Phyto-oestrogens and cardiovascular disease risk.
To present the currently available evidence on the cardiovascular benefits and risks associated with phyto-oestrogens. DATA-SYNTHESIS: Medline search from 1966-1999 updated with cross-check of references of papers with keywords such as phyto-oestrogens, isoflavones, lignans, genistein, daidzein, enterolactone, enterodiol, cardiovascular disease, cardiovascular disease risk factors. Phyto-oestrogens are plant chemicals divided into three main classes: isoflavones, coumestans, and lignans that display oestrogen-like activity due to their ability to bind to the oestrogen receptor. They are found in grains, beans, green vegetables, fruits, nuts, and grasses. Isoflavones are primarily found in soybeans and soy foods. For epidemiological studies of the relation between phyto-oestrogen intake and disease parameters, intake is estimated with several measures, such as biomarkers (concentrations in urine or blood) or dietary questionnaires, though the optimal method is not yet clear. Phyto-oestrogens are considered to act as selective oestrogen receptor modulators (SERM), exerting both oestrogen agonist and antagonist action. Supplementation with isolated soy protein containing the isoflavones genistein and daidzein reduces serum total and LDL-cholesterol and triglycerides in animals and in humans. Vascular reactivity might be improved by supplementation with isolated soy protein or isoflavones isolated from red clover. Studies on atherosclerosis in animals indicate a potential for risk reduction. Evidence in humans is still scanty. The little we know of the effects of regular dietary phyto-oestrogen intake comes from studies in which phyto-oestrogens were added to the usual diet. Most supplementation studies have been conducted with soy isoflavones, whereas the importance of lignans has not been determined, though they could be more important sources than isoflavones in Western populations. Research has been focused on risk factors. Studies of clinically manifest endpoints are urgently needed.


Motivational support programme to enhance health and well-being and promote weight loss in overweight and obese adolescents: A randomized controlled trial in Turkey.
The aim of this study is to investigate the effect on health, well-being and weight loss of a motivational support programme provided for adolescents who were overweight and obese. This was a randomized controlled trial. Sixty-four adolescents (39 girls and 25 boys) who were overweight and obese and consulted at our polyclinic from January 2015 to February 2016 comprised the study population. The sociodemographic characteristics, well-being levels and physical parameters of the adolescents were evaluated. Routine follow-ups were practiced for both groups. The adolescents in the experimental group had motivational interviews and were sent reminder messages over a 6-month period, and education programmes were conducted with the parents. After 6 months, the body mass index values had decreased in the experimental group compared with baseline, with no decrease in the controls. Scores for the Paediatric Quality of Life total scale and physical health and psychosocial health subscale points were increased in experimental and control groups, but the quality of life scale points of the experimental group were higher than the control group. In the experimental group, aspartate aminotransferase, alanine aminotransferase, insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and total cholesterol were decreased. The motivational support programme affected the adolescents' health positively and can be recommended as a routine nursing intervention.


Analysis of Aflatoxin Biomarkers in the Hair of Experimental Animals.
Analysis of body fluids and tissues of aflatoxin exposed individuals for the presence of aflatoxins and aflatoxin metabolites has emerged as a reliable indicator of exposure and metabolism of aflatoxins. However, current aflatoxin biomarkers are not appropriate for investigating the long-term effects of aflatoxin exposure. In this explorative study, we investigated the analysis of hair as a complementary or alternative matrix for the assessment of biomarkers of long-term aflatoxin exposure. Three groups of guinea pigs were orally dosed with 5 ugkg-1bw-1, 50 ugkg-1bw-1, and 100 ugkg-1bw-1 of AFB1. Urine and hair samples were collected on days 0, 1, 2, 3, 7, 30, 60, and 90 and analysed for AFB1 and AFM1 using UHPLC-MS/MS. AFB1 and AFM1 were detected in 75% and 13.6%, respectively, of the day 1 to day 7 urine samples. AFB1 was detected in hair samples collected from day 3 up to day 60. This is the first report to confirm the deposition of AFB1 in the hair of experimental animals. These findings indicate that hair analysis has the potential to provide an accurate long-term historical record of aflatoxin exposure with potentially important implications for the field of aflatoxin biomarkers.


An intense and unforgettable experience: the lived experience of malignant wounds from the perspectives of patients, caregivers and nurses.
Malignant wounds occur infrequently, but are typically described as devastating and overwhelming. However, there has been little formalised research, and the vast majority of existing malignant wound literature comprises reports of health care professionals from their management of the physical symptoms. Few studies have investigated the lived experience from the perspectives of patients and nurses and none have investigated the experiences of lay caregivers caring for a patient with a malignant wound. As a result, there has been little mention in existing literature of the non physical issues associated with malignant wounds or how they might be addressed. The purpose of this study was to address this gap in knowledge by investigating the lived experience of malignant wounds from the perspectives of those living it. In-depth interviews were conducted with patients, caregivers and nurses. The data were analysed thematically within a hermeneutic phenomenological methodology to show four themes: (i) malodour; (ii) new mode of being-in-the-world; (iii) still room for hope and (iv) enduring memories. Although this study confirmed previous findings that malodour was one of the worst aspects of malignant wounds, it was significant that the other three themes occurred in the previously largely overlooked psychosocial domain.


Inhibition of pancreatic carcinogenesis by retinoids in azaserine-treated rats.
Chemoprevention by retinoids of the progression of carcinomas induced in rats by azaserine was evaluated. Wistar/Lewis rats were given 15 weekly injections of azaserine, 10 mg/kg, while fed a chow diet; after the completion of carcinogen treatment, they were fed a chow diet supplemented with four different retinoids at the level of 0.5 to 2 mmol/kg diet for 1 year. The incidence of neoplasms was determined by autopsy and histological study. The incidence of pancreatic carcinoma among a male positive control group (azaserine treated, but not retinoid treated) was 42%. The incidence of pancreatic carcinoma among male rats treated with retinoids was: N-2-hydroxyethylretinamide, 6%; N-4-propionyloxyphenylretinamide, 17%; and retinylidene dimedone, 12%. The incidence in rats fed these three retinoids was significantly (p less than 0.05) below the control group incidence. Thus, these three retinoids appeared to be effective in inhibiting the progression of pancreatic carcinomas in the azaserine-induced model. A similar trend was demonstrated in females, but statistical significance was shown only in rats fed N-2-hydroxyethylretinamide. A fourth retinoid, N-4-carboxyphenylretinamide, was more toxic and less effective in chemoprevention. Since retinoids were fed after exposure to carcinogen, the effect was exerted during the postinitiation phase of carcinogenesis. The ratio of invasive pancreatic carcinomas to localized carcinomas (carcinoma in situ) was clearly higher among non-retinoid-treated rats than among those treated with retinoids. This is consistent with retarded progression in the retinoid-treated groups.


Influence of car seat firmness on seat pressure profiles and perceived discomfort during prolonged simulated driving.
During a driving task, the seat-driver interface is particularly influenced by the external environment and seat features. This study compares the effect of two different seats (S1 - soft & S2 - firm) and the effect of visual simulation of different road types (city, highway, mountain, country), on pressure distribution and perceived discomfort during prolonged driving. Twenty participants drove two 3-h sessions (one per seat) on a static simulator. Contact Pressure (CP), Contact Surface (CS), and Seat Pressure Distribution Percentage (SPD%) were analyzed throughout, using two pressure mats positioned on seat cushion and backrest. Whole-body and local discomfort for each body part were rated every 20 min. The softer seat, S1, induced a greater contact surface on cushion and backrest and a lower SPD%, reflecting better pressure distribution. Pressure profiles were asymmetrical for both S1 and S2, with higher CP under left buttock (LBu) and right lower back (RLb) and greater CS under thighs and RLb. Pressure distribution was less homogeneous on mountain and city roads than on monotonous roads (highway and country). Despite the pressure differences between the seats, however, both led to similar increases in perceived whole-body discomfort throughout the driving session. Moreover, the highest discomfort scores were in the neck and the lower back areas, whatever the seat. These findings on pressure variables may have implications for the design of backrests and cushions to ensure more homogeneous pressure distribution, even though this is not shown to minimize perceived driver discomfort.


The course of pregnancy and childbirth in three mothers with recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is an autosomal recessive skin disease caused by mutations in the type VII collagen gene (COL7A1), resulting in detachment of the entire epidermis due to loss or hypoplasticity of the anchoring fibrils that normally secure the basement membrane to the underlying dermis. Trauma-induced blistering is often complicated by chronic erosions and scarring. From that perspective, pregnancy in RDEB might be considered an indication for elective caesarean section in a bid to minimize perineal blistering. To date, only four cases of pregnancy and delivery in patients with RDEB have been reported. We report three more women, each with RDEB-generalized other (RDEB-GO), all of whom had successful vaginal deliveries without major cutaneous or mucosal complications. One woman also had a second child, by vaginal delivery, indicating a lack of vaginal stenosis after the first birth. These cases show that RDEB-GO is not an absolute primary indication for elective caesarean section and that, perhaps surprisingly, genital/perineal blistering and scarring are not inevitable consequences of childbirth. Moreover, breastfeeding is also feasible in women with RDEB-GO.


Food insecurity is associated with chronic pain and high-impact chronic pain in the United States.
This study evaluated whether food insecurity (U.S. Adult Food Security Survey) was associated with chronic pain (≥3 months) and high-impact chronic pain (i.e., pain that limits work and life) among United States (U.S.) adults. Cross-sectional analysis. Nationally representative sample of non-institutionalized adults in the United States. 79,686 adults from the National Health Interview Survey (2019-2021). Marginal, low, and very low food security were associated with increased prevalence odds of chronic pain (OR: 1.58 [95% CI: 1.44, 1.72], 2.28 [95% CI: 2.06, 2.52], and 3.37 [95% CI: 3.01, 3.78], respectively) and high-impact chronic pain (OR: 1.28 [95% CI: 1.14, 1.42], 1.55 [95% CI: 1.37, 1.75], and 1.90 [95% CI: 1.65, 2.18], respectively) in a dose-response fashion (p-trend<0.0001 for both), adjusted for sociodemographic, socioeconomic, and clinically relevant factors. Participation in Supplemental Nutrition Assistance Program (SNAP) and age modified the association between food insecurity and chronic pain. These findings illustrate the impact of socioeconomic factors on chronic pain and suggest that food insecurity may be a social determinant of chronic pain. Further research is needed to better understand the complex relationship between food insecurity and chronic pain and to identify targets for interventions. Moreover, the consideration of food insecurity in the clinical assessment of pain and pain-related conditions among socioeconomically disadvantaged adults may be warranted.


