NEDDylation promotes endothelial dysfunction: a role for HDAC2.
Emerging evidence strongly supports a role for HDAC2 in the transcriptional regulation of endothelial genes and vascular function. We have recently demonstrated that HDAC2 reciprocally regulates the transcription of Arginase2, which is itself a critical modulator of endothelial function via eNOS. Moreover HDAC2 levels are decreased in response to the atherogenic stimulus OxLDL via a mechanism that is apparently dependent upon proteasomal degradation. NEDDylation is a post-translational protein modification that is tightly linked to ubiquitination and thereby protein degradation. We propose that changes in NEDDylation may modulate vascular endothelial function in part through alterations in the proteasomal degradation of HDAC2. In HAEC, OxLDL exposure augmented global protein NEDDylation. Pre-incubation of mouse aortic rings with the NEDDylation activating enzyme inhibitor, MLN4924, prevented OxLDL-induced endothelial dysfunction. In HAEC, MLN enhanced HDAC2 abundance, decreased expression and activity of Arginase2, and blocked OxLDL-mediated reduction of HDAC2. Additionally, HDAC2 was shown to be a substrate for NEDD8 conjugation and this interaction was potentiated by OxLDL. Further, HDAC2 levels were reciprocally regulated by ectopic expression of NEDD8 and the de-NEDDylating enzyme SENP8. Our findings indicate that the observed improvement in endothelial dysfunction with inhibition of NEDDylation activating enzyme is likely due to an HDAC2-dependent decrease in Arginase2. NEDDylation activating enzyme may therefore be a novel target in endothelial dysfunction and atherogenesis.


Medical students as child abusers.
Medical students may abuse pediatric patients. Not only do such students represent a hazard to the patient, but they may themselves be seriously ill and in need of psychiatric treatment.


Irisin: A Potential Link between Physical Exercise and Metabolism-An Observational Study in Differently Trained Subjects, from Elite Athletes to Sedentary People.
We compared irisin levels among groups of differently trained healthy individuals to explore the role of irisin as a physiological linker between exercise and metabolic health. Irisin and biochemical parameters of glucose and lipid metabolism were assessed in 70 healthy volunteers stratified for sport performance level into four groups: (1) 20 elite athletes of national level, (2) 20 subelite athletes of local level, (3) 20 recreational athletes, and (4) 10 sedentary subjects. All biochemical parameters were within the ranges of normality. Fasting glucose, HOMA-IR, and total cholesterol levels were inversely related to the degree of physical activity. HbA1c was higher in elite athletes compared to all the other groups (p < 0.01). A U-shaped relation between free fatty acids and the degree of physical activity was observed. All groups showed similar plasma irisin levels. After correction for the degree of insulin resistance (irisin/HOMA-IR), elite athletes showed higher levels compared to sedentary and recreational subjects (p < 0.01 and p < 0.05, resp.). In addition, the number of metabolic parameters correlated with irisin increased at increasing the training status. Our study suggests a correlation between sport performance, insulin sensitivity, and irisin levels. Irisin may be one potential mediator of the beneficial effects of exercise on metabolic profile.


Left-to-right systolic ventricular interaction in patients undergoing biventricular stimulation for dilated cardiomyopathy.
Left-to-right systolic ventricular interaction (i.e., the phenomenon by which the left ventricle contributes to most of the flow and to two-thirds of the pressure generated by the right ventricle) originates from transmission of systolic forces between the ventricles through the interventricular septum and from the mechanical effect of the common muscle fibers encircling their free walls. As a consequence, any reduction of left ventricular free wall function translates in lower right ventricular pressure or function. We investigated whether systolic ventricular interaction could be evidenced in nine patients with dilated cardiomyopathy in whom a biventricular pacemaker was implanted. Changes in right and left ventricular pressures were measured with high-fidelity catheters, before and after periods of biventricular pacing from the right atrium with different stimulation intervals to the right and left ventricles, respectively. The steady-state changes of left and right ventricular systolic pressure obtained from any single pacing interval combination were considered. We then calculated, with a two-level mixed regression analysis of the entire data set, the relation between changes in left and right systolic pressures: the presence of a statistically significant slope was assumed as evidence of ventricular interaction. The slope of the regression replaced the crude pressure ratio as an estimate of the gain of the interaction; its value compared with values observed in experimental studies. Moreover, its dependence on septal elastance and on right ventricular volume was similar to that already demonstrated for ventricular interaction gain. In conclusion, the linear relationship we found between systolic pressure changes in the two ventricles of patients with dilated cardiomyopathy during biventricular pacing could be explained in terms of ventricular interaction.


