Anesthetic experience of a patient with Ohtahara syndrome -A case report-.
Ohtahara syndrome (OS) is a rare epileptic encephalopathy that is characterized by an abnormal electroencephalogram (EEG) and intractable seizures in the neonatal and early infantile period. The patient of this reported case was delivered normally at 39 weeks of gestation without any complication. One week after birth, seizures that were refractory to anticonvulsants started with repetitive clustered tonic spasms. The child had no abnormal findings on the initial laboratory investigations. But he was diagnosed with OS according to the frequent tonic spasms, an abnormal EEG pattern of suppression-burst and magnetic resonance imaging of cortical dysplasia. He was planned to undergo an operation for brain lesion. This report describes our experience with the general anesthetic management when we performed craniotomy and right hemispherotomy for a patient with OS.


Rosmarinic acid attenuates inflammation in experimentally induced arthritis in Wistar rats, using Freund's complete adjuvant.
The purpose of our investigation is to evaluate the anti-arthritic potential of isolated rosmarinic acid from the rind of Punica granatum. Rosmarinic acid was isolated by bioactivity-guided isolation from butanolic fraction of Punica granatum and acute toxicity of rosmarinic acid was carried out. The experiment was conducted at doses of 25 and 50 mg/kg, in Freund's complete adjuvant (FCA)-induced arthritic rats. Various parameters, that is arthritic score, paw volume, thickness of paw, hematological, antioxidant and inflammatory parameters such as glutathione (GSH), superoxide dismutase (SOD), malonaldehyde (MDA) and tumor necrosis factor-α (TNF-α) were also estimated. Rosmarinic acid significantly decreased the arthritic score, paw volume, joint diameter, white blood cell count and erythrocyte sedimentation rate. It also significantly increased body weight, hemoglobin and red blood cells. The significantly decreased levels of TNF-α were observed in treated groups as compared to arthritic control rats (P < 0.001). At the same time antioxidant parameters (like GSH and SOD) were increased significantly while levels of MDA were significantly decreased (P < 0.001). The outcome of the present research concludes that rosmarinic acid showed significant anti-arthritic potential in FCA-induced arthritis in Wistar rats. This study represented the therapeutic role of rosmarinic acid from Punica granatum for the management of arthritis/rheumatoid arthritis/osteoarthritis and related inflammatory complications with negligible side effects which was still far from complete mitigation with available conventional medicines.


Toxicity of phthalate esters to lettuce (Lactuca sativa) and the soil microbial community under different soil conditions.
Phthalate esters (PAEs) are globally used plasticizers and typical endocrine disruptors that can readily accumulate in agricultural products and represent a substantial risk to human health via the food chain. The range of soil properties has an important influence on the expression of PAE toxicity, and the mechanisms by which soil physical and chemical properties affect the expression of toxicity of target PAEs to plants and microorganisms requires further investigation. Important soil factors affecting the eco-toxicological effects of two typical PAEs, di-n-butyl phthalate (DnBP) and bis (2-ethylhexyl) phthalate (DEHP), on lettuce (Lactuca sativa) in a spiked soil were investigated in the present study. Soil at various pH values was spiked with three PAE concentrations (1, 5 and 20 mg DnBP or DEHP kg-1 soil), organic matter contents and water holding contents to simulate the greenhouse soil environment for 30 days. Their influence on the biomass, photosynthetic pigment contents, various physiological changes and soil microbial communities was determined as endpoints. The toxicity to lettuce of DnBP was higher than that of DEHP in the soil and soil pH was the most important factor affecting their single toxicity, followed by soil organic matter content and soil moisture content in agreement with the Biolog test results. Under different soil conditions total protein, total soluble sugar and free amino acid contents were positively correlated with concentrations of the target PAEs, but leaf area, biomass, •O2- activity, vitamin C content and soil microbial diversity indices showed the opposite trend. Chlorophyll a and carotenoid contents were more inhibited by DnBP together with impacts on indices of soil microbial diversity. The results suggest that soil conditions in greenhouses directly explain the patterns of pollutant toxicity displayed and impact the quantity, quality and food safety of vegetables produced using highly intensive production systems.


Perioperative GMCSF limits the proangiogenic plasma protein changes associated with colorectal cancer resection.
Colorectal resection (CR) increases plasma VEGF levels which may promote residual tumor growth. This study assessed the effect of perioperative GMCSF on plasma levels of sVEGFR1, Ang-1 and Ang-2 and also the impact of post-GMCSF plasma on in vitro endothelial cell (EC) growth and invasion. Ang-2 increases while sVEGFR1 and Ang-1 impede angiogenesis. Fifty-nine CR cancer patients were randomized to 7 perioperative doses of GMCSF or saline for 3days prior and 4days after CR. Blood samples were taken pre-drug (PreRx) and on several postoperative days (POD). Protein levels were assessed and PreRx and POD 5 plasma added to EC cultures after which branch point formation (ECBPF) and invasion (ECI) were measured. sVEGFR1 levels were significantly higher on POD 1 and POD 5 in both groups but the GMCSF POD 5 level was twice the control value (p=0.002). Ang-2 levels were higher on PODs 1 and 5 in both groups (p<0.05) but the control POD 5 value (vs. GMCSF) was greater (p=0.03). Ang-1 decreases were noted in all (p=not significant, ns). The control group POD 5 ECBPF was 35.8% greater than Pre Rx (p=0.001) while the GMCSF result was 18.0% lower (p=ns); the control POD 5 median percent change from baseline was greater than the GMCSF result(p=0.008). The POD 5 ECI was +12.2% for the control group vs. baseline (p=ns) and -17.2% for the GMCSF group (p=ns): the control median percent change was greater than in the GMCSF group(p=0.045). CR-related plasma changes are proangiogenic (>Ang-2) and anti-angiogenic (>sVEGFR1); the net effect is promotion of in vitro ECBPF. GMCSF limits the proangiogenic changes (higher POD 5 sVEGFR1 levels and lower Ang-2 elevations, lower POD 5 ECBPF and ECI). The clinical import of these effects is unclear; perioperative GMCSF has anti-angiogenic plasma effects that may limit tumor growth. Further investigation is warranted.


Strategic Modification of Gut Microbiota through Oral Bacteriotherapy Influences Hypoxia Inducible Factor-1α: Therapeutic Implication in Alzheimer's Disease.
Dysbiosis contributes to Alzheimer's disease (AD) pathogenesis, and oral bacteriotherapy represents a promising preventative and therapeutic opportunity to remodel gut microbiota and to delay AD onset and progression by reducing neuroinflammation and amyloid and tau proteins aggregation. Specifically, SLAB51 multi-strain probiotic formulation positively influences multiple neuro-chemical pathways, but exact links between probiotics oral consumption and cerebral beneficial effects remain a gap of knowledge. Considering that cerebral blood oxygenation is particularly reduced in AD and that the decreased neurovascular function contributes to AD damages, hypoxia conditioning represents an encouraging strategy to cure diseases of the central nervous system. In this work, 8-week-old 3xTg-AD and wild-type mice were chronically supplemented with SLAB51 to evaluate effects on hypoxia-inducible factor-1α (HIF-1α), a key molecule regulating host-microbial crosstalk and a potential target in neurodegenerative pathologies. We report evidence that chronic supplementation with SLAB51 enhanced cerebral expression of HIF-1α and decreased levels of prolyl hydroxylase 2 (PHD2), an oxygen dependent regulator of HIF-1α degradation; moreover, it successfully counteracted the increase of inducible nitric oxide synthase (iNOS) brain expression and nitric oxide plasma levels in AD mice. Altogether, the results demonstrate an additional mechanism through which SLAB51 exerts neuroprotective and anti-inflammatory effects in this model of AD.


Models of cardiovascular surgery biobanking to facilitate translational research and precision medicine.
Biobanking in health care has evolved over the last few decades from simple biological sample repositories to complex and dynamic units with multi-organizational infrastructure networks and has become an essential tool for modern medical research. Cardiovascular tissue biobanking provides a unique opportunity to utilize cardiac and vascular samples for translational research into heart failure and other related pathologies. Current techniques for diagnosis, classification, and treatment monitoring of cardiac disease relies primarily on interpretation of clinical signs, imaging, and blood biomarkers. Further research at the disease source (i.e. myocardium and blood vessels) has been limited by a relative lack of access to quality human cardiac tissue and the inherent shortcomings of most animal models of heart disease. In this review, we describe a model for cardiovascular tissue biobanking and databasing, and its potential to facilitate basic and translational research. We share techniques to procure endocardial samples from patients with hypertrophic cardiomyopathy, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction, in addition to aortic disease samples. We discuss some of the issues with respect to data collection, privacy, biobank consent, and the governance of tissue biobanking. The development of tissue biobanks as described here has significant scope to improve and facilitate translational research in multi-omic fields such as genomics, transcriptomics, proteomics, and metabolomics. This research heralds an era of precision medicine, in which patients with cardiovascular pathology can be provided with optimized and personalized medical care for the treatment of their individual phenotype.


Sex Lethal Gene Manipulates Gonadal Development of Medaka, Oryzias latipes, through Estrogenic Interventions.
Germ cells are pivotal for gonadal sexuality maintenance and reproduction. Sex lethal (sxl), the somatic sex determining gene of Drosophila, is the known regulator and initiator of germ cell femininity in invertebrates. However, the role of the Sxl homologue has rarely been investigated in vertebrates. So, we used medaka to clarify the role of sxl in vertebrate gonadogenesis and sexuality and identified two Sxl homologues, i.e., Sxl1a and Sxl1b. We found that sxl1a specifically expresses in the primordial germ cells (PGC), ovary, (early gonia and oocytes), while sxl1b distributions are ubiquitous. An mRNA overexpression of sxl1a accelerated germ cell numbers in 10 DAH XY fish, and sxl1a knockdown (KD), on the other hand, induced PGC mis-migration, aberrant PGC structuring and ultimately caused significant germ cell reduction in XX fish. Using an in vitro promoter analysis and in vivo steroid treatment, we found a strong link between sxl1a and estrogenic germ cell-population maintenance. Further, using sxl1a-KD and erβ2-knockout fish, we determined that sxl1 acts through erβ2 and controls PGC sexuality. Cumulatively, our study highlights the novel role of sxl1a in germ cell maintenance and sexual identity assignment and thus might become a steppingstone to understanding the commonalities of animal sexual development.