Genomic Epidemiology and Strain Taxonomy of Corynebacterium diphtheriae.
Corynebacterium diphtheriae is highly transmissible and can cause large diphtheria outbreaks where vaccination coverage is insufficient. Sporadic cases or small clusters are observed in high-vaccination settings. The phylogeography and short timescale evolution of C. diphtheriae are not well understood, in part due to a lack of harmonized analytical approaches of genomic surveillance and strain tracking. We combined 1,305 genes with highly reproducible allele calls into a core genome multilocus sequence typing (cgMLST) scheme. We analyzed cgMLST gene diversity among 602 isolates from sporadic clinical cases, small clusters, or large outbreaks. We defined sublineages based on the phylogenetic structure within C. diphtheriae and strains based on the highest number of cgMLST mismatches within documented outbreaks. We performed time-scaled phylogenetic analyses of major sublineages. The cgMLST scheme showed high allele call rate in C. diphtheriae and the closely related species C. belfantii and C. rouxii. We demonstrate its utility to delineate epidemiological case clusters and outbreaks using a 25 mismatches threshold and reveal a number of cryptic transmission chains, most of which are geographically restricted to one or a few adjacent countries. Subcultures of the vaccine strain PW8 differed by up to 20 cgMLST mismatches. Phylogenetic analyses revealed a short-timescale evolutionary gain or loss of the diphtheria toxin and biovar-associated genes. We devised a genomic taxonomy of strains and deeper sublineages (defined using a 500-cgMLST-mismatch threshold), currently comprising 151 sublineages, only a few of which are geographically widespread based on current sampling. The cgMLST genotyping tool and nomenclature was made publicly accessible (https://bigsdb.pasteur.fr/diphtheria). Standardized genome-scale strain genotyping will help tracing transmission and geographic spread of C. diphtheriae. The unified genomic taxonomy of C. diphtheriae strains provides a common language for studies of ecology, evolution, and virulence heterogeneity among C. diphtheriae sublineages.


Serum alkaline phosphatase and the risk of coronary heart disease, stroke and all-cause mortality: Tehran Lipid and Glucose Study.
To investigate the association of alkaline phosphatase (ALP) levels with the risk of the composite end point of cardiovascular disease (CVD), and all-cause mortality as well as each of them separately. Prospective cohort study. Within the framework of the Tehran Lipid and Glucose Study (TLGS) cohort, participants were followed from baseline examination (1999-2001) until March 2014. A total of 2578 participants, aged ≥30 years free of prevalent CVD at baseline examination. The main outcome measures were composite end point of coronary heart disease (CHD), stroke, all-cause mortality and each per se. During a median follow-up of 11.3 years, 369, 68, 420, 170 and 495 participants experienced CHD, stroke, CVD, all-cause mortality and the composite outcome, respectively. In the multivariable Cox regression models, the adjusted HRs (95% CI) for mentioned events per one SD increase in ALP level after full adjustment were 1.11 (1.01 to 1.22), 1.20 (0.97 to 1.49, p=0.058), 1.10 (1.01 to 1.21), 1.16 (1.01 to 1.33) and 1.11 (1.02 to 1.21), respectively. Furthermore, participants with ALP levels in the highest tertile had significant adjusted HRs (95% CI) for stroke (1.88 (1.00 to 3.61)), CVD (1.30 (1.01 to 1.68)) and composite outcome (1.27 (1.00 to 1.61)). The cut-off value of ALP ≥199 IU/L for predicting composite outcome was derived using Youden's index, based on which this cut-off point was associated with significant risk of 80%, 26%, 43% and 26% for incident stroke, CVD, all-cause mortality and composite outcome. Additionally, no improvement was seen in the predictive ability of traditional risk factors models after adding ALP values, considering the levels of Akaike information criterion, C-index and Net Reclassification Index. Independent associations between ALP levels and the risks of CVD and mortality events were shown, despite the fact that adding the data of ALP to known risk factors did not improve the prediction of these events.


IgG4-related Lung Pseudotumor and Pleural Inflammation with Autoimmune Hepatitis.
A 63-year-old man was admitted to our department following a secondary medical examination. Blood tests showed high levels of liver enzymes, IgG, IgG4, and antinuclear antibody. Computed tomography showed tumors in the bilateral lower lobes of the lungs and pleural thickening. After pleural and liver biopsy procedures, he was conclusively diagnosed with IgG4-related lung pseudotumor and pleural inflammation with autoimmune hepatitis. We started treatment with prednisolone 40 mg/day, and chest radiograph and blood tests showed signs of improvement. This was a rare case that suggested an association between IgG4-related disease and autoimmune hepatitis.


The retinoic-like juvenile hormone controls the looping of left-right asymmetric organs in Drosophila.
In vertebrate development, the establishment of left-right asymmetry is essential for sidedness and the directional looping of organs like the heart. Both the nodal pathway and retinoic acid play major and conserved regulatory roles in these processes. We carried out a novel screen in Drosophila to identify mutants that specifically affect the looping of left-right asymmetric organs. We report the isolation of spin, a novel mutant in which the looping of the genitalia and spermiduct are incomplete; under-rotation of the genitalia indicates that spin controls looping morphogenesis but not direction, thus uncoupling left-right asymmetry and looping morphogenesis. spin is a novel, rotation-specific allele of the fasciclin2 (Fas2) gene, which encodes a cell-adhesion protein involved in several aspects of neurogenesis. In spin mutants, the synapses connecting specific neurosecretory cells to the corpora allata are affected. The corpus allatum is part of the ring gland and is involved in the control of juvenile hormone titers during development. Our genetic and pharmacological results indicate that Fas2(spin) rotation defects are linked to an abnormal endocrine function and an elevated level of juvenile hormone. As juvenile hormone is an insect sesquiterpenoid related to retinoic acid, these results establish a new genetic model for studying organ looping and demonstrate an evolutionarily conserved role for terpenoids in this process.


Basilar membrane velocity noise.
Basilar membrane (BM) noise, measured as a velocity signal under the quiet acoustic condition, was investigated in the guinea pig. The cochleas of anesthetized young healthy guinea pigs were surgically exposed and a hole was made on the lateral wall of the scala tympani of the first cochlear turn for visualization of the BM and measurement of the BM velocity with a laser interferometer. The amplitude and frequency of the BM velocity noise were analyzed by a spectrum analyzer under different conditions. The spectrum of the BM velocity noise was a band limited function with a peak velocity at the topographic best frequency of the measured location on the BM. The peak velocity ranged to about 8 microm/s and depended on the physiological condition of the cochlea. Saline blockage of the external auditory canal or the middle ear did not change the BM noise. BM noise was much smaller, or was not evident, when the cochlear sensitivity decreased. The suppression tuning curve of the BM velocity noise indicates that the maximum suppression caused by an acoustic pure tone occurred at the best frequency location. A low sound level wide band acoustic noise given to the external ear canal produced a spectrum function having the same frequency and amplitude response as the BM noise. Electrical stimulation of the crossed olivocochlear bundle significantly depresses the BM velocity noise. These data demonstrate that the BM noise is a representation of internal rather than external noise. The amplitude and frequency of the BM noise reflect the usual cochlear sensitivity and frequency selectivity. Since the organ of Corti in the sensitive cochlea is a highly sensitive and tuned mechanical system, the internal (to the animal) noise responsible for the BM noise may originate from mechanical vibrations remote from the cochlea and propagated to the ear, or may be caused by Brownian motion of cellular structures in the cochlea.


Savings of loss-of-life expectancy and lifetime medical costs from prevention of spinal cord injuries: analysis of nationwide data followed for 17 years.
The objectives of this research were to determine the savings of loss-of-life expectancy (LE) and lifetime medical costs (LMC) from prevention of spinal cord injuries (SCI) in Taiwan. From the claims database of Taiwan National Health Insurance, we identified 6164 adult patients with newly diagnosed SCI with permanent functional disability from 2000 to 2015 and followed them until the end of 2016. We estimated survival function through the Kaplan-Meier method and extrapolated it to lifetime. For the SCI cohort, the LE and loss-of-LE were 17.6 and 13.3 years, respectively, while those for SCI with coding of external causes (E-code) were 18.1 and 13.0 years, respectively. For the SCI cohort with E-code, the loss-of-LE of motor vehicle (MV)-related SCI was significantly higher than that of fall-related SCI. In young and middle-aged patients with SCI with E-code, the loss-of-LE of MV-related paraplegia was significantly higher than that of MV-related quadriplegia and fall-related SCI. With a 3% discount rate, the LMC for patients with SCI after diagnosis were US$82 772, while those for patients with SCI with E-code were US$81 473. The LMC and the cost per year for those living with quadriplegia were significantly higher than those for paraplegia in all age groups, possibly related to the higher frequencies of stroke, chronic lung disease and dementia. We conclude that quadriplegia has a higher impact on medical costs than paraplegia, and MV-related SCI has a higher impact on loss-of-LE than fall-related SCI. We recommend comprehensive SCI prevention be established, including infrastructures of construction and transportation.


Trivalent ions activate abscisic acid-inducible promoters through an ABI1-dependent pathway in rice protoplasts.
The plant hormone abscisic acid (ABA) mediates many vital processes in plant growth and development, including seed dormancy, cell division, water use efficiency, and adaptation to drought, salinity, chilling, pathogen attack, and UV light. Our understanding of ABA signal transduction is fragmentary and would benefit from specific and facile probes of the process. Protoplasts from rice (Oryza sativa L. cv IR54) embryonic suspension cultures cotransformed with effector plasmids encoding the maize (Zea mays) VIVIPAROUS1 cDNA and/or the Arabidopsis dominant negative mutant (abi1-1) ABA-insensitive cDNA demonstrated genetic interactions of VIVIPAROUS1 and abi1-1 in transactivation of the ABA-inducible HVA1 promoter from barley (Hordeum vulgare), suggesting the mechanisms of these effectors are conserved among monocots and dicots. Trivalent ions have been shown to act as an effector of gene expression in plants and animals, although the mechanism of action is unknown. We show in two complementary transient ABA-inducible gene expression assays (beta-glucuronidase and luciferase enzymatic activities and quantitative flow cytometry of green fluorescent protein) that trivalent ions specifically interact with an ABI1-dependent ABA-signaling pathway leading to gene expression. Trivalent ions mimic ABA effects on gene expression and may be a useful tool to study ABA signaling.


