Scaling of a Large-Scale Simulation of Synchronous Slow-Wave and Asynchronous Awake-Like Activity of a Cortical Model With Long-Range Interconnections.
Cortical synapse organization supports a range of dynamic states on multiple spatial and temporal scales, from synchronous slow wave activity (SWA), characteristic of deep sleep or anesthesia, to fluctuating, asynchronous activity during wakefulness (AW). Such dynamic diversity poses a challenge for producing efficient large-scale simulations that embody realistic metaphors of short- and long-range synaptic connectivity. In fact, during SWA and AW different spatial extents of the cortical tissue are active in a given timespan and at different firing rates, which implies a wide variety of loads of local computation and communication. A balanced evaluation of simulation performance and robustness should therefore include tests of a variety of cortical dynamic states. Here, we demonstrate performance scaling of our proprietary Distributed and Plastic Spiking Neural Networks (DPSNN) simulation engine in both SWA and AW for bidimensional grids of neural populations, which reflects the modular organization of the cortex. We explored networks up to 192 × 192 modules, each composed of 1,250 integrate-and-fire neurons with spike-frequency adaptation, and exponentially decaying inter-modular synaptic connectivity with varying spatial decay constant. For the largest networks the total number of synapses was over 70 billion. The execution platform included up to 64 dual-socket nodes, each socket mounting 8 Intel Xeon Haswell processor cores @ 2.40 GHz clock rate. Network initialization time, memory usage, and execution time showed good scaling performances from 1 to 1,024 processes, implemented using the standard Message Passing Interface (MPI) protocol. We achieved simulation speeds of between 2.3 × 109 and 4.1 × 109 synaptic events per second for both cortical states in the explored range of inter-modular interconnections.


Tubulointerstitial renal disease in systemic lupus erythematosus.
Tubulointerstitial renal disease is found frequently in patients with systemic lupus erythematosus. Despite the frequency of this entity, little is known about the prognostic significance of this biopsy finding. We reviewed 46 consecutive renal biopsy specimens from patients with systemic lupus erythematosus who were followed up for a mean of 5.4 years. Tubulointerstitial abnormalities were present in 39% of the entire group of patients and in 51% of the patients who had clinical evidence of renal abnormalities. Tubulointerstitial inflammation was closely associated with diffuse proliferative glomerulonephritis, with elevation of serum creatinine (SCr) concentration at biopsy, and with increased frequency of proteinuria both at biopsy and at follow-up. Additionally, active interstitial inflammation was associated with an increased risk of doubling the entry SCr concentration. The presence or absence of tubulointerstitial disease, however, did not add additional prognostic information to the predictive power of the entry SCr concentration or the glomerular histologic features.


Livelihood Diversification and Shifting Social Networks of Exchange: A Social Network Transition?
In the developing world, traditional social networks of exchange and reciprocity are critical components of household security, disaster relief, and social wellbeing especially in rural areas. This research asks the question: How are traditional social networks of exchange related to emerging household strategies to diversify livelihoods? Within this context, this study uses a mixed methods design to examine the character of inter-household exchanges of material goods (IHE) and the association between IHE and livelihood diversification, in ethnically Maasai communities in northern Tanzania. Findings show that IHE are both evolving and declining and are negatively associated with livelihood diversification.


Using standard nomenclature to adequately name transgenes, knockout gene alleles and any mutation associated to a genetically modified mouse strain.
Mice provide an unlimited source of animal models to study mammalian gene function and human diseases. The powerful genetic modification toolbox existing for the mouse genome enables the creation of, literally, thousands of genetically modified mouse strains, carrying spontaneous or induced mutations, transgenes or knock-out/knock-in alleles which, in addition, can exist in hundreds of different genetic backgrounds. Such an immense diversity of individuals needs to be adequately annotated, to ensure that the most relevant information is kept associated with the name of each mouse line, and hence, the scientific community can correctly interpret and benefit from the reported animal model. Therefore, rules and guidelines for correctly naming genes, alleles and mouse strains are required. The Mouse Genome Informatics Database is the authoritative source of official names for mouse genes, alleles, and strains. Nomenclature follows the rules and guidelines established by the International Committee on Standardized Genetic Nomenclature for Mice. Herewith, both from the International Society for Transgenic Technologies (ISTT) and from the scientific journal Transgenic Research, we would like to encourage all our colleagues to adhere and follow adequately the standard nomenclature rules when describing mouse models. The entire scientific community using genetically modified mice in experiments will benefit.


[The effect of melatonin on rat behavior in a conflict situation].
The effect of melathonine on behavior of rats under conditions of conflict situation is studied in experiments conducted in morning evening hours. The drug suppressed the response of rats on painful irritation and increased a number of taking water from drinking bowl. This effect of melathonine was more pronounced in the evening trials. The effects of melathonine were comparable with the influence of conventional benzdiazepine tranquilizer, diazepine, on the animal behavior.


Association between the triglyceride glucose index and cardiovascular mortality in obese population.
The triglyceride and glucose (TyG) index, as a surrogate marker of insulin resistance, was related to increased mortality. Our study aimed to investigate the specific relationship between the TyG index and all-cause mortality among obese population. 6731 participants with obesity were enrolled from the National Health and Nutrition Examination Survey (NHANES). The TyG index was calculated as log [fasting triglycerides (mg/dL) x fasting glucose (mg/dL)/2]. The baseline levels of TyG associated with the risk of all-cause and cardiovascular mortality were evaluated by Cox proportional hazards models. After a follow-up of 16.7 years, 693 all-cause death and 133 cardiovascular deaths occurred. Dose-response curve showed that the association of the risk of all-cause mortality was non-linear (p = 0.019) and the corresponding TyG index ranged 8.78 to 9.64 for the lowest risk. Compared with the reference quartile of 8.79-9.22, the multivariate-adjusted hazards ratios were 1.32 ((95% confidence interval 1.03-1.70; p = 0.030) in the lowest quartile for all-cause mortality, and 0.55 (0.32-0.93; p = 0.025) in the second quartile for cardiovascular mortality. TyG index was associated with the risk of all-cause mortality in obese participants and the level associated with the lowest risk was 8.78-9.64.


The mechanism of GT element-mediated cell type-specific transcriptional control.
Promoter studies have revealed that sequences related to the GT-1 binding site, known as GT elements, are conserved in plant nuclear genes of diverse functions. In this work, we addressed the issue of whether GT elements are involved in cell type-specific transcriptional regulation. We found that the inactivation of GT-1 site-mediated transcription in roots is correlated with the absence of the GT-1 binding activity in root extracts. In addition, the mutation of the related GT-1 (from the pea rbcs-3A) and the S1F (from the spinach rps1) sites resulted in an increase of their transcriptional activity in roots that contain a distinct GT element-binding factor, referred to as RGTF. Although specific to GT elements, RGTF has a different sequence requirement and a lower sequence specificity than GT-1. Interestingly, RGTF has a higher binding affinity to the mutant GT-1 and S1F sites than to the wild-type sequences. This correlation suggests that RGTF may have some role in transcriptional regulation in roots. Furthermore, root cellular protein extracts contain an inhibitory activity that prevents GT-1 from binding to DNA. This helps to explain the absence of the GT-1 binding activity in roots in which the gene of GT-1 is expressed. Together, these data suggest that the cell type-specific transcription modulation by GT elements is achieved by using two different strategies.


ESPEN practical guideline: Home enteral nutrition.
This ESPEN practical guideline will inform physicians, nurses, dieticians, pharmacists, caregivers and other home enteral nutrition (HEN) providers in a concise way about the indications and contraindications for HEN, as well as its implementation and monitoring. This guideline will also inform interested patients requiring HEN. Home parenteral nutrition is not included but will be addressed in a separate ESPEN guideline. The guideline is based on the ESPEN scientific guideline published before, which consists of 61 recommendations that have been reproduced and renumbered, along with the associated commentaries that have been shorted compared to the scientific guideline. Evidence grades and consensus levels are indicated. The guideline was commissioned and financially supported by ESPEN and the members of the guideline group were selected by ESPEN.


Reproductive biology of the bat Sturnira lilium (Chiroptera, Phyllostomidae) in the Atlantic Forest of Rio de Janeiro, southeastern Brazil.
Bats can be monoestrous or polyestrous, and seasonal or non-seasonal in their reproductive patterns. The strategy adopted by each species or population depends on the regional climate. The objective this study was to analyze reproductive data of Sturnira lilium from long-term sampling carried out in several sites in Rio de Janeiro states, southeastern Brazil. We carried out sampling in 42 sites (with altitudes ranging from sea level to 1300 m a.s.l.) from May 1989 to December 2011. In total, we obtained 2602 captures of S. lilium: 1242 captures of adult females, 1225 captures of adult males, and 136 captures of subadults. The sex ratio was 0.99 males: 1 female. The reproductive season varied from eight to twelve months a year, and it was not related to the total accumulated rainfall. Sturnira lilium have continuously polyestrous reproduction with postpartum estrus and pregnant females can be observed in all months except July. In the present study, the highest proportions of pregnant females were observed in the months with the highest rainfall.


Botryllus schlosseri as a Unique Colonial Chordate Model for the Study and Modulation of Innate Immune Activity.
Understanding the mechanisms that sustain immunological nonreactivity is essential for maintaining tissue in syngeneic and allogeneic settings, such as transplantation and pregnancy tolerance. While most transplantation rejections occur due to the adaptive immune response, the proinflammatory response of innate immunity is necessary for the activation of adaptive immunity. Botryllus schlosseri, a colonial tunicate, which is the nearest invertebrate group to the vertebrates, is devoid of T- and B-cell-based adaptive immunity. It has unique characteristics that make it a valuable model system for studying innate immunity mechanisms: (i) a natural allogeneic transplantation phenomenon that results in either fusion or rejection; (ii) whole animal regeneration and noninflammatory resorption on a weekly basis; (iii) allogeneic resorption which is comparable to human chronic rejection. Recent studies in B. schlosseri have led to the recognition of a molecular and cellular framework underlying the innate immunity loss of tolerance to allogeneic tissues. Additionally, B. schlosseri was developed as a model for studying hematopoietic stem cell (HSC) transplantation, and it provides further insights into the similarities between the HSC niches of human and B. schlosseri. In this review, we discuss why studying the molecular and cellular pathways that direct successful innate immune tolerance in B. schlosseri can provide novel insights into and potential modulations of these immune processes in humans.


