Novel Therapeutic Potential of Mitogen-Activated Protein Kinase Activated Protein Kinase 2 (MK2) in Chronic Airway Inflammatory Disorders.
The primary focus of this review is to highlight the current and emerging proinflammatory role of MK2 kinase signaling in p38MAPK pathway and to provide a detailed evaluation on the prospects of MK2 inhibition with special emphasis on the etiology of chronic inflammatory airway diseases, such as asthma, idiopathic pulmonary fibrosis, lung cancer, acute lung injury and acute respiratory distress syndrome. MK2 belongs to serine-threonine kinase family and is activated directly by stress and inflammatory signal through p38MAPK phosphorylation in diverse inflammatory conditions through the Toll-like receptor signaling pathway. MK2 has been thought to be a critical factor involved in the regulation of synthesis and release of pro-inflammatory (TNF-α, IL-6 and IL-1β, etc.) proteins. Targeted inhibition of MK2 kinase has been shown to significantly reduce the production and release of these cytokine molecules. Therefore, MK2 has been identified as an effective strategy (alternative to p38MAPK) to block this pro-inflammatory signaling pathway. The inhibition of MK2 may lead to similar or better efficacy as that of p38 inhibitors, and interestingly avoids the systemic toxicity shown by the p38 inhibitors. Thus, MK2 has been the focus of intense interdisciplinary research and its specific inhibition can be a novel and potential therapeutic strategy for the treatment of chronic airway inflammatory diseases. Promising advancement in understanding and rigorous exploration of the role of MK2 kinase in inflammatory processes may contribute to the development of newer and safer therapy for the treatment of chronic airway inflammatory diseases in the future.


Studies on cell enzyme systems; the kinetics of heat inactivation of cypridina luciferase.
Solutions of the enzyme luciferase, extracted from Cypridina, were subjected at pH 6.8 to temperatures from 40-55 degrees C. for times up to 24 hours. After the desired exposures samples were cooled rapidly to room temperature, mixed with luciferin, and the first order velocity constants (representing luciferase activity) of the resulting luminescent reactions were determined by a photo electric method. The form of the curve relating luciferase activity to time of exposure to a temperature in the above range is compound in nature. If the exposure to the high temperature is not too long, about two-thirds of the lost activity is slowly regained on standing at room temperature. The data were described by an equation which represents the following mechanism: See PDF for Equation A plot of the logarithm of the rate constant, k(1), against the reciprocal of the absolute temperature yielded an experimental activation energy for this reaction of about 57,000 calories, typical of protein denaturation processes. Log k(2) plotted against 1/T was described by either a curve or two straight lines, high activation energies resulting in either case, again indicating protein denaturation. The plot of log k(3): vs. 1/T showed no apparent dependence upon temperature, k(3) being practically constant over the range studied. This may indicate that the underlying mechanism is not actually as simple as pictured. Two other mechanisms that were also considered were discarded because of lack of experimental support. Measurements of the decrease of luciferase activity at 48 degrees C. and at pH 6.7, pH 5.5, and pH 7.9 showed that inactivation of the enzyme at this temperature was much more rapid at pH 7.9 than at pH 6.7 and was even faster at pH 5.5. These results from the Cypridina luminescent system were compared with those of other investigators on other systems.


Neuropeptides and immunity.
Our studies have clearly shown that neuropeptides have a profound effect on immunoglobulin synthesis both in vivo and in vitro. The effects varied according to the neuropeptide added or the tissue from which the lymphocytes were obtained. Substance P caused the most pronounced enhancement of both functions, especially in Peyer's patch cells, where it selectively increased IgA synthesis. Somatostatin was inhibitory, and the effect of vasoactive intestinal peptide varied according to the source of the cells. We have previously shown that neuropeptides also cause mast cell secretion and that only substance P was effective in this regard on intestinal mucosal mast cells. Therefore, we looked for microanatomic relationships between peptidergic nerves and immune effector cells. Mast cells appear to have structural associations with neuropeptides-containing nerves in the intestine. Nerve growth factor, known to promote the growth of sensory afferent and sympathetic nerves, has significant direct effects on mast cells. In vitro, this substance caused enhanced antigen mediated histamine release and, in vivo, extensive mast cell hyperplasia. Also, in humans, we were able to produce increased numbers of mast cell/basophil colonies from peripheral blood in the presence of nerve growth factor.


Histone deacetylase 3 controls a transcriptional network required for B cell maturation.
Histone deacetylase 3 (Hdac3) is a target of the FDA approved HDAC inhibitors, which are used for the treatment of lymphoid malignancies. Here, we used Cd19-Cre to conditionally delete Hdac3 to define its role in germinal center B cells, which represent the cell of origin for many B cell malignancies. Cd19-Cre-Hdac3-/- mice showed impaired germinal center formation along with a defect in plasmablast production. Analysis of Hdac3-/- germinal centers revealed a reduction in dark zone centroblasts and accumulation of light zone centrocytes. RNA-seq revealed a significant correlation between genes up-regulated upon Hdac3 loss and those up-regulated in Foxo1-deleted germinal center B cells, even though Foxo1 typically activates transcription. Therefore, to determine whether gene expression changes observed in Hdac3-/- germinal centers were a result of direct effects of Hdac3 deacetylase activity, we used an HDAC3 selective inhibitor and examined nascent transcription in germinal center-derived cell lines. Transcriptional changes upon HDAC3 inhibition were enriched for light zone gene signatures as observed in germinal centers. Further comparison of PRO-seq data with ChIP-seq/exo data for BCL6, SMRT, FOXO1 and H3K27ac identified direct targets of HDAC3 function including CD86, CD83 and CXCR5 that are likely responsible for driving the light zone phenotype observed in vivo.


Strategies for improving early detection and diagnosis of neovascular age-related macular degeneration.
Treatment of the neovascular form of age-related macular degeneration (AMD) has been revolutionized by the introduction of such agents as ranibizumab, bevacizumab, and aflibercept. As a result, the incidence of legal blindness occurring secondary to AMD has fallen dramatically in recent years in many countries. While these agents have undoubtedly been successful in reducing visual impairment and blindness, patients with neovascular AMD typically lose some vision over time, and often lose the ability to read, drive, or perform other important activities of daily living. Efforts are therefore under way to develop strategies that allow for earlier detection and treatment of this disease. In this review, we begin by providing an overview of the rationale for, and the benefits of, early detection and treatment of neovascular AMD. To achieve this, we begin by providing an overview of the pathophysiology and natural history of choroidal neovascularization, before reviewing the evidence from both clinical trials and "real-world" outcome studies. We continue by highlighting an area that is often overlooked: the importance of patient education and awareness for early AMD detection. We conclude the review by reviewing an array of both established and emerging technologies for early detection of choroidal neovascularization, ranging from Amsler chart testing, to hyperacuity testing, to advanced imaging techniques, such as optical coherence tomography.


Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency.
Supravalvular aortic stenosis is an autosomal-dominant disease of elastin (Eln) insufficiency caused by loss-of-function mutations or gene deletion. Recently, we have modeled this disease in mice (Eln+/-) and found that Eln haploinsufficiency results in unexpected changes in cardiovascular hemodynamics and arterial wall structure. Eln+/- animals were found to be stably hypertensive from birth, with a mean arterial pressure 25-30 mmHg higher than their wild-type counterparts. The animals have only moderate cardiac hypertrophy and live a normal life span with no overt signs of degenerative vascular disease. Examination of arterial mechanical properties showed that the inner diameters of Eln+/- arteries were generally smaller than wild-type arteries at any given intravascular pressure. Because the Eln+/- mouse is hypertensive, however, the effective arterial working diameter is comparable to that of the normotensive wild-type animal. Physiological studies indicate a role for the renin-angiotensin system in maintaining the hypertensive state. The association of hypertension with elastin haploinsufficiency in humans and mice strongly suggests that elastin and other proteins of the elastic fiber should be considered as causal genes for essential hypertension.


The Arabidopsis splicing factor SR1 is regulated by alternative splicing.
The serine-arginine (SR)-rich splicing factors play essential roles in general splicing and regulate alternative splice site utilization in a concentration-dependent manner. SR1 is a plant homologue of the human general/alternative splicing factor SF2/ASF. We report here that alternative splicing regulates SR1 itself. Of the five detected SR1 transcripts only one encodes the full-length protein, while the other four are different variants of the essential arginine-serine-rich domain. The data suggest that SR1 pre-mRNA could be committed to two alternate splicing pathways. One, dependent on the alternative utilization of competing 3' splice sites in intron 9, generates SR1, SR1B and SR1C. The other, regulated by suppression of intron 9 5' splice site utilization, generates SR1D and SR1E. The splicing pattern and molecular structure of SR1D indicates an evolutionary conservation of splicing-based regulation between plants and vertebrates and suggests that the various isoforms perform important functions. Results from transient gene expression assays indicate that alternative splicing is not an autoregulatory mechanism used to control the transcript level of the full-length protein. The ratio of SR1/SR1B transcripts, which are generated by alternative 3' splice site utilization in intron 9, is under temperature control. The temperature-dependent increase in SR1B/SR1 ratio suggests a role of SR1B in the adaptation to high-temperature environments. In addition, based on the regulated co-expression of SR1 transcripts, it is possible that some SR1 functions could be determined by the combinatorial action of the various isoforms.


Motorized teleguided stereotactic micromanipulator for vitreous microsurgery.
A recently developed motorized stereotactic micromanipulator enhances the precision of the procedure, the comfort of the surgeon, and the safety of the patient during vitreous surgery. It can accommodate almost any type of vitreous surgical instrument by means of special adapters. The system is moved by the action of electrical motors remotely controlled by the surgeon operating a joystick on a separate control unit. Electrical reversal of motion, obtained by flipping a switch, allows observation through an altered version of the Panfundoscope that provides a 160 degrees inverted fundus view during all phases of the operation. In addition to improving many aspects of present vitreous surgical procedures, this stereotactic system may initiate the development of still finer surgical methods that cannot be performed with the free hand.