Amplification of anonymous DNA fragments using pairs of long primers generates reproducible DNA fingerprints that are sensitive to genetic variation.
The reproducibility and potential applications of anonymous amplification protocols can be improved by using pairs of primers, each of 18 to 24 bases, to replace the single 8 to 10 base primers normally used in randomly amplified polymorphic DNA (RAPD) or DNA amplification fingerprinting (DAF) methods. Amplification using large primer pairs (LP-RAPD) generates 5 to 30 bands that can be resolved on standard agarose gels. Complex fingerprints can be readily generated from viruses, bacteria, fungi, plants, invertebrates and vertebrates. We also present evidence that a number of polymerase chain reaction (PCR) methods, including those based on the use of enterobacterial repetitive intergenic consensus (ERIC-PCR) or microsatellite primed (MP-PCR) sequence, may in essence operate by the same mechanism as LP-RAPD. Using standard LP-RAPD protocols, reproducible fingerprints can be generated from a single specimen using different thermocyclers, regardless of the mechanism used for thermocycling (air-cooled, Peltier effect, or robotic arm). LP-RAPD is sensitive to intraspecific and interspecific genetic variation, demonstrated here by analysis of mites and apple cultivars. Approximately 50% of LP-RAPD products are expected to have different primers at either end. Polymorphic bands with this arrangement can be recovered from the gel and directly sequenced using the LP-RAPD primers themselves. The efficiency of sequencing is improved by the length of the LP-RAPD primers. This method has the potential to allow the production of allele-specific species markers in less than two days.


[Laparoscopic treatment of iatrogenic perforations of the colon].
Iatrogenic perforations of the colon are serious complications that have been observed in association with both diagnostic and therapeutic colonoscopies, and are not always avoidable, even in the hands of an experienced investigator. Patients suffering from a perforation during elective colonoscopy are starving, and have a clean bowel. If the perforation is quickly diagnosed with only local mild peritonitis, laparoscopic treatment is often possible. The therapeutic options available are: oversewing, wedge resection and, in the individual case, tubular resection, as well as laparoscopic-assisted reconstruction, if indicated including a protective stoma. The decision to perform a laparoscopic procedure should depend on the time of detection of the lesion, and on the skills of the existing surgical team; otherwise, a laparotomy is indicated. We describe four cases that reflect the relevance of the laparoscopic approach.


[Platinum derivatives in the clinical chemotherapy of malignant tumors].
Perspectives in clinical chemotherapy with a newly-developed class of compounds - complex derivatives of platinum-are discussed. The history of their development, mechanism of action as well as pharmacokinetics and side-effects of cis-diamminodichloroplatinum are presented. The efficacy of cis-platinum treatment of malignant tumors of the testicle, ovarian and breast carcinoma and other tumors is evaluated on the basis of the literature data and clinical findings of the research staff of the Center.


Identification of Subtypes of Dry Eye Disease, Including a Candidate Corneal Neuropathic Pain Subtype Through the Use of a Latent Class Analysis.
In the absence of a gold-standard diagnostic test for different subtypes of dry eye disease (DED), we aimed to identify latent subtypes of DED within a well-characterized cohort. This is a cross-sectional study of participants enrolled in the Sjögren International Collaborative Clinical Alliance (SICCA). A latent class analysis was applied to different dry eye-related signs/tests and symptoms of ocular pain (particularly those that aligned with corneal neuropathic pain) giving relative specificities and sensitivities of each diagnostic test or symptom in the SICCA population. Four subtypes of DED were identified with putative designations including normal, asymptomatic dry eye, symptomatic dry eye, and corneal neuropathic pain. More specific classification criteria are needed for DED. Latent class analysis applied to the signs and symptoms captured in the SICCA cohort may allow for the development and refinement of classification criteria for specific subtypes of dry eye.


Graft-specific immune tolerance is determined by residual antigenicity of xenogeneic extracellular matrix scaffolds.
Antigenicity remains the primary barrier towards expanding the use of unfixed xenogeneic biomaterials in clinical applications. An unfixed xenogeneic biomaterial devoid of antigenicity, with maintained structural and mechanical integrity, has potential to overcome the limitations of current clinically utilized glutaraldehyde-fixed xenogeneic biomaterials, such as heart valve bioprostheses. Unfortunately, the threshold level of residual antigenicity necessary to overcome graft-specific immune responses in unfixed xenogeneic tissue has yet to be determined. Furthermore, little information is known regarding the extent to which in vitro disruption of native ECM properties, resulting from decellularization or antigen removal procedures, are tolerated following in vivo implantation. This manuscript demonstrates that humoral adaptive immune responses are more sensitive to residual xenogeneic biomaterial antigen content than are cell-mediated adaptive responses. Critically, the threshold for tolerable residual antigenicity is identified, with removal of ≥92% of lipophilic antigens required to reduce adaptive immune responses to levels equivalent to glutaraldehyde fixed tissue. Finally, the results demonstrated that the innate immune system tolerates minor changes in protein organization provided that molecular structure is maintained. Antigen removed xenogeneic biomaterials achieving these in vitro success criteria induce in vivo adaptive and innate tolerance, while modulating pro-regenerative constructive remodeling. Removal of antigenic components from candidate xenogeneic biomaterials is the primary success criteria for development of extracellular matrix (ECM) scaffolds in tissue engineering applications. Currently, the threshold level of residual biomaterial antigenicity required to overcome recipient graft-specific adaptive immune responses is unknown. Additionally, the extent to which the innate immune response tolerates changes to the native ECM, resulting from the ECM scaffold production process, has yet to be determined. This manuscript not only establishes the threshold for tolerable residual antigenicity, but also demonstrates that deviations in protein organization are tolerated by the innate immune system, provided macromolecular structure remains intact. In doing so, we provide the foundation of an immunologically-acceptable unfixed xenogeneic biomaterial for use in clinical applications.


Collaborative pre-competitive preclinical drug discovery with academics and pharma/biotech partners at Sanford|Burnham: infrastructure, capabilities & operational models.
There has been increased concern that the current "blockbuster" model of drug discovery and development practiced by "Big Pharma" are unsustainable in terms of cost (> $1 billion/approved drug) and time to market (10 - 15 years). The recent mergers and acquisitions (M&A), shuttering of internal research programs, closure of "redundant" sites of operations, senior management turnover and continued workforce reductions among the top 10 major pharmaceutical companies reflect draconian responses to reduce costs. However, the resultant exodus of intellectual capital, loss in motivation and momentum, and exit from early stage discovery programs by pharmaceutical companies has contributed to an "innovation deficit". Disease advocacy groups, investment communities and the government are calling for new innovative business models to address this deficit. In particular they are looking towards academia and clinical trials centers to catalyze new innovations in translational research. Indeed over the last decade many academic institutions have launched drug discovery centers largely comprising high-throughput screening (HTS) to accelerate "translational" research. A major impetus for this "open innovation" effort has been the National Institutes of Health (NIH) "Roadmap" and Molecular Libraries Initiative/Program (MLI/MLP), which is in its last year, and will be transitioned into the National Center for the Advancement of Translational Sciences (NCATS). With the end of Roadmap funding, general reduction in Federal government funding and its recent sequestration, academic drug discovery centers are being challenged to become selfsustaining, adding financial value, while remaining aligned with the missions of their respective academic non-profit institutions. We describe herein, a brief history of our bi-coastal Conrad Prebys Center for Chemical Genomics (Prebys Center) at the Sanford|Burnham Medical Research Institute (SBMRI), the key components of its infrastructure, core competencies of its fully integrated drug discovery expertise, best practices adopted in our day-to-day operations, and finally some of our current funding and collaboration and/or strategic alliance models for pre-competitive drug discovery with other academic/clinical partners, other governmental agencies, and with pharmaceutical and biotechnology companies.


Relationship Between Fibrinogen to Albumin Ratio and Prognosis of Gastrointestinal Stromal Tumors: A Retrospective Cohort Study.
The fibrinogen to albumin ratio (FAR) is an important parameter that reflects the coagulation state, systemic inflammation, and nutritional status of a patient and plays an essential role in tumor progression. Here, we evaluate the prognostic significance of FAR in gastrointestinal stromal tumor (GIST) patients that underwent radical surgery. We retrospectively analyzed the data of 227 GIST patients that underwent radical surgery in Beijing Hospital from October 2004 to July 2018. We drew a curve of receiver operating characteristics to confirm the optimal critical values for hemoglobin (Hb), prognostic nutrition index (PNI), and FAR. Cox regression analysis and the Kaplan-Meier method were used to assess the prognostic factors. The FAR optimal critical value for postoperative recurrence-free survival (RFS) was 0.09. Many significant factors, including approach, the location and size of the tumor, mitotic index, risk classification, Hb levels, PNI, and recurrence, affect FAR. Multivariate analysis indicated that for patients with GISTs who underwent surgery, the tumor location (hazard ratio [HR]=3.393, 95% confidence interval [CI]: 1.539-7.479, P=0.002), mitotic index (HR=4.788, 95% CI: 1.836-12.486, P=0.001), tumor rupture (HR=10.954, 95% CI: 2.170-55.296, P=0.004), and FAR (HR=3.093, 95% CI: 1.303-7.339, P=0.010) were independent factors affecting RFS. Moreover, the FAR remained of prognostic significance for GIST stratified by subgroup analysis. Preoperative FAR is a reliable marker for evaluating the prognosis of GIST, the prognostic ability of FAR is significantly better than Hb and PNI.


[Organization of treating patients with major vessel injuries at stages of evacuation].
The experience in treatment of 236 patients with primary injuries of major vessels is presented. A pressure dressing and tense surgical pack of the wound were used in a prehospital treatment. Use of a hemostatic tourniquet (37.3%) led to increased ischemia of injured extremity tissues. Maximal shortening of evacuation time is another important factor. Time to qualified surgical care was 3.2 +/- 0.4 hrs from injury moment, specialized--5.5 +/- 0.7 hrs. Shock was seen in 94.9% wounded. It is necessary to begin anti-shock treatment immediately after injury. Surgery was started only after shock compensation. If shock was caused by continued bleeding, surgery was started at the same time with anti-shock treatment (5.7%). Temporary shunt was used in field conditions in 35.9% wounded. In 11 (19.7%) cases endoprosthesis of original construction (two-lumen tube with microirrigator) was used. If this device was used there were no cases of arterial or venous thrombosis at the stage of specialized treatment. Since using of temporary endoprosthesis leads to delay of evacuation for specialized care it was performed only in cases of gangrene's threat when arrest of bleeding could not be performed with other methods.