Transmission of sheep scrapie to elk (Cervus elaphus nelsoni) by intracerebral inoculation: final outcome of the experiment.
This is a final report of an experimental transmission of sheep scrapie agent by intracerebral inoculation to Rocky Mountain elk (Cervus elaphus nelsoni). It documents results obtained in experimental (n = 6) and control (n = 2) elk. During the first 2 years postinoculation (PI), 3 animals died or were euthanized because of infection or injuries other than spongiform encephalopathy (SE). In years 3 and 4 PI, 3 other inoculated elk died after brief terminal neurological episodes. Necropsy of these animals revealed moderate weight loss but no other gross lesions. Microscopically, characteristic lesions of SE were seen throughout the brain and spinal cord, and the tissue was positive for proteinase K-resistant prion protein (PrPres) by immunohistochemistry (IHC) and by Western blot. Scrapie-associated fibrils (SAF) were observed by negative-stain electron microscopy in the brain of elk with neurologic signs. PrPres and SAF were not detected in the 3 inoculated elk necropsied during the first 2 years or in the 2 control animals. Retrospective analysis of the gene-encoding cervid PrP revealed a polymorphism at codon 132. The elk with SE were either homozygous (MM) or heterozygous (LM). These findings confirm that intracerebral inoculation of sheep scrapie agent results in SE with accumulations of PrPres in the central nervous system of elk. Based on morphologic and IHC findings, the experimentally induced SE cannot be distinguished from chronic wasting disease of elk with currently available diagnostic techniques.


Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as early biomarkers for predicting vancomycin-associated acute kidney injury: a prospective study.
Previous studies have demonstrated that urinary kidney injury molecule-1 (uKIM-1) and neutrophil gelatinase-associated lipocalin (uNGAL) were superior to serum creatinine (Scr) in detecting acute kidney injury (AKI), but their ability to predict clinical vancomycin-associated AKI has not been investigated. This study aimed to investigate the abilities of uKIM-1 and uNGAL individually and in combination to predict vancomycin-associated AKI. Scr, uKIM-1, and uNGAL were measured on the day before and days 1, 2, and 3 of vancomycin therapy in a generalized adult population. Levels of these biomarkers between AKI and non-AKI groups were comparatively analyzed. Predictive performances were evaluated by receiver operating characteristic curve (ROC) analysis. A total of 87 patients were enrolled, and among them, 11 (12.6%) patients developed AKI. Urinary KIM-1 and NGAL levels in the AKI group were higher than in the non-AKI group at all time points (p < 0.05), and the areas under the receiver operating characteristic curves (AUC) were 0.849 (95% confidence interval [CI] 0.750-0.948) for uKIM-1 and 0.824 (95% CI 0.726-0.922) for uNGAL, with cut-off values of 1.72 ng/mL and 9.07 ng/mL respectively. The AUC of uKIM-1 and uNGAL combined was 0.852 (95% CI 0.754-0.949), and the sensitivity and specificity were 90.9% and 75.0%, respectively. Urinary KIM-1 and NGAL could efficiently discriminate patients with or without vancomycin-associated AKI earlier than Scr, and the combined urinary biomarkers showed fair discrimination compared with the individual biomarkers.


A prospective 1-year comparative study of transaxillary total thyroidectomy regarding functional outcomes: Is it really promising?
The purpose of this study was to evaluate postoperative voice outcomes and functional parameters in total thyroidectomy via a transaxillary (TA) approach. Seventy-six patients who underwent total thyroidectomy via a TA approach (TA group) were included. A total of 204 patients who underwent conventional open total thyroidectomy (conventional group) in the same time period were analyzed as a control group. All patients underwent prospective functional evaluations before surgery and at 1 week and 1, 3, 6, and 12 months postoperatively using a comprehensive battery of functional assessments. There was no conversion to conventional open thyroidectomy in the TA group. Operation time and the amount of drainage were significantly higher in the TA group than in the conventional group (p < 0.001 and p = 0.033, respectively), while vocal cord paralysis, hypoparathyroidism, and hematoma were not different among two groups (p = 0.215, 0.290, and 0.385, respectively). Regarding GRBAS, the TA group showed a more aggravated tendency postoperatively, although statistical significance was attained only at postoperative 6 months (p = 0.043). The voice handicap index abruptly increased postoperatively in the TA group, showing significant differences with the conventional group at postoperative 1 week and 1 month (p < 0.001 and p = 0.001, respectively). Fundamental frequency and maximal vocal pitch did not significantly change postoperatively in either group. The conventional group showed a more rapid decline in pain than the TA group, and paresthesias on the neck and chest were more aggravated in the TA group during the early postoperative period. The dysphagia handicap index was higher in the TA group, while cosmesis was better in the TA group at all postoperative periods. Although cosmetic outcome was better with the TA approach, the longer operation time, aggravated subjective voice outcomes, paresthesia, and swallowing function need to be considered in selecting the operative approach.