Advances in mechanisms of systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease associated with hormonal, environmental, and genetic factors and linked to the tolerance breakdown of B and T cells to self-antigens. SLE is characterized by the presence in patient serum of autoantibodies raised against nuclear components. Association of these antibodies to self-antigens, complement factors, DNA, and particular proteins will form circulating immune complexes (CIC) which can deposit in several organs, causing tissue damage and clinical manifestations. Historically, SLE is considered as an adaptive immune system disorder. Over the past decade, advances in the understanding of SLE pathogenesis placed the innate immune system as a key player in perpetuating and amplifying this systemic disease. In this review, we summarize some recent key advances in understanding the SLE immune-pathogenesis with a particular focus on newly discovered key factors from the innate immune system and how they influence the pathogenic adaptive immune system: neutrophils and neutrophil extracellular traps (NETs), plasmacytoid dendritic cells (pDCs) and type I interferons, basophils and autoreactive IgE, monocytes/macrophages and the inflammasome. Recent advances on B and T cell involvement in the SLE pathogenesis mechanisms are also discussed. Although the disease is clinically, genetically, and immunologically heterogeneous between affected individuals, the latest discoveries are offering new promising therapeutic strategies.


Asymptomatic Plasmodium falciparum and vivax infection in the neighborhood of Blondin, Saint-Georges-de-l'Oyapock District, French Guiana.
Optimized elimination strategies are needed to control transmission of malaria. As part of an elimination campaign, active detection of asymptomatic Plasmodium carriers by highly sensitive methods is deemed necessary. Asymptomatic carriage leads to complex scientific, ethical, and operational issues regarding individual or collective detection and treatment. To address this issue, a crosssectional study was carried out in French Guiana to determine the prevalence of asymptomatic Plasmodium carriage during an inter-epidemic season in the whole population of a neighborhood of Saint-Georges-de-l'Oyapock, along the Brazilian border. Fifty-eight participants out of 63 residents were screened. The median age was 23.3 years (range: 2 months-72 years), with a male/female sex-ratio of 0.56. The majority of the participants (74%, N = 43/58) reported a history of malaria, 12% (N = 7/58) during the past 12 months. All rapid diagnostic tests for malaria were negative. Among the 58 participants, malaria prevalence detected by nested-PCR (Polymerase Chain Reaction) was 3.6% (N = 2/56). Two asymptomatic carriers of Plasmodium were identified: one child with Plasmodium vivax and one adult with Plasmodium falciparum. These two carriers were treated and did not develop malaria within the eight months following the diagnosis. This study confirmed the presence of asymptomatic parasitaemias outside hyperendemic areas. However, the benefits of such an active detection and patient treatment to eliminate malaria in French Guiana need to be evaluated at a larger scale.


Growth and organization of an organic molecular monolayer on TiO2: catechol on anatase (101).
Anatase TiO(2) is a widely used photocatalytic material, and catechol (1,2-benzendiol) is a model organic sensitizer for dye-sensitized solar cells. The growth and the organization of a catecholate monolayer on the anatase (101) surface were investigated with scanning tunneling microscopy and density functional theory calculations. Isolated molecules adsorb preferentially at steps. On anatase terraces, monodentate ('D1') and bidentate ('D2') conformations are both present in the dilute limit, and frequent interconversions can take place between these two species. A D1 catechol is mobile at room temperature and can explore the most favorable surface adsorption sites, whereas D2 is essentially immobile. When a D1 molecule arrives in proximity of another adsorbed catechol in an adjacent row, it is energetically convenient for them to pair up in nearest-neighbor positions taking a D2-D2 or D2-D1 configuration. This intermolecular interaction, which is largely substrate mediated, causes the formation of one-dimensional catecholate islands that can change in shape but are stable to break-up. The change between D1 and D2 conformations drives both the dynamics and the energetics of this model system and is possibly of importance in the functionalization of dye-sensitized solar cells.


Early feeds not force feeds: Enteral nutrition in traumatic brain injury.
Brain Trauma Foundation guidelines recommend the early use of enteral nutrition to optimize recovery following traumatic brain injury (TBI). Our aim was to examine the effect of early feeds (≤24 hours) on clinical outcomes after TBI. We performed a 3-year retrospective study of patients with severe TBI (Glasgow Coma Scale score <8) who were intubated, admitted to the intensive care unit (ICU), and received tube feeds. Early tube feeds (early TF) were defined as initiation of tube feeds within 24 hours, whereas late tube feeds (late TF) were defined as initiation of tube feeds after 24 hours. Outcome measures included pneumonia rates, days on ventilator, hospital and ICU stay, and mortality rates. A total of 90 patients (early TF: 58, late TF: 32) were included, of which 73.3% were male, mean age was 42 (SD, 20) years, and median head Abbreviated Injury Scale score was 4 (range, 3-5). There was no difference in age (p = 0.1), head Abbreviated Injury Scale score (p = 0.5), or admission Glasgow Coma Scale score (p = 0.9) between the two groups. Patients with early TF were associated with higher number of ICU days (p = 0.03) and higher pneumonia rates (p = 0.04), but there was no significant difference in mortality (p = 0.44) as compared with those who underwent late TF. Although early tube feeds are known to improve outcomes in TBI patients, our data suggest that early feeds in TBI patients are associated with higher rates of pneumonia and greater hospital resource utilization. Therapeutic study, level IV.


The Effect of Language Dominance on Classic Semantic, Action, Emotional, and Phonemic Fluency in Unbalanced Bilinguals.
Verbal fluency evaluation in bilingual speakers should include dual-language assessment to obtain a comprehensive profile of word retrieval abilities. This study is the first to compare classic semantic, action, emotional, and phonemic fluency in terms of the magnitude of their performance gaps between the dominant and nondominant language in unbalanced bilingual speakers. We also examined the quantitative relationship between language dominance and verbal fluency performance. Twenty-six bilingual adults completed a comprehensive set of classic semantic ("animals," "vegetables"), action ("do"), emotional ("happy," "sad," "afraid"), and phonemic ("F," "A," "S") fluency tasks in their dominant language (English) and nondominant language (Spanish) in two sessions on separate days. Participants also completed subjective and objective measures of language proficiency. All tasks yielded fewer correct responses in the nondominant language. The between-languages performance gap was the largest for "animals" and the smallest for emotional fluency. "Happy" yielded the most balanced performance among all semantic tasks and a positivity bias that was unaffected by language dominance. Finally, language dominance scores computed by a newly developed formula indicated relationships between self-rated proficiency and fluency performance. This study provides preliminary, normative data of classic semantic, action, emotional, and phonemic fluency that could be used to gauge unbalanced bilingual speakers' performance. Significant impacts of language dominance on "animals" demand caution in using this widely used classic semantic category in evaluating bilingual speakers' performance. The data also underscore the robustness of positivity biases in emotional fluency and the validity of using subjective measures to supplement neuropsychological assessment of fluency performance.


[Lack of effectiveness of coenzyme Q10 (ubiquinone) in long-term treatment of dilated cardiomyopathy].
In a chronic, placebo-controlled, double-blind cross-over study a potential therapeutic effect of coenzyme Q10 (ubiquinone) was investigated in 25 patients suffering from dilative cardiomyopathy (NYHA functional class I, II, III). During a period of four months patients were treated with 3x 33.3 mg of coenzyme Q10 per day, given orally, 15 patients received verum during the first four months and placebo during the following four months (V/P). In the second group of patients (n = 10) the sequence of treatment was reversed (P/V). Therapeutic effect was assessed by means of echocardiogram, chest x-ray, radionuclide ventriculography combined with exercise test and impedance cardiography. Control values for left ventricular function parameters were similar in both groups (left ventricular ejection fraction: 39.5 +/- 11.5% (P/V), 37.6 +/- 17.0% (V/P); left ventricular enddiastolic diameter: 65 +/- 9 mm (P/V), 67 +/- 8 mm (V/P); Cl: 5.1 +/- 1.4 l/min (P/V), 5.1 +/- 1.1 l/min (V/P]. Chronic treatment by coenzyme Q10 did not exhibit any influence on hemodynamic parameters, on the electrocardiogram, on incidence of ventricular arrhythmias, or on exercise tolerance. It was not possible to demonstrate any therapeutic effect of coenzyme Q10 in patients with dilative cardiomyopathy.


Mesodiencephalic and cerebellar terminals terminate upon the same dendritic spines in the glomeruli of the cat and rat inferior olive: an ultrastructural study using a combination of [3H]leucine and wheat germ agglutinin coupled horseradish peroxidase anterograde tracing.
The mesodiencephalic and cerebellar afferents in the rostral medial accessory and principal olive of the cat and rat were studied following anterograde transport of tritiated leucine combined with anterograde transport of wheat germ agglutinin coupled horseradish peroxidase in the same animals. In all studied areas at least one-third of the labelled glomeruli appeared to contain both mesodiencephalic and cerebellar terminals. In many of these cases it was found that the terminals from both afferent systems contacted the same dendritic spines. Therefore, these olivary spines may be, as will be discussed, well suited for being involved in a timing process.


Systematic discovery and characterization of fly microRNAs using 12 Drosophila genomes.
MicroRNAs (miRNAs) are short regulatory RNAs that inhibit target genes by complementary binding in 3' untranslated regions (3' UTRs). They are one of the most abundant classes of regulators, targeting a large fraction of all genes, making their comprehensive study a requirement for understanding regulation and development. Here we use 12 Drosophila genomes to define structural and evolutionary signatures of miRNA hairpins, which we use for their de novo discovery. We predict >41 novel miRNA genes, which encompass many unique families, and 28 of which are validated experimentally. We also define signals for the precise start position of mature miRNAs, which suggest corrections of previously known miRNAs, often leading to drastic changes in their predicted target spectrum. We show that miRNA discovery power scales with the number and divergence of species compared, suggesting that such approaches can be successful in human as dozens of mammalian genomes become available. Interestingly, for some miRNAs sense and anti-sense hairpins score highly and mature miRNAs from both strands can indeed be found in vivo. Similarly, miRNAs with weak 5' end predictions show increased in vivo processing of multiple alternate 5' ends and have fewer predicted targets. Lastly, we show that several miRNA star sequences score highly and are likely functional. For mir-10 in particular, both arms show abundant processing, and both show highly conserved target sites in Hox genes, suggesting a possible cooperation of the two arms, and their role as a master Hox regulator.


Sequential delta-integration for the regulated insertion of cloned genes in Saccharomyces cerevisiae.
A novel delta-integration vector was developed to allow the sequential insertion of multiple cloned genes in the yeast Saccharomyces cerevisiae. To allow repetitive integrations, the reusable URA3 Blaster selection cassette was employed; the insertions (of CUP1p-lacZ in this study) were selected using the URA3 marker which was subsequently "popped" out by recombination between flanking direct repeats. Transformants contained only one new integrated copy after the loss of the URA3 marker, and subsequent transformations were effective for the sequential insertion of a series of genes (one at a time) into dispersed chromosomal delta sequences. The structural stability of the integrations was location-dependent (ranging from 75% to 100% after 50 generations in complex medium with or without gene expression), and the integrations (at least up to five) had no significant effects on the growth of the cells. In addition, beta-galactosidase specific activity levels varied linearly with integrated copy number. The repetitive, regulated nature of integration with this vector is not possible with traditional delta-integration or other homologous recombination methods, and is promising for fine-tuning cloned gene copy number and for the insertion of metabolic pathway genes.