Loss of FHR variability diagnosed by frequency analysis.
To determine the loss of fetal heart rate (FHR) baseline variability by frequency analysis. The FHR tracings of 12 normal fetuses and others with various conditions, as well as flat FHR tracings of a late deceleration (LD) and anencephaly recorded with Doppler fetal monitors, were scanned and processed using fast Fourier transform (FFT) analysis. The ratio of the area under the low frequency spectrum divided by the area under the whole spectrum (La/Ta) and the peak power spectrum density (PPSD) were determined. Long-term variability (LTV) measures >10 bpm revealed significantly more La/Ta and PPSD than LTV <10 bpm in normal FHR tracings. The La/Ta and PPSD were >15% and 60 bpm(2)/Hz, respectively, in representative values of normal FHR cases and in those of fetal respiration, hiccupps and non-reactive FHR, whereas those of the flat baseline of LD and anencephaly were <15% and 60 bpm(2)/Hz. Loss of baseline variability is diagnosed when the La/Ta ratio and PPSD are <15% and 60 bpm(2)/Hz, respectively, based on the FFT frequency analysis of the FHR baseline.


Diffusion-limited contact formation in unfolded cytochrome c: estimating the maximum rate of protein folding.
How fast can a protein fold? The rate of polypeptide collapse to a compact state sets an upper limit to the rate of folding. Collapse may in turn be limited by the rate of intrachain diffusion. To address this question, we have determined the rate at which two regions of an unfolded protein are brought into contact by diffusion. Our nanosecond-resolved spectroscopy shows that under strongly denaturing conditions, regions of unfolded cytochrome separated by approximately 50 residues diffuse together in 35-40 microseconds. This result leads to an estimate of approximately (1 microsecond)-1 as the upper limit for the rate of protein folding.


[The microflora of the reproductive tract in women during intrauterine interventions].
The species compositions and persistence factors of the vaginal and cervical microflora of the reproductive tract of women in cases of intrauterine interventions (medical abortion, intrauterine contraception) were studied. Women with inflammatory complications following intrauterine interventions were found to have the same species of bacteria in their vaginal and cervical microflora. In addition, an increase in the values of the persistence factors of vaginal microflora was registered in women practicing intrauterine contraception and a decrease in the persistence potential of vaginal microflora was registered after abortion.


Disease dynamics in a coupled cholera model linking within-host and between-host interactions.
A new modelling framework is proposed to study the within-host and between-host dynamics of cholera, a severe intestinal infection caused by the bacterium Vibrio cholerae. The within-host dynamics are characterized by the growth of highly infectious vibrios inside the human body. These vibrios shed from humans contribute to the environmental bacterial growth and the transmission of the disease among humans, providing a link from the within-host dynamics at the individual level to the between-host dynamics at the population and environmental level. A fast-slow analysis is conducted based on the two different time scales in our model. In particular, a bifurcation study is performed, and sufficient and necessary conditions are derived that lead to a backward bifurcation in cholera epidemics. Our result regarding the backward bifurcation highlights the challenges in the prevention and control of cholera.


Stochastic and regulatory role of chromatin silencing in genomic response to environmental changes.
Phenotypic diversity and fidelity can be balanced by controlling stochastic molecular mechanisms. Epigenetic silencing is one that has a critical role in stress response. Here we show that in yeast, incomplete silencing increases stochastic noise in gene expression, probably owing to unstable chromatin structure. Telomere position effect is suggested as one mechanism. Expression diversity in a population achieved in this way may render a subset of cells to readily respond to various acute stresses. By contrast, strong silencing tends to suppress noisy expression of genes, in particular those involved in life cycle control. In this regime, chromatin may act as a noise filter for precisely regulated responses to environmental signals that induce huge phenotypic changes such as a cell fate transition. These results propose modulation of chromatin stability as an important determinant of environmental adaptation and cellular differentiation.


Inhaled tiotropium for stable chronic obstructive pulmonary disease.
Tiotropium is a new anticholinergic therapy for chronic obstructive pulmonary disease (COPD) that differs from ipratropium by its functional relative selectivity for muscarinic receptor subtypes and which allows once-per-day dosing. To determine the efficacy of tiotropium on clinical endpoints such exacerbations and hospitalisations, symptom scales and pulmonary function compared to placebo and other bronchodilators used for stable COPD. Randomised controlled trials (RCTs) were identified from the Cochrane Airways Review Group Specialised Register, a compilation of systematic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL, and hand searching of 20 respiratory journals. Bibliographies from included studies and reviews were searched. The date of the last search was October 2004. Randomised clinical trials comparing tiotropium with placebo, ipratropium bromide, or long-acting ss2-agonists for greater than, or equal to, one month's duration. Two reviewers independently extracted data. Missing data were obtained from authors or the manufacturer of tiotropium. The data were analysed using the Cochrane Review Manager RevMan 4.2. Studies were pooled to yield weighted mean differences (WMD) or odds ratios (OR) and reported using 95% confidence intervals (CI). From 69 identified references, nine RCTs (6,584 patients) met inclusion criteria. Tiotropium reduced the odds of a COPD exacerbation (OR 0.74; 95% CI 0.66 to 0.83) and related hospitalisations (OR 0.64; 95% CI 0.51 to 0.82) compared to placebo or ipratropium. When applied to an annual baseline risk of 45% for exacerbations and 10% for hospitalisation, the number of patients needed to treat with tiotropium for one year were 14 (95% CI 11 to 22) to prevent one exacerbation and 30 (95% CI 22 to 61) to prevent one hospitalisation compared to placebo and ipratropium. Reductions in these endpoints compared to long-acting ss2-agonists were not statistically significant. Similar patterns were evident for quality-of-life and symptom scales. Increases in FEV1 and FVC from baseline were significantly larger with tiotropium than with placebo, ipratropium and long-acting ss2-agonists over 6 to 12 months. The decline in trough FEV1 from steady state was 30 ml (95% CI 7 to 53 ml) less with tiotropium than with placebo or ipratropium over one year; no data on decline in FEV1 from steady state were available for long-acting ss2-agonists. Dry mouth was increased by tiotropium. Tiotropium reduced COPD exacerbations and related hospitalisations compared to placebo and ipratropium. It also improved health-related quality-of-life and symptom scores among patients with moderate and severe disease, and may have slowed decline in FEV1. Additional long-term studies are required to evaluate its effect on mortality and change in FEV1 to clarify its role in comparison to, or in combination with, long-acting ss2-agonists and to assess its effectiveness in mild and very severe COPD.


Childhood thyroid function, body composition and cardiovascular function.
The cardiovascular system is a known target for thyroid hormone. Early-life cardiovascular alterations may lead to a higher risk of cardiovascular disease in adulthood. Little is known about the effects of thyroid hormone on cardiovascular function during childhood, including the role of body composition in this association. Population-based prospective cohort of children (n = 4251, median age 6 years, 95% range: 5.7-8.0 years). Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) concentrations were measured to assess thyroid function. Left ventricular (LV) mass was assessed with echocardiography. Arterial stiffness was assessed with carotid-femoral pulse wave velocity (CFPWV). Systolic and diastolic blood pressure (BP) was measured. Body composition was assessed by dual-energy X-ray absorptiometry scan. FT4 was inversely associated with LV mass (P = 0.002), and with lean body mass (P < 0.0001). The association of FT4 with LV mass was partially mediated through variability in lean body mass (55% mediated effect). TSH was inversely associated with LV mass (P = 0.010), predominantly in boys. TSH was positively associated with systolic and diastolic BP (both P < 0.001). FT4 was positively associated with CFPWV and diastolic BP (P < 0.0001, P = 0.008, respectively), and the latter association attenuated after adjustment for CFPWV. At the age of 6 years, higher FT4 is associated with lower LV mass (partially through effects on lean body mass) and with higher arterial stiffness, which may lead to higher BP. Our data also suggest different mechanisms via which TSH and FT4 are associated with cardiovascular function during early childhood.


In Matrix Derivatization Combined with LC-MS/MS Results in Ultrasensitive Quantification of Plasma Free Metanephrines and Catecholamines.
Plasma-free metanephrines and catecholamines are essential markers in the biochemical diagnosis and follow-up of neuroendocrine tumors and inborn errors of metabolism. However, their low circulating concentrations (in the nanomolar range) and poor fragmentation characteristics hinder facile simultaneous quantification by liquid chromatography and tandem mass spectrometry (LC-MS/MS). Here, we present a sensitive and simple matrix derivatization procedure using propionic anhydride that enables simultaneous quantification of unconjugated l-DOPA, catecholamines, and metanephrines in plasma by LC-MS/MS. Dilution of propionic anhydride 1:4 (v/v) in acetonitrile in combination with 50 μL of plasma resulted in the highest mass spectrometric response. In plasma, derivatization resulted in stable derivatives and increased sensitivity by a factor of 4-30 compared with a previous LC-MS/MS method for measuring plasma metanephrines in our laboratory. Furthermore, propionylation increased specificity, especially for 3-methoxytyramine, by preventing interference from antihypertensive medication (β-blockers). The method was validated according to international guidelines and correlated with a hydrophilic interaction LC-MS/MS method for measuring plasma metanephrines (R2 > 0.99) and high-performance liquid chromatography with an electrochemical detection method for measuring plasma catecholamines (R2 > 0.85). Reference intervals for l-DOPA, catecholamines, and metanephrines in n = 115 healthy individuals were established. Our work shows that analytes in the subnanomolar range in plasma can be derivatized in situ without any preceding sample extraction. The developed method shows improved sensitivity and selectivity over existing methods and enables simultaneous quantification of several classes of amines.


Self-adaptive regularization.
Often an image g(x,y) is regularized and even restored by minimizing the Mumford-Shah functional. Properties of the regularized image u(x,y) depends critically on the numerical value of the two parameters alpha and gamma controlling smoothness and fidelity. When alpha and gamma are constant over the image, small details are lost when an extensive filtering is used in order to remove noise. In this paper, it is shown how the two parameters alpha and gamma can be made self-adaptive. In fact, alpha and gamma are not constant but automatically adapt to the local scale and contrast of features in the image. In this way, edges at all scales are detected and boundaries are well-localized and preserved. In order to preserve trihedral junctions alpha and gamma become locally small and the regularized image u(x,y) maintains sharp and well-defined trihedral junctions. Images regularized by the proposed procedure are well-suited for further processing, such as image segmentation and object recognition.