Treatment for intracranial dural arteriovenous malformations: a meta-analysis from the English language literature.
The treatment of intracranial dural arteriovenous malformations (DAVMs) remains problematic. Options include ligature of feeding vessels, endovascular procedures, surgical obliteration, or a combination of the latter two. We conducted a meta-analysis of the English language literature on DAVMs to determine the most effective treatment option related to location and angiographic characteristics. The criteria for inclusion were pre- and post-treatment angiography, a description of the type of treatment, and clinical outcome. The analysis included a total of 258 patients, 248 from a review of 223 published articles and 10 from the authors' series. DAVMs were divided into six categories by location, and the results of treatment were compared based on obliteration rates using chi 2 analysis. In transverse-sigmoid sinus DAVMs (n = 64), combined therapy (endovascular plus surgical treatment) proved significantly more effective than either therapy alone (P < 0.01). For lesions of the tentorial incisura (n = 66), combined therapy and surgical obliteration alone proved superior to embolization (P < 0.001). For lesions of the cavernous sinus (n = 67), treatment was primarily endovascular, with success rates of 62 to 78% for transarterial and transvenous approaches, respectively. In the anterior fossa (n = 23), surgical obliteration was highly effective, with a success rate of 95%. The small number of cases in both the superior sagittal sinus (n = 28) and middle fossa (n = 10) regions, precluded any statistical analysis. Finally, simple ligature of feeding vessels produced success rates of only 0 to 8% and can no longer be recommended. There is no single ideal treatment for the obliteration of DAVMs. The management of each case is best considered individually. The results of this review serve as a rational starting point for the selection of treatment options.


[Pathogenesis of ophthalmoherpes basing on the analysis of enzymes of the eye tissue and fluids].
To specify mechanisms of pathology development, we studied the activity of lysosomal glycosides in rabbit ocular tissues in experimental ophthalmoherpes. Rabbits with herpetic kepatitis show activation of beta-glucuronidase, beta-glycosidase, alpha-mannosidase in cornial epithelium and stroma, iris, aqueous humor of herpes-infected and contralateral eye. The activity of the above three glycosidases in the tears of children with herpetic keratitis was enhanced. If their activity does not regress after the treatment, ophthalmoherpes recurrence may be expected in the near future. For realization of its genetic program herpes simplex virus in infected cells activates synthesis of acid glycosidases this leading to degradation of cornial cell membranes, virus spread in the tissues and release of lysosomal enzymes into tear fluid.


Hereditary breast cancer. Psychosocial issues and family physicians' role.
To outline the psychosocial issues in hereditary breast cancer (HBC) assessment and discuss the role of family physicians. A literature search using MEDLINE, CINAHL, CancerLit, and HealthStar databases was conducted from January 1990 to April 1998, using the key words breast cancer or neoplasm and familial or hereditary, genetic testing or screening, primary care or family physician or counseling, genetic counseling, psychosocial or psychological. We found only a few studies focusing on a small number of well-studied "research families." Women with a family history of breast cancer were likely to be highly interested in genetic testing for cancer risk. The benefit of testing for those with negative results is reassurance. Those found to be carriers of genetic mutations might benefit from increased surveillance and prophylactic therapy. Risks of testing include anxiety, depression, guilt, altered self-image, and insurance and employment discrimination. A family physician's role is to assess risk, to provide information and support so women can make informed choices about referral to familial cancer clinics, to offer cancer surveillance, and to provide support once genetic test results are available. Genetic testing is rapidly moving from research to clinical applications. Family physicians play an integral role in educating and managing women at risk for HBC. Physicians must prepare themselves with knowledge and counseling skills to meet the challenges of this new technology.


[Bilateral retrotonsillar velopexy. A new technique for corrective pharyngoplasty in open rhinolalia].
Open rhinolalia, a congenital or acquired phonatory abnormality, results from functional impotence of the soft palate and is a not infrequent disorder. Orthophony is often ineffective, and surgical procedures, including pharyngoplasty by means of a pharyngeal flap which provides the best results, are not very satisfactory. A new surgical technique, which has been named "bilateral retrotonsillar velopexy", is simple to perform a rapid and satisfactory functional results are obtained. The operation was performed in three patients with good results.


Rearrangement of the chromosome 11 bcl-1 locus in centrocytic lymphoma: analysis with multiple breakpoint probes.
Centrocytic lymphoma is a B-cell non-Hodgkin's lymphoma (NHL) composed of lymphocytes resembling cleaved follicular center cells (centrocytes). Previous studies have suggested an association between t(11;14) chromosomal translocations and bcl-1 rearrangement in centrocytic and related intermediate lymphocytic lymphomas. To further characterize the association between bcl-1 and centrocytic lymphoma, Southern blot analysis was performed on samples from 23 patients using four separate bcl-1 breakpoint probes spanning 63 kb of the chromosome 11 bcl-1 locus. Rearrangements were identified in six patients with the major translocation cluster (MTC) probe and in another six with probe p94PS, located about 24 kb 5' of MTC. Eleven of these 12 cases showed comigration of rearranged bcl-1 and Ig heavy chain-joining genes, consistent with the t(11;14) chromosomal translocation. No rearrangements were observed with the bcl-1 locus probes p210 or p11EH located 5' of p94PS, nor with bcl-2 or c-myc oncogene probes. No bcl-1 rearrangements were identified in B-cell follicular NHL (15), small noncleaved cell (Burkitt's and non-Burkitt's) NHL (8), T-cell NHL (4), multiple myeloma (14), and pre-B-cell acute lymphoblastic leukemia (9). One of 23 B-cell NHL of large cell type and one of 19 chronic lymphocytic leukemias or small lymphocytic NHL had MTC rearrangement. Thus, bcl-1 rearrangement occurred at MTC or p94PS in 12 of 23 centrocytic lymphomas (52%), confirming a nonrandom association and suggesting a pathogenetic role for the bcl-1 locus in this immunohistologic subtype of NHL.


Prokaryotic expression, purification and antigenicity analysis of African swine fever virus pK205R protein.
African swine fever is an acute, febrile and highly virulent porcine disease causing serious economic losses worldwide. The pK205R protein of the African swine fever virus (ASFV) is largely expressed in the early stages of infection, which has given the K205R gene extensive attention. In this study, the ASFV K205R was cloned and expressed in Escherichia coli BL21 (DE3). Expression of histidine-tagged pK205R with a molecular mass of 44 kDa was determined by 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis. Optimisation of culture conditions allowed induction of the recombinant protein with 0.4 mM Isopropyl β-D-thiogalactoside (IPTG) at 37°C for 2 h. The protein existed in cellular supernatant and was purified using a Ni-NTA resin column. The purified protein was used to immunize rabbits four times to enable the production of polyclonal antibodies, and the antiserum titre was detected by ELISA. The results showed that the purified pK205R can react with ASFV positive serum specifically by Western blotting. The pK205R had high antigenicity, which indicated that pK205R could be used as an antigen for detection of ASFV-specific antibodies in ELISA testing, and the recombinant protein could contribute to further research of the action and structure of pK205R.


Alopecia totalis and universalis long-term outcomes: a review.
Alopecia totalis (AT) and universalis (AU) represent the most severe subtypes of alopecia areata with more dramatic features and worse prognosis. The goal of this review is to identify all studies with long-term prognostic data on patients with AT and AU and provide a long-term outcome estimate. The PubMed database was queried to identify all articles discussing the long-term prognosis of AT and AU. A total of nine articles discussing long-term recovery rates of AT and AU were identified. The articles described 689 (162 = AT, 245 = AU, 282 = not specified) total patients. Six of the nine studies identified complete recovery as a potential end point in a total of 375 (39 = AT, 75 = AU, 261 = not specified) patients. According to these studies 8.5% (32/375) of AT and AU patients achieved complete recovery. A larger proportion of patients will obtain at least transient recovery periods of partial or total hair regrowth. The poor long-term outcomes of AT and AU may cause patients to lose hope with treatment. Response to treatment is often unpredictable, and physicians should be aware of the prognosis and its effects in order to properly counsel patients.


Mitochondria are targets of photodynamic therapy.
Photodynamic Therapy (PDT) is an evolving cancer treatment that depends on three known and variable components: photosensitizer, light and oxygen. Optimization of these variables yields reactive oxygen species, mainly singlet oxygen, that damage cellular components leading to cytotoxicity. Our research has demonstrated that porphyrin sensitizers, in particular, significantly inhibit the inner mitochondrial membrane enzymes cytochrome c oxidase and F(0)F(1) ATP synthase. These results were obtained from an in vivo-in vitro experimental protocol that exposes sensitizers to metabolic and pharmacokinetic events. The resulting inhibition of oxidative phosphorylation was expected to reduce ATP levels, which were quantitated in cells and were confirmed by (31)P-NMR spectroscopy of tumors in situ in animals treated with PDT. Based on these findings, and more recent investigations of apoptosis, there is little doubt that mitochondria are critical targets in the actions of PDT.


Assessing the determinants of intentions and behaviors of organizations towards a circular economy for plastics.
The production and consumption of plastics, although inevitable in our modern life, are predominantly unsustainable and inefficient. Hence, the concept of a circular economy for plastics has been proposed as a sustainable approach to thrive both economy and our modern life. To implement a circular economy for plastics, an understanding of both individuals' and organizations' behaviors is needed since psychological effects often undermine technical solutions. We particularly focus on organizations' behaviors since commercial plastic waste has not been thoroughly investigated compared to household plastic waste. Using the Theory of Planned Behavior (TPB) and Partial Least Squares Structural Equation Modeling (PLS-SEM), we assess the determinants of intentions and behaviors of 637 organizations in Belgium towards a circular economy for plastics. Our PLS-SEM analysis support that attitudes, subjective norms, and perceived behavioral control of decision makers positively influence organizations' intentions to implement best practices of plastic recycling. Furthermore, organizations' intentions, perceived behavioral control, pressures, and enablers positively, whereas barriers negatively, influence organizations' behaviors. Our study shows that most organizations have positive intentions, yet they seem to be failing in implementing best practices of plastic recycling due to some critical barriers. To overcome this intention-behavior gap and to attain a circular economy for plastics, our study suggests some measures.