An image retrieval system based on fractal dimension.
This paper presents a new kind of image retrieval system which obtains the feature vectors of images by estimating their fractal dimension; and at the same time establishes a tree-structure image database. After preprocessing and feature extracting, a given image is matched with the standard images in the image database using a hierarchical method of image indexing.


[Effect of adrenalectomy on the capacity of brown adipose tissue for thermogenesis and the development of obesity in the fa/fa Zucker rat].
This study was undertaken to examine whether adrenalectomy performed during the weaning period could correct some of the first metabolic abnormalities to develop in obese fa/fa rats: impaired thermogenesis in brown adipose tissue and hyperlipogenesis in interscapular brown and white (inguinal) adipose tissues. Pups were adrenalectomized or sham-operated at 23 days of age and studied at 30 days of age. Body weight, interscapular brown adipose tissue and inguinal white adipose tissue weight were decreased after adrenalectomy in Fa/fa and fa/fa pups. Adrenalectomy had no effect on the thermogenic capacity of brown adipose tissue (as assessed by GDP binding to mitochondria) which remained significantly lower in fa/fa than in Fa/fa rats. In both Fa/fa and fa/fa rats the lipogenic capacity of brown and white adipose tissues (as assessed by fatty acid synthetase activity) was dramatically reduced by adrenalectomy. However, in adrenalectomized rats, the fatty acid synthetase activity of brown and white adipose tissue remained 2 and 5-fold higher, respectively, in fa/fa than in Fa/fa rats. These results show that adrenalectomy at postweaning, did not affect specifically the rats bearing the fatty genotype but induced large alterations in both groups of rats. Adrenalectomized fa/fa animals remained obese as compared to the appropriate controls.


The cardioprotective effects of cerium oxide nanoparticles against the poisoning generated by aluminum phosphide pesticide: Controlling oxidative stress and mitochondrial damage.
Aluminum phosphide (AlP) is a well-known toxic compound used as an agricultural pesticide to prevent insect damage to stored crops. However, even if just a small amount was consumed, it caused lasting harm to the human body and, in acute concentrations, death. The current study employed cerium oxide nanoparticles (CeO2 NPs) to reduce oxidative stress and various harmful outcomes of AlP poisoning. Following finding effective concentrations of CeO2 NPs via MTT assay, Human Cardiac Myocyte (HCM) cells were pre-treated with CeO2 NPs for 24 h. After that, they were exposed to 2.36 μM AlP. The activity of oxidative stress and mitochondrial biomarkers, including mitochondrial swelling, mitochondrial membrane potential, and cytochrome c release, were evaluated in HCM cells. Finally, the population of apoptotic and necrotic cells was assessed via flow cytometry. After 24 h, data revealed that all tested concentrations of CeO2 NPs were safe, and 25 and 50 μM of that were selected as effective concentrations. Oxidative stress markers (malondialdehyde, protein carbonyl, superoxide dismutase, and catalase) showed that CeO2 NPs could successfully decrease AlP poisoning due to their antioxidant characteristics. Mitochondrial markers were also recovered by pre-treatment of HCM cells with CeO2 NPs. Furthermore, pre-treating with CeO2 NPs could compensate for the reduction of live cells with AlP and cause a diminishing in the population of early and late apoptotic cells. As a result, it is evident that CeO2 NPs, through the recovery of oxidative stress and mitochondrial damages caused by AlP, reduce apoptosis and have therapeutic potentials on HCM cells.


Ten years of specialized adult care for phenylketonuria - a single-centre experience.
Specialized adult care of phenylketonuria (PKU) patients is of increasing importance. Adult outpatient clinics for inherited errors of metabolism can help to achieve this task, but experience is limited. Ten years after establishment of a coordinated transition process and specialised adult care for inherited metabolic diseases, adult PKU care was evaluated with respect to metabolic control, therapy satisfaction, life satisfaction, sociodemographic data, economical welfare as well as pregnancy outcome. All PKU patients transferred from paediatric to adult care between 2005 and 2015 were identified. A retrospective data analysis and a cross-sectional survey in a sub-cohort of 30 patients including a questionnaire for assessing quality of life (FLZm) were performed as a single-centre investigation at the metabolic department of the University Hospital Leipzig, Germany. For statistical analysis, Mann-Whitney-U-test, t-test for independent samples, ANOVA and chi square test were used as appropriate. 96 PKU patients (56 females/40 males; median age 32 years, range 18-62) were included. In the last 3-year period, 81% of the transferred patients still kept contact to the adult care centre. Metabolic control was stable over the evaluation period and dried blood phenylalanine concentrations mostly remained within the therapeutic range (median 673.0 μmol/l, range 213.0-1381.1). Sociodemographic data, economical welfare and life satisfaction data were comparable to data from the general population. However, differences could be revealed when splitting the cohort according to time of diagnosis and to management during childhood. 83% of the PKU adults were satisfied with the transition process and current adult care. 25 completed pregnancies were supervised; three newborns, born after unplanned pregnancy, showed characteristic symptoms of maternal PKU syndrome. Continuous care for adult PKU patients in a specialized outpatient clinic is successful, leading to good to satisfactory metabolic control and social outcomes. Uninterrupted good metabolic treatment throughout childhood and adolescence positively influences educational, professional and economic success in later life. Further effort in specialized paediatric and adult metabolic care is needed to prevent loss of follow-up and to support the recommended life-long treatment and/or care.


Patients' expectation of postoperative course and satisfaction following cardiac surgery.
In patients undergoing cardiac surgery, preoperative concerns, expectations of the impact of surgery, anticipated recovery timelines, and pre- and postoperative education, which impact recovery and quality-of-life, are not well documented. These factors are important with the increase in virtual consultations, the availability of internet-based information and increased use of minimally invasive surgical procedures. Patients who underwent cardiac surgery between January 2016 and December 2019 took part in an online survey examining preoperative concerns, information provision, use of digital channels, satisfaction with surgery, impact on health and resumption of daily activity. 80 patients completed the survey. There was a high rate of overall post-surgical satisfaction (86%); 71% of respondents reported an improvement in physical health, 45% in mental health and 70% in their quality-of-life. The usefulness of information provided by the National Health Service varies across different stages of the patient experience. Although approximately 90% of respondents found the information provided at each stage at least 'somewhat' helpful, the proportion who found the information 'very' helpful was lower (68% for pre-procedure; 55% for post-discharge). The majority (79%) said that they felt prepared for their operation. Survey responses highlighted areas of lower understanding, including survival rate, levels of postoperative pain, duration of hospital stay and when the patient could return to normal physical activity. Levels of satisfaction with the outcomes of heart surgery are high, and the majority of patients report positive health outcomes. However, there is room for improvement in patients' understanding of survival rate and level of pain post-procedure. There is also a clear desire among patients for a more surgical team-based face-to-face consultation.


Frequency and pattern of heteroplasmy in the complete human mitochondrial genome.
Determining the levels of human mitochondrial heteroplasmy is of utmost importance in several fields. In spite of this, there are currently few published works that have focused on this issue. In order to increase the knowledge of mitochondrial DNA (mtDNA) heteroplasmy, the main goal of this work is to investigate the frequency and the mutational spectrum of heteroplasmy in the human mtDNA genome. To address this, a set of nine primer pairs designed to avoid co-amplification of nuclear DNA (nDNA) sequences of mitochondrial origin (NUMTs) was used to amplify the mitochondrial genome in 101 individuals. The analysed individuals represent a collection with a balanced representation of genders and mtDNA haplogroup distribution, similar to that of a Western European population. The results show that the frequency of heteroplasmic individuals exceeds 61%. The frequency of point heteroplasmy is 28.7%, with a widespread distribution across the entire mtDNA. In addition, an excess of transitions in heteroplasmy were detected, suggesting that genetic drift and/or selection may be acting to reduce its frequency at population level. In fact, heteroplasmy at highly stable positions might have a greater impact on the viability of mitochondria, suggesting that purifying selection must be operating to prevent their fixation within individuals. This study analyses the frequency of heteroplasmy in a healthy population, carrying out an evolutionary analysis of the detected changes and providing a new perspective with important consequences in medical, evolutionary and forensic fields.


Can mammographic and sonographic imaging features predict the Oncotype DX™ recurrence score in T1 and T2, hormone receptor positive, HER2 negative and axillary lymph node negative breast cancers?
To determine whether mammographic or sonographic features can predict the Oncotype DX™ recurrence scores (RS) in patients with TI-II, hormone receptor (HR) positive, HER2/neu negative and node negative breast cancers. Institutional board review was obtained and informed consent was waived for this retrospective study. Seventy-eight patients with stage I-II invasive breast cancer that was HR positive, HER2 negative, and lymph node negative for whom mammographic and or sonographic imaging and Oncotype DX™ assay scores were available were included in the study Four breast dedicated radiologists blinded to the RS retrospectively described the lesions according to BI-RADS lexicon descriptors. Multivariable logistic regression was used to test for significant independent predictors of low (<18) versus intermediate to high range (≥18). Two imaging features reached statistical significance in predicting low from intermediate or high risk RS: pleomorphic microcalcifications within a mass (P = 0.017); OR 8.37, 95 % CI (1.47-47.79) on mammography and posterior acoustic enhancement in a mass on ultrasound (P = 0.048); OR 4.35, 95 % CI (1.01-18.73) on multivariable logistic regression. A mass with pleomorphic microcalcifications on mammography or the presence of posterior acoustic enhancement on ultrasound may predict an intermediate to high RS as determined by the Oncotype DX(TM) assay in patients with stage I-II HR positive, HER2 negative, and lymph node negative invasive breast cancer.