Neutrophil function in a rat model of endotoxin-induced lung injury.
Polymorphonuclear neutrophil leukocytes (PMNs) are known to cross the alveolar-capillary barrier and enter the alveolus in acute adult respiratory distress syndrome (ARDS). The pathogenic role of PMNs in both the acute lung injury and subsequent infectious susceptibility in ARDS is not clear. In the present study we investigated the functional status of various neutrophil populations using a chronic, endotoxemia-induced ARDS model. Rats infused with Escherichia coli endotoxin for three days develop an acute lung injury with a histologic picture closely resembling human ARDS. The PMNs recovered from the circulation and by bronchoalveolar lavage were compared with normal rat PMNs. In endotoxemic animals, superoxide production was markedly enhanced in circulating PMNs, indicating production of high levels of potentially cytotoxic oxygen intermediates, while myeloperoxidase activity was decreased in both circulating and lavage PMNs, indicating depressed myeloperoxidase-dependent antimicrobial activity.


Palm Olein Emulsion: a Novel Vehicle for Topical Drug Delivery of Betamethasone 17-Valerate.
This study aims to investigate the use of palm olein as the oil phase for betamethasone 17-valerate (BV) emulsions. The physicochemical properties of the formulations were characterized. In vitro drug release study was performed with the Hanson Vertical Diffusion Cell System; the samples were quantified with HPLC and the results were compared with commercial products. Optimized emulsion formulations were subjected to stability studies for 3 months at temperatures of 4, 25, and 40°C; the betamethasone 17-valerate content was analyzed using HPLC. The formulations produced mean particle size of 2-4 μm, viscosities of 50-250 mPa.s, and zeta potential between -45 and -68 mV. The rheological analyses showed that the emulsions exhibited pseudoplastic and viscoelastic behavior. The in vitro release of BV from palm olein emulsion through cellulose acetate was 4.5 times higher than that of commercial products and more BV molecules deposited in rat skin. Less than 4% of the drug was degraded in the formulations during the 3-month period when they were subjected to the three different temperatures. These findings indicate that palm olein-in-water emulsion can be an alternative vehicle for topical drug delivery system with superior permeability.


Protection of chickens from Newcastle disease with a recombinant baculovirus subunit vaccine expressing the fusion and hemagglutininneuraminidase proteins.
Recombinant baculoviruses containing the fusion (F) and hemagglutinin-neuraminidase (HN) glycoprotein gene of the viscerotropic velogenic (vv) Newcastle disease virus (NDV) isolate, Kr-005/00, and a lentogenic La Sota strain of the NDV were constructed in an attempt to develop an effective subunit vaccine to the recent epizootic vvNDV. The level of protection was determined by evaluating the clinical signs, mortality, and virus shedding from the oropharynx and cloaca of chickens after a challenge with vvNDV Kr-005/00. The recombinant ND F (rND F) and recombinant HN (rND HN) glycoproteins derived from the velogenic strain provided good protection against the clinical signs and mortality, showing a 0.00 PI value and 100% protection after a booster immunization. On the other hand, the combined rND F + HN glycoprotein derived from the velogenic strain induced complete protection (0.00 PI value and 100% protection) and significantly reduced the amount of virus shedding even after a single immunization. The rND F and rND HN glycoproteins derived from the velogenic strain had a slightly, but not significantly, greater protective effect than the lentogenic strain. These results suggest that the combined rND F + HN glycoprotein derived from vvNDV can be an ideal subunit marker vaccine candidate in chickens in a future ND eradication program.


Ribosomes slide on lysine-encoding homopolymeric A stretches.
Protein output from synonymous codons is thought to be equivalent if appropriate tRNAs are sufficiently abundant. Here we show that mRNAs encoding iterated lysine codons, AAA or AAG, differentially impact protein synthesis: insertion of iterated AAA codons into an ORF diminishes protein expression more than insertion of synonymous AAG codons. Kinetic studies in E. coli reveal that differential protein production results from pausing on consecutive AAA-lysines followed by ribosome sliding on homopolymeric A sequence. Translation in a cell-free expression system demonstrates that diminished output from AAA-codon-containing reporters results from premature translation termination on out of frame stop codons following ribosome sliding. In eukaryotes, these premature termination events target the mRNAs for Nonsense-Mediated-Decay (NMD). The finding that ribosomes slide on homopolymeric A sequences explains bioinformatic analyses indicating that consecutive AAA codons are under-represented in gene-coding sequences. Ribosome 'sliding' represents an unexpected type of ribosome movement possible during translation.


Patient-Reported Outcomes in Oncology, Beyond Randomized Controlled Trials.
The goal of the treatment of a disease has moved from treating organs and diseases through symptoms, biological parameters and imaging towards treating a human being as a whole. The treatments should deliver benefits that patients can personally perceive. However, the patient's perspective does not always match the one of those surrounding them. Illustratively, patients' symptom assessments are more predictable for daily health status, whereas clinicians' symptom measurements are more related to clinical outcomes. The term, patient-reported outcomes (PROs), includes any data that are reported directly by the patient without an intermediary, such as a family member or a healthcare professional. The use of PROs in oncology trials is increasing and the U.S. Food and Drug Administration has published guidelines on the review and evaluation of PROs. However, while PROs are increasingly used in clinical trials, they are rarely used in daily clinical practice. Further, healthcare payers are concerned with issues related to relevance, quality, and interpretability of these outcomes.


Mosaicism for oncogenic G12D KRAS mutation associated with epidermal nevus, polycystic kidneys and rhabdomyosarcoma.
Epidermal nevus (EN) is a congenital disorder characterised by hyperpigmented epidermal thickening following a Blaschko's line. It is due to somatic mutations in either FGFR3 or PIK3CA in half of the cases, and remains of unknown genetic origin in the other half. EN is also seen as part of complex developmental disorders or in association with bladder carcinomas, also related to FGFR3 and PIK3CA mutations. Mosaic mutations of these genes have been occasionally found in syndromic EN. The co-occurrence of EN, rhabdomyosarcoma, polycystic kidneys and growth retardation in an infant is described. An oncogenic G12D KRAS mutation was detected in both the epidermal component of the EN and in the rhabdomyosarcoma but not in the dermal component of the EN lesion or in unaffected tissues, including normal skin or blood. This report shows for the first time that a KRAS mutation in epiderma causes EN. Observation of the same G12D KRAS mutation in two distinct regions of the body strongly suggests a somatic mosaicism. Finally, this report highlights the potentially underestimated importance of mosaic oncogene mutations in childhood cancers.


Mitochondrial thermogenin content is unchanged during atrophy of BAT of fasting mice.
The objectives of this study were to evaluate the rate at which brown adipose tissue (BAT) from mice atrophies when its thermogenic activity is suppressed during fasting or exposure to a thermoneutral environment (33 degrees C) and whether such atrophy is accompanied by loss from BAT mitochondria of "thermogenin," the GDP binding protein associated with the calorigenic proton conductance pathway. Atrophy of mouse BAT was characterized by rapid loss of protein but unchanged tissue DNA content. The rate of protein loss varied from 2 to 6 mg protein/day depending on the environmental and feeding status of the mice. In synchrony with tissue protein loss, there was a marked reduction in the tissue content of mitochondrial proteins and of thermogenin, measured by immunoassay. However, the concentration of thermogenin in isolated mitochondria was unchanged by fasting or exposure of the mice to 33 degrees C for 48 h. By contrast, marked reduction in [3H]GDP binding to isolated mitochondria were observed after exposure of the mice to 33 degrees C. Mice acclimated at 4 but not those acclimated at 21 degrees C showed reduction in GDP binding to isolated mitochondria during fasting. These results clearly indicate that changes in purine nucleotide binding to isolated mitochondria can occur in the absence of changes in the mitochondrial concentration of thermogenin. Thus rapid decrease in BAT thermogenic capacity (e.g., during fasting or 33 degrees C exposure) appears dependent on extensive loss of tissue protein, probably whole mitochondria, rather than rapid and selective removal of thermogenin from the mitochondria.


Prejunctional cholinergic modulation of adrenergic neurotransmission in the cardiovascular system.
In the heart and in the blood vessel walls, complex adrenergic-cholinergic interactions occur both prejunctionally, at the level of the autonomic nerve terminals, and postjunctionally, at the level of the responding cells themselves. The principal prejunctional interaction appears to be an inhibition of the release of norepinephrine from adrenergic nerve terminals by the acetylcholine liberated from nearby cholinergic nerve endings. This inhibitory effect is mediated by muscarinic receptors located on the postganglionic sympathetic nerve terminals. The inhibitory effect of acetylcholine on cardiac and vascular tissues are therefore achieved in part by a direct influence of the cholinergic neurotransmitter on the cardiac and vascular muscle cells, and in part by an indirect influence on sympathetic neurotransmission.


Update and review of chemonucleolysis.
To update the status of chymopapain in the treatment of herniated intervertebral discs, a review of the current literature and data from an unpublished Texas study are presented. Studies in animals and humans have consistently demonstrated that chymopapain can dissolve the nucleus pulposus. Twenty-eight uncontrolled and unblinded clinical trials involving 2845 patients showed a positive response rate of 75%. Side effects occurred in 2.4% of chymopapain-treated patients. Anaphylaxis, the most serious adverse reaction associated with chemonucleolysis, was noted in less than 1% of patients. No deaths were reported. The first double-blind, placebo-controlled study of chymopapain in the United States demonstrated no significant efficacy, but both the design and execution of the study have been criticized. Two recent double-blind, placebo-controlled studies showed success rates of 73% and 80% for chymopapain, significantly higher than for placebo treatment. Postinjection back pain and muscle spasm were the most common side effects related to chymopapain administration in one of the trials. In the uncontrolled Texas study the success rate in 408 patients treated by chymopapain was 93%. Chemonucleolysis has achieved a success rate comparable with that of surgery in the treatment of symptomatic herniated discs. Appropriate use of chymopapain can result in substantial savings in time and hospital costs.