Using informatics and the electronic medical record to describe antimicrobial use in the clinical management of diarrhea cases at 12 companion animal practices.
Antimicrobial drugs may be used to treat diarrheal illness in companion animals. It is important to monitor antimicrobial use to better understand trends and patterns in antimicrobial resistance. There is no monitoring of antimicrobial use in companion animals in Canada. To explore how the use of electronic medical records could contribute to the ongoing, systematic collection of antimicrobial use data in companion animals, anonymized electronic medical records were extracted from 12 participating companion animal practices and warehoused at the University of Calgary. We used the pre-diagnostic, clinical features of diarrhea as the case definition in this study. Using text-mining technologies, cases of diarrhea were described by each of the following variables: diagnostic laboratory tests performed, the etiological diagnosis and antimicrobial therapies. The ability of the text miner to accurately describe the cases for each of the variables was evaluated. It could not reliably classify cases in terms of diagnostic tests or etiological diagnosis; a manual review of a random sample of 500 diarrhea cases determined that 88/500 (17.6%) of the target cases underwent diagnostic testing of which 36/88 (40.9%) had an etiological diagnosis. Text mining, compared to a human reviewer, could accurately identify cases that had been treated with antimicrobials with high sensitivity (92%, 95% confidence interval, 88.1%-95.4%) and specificity (85%, 95% confidence interval, 80.2%-89.1%). Overall, 7400/15,928 (46.5%) of pets presenting with diarrhea were treated with antimicrobials. Some temporal trends and patterns of the antimicrobial use are described. The results from this study suggest that informatics and the electronic medical records could be useful for monitoring trends in antimicrobial use.


Identification of Gas6 as a growth factor for human Schwann cells.
Schwann cells are one of the principal components of the peripheral nervous system. They play a crucial role in nerve regeneration and can be used clinically in the repair of injured nerves. We have established serum-free, defined culture conditions that rapidly expand adult human Schwann cells without fibroblast growth. We find that Gas6, a ligand for the Axl and Rse/Tyro3 receptor protein tyrosine kinase family, stimulates human Schwann cell growth, increasing both cell number and thymidine incorporation. Gas6 has synergistic effects with the other known human Schwann cell mitogens, heregulin/glial growth factor and forskolin. Addition of Gas6 causes phosphorylation of Axl and Rse/Tyro3 simultaneously and results in ERK-2 activation. A combination of Gas6 with heregulin and forskolin, on a defined background, supports maximal Schwann cell proliferation, while preserving the typical Schwann cell morphology and expression of the Schwann cell markers S-100, glial fibrillary acidic protein, and low-affinity nerve growth factor receptor. Gas6 mRNA is present in both spinal motor neurons and large neurons of the dorsal root ganglia, and neural injury has been reported to upregulate Rse/Axl in the schwann cell. This is the first demonstration of a potentially important biological role for the human Gas6/Rse-Axl system.


Post-marketing surveillance of sertindole.
The atypical antipsychotic drug, sertindole, like several other drugs, causes QT interval prolongation. Prolongation of the QT interval on the electrocardiogram has been associated with an increased risk of ventricular arrhythmia, including the more serious form, torsades de pointes, and is thus a safety concern for the authorities. In the case of sertindole, however, the available pharmacoepidemiological studies gathering data from about 10 000 patients documented the lack of increased risk associated to sertindole in comparison to other atypical antipsychotics. On the basis of these data, as well as non-clinical and clinical safety data, the CPMP expert group concluded that, although sertindole has the potential to prolong the QT interval, &#164 &#164 QT interval prolongation does not seem to be a reliable proxy for the risk of severe cardiac arrhythmias'', and there are no clinical data suggesting that sertindole is more arrhythmogenic than are other atypical antipsychotics. To further substantiate this conclusion, two post-marketing surveillance studies have been initiated. One is a randomized comparison of sertindole and risperidone under normal conditions of use. Randomization minimizes selection bias and the intention is that allocation to the two treatment arms will yield comparable treatment groups. While the two drugs will be given in an open-label fashion, all safety data will be blinded and reviewed by an independent safety committee. The other study is an observational study that includes all patients prescribed sertindole who, for whatever reason, will not be included in the randomized study. In all, 10 000 patients are expected to take part in the studies, which will run for at least 1 year.


Uncoupling protein downregulation in doxorubicin-induced heart failure improves mitochondrial coupling but increases reactive oxygen species generation.
Doxorubicin-based chemotherapy is limited by the development of dose-dependent left ventricular dysfunction and congestive heart failure caused by reactive oxygen species (ROS). Uncoupling proteins (UCP) can inhibit mitochondrial ROS production as well as decrease myocyte damage from exogenous ROS. Prior studies have shown that cardiac UCP2 and UCP3 mRNA expression is decreased with acute doxorubicin treatment. However, the expression of UCP protein in hearts with doxorubicin cardiotoxicity and the resultant changes in mitochondrial function and oxidant stress have not been determined. Heart failure was induced in Sprague-Dawley rats with intraperitoneal injections of doxorubicin (2 mg/kg t.i.w., total dose: 18 mg/kg). Mitochondria were isolated from mice receiving doxorubicin or saline injections for determination of UCP2 and UCP3 expression. In addition, mitochondrial respiration, ATP synthesis and ROS production were determined. Doxorubicin-induced heart failure was associated with significant decreases in UCP2 and UCP3 protein expression compared with nonfailing hearts (P < 0.05). While the rates of state 3 and state 4 respiration and ATP synthesis were lower in mitochondria isolated from failing hearts, the respiratory control ratio was 15% higher (P < 0.05), and the ratio of ATP production to oxygen consumption was 25% higher (P < 0.05) in mitochondria from failing hearts, indicating greater coupling between citric acid cycle flux and mitochondrial ATP synthesis. However, the decrease in UCP expression was associated with 50% greater mitochondrial ROS generation (P < 0.05). Downregulation of myocardial UCP2 and UCP3 in the setting of doxorubicin-induced heart failure is associated with improved efficiency of ATP synthesis, which might compensate for abnormal energy metabolism. However, this beneficial effect is counterbalanced by greater oxidant stress.


[Histogenesis of infantile fibrosarcoma].
Eight cases of infantile deep soft tissue fibrosarcoma were examined. The tumor consists of neoplastic fibroblasts and myofibroblasts which differ from each other ultrastructurally. Well-differentiated collagen-forming neoplastic fibroblasts form one-half of infantile fibrosarcoma. Immunohistochemically and ultrastructurally immature embryonic-like fibroblasts were also identified. The latter closely resemble an embryonic perichondrial fibroblast of the embryonic limb during 6 weeks of development.


The Serine Carboxypeptidase-Like Gene SCPL41 Negatively Regulates Membrane Lipid Metabolism in Arabidopsis thaliana.
The Arabidopsis has 51 proteins annotated as serine carboxypeptidase-like (SCPL) enzymes. Although biochemical and cellular characterization indicates SCPLs involved in protein turnover or processing, little is known about their roles in plant metabolism. In this study, we identified an Arabidopsis mutant, bis4 (1-butanol insensitive 4), that was insensitive to the inhibitory effect of 1-butanol on seed germination. We cloned the gene that was defective in bis4 and found that it encoded an SCPL41 protein. Transgenic Arabidopsis plants constitutively expressing SCPL41 were generated, oil body staining and lipidomic assays indicated that SCPL41-overexpressing plants showed a decrease in membrane lipid content, especially digalactosyl diglyceride (DGDG) and monogalactosyl diglyceride (MGDG) contents, while the loss of SCPL41 increased the membrane lipid levels compared with those in wild-type plants. These findings suggested that SCPL41 had acquired novel functions in membrane lipid metabolism.


Effectiveness of microwave disinfection of complete dentures on the treatment of Candida-related denture stomatitis.
The effectiveness of microwave disinfection of maxillary complete dentures on the treatment of Candida-related denture stomatitis was evaluated. Patients (n = 60) were randomly assigned to one of four treatment groups of 15 subjects each; patients performed the routine denture care; Mw group: patients had their upper denture microwaved (650 W per 6 min) three times per week for 30 days; group MwMz: patients received the treatment of Mw group in conjunction with topical application of miconazole three times per day for 30 days; group Mz: patients received the antifungal therapy of group MwMz. Cytological smears and mycological cultures were taken from the dentures and the palates of all patients before treatment at day 15 and 30 of treatment and at follow-up (days 60 and 90). The effectiveness of the treatments was evaluated by Kruskal-Wallis and Mann-Whitney tests. Microbial and clinical analysis of the control group demonstrated no significant decrease in the candidal infection over the clinical trial. Smears and cultures of palates and dentures of the groups Mw and MwMz exhibited absence of Candida at day 15 and 30 of treatment. On day 60 and 90, few mycelial forms were observed on 11 denture smears (36.6%) from groups Mw and MwMz, but not on the palatal smears. Miconazole (group Mz) neither caused significant reduction of palatal inflammation nor eradicated Candida from the dentures and palates. Microwaving dentures was effective for the treatment of denture stomatitis. The recurrence of Candida on microwaved dentures at follow-up was dramatically reduced.


Lipopolysaccharide of Burkholderia cepacia complex.
Burkholderia cepacia complex (Bcc) is a group of phenotypically similar, genetically distinct bacteria that are beneficial to the environment but can also cause severe human infections. Bcc are being exploited for use as bioremediation agents and as a way to combat agricultural plant diseases. However, Bcc can cause lung infections in patients with chronic granulomatous disease or cystic fibrosis often resulting in mortality of these patients. Since it is unclear what bacterial components are necessary for causing human infections, studies of Bcc have focused on identifying putative virulence factors. As in other Gram-negative bacteria, the lipopolysaccharide (LPS) of Bcc induces a strong immune response that can contribute to host cell damage. The unusual structure of Bcc LPS lowers the anionic charge of the Bcc cell surface, which inhibits the binding and subsequent effects of cationic antibiotics. These distinguishing features include the substitution of a Ko for a Kdo residue in the inner core oligosaccharide and Ara4N residues bound to phosphates of the lipid A backbone. The structures of O antigen subunits and the consequent serotypes will also be discussed, with particular reference to the O antigen biosynthetic loci of two Bcc strains.


Decreased serum neurotrophin 3 in chronically medicated schizophrenic males.
There is evidence that major psychiatric disorders such as schizophrenia (SZ) are associated with deregulation of synaptic plasticity with downstream alterations of neurotrophins. NT3 is an important neurotrophin in the central nervous system, and performs key biological functions, such as promoting the survival, differentiation, and plasticity of neurons. NT3 has a central role in the early neuronal development; enhancing the survival of dopaminergic neurons, suggesting possible involvement in the physiopathology of dopamine related neuropsychiatric disorders such as SZ. Variations in the NT3 gene increase the risk of SZ. Three groups of chronically medicated DSM-IV patients with SZ, on treatment with clozapine (n=12), haloperidol (n=12), risperidone (n=12) and 10 healthy controls had 5 ml blood samples collected by venipuncture. NT3 serum levels were assessed using sandwich-ELISA and were significantly lower in SZ patients (p<0.005) when compared to either controls. These findings suggest that the NT3 signaling system may play a role in the pathophysiology of SZ and might be related to the course of illness or to treatment variables. Longitudinal studies are warranted.