The Role of Conformational Dynamics and Allostery in Modulating Protein Evolution.
Advances in sequencing techniques and statistical methods have made it possible not only to predict sequences of ancestral proteins but also to identify thousands of mutations in the human exome, some of which are disease associated. These developments have motivated numerous theories and raised many questions regarding the fundamental principles behind protein evolution, which have been traditionally investigated horizontally using the tip of the phylogenetic tree through comparative studies of extant proteins within a family. In this article, we review a vertical comparison of the modern and resurrected ancestral proteins. We focus mainly on the dynamical properties responsible for a protein's ability to adapt new functions in response to environmental changes. Using the Dynamic Flexibility Index and the Dynamic Coupling Index to quantify the relative flexibility and dynamic coupling at a site-specific, single-amino-acid level, we provide evidence that the migration of hinges, which are often functionally critical rigid sites, is a mechanism through which proteins can rapidly evolve. Additionally, we show that disease-associated mutations in proteins often result in flexibility changes even at positions distal from mutational sites, particularly in the modulation of active site dynamics.


Oral carcinoma cuniculatum, a rare variant of squamous cell carcinoma.
Carcinoma cuniculatum (CC) is a rare variant of squamous cell carcinoma (SCC). Lack of awareness of this tumor and its difficult diagnosis delay management and complicate treatment. The aim of this study is to describe the clinical and histological features, predisposing factors, treatment and survival rate of oral carcinoma cuniculatum. All patients with histologically confirmed CC of the oral cavity treated between January 2013 and August 2022 in a specialized center were retrospectively included. Patients were identified using the database ADICAP ("Association pour le Développement de l'Informatique en Cytologie et Anatomie Pathologique"). Once identified, the charts were reviewed. Ten patients were included. CC lesions were mainly located in the mandibular or maxillary gingiva, while the 2 remaining lesions were located in the mobile tongue. The tumor showed local aggressiveness: mandibular or maxillary osteolysis was systematically found for gingival CC, while tongue lesions were classified cT3. Fifteen biopsies were performed in these 10 patients, histological diagnosis is difficult on a limited tissue sample. All patients underwent curative management with oncological excision surgery combined with neck lymph node dissection, and adjuvant radiotherapy (except one patient). The main problem is the difficulty of diagnosis when biopsies are performed, which leads to a significant delay in diagnosis compared with SCC. In the event of clinico-histological discordance after biopsy, CC should be considered.


Response of Campylobacter jejuni to sodium chloride.
Studies were done to provide more comprehensive information on the response of Campylobacter jejuni and nalidixic acid-resistant, thermophilic Campylobacter (NARTC) to sodium chloride at 4, 25, and 42 degrees C. Three strains of C. jejuni were studies, and all could grow at 42 degrees C in the presence of 1.5% NaCl, but not 2.0% NaCl. At the same temperature, NARTC could grow in 2.0% NaCl and was substantially more tolerant to 2.5 and 4.5% NaCl than was C. jejuni. Both C. jejuni and NARTC grew poorly in the absence of added NaCl and grew best in the presence of 0.5% NaCl at 42 degrees C. At 25 degrees C, NaCl concentrations of 1.0 to 2.5% were protective to NARTC, but the same concentrations of salt generally enhanced the rate of death of C. jejuni. At 4 degrees C, both C. jejuni and NARTC were sensitive to 1.0% or more NaCl; however, the rate of death at this temperature was substantially less than that which occurred at 25 degrees C. A 3 log10 decrease of cells occurred in 4.5% NaCl after 1.2 to 2.1 days at 25 degrees C, and a similar reduction in cells took approximately 2 weeks at the same salt concentration and 4 degrees C. Although C. jejuni grows best in the presence of 0.5% NaCl, the presence of NaCl at concentrations as low as 1.0% may retard growth or increase rate of death; hence, it is advisable that growth media used for recovering or enumerating this organism contain 0.5% NaCl, but not 1.0% or more NaCl.


Gene therapy for leukocyte adhesion deficiency.
Leukocyte adhesion deficiency (LAD) is an autosomal recessive immunodeficiency disease characterized by severe, recurrent bacterial infections. In patients with LAD, the leukocytes, particularly the neutrophils, fail to adhere to the endothelial cell wall and migrate to the site of infection. LAD results from heterogeneous molecular defects in the leukocyte integrin CD18, which prevent CD11/CD18 heterodimer formation and surface expression. To date, hematopoietic stem cell transplantation remains the only curative treatment for LAD, however, this approach is limited by transplant-related toxicities and graft-versus-host disease. During the course of the preceding decade we have conducted extensive experimental studies demonstrating that gene transfer of the CD18 subunit corrects the structural and functional defect in LAD leukocytes. These studies provided the support for the initiation of a clinical trial of retroviral-mediated gene transfer of CD18 in two patients with the severe deficiency phenotype or LAD. This review will present an overview of LAD, preclinical CD18 gene transfer studies and the initial results from the current clinical trial.


[The effect of fixed water molecules on fractal properties of globular protein surfaces].
On the base of the technique developed by the authors together with Schmidt the fractal properties of the 17 globular proteins have been analysed using the crystal structure data at high resolution. For all the proteins there are the coordinates of fixed water molecules in the protein data bank. For each protein the fractal dimension of its surface D has been calculated with and without taking into account the fixed water molecules located inside a 3-Angstrom hydrated layer. Small but systematic decrease of the DS values for the proteins with the fixed water molecules has been demonstrated. It means that the fixed water molecules tend to fill gaps on the protein surfaces and in that way to smooth the surfaces. The volumes and the molecular surfaces of the proteins have been also calculated on the base of the cube technique. The molecular surfaces of the proteins with the fixed water molecules prove to decrease. This fact can be considered as the indirect evidence that the protein surfaces become to be smoother.


Aliifodinibius saliphilus sp. nov., a moderately halophilic bacterium isolated from sediment of a crystallizing pond of a saltern.
Two Gram-stain-negative, moderately halophilic bacteria, designated strains ECH52T and KHM46, were isolated from the sediment of a grey saltern located in Sinui island at Shinan, Korea. The isolates were aerobic, non-motile, short rods and grew at 15-45 °C (optimum, 37 °C), at pH 6.0-10.0 (optimum, pH 8.0) and with 3-25 % (w/v) NaCl (optimum, 10 % NaCl). Phylogenetic analyses based on 16S rRNA gene sequences indicated that strains ECH52T and KHM46 belonged to the genus Aliifodinibius in the family Balneolaceae with sequence similarities of 94.3-98.6 % and showed the highest sequence similarity to Aliifodinibius halophilus 2W32T (98.6 %), A. sediminis YIM J21T (94.7%), A. salicampi KHM44T (94.6 %) and A. roseus YIM D15T (94.3 %). The DNA G+C content of the genomic DNA of strain ECH52T was 40.8 mol%. The predominant isoprenoid quinone was menaquinone-7 (MK-7) and the major cellular fatty acids were iso-C17 : 1ω9c, iso-C15 : 0, and C16 : 1ω7c and/or iso-C15 : 0 2-OH. The major polar lipids were identified as diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, two unidentified glycolipids and four unidentified lipids. Based on the phylogenetic, phenotypic and chemotaxonomic data, strains ECH52T and KHM46 are considered to represent a novel species of the genus Aliifodinibius , for which the name Aliifodinibius saliphilus sp. nov. is proposed. The type strain is ECH52T (=KACC 19126T=NBRC 112664T).


Interobserver reliability of the gross motor performance measure: preliminary results.
Although assessment of the quality of movement in children with cerebral palsy (CP) is difficult, the development of the Gross Motor Performance Measure (GMPM) has facilitated this process. In order to determine the interobserver reliability of the GMPM, 36 children with spastic neuromuscular disorders (mean age 7 years, range 4 to 15 years) were evaluated using four of the five dimensions of the GMPM. Percent Agreement, Intraclass Correlations, and Kappas were calculated by both dimension and attribute to determine reliability. In addition, reliability measures were evaluated over time to determine whether reliability improved with continual use of the GMPM. Overall, interobserver reliability was in the 'fair to good' category regardless of the reliability measure used in the analysis. Reliability scores improved over time with a greater number of individual item scores moving from the 'fair to good' category to the 'excellent' category. Results from this study indicate that it is possible to assess reliably the quality of movement in children with CP.


[Polymorphisms within the interferon-Gamma receptor associated with systemic lupus erythematosus].
To assess the association between polymorphisms within the interferon-Gamma receptor gene(IFN-GammaR) and systemic lupus erythematosus (SLE) in Chinese people. The IFN-GammaR genotypes of 94 SLE patients and 80 healthy subjects were examined by the reverse transcription-polymerase chain reaction (RT-PCR)-single-strand conformation polymorphism (SSCP) method, RT-PCR-restriction fragment length polymorphism (RFLP) method and DNA sequencing. There was no statistically significant difference in the IFN-GammaR genotype frequencies between the two groups. The IFN-Gamma R2 Arg64/Arg64 genotype decreased the risk of SLE (OR = 2.481, 95% CI 0.992 - 6.203, P = 0.047). The decreased risk of the development of SLE was detected in the individuals who had the combination of IFN-GammaR2 Arg64/Arg64 genotype and IFN-GammaR1 Val14/Val14 genotype (OR = 2.481, 95% CI 0.992 - 6.203, P = 0.047). The IFN-GammaR2 Arg64/Arg64 genotype does not determine susceptibility to SLE in Chinese people, and the combination of IFN-Gamma R2 Arg64/Arg64 genotype and IFN-Gamma R1 Val14/Val14 genotype does not, either.


Tyrosine kinase signalling in embryonic stem cells.
Pluripotent ES (embryonic stem) cells can be expanded in culture and induced to differentiate into a wide range of cell types. Self-renewal of ES cells involves proliferation with concomitant suppression of differentiation. Some critical and conserved pathways regulating self-renewal in both human and mouse ES cells have been identified, but there is also evidence suggesting significant species differences. Cytoplasmic and receptor tyrosine kinases play important roles in proliferation, survival, self-renewal and differentiation in stem, progenitor and adult cells. The present review focuses on the role of tyrosine kinase signalling for maintenance of the undifferentiated state, proliferation, survival and early differentiation of ES cells.