Blood lipid peroxidation (superoxide dismutase, malondialdehyde, glutathione) levels in Egyptian type 2 diabetic patients.
The existence of hyperglycaemia produces increased oxidative stress. The depletion of antioxidants as a defensive body mechanism may increase the risk of diabetic complications. Diabetes mellitus is associated with derangements in the serum levels of several biochemical parameters, and type 2 diabetes mellitus (or non-insulin-dependent diabetes mellitus) is a risk factor for cardiovascular diseases. Data of 80 control subjects (male:female, 40:40) and 80 diabetic patients (male:female, 40:40), of similar age, gender, body mass index and duration of diabetes mellitus (for diabetic group), were collected from government and non-government organisations during the period, 2001-2004. Blood samples were also collected. Glucose, glucosylated haemoglobin, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDLC), TC/HDL-C, HDL-C/LDL-C, triacylglycerol, malondialdehyde, glutathione and superoxide dismutase levels were determined. Mean cholesterol, LDL-C, VLDL-C and triacylglycerol levels were significantly higher in patients with type 2 diabetes mellitus in comparison to the control subjects, while the mean value of HDL-C was significantly lower. A significant elevation in malondialdehyde level and decrease in glutathione content were observed in both male and female diabetic patients in comparison to the control subjects. The results suggest that the increase in lipid peroxidation, and the decline in antioxidant defences, may appear early in type 2 diabetic patients, before the development of secondary complications. This phenomenon might play an important role in the initiation and progression of diabetic complications. Our results also suggest that there seems to be an imbalance between plasma oxidant and antioxidant systems in patients with type 2 diabetes mellitus.


Deoxyhypusine synthase from tobacco. cDNA isolation, characterization, and bacterial expression of an enzyme with extended substrate specificity.
Deoxyhypusine synthase catalyzes the formation of a deoxyhypusine residue in the translation eukaryotic initiation factor 5A (eIF5A) precursor protein by transferring an aminobutyl moiety from spermidine onto a conserved lysine residue within the eIF5A polypeptide chain. This reaction commences the activation of the initiation factor in fungi and vertebrates. A mechanistically identical reaction is known in the biosynthetic pathway leading to pyrrolizidine alkaloids in plants. Deoxyhypusine synthase from tobacco was cloned and expressed in active form in Escherichia coli. It catalyzes the formation of a deoxyhypusine residue in the tobacco eIF5A substrate as shown by gas chromatography coupled with a mass spectrometer. The enzyme also accepts free putrescine as the aminobutyl acceptor, instead of lysine bound in the eIF5A polypeptide chain, yielding homospermidine. Conversely, it accepts homospermidine instead of spermidine as the aminobutyl donor, whereby the reactions with putrescine and homospermidine proceed at the same rate as those involving the authentic substrates. The conversion of deoxyhypusine synthase-catalyzed eIF5A deoxyhypusinylation pinpoints a function for spermidine in plant metabolism. Furthermore, and quite unexpectedly, the substrate spectrum of deoxyhypusine synthase hints at a biochemical basis behind the sparse and skew occurrence of both homospermidine and its pyrrolizidine derivatives across distantly related plant taxa.


Particulate respirator use and blood pressure: A systematic review and meta-analysis.
People use a particulate respirator in order to reduce exposure to ambient fine particulate matter (PM2.5). Acute exposure to PM2.5 is known to increase blood pressure. However, systematic reviews or meta-analyses on blood pressure-related benefits of using a particulate respirator is lacking. Therefore, we reviewed randomized crossover intervention studies on blood pressure-related effects of particulate matter respirator use. We conducted a literature review of articles found on Embase, Medline, and Cochrane library on August 31, 2020. The study outcomes were systolic and diastolic blood pressure and mean arterial pressure. A random-effect model was used in the meta-analysis. Subgroup analyses, based on age (adult < 60 years, elderly ≥ 60 years), personal PM2.5 exposure levels (High: ≥ 25 μg/m3, Low: < 25 μg/m3), and types of monitoring methods (ambulatory and resting blood pressure) were conducted. We identified 297 references, and seven studies were included in our systematic review. None of the studies used a sham respirator as control and complete allocation concealment and blinding were impossible. The use of a particulate respirator was associated with a -1.23 mmHg (95% confidence interval (CI): -2.53, 0.07) change in systolic blood pressure and a -1.57 mmHg (95% CI: -3.85, 0.71) change in mean arterial pressure. There were significant heterogeneities and possibilities for publication bias. The subgroup analyses revealed that studies involving elderly individuals, those conducted in high PM2.5 personal exposure, and those in which resting blood pressure was monitored demonstrated a larger decrease in blood pressure resulting from respirator use. Further intervention studies with a large sample size and subjects with diverse characteristics and different personal PM2.5 levels may add the evidence to current literature.


Combined effects of lifestyle risk factors on fatty liver index.
Factors of lifestyle may have a major impact on liver-related morbidity and mortality. We examined independent and joint effects of lifestyle risk factors on fatty liver index (FLI), a biomarker of hepatic steatosis, in a population-based cross-sectional national health survey. The study included 12,368 participants (5784 men, 6584 women) aged 25-74 years. Quantitative estimates of alcohol use, smoking, adiposity and physical activity were used to establish a total score of risk factors, with higher scores indicating an unhealthier lifestyle. FLI was calculated based on an algorithm including body mass index, waist circumference, serum gamma-glutamyltransferase and triglycerides. The occurrence of FLI ≥ 60% indicating fatty liver increased from 2.4% in men with zero risk factors to 81.9% in those with a total risk score of 7-8 (p < 0.0005 for linear trend) and in women from 0 to 73.5% (p < 0.0005). The most striking individual impacts on the likelihood for FLI above 60% were observed for physical inactivity (p < 0.0005 for both genders) and alcohol consumption (p < 0.0005 for men). Interestingly, coffee consumption was also found to increase with increasing risk factor scores (p < 0.0005 for linear trend in both genders). The data indicates that unfavorable combinations of lifestyle risk factors lead to a high likelihood of hepatic steatosis. Use of FLI as a diagnostic tool may benefit the assessment of interventions aimed at maintaining a healthy lifestyle and prevention of liver-related morbidity.


Incidence of pulmonary metastases for various neoplasms in BALB/cStCrlfC3H/Nctr female fed N-2-fluorenylacetamide.
Incidence of pulmonary metastases for a variety of neoplasms was studied in many inbred BALB/cStCrlfC3H/Nctr female mice fed 2-fluorenylacetamide. Bladder carcinomas and hepatocellular carcinomas appeared to be the only neoplasms that were dose related. Hepatocellular carcinomas metastasized to the lungs at an incidence of 4.8%, and bladder carcinomas metastasized at an incidence of 0.28%. Osteogenic sarcomas metastasized to the lungs at an incidence of 46.2%; renal adenocarcinomas, at 20%; fibrosarcomas, at 16.7%; mammary adenocarcinomas, at 9.8%; and myoepitheliomas, at 10.5%. Other malignant neoplasms, including leiomyosarcomas, granulosa cells tumors, adrenocortical carcinomas, angiosarcomas, squamous cell carcinomas, and harderian gland tumors, metastasized at an incidence of less than 5%.


Parental risk factors and anorectal malformations: systematic review and meta-analysis.
Anorectal malformations (ARM) are rare forms of congenital uro-rectal anomalies with largely unknown causes. Besides genetic factors, prenatal exposures of the parents to nicotine, alcohol, caffeine, illicit drugs, occupational hazards, overweight/obesity and diabetes mellitus are suspected as environmental risk factors. Relevant studies published until August 2010 were identified through systematic search in PubMed, EMBASE, ISI Web of Knowledge and the Cochrane Library databases. Furthermore, related and cross-referencing publications were reviewed. Pooled odds ratios (95% confidence intervals) were determined to quantify associations of maternal and paternal smoking, maternal alcohol consumption, underweight (body mass index [BMI] < 18.5), overweight (BMI 25-29.9), obesity (BMI ≥30) and maternal diabetes mellitus with ARM using meta-analyses. 22 studies that reported on the association between prenatal environmental risk factors and infants born with ARM were included in this review. These were conducted in the United States of America (n = 12), Spain (n = 2), Sweden (n = 2), the Netherlands (n = 2), Japan (n = 1), France (n = 1), Germany (n = 1) and Hungary (n = 1). However, only few of these studies reported on the same risk factors. Studies were heterogeneous with respect to case numbers, control types and adjustment for covariates. Consistently increased risks were observed for paternal smoking and maternal overweight, obesity and diabetes, but not for maternal smoking and alcohol consumption. In meta-analyses, pooled odds ratios (95% confidence intervals) for paternal smoking, maternal overweight, obesity, pre-gestational and gestational diabetes were 1.53 (1.04-2.26), 1.25 (1.07-1.47), 1.64 (1.35-2.00), 4.51 (2.55-7.97) and 1.81 (1.23-2.65), respectively. Evidence on risk factors for ARM from epidemiological studies is still very limited. Nevertheless, the few available studies indicate paternal smoking and maternal overweight, obesity and diabetes to be associated with increased risks. Further, ideally large-scale multicentre and register-based studies are needed to clarify the role of key risk factors for the development of ARM.


Improved biochemical preservation of lung slices during cold storage.
Development of lung preservation solutions typically requires whole-organ models which are animal and labor intensive. These models rely on physiologic rather than biochemical endpoints, making accurate comparison of the relative efficacy of individual solution components difficult. We hypothesized that lung slices could be used to assess preservation of biochemical function during cold storage. Whole rat lungs were precision cut into slices with a thickness of 500 microm and preserved at 4 degrees C in the following solutions: University of Wisconsin (UW), Euro-Collins (EC), low-potassium-dextran (LPD), Kyoto (K), normal saline (NS), or a novel lung preservation solution (NPS) developed using this model. Lung biochemical function was assessed by ATP content (etamol ATP/mg wet wt) and capacity for protein synthesis (cpm/mg protein) immediately following slicing (0 h) and at 6, 12, 18, and 24 h of cold storage. Six slices were assayed at each time point for each solution. The data were analyzed using analysis of variance and are presented as means +/- SD. ATP content was significantly higher in the lung slices stored in NPS compared with all other solutions at each time point (P < 0.0001). Protein synthesis was significantly higher in the lung slices stored in NPS compared with all other solutions at 6, 12, and 18 h of preservation (P < 0.05). This lung slice model allows the rapid and efficient screening of lung preservation solutions and their components using quantifiable biochemical endpoints. Using this model, we have developed a novel solution that improves the biochemical preservation of lung slices during cold storage.