Linewidth measurement with an optical microscope: the effect of operating conditions on the image profile.
A theoretical model of the optical microscope based on the theory of partial coherence is used to predict the image profiles of lines on IC photomasks and assess factors contributing to measurement errors for different conditions of microscope operation. A comparison of experimental and theoretical image profiles is given, showing good agreement with theory for a 0.9 N.A. and linewidths as small as 0.5 microm. The primary sources of differences appear to be edge quality and accuracy of focus. The theory indicates that for well-corrected microscope optical systems, spectrally filtered to eliminate longitudinal chromatic aberration and chromatic difference of magnification, accurate determinations of linewidth may be made from the image profile using a threshold of 25% of maximum intensity (corrected for finite background transmittance in the opaque region). The correspondence between the edge location and the 25% threshold appears to be nearly invariant with small amounts of defocus and spherical aberration as well as variation in the numerical aperture of the condenser.


Effect of antidiabetic drugs on the risk of atrial fibrillation: mechanistic insights from clinical evidence and translational studies.
Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF), which is the most common sustained arrhythmia and is associated with substantial morbidity and mortality. Advanced glycation end product and its receptor activation, cardiac energy dysmetabolism, structural and electrical remodeling, and autonomic dysfunction are implicated in AF pathophysiology in diabetic hearts. Antidiabetic drugs have been demonstrated to possess therapeutic potential for AF. However, clinical investigations of AF in patients with DM have been scant and inconclusive. This article provides a comprehensive review of research findings on the association between DM and AF and critically analyzes the effect of different pharmacological classes of antidiabetic drugs on AF.


A sense inventory for clinical abbreviations and acronyms created using clinical notes and medical dictionary resources.
To create a sense inventory of abbreviations and acronyms from clinical texts. The most frequently occurring abbreviations and acronyms from 352,267 dictated clinical notes were used to create a clinical sense inventory. Senses of each abbreviation and acronym were manually annotated from 500 random instances and lexically matched with long forms within the Unified Medical Language System (UMLS V.2011AB), Another Database of Abbreviations in Medline (ADAM), and Stedman's Dictionary, Medical Abbreviations, Acronyms & Symbols, 4th edition (Stedman's). Redundant long forms were merged after they were lexically normalized using Lexical Variant Generation (LVG). The clinical sense inventory was found to have skewed sense distributions, practice-specific senses, and incorrect uses. Of 440 abbreviations and acronyms analyzed in this study, 949 long forms were identified in clinical notes. This set was mapped to 17,359, 5233, and 4879 long forms in UMLS, ADAM, and Stedman's, respectively. After merging long forms, only 2.3% matched across all medical resources. The UMLS, ADAM, and Stedman's covered 5.7%, 8.4%, and 11% of the merged clinical long forms, respectively. The sense inventory of clinical abbreviations and acronyms and anonymized datasets generated from this study are available for public use at http://www.bmhi.umn.edu/ihi/research/nlpie/resources/index.htm ('Sense Inventories', website). Clinical sense inventories of abbreviations and acronyms created using clinical notes and medical dictionary resources demonstrate challenges with term coverage and resource integration. Further work is needed to help with standardizing abbreviations and acronyms in clinical care and biomedicine to facilitate automated processes such as text-mining and information extraction.


Iritis and hypotony after treatment with intravenous cidofovir for cytomegalovirus retinitis.
To describe intraocular inflammation due to treatment with intravenous cidofovir dihydrate for cytomegalovirus retinitis. Retrospective cohort. Three university outpatient ophthalmology clinics. All patients treated with intravenous cidofovir therapy before October 31, 1996. Treatment with intravenous cidofovir was given according to standardized protocols. Intraocular inflammation was treated according to the best medical judgment. The presence of new intraocular inflammation, the severity of inflammation, visual acuity, and intraocular pressure. Eleven cases of iritis (26%) occurred among 43 patients. In 6 cases, the iritis was bilateral. Patients who experienced iritis were more likely to have been previously treated for cytomegalovirus retinitis (P = .03), to be diabetic (P = .05), or to be receiving protease inhibitors (P < .001). Four patients and 15 control subjects had also taken rifabutin (P = .70). The onset of iritis occurred at a mean (+/-SD) of 4.9 +/- 1.8 days after a cidofovir dose and after a mean (+/-SD) of 4.2 +/- 1.6 doses of cidofovir. Six eyes of 4 patients had hypotony. Five eyes of 5 patients had a persistent decrease in visual acuity of at least 2 Snellen lines. Acute intraocular inflammation may occur with or without hypotony after intravenous cidofovir therapy, similar to the reactions seen after intravitreous administration. Although the manifestations may be severe, they are manageable with topical corticosteroid therapy in most cases. Cidofovir therapy can be continued in some patients if medical necessity warrants, but recurrent inflammation or permanent hypotony may occur.


Effect of cryopreservation and in vitro culture of bovine fibroblasts on histone acetylation levels and in vitro development of hand-made cloned embryos.
In this study, the relative acetylation levels of histone 3 in lysine 9 (H3K9ac) in cultured and cryopreserved bovine fibroblasts was measured and we determined the influence of the epigenetic status of three cultured (C1, C2 and C3) donor cell lines on the in vitro development of reconstructed bovine embryos. Results showed that cryopreservation did not alter the overall acetylation levels of H3K9 in bovine fibroblasts analysed immediately after thawing (frozen/thawed) compared with fibroblasts cultured for a period of time after thawing. However, reduced cleavage rates were noted in embryos reconstructed with fibroblasts used immediately after thawing. Cell passage affects the levels of H3K9ac in bovine fibroblasts, decreasing after P1 and donor cells with lower H3K9ac produced a greater frequency of embryo development to the blastocyst stage. Cryopreservation did not influence the total cell and ICM numbers, or the ICM/TPD ratios of reconstructed embryos. However, the genetic source of donor cells did influence the total number of cells and the trophectoderm cell numbers, and the cell passage influenced the total ICM cell numbers.


A qualitative assessment on the acceptability of providing cash transfers and social health insurance for tuberculosis-affected families in Ho Chi Minh City, Vietnam.
To achieve the Sustainable Development Goal's targets of universal health coverage (UHC) and poverty reduction, interventions are required that strengthen and harmonize both UHC and social protection. Vietnam is committed to achieving financial protection and over 90% of the general population has enrolled in its social health insurance (SHI) scheme. However, an estimated 63% of tuberculosis (TB)-affected households in Vietnam still face catastrophic costs and little is known about the optimal strategies to mitigate the costs of TB care for vulnerable families. This study assessed the acceptability of a social protection package containing cash transfers and SHI using individual interviews (n = 19) and focus group discussions (n = 3 groups). Interviews were analyzed through framework analysis. The study's main finding indicated that both conditional and unconditional cash transfers paired with SHI were acceptable, across six dimensions of acceptability. Cash transfers were considered beneficial for mitigating out-of-pocket expenditure, increasing TB treatment adherence, and improving mental health and general well-being, but the value provided was inadequate to fully alleviate the economic burden of the illness. The conditionality of the cash transfers was not viewed by participants as inappropriate, but it increased the workload of the TB program, which brought into question the feasibility of scale-up. SHI was viewed as a necessity by almost all participants, but people with TB questioned the quality of care received when utilizing it for auxiliary TB services. Access to multiple sources of social protection was deemed necessary to fully offset the costs of TB care. Additional research is needed to assess the impact of cash transfer interventions on health and economic outcomes in order to create an enabling policy environment for scale-up.


Identification of a major QTL together with several minor additive or epistatic QTLs for resistance to fire blight in apple in two related progenies.
Although fire blight, caused by the bacterium Erwinia amylovora, is one of the most destructive diseases of apple (Malus x domestica) worldwide, no major, qualitative gene for resistance to this disease has been identified to date in apple. We conducted a quantitative trait locus (QTL) analysis in two F(1) progenies derived from crosses between the cultivars Fiesta and either Discovery or Prima. Both progenies were inoculated in the greenhouse with the same strain of E. amylovora, and the length of necrosis was scored 7 days and 14 days after inoculation. Additive QTLs were identified using the MAPQTL: software, and digenic epistatic interactions, which are an indication of putative epistatic QTLs, were detected by two-way analyses of variance. A major QTL explaining 34.3--46.6% of the phenotypic variation was identified on linkage group (LG) 7 of Fiesta in both progenies at the same genetic position. Four minor QTLs were also identified on LGs 3, 12 and 13. In addition, several significant digenic interactions were identified in both progenies. These results confirm the complex polygenic nature of resistance to fire blight in the progenies studied and also reveal the existence of a major QTL on LG7 that is stable in two distinct genetic backgrounds. This QTL could be a valuable target in marker-assisted selection to obtain new, fire blight-resistant apple cultivars and forms a starting point for discovering the function of the genes underlying such QTLs involved in fire blight control.


Subchronic exposures to fungal bioaerosols promotes allergic pulmonary inflammation in naïve mice.
Epidemiological surveys indicate that occupants of mold contaminated environments are at increased risk of respiratory symptoms. The immunological mechanisms associated with these responses require further characterization. The aim of this study was to characterize the immunotoxicological outcomes following repeated inhalation of dry Aspergillus fumigatus spores aerosolized at concentrations potentially encountered in contaminated indoor environments. Aspergillus fumigatus spores were delivered to the lungs of naïve BALB/cJ mice housed in a multi-animal nose-only chamber twice a week for a period of 13 weeks. Mice were evaluated at 24 and 48 h post-exposure for histopathological changes in lung architecture, recruitment of specific immune cells to the airways, and serum antibody responses. Germinating A. fumigatus spores were observed in lungs along with persistent fungal debris in the perivascular regions of the lungs. Repeated exposures promoted pleocellular infiltration with concomitant epithelial mucus hypersecretion, goblet cell metaplasia, subepithelial fibrosis and enhanced airway hyperreactivity. Cellular infiltration in airways was predominated by CD4(+) T cells expressing the pro-allergic cytokine IL-13. Furthermore, our studies show that antifungal T cell responses (IFN-γ(+) or IL-17A(+) ) co-expressed IL-13, revealing a novel mechanism for the dysregulated immune response to inhaled fungi. Total IgE production was augmented in animals repeatedly exposed to A. fumigatus. Repeated inhalation of fungal aerosols resulted in significant pulmonary pathology mediated by dynamic shifts in specific immune populations and their cytokines. These studies provide novel insights into the immunological mechanisms and targets that govern the health outcomes that result from repeated inhalation of fungal bioaerosols in contaminated environments.