Oral administration of Moringa oleifera oil but not coconut oil prevents mercury-induced testicular toxicity in rats.
This study was conducted to compare the effects of administration of coconut oil (CO) and Moringa oleifera oil (MO) on testicular oxidative stress, sperm quality and steroidogenesis parameters in rats treated with mercury chloride (HgCl2 ). After 15 days of oral administration of CO (2 ml kg-1 body weight) and MO (2 ml kg-1 body weight) along with intraperitoneal (i.p.) administration of HgCl2 (5 mg kg-1 body weight) alone or in combination, we found that CO treatment did not protect against HgCl2 -induced poor sperm quality (motility, count) as well as decreased testosterone level and 17β-hydroxysteroid dehydrogenase (17β-HSD) activity. Treatment with CO alone decreased glutathione (GSH), and glutathione peroxidase (GSH-Px) activities and increased malondialdehyde (MDA) level in rat's testis, whereas MO did not change these parameters. Cotreatment with MO prevented HgCl2 -induced testicular catalase (CAT) and superoxide dismutase (SOD) activities, poor sperm quality and low testosterone level and also blocks the adverse effect of CO+HgCl2 (2 ml kg-1 body weight + 5 mg kg-1 body weight) on the investigated endpoints. In conclusion, MO and not CO decreased the deleterious effects of HgCl2 on sperm quality and steroidogenesis in rats and also strengthen the antioxidant defence of the testes. Therefore, MO is beneficial as an antioxidant in HgCl2 -induced oxidative damage.


RTE1 is a Golgi-associated and ETR1-dependent negative regulator of ethylene responses.
Arabidopsis (Arabidopsis thaliana) RTE1 encodes a membrane protein and negatively regulates ethylene responses. Genetic and transformation studies suggest that the function of the wild-type RTE1 is primarily dependent on ETR1 and can be independent on the other receptors. Ethylene insensitivity caused by the overexpression of RTE1 is largely masked by the etr1-7 mutation, but not by any other receptor mutations. The wild-type ETR1 N terminus is sufficient to the activation of the RTE1 function and the ectopic expression of etr1(1-349) restored ethylene insensitivity conferred by 35SgRTE1 in etr1-7. The RTE1 N terminus is not essential to the etr1-2 function and the expression of rte1(NDelta49), which has an N-terminal deletion of 49 amino acid residues, restored ethylene insensitivity in etr1-2 rte1-2. The ectopic expression of GREEN FLUORESCENT PROTEIN (GFP)-RTE1 conferred ethylene insensitivity in wild type and the GFP fusion displayed fast movement within the cytoplasm. The GFP-RTE1 and EYFP-NAG proteins colocalized and the Brefeldin A treatment caused aggregation of GFP-RTE1, suggesting RTE1 is a Golgi-associated protein. Our results suggest specificity of the RTE1 function to ETR1 and that endomembranes may play a role in the ethylene signal transduction.


Medical interventions for acanthamoeba keratitis.
Acanthamoeba are microscopic, free-living, single-celled organisms which can infect the eye and lead to Acanthamoeba keratitis (AK). AK can result in loss of vision in the infected eye or loss of eye itself; however, there are no formal guidelines or standards of care for the treatment of AK. To evaluate the relative effectiveness and safety of medical therapy for the treatment of AK. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015, Issue 1), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to January 2015), EMBASE (January 1980 to January 2015), PubMed (1948 to January 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to January 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 9 January 2015. We included randomized controlled trials (RCTs) of medical therapy for AK, regardless of the participants' age, sex, or etiology of disease. We included studies that compared either anti-amoeba therapy (drugs used alone or in combination with other medical therapies) with no anti-amoeba therapy or one anti-amoeba therapy with another anti-amoeba therapy. Two authors independently screened search results and full-text reports, assessed risk of bias, and abstracted data. We used standard methodological procedures as set forth by the Cochrane Collaboration. We included one RCT (56 eyes of 55 participants) in this review. The study compared two types of topical biguanides for the treatment of AK: chlorhexidine 0.02% and polyhexamethylene biguanide (PHMB) 0.02%. All participants were contact lens wearers with a median age of 31 years. Treatment duration ranged from 51 to 145 days. The study, conducted in the UK, was well-designed and had low risk of bias overall.Outcome data were available for 51 (91%) of 56 eyes. Follow-up times for outcome measurements in the study were not reported. Resolution of infection, defined as control of ocular inflammation, relief of pain and photosensitivity, and recovery of vision, was 86% in the chlorhexidine group compared with 78% in the PHMB group (relative risk (RR) 1.10, 95% confidence intervals (CI) 0.84 to 1.42). In the chlorhexidine group, 20 of 28 eyes (71%) had better visual acuity compared with 13 of 23 eyes (57%) in the PHMB group at final follow-up (RR 1.26, 95% CI 0.82 to 1.94). Five participants required therapeutic keratoplasty: 2 in the chlorhexidine group compared with 3 in the PHMB group (RR 0.55, 95% CI 0.10 to 3.00). No serious adverse event related to drug toxicity was observed in the study. There is insufficient evidence to evaluate the relative effectiveness and safety of medical therapy for the treatment of AK. Results from the one included study yielded no difference with respect to outcomes reported between chlorhexidine and PHMB. However, the sample size was inadequate to detect clinically meaningful differences between the two groups as indicated by the wide confidence intervals of effect estimates.


RR-interval irregularity precedes ventricular fibrillation in ST elevation acute myocardial infarction.
Sudden cardiac arrest is a leading cause of death in industrialized countries, and ischemic ventricular fibrillation (VF) is a frequent cause. The purpose of this study was to determine whether patients with ST elevation myocardial infarction (STEMI) who develop ischemic VF show more overall RR-interval irregularity (RRI) than do STEMI patients without ischemic VF. Ischemic VF was identified in 41 patients from 1,473 digital 12-lead Holter recordings from three separate STEMI studies. Continuous 3-lead and 12-lead electrocardiogram (ECG) snapshots recorded every minute were compared between all ischemic VF patients and 123 random patients without ischemic VF. Time intervals from start of Holter to ischemic VF and equivalent intervals in the controls were used for calculations. ECG variables related to conduction intervals and severity of ischemia were measured using the most ischemic 12-lead ECG. RRI was calculated as the square root of the mean squared differences of successive RR intervals. For RRI, all QRS complexes, including ventricular ectopic beats, were used. No baseline differences were observed between the study and control groups, except for male preponderance among ischemic VF patients (90% vs 72%, P = .019). QRS interval, ECG ischemia severity, RRI, and number of ventricular ectopic beats were significantly associated with ischemic VF. Multivariate analysis revealed RRI (odds ratio 1.006, 95% confidence interval 1.001-1.010, P = .016) and ST deviation score (odds ratio 1.073, 95% confidence interval 1.041-1.106, P <.001) as the only statistically significant predictors of ischemic VF. In the period before ischemic VF, RRI and ST deviation score are associated with ischemic VF in STEMI patients. These findings could have important pathophysiologic and clinical implications.


[Effects of eleutherococcus, elton, leuzea, and leveton on the blood coagulation system during training in athletes].
Comparative study was conducted of formal preparations of tinctures of eleutherococcus and leuzea and the newly developed preparations Elton and Leveton containing, respectively, eleutherosids and ecdisten. Intensive physical activity of high-class athletes leads to increase of blood coagulation expressed in shortening of the thromboelastogram r and K intervals and increased activity of the proth rombin complex according to Quick, and increased activity of factors II, VII, X, XIII, and fibrinolysis. The concentration of fibrinogen increases. A 20-day course of eleuthrococcus tincture causes a decrease in the blood coagulation potential and activity of the blood coagulation factors induced by intensive training of the athletes. Twenty-day treatment with the new broad-spectrum adaptogens Elton and Leveton causes a more marked reduction of the coagulation potential in athl etes. The activity of the factors and fibrinolys are normalized in this case. The indicated shifts are accompanied with increase of working capacity and rehabilitation of the athletes.


Anticonvulsant Activity of Hydroalcoholic Extract and Aqueous Fraction of Ebenus stellata in Mice.
Fabaceae is the third largest family of flowering plants. Lack of essential oils in the plants of this family can be considered as an advantage and can favor them in search for safe and antiepileptic medicines. The effects of Fabacea family plants including Ebenus stellata (E. stellata), Sophora alopecuroides and Caesalpinia gilliiesii were evaluated in pentylenetetrazole (PTZ) and maximal electroshock (MES) seizure tests. The hydroalcoholic extracts were obtained by percolation of 100 g aerial parts of each plant in 900 ml ethanol 80%. Acute toxicity of the extracts was assessed. Non-toxic doses of the extracts were injected to the mice intraperitoneally (i.p.) and occurrence of clonic seizures induced by PTZ (60 mg/kg, i.p.) or tonic seizures induced by MES (50 mA, 50 Hz, 1 sec), were monitored up to 30 min after each administration. The anticonvulsant extract was then fractionated by dichloromethane and water. Phytochemical screening of the effective extract was also carried out by thin layer chromatography to verify active constituents. Among the extracts used, only E. stellata had no toxicity and inhibited clonic seizures in a significant and dose-dependent (3-7 g/kg) manner with ED50 of 4 g/kg. Fractionation of the extract resulted in dose-dependent (1-5 g/kg) anticonvulsant activity, which was observed in aqueous fraction with ED50 of 1.74 g/kg. Phytochemical screening revealed the presence of terpens/sterols, alkaloids, flavonoids, tannin and saponins in the extract. The presence of anticonvulsant compounds in E. stellata suggests further activity-guided fractionation and analytical studies to find the potential of this plant as a source of anticonvulsant agents.


Reaction mechanism of the gastric H+ +K+-dependent ATPase. Effects of inhibitor and pH.
The effect of nolinium bromide [2-(3,4-dichlorophenylamino)quinolizium bromide], which acts as a K+ antagonist in the gastric H+ +K+-dependent ATPase reaction, was investigated at the level of 32P-labelled intermediates of the gastric ATPase reaction. A concentration-dependent effect of nolinium bromide was observed on the concentrations of phosphorylated intermediates. At low (up to 50 microM) concentrations the drug did not interfere with the concentrations of intermediates but exhibited a competition with K+ at the level of both 32P-labelled intermediates and hydrolysis of ATP at pH 7.0. Similar competition was noted in the H+ +K+-dependent ATPase reaction. Low nolinium bromide concentrations also drastically slowed the enzyme turnover. The concentrations of the intermediates were lowered appreciably between 50 microM- and 100 microM-nolinium bromide without affecting the ATP hydrolysis, and the effects were independent of pH. Similar to the effects at pH 7.0, the drug also exhibited competition with K+ in lowering the E approximately P concentration at pH 5.0. A dramatic effect of pH on the K+-sensitivity as well as on turnover of the 32P-labelled intermediates was observed. Although the concentrations of intermediates remained nearly unaltered at various pH values, the K+-stimulated hydrolysis of ATP showed an optimum at pH 7.0 with sharp declines at pH 5 and 8. The data suggest a critical involvement of H+ in the conversion of the K+-insensitive E1 approximately P into the K+-sensitive E2 approximately P form of the enzyme. Nolinium bromide appears to function as a K+ analogue and seems to block the entry of K+ at the K X E2 step, thereby interfering with the enzyme turnover.