Interactions of hormone replacement therapy, body weight, and bilateral oophorectomy in breast cancer risk.
To examine potential modifying effects of body weight and bilateral oophorectomy on the association of hormone replacement therapy (HRT) with risk of breast cancer, overall and by subtypes according to status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) among postmenopausal women. This analysis included 2,510 postmenopausal white women recruited in the Nashville Breast Health Study, a population-based case-control study of breast cancer. Multivariable logistic regression was used to estimate ORs and 95% confidence intervals (CI) for associations between HRT use and risk of breast cancer overall and by subtypes, adjusted for age and education. Among women with natural menopause and body mass index (BMI) < 25 kg/m(2), ever-use of HRT was associated with increased breast cancer risk (OR, 1.95; 95% CI, 1.32-2.88). Risk was elevated with duration of HRT use (P for trend = 0.002). Similar association patterns were found for ER(+), ER(+)PR(+), and luminal A cancer subtypes but not ER(-), ER(-)PR(-), and triple-negative cancer. In contrast, ever-HRT use in overweight women (BMI ≥ 25 kg/m(2)) showed no association with risk of breast cancer overall or by subtypes; interaction tests for modifying effect of BMI were statistically significant. Ever-HRT use was associated with decreased breast cancer risk (OR, 0.70; 95% CI, 0.38-1.31) among women with prior bilateral oophorectomy but elevated risk (OR, 1.45; 95% CI, 0.92-2.29) among those with hysterectomy without bilateral oophorectomy (P for interaction = 0.057). Similar associations were seen for virtually all breast cancer subtypes, although interaction tests were statistically significant for ER(+) and luminal A only. Body weight and bilateral oophorectomy modify associations between HRT use and breast cancer risk, especially the risk of hormone receptor-positive tumors.


Pattern recognition as conceptual morphogenesis.
Pattern recognition is our mental activity in which we formulate, select, modify, and adjust our concepts or our frames of reference so that we can see a ``form'' in objects. We can tentatively formulate this viewpoint as the principle of minimum entropy (or entropy-like function). Different algorithms in clustering and pattern recognition are given new interpretations in the light of this unifying principle.


Adverse drug reactions in hospital in-patients: a prospective analysis of 3695 patient-episodes.
Adverse drug reactions (ADRs) are a major cause of hospital admissions, but recent data on the incidence and clinical characteristics of ADRs which occur following hospital admission, are lacking. Patients admitted to twelve wards over a six-month period in 2005 were assessed for ADRs throughout their admission. Suspected ADRs were recorded and analysed for causality, severity and avoidability and whether they increased the length of stay. Multivariable analysis was undertaken to identify the risk factors for ADRs. The 5% significance level was used when assessing factors for inclusion in multivariable models. Out of the 3695 patient episodes assessed for ADRs, 545 (14.7%, 95% CI 13.6-15.9%) experienced one or more ADRs. Half of ADRs were definitely or possibly avoidable. The patients experiencing ADRs were more likely to be older, female, taking a larger number of medicines, and had a longer length of stay than those without ADRs. However, the only significant predictor of ADRs, from the multivariable analysis of a representative sample of patients, was the number of medicines taken by the patient with each additional medication multiplying the hazard of an ADR episode by 1.14 (95% CI 1.09, 1.20). ADRs directly increased length of stay in 147 (26.8%) patients. The drugs most frequently associated with ADRs were diuretics, opioid analgesics, and anticoagulants. In conclusion, approximately one in seven hospital in-patients experience an ADR, which is a significant cause of morbidity, increasing the length of stay of patients by an average of 0.25 days/patient admission episode. The overall burden of ADRs on hospitals is high, and effective intervention strategies are urgently needed to reduce this burden.


A Driver Training Program Intervention for Student Drivers with Autism Spectrum Disorder: A Multi-site Randomised Controlled Trial.
The purpose of this multi-site randomised controlled trial was to evaluate the effectiveness of a Driving Training Program, an intervention designed for student drivers with autism spectrum disorder (ASD). Participants were 72 student drivers with ASD (ages 16-31) who were randomly assigned to an intervention or control group. Student drivers received ten driving lessons with a professional driving instructor via a standardised driving route. The Driving Performance Checklist was used as the outcome measure to evaluate the driving performance of student drivers during on-road pre- and post-observational drives. Both groups showed an improvement in driving performance, however, the extent of improvement between groups was not significant. Findings showed promising intervention efficacy for training student drivers with ASD to drive.


Ring chromosome 18 in a child with febrile seizures.
Ring chromosomes are uncommon cytogenetic findings but have meanwhile been reported for nearly all human chromosomes. Among the rare observations of ring chromosomes in man, the diagnosis of ring chromosome 18 represents a prominent group. We here describe on the cytogenetic analysis results obtained for a 9 years old male patient of non-consanguineous parents. He had growth and developmental delay, mental and motor retardation, microcephaly, microphtalmia, triangle face, small dysplastic ears, strabismus, epicanthal folds on the left, short stature, cryptorchidism, spasticity, pes equinovarus, pes planus, hypothroidism, stereotypic movements and febrile seizures. Also he had hypomyelinization and multiple hyperintense focuses within the white matter on the MRI. The generalized epileptiform abnormality originated from bilateral Centroparietal region. The metabolic investigations including blood and urine amino acids and lysosomal screening tests were normal. The chromosome analysis identified [46,XY,r(18)/46,XY] in 35% of cells a ring 18 and in 65% of cells normal karyotype in peripheral blood cells examined by standard G-bands by Trypsin using Giemsa (GTG) analysis. The dysmorphic features of the presented patient are discussed to the identification of the genotype-phenotype correlation related to his karyotype.


Thiamine transporter 2 is involved in high glucose-induced damage and altered thiamine availability in cell models of diabetic retinopathy.
Thiamine prevents high glucose-induced damage in microvasculature, and progression of retinopathy and nephropathy in diabetic animals. Impaired thiamine availability causes renal damage in diabetic patients. Two single-nucleotide polymorphisms in SLC19A3 locus encoding for thiamine transporter 2 are associated with absent/minimal diabetic retinopathy and nephropathy despite long-term type 1 diabetes. We investigated the involvement of thiamine transporter 1 and thiamine transporter 2, and their transcription factor specificity protein 1, in high glucose-induced damage and altered thiamine availability in cells of the inner blood-retinal barrier. Human endothelial cells, pericytes and Müller cells were exposed to hyperglycaemic-like conditions and/or thiamine deficiency/over-supplementation in single/co-cultures. Expression and localization of thiamine transporter 1, thiamine transporter 2 and transcription factor specificity protein 1 were evaluated together with intracellular thiamine concentration, transketolase activity and permeability to thiamine. The effects of thiamine depletion on cell function (viability, apoptosis and migration) were also addressed. Thiamine transporter 2 and transcription factor specificity protein 1 expression were modulated by hyperglycaemic-like conditions. Transketolase activity, intracellular thiamine and permeability to thiamine were decreased in cells cultured in thiamine deficiency, and in pericytes in hyperglycaemic-like conditions. Thiamine depletion reduced cell viability and proliferation, while thiamine over-supplementation compensated for thiamine transporter 2 reduction by restoring thiamine uptake and transketolase activity. High glucose and reduced thiamine determine impairment in thiamine transport inside retinal cells and through the inner blood-retinal barrier. Thiamine transporter 2 modulation in our cell models suggests its major role in thiamine transport in retinal cells and its involvement in high glucose-induced damage and impaired thiamine availability.


Patient- and Family-Centered Electroconvulsive Therapy.
This article builds upon prior efforts to improve the quality of electroconvulsive therapy (ECT) practice and care by encouraging the participation of family members in the ECT process. This participation included the presence of a family member or significant other (SO) in the treatment room during the ECT procedure. Suggestions for limiting that presence to the induction process and for providing limited physical contact with the patient are proposed. The participation of the SO during the pretreatment assessment process is encouraged. Because of possible impairment of memory and judgment, accurate information about the patient's condition and intercurrent life events, as provided by the SO, is often crucial. Furthermore, the patient's report may be influenced by the common experience of fear of ECT. Under these circumstances, an alliance with the SO may at times be more crucial than the alliance with the patient. The importance of establishing a therapeutic alliance with both patient and SO is emphasized. An illustrative clinical vignette is provided.


[The effect of vasoactive intestinal polypeptide on the eye (authors transl)].
Vasoactive intestinal polypeptide (VIP), in doses of 1, 3, 5, 10 and 30 micrograms dissolved in 10 microliters of physiologic saline, was injected into the anterior chamber of albino rabbit eyes, which had been pretreated with topical 0.5 percent indomethacin. While the blood pressure remained unchanged, the intraocular pressure (IOP) began to rise shortly after injection and reached a maximum in about 20 minutes. An evident dose-response relationship was established between the percentage IOP increase and the dose of VIP. The protein content of the aqueous humor also increased in a dose-dependent manner, and the increases in the IOP and protein content could be significantly correlated. The pupil diameter did not change significantly during the experiments. The sphincter and dilator muscle strips were dissected from the iris of the albino rabbit eye pretreated with 0.5 percent topical indomethacin and incubated in Krebs-Ringer's solution to which VIP was added. A dose-dependent relaxation was induced in the sphincter muscle strip under contraction by 10(-6) M carbachol and also in the dilator muscle under contraction by 3 x 10(-5) M phenylephrine. The ED50 was calculated to be 1.78 x 0.49 x 10(-8) M for the former and 1.91 +/- 0.44 x 10(-9) M (Mean +/- s.e.m.) for the latter muscle strip.


Establishment of the relationship between the electron energy and the electron injection for AlGaN based ultraviolet light-emitting diodes.
This work establishes the relationship between the electron energy and the electron concentration within the multiple quantum wells (MQWs) for AlGaN based deep ultraviolet light-emitting diodes (DUV LEDs). The electron energy of different values can be obtained by modulating the Si doping concentration in the n-AlGaN layer and/or engineering the polarization induced interface charges. The modulated Si doping concentration in the n-AlGaN layer will cause the interface depletion region within which the electric field can be generated and then tunes the electron energy. The polarization induced charges and the polarization induced electric field can be obtained by stepwisely reducing the AlN composition for the n-AlGaN layer along the [0001] orientation. We find that the electron concentration in the MQWs can be increased once the electron energy is reduced to a proper level, which correspondingly improves the external quantum efficiency (EQE) for DUV LEDs. According to our investigations, it is more advisable to adopt the n-AlGaN layer with the stepwise AlN composition, which can make both the EQE and the wall plug efficiency high.