Association between non-melanoma and melanoma skin cancer rates, vitamin D and latitude.
Vitamin D synthesis takes place in the skin due to solar ultraviolet-B (UVB) radiation. Several studies have shown the association between low sun exposure, non-melanoma skin cancer (NMSC) and a lack of vitamin D synthesis. Since such synthesis in the body depends on the exposure of the skin to solar UVB radiation (290-320 nm), experimental measurements of this type of solar radiation are important. Tarapaca University in Arica, Chile, established a solar UV radiation laboratory in 2006 and since then this laboratory has performed systematic experimental solar UVB measurements using a calibrated biometer instrument. The results, which are presented in the current study, showed the association between NMSC and MSC rates, and the time required to produce 1,000 IU vitamin D with latitudinal variation. Solar UV index (UVI) levels reported in 6 cities from the north to the south of Chile indicated that the UVI ratio of monthly mean values was 1.8 times higher in Arica than in Punta Arenas in January (summer in Chile), whereas it was 14 times higher in June (winter). This factor is an important consideration, since vitamin D synthesis is directly associated with the exposure of individuals to solar UVB radiation. A similar trend was observed in Antofagasta, Santiago, Concepcion, Valdivia and Punta Arenas. It can be concluded from these data that there is a direct association between NMSC rates and mortality, and UVB radiation, meaning that this type of cancer would not depend on vitamin D synthesis and therefore on calcium uptake. By contrast, MSC rates increased with decreased levels of vitamin D, and thus calcium uptake, in all cities, with the only exception being Punta Arenas.


Reliability of a new measure to assess modern screen time in adults.
Screen time among adults represents a continuing and growing problem in relation to health behaviors and health outcomes. However, no instrument currently exists in the literature that quantifies the use of modern screen-based devices. The primary purpose of this study was to develop and assess the reliability of a new screen time questionnaire, an instrument designed to quantify use of multiple popular screen-based devices among the US population. An 18-item screen-time questionnaire was created to quantify use of commonly used screen devices (e.g. television, smartphone, tablet) across different time points during the week (e.g. weekday, weeknight, weekend). Test-retest reliability was assessed through intra-class correlation coefficients (ICCs) and standard error of measurement (SEM). The questionnaire was delivered online using Qualtrics and administered through Amazon Mechanical Turk (MTurk). Eighty MTurk workers completed full study participation and were included in the final analyses. All items in the screen time questionnaire showed fair to excellent relative reliability (ICCs = 0.50-0.90; all < 0.000), except for the item inquiring about the use of smartphone during an average weekend day (ICC = 0.16, p = 0.069). The SEM values were large for all screen types across the different periods under study. Results from this study suggest this self-administered questionnaire may be used to successfully classify individuals into different categories of screen time use (e.g. high vs. low); however, it is likely that objective measures are needed to increase precision of screen time assessment.


Randomised phase II study to optimise melphalan, prednisolone, and bortezomib in untreated multiple myeloma (JCOG1105).
We conducted a randomised phase II study to determine the optimal dose and schedule of melphalan, prednisone, and bortezomib (MPB) (jRCTs031180097). Transplant-ineligible untreated multiple myeloma patients were randomised to Arm A (twice weekly bortezomib in one six-week cycle followed by eight five-week cycles of four times once weekly bortezomib with melphalan and prednisolone on days 1-4) or Arm B (nine four-week cycles of three times once weekly bortezomib with melphalan and prednisolone on days 1-4). The primary end-point was complete response (CR) rate. Of 91 patients randomised to two arms, 88 were eligible. The median cumulative bortezomib doses were 45·8 and 35·1 mg/m2 , CR rate was 18·6% [95% confidence interval (CI) 8·4-33·4] and 6·7% (95% CI 1·4-18·3), and the median progression-free survival (PFS) was 2·5 and 1·4 years in Arms A and B [hazard ratio (HR) 1·93 (95% CI 1·09-3·42)], respectively. Frequent grade ≥3 haematologic toxicities in Arms A and B were neutropenia (64·4% vs. 28·3%) and thrombocytopenia (35·6% vs. 10·9%). Grade 2/3 peripheral neuropathy was observed in 24·4/2·2% in Arm A and 8·7/0% in Arm B. In conclusion, Arm A was the more promising regimen, suggesting that the twice weekly schedule of bortezomib in the first cycle and higher cumulative dose of both bortezomib and melphalan influences the efficacy of modified MPB.


Structural organization of the barley D-hordein locus in comparison with its orthologous regions of wheat genomes.
D hordein, a prolamin storage protein of barley endosperms, is highly homologous to the high molecular weight (HWM) glutenin subunits, which are the major determinants of bread-making quality in wheat flour. In hexaploid wheat (AABBDD), each genome contains two paralogous copies of HMW-glutenin genes that encode the x- and y-type HMW-glutenin subunits. Previously, we reported the sequence analysis of a 102-kb genomic region that contains the HMW-glutenin locus of the D genome from Aegilops tauschii, the donor of the D genome of hexaploid wheat. Here, we present the sequence analysis of a 120-kb D-hordein region of the barley genome, a more distantly related member of the Triticeae grass tribe. Comparative sequence analysis revealed that gene content and order are generally conserved. Genes included in both of these orthologous regions are arranged in the following order: a Xa21-like receptor kinase, an endosperm globulin, an HMW prolamin, and a serine (threonine) protein kinase. However, in the wheat D genome, a region containing both the globulin and HMW-glutenin gene was duplicated, indicating that this duplication event occurred after the separation of the wheat and barley genomes. The intergenic regions are divergent with regard to the sequence and structural organization. It was found that different types of retroelements are responsible for the intergenic structure divergence in the wheat and barley genomes. In the barley region, we identified 16 long terminal repeat (LTR) retrotransposons in three distinct nested clusters. These retroelements account for 63% of the contig sequence. In addition, barley D hordein was compared with wheat HMW glutenins in terms of cysteine residue conservation and repeat domain organization.


[Acute generalised exanthematous pustolosis in a 2-year-old girl following treatment with amoxicillin].
A two-year-old girl had had fever for one week, and since the previous day general malaise, cutaneous pustolosis with swollen hands and feet. The skin condition had developed three days after the start of amoxicillin therapy. Laboratory tests at the time of admission indicated an infection. The diagnosis was 'acute generalised exanthematous pustulosis' (AGEP). During treatment with a soothing lotion, lasting one week, the patient improved and the skin condition disappeared. AGEP is characterised by acute onset of a pustular eruption in association with fever. It is usually seen after the use of drugs. This is an uncommon disease in children.


Ex-vivo gene therapy of human vascular bypass grafts with E2F decoy: the PREVENT single-centre, randomised, controlled trial.
Cell-cycle blockade by ex-vivo gene therapy of experimental vein grafts inhibits the neointimal hyperplasia and subsequent accelerated atherosclerosis that lead to human bypass-graft failure. In a prospective, randomised, controlled trial, we investigated the safety and biological efficacy of intraoperative gene therapy in patients receiving bypass vein grafts. We studied gene therapy that uses decoy oligodeoxynucleotide, which binds and inactivates the pivotal cell-cycle transcription factor E2F. 41 patients were randomly assigned untreated (16), E2F-decoy-treated (17), or scrambled-oligodeoxynucleotide-treated (eight) human infrainguinal vein grafts. Oligonucleotide was delivered to grafts intraoperatively by ex-vivo pressure-mediated transfection. The primary endpoints were safety and inhibition of target cell-cycle regulatory genes and of DNA synthesis in the grafts. Analysis was by intention to treat. Mean transfection efficiency was 89.0% (SD 1.9). Proliferating-cell nuclear antigen and c-myc mRNA concentrations and bromodeoxyuridine incorporation were decreased in the EF2-decoy group by medians of 73% [IQR 53-84], 70% [50-79], and 74% [56-83], respectively) but not in the scrambled-oligodeoxynucleotide group (p<0.0001). Groups did not differ for postoperative complication rates. At 12 months, fewer graft occlusions, revisions, or critical stenoses were seen in the E2F-decoy group than in the untreated group (hazard ratio 0.34 [95% CI 0.12-0.99]). Intraoperative transfection of human bypass vein grafts with E2F-decoy oligodeoxynucleotide is safe, feasible, and can achieve sequence-specific inhibition of cell-cycle gene expression and DNA replication. Application of this genetic-engineering strategy may lower failure rates of human primary bypass vein grafting.


Telangiectatic osteosarcoma.
Telangiectatic osteosarcoma is a rare variant of osteosarcoma. In the original report from the authors' institution, a poor prognosis was noted. The authors have updated their experience with this entity. The prognosis for patients with telangiectatic osteosarcoma has improved remarkably. The prognosis in the present series seems to be the same as that for conventional osteosarcoma. Adjuvant chemotherapy seems to help in salvaging patients with metastatic disease. However, in this small series, survival of patients without metastasis is apparently not influenced by whether they received chemotherapy.


Postoperative Utilization of Oral Nutrition Supplements in Surgical Patients in US Hospitals.
Postoperative nutrition delivery is essential to surgical recovery; unfortunately, postoperative dietary intake is often poor. Recent surgical guidelines recommend use of oral nutritional supplements (ONS) to improve nutrition delivery. Our aim was to examine prevalence of coded ONS use over time and coded malnutrition rates in postoperative patients. The Premier Healthcare Database (PHD) was queried for postoperative patients found to have charges for ONS between 2008-2014. ONS use identified via charge codes. Descriptive statistics utilized to examine prevalence of malnutrition and ONS utilization. Multilevel, multivariable logistic regression models were fit to examine factors associated with ONS use. A total of 2,823,532 surgical encounters were identified in PHD in 172 hospitals utilizing ONS charge codes. ONS-receiving patients were 72% Caucasian, 65% Medicare patients with mean age of 66 ± 16.5 years. Compared with patients not receiving ONS, ONS patients had higher van Walraven severity scores (7.3 ± 7.8 vs 2.3 ± 5.6, P < .001) with greater comorbidities. Overall coded malnutrition prevalence was 4.3%. Coded malnutrition diagnosis increased from 4.4% to 5.2% during study period. Only 15% of malnourished patients received ONS. Individual hospital practice explained much of variation in early postoperative ONS use. In this large surgical population, inpatient ONS use is most common in older, Caucasian, Medicare patients with high comorbidity burden. Despite increased malnutrition during study period, observed ONS prescription rate did not increase. Our data indicate current ONS utilization in surgical patients, even coded with malnutrition, is limited and is a critical perioperative quality improvement opportunity.