UniProt archive.
UniProt Archive (UniParc) is the most comprehensive, non-redundant protein sequence database available. Its protein sequences are retrieved from predominant, publicly accessible resources. All new and updated protein sequences are collected and loaded daily into UniParc for full coverage. To avoid redundancy, each unique sequence is stored only once with a stable protein identifier, which can be used later in UniParc to identify the same protein in all source databases. When proteins are loaded into the database, database cross-references are created to link them to the origins of the sequences. As a result, performing a sequence search against UniParc is equivalent to performing the same search against all databases cross-referenced by UniParc. UniParc contains only protein sequences and database cross-references; all other information must be retrieved from the source databases.


Surgical versus conservative management of acute patellar dislocation in children and adolescents: a systematic review.
The goal of this study was to perform a comparative review to determine whether there is a significant difference in the rate of repeat dislocation and clinical outcome between surgical and conservative management of acute patellar dislocation in children and adolescents. A systematic review of the MEDLINE database was performed. English-language clinical outcome studies with a primary outcome/treatment specific to acute patella dislocation in a paediatric population were included. Eleven studies met inclusion criteria; Chi-square analysis, independent t tests and weighted mean pooled cohort statistics were performed where appropriate. A total of 470 conservatively managed and 157 operatively treated knees were included. Conservatively managed patients were on average 17.0 years and had a mean follow-up of 3.9 years; surgically managed patients were on average 16.1 years and had a mean follow-up of 4.7 years. Conservatively managed knees had a 31% rate of recurrent dislocation rate compared to 22% in surgical knees (p = 0.04). Trochlear dysplasia and skeletal immaturity confer greater risk for recurrent instability. Surgical treatment may provide clinically important quality of life and sporting benefit. Surgical treatment of first time patella dislocation in children and adolescents is associated with a lower risk of recurrent dislocation and higher health-related quality of life and sporting function. There is a paucity of evidence on MPFL reconstruction for first time traumatic patella dislocation in this population. IV.


Reduced beta 1 receptor messenger RNA abundance in the failing human heart.
Heart failure in humans is characterized by alterations in myocardial adrenergic signal transduction, the most prominent of which is down-regulation of beta 1-adrenergic receptors. We tested the hypothesis that down-regulation of beta 1-adrenergic receptors in the failing human heart is related to decreased steady-state levels of beta 1 receptor mRNA. Due to the extremely low abundance of beta 1 receptor mRNA, measurements were possible only by quantitative polymerase chain reaction (QPCR) or by RNase protection methods. Because the beta 1 receptor gene is intronless and beta 1 receptor mRNA abundance is low, QPCR yielded genomic amplification in total RNA, and mRNA measurements had to be performed in poly (A)(+)-enriched RNA. By QPCR the concentration of beta 1 receptor mRNA varied from 0.34 to 7.8 x 10(7) molecules/microgram poly(A)(+)-enriched RNA, and the assay was sensitive to 16.7 zeptomol. Using 100-mg aliquots of left ventricular myocardium obtained from organ donors (nonfailing ventricles, n = 12) or heart transplant recipients (failing ventricles, n = 13), the respective beta 1 mRNA levels measured by QPCR were 4.2 +/- 0.7 x 10(7)/micrograms vs. 2.10 +/- 0.3 x 10(7)/micrograms (P = 0.006). In these same nonfailing and failing left ventricles the respective beta 1-adrenergic receptor densities were 67.9 +/- 6.9 fmol/mg vs. 29.6 +/- 3.5 fmol/mg (P = 0.0001). Decreased mRNA abundance in the failing ventricles was confirmed by RNase protection assays in total RNA, which also demonstrated a 50% reduction in beta 1 message abundance. We conclude that down-regulation of beta 1 receptor mRNA contributes to down-regulation of beta 1 adrenergic receptors in the failing human heart.


Trends in endovascular therapy and clinical outcomes within the nationwide Get With The Guidelines-Stroke registry.
We sought to determine hospital and patient characteristics associated with the use of endovascular therapy for acute ischemic stroke and to analyze trends in clinical outcome. Data were from Get With The Guidelines-Stroke hospitals from April 1, 2003, to June 30, 2013. We looked at trends in number of hospitals providing endovascular therapy, the use of endovascular therapy in these hospitals and clinical outcomes. We analyzed hospital and patient characteristics associated with endovascular therapy use. Of 1087 hospitals, 454 provided endovascular therapy to ≥1 patient in the study period. From 2003 to 2012, proportion of hospitals providing endovascular therapy increased by 1.6% per year (from 12.9% to 28.9%; P<0.0001), with a modest drop to 23.4% in 2013. Utilization of endovascular therapy increased from 0.7% to 2% (P<0.001) with a modest drop to 1.9% in 2013. The overall rate of symptomatic intracerebral hemorrhage among endovascular therapy treated patients was 9.7%. In multivariable analyses, patient outcomes after endovascular therapy improved over time, with reductions in in-hospital mortality (29.6% in 2004 to 16.2% in 2013; P=0.002); and from late 2010, reduction in symptomatic intracerebral hemorrhage (11% in 2010 to 5% in 2013; P<0.0001), increased independent ambulation at discharge (24.5% in 2010 to 33% in 2013; P<0.0001) and discharge home (17.7% in 2010 to 26.1% in 2013; P<0.0001). Trends for these outcomes persist in the analyses adjusted for baseline National Institutes of Health Stroke Scale. The use of endovascular therapy increased modestly nationally from 2003 to 2012 and decreased in 2013. Clinical outcomes improved notably from 2010 to 2013, coincident with more experience and newer thrombectomy devices.


Machine learning for predicting psychotic relapse at 2 years in schizophrenia in the national FACE-SZ cohort.
Predicting psychotic relapse is one of the major challenges in the daily care of schizophrenia. To determine the predictors of psychotic relapse and follow-up withdrawal in a non-selected national sample of stabilized community-dwelling SZ subjects with a machine learning approach. Participants were consecutively included in the network of the FondaMental Expert Centers for Schizophrenia and received a thorough clinical and cognitive assessment, including recording of current treatment. Relapse was defined by at least one acute psychotic episode of at least 7 days, reported by the patient, her/his relatives or by the treating psychiatrist, within the 2-year follow-up. A classification and regression tree (CART) was used to construct a predictive decision tree of relapse and follow-up withdrawal. Overall, 549 patients were evaluated in the expert centers at baseline and 315 (57.4%) (mean age = 32.6 years, 24% female gender) were followed-up at 2 years. On the 315 patients who received a visit at 2 years, 125(39.7%) patients had experienced psychotic relapse at least once within the 2 years of follow-up. High anger (Buss&Perry subscore), high physical aggressiveness (Buss&Perry scale subscore), high lifetime number of hospitalization in psychiatry, low education level, and high positive symptomatology at baseline (PANSS positive subscore) were found to be the best predictors of relapse at 2 years, with a percentage of correct prediction of 63.8%, sensitivity 71.0% and specificity 44.8%. High PANSS excited score, illness duration <2 years, low Buss&Perry hostility score, high CTQ score, low premorbid IQ and low medication adherence (BARS) score were found to be the best predictors of follow-up withdrawal with a percentage of correct prediction of 52.4%, sensitivity 62%, specificity 38.7%. Machine learning can help constructing predictive score. In the present sample, aggressiveness appears to be a good early warning sign of psychotic relapse and follow-up withdrawal and should be systematically assessed in SZ subjects. The other above-mentioned clinical variables may help clinicians to improve the prediction of psychotic relapse at 2 years.


Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study.
Middle East respiratory syndrome (MERS) is a new human disease caused by a novel coronavirus (CoV). Clinical data on MERS-CoV infections are scarce. We report epidemiological, demographic, clinical, and laboratory characteristics of 47 cases of MERS-CoV infections, identify knowledge gaps, and define research priorities. We abstracted and analysed epidemiological, demographic, clinical, and laboratory data from confirmed cases of sporadic, household, community, and health-care-associated MERS-CoV infections reported from Saudi Arabia between Sept 1, 2012, and June 15, 2013. Cases were confirmed as having MERS-CoV by real-time RT-PCR. 47 individuals (46 adults, one child) with laboratory-confirmed MERS-CoV disease were identified; 36 (77%) were male (male:female ratio 3·3:1). 28 patients died, a 60% case-fatality rate. The case-fatality rate rose with increasing age. Only two of the 47 cases were previously healthy; most patients (45 [96%]) had underlying comorbid medical disorders, including diabetes (32 [68%]), hypertension (16 [34%]), chronic cardiac disease (13 [28%]), and chronic renal disease (23 [49%]). Common symptoms at presentation were fever (46 [98%]), fever with chills or rigors (41 [87%]), cough (39 [83%]), shortness of breath (34 [72%]), and myalgia (15 [32%]). Gastrointestinal symptoms were also frequent, including diarrhoea (12 [26%]), vomiting (ten [21%]), and abdominal pain (eight [17%]). All patients had abnormal findings on chest radiography, ranging from subtle to extensive unilateral and bilateral abnormalities. Laboratory analyses showed raised concentrations of lactate dehydrogenase (23 [49%]) and aspartate aminotransferase (seven [15%]) and thrombocytopenia (17 [36%]) and lymphopenia (16 [34%]). Disease caused by MERS-CoV presents with a wide range of clinical manifestations and is associated with substantial mortality in admitted patients who have medical comorbidities. Major gaps in our knowledge of the epidemiology, community prevalence, and clinical spectrum of infection and disease need urgent definition. None.


An earthquake disaster in Turkey: an overview of the experience of the Israeli Defence Forces Field Hospital in Adapazari.
On 17 August 1999 at 3:04 a.m., an earthquake of 7.4 magnitude (Richter scale) struck the Marmara region in Turkey. The city of Adapazari suffered 2,680 fatalities with approximately 5,300 injured. The Israeli Defence Forces (IDF) field hospital arrived at Adapazari, on day four after the quake. The team consisted of 102 personnel. The field hospital acted as a secondary referral centre. A total of 1,205 patients were treated in the field hospital between day four and day 14 of the earthquake. The frequency distribution of the medical problems seen in the field hospital was 32 per cent internal medicine, 13 per cent general surgery including plastic, 21 per cent orthopaedic surgery, 23 per cent paediatric disease, 10 per cent obstetrics and gynaecology and 1 per cent major psychiatric disorders. A mean number of 35 patients per day were hospitalised in the field hospital for between 24 hours to one week. The rapid establishment of the field hospital enabled the local medical facilities to 'buy time' in order to organise and restore surgical and hospitalisation abilities in this disastrous situation.