Immunological Markers of Chlamydia trachomatis Infection in Epithelial Ovarian Cancer.
Pelvic inflammatory disease (PID) is a risk factor for epithelial ovarian cancer (EOC). Chlamydia trachomatis infection, a major cause of PID, may persist in some women. Serum IgG antibodies to chlamydial TroA and HtrA are more common in ascending or repeat chlamydial infection than in uncomplicated infection. The aim of this study was to explore the role of C. trachomatis infection in EOC by analyzing chlamydial TroA, HtrA and major outer membrane protein (MOMP) IgG serum antibody responses. The study is based on the review of Oulu University Hospital medical records of 162 women diagnosed with EOC between March 2008 and May 2018. Serum IgG antibody responses to recombinant C. trachomatis TroA, HtrA and MOMP were analyzed using enzyme-linked immunoassay. Complete response to the first line therapy and the three-year survival were the study endpoints. Altogether, 16.7%, 11.1% and 12.3% women were C. trachomatis TroA, HtrA and MOMP IgG positive, respectively. Women with these antibodies were more likely to have a complete response to the first-line treatment, compared to women without these antibodies (63.0% vs. 34.1% for TroA IgG, 50.0% vs. 37.5% for HtrA IgG and 50% vs. 37.3% for MOMP IgG, respectively). The presence of these antibodies predicted better three-year survival. Women with EOC and positive markers of persistent C. trachomatis infection have better response to the first-line treatment and seem to have better three-year survival.


Retraction.
Retraction: Francis Domain, Xiaowen R. Bina and Stuart B. Levy, "Transketolase A, an enzyme in central metabolism, derepresses the marRAB multiple antibiotic resistance operon of Escherichia coli by interaction with MarR", Molecular Microbiology 2007, 66(2), 383-393 (https://doi/10.1111/j.1365-2958.2007.05928.x). The above article, published online on 14 September 2007 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief John Helmann, and John Wiley & Sons Ltd. The retraction has been agreed because additional work in the authors' laboratory (L.M. McMurry) failed to confirm that the tktA gene overexpressed from pSPOK-TktA enhanced the expression in vivo of the mar promoter fusion marO-lacZ, or that deletion of chromosomal tktA reduced marO-lacZ expression. The original conclusions probably resulted from a yet unexplained variability of LacZ activity later discovered among different isolates of the marO-lacZ indicator strain SPC105. Moreover, the apparent binding of MarR to TktA-6H immobilized on NiNTA resin (Fig. 1B) was an artefact caused by non-specific binding of MarR alone to the resin that occurred when the wash contained no imidazole. Most MarR eluted in 20 mM imidazole without TktA-6H. Therefore, the conclusion that TktA interacts physically with MarR is not warranted. It is noted that Xiaowen R. Bina was not involved in work related to these errors. Note that previously a corrigendum was published to note these concerns (Molecular Microbiology (2011) 80(3), 853).


Social approach, anxiety, and altered tryptophan hydroxylase 2 activity in juvenile BALB/c and C57BL/6J mice.
Autism spectrum disorder (ASD) is a heterogeneous and highly heritable condition with multiple aetiologies. Although the biological mechanisms underlying ASD are not fully understood, evidence suggests that dysregulation of serotonergic systems play an important role in ASD psychopathology. Preclinical models using mice with altered serotonergic neurotransmission may provide insight into the role of serotonin in behaviours relevant to clinical features of ASD. For example, BALB/c mice carry a loss-of-function single nucleotide polymorphism (SNP; C1473 G) in tryptophan hydroxylase 2 (Tph2), which encodes the brain-specific isoform of the rate-limiting enzyme for serotonin synthesis, and these mice frequently have been used to model symptoms of ASD. In this study, juvenile male BALB/c (G/G; loss-of-function variant) and C57BL/6 J (C/C; wild type variant) mice, were exposed to the three-chamber sociability test, and one week later to the elevated plus-maze (EPM). Tryptophan hydroxylase 2 (TPH2) activity was measured following injection of the aromatic amino acid decarboxylase (AADC)-inhibitor, NSD-1015, and subsequent HPLC detection of 5-hydroxytryptophan (5-HTP) within subregions of the dorsal raphe nucleus (DR) and median raphe nucleus (MnR). The BALB/c mice showed reduced social behaviour and increased anxious behaviour, as well as decreased 5-HTP accumulation in the rostral and mid-rostrocaudal DR. In the full cohort of mice, TPH2 activity in the mid-rostrocaudal DR was correlated with anxious behaviour in the EPM, however these correlations were not statistically significant within each strain, suggesting that TPH2 activity was not directly associated with either anxiety or sociability. Further research is therefore required to more fully understand how serotonergic systems are involved in mouse behaviours that resemble some of the clinical features of ASD.


Update in Mechanical Ventilation, Sedation, and Outcomes 2014.
Novel approaches to the management of acute respiratory distress syndrome include strategies to enhance alveolar liquid clearance, promote epithelial cell growth and recovery after acute lung injury, and individualize ventilator care on the basis of physiological responses. The use of extracorporeal membrane oxygenation (ECMO) is growing rapidly, and centers providing ECMO must strive to meet stringent quality standards such as those set out by the ECMONet working group. Prognostic tools such as the RESP score can assist clinicians in predicting outcomes for patients with severe acute respiratory failure but do not predict whether ECMO will enhance survival. Evidence continues to grow that novel modes of mechanical ventilation such as neurally adjusted ventilatory assist are feasible and improve patient physiology and patient-ventilator interaction; data on clinical outcomes are limited but supportive. Critical illness causes long-term psychological and function sequelae: the risk of a new psychiatric diagnosis and severe physical impairment is significantly increased in the months after discharge from the intensive care unit. These long-term effects might be amenable to changes in sedation practice and increased early mobilization. Daily sedation discontinuation enhances the validity of routine delirium assessment. Many critically ill patients merit assessment by palliative care clinicians; the demand for palliative care services among critically ill patients is expected to grow. Future trials to test therapies for critical illness must ensure that study designs are adequately powered to detect benefit using realistic event rates. Integrating "big data" approaches into treatment decisions and trial designs offers a potential means of individualizing care to enhance outcomes for critically ill patients.


[Xerostomia caused by radiotherapy of patients with head and neck cancer].
Xerostomia causes great inconvenience in patients treated with irradiation for cancer of the head and neck. For all practical purposes, salivary gland tissue becomes irreversibly incapable of functioning after doses of 40 Gy (standard fractioning). Curative doses are 60-70 Gy and, therefore, xerostomia can only be limited by attempting to involve as little as possible of salivary gland tissue in the irradiation fields. The limits of the tumour should be diagnosed as exactly as possible so that the irradiation fields are not made any larger than necessary "for safety". Therapeutic techniques which involve salivary gland tissue on only one side should be elected when this is justifiable. It is important to inform the patient about caries prohylaxis and the patient's own dentist should be involved in the problem as early as possible. Prophylatic fluorine treatment should be offered to alle of the patients.


[Double-stranded RNA from phage F6: its interferon-inducing and antiviral properties].
Double stranded RNA was isolated from bacteriophage phi 6 parasitizing on phytobacteria. Its interferon-inducing and antiviral activities were shown in vitro and in vivo. In the culture of L-929 cells, interferon resistant to heat and acids was synthesized. The interferon could be practically completely neutralized by specific anti-interferon serum. The phage phi 6 preparation dsRNA in the lyophilized form was studied. The preparation retained its biological activity. It was shown that a preparation containing 30 per cent of dsRNA was less toxic than a preparation containing 100 per cent of dsRNA, the difference in the interferon-inducing activity being insignificant.


An integratable microfluidic cartridge for forensic swab samples lysis.
Fully automated rapid forensic DNA analysis requires integrating several multistep processes onto a single microfluidic platform, including substrate lysis, extraction of DNA from the released lysate solution, multiplexed PCR amplification of STR loci, separation of PCR products by capillary electrophoresis, and analysis for allelic peak calling. Over the past several years, most of the rapid DNA analysis systems developed started with the reference swab sample lysate and involved an off-chip lysis of collected substrates. As a result of advancement in technology and chemistry, addition of a microfluidic module for swab sample lysis has been achieved in a few of the rapid DNA analysis systems. However, recent reports on integrated rapid DNA analysis systems with swab-in and answer-out capability lack any quantitative and qualitative characterization of the swab-in sample lysis module, which is important for downstream forensic sample processing. Maximal collection and subsequent recovery of the biological material from the crime scene is one of the first and critical steps in forensic DNA technology. Herein we present the design, fabrication and characterization of an integratable swab lysis cartridge module and the test results obtained from different types of commonly used forensic swab samples, including buccal, saliva, and blood swab samples, demonstrating the compatibility with different downstream DNA extraction chemistries. This swab lysis cartridge module is easy to operate, compatible with both forensic and microfluidic requirements, and ready to be integrated with our existing automated rapid forensic DNA analysis system. Following the characterization of the swab lysis module, an integrated run from buccal swab sample-in to the microchip CE electropherogram-out was demonstrated on the integrated prototype instrument. Therefore, in this study, we demonstrate that this swab lysis cartridge module is: (1) functionally, comparable with routine benchtop lysis, (2) compatible with various types of swab samples and chemistries, and (3) integratable to achieve a micro total analysis system (μTAS) for rapid DNA analysis.


Extracellular ATP modulates synaptic plasticity induced by activation of metabotropic glutamate receptors in the hippocampus.
Synaptic plasticity is believed to be a cellular mechanism for memory formation in the brain. It has been known that the metabotropic glutamate receptor (mGluR) is required for persistent forms of memory and induction of synaptic plasticity. Application of mGluR agonists induces synaptic plasticity in the absence of electrical conditioning stimulation, such as high or low frequency stimulation. The direction of the mGluR-induced synaptic plasticity, i.e., either long-term potentiation (LTP) or long-term-depression (LTD), is dependent on whether N-methyl-D-aspartate receptors (NMDARs) are co-activated with mGluRs. ATP has modulatory effects on neuronal functions and, in particular, there is increasing evidence that it plays a crucial role in synaptic plasticity. LTP can be induced by application of ATP, and this effect is inhibited by NMDAR antagonist. Although cooperative effects of NMDARs and mGluRs and of NMDARs and extracellular ATP in synaptic plasticity have been revealed, the effect of extracellular ATP on mGluR-induced synaptic plasticity is unknown. In this article, we summarize published data on mGluR- and ATP-induced synaptic plasticity, and present new data showing that extracellular ATP facilitates both the LTP and LTD induced by mGluR activation.


[Analysis of modern blood reinfusion apparatuses].
The paper gives a brief review of the engineering solutions now applied to the clinical use of a blood reinfusion procedure. It considers simple, transient, and sophisticated (automatic) blood reinfusion methods, their advantages and disadvantages, and the areas of their possible clinical application.