[Psychogenic joint contractures exemplified by somatoform hysteria].
We would like to report about a 25-year-old female patient with a psychogenic knee contracture as part of a hysterical personality disorder. After having had multiple surgical procedures including 5 knee arthroscopies in 5 different orthopedic departments, we found a nearly full range of movement during an examination under general anaesthesia. Psychoanalytical investigations finally revealed a surprising, past history of the patient and her family. In addition we highlight the relevant literature.


Differential impact of beliefs on valence and arousal.
Many cognitive accounts of emotional processing assume that emotions have representational content that can be influenced by beliefs and desires. It is generally thought that emotions also have non-cognitive, affective components, including valence and arousal. To clarify the impact of cognition on these affective components we asked participants to rate sentences along cognitive and affective dimensions. For the former case, participants rated the believability of the material. For the latter case, they provided valence and arousal ratings. Across two experiments, we show that valence and arousal are differently influenced by beliefs, suggesting that these two largely independent affective components of emotion differ in their cognitive penetrability. While both components depended upon overall comprehension of sentence meaning, only valence was influenced by the consistency of the sentences with participants' beliefs (i.e., whether it was believable or unbelievable). We discuss the implications of these findings for understanding cognition-emotion relationships.


[Predictive factors of unplanned hospital readmission in patients discharged at a short stay medical unit].
To determine the independent factors that predict unplanned hospital readmission in patients who are admitted to a Short-Stay Medical Unit (SSMU). DESIGN AND FIELD OF THE STUDY: Prospective cohort. Sanitary area: 500,000 inhabitants. Patients who survived to an hospital admission in the SSMU of our hospital (n = 196, a = 0.05, d = 7). We studied demographic variables, social situation, history of previous admissions to hospital, from each patient. From the index admission we included diagnosis, severity of the disease, complications, type of admission and co-morbility. Validated tests were done to measure functional capability, grade of dependence and psychologic situation. After a three month interval readmission was determined if there had been an urgent admission to any hospital in a 10-day, 28-day or 3-month interval after discharge caused by the same principal diagnosis. A descriptive analysis of the variables was made, and a univariate analysis to stablish their association to readmission. The predicting factors for readmission were calculated by means of logistic regression. The 60.2% were males, the median of the age was 72 years. 75% started or carried out only primary school; 40% were single, separated or widowed; 12% lived alone and 1.5% in an institution. Principal diagnosis at the time of index admission were: chronic obstructive pulmonary disease, congestive cardiac failure, ischemic heart disease, asthma, pneumonia, cardiac arrhythmia and acute cerebrovascular disease. Readmission rate at 10, 28 days and 3 months was 3.6%, 9.7% and 13.3%, respectively. The independent predicting factor for readmission in the 10 days interval from discharge was the number of days of hospitalization in the last year (OR: 1.02, 95% CI: 1.0-1.05). For readmission in a 28-day and 3-month interval from discharge, the only independent predicting factor was the number of admissions to any hospital in the last 3 years (OR: 1.71, 95% CI: 1.32-2.22 and OR: 1.62, 95% CI: 1.28-2.05 respectively). From the studied factors, those that predict unplanned hospital readmission of patients discharged from a Short-Stay Medical Unit cannot be modified.