Novel Negative Pressure Helmet Reduces Aerosolized Particles in a Simulated Prehospital Setting.
The coronavirus disease 2019 (COVID-19) pandemic has created challenges in maintaining the safety of prehospital providers caring for patients. Reports have shown increased rates of Emergency Medical Services (EMS) provider infection with COVID-19 after patient care exposure, especially while utilizing aerosol-generating procedures (AGPs). Given the increased risk and rising call volumes for AGP-necessitating complaints, development of novel devices for the protection of EMS clinicians is of great importance.Drawn from the concept of the powered air purifying respirator (PAPR), the AerosolVE helmet creates a personal negative pressure space to contain aerosolized infectious particles produced by patients, making the cabin of an EMS vehicle safer for providers. The helmet was developed initially for use in hospitals and could be of significant use in the prehospital setting. The objective of this study was to determine the efficacy and safety of the helmet in mitigating simulated infectious particle spread in varied EMS transport platforms during AGP utilization. Fifteen healthy volunteers were enrolled and distributed amongst three EMS vehicles: a ground ambulance, a medical helicopter, and a medical jet. Sodium chloride particles were used to simulate infectious particles, and particle counts were obtained in numerous locations close to the helmet and around the patient compartment. Counts near the helmet were compared to ambient air with and without use of AGPs (non-rebreather mask [NRB], continuous positive airway pressure mask [CPAP], and high-flow nasal cannula [HFNC]). Without the helmet fan on, the particle generator alone and with all AGPs produced particle counts inside the helmet significantly higher than ambient particle counts. With the fan on, there was no significant difference in particle counts around the helmet compared to baseline ambient particle counts. Particle counts at the filter exit averaged less than one despite markedly higher particle counts inside the helmet. Given the risk to EMS providers by communicable respiratory diseases, development of devices to improve safety while still enabling use of respiratory therapies is of paramount importance. The AerosolVE helmet demonstrated efficacy in creating a negative pressure environment and provided significant filtration of simulated respiratory droplets, thus making the confined space of transport vehicles potentially safer for EMS personnel.


Health care costs for prostate cancer patients receiving androgen deprivation therapy: treatment and adverse events.
Serious adverse events have been associated with androgen deprivation therapy (adt) for prostate cancer (pca), but few studies address the costs of those events. All pca patients (ICD-9-CM 185) in Ontario who started 90 days or more of adt or had orchiectomy at the age of 66 or older during 1995-2005 (n = 26,809) were identified using the Ontario Cancer Registry and drug and hospital data. Diagnosis dates of adverse events-myocardial infarction, acute coronary syndrome, congestive heart failure, stroke, deep vein thrombosis or pulmonary embolism, any diabetes, and fracture or osteoporosis-before and after adt initiation were determined from administrative data. We excluded patients with the same diagnosis before and after adt, and we allocated each patient's time from adt initiation to death or December 31, 2007, into health states: adt (no adverse event), adt-ae (specified single adverse event), Multiple (>1 event), and Final (≤180 days before death). We used methods for Canadian health administrative data to estimate annual total health care costs during each state, and we examined monthly trends. Approximately 50% of 21,811 patients with no pre-adt adverse event developed 1 or more events after adt. The costliest adverse event state was stroke ($26,432/year). Multiple was the most frequent (n = 2,336) and the second most costly health state ($24,374/year). Costs were highest in the first month after diagnosis (from $1,714 for diabetes to $14,068 for myocardial infarction). Costs declined within 18 months, ranging from $784 per 30 days (diabetes) to $1,852 per 30 days (stroke). Adverse events increased the costs of adt by 100% to 265%. The economic burden of adverse events is relevant to programs and policies from clinic to government, and that burden merits consideration in the risks and benefits of adt.


[Cultural conflicts in the management of hydrographic watersheds in the Central American isthmus].
Productivity of natural ecosystems in watersheds in the Central American Isthmus is being seriously endangered by the disproportionate increase in population, which hampers an adequate development of water and agricultural resources. The logical consequences of the lack of planning in the use of these resources are rapid degradation of the soil and high levels of environmental pollution. Among the human activities which destroy the natural ecological balance are slash burning, overgrazing and farming on lands not suited for this purpose. These activities form part of the socio-economic and cultural aspects of the region and are associated with systems of land occupancy and distribution, and with inefficient practices, such as tenant farming and share cropping. Recent apprehensions by nature-loving groups and the general public are pressing for more realistic conservation and legislative policies, and for the creation of more dynamic government agencies that would not only actively participate in the planning and utilization of natural resources, but also in the technical studies of watersheds that after the socio-cultural aspects of the central American region.


Constitutive expression and enzymatic cleavage of ICAM-1 in the spontaneously hypertensive rat.
Leukocyte adhesion to the endothelium is abnormal in hypertension. We have recently shown that spontaneously hypertensive rats (SHRs) have circulating leukocytes with enhanced CD18 receptor cleavage. In the current study, we investigate expression levels of its counter receptor, intercellular adhesion molecule (ICAM-1), and its possible proteolytic cleavage in the SHR and control Wistar rat. ICAM-1 was labeled on tissue sections with two antibodies targeting its extracellular and intracellular domains and evaluated by light absorption measurements. The in situ cleavage of ICAM-1 was assessed by treating vessel sections with matrix metalloproteinase (MMP)-7, MMP-9 and elastase. SHRs showed a significant increase in ICAM-1 expression in liver and kidney compared with Wistar rats. The liver and kidney glomeruli exhibit a discrepancy in label density between intra- and extracellular antibodies, which suggests that enzymatic cleavage may be a factor determining ICAM-1 distribution. MMP-7 and MMP-9, which are elevated in SHR plasma, and elastase, which has elevated activity in SHR neutrophils, cleave the extracellular domain of ICAM-1 when applied to the tissue. ICAM-1 expression in SHRs is upregulated in a tissue-specific manner. Proteolytic cleavage of the extracellular domain of ICAM-1 and accumulation in kidney glomeruli may play a role in the renal involvement of inflammation.


Salmonella bacteremia as manifestation of acquired immunodeficiency syndrome.
Multiple opportunistic infections are characteristic of the acquired immunodeficiency syndrome (AIDS). Although bacterial pathogens have presented few problems, we have noted an emerging problem with salmonellal infection among patients with AIDS. A review of all stool and blood cultures from adults between January 1982 and July 1984 showed that 80 stool cultures were positive for Salmonella species; serogroup B was the most common isolated. Eight (10%) were isolated from patients with AIDS. Nineteen blood cultures were positive for Salmonella species. Six (32%) were isolated from patients with AIDS: three were positive for Salmonella serogroup B; two yielded Salmonella choleraesuis; and one yielded Salmonella serogroup D. In three (50%), Salmonella bacteremia was a presenting manifestation of AIDS. Bacteremias were recurrent in five patients. Thus, it appears that AIDS not only predisposes patients to serious salmonellal infections but also compromises their ability to eradicate these bacteria.


Lower Blood Pressure After Transcatheter or Surgical Aortic Valve Replacement is Associated with Increased Mortality.
Background Blood pressure (BP) guidelines for patients with aortic stenosis or a history of aortic stenosis treated with aortic valve replacement (AVR) match those in the general population, but this extrapolation may not be warranted. Methods and Results Among patients enrolled in the Medtronic intermediate, high, and extreme risk trials, we included those with a transcatheter AVR (n=1794) or surgical AVR (n=1103) who were alive at 30 days. The associations between early (average of discharge and 30 day post-AVR) systolic BP (SBP) and diastolic BP (DBP) measurements and clinical outcomes between 30 days and 1 year were evaluated. Among 2897 patients, after adjustment, spline curves demonstrated an association between lower SBP (<120 mm Hg, representing 21% of patients) and DBP (<60 mm Hg, representing 30% of patients) and increased all-cause and cardiovascular mortality and repeat hospitalization. These relationships were unchanged when patients with moderate-to-severe aortic regurgitation post-AVR were excluded. After adjustment, compared with DBP 60 to <80 mm Hg, DBP 30 to <60 mm Hg was associated with increased all-cause (adjusted hazard ratio 1.62, 95% CI 1.23-2.14) and cardiovascular mortality (adjusted hazard ratio 2.13, 95% CI 1.52-3.00), but DBP 80 to <100 mm Hg was not. Similarly, after adjustment, compared with SBP 120 to <150 mm Hg, SBP 90 to <120 mm Hg was associated with increased all-cause (adjusted hazard ratio 1.63, 95% CI 1.21-2.21) and cardiovascular mortality (adjusted hazard ratio 1.81, 95% CI 1.25-2.61), but SBP 150 to <180 mm Hg was not. Conclusions Lower BP in the first month after transcatheter AVR or surgical AVR is common and associated with increased mortality and repeat hospitalization. Clarifying optimal BP targets in these patients ought to be a priority and may improve patient outcomes. Clinical Trial Registration Information URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01586910, NCT01240902.


Inhibition of Type IV Secretion Activity and Growth of Helicobacter pylori by Cisplatin and Other Platinum Complexes.
Type IV secretion systems are protein secretion machineries that are frequently used by pathogenic bacteria to inject their virulence factors into target cells of their respective hosts. In the case of the human gastric pathogen Helicobacter pylori, the cytotoxin-associated gene (Cag) type IV secretion system is considered a major cause for severe disease, such as gastric cancer, and thus constitutes an attractive target for specific treatment options against H. pylori infections. Here, we have used a Cag type IV secretion reporter assay for screening a repurposing compound library for inhibitors targeting this system. We found that the antitumor agent cisplatin, a platinum coordination complex that kills target cells by formation of DNA crosslinks, is a potent inhibitor of the Cag type IV secretion system. Strikingly, we found that this inhibitory activity of cisplatin depends on a ligand exchange reaction which incorporates a solvent molecule (dimethylsulfoxide) into the complex, a modification which is known to be deleterious for DNA crosslinking, and for its anticancer activity. We extended our analysis to several analogous platinum complexes containing N-heterocyclic carbene, as well as DMSO or other ligands, and found varying inhibitory activities toward the Cag system which were not congruent with their DNA-binding properties, suggesting that protein interactions may cause the inhibitory effect. Inhibition experiments under varying conditions revealed effects on adherence and bacterial viability as well, and showed that the type IV secretion-inhibitory capacity of platinum complexes can be inactivated by sulfur-containing reagents and in complex bacterial growth media. Taken together, our results demonstrate DNA binding-independent inhibitory effects of cisplatin and other platinum complexes against different H. pylori processes including type IV secretion.