Adrenaline: insights into its metabolic roles in hypoglycaemia and diabetes.
Adrenaline is a hormone that has profound actions on the cardiovascular system and is also a mediator of the fight-or-flight response. Adrenaline is now increasingly recognized as an important metabolic hormone that helps mobilize energy stores in the form of glucose and free fatty acids in preparation for physical activity or for recovery from hypoglycaemia. Recovery from hypoglycaemia is termed counter-regulation and involves the suppression of endogenous insulin secretion, activation of glucagon secretion from pancreatic α-cells and activation of adrenaline secretion. Secretion of adrenaline is controlled by presympathetic neurons in the rostroventrolateral medulla, which are, in turn, under the control of central and/or peripheral glucose-sensing neurons. Adrenaline is particularly important for counter-regulation in individuals with type 1 (insulin-dependent) diabetes because these patients do not produce endogenous insulin and also lose their ability to secrete glucagon soon after diagnosis. Type 1 diabetic patients are therefore critically dependent on adrenaline for restoration of normoglycaemia and attenuation or loss of this response in the hypoglycaemia unawareness condition can have serious, sometimes fatal, consequences. Understanding the neural control of hypoglycaemia-induced adrenaline secretion is likely to identify new therapeutic targets for treating this potentially life-threatening condition.


Repair of obstetric perineal lacerations.
Family physicians who deliver babies must frequently repair perineal lacerations after episiotomy or spontaneous obstetric tears. Effective repair requires a knowledge of perineal anatomy and surgical technique. Perineal lacerations are classified according to their depth. Sequelae of obstetric lacerations include chronic perineal pain, dyspareunia, urinary incontinence, and fecal incontinence. With lacerations involving the anal sphincter complex, particular attention must be given to anatomy and surgical technique because of the high incidence of poor functional outcomes after repair. An overlapping technique to repair the external anal sphincter, rather than the traditional end-to-end technique, is being investigated to determine if it might decrease the incidence of anal incontinence. Minimizing the use of episiotomy and forceps deliveries can decrease the occurrence of severe perineal lacerations.


Indirect impact of the COVID-19 pandemic on the care and outcomes of people with MS: A combined survey and insurance claims study.
In the context of the COVID-19 pandemic, people with multiple sclerosis (pwMS) have been particularly vulnerable to adverse outcomes due to increased risk of severe infection and/or widespread disruptions in care. The CopeMS study led by The University of Texas at Austin and the MS Association of America investigates the long-term impact of the COVID-19 pandemic on healthcare access, disease modifying therapy (DMT) utilization and outcomes of pwMS. This retrospective cohort analysis used Optum's de-identified Clinformatics® Data Mart Database (CDM), a large de-identified administrative healthcare claims database to identify pwMS who were continuously enrolled from 01/01/2019 to 12/31/2020 and assessed changes in the utilization of DMTs and healthcare services during the COVID-19 pandemic compared to the year prior. Additionally, a national survey of pwMS and healthcare providers (HCPs) was conducted to further understand the indirect impact of the pandemic on healthcare resource utilization (HCRU), outcomes and prescription patterns. Out of 529 pwMS in our national survey, over 47 % reported that their overall health and neurologic symptoms had deteriorated during the COVID-19 pandemic, with increased anxiety, and inability to maintain exercise habits as leading perceived causes for worsening. Survey respondents reported widespread disruption of MS-related services during the pandemic. In the Optum database, we identified 39,209 pwMS validating inclusion criteria. We observed a decrease in the utilization of MS-related services in 2020 compared to 2019. Significantly fewer pwMS had visits with their neurologist, primary care provider, physical or occupational therapist despite an increased utilization of telemedicine services. Fewer pwMS had magnetic resonance imaging (MRI) studies of the brain or spinal cord during the pandemic. Only 22.2 % of HCPs surveyed agreed that the perceived risk of more severe COVID-19 infection on a specific DMT influenced their therapeutic decisions. In the Optum database, individuals with an established diagnosis of MS prior to 2019 saw decreases in utilization of platform and moderate efficacy DMTs. In this group, those over the age of 55 saw a decrease in utilization of B-cell therapies (rate ratio 0.79, CI 0.75-0.83), whereas individuals under the age of 55 saw an increase in utilization of B-cell therapies (rate ratio 1.10, CI 1.03-1.17). We did not see any difference in rates of starting DMTs in persons diagnosed in 2019 prior to the pandemic and those diagnosed in 2020. Compared to 2019, B-cell therapies were prescribed more frequently in pwMS diagnosed in 2020 who were younger than 55 or commercially insured (rate ratio 1.35, CI 1.11-1.63). The COVID-19 pandemic was associated with perceived worsening of neurological symptoms in pwMS. Despite the expansion of telemedicine, we observed decreased access to healthcare services important to the comprehensive care of pwMS. Additionally, we observed changes in DMT utilization in pwMS during the pandemic, particularly in older adults with an established diagnosis of MS.


Assement of the fluoride concentration and pH in different mouthrinses on the brazilian market.
In this study, the fluoride concentration and pH of 14 commercial brands of mouthrinses were assessed in order to compare them with the values expressed on the labels and with those established by the National Sanitary Surveillance Agency. Forty-two (42) products were obtained from three places, with different manufacturing batches. The fluoride concentration was determined in diluted solutions, using a combined specific electrode for fluoride ion (9609 BN Orion Research) and ion analyzer (290 A Orion Research). The results showed that 50% of the solutions had statistically significant differences, with higher fluoride concentrations than those expressed on the labels, and the pH ranged from 4.23 to 7.34, but only one of the products registered the pH value on its label.


Environmental attitudes of stakeholders and their perceptions regarding protected area-community conflicts: a case study in China.
Large numbers of people living in and around protected areas are highly dependent on the natural resources. However, simply excluding them from the area management has always inevitably resulted in conflicts. We conducted a case study of the Protected Area of Jinyun Mountain (PJM) in China to evaluate social context variables, environmental attitudes, and perceptions regarding protected area-community conflicts. Data were collected through questionnaire surveys administered to four stakeholder groups (i.e. local farmers, government staff, business persons, and tourists). A total of 112 questionnaires were completed in December 2008, after the Sichuan Earthquake. The questionnaire consisted of three parts, social context (gender, race, age, income, and education level), protected area-community conflicts, and environmental attitudes. The New Ecological Paradigm (NEP) scores, which were employed to evaluate environmental attitudes, differed significantly among the stakeholder groups (P<0.01). Specifically, government staff reported the highest and business persons did the lowest. Among the five items evaluated, anti-exemptionalism received the lowest score, while nature's balance did the highest. Evaluation of the protected area-community relationship indicated that harmony and conflict both exist in the PJM, but have different forms among different stakeholders, and seem to be opposite between government staff and local farmers. Among the indexes, tourism primarily contributed to the harmonious aspect, while collection of NTFPs did to the conflicting one. Conflict scores were positively related to age and negatively related to education level. Respondents with higher NEP scores were more partial to the park management. Besides, the respondents with higher annual incomes tended to support the policy of harmonizing the relationship and lessening the harm of local communities to the area. To promote proenvironmental attitudes and alleviate the protected area-community conflicts, we recommend improving environmental education, establishing community co-management, and launching substitute sources of cash for traditional cultivation.


Expression and regulation of P2U-purinergic receptor in human granulosa-luteal cells.
The P2U purinoceptor (P2UR) has been identified pharmacologically in the ovary. However, the expression and regulation of the P2UR messenger RNA (mRNA) in human ovarian cells are still poorly characterized. The present study was designed to examine the expression and regulation of the P2UR in human granulosa-luteal cells (hGLCs) by RT-PCR and Northern blot analysis. A PCR product corresponding to the expected 599-bp P2UR complementary DNA was obtained from hGLCs. Molecular cloning and sequencing of the PCR product revealed an identical sequence to the reported P2UR complementary DNA. Two mRNA transcripts of 2.0 kb and 4.6 kb were identified in hGLCs using Northern blot analysis. The expression of the P2UR mRNA was down-regulated by human CG in a dose- and time-dependent manner. Treatment with 8-bromo-cAMP and forskolin also attenuated P2UR mRNA levels. Calcium signaling following the activation of the P2UR in single hGLCs was studied using microspectrofluorimetry. It revealed that, like ATP, uridine triphosphate (UTP) also induced cytosolic calcium mobilization in a dose-dependent manner. These results demonstrate for the first time that the P2UR mRNA is expressed in hGLCs and that P2UR mRNA is regulated by human CG, cAMP, and forskolin. The P2UR expressed in hGLCs functional because activation of the P2UR by ATP or UTP resulted in rapid and transient mobilization of cytosolic calcium at the single cell level. These findings further support a potential role of this neurotransmitter receptor in the human ovary.


North American Contact Dermatitis Group patch test results for 2007-2008.
The North American Contact Dermatitis Group (NACDG) tests patients with suspected allergic contact dermatitis to a broad series of screening allergens and publishes periodic reports. The aims of this study were to report the NACDG patch-testing results from January 1, 2007, to December 31, 2008, and to compare results to pooled test data from the previous 2 and 10 years to analyze trends in allergen sensitivity. Standardized patch testing with 65 allergens was used at 13 centers in North America. χ analysis was used for comparisons. A total of 5085 patients were tested; 11.8% (598) had an occupationally related skin condition, and 65.3% (3319) had at least 1 allergic patch test reaction, which is identical to the NACDG data from 2005 to 2006. The top 15 most frequently positive allergens were nickel sulfate (19.5%), Myroxylon pereirae (11.0%), neomycin (10.1%), fragrance mix I (9.4%), quaternium-15 (8.6%), cobalt chloride (8.4%), bacitracin (7.9%), formaldehyde (7.7%), methyldibromoglutaronitrile/phenoxyethanol (5.5%), p-phenylenediamine (5.3%), propolis (4.9%), carba mix (4.5%), potassium dichromate (4.1%), fragrance mix II (3.6%), and methylchloroisothiazolinone/methylisothiazolinone (3.6%). There were significant increases in positivity rates to nickel, methylchloroisothiazolinone/methylisothiazolinone, and benzophenone-3. During the same period of study, there were significant decreases in positivity rates to neomycin, fragrance mix I, formaldehyde, thiuram mix, cinnamic aldehyde, propylene glycol, epoxy resin, diazolidinyl urea, amidoamine, ethylenediamine, benzocaine, p-tert-butylphenol formaldehyde resin, dimethylol dimethyl hydantoin, cocamidopropyl betaine, glutaraldehyde, mercaptobenzothiazole, tosylamide formaldehyde resin, budesonide, disperse blue 106, mercapto mix, and chloroxylenol. Twenty-four percent (1221) had a relevant positive reaction to a non-NACDG supplementary allergen; and 180 of these reactions were occupationally relevant. Periodic analysis, surveillance, and publication of multicenter study data sets document trends in allergen reactivity incidence assessed in the patch test clinic setting and provide information on new allergens of relevance.


