging.


[Treatment of the partial epilepsy in the first two years of life. Experience in 26 cases].
We performed a retrospective study with 26 patients with partial epilepsy (16 male, 10 female), aged between 1 and 24 months. We excluded those patients with seizures secondary to cerebral and extracerebral acute diseases, febrile convulsions, infantile spasms and other epileptic syndromes frequently diagnosed at this age. Etiology was of prenatal origin in 8 cases, perinatal in 9, postnatal in 3, and 6 were cryptogenic. They were all initially treated with phenobarbital (PB), 5 mg/kg/day. If seizures did not disappear, clonazepam (CZP) 0.1 mg/kg/day was added. Fifteen patients were controlled with PB in monotherapy, 7 need the association of CZP, and 4 patients could not be controlled. Among the last ones, 2 were controlled with PB and phenytoin, and the other 2 showed no response to any other drugs. Side effects (drowsiness and increased oropharyngeal secretions) were mild and transient. According to our experience, PB, alone or associate with CZP, is a safe and efficient treatment for seizures in symptomatic and cryptogenic partial epilepsy.


A pilot study of the use of a low oxalate diet in the treatment of vulval vestibulitis.
Thirty-one women with vulval vestibulitis were evaluated for evidence of abnormal dietary oxalate intake and a wide range of dietary intakes was recorded. No woman was found to have abnormal urinary excretion. Sixteen women agreed to undertake a low oxalate diet and there was an apparent response in six (37%).


Animal models of leukodystrophy: a new perspective for the development of therapies.
The leukodystrophies are a family of heritable disorders characterised by white matter degeneration, accompanied by variable clinical symptoms including loss of motor function and cognitive decline. Now thought to include over 50 distinct disorders, there are a vast array of mechanisms underlying the pathology of these monogenic conditions and, accordingly, a range of animal models relating to each disorder. While both murine and zebrafish models continue to aid in the development of potential therapies, many of these models fail to truly recapitulate the human condition - thus leaving substantial weaknesses in our understanding of leukodystrophy pathogenesis. Additionally, the heterogeneity in leukodystrophy presentation - both in patients and in vivo models - often results in a narrow focus on single disorders in isolation across much of the literature. Thus, this review aims to synthesise prominent research regarding the most common leukodystrophies in order to provide an overview of key animal models and their utility in developing novel treatments. We begin by discussing the ongoing revolution across the leukodystrophy field following the rise of next generation sequencing, before focusing more extensively on existing animal models from the mouse and zebrafish fields. Finally, we explore how these preclinical models have shaped the development of therapeutic strategies currently in development. We propose future directions for the field and suggest a more critical view of the dogma which has underpinned leukodystrophy research for decades.


Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses.
Factor V Leiden (FVL) is associated with venous thrombosis; however, an association between FVL and arterial thrombosis remains controversial. We investigated FVL as a risk factor for myocardial infarction (MI), ischemic stroke (IS), or non-MI ischemic heart disease (non-MI-IHD). The design was 3 case-control studies and 3 prospective studies with 21 years' follow-up. The setting was the general population in Copenhagen, Denmark. The participants for The Copenhagen City Heart Study were 20- to 95-year-old participants without cardiovascular disease (control population, n = 7907) or participants diagnosed with MI (n = 469), IS (n = 231), or non-MI-IHD (n = 365). In addition, 3 independent patient populations from Copenhagen University Hospital with MI (n = 493), IS (n = 231), or non-MI-IHD (n = 448) were included. We measured FVL genotype; major cardiovascular risk factors; and MI, IS, and non-MI-IHD incidence and prevalence. Prevalences of FVL heterozygotes and homozygotes in control subjects from the general population were 7.7% and 0.2%. Odds ratios and relative risks of MI in FVL carriers (heterozygotes + homozygotes) versus noncarriers were 1.24 (95% confidence interval [CI], 0.91-1.69) and 0.83 (0.58-1.20) in case-control and prospective studies, respectively. Corresponding risks for IS were 0.92 (95% CI, 0.56-1.53) and 0.68 (0.45-1.04), and for non-MI-IHD 1.01 (95% CI, 0.71-1.44) and 0.97 (0.66-1.42). Findings from The Copenhagen City Heart Study suggest that FVL is not associated with MI, IS, or non-MI-IHD.