Royal jelly reduces melanin synthesis through down-regulation of tyrosinase expression.
For cosmetic reasons, the demand for effective and safe skin-whitening agents is high. Since the key enzyme in the melanin synthetic pathway is tyrosinase, many depigmenting agents in the treatment of hyperpigmentation act as tyrosinase inhibitors. In this study, we have investigated the hypo-pigmentary mechanism of royal jelly in a mouse melanocyte cell line, B16F1. Treatment of B16F1 cells with royal jelly markedly inhibited melanin biosynthesis in a dose-dependent manner. Decreased melanin content occurred through the decrease of tyrosinase activity. The mRNA levels of tyrosinase were also reduced by royal jelly. These results suggest that royal jelly reduces melanin synthesis by down-regulation of tyrosinase mRNA transcription and serves as a new candidate in the design of new skin-whitening or therapeutic agents.


Comparative proteome analysis of spontaneous outer membrane vesicles and purified outer membranes of Neisseria meningitidis.
Outer membrane vesicles (OMVs) of Gram-negative bacteria receive increasing attention because of various biological functions and their use as vaccines. However, the mechanisms of OMV release and selective sorting of proteins into OMVs remain unclear. Comprehensive quantitative proteome comparisons between spontaneous OMVs (SOMVs) and the outer membrane (OM) have not been conducted so far. Here, we established a protocol for metabolic labeling of neisserial proteins with (15)N. SOMV and OM proteins labeled with (15)N were used as an internal standard for proteomic comparison of the SOMVs and OMs of two different strains. This labeling approach, coupled with high-sensitivity mass spectrometry, allowed us to comprehensively unravel the proteome of the SOMVs and OMs. We quantified the relative distribution of 155 proteins between SOMVs and the OM. Complement regulatory proteins, autotransporters, proteins involved in iron and zinc acquisition, and a two-partner secretion system were enriched in SOMVs. The highly abundant porins PorA and PorB and proteins connecting the OM with peptidoglycan or the inner membrane, such as RmpM, MtrE, and PilQ, were depleted in SOMVs. Furthermore, the three lytic transglycosylases MltA, MltB, and Slt were less abundant in SOMVs. In conclusion, SOMVs are likely to be released from surface areas with a low local abundance of membrane-anchoring proteins and lytic transglycosylases. The enrichment of complement regulatory proteins, autotransporters, and trace metal binding and transport proteins needs to be explored in the context of the pathogenesis of meningococcal disease.


Two different clinical and genetic forms of hereditary palmoplantar keratoderma in the northernmost county of Sweden.
A follow-up study of clinical and genetic observations, made on patients with hereditary palmoplantar keratoderma living in the northernmost county of Sweden (Norrbotten) in 1967, was performed. Two clinical types could be distinguished, a common form with an autosomal dominant mode of inheritance, corresponding to the description of the Unna Thost variety and a severe form with evidently an autosomal recessive inheritance. One of the patients with the severe form had a mutilating palmoplantar keratoderma. Neither employment nor dermatophytosis influenced the severity of the hyperkeratosis in any of these two types. Occurrence of hereditary palmoplantar keratoderma together with other genodermatoses of dermatoses with a polygenic mode of inheritance was also found in this study.


Image denoising in fluorescence microscopy using feature based gradient reconstruction.
The utility of fluorescence microscopy imaging comes with the challenge of low resolution acquisitions, which severely limits information extraction and quantitative analysis. Image denoising is a technique that aims to remove noise from microscopy acquisitions by taking into account prior statistics of the corrupting noise. In this work, we propose an image denoising technique for fluorescence microscopy imaging. The proposed technique is based on the principle of multifractal feature extraction from a noisy sample followed by a reconstruction technique from these features. It is observed that by following a proper hierarchical classification procedure, meaningful features can be extracted from a noisy image. A denoised image is then estimated from this sparse feature set through proper formulation of an optimization problem. Experiments are performed on both synthetic image databases as well as on real fluorescence microscopy data. Superior denoising results, in comparison to multiple comparing techniques, validate the potential of the proposed approach. The proposed method gives superior denoising results for low resolution fluorescence microscopy image acquisitions and can be used for post processing of data by biologists.


Pelvic support and urinary function improve in women after surgically induced weight reduction.
: The objective of this study was to assess pelvic organ support and symptoms in morbidly obese women before and after weight reductive surgery. : Fifty-four women were enrolled in this institutional review board-approved protocol. Data collection at baseline and 6 months following surgery included a Pelvic Organ Prolapse Quantification examination, questionnaires including the Pelvic Floor Distress Inventory, the Pelvic Floor Impact Questionnaire, and the Pelvic Organ Prolapse-Urinary Incontinence Sexual Function Questionnaire short form, and a 3-day voiding diary. Before-surgery and after-surgery measures were compared using paired Student t tests for continuous, normally distributed data or the Wilcoxon signed rank test for ordinal data. : Baseline and 6-month data were available for 34 women. The mean body mass index was 46 ± 6 kg/m at baseline and 33 ± 6 kg/m after 6 months. Subjects with ≥stage 2 prolapse at baseline demonstrated an improvement of 0.5 cm (baseline, 0.9 ± 0.8 cm; after 6 months, -1.4 ± 0.9 cm) in the anterior vaginal compartment (points Aa/Ba) 6 months following weight reductive surgery (P = 0.05). Of 24 women who completed 3-day voiding diaries, 12 were incontinent at baseline with a median number of incontinent episodes of 6.5 per day (range, 3-34). After surgery, 6 incontinent women became continent. In the 6 women who remained incontinent after surgery, the number of incontinent episodes per day decreased by a median of 2.5 (range, 1-11). Pelvic Floor Distress Inventory scores improved following weight reduction (baseline, 115 ± 80; after 6 months, 58 ± 70; P < 0.01). : Obese women, after surgically induced weight loss, demonstrate an improvement in anterior vaginal support, urinary leakage and pelvic floor symptoms.


Physicians' views and practice of smoking cessation.
To assess recent smoking cessation practices of physicians in East Texas and to determine whether physicians' practices meet current standards, a 43-item questionnaire was mailed in May 2000 to 1955 physicians in East Texas. The 406 physicians who finished and returned the survey were included in this study. The questionnaire covered a wide range of sociodemographic variables, and physicians' attitudes and activities related to patients' smoking cessation. The survey results indicated that most physicians frequently ask their patients about smoking and advise patients who smoke to quit, but only half of all respondents always ask about their patients' smoking status and advise smokers to quit. Furthermore, less than half of surveyed physicians are willing to spend additional time to conduct additional activities that involve other office personnel or to provide additional smoking cessation assistance to help their patients quit.


Considerations for treating dyslipidemia in special diabetic populations.
This is a review of the problem of dyslipidemia and cardiovascular disease (CVD) in special diabetic populations. Clearly all patients with diabetes are at increased risk for CVD compared to non-diabetic populations. But within the subset that is patients with diabetes there are individuals who are particularly vulnerable. These groups include women, who are often overlooked and undertreated for their cardiovascular risk. Additionally, it includes those with fewer resources, many from minority populations, who are at very high risk for poor preventive care and serious cardiovascular morbidity. This review details the risk for CVD in a variety of different diabetic high-risk groups. It then discusses treatment options and approaches that should be employed in these populations.


Harmonizing neuropsychological assessment for mild neurocognitive disorders in Europe.
Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts. To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives. With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes. This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.


Interleukin-1 beta prevents the stimulatory effect of transforming growth factor-beta on collagen gene expression in human skin fibroblasts.
Transforming growth factors beta 1 and beta 2 (TGF-beta 1 and TGF-beta 2) are well-characterized strong inducers of collagen gene expression. A 100 pM concentration of TGF-beta 1 or TGF-beta 2 increases pro alpha 1(I) collagen mRNA levels in human skin fibroblasts 6.6-fold and 7.0-fold respectively, and also increases the accumulation of procollagens in the cell culture medium. Interleukin-1 beta (IL-1 beta) is an inflammatory mediator which also regulates connective tissue metabolism. A small concentration of IL-1 beta (0.01-1.0 unit/ml) slightly increases pro alpha 1(I) collagen mRNA levels (2.2-fold). Here we provide evidence that IL-1 beta prevents the stimulatory effect of TGFs-beta on collagen synthesis in human skin fibroblasts. An IL-1 beta concentration of 1 unit/ml is enough to keep pro alpha 1(I) collagen mRNA levels at control values in cells stimulated by 100 pM-TGF-beta 1. Thus the results indicate that IL-1 beta inhibits collagen synthesis in cells activated by TGFs-beta, whereas it does not significantly change or might even stimulate collagen gene expression in non-activated cells.


Treatment of venous thromboembolism with new oral anticoagulants according to patient risk.
Recent developments in antithrombotic therapy have provided us with choices between unfractionated heparin, low-molecular-weight heparin (LMWH), vitamin K antagonists (VKA), and inhibitors against factor Xa or against thrombin for the management of venous thromboembolism. The factors that influence our decision should be efficacy, safety, convenience, and, when there is weak evidence, also patient values and preferences. The available options have largely similar efficacy, the documented exception being LMWH as superior to VKA in patients with active cancer. For the majority of patients we have today strong evidence regarding safety from large randomized trials, but this does not apply to many of the subsets of patients. In this review the choice of treatment is focused on the risks that are known or can be predicted for the individual patient. Three principal decision points on how to tailor the therapy individually are discussed-at diagnosis, for hospitalized patients at the time of discharge and finally after 3 to 6 months.


Investigating Veterinary Medicine Faculty Perceptions of Lecture Capture: Issues, Concerns, and Promises.
Lecture capture technology is becoming more pervasive in today's classrooms. Students are demanding their lectures be recorded, but many instructors remain resistant. The goal of this study was to investigate faculty perceptions of lecture capture and to understand their concerns with the technology. Through a review of the existing literature, three common reasons for not recording were identified: impact on class attendance, incompatible pedagogy, and technical concerns. To test the hypotheses, an electronic survey was created and distributed to the faculty of a veterinary college in the southeastern US. The survey included both quantitative and qualitative questions. An invitation was emailed to all 134 faculty members, garnering 50 responses. Results were consistent with the hypotheses. Impact on class attendance, teaching styles, and technical considerations have dissuaded many instructors from adopting lecture capture technology. However, a fourth theme that emerged was faculty lack of awareness/familiarity. According to the qualitative responses, many faculty either did not know lecture recording was available in their teaching spaces or were not trained in how to use the technology. Recommendations for future research include distributing the survey campus-wide and providing more opportunities for faculty training. It would also be worthwhile to repeat the survey after providing more information and training materials to faculty, or after switching from an opt-in to an opt-out approach, to see whether perceptions have changed among the college's faculty.