Veterans Administration Cooperative Study on Vasodilator Therapy of Heart Failure: influence of prerandomization variables on the reduction of mortality by treatment with hydralazine and isosorbide dinitrate.
The Veterans Administration Cooperative Study on Vasodilator Therapy of Heart Failure was designed to determine whether vasodilator drugs could alter the survival of patients with chronic congestive heart failure treated with digoxin and diuretics. Among the 642 patients entered into the study, 273 were randomly assigned to placebo, 186 were randomly assigned to the combination of hydralazine and isosorbide dinitrate, and 183 patients were randomly assigned to prazosin; all patients were followed for periods ranging from 6 months to 5.7 years. Treatment with hydralazine-nitrate produced a 28% reduction in mortality compared with that in patients receiving placebo (95% confidence interval, 3% to 46%), whereas prazosin exerted no apparent beneficial effect. Data were further examined to determine if any baseline variables had an impact on the response to treatment. Mortality in the placebo group was higher in those with coronary artery disease, with a history of antiarrhythmic drug use, and with values lower than the median for ejection fraction and exercise tolerance. A reduction in mortality with hydralazine-isosorbide dinitrate was observed in all of the above pairs of subgroups as well as in those above and below 60 years of age and those with and without a history of hypertension or excess alcohol ingestion. The benefit of hydralazine and isosorbide dinitrate was particularly prominent in younger patients with a lower ejection fraction and those with a history of hypertension and without an alcoholic history.(ABSTRACT TRUNCATED AT 250 WORDS)


Predictors for treating obstructive sleep apnea with an open nasal cannula system (transnasal insufflation).
Obstructive sleep apnea (OSA) is a disorder that is associated with increased morbidity and mortality. Although continuous positive airway pressure effectively treats OSA, compliance is variable because of the encumbrance of wearing a sealed nasal mask throughout sleep. In a small group of patients, it was recently shown that an open nasal cannula (transnasal insufflation [TNI]) can treat OSA. The aim of this larger study was to find predictors for treatment responses with TNI. Standard sleep studies with and without TNI were performed in 56 patients with a wide spectrum of disease severity. A therapeutic response was defined as a reduction of the respiratory disturbance index (RDI) below 10 events/h associated with a 50% reduction of the event rate from baseline and was used to identify subgroups of patients particularly responsive or resistant to TNI treatment. For the entire group (N = 56), TNI decreased the RDI from 22.6 +/- 15.6 to 17.2 +/- 13.2 events/h (P < .01). A therapeutic reduction in the RDI was observed in 27% of patients. Treatment responses were similar in patients with a low and a high RDI, but were greater in patients who predominantly had obstructive hypopneas or respiratory effort-related arousals and in patients who predominantly had rapid eye movement (REM) events. The presence of a high percentage of obstructive and central apneas appears to preclude efficacious treatment responses. TNI can be used to treat a subgroup of patients across a spectrum from mild-to-severe sleep apnea, particularly if their sleep-disordered breathing events predominantly consist of obstructive hypopneas or REM-related events but not obstructive and central apneas.


Increased epithelial cell proliferation and abnormal extracellular matrix in rat polycystic kidney disease.
Proliferation of renal tubular epithelial cells is considered a major factor leading to cyst formation in human polycystic kidney disease (PKD). The Han:SPRD rat model for inherited PKD permits a close scrutiny, especially for early stages of the disease, and shows numerous similarities to human autosomal dominant PKD (ADPKD). In this study, the exact in vivo proliferation rate in Han:SPRD rat kidneys was evaluated in a cell type-specific manner, using immunohistochemistry with antibody to proliferating cell nuclear antigen (PCNA). The proliferation index (PI; percentage of PCNA-positive cell nuclei) was determined in normal and cystically altered tissue, and a relationship between proliferative activity and alterations in extracellular matrix expression was established using in situ hybridization for collagen I and IV mRNA. Heterozygously affected rats (cy/+) showed strong increases of PI values in cystically altered nephron portions that were mostly derived from proximal tubule. Cell proliferation obviously preceded cyst formation, because early in the progression of the disease, the normal-appearing tubules from PKD kidneys had markedly increased PI values compared with healthy controls (14.1-fold in 3-mo-old rats and 11.9-fold in 12-mo-old rats; P < 0.05), whereas later stages revealed a more generalized cystic degeneration of the nephron, with increases in PI between 14- and 82-fold, depending on the respective category of cystic epithelia. In cysts with a distal phenotype, changes were less pronounced. No significant differences were encountered between the two age groups. Proliferation was also present in interstitial cells, whereas glomeruli were unchanged. Increases in epithelial and interstitial proliferation coincided with an overexpression of matrix compounds. For comparison, changes in homozygously affected rats (cy/cy) showed up to several hundred-fold elevated PI values. These results indicate that in the Han:SPRD model for ADPKD, cystic malformation of the nephron is preceded by and coincides with enhanced epithelial and interstitial cell proliferation. Altered cell-matrix interactions seem to be directly involved in the disruption of epithelial differentiation.


Circular RNA expression in human hematopoietic cells is widespread and cell-type specific.
Hematopoietic stem cells differentiate into a broad range of specialized blood cells. This process is tightly regulated and depends on transcription factors, micro-RNAs, and long non-coding RNAs. Recently, also circular RNA (circRNA) were found to regulate cellular processes. Their expression pattern and their identity is however less well defined. Here, we provide the first comprehensive analysis of circRNA expression in human hematopoietic progenitors, and in differentiated lymphoid and myeloid cells. We here show that the expression of circRNA is cell-type specific, and increases upon maturation. CircRNA splicing variants can also be cell-type specific. Furthermore, nucleated hematopoietic cells contain circRNA that have higher expression levels than the corresponding linear RNA. Enucleated blood cells, i.e. platelets and erythrocytes, were suggested to use RNA to maintain their function, respond to environmental factors or to transmit signals to other cells via microvesicles. Here we show that platelets and erythrocytes contain the highest number of circRNA of all hematopoietic cells, and that the type and numbers of circRNA changes during maturation. This cell-type specific expression pattern of circRNA in hematopoietic cells suggests a hithero unappreciated role in differentiation and cellular function.


Double-Vacancy Controlled Friction on Graphene: The Enhancement of Atomic Pinning.
The vacancy-enhanced contact friction of graphene is mainly attributed to the vacancy-enhanced out-of-plane deformation flexibility of the graphene and the climbing of the tip out of the vacancy trap (which actually acts as a step edge). However, this mechanism does not apply for explaining the enhanced friction caused by small-sized vacancies that are unable to accommodate the tip, such as single vacancy and double vacancies, which also commonly exist in the graphene. In the present study, by performing a set of classic molecular dynamics simulations, we demonstrated that the double-vacancy defect in graphene substantially enhanced the contact friction when the tip slides over it and the pinning effect of the reconstructed lattice of the double-vacancy defect with atoms at the bottom of the tip dominated such an influence. The underlying mechanism of such an atomic pinning effect and the influence of the normal load, sliding direction, and the sliding velocity were unveiled by analyzing the obtained friction evolution and the atomic configuration and interaction between the tip and the graphene. We believe that the findings presented in this study complete the state-of-art understanding of the nanoscale friction behaviors of vacancy-defected graphene, which is essential for the implementation of their potential control.


Clinical implications of the novel cytokine IL-38 expressed in lung adenocarcinoma: Possible association with PD-L1 expression.
Interleukin (IL)-38, a novel member of the IL-1 cytokine family, is homologous to IL-1 receptor antagonist (IL-1Ra) and IL-36Ra, and has been reported to act as an antagonist. IL-38 expression is found in tonsil, placenta, and spleen, and recent studies suggest an association between IL-38 and autoimmune diseases. However, whether IL-38 plays a role in carcinogenesis or cancer growth is unclear. In the present study, we identified increases in IL-38 expression by immunohistochemistry in multiple types of cancer cells. In the examination of 417 surgically resected primary lung adenocarcinomas, Fisher's exact tests showed significant associations between high IL-38 expression and high tumor grades, an advanced T status, advanced N status, advanced stage, and the presence of pleural and vessel invasions. Survival analyses by the Kaplan-Meier method showed that patients with high expression of IL-38 had significantly shorter disease-free survival and shorter overall survival after surgery than patients with low expression of IL-38 (log-rank test: P = 0.0021 and P = 0.0035, respectively). Moreover, programmed cell death-ligand 1 (PD-L1)-positive cases showed higher expression of IL-38 than PD-L1-negative cases (Wilcoxon rank-sum test: P < 0.0001). In conclusion, IL-38 was expressed in tumor cells of various cancers, and IL-38 expression was associated with poor survival of lung adenocarcinoma patients. IL-38 may affect host immunity or the tumor microenvironment, and contribute to the progression of lung adenocarcinoma.


A Rare Cause of Epilepsy: Ulegyria Revisited in a Series of 10 Patients.
Introduction. Ulegyria results from perinatal hypoxic-ischemic brain injury in term infants. The specific mushroom-shaped configuration of ulegyria results from small atrophic circumvolutions at the bottom of a sulcus underlying an intact gyral apex. Clinically, ulegyria is generally associated with epilepsy. Here, we aimed to delineate the characteristics of patients with ulegyria and the epileptic seizures they experience. Material and methods. Medical records including radiology and pathology reports, video-electroencephalographic (EEG) analysis, operative notes, hospital progress and outpatient clinic notes were reviewed retrospectively in a total of 10 ulegyria patients. Results. Patients ages ranged between 24 and 58 years (mean, 32 ± 9.8 years). Past medical history was confirmed for neonatal asphyxia in 2 (20%). Neurological examination was remarkable for spastic hemiparesis in 1 (10%) patient with perisylvian ulegyria and for visual field deficits in 2 patients (20%) with occipital ulegyria. Ulegyria most commonly involved the temporoparietal region (n = 5, 50%) followed by the perisylvian area (n = 2, 20%). Except the one with bilateral perisylvian ulegyria, all patients had unilateral lesions (n = 9, 90%). Hippocampal sclerosis accompanied ulegyria in 2 patients (20%). All patients experienced epileptic seizures. Mean age at seizure onset was 8.8 ± 5.4 years (range, 2-20 years). Interictal scalp EEG and EEG-video monitoring records demonstrated temporoparietal and frontotemporal activities in 5 (50%) and 2 (20%) patients, respectively. The seizures were successfully controlled by antiepileptic medication in 8 patients (n = 8, 80%). The remaining 2 patients (%20) with concomitant hippocampal sclerosis required microsurgical resection of the seizure foci due to medically resistant seizures. Discussion. Ulegyria is easily recognized with its unique magnetic resonance imaging characteristics and clinical presentation in the majority of cases. It is highly associated with either medically resistant or medically controllable epileptic seizures. The treatment strategy depends on the age at onset and extends of the lesion that has a significant impact on the severity of the clinical picture.