Inhibitory effect of fucoidan on the activities of crotaline snake venom myotoxic phospholipases A(2).
Myotoxic phospholipases A(2) account for most of the muscle necrosis that results from envenenomation by crotaline snakes. In this study, we investigated the protective effect of fucoidan, a natural sulfated polysaccharide obtained from the brown seaweed Fucus vesiculosus, against the cytotoxic and myotoxic activities of a group of phospholipase A(2) myotoxins from crotaline snake venoms: Bothrops asper myotoxins I, II, III, and IV, Cerrophidion godmani myotoxins I and II, Atropoides nummifer myotoxins I and II, and Bothriechis schlegelii myotoxin I. All of the toxins tested were efficiently inhibited by fucoidan, in both their cytotoxic and myotoxic effects. The basis for this inhibition appears to be the rapid formation of complexes between fucoidan and myotoxins, as evidenced by turbidimetric analysis. The possible binding site of fucoidan on the myotoxins was investigated using short synthetic peptides that represent the membrane-damaging region (residues 115-129) for three of these toxins. Fucoidan clearly inhibited the cytolytic activity of the peptides, indicating its ability to interact with the C-terminal myotoxic region of these phospholipases A(2). Fucoidan significantly inhibited muscle damage in mice, when administered locally, immediately after experimental envenomation with crude venom from B. asper. These results encourage further studies of sulfated fucans as compounds of potential use to improve the treatment of envenomations by crotaline snakes.


Utilizing a Structural Mechanics Approach to Assess the Primary Effects of Injury Loads Onto the Axon and Its Components.
Diffuse axonal injury (DAI) occurs as a result of the transmission of rapid dynamic loads from the head to the brain and specifically to its neurons. Despite being one of the most common and most deleterious types of traumatic brain injury (TBI), the inherent cell injury mechanism is yet to be understood. Experimental observations have led to the formulation of different hypotheses, such as mechanoporation of the axolemma and microtubules (MTs) breakage. With the goal of singling out the mechanical aspect of DAI and to resolve the ambiguity behind its injury mechanism, a composite finite element (FE) model of a representative volume of an axon was developed. Once calibrated and validated against published experimental data, the axonal model was used to simulate injury scenarios. The resulting strain distributions along its components were then studied in dependence of strain rate and of typical modeling choices such as the applied MT constraints and tau proteins failure. Results show that oversimplifying the MT bundle kinematic entails a systematic attenuation (cf = 2.33) of the computed maximum MT strain. Nevertheless, altogether, results support the hypothesis of axolemma mechanoporation as a cell-injury trigger. Moreover, for the first time the interconnection between the axolemma and the MT bundle is shown to play a role in damage localization. The proposed FE axonal model is a valuable tool to understand the axonal injury mechanism from a mechanical perspective and could be used in turn for the definition of well-informed injury criteria at the tissue and organ level.


[Interaction of the endo- and exocrine pancreas].
The pancreas has both exocrine and endocrine components. The exocrine component of the pancreas manufactures, stores, and packages digestive enzymes for digestion of food, whereas the endocrine secretes hormones that regulate the metabolism and utilization of the absorbed nutrient components. Both components are closely related, not only anatomically but also functionally. The available evidence to support the concept of a close interrelationship of endocrine and exocrine pancreatic function is summarized. It is shown that the endocrine part exerts a profound effect upon the digestive activities of the organ, and that impairment of endocrine function, such as diabetes, severely affects the exocrine component of the gland. Furthermore, dysfunction of the exocrine gland, as in chronic pancreatitis, progressively disturbs the function of the islet cell hormones. The interactions are governed by a complicated control system, the details of which are not yet clarified. As in any partnership, dysfunction of one partner severely affects the other and vice versa.


Satisfaction with facial appearance and its determinants in adults with severe congenital facial disfigurement: a case-referent study.
Patients with severe congenital facial disfigurement have a long track record of operations and hospital visits by the time they are 18 years old. The fact that their facial deformity is congenital may have an impact on how satisfied these patients are with their appearance. This study evaluated the level of satisfaction with facial appearance of congenital and of acquired facially disfigured adults, and explored demographic, physical and psychological determinants of this satisfaction. Differences compared with non-disfigured adults were examined. Fifty-nine adults with a rare facial cleft, 59 adults with a facial deformity traumatically acquired in adulthood, and a reference group of 201 non-disfigured adults completed standardised demographic, physical and psychological questionnaires. The congenital and acquired groups did not differ significantly in the level of satisfaction with facial appearance, but both were significantly less satisfied than the reference group. In facially disfigured adults, level of education, number of affected facial parts and facial function were determinants of the level of satisfaction. High fear of negative appearance evaluation by others (FNAE) and low self-esteem (SE) were strong psychological determinants. Although FNAE was higher in both patient groups, SE was similar in all three groups. Satisfaction with facial appearance of individuals with a congenital or acquired facial deformity is similar and will seldom reach the level of satisfaction of non-disfigured persons. A combination of surgical correction (with attention for facial profile and restoring facial functions) and psychological help (to increase SE and lower FNAE) may improve patient satisfaction.


Total circular hemorrhoidectomy.
For the surgical treatment of hemorrhoids, the Whitehead-operation is considered bad because it leads to complications like anal stenosis, incontinence and mucous ectropion or prolapsus. Modifications suggested by A. Toupet help to avoid these inconveniencies. But it still requires excellent understanding and training in ano-rectal surgery. The Whitehead-operation, modified by A. Toupet, is indicated in the following cases total hemorrhoidal prolapsus, especially with thrombosis and mucous prolapsus.


Host range mutants of human rhinovirus in which nonstructural proteins are altered.
Human rhinovirus type 2 did not replicate in nonpermissive mouse cells; the restriction was not in adsorption but in the early events of virus replication. Mutants which had been adapted to grow in mouse cells had the following characteristics: (i) no change in the structural protein, (ii) a larger nonstructural protein and its precursor protein, and (iii) an altered viral RNA synthesis. The altered nonstructural proteins correlated with a change in host range of the virus and may be involved in viral RNA synthesis.


Syngeneic Mouse Model of Glioblastoma: Intracranial Implantation of GL261 Cells.
Glioblastoma (GBM) is the most aggressive and prevalent primary brain malignancy in adults. Current treatments provide limited benefit, and thus, the median overall survival of GBM patients is only 15 months. GBM progression is highly dependent on its ability to evade immune response, so understanding the mechanisms behind GBM-driven immunosuppression seems crucial for designing more efficient therapies. Animal models of GBM constitute a convenient tool in glioma research, and several different approaches have been already developed to model this disease in vivo, including genetic and xenograft models. Here, we describe a murine syngeneic model of glioma which recapitulates many of the key features of human disease, including complex tumor microenvironment. We present an optimized protocol for stereotactic intracranial implantation of GL261 cells into C57BL/6 mice which results in tumor growth in the striatum. This model has been widely used to get insight into glioma biology, as well as in the studies aiming at the development and validation of new therapeutic approaches.


Multi-ethnic transcriptome-wide association study of prostate cancer.
The genetic risk for prostate cancer has been governed by a few rare variants with high penetrance and over 150 commonly occurring variants with lower impact on risk; however, most of these variants have been identified in studies containing exclusively European individuals. People of non-European ancestries make up less than 15% of prostate cancer GWAS subjects. Across the globe, incidence of prostate cancer varies with population due to environmental and genetic factors. The discrepancy between disease incidence and representation in genetics highlights the need for more studies of the genetic risk for prostate cancer across diverse populations. To better understand the genetic risk for prostate cancer across diverse populations, we performed PrediXcan and GWAS in a case-control study of 4,769 self-identified African American (2,463 cases and 2,306 controls), 2,199 Japanese American (1,106 cases and 1,093 controls), and 2,147 Latin American (1,081 cases and 1,066 controls) individuals from the Multiethnic Genome-wide Scan of Prostate Cancer. We used prediction models from 46 tissues in GTEx version 8 and five models from monocyte transcriptomes in the Multi-Ethnic Study of Atherosclerosis. Across the three populations, we predicted 19 gene-tissue pairs, including five unique genes, to be significantly (lfsr < 0.05) associated with prostate cancer. One of these genes, NKX3-1, replicated in a larger European study. At the SNP level, 110 SNPs met genome-wide significance in the African American study while 123 SNPs met significance in the Japanese American study. Fine mapping revealed three significant independent loci in the African American study and two significant independent loci in the Japanese American study. These identified loci confirm findings from previous GWAS of prostate cancer in diverse populations while PrediXcan-identified genes suggest potential new directions for prostate cancer research in populations across the globe.


Meaning-based guidance of attention in scenes as revealed by meaning maps.
Real-world scenes comprise a blooming, buzzing confusion of information. To manage this complexity, visual attention is guided to important scene regions in real time 1-7 . What factors guide attention within scenes? A leading theoretical position suggests that visual salience based on semantically uninterpreted image features plays the critical causal role in attentional guidance, with knowledge and meaning playing a secondary or modulatory role 8-11 . Here we propose instead that meaning plays the dominant role in guiding human attention through scenes. To test this proposal, we developed 'meaning maps' that represent the semantic richness of scene regions in a format that can be directly compared to image salience. We then contrasted the degree to which the spatial distributions of meaning and salience predict viewers' overt attention within scenes. The results showed that both meaning and salience predicted the distribution of attention, but that when the relationship between meaning and salience was controlled, only meaning accounted for unique variance in attention. This pattern of results was apparent from the very earliest time-point in scene viewing. We conclude that meaning is the driving force guiding attention through real-world scenes.