Test-Retest Reliability and Walk Score® Neighbourhood Walkability Comparison of an Online Perceived Neighbourhood-Specific Adaptation of the International Physical Activity Questionnaire (IPAQ).
There is a growing public health interest in the contributions of the built environment in enabling and supporting physical activity. However, few tools measuring neighbourhood-specific physical activity exist. This study assessed the reliability of an established physical activity tool (International Physical Activity Questionnaire: IPAQ) adapted to capture perceived neighbourhood-specific physical activity (N-IPAQ) administered via the internet and compared N-IPAQ outcomes to differences in neighbourhood Walk Score®. A sample of n = 261 adults completed an online questionnaire on two occasions at least seven days apart. Questionnaire items captured walking, cycling, moderate-intensity, and vigorous-intensity physical activity, undertaken inside the participant's perceived neighbourhood in the past week. Intraclass correlations, Spearman's rank correlation, and Cohen's Kappa coefficients estimated item test-retest reliability. Regression estimated the associations between self-reported perceived neighbourhood-specific physical activity and Walk Score®. With the exception of moderate physical activity duration, participation and duration for all physical activities demonstrated moderate reliability. Transportation walking participation and duration was higher (p < 0.05) in more walkable neighbourhoods. The N-IPAQ administered online found differences in neighbourhoods that vary in their walkability. Future studies investigating built environments and self-reported physical activity may consider using the online version of the N-IPAQ.


Copy number variations and expression of MPDZ are prognostic biomarkers for clear cell renal cell carcinoma.
The vital copy number variation (CNV) plays a crucial role in clear cell renal cell carcinoma (ccRCC). MPDZ inhibit cell polarity associate with osmotic pressure response and cancer-related biological processes. In order to clarify the role of the CNV of MPDZ in the progression of ccRCC, we analyzed the CNV and expression of MPDZ and prognosis in ccRCC patients from The Cancer Genome Atlas data portal. Notably, we found that the deletion of MPDZ was the common CNV, which was present in 28.65% of ccRCC patients. With the development of tumors, the percentage of MPDZ deletion increased significantly (19.38% in stage I; 20.00% in stage II; 40.94% in stage III; and 45.00% in stage IV). The deletion of MPDZ significantly increased ccRCC risk (P=0.0025). Low MPDZ expression associated with its deletion was significantly associated with adverse outcomes in ccRCC patients (P=0.0342). Furthermore, immunohistochemical analysis by tissue microarray showed that MPDZ was expressed at lower levels in tumor tissues compared with adjacent tissues (P<0.01). Kaplan-Meier survival curves showed that ccRCC patients with low MPDZ expression had significantly shorter survival than those with high MPDZ expression (P=0.002). These results indicated that low MPDZ expression associated with CNV is a potential biomarker for the prognosis of ccRCC patients.


Surgical treatment of mal perforans.
Mal perforans is a chronic foot ulcer commonly found in diabetics with neuropathy. Although it will often respond to conservative measures, recurrence is frequent and brings with it the risk of spreading infection and serious destruction of tissues. Surgical treatment of seven patients, based on excision of the distal metatarsal bone (five patients), or excision of the distal metatarsal and amputation of the first toe (two patients), gave satisfactory results and is indicated to achieve long-term healing. A special shoe, designed to remove pressure from the healing areas as well as from potential new pressure points, was used in the last four patients.


Oviductal sperm storage in the ground skink Scincella laterale holbrook (Reptilia: Scincidae).
The reproductive tracts of female ground skinks, Scincella laterale, collected at various times throughout their reproductive cycle were examined by light and transmission electron microscopy. Examination of the tracts revealed that sperm are retained in the posterior vagina after mating but prior to the ovulation of oocytes. The sperm are not sequestered in specialized glands but occur in scattered clusters in the lumen or among the deep, narrow rugae. The simple columnar lining of the vagina consists mostly of ciliated cells interspersed with occasional secretory cells. After ovulation, as indicated by the presence of eggs in the uterus, sperm are not found in the vagina. No sperm or sperm storage tubules occur in the infundibulum, the characteristic location for sperm storage in scleroglossid squamates that have been studied. Our results are a further indication that too few species have been examined to construct a rigorous phylogenetic hypothesis about the occurrence of sperm storage tubules in lizards.


The apical protein Apnoia interacts with Crumbs to regulate tracheal growth and inflation.
Most organs of multicellular organisms are built from epithelial tubes. To exert their functions, tubes rely on apico-basal polarity, on junctions, which form a barrier to separate the inside from the outside, and on a proper lumen, required for gas or liquid transport. Here we identify apnoia (apn), a novel Drosophila gene required for tracheal tube elongation and lumen stability at larval stages. Larvae lacking Apn show abnormal tracheal inflation and twisted airway tubes, but no obvious defects in early steps of tracheal maturation. apn encodes a transmembrane protein, primarily expressed in the tracheae, which exerts its function by controlling the localization of Crumbs (Crb), an evolutionarily conserved apical determinant. Apn physically interacts with Crb to control its localization and maintenance at the apical membrane of developing airways. In apn mutant tracheal cells, Crb fails to localize apically and is trapped in retromer-positive vesicles. Consistent with the role of Crb in apical membrane growth, RNAi-mediated knockdown of Crb results in decreased apical surface growth of tracheal cells and impaired axial elongation of the dorsal trunk. We conclude that Apn is a novel regulator of tracheal tube expansion in larval tracheae, the function of which is mediated by Crb.


Unconscious detection of implicit expectancies.
The detection of unexpected events is a fundamental process of learning. Theories of cognitive control and previous imaging results indicate a prominent role of the prefrontal cortex in the evaluation of the congruency between expected and actual outcome. In most cases, this attributed function is based on results where the person is consciously aware of the discrepancy. In this functional magnetic imaging (fMRI) study, we examined violations of predicted outcomes that did not enter conscious awareness. Two groups were trained with nearly identical material and the effects of new stimuli were assessed after learning. For the first group, the material was arranged with a hidden regularity. In this incidental learning situation, volunteers acquired implicit knowledge about structural response regularities as was demonstrated by an increase in reaction time when introducing new stimuli that violated the learned relations. To differentiate the detection process of stimuli that deviate from learned expectations from more unspecific effects generated by novel, unfamiliar stimuli, the second group was trained with rearranged material without a hidden regularity. No behavioral effects were found for the introduction of new stimuli in the group without implicit learning. Comparing the two groups, specific fMRI effects concerning the violation of implicitly learned expectations were found in the ventral prefrontal cortex and in the medialtemporal lobe. In accord with theories of learning, the results show a direct influence of the detection of prediction errors on the neuronal activity in learning related structures even in the absence of conscious knowledge about the predictions or their violations.


Comparison of ultrasound-secretin test and sphincter of Oddi manometry in patients with recurrent acute pancreatitis.
Manometry is considered the gold standard for evaluating sphincter of Oddi dysfunction. It has recently been demonstrated that the ultrasound (US) secretin test proposed a few years ago as a noninvasive test for the study of sphincter of Oddi dysfunction yields a substantial percentage of pathological findings in patients with acute recurrent pancreatitis. The aim of this study was to compare the results of the US secretin test with sphincter of Oddi manometry findings in a consecutive series of patients with recurrent acute pancreatitis. Forty-seven patients admitted to our gastrointestinal unit suffering from recurrent acute pancreatitis underwent ultrasonographic measurement of the main pancreatic duct at baseline and for 60 min after maximal stimulation with secretin at 1 IU/kg. According to the US secretin test findings in 35 healthy control subjects, the test results were considered to indicate pathology when the duct was still dilated after 20 min. Within three to seven days the same patients underwent perendoscopic manometry. Thirty-six patients (17 men, 19 women; mean age 41 +/- 15 years) had a successful US secretin test and sphincter of Oddi manometry. Eleven patients (30.6%) presented normal manometric findings. Two of these had an abnormal US secretin test. Twenty-five patients had abnormal manometry findings, revealing stenosis in 19 (52.7%) (17 with abnormal US secretin test) and dyskinesia in six (five with an abnormal US secretin test). Compared to manometry findings, the US secretin test sensitivity and specificity for sphincter of Oddi dysfunction were 88% and 82%, respectively. In conclusion, most patients with recurrent acute pancreatitis have sphincter of Oddi dysfunction documented by both at the US secretin test and sphincter of Oddi manometry; results of the US secretin test are reliable compared to sphincter of Oddi manometry, and therefore the US secretin test may offer a valid alternative to the more expensive and invasive manometric procedure for assessing sphincter of Oddi dysfunction in patients with recurrent acute pancreatitis.


Penetrating Internal and Common Carotid Artery Injuries Shunts versus no shunts during repair effect on neurological outcomes.
Penetrating Carotid artery injuries are rarely encountered even in busy in urban Trauma Centers. Repair is preferred over ligation for Internal (IC) and Common Carotid (CC) arteries. To date, the use of temporary shunts correlated to neurological outcomes has not been reported. In patients with penetrating IC or CC injury requiring repair, does use of temporary shunts decrease mortality and/or improve neurologic outcomes? We hypothesized that the use of temporary shunts during revascularization might produce improvements in both areas. A literature search was performed through Medline Complete-PubMed, Cochrane, Ovid, and Embase for the period of 1900-2019. PRISMA guidelines were utilized. Thirty-two articles met inclusion criteria, ranging from 1960-2018. These were analyzed to determine whether surgical repair was performed with or without the use of temporary shunts. External Carotid artery injuries were excluded. Pre- and postoperative neurological outcomes and overall outcomes were analyzed. Non-parametric data were analyzed with Fisher's Exact or Chi-square tests as applicable. Statistical significance was set to a p-value < 0.05. There were a total of 973 patients with penetrating IC and CC injuries; 136 (14%) patients underwent ligation and were excluded. Our study population consisted of 837 patients; 126 (15.1%) with shunts (WS), 711 (84.9%) without shunts (WOS). Mortality stratified to patients repaired WS versus WOS was 5.6% versus 11.1% (p=0.058). Neurological improvement was noted to be similar for patients undergoing repair WS - 14.2% versus WOS - 13.7% (p=0.8). Worsening neurological status for patients shunted WS - 3.4%, versus WOS - 9.0% (p=0.038). Data were analyzed for outcome variables including neurological deficits with or without mortality. Patients shunted had an improved and/or unchanged neurological outcome compared to patients not shunted during repair - 91.3% versus 80.9% (p=0.0047). Patients sustaining penetrating Internal and Common Carotid injuries repaired with temporary shunts have a slightly lower mortality rate and similar or unchanged neurological outcomes versus those repaired without shunts. Based on this evidence, we recommend thoughtful interoperative consideration for the use of temporary shunts for patients requiring complex repairs of these injuries.