Childhood Asthma Hospital Discharge Medication Fills and Risk of Subsequent Readmission.
To assess the relationship between posthospitalization prescription fills for recommended asthma discharge medication classes and subsequent hospital readmission. This was a retrospective cohort analysis of Medicaid Analytic Extract files from 12 geographically diverse states from 2005-2007. We linked inpatient hospitalization, outpatient, and prescription claims records for children ages 2-18 years with an index hospitalization for asthma to identify those who filled a short-acting beta agonist, oral corticosteroid, or inhaled corticosteroid within 3 days of discharge. We used a multivariable extended Cox model to investigate the association of recommended medication fills and hospital readmission within 90 days. Of 31,658 children hospitalized, 55% filled a beta agonist prescription, 57% an oral steroid, and 37% an inhaled steroid. Readmission occurred for 1.3% of patients by 14 days and 6.3% by 90 days. Adjusting for patient and billing provider factors, beta agonist (hazard ratio [HR] 0.67, 95% CI 0.51, 0.87) and inhaled steroid (HR 0.59, 95% CI 0.42, 0.85) fill were associated with a reduction in readmission at 14 days. Between 15 and 90 days, inhaled steroid fill was associated with decreased readmission (HR 0.87, 95% CI 0.77, 0.98). Patients who filled all 3 medications had the lowest readmission hazard within both intervals. Filling of beta agonists and inhaled steroids was associated with diminished hazard of early readmission. For inhaled steroids, this effect persisted up to 90 days. Efforts to improve discharge care for asthma should include enhancing recommended discharge medication fill rates.


In vivo electromechanical assessment of heart failure patients with prolonged QRS duration.
Combined measurement of electrical activation and mechanical dyssynchrony in heart failure (HF) patients is scarce but may contain important mechanistic and diagnostic clues. The purpose of this study was to characterize the electromechanical (EM) coupling in HF patients with prolonged QRS duration. Ten patients with QRS width >120 ms underwent left ventricular (LV) electroanatomic contact mapping using the Noga® XP system (Biosense Webster). Recorded voltages during the cardiac cycle were converted to maps of depolarization time (TD). Electrode positions were tracked and converted into maps of time-to-peak shortening (TPS) using custom-made deformation analysis software. Correlation analysis was performed between the 2 maps to quantify EM coupling. Simulations with the CircAdapt cardiovascular system model were performed to mechanistically unravel the observed relation between TD and TPS. The delay between earliest LV electrical activation and peak shortening differed considerably between patients (TPSmin-TDmin = 360 ± 73 ms). On average, total mechanical dyssynchrony exceeded total electrical activation (ΔTPS = 177 ± 47 ms vs ΔTD = 93 ± 24 ms, P <.001), but a large interpatient variability was observed. The TD and TPS maps correlated strongly in all patients (median R = 0.87, P <.001). These correlations were similar for regions with unipolar voltages above and below 6mV (Mann-Whitney U test, P = .93). Computer simulations revealed that increased passive myocardial stiffness decreases ΔTPS relative to ΔTD and that lower contractility predominantly increases TPSmin-TDmin. EM coupling in HF patients is maintained, but the relationship between TD and TPS differs strongly between patients. Intra-individual and inter-individual differences may be explained by local and global differences in passive and contractile myocardial properties.


Cross-sectional study of electrocardiographic pattern in healthy children resident at high altitude.
Electrocardiographic studies have reported persistent right ventricle predominance in high altitude children as an adaptive response. No information was provided on ethnicity and environmental factors in those studies. We assessed the electrocardiographic characteristics in healthy high altitude children with mixed ancestry and relatively high mobility to lower altitudes. A cross-sectional study of 321 children aged 2 months through 19 years old and living at high altitude (Tintaya, Peru, 4,100 m) was conducted. Standard 12-lead electrocardiography was performed. Information was obtained on ethnicity, medical history, place and altitude of pregnancy and birth, mobility of children and their parents and grandparents to lower altitudes, and housing conditions. A medical examination, echocardiography, hemoglobin, oxygen saturation, and anthropometric measurements were performed. Means between sexes were compared through Mann-Whitney test for independent samples not normally distributed. Potentially influential variables on electrocardiographic values were controlled through a general linear model. Electrocardiographic parameters including QRS axis, RV1, RSV1, RV1SV5, RSV5, RSV6, and SV1RV5 did not show a right predominance pattern at any age. Values were within sea level norms. None of the genetic or environmental factors controlled showed a consistent influence on the electrocardiographic variables. Our study showed an electrocardiographic pattern similar to that of sea level in high altitude children with some degree of high-altitude ancestry, comparatively well-nourished and with relatively high mobility to low altitudes.


A neutral trehalase gene from Candida albicans: molecular cloning, characterization and disruption.
A neutral trehalase gene, NTC1, from the human pathogenic yeast Candida albicans was isolated and characterized. An ORF of 2724 bp was identified encoding a predicted protein of 907 amino acids and a molecular mass of 104 kDa. A single transcript of approximately 3.2 kb was detected by Northern blot analysis. Comparison of the deduced amino acid sequence of the C. albicans NTC1 gene product with that of the Saccharomyces cerevisiae NTH1 gene product revealed 57% identity. The NTC1 gene was localized on chromosome 1 or R. A null mutant (delta ntc1/delta ntc1) was constructed by sequential gene disruption. Extracts from mutants homozygous for neutral trehalase deletion had only marginal neutral trehalase activity. Extracts from heterozygous mutants showed intermediate activities between extracts from the wild-type strain and from the homozygous mutants. The null mutant showed no significant differences in pathogenicity as compared to the wild-type strain in a mouse model of systemic candidiasis. This result indicates that the neutral trehalase of C. albicans is not a potential target for antifungal drugs.


RhoA/Rho kinase (ROCK) alters fetuin-A uptake and regulates calcification in bovine vascular smooth muscle cells (BVSMC).
RhoA/Rho kinases (ROCK) play a critical role in vascular smooth muscle cell (VSMC) actin cytoskeleton organization, differentiation, and function and are implicated in the pathogenesis of cardiovascular disease. We have previously determined that an important step in the regulation of calcification is fetuin-A endocytosis, a process that is dependent on changes in the cytoskeleton, which, in turn, is known to be affected by the RhoA/ROCK signaling pathway. In the present study, bovine VSMC (BVSMC) were treated with the ROCK inhibitor Y-27632 or transfected with ROCK small interfering (si) RNA to knock down ROCK expression. Both conditions resulted in reduced actin stress fibers and increased Cy5-labeled fetuin-A uptake. Inhibition of ROCK by Y-27632 or siRNA also significantly increased BVSMC alkaline phosphatase (ALP) activity and calcification of BVSMC and rat aorta organ cultures. Cells were then incubated in calcification media in the presence or absence of Y-27632 and matrix vesicles (MV) isolated by collagenase digestion. These MV, isolated from BVSMC incubated with Y-27632, had increased ALP activity and increased ability of MV to subsequently calcify collagen by 66%. In contrast, activation of RhoA, which is upstream of ROCK, by transfecting plasmids encoding the dominant active Rho GTPase mutant (Rho-L63) led to decreased fetuin-A uptake and reduced calcification in BVSMC. These results demonstrate that the RhoA/ROCK signaling pathway is an important negative regulator of vascular calcification.


Nitrogen fertilization application strategies improve yield of the rice cultivars with different yield types by regulating phytohormones.
Rice (Oryza sativa L.) is the most important food crop worldwide, and its sustainable development is essential to ensure global food security. Panicle morphological and physiological characteristics plays an important role in rice yield formation. However, under different nitrogen (N) fertilization strategies, it is not clear whether the morphological and physiological state of panicles at panicle development stage affects the formation of yield. To understand how the panicle differentiation and development, and grain yield are affected by the N fertilization strategies, and clarify the relationship between related traits and yield in the process of panicle development in different cultivars. In this study consisted of no N fertilizer and four N fertilization strategies, a panicle weight type (PWT) rice cultivar, Dongfu 114 (DF114) and a panicle number type (PNT) rice cultivar, Longdao 11 (LD11) were grown in the field. The results showed that N fertilization strategies could improve the nitrogen use efficiency and yield of rice, but the response of different rice varieties to N fertilizer strategies was different. Different from the DF114, the further increase of panicle N fertilizer ratio could not further improve the yield of LD11, and the highest grain yield of DF114 and LD11 was obtained under N4 and N3 conditions, respectively. In addition, this study found that N fertilizer strategies can affect the content of phytohormones in rice at the panicle differentiation stage, and then regulate the differentiation and development of rice panicles to affect yield. It is of great significance to optimize the application mode of N fertilizer according to the characteristics of varieties to improve rice yield and ensure food security.


Circulating endothelial cells as a marker of ongoing vascular disease in systemic sclerosis.
Circulating endothelial cells (CECs) have been described in different conditions involving vascular injury. Vascular abnormalities play a key role in the pathogenesis of systemic sclerosis (SSc). The aim of this study was to search for the presence of CECs in patients with SSc and to evaluate their clinical associations and possible pathogenic role. The study cohort included 46 patients with SSc and 40 healthy controls. Five-parameter, 3-color flow cytometry was performed with a FACScan. CECs were defined as CD45 negative, CD34 positive, and P1H12 positive, and activated CECs were defined as CD45 negative and P1H12 positive, CD62 positive, or CD106 positive. Progenitors were identified as CD34 positive and CD133 positive. Total and activated CEC counts were significantly higher in SSc patients compared with healthy controls and were positively correlated with the disease activity score. With respect to visceral involvement, significant correlation was observed between the CEC number and the severity of pulmonary hypertension. High levels of endothelial progenitors were observed in patients with SSc, and the counts were higher in the early stages of disease. The presence of CECs in patients with SSc may represent direct evidence of endothelial disease and may be a promising new clinical marker for active SSc. Notably, the association between CECs and pulmonary hypertension and impaired carbon monoxide diffusing capacity was evident in patients with limited cutaneous SSc only, suggesting an important role for CECs in this disease subset with prominent vascular changes. Detection of circulating endothelial progenitors may represent a response to vascular ischemia in early SSc, as an attempt at revascularization.