Low molecular weight heparin, heparin, and warfarin.
Low molecular weight heparin is effective for the prevention and treatment of venous thromboembolism. Low molecular weight heparin has the practical advantage that it does not require anticoagulant monitoring and dose adjustment. The simplified therapy provided by low molecular weight heparin may allow many patients with venous thromboembolism to be cared for in an outpatient setting, with the potential for major savings in health care costs. In the setting of preventing venous thromboembolism after hip or knee replacement surgery, further cost-effectiveness studies are required to determine the ultimate clinical role of low molecular weight heparin. Extensive data document a consistent high rate of inadequate therapy when empirical or intuitive approaches are used to administer intravenous unfractionated heparin in patients with venous thromboembolism or cardiovascular disease. A validated protocol should be used for intravenous heparin treatment. The evidence is accumulating that warfarin is more effective than aspirin for preventing thromboembolism in patients with atrial fibrillation.


Histone Deacetylase Inhibition Restores Retinal Pigment Epithelium Function in Hyperglycemia.
In diabetic individuals, macular edema is a major cause of vision loss. This condition is refractory to insulin therapy and has been attributed to metabolic memory. The retinal pigment epithelium (RPE) is central to maintaining fluid balance in the retina, and this function is compromised by the activation of advanced glycation end-product receptors (RAGE). Here we provide evidence that acute administration of the RAGE agonist, glycated-albumin (gAlb) or vascular endothelial growth factor (VEGF), increased histone deacetylase (HDAC) activity in RPE cells. The administration of the class I/II HDAC inhibitor, trichostatin-A (TSA), suppressed gAlb-induced reductions in RPE transepithelial resistance (in vitro) and fluid transport (in vivo). Systemic TSA also restored normal RPE fluid transport in rats with subchronic hyperglycemia. Both gAlb and VEGF increased HDAC activity and reduced acetyl-α-tubulin levels. Tubastatin-A, a relatively specific antagonist of HDAC6, inhibited gAlb-induced changes in RPE cell resistance. These data are consistent with the idea that RPE dysfunction following exposure to gAlb, VEGF, or hyperglycemia is associated with increased HDAC6 activity and decreased acetyl-α-tubulin. Therefore, we propose inhibiting HDAC6 in the RPE as a potential therapy for preserving normal fluid homeostasis in the hyperglycemic retina.


Adaptation and validation of an oral anticoagulation measurement of treatment adherence instrument.
This methodological study adapted and analyzed the psychometric properties of the Measurement of Treatment Adherence (MTA) instrument for Brazilian users of oral anticoagulation therapy. Its final version was tested with 178 individuals. The average of answers for all questions ranged from 4.6 to 5.8 and 97.2% of the individuals were considered adherent. Moderate correlations were obtained between the adherence measure and the Mental health and Vitality domains of the SF-36. Cronbach's alpha was 0.60 and the ceiling effect occurred in answers to all items. These results indicate weak evidence of the validity, reliability and responsiveness of the MTA-adapted version for users of oral anticoagulant therapy.


Implication of peroxisome proliferator-activated receptor gamma and proinflammatory cytokines in gastric carcinogenesis: link to Helicobacter pylori-infection.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor involved in various processes including the inflammation and carcinogenesis. The aim of the present study was 1) to examine the mRNA and protein expression of PPARgamma in gastric cancer (GC); 2) to evaluate the effect of PPARgamma ligand (ciglitazone) on the proliferation and apoptosis of GC cell line; and 3) to assess the levels of gastric tissue proinflammatory cytokines, IL-1beta and IL-8, and plasma gastrin in GC patients before and after Helicobacter pylori (H. pylori) eradication. The trial material included 30 H. pylori-negative controls and 30 sex- and age-matched GC patients without or with H. pylori before and after its eradication. Expression of tissue PPARgamma, tissue levels of IL-1beta and IL-8, and plasma concentration of gastrin were significantly higher in H. pylori-positive GC compared to controls, but H. pylori eradication significantly reduced these parameters. Kato III cells incubated with alive H. pylori upregulated PPARgamma expression and ciglitazone inhibited cell proliferation and induced apoptosis. PPARgamma, proinflammatory cytokines and plasma gastrin appear to be implicated in H. pylori-related gastric carcinogenesis and PPARgamma agonists may have potential in cancer therapy.