HLA-C and HLA-E reduce antibody-dependent natural killer cell-mediated cytotoxicity of HIV-infected primary T cell blasts.
To determine whether the presence of HLA-C and HLA-E on HIV-infected cells modulates autologous natural killer (NK) cells from implementing antibody-dependent cell-mediated cytotoxicity (ADCC) of HIV-infected cells. The capability of HLA-C and HLA-E to control NK cell killing of HIV-infected autologous T cells coated with anti-gp120 monoclonal antibody was determined by blocking the interaction between the inhibitory receptors on NK cells and the MHC class I molecules on infected cells. Phytohemagglutinin-treated CD4 T cells were infected in vitro with HIV-1. Infected cells were separated from uninfected cells by removal of CD4 T cells. Infected cells were labeled with chromium-51, treated with a cocktail of four different monoclonal antibodies against HIV gp120, and co-cultured with freshly isolated autologous NK cells that were incubated with or without anti-CD159a, anti-CD158a, and CD158b, or all three antibodies combined. Killing of the HIV-infected cells by NK cells was assessed in a 4 h cytotoxic assay. When the interaction between NK cell inhibitory receptors (i.e., CD158a, CD158b, and CD159a) and MHC class I molecules (i.e., HLA-C and HLA-E) on HIV-infected autologous T cells was blocked, a drastic increase in killing of anti-gp120-coated HIV-infected cells by NK cells was observed. These studies indicate that the presence of HLA-C and HLA-E molecules on HIV-infected cells may facilitate evasion of NK-mediated killing of antibody-coated HIV-infected cells.


The SUMO isopeptidase Ulp2p is required to prevent recombination-induced chromosome segregation lethality following DNA replication stress.
SUMO conjugation is a key regulator of the cellular response to DNA replication stress, acting in part to control recombination at stalled DNA replication forks. Here we examine recombination-related phenotypes in yeast mutants defective for the SUMO de-conjugating/chain-editing enzyme Ulp2p. We find that spontaneous recombination is elevated in ulp2 strains and that recombination DNA repair is essential for ulp2 survival. In contrast to other SUMO pathway mutants, however, the frequency of spontaneous chromosome rearrangements is markedly reduced in ulp2 strains, and some types of rearrangements arising through recombination can apparently not be tolerated. In investigating the basis for this, we find DNA repair foci do not disassemble in ulp2 cells during recovery from the replication fork-blocking drug methyl methanesulfonate (MMS), corresponding with an accumulation of X-shaped recombination intermediates. ulp2 cells satisfy the DNA damage checkpoint during MMS recovery and commit to chromosome segregation with similar kinetics to wild-type cells. However, sister chromatids fail to disjoin, resulting in abortive chromosome segregation and cell lethality. This chromosome segregation defect can be rescued by overproducing the anti-recombinase Srs2p, indicating that recombination plays an underlying causal role in blocking chromatid separation. Overall, our results are consistent with a role for Ulp2p in preventing the formation of DNA lesions that must be repaired through recombination. At the same time, Ulp2p is also required to either suppress or resolve recombination-induced attachments between sister chromatids. These opposing defects may synergize to greatly increase the toxicity of DNA replication stress.


Common and ethnic-specific genetic determinants of hemoglobin concentration between Taiwanese Han Chinese and European Whites: findings from comparative two-stage genome-wide association studies.
Human iron nutrition is a result of interplays between genetic and environmental factors. However, there has been scarcity of data on the genetic variants associated with altered iron homeostasis and ethnic-specific associations are further lacking. In this study, we compared between the Taiwanese Han Chinese (HC) and European Whites the genetic determinants of hemoglobin (Hb) concentration, a biochemical parameter that in part reflects the amount of functional iron in the body. Through sex-specific two-stage genome-wide association studies (2S-GWAS), we observed the consistent Hb-association of SNPs in TMPRSS6 (chr 22), ABO (chr 9), and PRKCE (chr 2) across sexes in both ethnic groups. Specific to the Taiwanese HC, the Hb-association of AXIN1, together with other loci near the chr 16 alpha-globin gene cluster, was found novel. On the other hand, majority of the Hb-associated SNPs among Europeans were identified along the chr 6 major histocompatibility complex (MHC) region, which has established roles in immune system control. We report here strong Hb-associations of HFE and members of gene families (SLC17; H2A, H2B, H3, H4, H1; TRIM; ZSCAN, ZKSCAN, ZNF; HLA; BTN, OR), numerous SNPs in/nearby CARMIL1, PRRC2A, PSORS1C1, NOTCH4, TSBP1, C6orf15, and distinct associations with non-coding RNA genes. Our findings provide evidence for both common and ethnic-specific genetic determinants of Hb between East Asians and Caucasians. These will help to further our understanding of the iron and/or erythropoiesis physiology in humans and to identify high risk subgroups for iron imbalances - a primary requirement to meet the goal of precision nutrition for optimal health.


107 Gb/s coherent optical OFDM transmission over 1000-km SSMF fiber using orthogonal band multiplexing.
Coherent optical OFDM (CO-OFDM) has emerged as an attractive modulation format for the forthcoming 100 Gb/s Ethernet. However, even the spectral-efficient implementation of CO-OFDM requires digital-to-analog converters (DAC) and analog-to-digital converters (ADC) to operate at the bandwidth which may not be available today or may not be cost-effective. In order to resolve the electronic bandwidth bottleneck associated with DAC/ADC devices, we propose and elucidate the principle of orthogonal-band-multiplexed OFDM (OBM-OFDM) to subdivide the entire OFDM spectrum into multiple orthogonal bands. With this scheme, the DAC/ADCs do not need to operate at extremely high sampling rate. The corresponding mapping to the mixed-signal integrated circuit (IC) design is also revealed. Additionally, we show the proof-of-concept transmission experiment through optical realization of OBM-OFDM. To the best of our knowledge, we present the first experimental demonstration of 107 Gb/s QPSK-encoded CO-OFDM signal transmission over 1000 km standard-single- mode-fiber (SSMF) without optical dispersion compensation and without Raman amplification. The demonstrated system employs 2x2 MIMO-OFDM signal processing and achieves high electrical spectral efficiency with direct-conversion at both transmitter and receiver.


International moves to strengthen food policies.
The present paper considers the need to move from a 'health education' approach to dietary health to an approach that focuses on food and nutrition policies at the population level, and especially those policies that avoid widening the inequalities in health between different socio-economic groups and those policies that promote healthy diets among children. Recent moves at the international level include measures to protect children from promotional marketing of fatty and sugary foods and the funding of free fruit for schoolchildren. By improving child health, improvements can be expected in the health of future generations.


Identification and characterization of a novel microtubule-based motor associated with membranous organelles in tobacco pollen tubes.
Pollen tube growth depends on the differential distribution of organelles and vesicles along the tube. The role of microtubules in organelle movement is uncertain, mainly because information at the molecular level is limited. In an effort to understand the molecular basis of microtubule-based movement, we isolated from tobacco pollen tubes polypeptides that cosediment with microtubules in an ATP-dependent manner. Major polypeptides released from microtubules by ATP (ATP-MAPs) had molecular masses of 90, 80, and 41 kD. Several findings indicate that the 90-kD ATP-MAP is a kinesin-related motor: binding of the polypeptide to microtubules was enhanced by the nonhydrolyzable ATP analog AMP-PNP; the 90-kD polypeptide reacted specifically with a peptide antibody directed against a highly conserved region in the motor domain of the kinesin superfamily; purified 90-kD ATP-MAP induced microtubules to glide in motility assays in vitro; and the 90-kD ATP-MAP cofractionated with microtubule-activated ATPase activity. Immunolocalization studies indicated that the 90-kD ATP-MAP binds to organelles associated with microtubules in the cortical region of the pollen tube. These findings suggest that the 90-kD ATP-MAP is a kinesin-related microtubule motor that moves organelles in the cortex of growing pollen tubes.


Long-term adsorption kinetics of asphaltenes at the oil-water interface: a random sequential adsorption perspective.
Previous studies indicated that asphaltenes adsorbed as monomers on oil-water interfaces and the early stage kinetics of the process was controlled by diffusion and hence dependent on oil viscosity. By measuring interfacial tension (IFT) as a function of surface coverage during droplet expansions in pendant drop experiments, it was also concluded that the IFT data could be interpreted with a Langmuir equation of state (EoS), which was independent of oil viscosity, time of adsorption, and bulk asphaltenes concentration. The surface excess coverage was calculated to be ∼0.3 nm(2)/molecule, which suggested adsorption in face-on configuration of asphaltenes monomers at the interface and average PAH core per molecule of about 6 for the asphaltenes investigated, consistent with the Yen-Mullins model. The current study focuses on the kinetics of asphaltenes adsorption at longer times and higher interfacial coverage. Long-term IFT data have been measured by the pendant drop method for different asphaltenes concentrations and for different bulk viscosities of the oil phase (0.5-28 cP). The data indicate that when coverage reaches 35-40%, the adsorption rates slow down considerably compared to the diffusion-controlled rates at the very early stages. The surface pressure increase rate (or IFT decrease rate) at these higher coverages is now independent of oil viscosity but dependent upon both surface pressure itself and asphaltene monomer concentration. The long-term asymptotic behavior of surface coverage is found to be consistent with the predictions from surface diffusion-mediated random sequential adsorption (RSA) theory which indicates a linear dependency of surface coverage on 1/√t and an asymptotic limit very close to 2D random close packing of polydispersed disks (85%). From these observations RSA theory parameters were extracted that enabled description of adsorption kinetics for the range of conditions above surface coverage of 35%.


Guilt, shame and their associations with chronic diseases in Czech adults.
The interest in the association between feelings of guilt and shame and psychological health is growing. However, less attention so far has been paid to the associations with chronic disease. Therefore, the aim of this study was to explore whether feelings of guilt and shame are related to physical health in chronic disease and in selected ones. A nationally representative sample of Czech adults (n = 1000, age = 46.0 ± 17.3 years, 48.6% men) participated in the survey. Feelings of guilt and shame (items from The Positive and Negative Affect Schedule) and health problems in selected chronic diseases were measured. Respondents with higher feelings of guilt - but not of shame - were more likely to suffer from a chronic disease; we found this in arthritis, back pain, cardiovascular disease, asthma, cancer and depression or anxiety. The association was strongest in the case of cancer with odds ratios (OR) 5.83 (95% confidence interval (CI) 2.27-16.69). There were no significant associations in case of diabetes and stroke. Feelings of shame were not related to chronic diseases. Our findings suggest that feelings of guilt are associated with worse physical health. Further research is needed in this area.