Duchenne muscular dystrophy: preliminary experience with sacubitril-valsartan in patients with asymptomatic left ventricular dysfunction.
Duchenne muscular dystrophy (DMD) is an inherited X-linked recessive neuromuscular disease caused by mutations of the dystrophin gene, leading to early and progressive muscle deterioration and dilated cardiomyopathy. The aim of this investigation was to assess whether treatment with sacubitril/valsartan (S/V) is well tolerated and may have beneficial effects in DMD patients with left ventricle (LV) dysfunction. We administered S/V to 3 DMD patients (19-29 yeard old) with LV ejection fraction <35% at echocardiography but no symptoms of heart failure. All patients were on optimal medical therapy. S/V was initiated at a very low dose of 12/13 mg/die, after withdrawal of angiotensin-converting enzyme inhibitor therapy, and slowly titrated to the dose of 49/51 mg twice daily or the maximally tolerated dose. Clinical and echocardiographic follow-up was performed after 3, 6 and 12 months. At baseline, the LV ejection fraction was 32±1%. A significant improvement of LV ejection fraction was observed at 3 months (44.0±6.0%; p<0.05), which was maintained at 6 (45.7±5.0%) and 12 (43.3±3.2%) months (p<0.05 for both). No relevant side effects were reported throughout the period of the study. Our preliminary data suggest that, in DMD patients with reduced LV ejection fraction, S/V is safe and may improve LV function.


Clinicopathological analysis of 12 patients with Epstein-Barr virus-positive primary intestinal T/natural killer-cell lymphoma (EBV+ ITNKL).
Epstein-Barr virus-positive (EBV+ ) intestinal T/natural killer (NK) cell lymphoma (ITNKL) is an uncommon tumour with an extremely aggressive clinical behaviour. However, the clinicopathological characteristics of this tumour, including T cell receptor (TCR) phenotype and the patient's background, remain unknown. The aim of this study was to elucidate the detailed clinicopathological profile of EBV+ ITNKL. We enrolled 12 patients with EBV+ ITNKL without nasal involvement into the study. All patients were characterized by involvement of the small intestine with concurrent lesions of the large intestine in two patients. Seven patients (58%) had Lugano stages IIE/IV disease and eight (67%) were categorized as high-intermediate/high-risk according to the Prognostic Index for PTCL (PIT). Three patients (25%) with an age of onset of less than 50 years had chronic active EBV infection (CAEBV). Five CD56-positive patients (42%) had a poorer prognosis than those without CD56 expression (P = 0.008). NK cell-type lymphoma defined by the absence of any TCR expression or clonal TCR-γ rearrangement was found in six patients (50%). Interestingly, EBV+ intra-epithelial lymphocytosis was observed in one case with a background of CAEBV. This study is the first to shed light on the significant heterogeneity of EBV+ ITNKL and its relationship with CAEBV, especially in patients younger than 50 years of age. These observations will provide a guide for diagnostic and therapeutic approaches in routine practice.


Conservation of hearing in acoustic schwannoma surgery.
Hearing conservation in acoustic schwannoma surgery is possible in approximately 50% of patients those tumors measure 15 mm or less in size (medial to the porus acusticus) and whose speech discrimination score in the ear with the tumor is 80% or better. The concepts of total tumor removal and maximum sparing of adjacent normal neural tissue are consistent with efforts to retain cochlear function. A retrosigmoid approach is favored over the middle cranial fossa approach because of its superior exposure and less morbidity. An operating table capable of 35 degrees side rotation is used because it allows the majority of patients with acoustic neuromas to be operated on in the horizontal supine position. The posterior lip of the internal auditory canal is removed to within approximately 1.5 mm of the falciform crest. Tumors not extending to the fundus afford an ideal situation for total removal, early identification of the seventh cranial nerve, and preservation of hearing. The carbon dioxide laser is a useful surgical tool with its properties of vaporization, cutting, and coagulation.


Human fetuin/alpha2HS-glycoprotein level as a novel indicator of liver cell function and short-term mortality in patients with liver cirrhosis and liver cancer.
Human fetuin/alpha2HS-glycoprotein (AHSG) is synthesized by hepatocytes. We intended to determine whether liver dysfunction or acute phase reaction is dominant in the regulation of its serum concentrations and to see if decreased AHGS levels are associated with short-term mortality. We determined the serum AHSG levels in patients with acute alcoholic, acute A, B, and Epstein-Barr virus hepatitis, alcoholic cirrhosis, and hepatocellular cancer and correlated them to conventional laboratory parameters of inflammation and liver function. Patients were followed for 1 month. Serum AHSG was determined by radial immunodiffusion. Compared to controls, significantly lower AHSG levels were found in patients with liver cirrhosis and hepatocellular cancer but not the acute viral hepatitides. Strong positive correlation with serum transferrin, albumin and prothrombin was found. Febrile episodes were not associated with significantly decreased AHSG levels. Concentrations below 300 microg/ml were associated with high mortality rate (52.0%; relative risk, 5.497; 95% confidence interval, 2.472-12.23; P < 0.0001). Of all laboratory parameters studied serum AHSG levels showed the greatest difference between deceased and survived patients with cirrhosis and cancer. Moreover, other acute phase reactants did not differ significantly. The multiple logistic regression analysis indicated that the decrease of serum AHSG is independent of all other variables that were found decreased in deceased patients. Decreased serum AHSG concentration is due rather to hepatocellular dysfunction than the acute phase reaction and is an outstanding predictor of short-term mortality in patients with liver cirrhosis and liver cancer.


Deniers and Admitters: Examining Smoker Identities in a Changing Tobacco Landscape.
Smoking prevalence has declined considerably over the past 30 years. This decline has coincided with a growing stigma against smokers and a trend toward nondaily or occasional smoking. Some individuals now deny being a smoker despite current cigarette use-i.e., "deniers"; conversely, occasional smokers who admit to being a smoker are defined as "admitters." Although the "denier" phenomenon has been the focus of recent research, no studies have examined smoker identity in the context of emerging tobacco products and ongoing, statewide tobacco control programs. Recent data from the 2014 Minnesota Adult Tobacco Survey provided an opportunity to address these research gaps. Using the Minnesota Adult Tobacco Survey, participants were 242 adults who reported smoking 100 cigarettes lifetime, currently smoking "some days," and past 30-day smoking. Questions also assessed smoker identity, emerging product use and perceptions, and changes in smoking behavior in response to a recent statewide tobacco tax increase. Regression models revealed no difference in e-cigarette or hookah use between deniers and admitters, but deniers were more likely to perceive that hookah use was less harmful than smoking cigarettes. In response to the tax increase, we found that admitters were more likely than deniers to report thinking about quitting, reducing cigarette amount, and making a quit attempt. Findings suggest that deniers perceive lower harm from using tobacco products. Tax increases may be less effective at motivating quit attempts in deniers compared to admitters, implying that cessation programs tailored to specific smoking identities could usefully complement tax increases. Findings from this study suggest that tobacco tax increases should be coordinated with health promotion interventions to address occasional and social smoking. The denier phenomenon in particular is an important identity-based construct that population-level public health practice should consider in order to design effective tobacco control interventions. In addition, findings from our study and previous research suggest that occasional or social smokers who deny the smoker identity may be slowing progress in reducing smoking rates. Interventions targeting occasional smokers, and in particular, deniers, are needed to accelerate cessation efforts.


General Practitioner's use of online resources during medical visits: managing the boundary between inside and outside the clinic.
In an increasingly connected world, information about health can be exchanged at any time, in any location or direction, and is no longer dominated by traditional authoritative sources. We consider the ways information and advice given in consultations by doctors transcends the boundary between the clinic and the home. We explore how information that is widely accessible outside the consultation is transformed by General Practitioners (GPs) into a medical offering. Data comprise 18 consultations identified from 144 consultations between unselected patients and five GPs. We use conversation analytic methods to explore four ways in which GPs used online resources; (i) to check information; (ii) as an explanatory tool; (iii) to provide information for patients for outside the consultation; (iv) to signpost further explanation and self-help. We demonstrate the interactional delicacy with which resources from the Internet are introduced and discussed, developing and extending Nettleton's (2004) idea of 'e-scaped medicine' to argue that Internet resources may be 'recaptured' by GPs, with information transformed and translated into a medical offering so as to maintain the asymmetry between patients and practitioners necessary for the successful functioning of medical practice.


Impact of the Percentage of Overlapping Surgery on Patient Outcomes: A Retrospective Cohort Study of 87,000 Surgical Cases.
The primary objective of this study was to analyze the relationship of percentage of surgical overlap with patient outcomes to determine if a detrimental level of overlap exists. Overlapping surgery is defined as 1 attending physician supervising 2 or more operative cases simultaneously, without the critical portions of the cases occurring concurrently. To date, no study has examined the relationship of percent overlap, or the percentage of 1 case that is spent overlapping with another, to outcomes, efficiency, safety, and complications. This study is a retrospective cohort study conducted at a large tertiary referral center. The primary outcomes of interest included operative duration, in-hospital mortality, 30-day readmission, and patient safety indicators (PSIs). The Cochran-Armitage test for trend was used to evaluate the outcomes of interest. P values of ≤0.05 were considered statistically significant. A total of 87,426 cases were included in this study. There were 62,332 cases without overlap (Group 0), 10,514 cases with 1% to 25% overlap (Group 1), 5303 cases with 26% to 50% overlap (Group 2), 4296 cases with 51% to 75% overlap (Group 3), and 4981 cases with >75% overlap (Group 4). In-hospital mortality decreased as overlap increased ( Ptrend <0.0001). Operative time increased with increasing overlap ( Ptrend <0.0001) while readmission rates showed no statistical significance between groups ( Ptrend =0.5078). Rates of PSIs were lower for Groups 1, 2, and 3 (1.69%, 2.01%, and 2.08%) when compared to Group 0 (2.24%). Group 4 had the highest rate of PSIs at 2.35% ( P =0.0086). Overlapping surgery was shown to have reduced in-hospital mortality and similar PSI and readmission rates when compared to nonoverlapping cases. Operative time was shown to increase in overlapping surgeries when compared to nonoverlapping surgeries. The results from this study indicate that the percentage of surgical overlap does not detrimentally affect most patient outcomes, especially with overlap of <75%.