De-implementing and sustaining an intervention to eliminate nursing home resident bed and chair alarms: interviews on leadership and staff perspectives.
Improving nursing home quality of care relies partly on reducing or stopping ineffective or harmful practices, a process known as de-implementation. We know little about de-implementation in this setting. Relatively recent policy changes reclassified resident position-change (bed and chair) alarms, which monitor resident movement, as restraints. This created an optimal environment in which to study impressions of an alarm de-implementation and sustainment intervention. This cross-sectional interview study focused on understanding participants' experience of a quality improvement program in the Department of Veterans Affairs Community Living Centers (nursing homes). The program's goal was to improve resident outcomes and staff communication and teamwork through, among other foci, eliminating resident position-change alarms. The Community Living Centers were located in geographically dispersed areas of the continental United States. Interview participants were leadership and staff members from seven Community Living Centers. We conducted in-depth, semi-structured qualitative interviews using a convenience sample and used a thematic analytic approach. We conducted seventeen interviews. We identified five main themes: Initiating De-implementation (compelling participants with evidence, engaging local leadership, and site-level education and training), Changing Expectations (educating staff and family members), Using Contrasting Approaches (gradual or abrupt elimination of alarms), Witnessing Positive Effects of De-implementation (reduction in resident falls, improved resident sleep, reduction in distressing behaviors, and increased resident engagement), and Staying the Course (sustainment of the initiative). Findings highlight how participants overcame barriers and successfully eliminated resident position-change alarms and sustained the de-implementation through using convincing evidence for the initiative, local leadership involvement and support, and staff and family member education and engagement. These findings and the resulting three-phase process to support nursing homes' de-implementation efforts expand the de-implementation science knowledge base and provide a promising framework for other nursing home-based de-implementation initiatives.


Integrative therapies in hospice and home health: introduction and adoption.
Integrative therapies comprise a variety of nonpharmacologic methods that provide pain and symptom management. These therapies are increasingly gaining acceptance in the healthcare community as complementary to traditional treatments for pain. This article details the introduction, scope, and challenges healthcare organizations face when incorporating integrative therapies into their care plans.


Excessive weight gain onset-age and risk of developing diabetes mellitus: a large, prospective Chinese cohort study.
Excessive weight gain and obesity are widely accepted as risk factors for diabetes mellitus, and the age at which obesity onsets may be related to the development of cardiovascular diseases and certain cancers. Here, we aimed to investigate associations between the onset-age of overweight/obesity and risk of developing diabetes mellitus in China. 42,144 people with the normal weight range and without diabetes at baseline, were enrolled from the Kailuan cohort which began on the 1st June 2006. All participants were followed-up, biennially, until 31st December 2017. During follow-up, 11,220 participants had become overweight/obese. For each case, one normal-weight control was matched according to age ( ± 1 year) and sex. Our final analysis included 10,858 case-control pairs. An age-scaled Cox model was implemented to estimate hazard ratios (HR) with corresponding 95% confidence intervals (CI) for diabetes mellitus incidence across age-groups. At a median follow-up of 5.46 years, 1,403 cases of diabetes mellitus were identified. After multivariate adjustments, age-scaled Cox modelling suggested that risk gradually attenuated with every 10 year increase in age of onset of overweight/obesity. Diabetes mellitus adjusted HRs (aHRs) for new-onset overweight/obesity at <45years, 45-54 years, and 55-64 years were 1.47 (95%CI, 1.12-1.93), 1.38 (95%CI, 1.13-1.68), 1.32 (95%CI, 1.09-1.59), respectively. However, new-onset of overweight/obesity at ≥65 years did not relate to diabetes mellitus (aHR, 1.20; 95%CI, 0.92-1.57). This trend was not observed in women or the new-onset obesity subgroup but was evident in men and the new overweight onset subgroup. Participants with early onset of excessive weight gain issues are at considerably higher risk of developing diabetes mellitus compared to those who maintain a normal weight.


Effects of the differentiating agent hexamethylene bisacetamide on normal and myelodysplastic hematopoietic progenitors.
Hexamethylene bisacetamide (HMBA; NSC 95580) is a potent polar-planar differentiating agent of leukemia and solid tumor cell lines in vitro at clinically achievable concentrations. HMBA is currently being studied in patients with myelodysplastic syndrome. Previous phase I trials have demonstrated that HMBA produces hematologic toxicity in morphologically normal bone marrows of patients with solid tumors. Because of concern that HMBA may produce more severe myelotoxicity in patients with myelodysplastic syndrome since these patients have limited hematopoietic reserves, we studied the effects of HMBA on myelodysplastic and normal hematopoietic progenitors in vitro. HMBA concentrations that are optimal for differentiation in vitro (2 to 5 mmol/L) and HMBA concentrations that are being achieved in clinical trials (1 to 2 mmol/L) inhibited the growth of granulocyte-macrophage colony-forming units and erythroid burst-forming units from all 15 patients with myelodysplastic syndrome and all 4 normal subjects, HMBA did not induce proliferation of myelodysplastic or normal progenitors at any concentration; rather, it produced nearly identical inhibition of normal and myelodysplastic hematopoietic progenitors. HMBA also produced quantitatively similar inhibition of clonogenic leukemic growth of two myeloid leukemia cell lines. For a differentiating agent to be effective, it will likely have to either produce both differentiation and proliferation of abnormal hematopoietic progenitors or show selective inhibitory effects on abnormal as compared with normal progenitors. Although the mechanisms responsible for the antiproliferative effects of HMBA cannot be determined from this study, similar inhibitory effects of HMBA on normal and abnormal hematopoietic progenitors suggest that HMBA may be of limited utility in producing and sustaining elevations of peripheral blood cell counts in patients with myelodysplastic syndrome.


Comparison of cone directionality determined by psychophysical and reflectometric techniques.
We measured the directionality of the cones with both a psychophysical (Stiles-Crawford I) technique and an optical technique. The two sets of measurements were made in the same subjects, with stimuli as similar as possible used. The two types of measurements gave similar estimates of the location in the pupil toward which the cones were optimally aligned. However, the two measurements gave quite dissimilar estimates of the width of the directional sensitivity. On average, optical measurements were half as broad as psychophysical measurements in the fovea, but there were substantial individual differences. At 2-deg retinal eccentricity the difference between techniques was even more marked.


A Novel Approach to Assessing Infants With Neonatal Abstinence Syndrome.
Neonatal abstinence syndrome (NAS) is a growing problem and poses a significant burden on the health care system. The traditional Finnegan Neonatal Abstinence Scoring System (FNASS) assessment approach may lead to unnecessary opioid treatment of infants with NAS. We developed a novel assessment approach and describe its effect on the management of infants with NAS. We retrospectively compared treatment decisions of 50 consecutive opioid-exposed infants managed on the inpatient unit at the Yale New Haven Children's Hospital. All infants had FNASS scores recorded every 2 to 6 hours but were managed by using the Eat, Sleep, Console (ESC) assessment approach. Actual treatment decisions made by using the ESC approach were compared with predicted treatment decisions based on recorded FNASS scores. The primary outcome was postnatal treatment with morphine. By using the ESC approach, 6 infants (12%) were treated with morphine compared with 31 infants (62%) predicted to be treated with morphine by using the FNASS approach (P < .001). The ESC approach started or increased morphine on 8 days (2.7%) compared with 76 days (25.7%) predicted by using the FNASS approach (P < .001). There were no readmissions or adverse events reported. Infants managed by using the ESC approach were treated with morphine significantly less frequently than they would have been by using the FNASS approach. The ESC approach is an effective method for the management of infants with NAS that limits pharmacologic treatment and may lead to substantial reductions in length of stay.


A Computational Study of the Intermolecular [2+2+2] Cycloaddition of Acetylene and C60 Catalyzed by Wilkinson's Catalyst.
The functionalization of fullerenes helps to modulate their electronic and physicochemical properties, generating fullerene derivatives with promising features for practical applications. Herein, DFT is used to explore the attachment of a cyclohexadiene ring to C60 through a rhodium-catalyzed intermolecular [2+2+2] cycloaddition of C60 and acetylene. All potential reaction paths are analyzed and it can be concluded that the [2+2+2] cycloaddition of C60 and two acetylene molecules catalyzed by [RhCl(PPh3 )3 ], yielding a cyclohexadiene ring fused to a [6,6] bond of C60 , is energetically feasible.


Expression of the β-glucosidase gene Pgβglu-1 underpins natural resistance of white spruce against spruce budworm.
Periodic outbreaks of spruce budworm (SBW) affect large areas of ecologically and economically important conifer forests in North America, causing tree mortality and reduced forest productivity. Host resistance against SBW has been linked to growth phenology and the chemical composition of foliage, but the underlying molecular mechanisms and population variation are largely unknown. Using a genomics approach, we discovered a β-glucosidase gene, Pgβglu-1, whose expression levels and function underpin natural resistance to SBW in mature white spruce (Picea glauca) trees. In phenotypically resistant trees, Pgβglu-1 transcripts were up to 1000 times more abundant than in non-resistant trees and were highly enriched in foliage. The encoded PgβGLU-1 enzyme catalysed the cleavage of acetophenone sugar conjugates to release the aglycons piceol and pungenol. These aglycons were previously shown to be active against SBW. Levels of Pgβglu-1 transcripts and biologically active acetophenone aglycons were substantially different between resistant and non-resistant trees over time, were positively correlated with each other and were highly variable in a natural white spruce population. These results suggest that expression of Pgβglu-1 and accumulation of acetophenone aglycons is a constitutive defence mechanism in white spruce. The progeny of resistant trees had higher Pgβglu-1 gene expression than non-resistant progeny, indicating that the trait is heritable. With reported increases in the intensity of SBW outbreaks, influenced by climate, variation of Pgβglu-1 transcript expression, PgβGLU-1 enzyme activity and acetophenone accumulation may serve as resistance markers to better predict impacts of SBW in both managed and wild spruce populations.