Preparation and Characterization of Self-Healing Polyurethane Powder Coating Using Diels-Alder Reaction.
Although powder coating systems offer many environmental, ecological and energy related benefits over liquid based coatings, in the case of uretdione based polyurethane systems, high curing temperature is still an issue. On the other hand, powder coating systems make it possible to reduce the costs and enhance the process of forming complex 3D structures using the deep drawing method by pre-coated metal substrates. During this processing method, there is a probability of micro crack formation in the coated film due to strain impact on the coating layer. A powder coating with self-healing ability is an ultimate solution to face not only this kind of fraction but also any other possible ones (such as defects caused by any impact on film surface during processing, transporting or even service). Here, a single molecule that is prepared via Diels-Alder cycloaddition reaction and retro Diels-Alder cleavage reaction was utilized as a self-healing additive to achieve self-healing ability in the powder coating system that is based on a commercially available uretdione cross-linker and OH-polyester resin. Coatings were prepared through melt mixing of components in a lab mixer, milling, sieving, and then application on the metal substrate through the electrostatic spraying method. To illustrate the role of self-healing additive, various concentrations (4 and 9% wt.) in combination with different curing temperatures (80 °C to 200 °C) were investigated. Both samples containing HA showed self-healing ability at elevated temperature around 120 °C for about 30 min with acceptable roughness and surface properties. Hardness measurement of cured film as well as thermal investigation indicate the chemical reaction of HA in a cross-linked network of cross-linker and resin. In addition, using HA leads to a 40 K drop in curing temperature of the system without using any catalyst. A 2.58% improvement in hardness values at a lower curing temperature and healing time of around 12.5 min at 120 °C to recover 100% of initial scratch (more than 10 cycles) in the sample containing 9% wt. HA was observed.


Animal models of chronic obstructive pulmonary disease.
The mechanisms involved in the genesis of chronic obstructive pulmonary disease (COPD) are poorly defined. This area is complicated and difficult to model because COPD consists of four separate anatomic lesions (emphysema, small airway remodeling, pulmonary hypertension, and chronic bronchitis) and a functional lesion, acute exacerbation; moreover, the disease in humans develops over decades. This review discusses the various animal models that have been used to attempt to recreate human COPD and the advantages and disadvantages of each. None of the models reproduces the exact changes seen in humans, but cigarette smoke-induced disease appears to come the closest, and genetically modified animals also, in some instances, shed light on processes that appear to play a role.


Simulated sunlight inactivation of norovirus and FRNA bacteriophage in seawater.
To investigate norovirus (NoV) and F-specific RNA (FRNA) bacteriophage inactivation in seawater under simulated sunlight and temperature conditions representative of summer (235 W m(-2) ; 17°C) and winter (56 W m(-2) ; 10°C) conditions in Ireland. Inactivation experiments were carried out using a collimated beam of simulated sunlight and 100 ml of filtered seawater seeded with virus under controlled temperature conditions. NoV concentrations were determined using RT-qPCR, and FRNA bacteriophage concentrations were determined using RT-qPCR and by plaque assay. For all virus types, the fluence required to achieve a 90% reduction in detectable viruses (S90 value) using RT-qPCR was not significantly different between summer and winter conditions. S90 values for FRNA bacteriophage determined by plaque assay were significantly less than those determined by RT-qPCR. Unlike S90 values determined by RT-qPCR, a significant difference existed between summer and winter S90 values for infectious FRNA bacteriophage. This study demonstrated that RT-qPCR significantly overestimates the survival of infectious virus and is therefore unsuitable for determining the inactivation rates of viruses in seawater. Results from this study provide initial data on the inactivation of NoV and FRNA bacteriophage in seawater under representative summer and winter conditions and will be of interest to shellfish and water management agencies alike.


Evidence That in Uncontrolled Diabetes, Hyperglucagonemia Is Required for Ketosis but Not for Increased Hepatic Glucose Production or Hyperglycemia.
Several lines of evidence implicate excess glucagon secretion in the elevated rates of hepatic glucose production (HGP), hyperglycemia, and ketosis characteristic of uncontrolled insulin-deficient diabetes (uDM), but whether hyperglucagonemia is required for hyperglycemia in this setting is unknown. To address this question, adult male Wistar rats received either streptozotocin (STZ) to induce uDM (STZ-DM) or vehicle and remained nondiabetic. Four days later, animals received daily subcutaneous injections of either the synthetic GLP-1 receptor agonist liraglutide in a dose-escalating regimen to reverse hyperglucagonemia or its vehicle for 10 days. As expected, plasma glucagon levels were elevated in STZ-DM rats, and although liraglutide treatment lowered glucagon levels to those of nondiabetic controls, it failed to attenuate diabetic hyperglycemia, elevated rates of glucose appearance (Ra), or increased hepatic gluconeogenic gene expression. In contrast, it markedly reduced levels of both plasma ketone bodies and hepatic expression of the rate-limiting enzyme involved in ketone body production. To independently confirm this finding, in a separate study, treatment of STZ-DM rats with a glucagon-neutralizing antibody was sufficient to potently lower plasma ketone bodies but failed to normalize elevated levels of either blood glucose or Ra. These data suggest that in rats with uDM, hyperglucagonemia is required for ketosis but not for increased HGP or hyperglycemia.


Regulation of phosphate metabolism in Neurospora crassa. Characterization of regulatory mutants.
A mutant of Neurospora crassa, called UW-6, differs from wild type in being partially constitutive for synthesis of a species of alkaline phosphatase, and also for a species of phosphate permease that has a high affinity for phosphate at high pH. UW-6 is possibly allelic with a mutant called nuc-2 that was previously isolated by Ishikawa. nuc-2 has the converse phenotype, in that it cannot be derepressed for either of these two activities. UW-6 is co-dominant with its wild-type allele in heterokaryons and in partial diploids. An unlinked mutant, nuc-1, is like nuc-2 in that it fails to make the alkaline phosphatase or the permease referred to above. nuc-1 is epistatic to UW-6 in the double mutant. The control of phosphorus metabolism is discussed, and is compared with some other control systems in filamentous fungi.


A model for glucose, insulin, and beta-cell dynamics in subjects with insulin resistance and patients with type 2 diabetes.
Type 2 diabetes mellitus (T2DM) is a progressive, metabolic disorder characterized by reduced insulin sensitivity and loss of beta-cell mass (BCM), resulting in hyperglycemia. Population pharmacokinetic-pharmacodynamic (PKPD) modeling is a valuable method to gain insight into disease and drug action. A semi-mechanistic PKPD model incorporating fasting plasma glucose (FPG), fasting insulin, insulin sensitivity, and BCM in patients at various disease stages was developed. Data from 3 clinical trials (phase II/III) with a peroxisome proliferator-activated receptor agonist, tesaglitazar, were used to develop the model. In this, a modeling framework proposed by Topp et al was expanded to incorporate the effects of treatment and impact of disease, as well as variability between subjects. The model accurately described FPG and fasting insulin data over time. The model included a strong relation between insulin clearance and insulin sensitivity, predicted 40% to 60% lower BCM in T2DM patients, and realistic improvements of BCM and insulin sensitivity with treatment. The treatment response on insulin sensitivity occurs within the first weeks, whereas the positive effects on BCM arise over several months. The semi-mechanistic PKPD model well described the heterogeneous populations, ranging from nondiabetic, insulin-resistant subjects to long-term treated T2DM patients. This model also allows incorporation of clinical-experimental studies and actual observations of BCM.


Retinal microvascular alterations related to diabetes assessed by optical coherence tomography angiography: A cross-sectional analysis.
Fluorescein angiography has been so far the gold-standard test to assess diabetic macular ischemia (DMI), a cause of irreversible visual impairment in diabetic patients. The aim of this study was to investigate foveal avascular zone (FAZ) and perifoveal microcirculation changes in eyes with nonproliferative diabetic retinopathy (NPDR) using optical coherence tomography angiography (OCTA), a new and noninvasive vascular imaging technique.Cross-sectional study including eyes of diabetic patients with NPDR.All patients underwent medical history, best-corrected visual acuity (BCVA) measurement, slit-lamp and fundus examination, multicolor imaging, SD-OCT, and swept-source OCT. OCTA was performed in order to assess macular superficial and deep capillary plexus, and swept-source OCT was performed to evaluate the central choroidal thickness.Fifty-eight eyes of 35 patients with a mean age of 61.8 years (±12.1) with mean HbA1C level of 7.6% (±1.5) were included in this study. Among them, 19 eyes had mild NPDR, 24 eyes had moderate NPDR, and 15 eyes had severe NPDR. There was a significant progression between NPDR stages for FAZ grade (P < 0.0001), surface (P = 0.0036) and perimeter (P = 0.0001), and for superficial capillary plexus nonperfusion index (NPI) (P = 0.0009). Moreover, a significant correlation was found between NPI and BCVA (P = 0.007).OCT angiography is a useful noninvasive tool to explore early phases of diabetic retinopathy, which are not routinely explore with fluorescein angiography and not precisely enough with color photographs. NPI and foveal avascular zone parameters are correlated with glycated hemoglobin in patients with NPDR. If confirmed by further studies, these results could represent a mean to sensibilize diabetic patients to their disease.


Hyperexcitability to electrical stimulation and accelerated muscle fatiguability of taut bands in rats.
Myofascial trigger points contribute significantly to musculoskeletal pain and motor dysfunction and may be associated with accelerated muscle fatiguability. The aim of this study was to investigate the electrically induced force and fatigue characteristics of muscle taut bands in rats. Muscle taut bands were dissected out and subjected to trains of electrical stimulation. The electrical threshold intensity for muscle contraction and maximum contraction force (MCF), electrical intensity dependent fatigue and electrical frequency dependent fatigue characteristics were assessed in three different sessions (n=10 each) and compared with non-taut bands in the biceps femoris muscle. The threshold intensity for muscle contraction and MCF at the 10th, 15th and 20th intensity dependent fatigue stimuli of taut bands were significantly lower than those of non-taut bands (all p<0.05). The MCF at the 15th and 20th intensity dependent fatigue stimuli of taut bands were significantly lower than those at the 1st and 5th stimuli (all p<0.01). The MCF in the frequency dependent fatigue test was significantly higher and the stimulus frequency that induced MCF was significantly lower for taut bands than for non-taut bands (both p<0.01). The present study demonstrates that the muscle taut band itself was more excitable to electrical stimulation and significantly less fatigue resistant than normal muscle fibres.


Healing of surgically created defects in the equine superficial digital flexor tendon: collagen-type transformation and tissue morphologic reorganization.
Full-thickness defects were surgically created in the superficial digital flexor tendons of the front limbs of 20 horses. Tissues formed within the defect were evaluated histologically, and the collagen composition of the tissue was determined by immunofluorescence. Transformation occurred from loose fibrillar areas of types I and III collagen and pericellular types IV and V collagen to dense bundles of type I collagen fibers. Loose fibrillar areas of types I and III collagen were present after 24 weeks. Histologically, in horses killed after 2 weeks, the tissue within the defect was a randomly oriented mass of fibrovascular tissue. In horses killed after 24 weeks the tissue within the defect resembled normal tendon tissue.