Working Memory Capacity Limits Memory for Bindings.
I propose that the capacity of working memory places a specific limit on the maintenance of temporary bindings. Two experiments support this binding hypothesis: Participants remembered word lists of varying length. When tested on a randomly selected word, their error rates increased with the length of the list, reflecting a limited capacity for short-term maintenance. This increase in errors was predominantly due to binding errors: People confused the correct word with other words of the current memory list, but very rarely with words not in the list. The frequencies of response choices were analyzed through two measurement models - one based on the assumption of discrete memory states, one on the assumption of continuous memory strength - that capture memory for items and for bindings in separate parameters. Increasing memory set size impaired binding memory but not item memory, supporting the binding hypothesis.


New types of clotting factors and defense molecules found in horseshoe crab hemolymph: their structures and functions.
Invertebrate animals, which lack adaptive immune systems, have developed defense systems, so-called innate immunity, that respond to common antigens on the surface of potential pathogens. One such defense system is involved in the cellular responses of horseshoe crab hemocytes to invaders. Hemocytes contain two types, large (L) and small (S), of secretory granules, and the contents of these granules are released in response to invading microbes via exocytosis. Recent biochemical and immunological studies on the granular components of L- and S-granules demonstrated that the two types of granules selectively store granule-specific proteins participating in the host defense systems. L-Granules contain all the clotting factors essential for hemolymph coagulation, protease inhibitors including serpins and cystatin, and anti-lipopolysaccharide (LPS) factor and several tachylectins with LPS binding and bacterial agglutinating activities. On the other hand, S-granules contain various new cysteine-rich basic proteins with antimicrobial or bacterial agglutinating activities, such as tachyplesins, big defensin, tachycitin, and tachystatins. The co-localization of these proteins in the granules and their release into the hemolymph suggest that they serve synergistically to construct an effective host defense system against invaders. Here, the structures and functions of these new types of defense molecules found in the Japanese horseshoe crab (Tachypleus tridentatus) are reviewed.


The recognition of reduced word forms.
This article addresses the recognition of reduced word forms, which are frequent in casual speech. We describe two experiments on Dutch showing that listeners only recognize highly reduced forms well when these forms are presented in their full context and that the probability that a listener recognizes a word form in limited context is strongly correlated with the degree of reduction of the form. Moreover, we show that the effect of degree of reduction can only partly be interpreted as the effect of the intelligibility of the acoustic signal, which is negatively correlated with degree of reduction. We discuss the consequences of our findings for models of spoken word recognition and especially for the role that storage plays in these models.


Gentamicin-Induced Readthrough and Nonsense-Mediated mRNA Decay of SERPINB7 Nonsense Mutant Transcripts.
Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive skin disorder with a high, unmet medical need that is caused by mutations in SERPINB7. Almost all NPPK patients carry the founder nonsense mutation c.796C>T (p.Arg266Ter) in the last exon of SERPINB7. Here we sought to determine whether topical nonsense-suppression (readthrough) therapy using gentamicin is applicable to NPPK. First, we demonstrated that gentamicin enhanced readthrough activity in cells transfected with SERPINB7 cDNA carrying the mutation and promoted full-length SERPINB7 protein synthesis in NPPK keratinocytes. We next conducted an investigator-blinded, randomized, bilaterally controlled compassionate use study of topical gentamicin in which five NPPK patients with c.796C>T were enrolled. Patients' self-reported improvement of hyperkeratosis was significantly greater on the gentamicin side than the control side (P = 0.0349). In two patients, hyperkeratosis was improved on the gentamicin side, as determined by a blinded-investigator assessment. These results indicate the therapeutic potential of topical gentamicin for NPPK. Unexpectedly, we also found that mutant SERPINB7 mRNAs harboring r.796c>u were degraded by nonsense-mediated mRNA decay. Furthermore, the truncated SERPINB7 protein was degraded via a proteasome-mediated pathway. These findings provide important insights into the mRNA/protein quality-control system in humans, which could be a potential therapeutic target for genetic diseases.


Function and morphology of the antennal lobe: new developments.
The antennal lobe of insects has emerged as an excellent model for olfactory processing in the CNS. In the present review we compile data from areas where substantial progress has been made during recent years: structure-function relationships within the glomerular array, integration and blend specificity, time coding and the effects of neuroactive substances and hormones on antennal lobe processing.