Trastuzumab Emtansine-Induced Nodular Regenerative Hyperplasia: Is Dose Reduction Enough as a Preventable Measure?
Trastuzumab emtansine (T-DM1) is a novel antibody-drug conjugate targeting the human epidermal growth factor receptor 2, used in some recurrent metastatic cancers. It was linked to modest increases in serum aminotransferase elevations and bilirubin. More recently, some cases of noncirrhotic portal hypertension have been described in patients on long-term T-DM1. The underlying liver condition is usually nodular regenerative hyperplasia (NRH) with elements of sinusoidal obstruction. We report the case of a 52-year-old woman who started T-DM1 therapy for recurrent metastatic lung adenocarcinoma. Although a progressive reduction in lung nodules was noticed, there was a new-onset cytocholestasis and elevation in bilirubin. A reduction in platelet count was also apparent over several months during the T-DM1 therapy. Liver biopsy revealed NRH and so the dose of T-DM1 was reduced. Thereafter, the patient had normalization of liver tests and platelet count. T-DM1 was continued for more than 9 months with no signs of portal hypertension or cancer progression. We presented a rare case of NRH induced by T-DM1 in a patient with lung adenocarcinoma. A high index of suspicion for liver injury and NRH must be maintained for patients who develop liver test abnormalities and/or signs of portal hypertension during treatment with T-DM1. This is the first report of a successful dose reduction in a patient with NRH induced by T-DM1, suggesting that it is possible to maintain the drug while it is being effective for lung cancer treatment.


Predicting pituitary iron and endocrine dysfunction.
Patients with thalassemia major (TM) require lifelong transfusion therapy to survive, leading to toxic iron overload in the endocrine glands and heart. The pituitary gland is one of the most vulnerable targets, leading to irreversible hypogonadotropic hypogonadism in approximately half of patients. Improvements in magnetic resonance imaging (MRI) technology and understanding have allowed earlier recognition of preclinical iron deposition in the heart, pancreas, and liver; prior work also supports a similar role for the pituitary. The purpose of this study is threefold, (1) to develop age-specific nomograms for pituitary iron and volume metrics; (2) to determine the prevalence, severity, and age of onset of pituitary iron deposition and volume loss in TM patients, and (3) to determine whether deferasirox monotherapy can modify the trajectory of pituitary iron accumulation and damage over a two-year period. This article outlines relevant background studies and methodological details as well as providing preliminary results from our first two aims.


The association between anxiety and esophageal cancer: A nationwide population-based study.
Research on generalized anxiety disorder (GAD) and its association with esophageal cancer (EC) is sparse. The study aimed to explore the association between GAD and EC. A multicenter, population-based study in high-risk regions for EC (ECHRRs) was conducted from 2017 to 2019. All participants received free endoscopy screening. If the esophageal endoscopy results were suspicious, the pathological biopsy was performed to confirm normal, esophagitis, low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and EC. Information on participants' exposure to risk factors was collected. GAD was assessed with Generalized Anxiety Disorder Scale-7. With esophageal endoscopy, 25,650 participants in ECHRRs were examined, 9586 of whom were suspicious and confirmed by esophageal pathology. The detection rate of EC and precancerous lesions was 6.83% (1751/25,650), with 1377 LGIN (5.37%), 272 HGIN (1.06%), and 102 EC (0.40%) cases. The overall mean GAD score (95% CI) and prevalence among 25,650 participants with endoscopy were 1.96 (1.93-1.99) and 16.90%, respectively. The mean GAD score and prevalence among 9586 participants with pathology were 1.96 (1.91-2.02) and 17.98%, respectively. The mean GAD scores of patients confirmed with normal, esophagitis, LGIN, HGIN, and EC were 1.73 (1.62-1.85), 1.91 (1.85-1.97), 1.94 (1.80-2.08), 3.98 (3.73-4.23). and 2.97 (2.49-3.45), respectively (p < 0.001). The corresponding prevalence of GAD were 5.21%, 18.72%, 17.72%, 43.75%, and 36.27%, respectively (p < 0.001). The age- and gender-adjusted odds ratios (ORs) between GAD and each esophageal lesion type were 1.02 (0.99-1.04), 1.01 (0.98-1.04), 1.27 (1.21-1.33), and 1.16 (1.08-1.24), respectively. The ORs (95% CIs) of the positive associations were 1.08 (1.05-1.12), 1.03 (0.99-1.07), 1.35 (1.29-1.42), and 1.19 (1.10-1.29) after further adjustment for potential confounders (all p < 0.001). Sensitivity analysis showed that the positive association persisted. GAD was significantly higher in patients with EC and precancerous lesions. Focusing on and alleviating anxiety in high-risk groups (including patients with HGIN and EC) may be an effective strategy for EC prevention and control. Further prospective studies are warranted to validate the results.