NT-proBNP for prognostic and diagnostic evaluation in patients with acute coronary syndromes.
N terminal-proB-type natriuretic peptide (NT-proBNP) is synthesised and secreted from the ventricular myocardium. This marker is known to be elevated in patients with acute coronary syndromes (ACS). We evaluated NT-proBNP asa significant diagnostic marker and an important independent predictor of short-term mortality (one month) in patients with ACS. NT-proBNP and cardiac troponin I (cTI) were assessed in 134 consecutive patients (median age 66 years, 73% male)hospitalised for ACS in a cardiological university department. The patients were classified into ST-elevation ACS (STE-ACS, n = 74) and non-ST-elevation ACS (NSTE-ACS, n = 60) groups based on the ECG findings on admission. Patients with Killip class ≥ II were excluded. The serum level of NT-proBNP on admission was significantly higher (p < 0.0005), while there was no difference in cTI serum level in the NSTE-ACS patients compared to STE-ACS patients. There was a significant positive correlation between NT-proBNP and cTI in the NSTE-ACS (r = 0.338, p = 0.008) and STE-ACS (r = 0.441, p < 0.0005) patients. There was a significant difference in NT-proBNP (p < 0.0005) and cTI (p < 0.0005) serum level between ACS patients who died within 30 days or who survived after one month. The increased NT-proBNP level is the strongest predictor of mortality in ACS patients, also NT-proBNP cut-point level of 1,490 pg/mL is a significant independent predictor of mortality. We demonstrated the differences and the correlation in the secretion of NT-proBNP and cTI in patients with STE-ACS vs. NSTE-ACS. Our results provide evidence that NT-proBNP is a significant diagnostic marker and an important independent predictor of short-term mortality in patients with ACS.


Insight into the esterase like activity demonstrated by an imidazole appended self-assembling hydrogelator.
A low molecular weight hydrogelator with a covalently appended imidazole moiety is reported. Capable of percolating water in the pH range of 6 to 8, it proves to be an efficient catalyst upon self-assembly, showing Michaelis-Menten type kinetics. Activities at different pH values correlated with dramatic structural changes were observed. It can hydrolyse p-nitrophenyl acetate (pNPA) as well as inactivated esters, and L and D-phenylalanine methyl esters. The enhanced activity can be related to the conglomeration of catalytic groups upon aggregation resulting in their close proximity and the formation of hydrophobic pockets.


Comparison of core needle biopsy (CNB) and surgical specimens for accurate preoperative evaluation of ER, PgR and HER2 status of breast cancer patients.
The roles of core needle biopsy (CNB) have become well established as an important preoperative diagnostic method for breast lesions. We examined the concordance of histological types, nuclear grades, hormone receptors, and human epidermal growth factor receptor 2 (HER2) status between CNB and surgical specimens in 353 cases. In addition, we analyzed the correlation between the number of CNB specimens obtained and accuracy of histological factors in order to explore the optimal number of CNB specimens. Between CNB and surgical specimens, concordance rates of histological type, nuclear grade, estrogen receptor (ER), and progesterone receptor (PgR) status (cut-off 0-<1%, 1-10%, and 10%<), and HER2 were 84.4%, 81.3%, 92.9%, and 89.3%, respectively. In 52 of 353 patients who were histopathologically diagnosed as ductal carcinoma in situ (DCIS) by CNB, final diagnosis was changed in to invasive ductal carcinoma (IDC) in surgical specimens. Statistically significant differences were detected in the discrepancy of the following factors between CNB and subsequent surgical specimens: histological types, nuclear grade, and PgR, between patients who received four or more cores and those who had received three or less cores. In addition, a similar tendency was also detected in estrogen receptor (ER) and HER2 as in the above, and the cases that received four cores reached to 100% concordance in diagnosis between CNB and surgical specimens. Therefore, the optimal numbers of CNB were considered four at least in assessing the histological type, invasion, nuclear grade, hormone receptor status, and HER2 status of individual patients in the preoperative setting.


[Neurologic and psychiatric manifestations of lead poisoning in adults (case report and review of the literature)].
A 59-year-old potter presented with lead polyneuropathy after 37 years of occupational exposure. There was a 25-year history of normochromic normocytic anaemia with moderate basophilic stippling, mild renal failure, hyperuricaemia and abnormal porphyrins. Since 1964 three short psychotic episodes were noted. Cranial computed tomography showed extensive bilateral symmetrical calcification in the cerebellar hemispheres and slight calcification in the subcortical area of the cerebral hemispheres and basal ganglia. T2-weighted magnetic resonance imaging disclosed high signal intensities in the periventricular white matter, basal ganglia, insula, posterior thalamus and pons. Differential diagnostic aspects are discussed with special regard to CT and MRI findings. A review of the literature on neurological and psychiatric manifestations of lead intoxication in adults is given.


Mutant ras elevates dependence on serum lipids and creates a synthetic lethality for rapamycin.
The conversion of normal cells to cancer cells involves a shift from catabolic to anabolic metabolism involving increased glucose uptake and the diversion of glycolytic intermediates into nucleotides, amino acids, and lipids needed for cell growth. An underappreciated aspect of nutrient uptake is the utilization of serum lipids. We investigated the dependence of human cancer cells on serum lipids and report here that Ras-driven human cancer cells are uniquely dependent on serum lipids for both proliferation and survival. Removal of serum lipids also sensitizes Ras-driven cancer cells to rapamycin-indicating that the enhanced need for serum lipids creates a synthetic lethal phenotype that could be exploited therapeutically. Although depriving humans of serum lipids is not practical, suppressing uptake of lipids is possible. Suppressing macropinocytosis in Ras-driven cancer cells also created sensitivity to suppression of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1). It is speculated that this property displayed by Ras-driven cancer cells represents an Achilles' heel for the large number of human cancers that are driven by activating Ras mutations.


MORE THAN MONEY: THE EXPONENTIAL IMPACT OF ACADEMIC TECHNOLOGY TRANSFER.
Academic technology transfer in its current form began with the passage of the Bayh-Dole Act in 1980, which allowed universities to retain ownership of federally funded intellectual property. Since that time, a profession has evolved that has transformed how inventions arising in universities are treated, resulting in significant impact to US society. While there have been a number of articles highlighting benefits of technology transfer, now, more than at any other time since the Bayh-Dole Act was passed, the profession and the impacts of this groundbreaking legislation have come under intense scrutiny. This article serves as an examination of the many positive benefits and evolution, both financial and intrinsic, provided by academic invention and technology transfer, summarized in Table 1.


Isolation of P22 specialized transducing phage followong F'-episome fusion.
A P22 specialized transducing phage has been constructed which carries the structural gene for aspartate transcarbamylase (ATCase). This gene (pyrB) was first brought close to the P22 attachment site by fusing an F' pyrB(+) episome to an F' prolac episome which carries a P22 prophage attachment site. A prophage was added to these fused F' episomes and the lysogen was UV-induced. The specialized transducing phage was isolated from the resulting lysate. The phage also carries argI, the structure gene for ornithine transcarbamylase.


Dorsal raphe stimulation relays a reward signal to the ventral tegmental area via GluN2C NMDA receptors.
Glutamate relays a reward signal from the dorsal raphe (DR) to the ventral tegmental area (VTA). However, the role of the different subtypes of N-methyl-D-aspartate (NMDA) receptors is complex and not clearly understood. Therefore, we measured NMDA receptors subunits expression in limbic brain areas. In addition, we studied the effects of VTA down-regulation of GluN2C NMDA receptor on the reward signal that arises from DR electrical stimulation. Using qPCR, we identified the relative composition of the different Grin2a-d subunits of the NMDA receptors in several brain areas. Then, we used fluorescent in situ hybridization (FISH) to evaluate the colocalization of Grin2c and tyrosine hydroxylase (TH) mRNA in VTA neurons. To assess the role of GluN2C in brain stimulation reward, we downregulated this receptor using small interfering RNA (siRNA) in rats self-stimulating for electrical pulses delivered to the DR. To delineate further the specific role of GluN2C in relaying the reward signal, we pharmacologically altered the function of VTA NMDA receptors by bilaterally microinjecting the NMDA receptor antagonist PPPA. We identified GluN2C as the most abundant subunit of the NMDA receptor expressed in the VTA. FISH revealed that about 50% of TH-positive neurons colocalize with Grin2c transcript. siRNA manipulation produced a selective down-regulation of the GluN2C protein subunit and a significant reduction in brain stimulation reward. Interestingly, PPPA enhanced brain stimulation reward, but only in rats that received the nonactive RNA sequence. The present results suggest that VTA glutamate neurotransmission relays a reward signal initiated by DR stimulation by acting on GluN2C NMDA receptors.


New phenotypes associated with mucAB: alteration of a MucA sequence homologous to the LexA cleavage site.
Most mutagenesis by UV and many chemicals in Escherichia coli requires the products of the umuDC operon or an analogous plasmid-derived operon mucAB. Activated RecA protein is also required for, or enhances, this process. MucA and UmuD proteins share homology with the LexA protein, suggesting that they might interact with the RecA protein as LexA does. We used oligonucleotide-directed mutagenesis to alter a site in MucA homologous to the Ala-Gly cleavage site of LexA. The mutation, termed mucA101(Glu26), results in a change of Gly26 of MucA to Glu26. A lexA(Def) recA441 umuC122::Tn5 strain carrying a mucA101(Glu26)B+ plasmid did not exhibit the greatly increased frequency of spontaneous mutagenesis in response to RecA activation that a strain carrying a mucA+B+ plasmid did but retained a basal recA-dependent ability to confer increased spontaneous mutagenesis that was independent of the state of RecA activation. These results are consistent with a model in which RecA plays two distinct roles in mutagenesis apart from its role in the cleavage of LexA. A pBR322-derived plasmid carrying mucA+B+, but not one carrying mucA101(Glu26)B+, inhibited the UV induction of SOS genes, suggesting that MucA+ and MucA(Glu26) proteins may have different abilities to compete with LexA for activated RecA protein. The spectrum of UV-induced mutagenesis was also altered in strains carrying the mucA101(Glu26) mutation. These results are consistent with the hypothesis that activated RecA protein interacts with wild-type MucA protein, possibly promoting proteolytic cleavage, and that this interaction is responsible for facilitating certain mutagenic processes.