The DAMA trial: a diet and physical activity intervention trial to reduce mammographic breast density in postmenopausal women in Tuscany, Italy. Study protocol and baseline characteristics.
Aims and background. High mammographic breast density (MBD) is an established risk factor for breast cancer (BC). The influence of diet and physical activity (PA) on MBD has long been investigated. In an observational study of a cohort in Florence, we observed inverse associations between consumption of vegetables and olive oil and moderate leisure-time PA and MBD, while high alcohol intake and high glycemic load diets were positively associated with MBD. We set out to investigate whether dietary and PA interventions were able to reduce MBD in postmenopausal women with high MBD (>50%). Methods and study design. The DAMA (Diet, physical Activity and MAmmography) trial, a factorial randomized trial involving healthy nonsmoking postmenopausal women not using hormone replacement therapy and having MBD >50%, is aimed at evaluating the ability of a 24-month intervention based on moderate-intensity PA and/or dietary modification focused on plant foods with a low glycemic load, low in saturated fats and alcohol, and rich in antioxidants and fiber, to reduce the percent MBD. Participants have been randomized to 1 of 4 study arms (diet, PA, diet + PA, control). Dietary and PA habits and anthropometry are collected at baseline and at the end of the intervention phase together with repeated blood and urine samples. The primary outcome of the study is the absolute change in percent MBD as assessed on baseline and follow-up digital mammograms performed in the framework of the local screening program. Results. Of 728 eligible women, 234 (32.1%) agreed to participate. We did not observe any difference across study arms in the baseline distribution of variables of interest related to diet and lifestyle. Conclusions. The DAMA trial may contribute to a better understanding of MBD determinants. This will provide insight into the pathogenesis of BC and may allow the development of strategies for primary prevention focused on high-MBD groups that are easily identifiable in large-scale BC screening programs. ISRCTN28492718.


In Vitro Antibacterial Activity of Several Plant Extracts and Oils against Some Gram-Negative Bacteria.
Medicinal plants are considered new resources for producing agents that could act as alternatives to antibiotics in the treatment of antibiotic-resistant bacteria. The aim of this study was to evaluate the antibacterial activity of 28 plant extracts and oils against four Gram-negative bacterial species. Experimental, in vitro, evaluation of the activities of 28 plant extracts and oils as well as some antibiotics against E. coli O157:H7, Yersinia enterocolitica O9, Proteus spp., and Klebsiella pneumoniae was performed. The activity against 15 isolates of each bacterium was determined by disc diffusion method at a concentration of 5%. Microdilution susceptibility assay was used in order to determine the minimal inhibitory concentrations (MICs) of the plant extracts, oils, and antibiotics. Among the evaluated herbs, only Origanum syriacum L., Thymus syriacus Boiss., Syzygium aromaticum L., Juniperus foetidissima Wild, Allium sativum L., Myristica fragrans Houtt, and Cinnamomum zeylanicum L. essential oils and Laurus nobilis L. plant extract showed anti-bacterial activity. The MIC50 values of these products against the Gram-negative organisms varied from 1.5 (Proteus spp. and K. pneumoniae( and 6.25 µl/ml (Yersinia enterocolitica O9 ) to 12.5 µl/ml (E. coli O:157). Among the studied essential oils, O. syriacum L., T. syriacus Boiss., C. zeylanicum L., and S. aromaticum L. essential oils were the most effective. Moreover, Cephalosporin and Ciprofloxacin were the most effective antibiotics against almost all the studied bacteria. Therefore, O. syriacum L., T. syriacus Boiss., C. zeylanicum L., and S. aromaticum L. could act as bactericidal agents against Gram-negative bacteria.


Food ingredients and cognitive performance.
To integrate recent discoveries in the cognitive neuroscience field on overall brain development, performance and energy requirements, with insight obtained on the cellular and molecular mechanisms of stimulation with food at the periphery. A clear picture emerges of the brain energy demand, its changes through life and the nutritional requirements to provide an optimally functioning intellect at any time. Of particular importance is the dynamic range resulting from differences between 'poor diet' and 'optimal diet'. On the basis of a healthy brain, the question becomes: what drives transient cognitive performance, and to what extent does food-related input from the periphery modulate cognition in general? Over the last decade, vast achievements in the understanding of chemosensory signal transduction on the tongue have been made. Most molecular receptors for various taste modalities have been identified, and the logic of their coding into the brain has been largely unravelled. Moreover, an intriguing discovery has been made that most of the known taste receptors are also expressed in the gastrointestinal tract. Brain energy supply and balanced diet are being unravelled on the molecular and cellular levels as prerequisites for proper cognitive development. With additional insight emerging into the fundamentals of sensory stimulation and perception, we are entering a scientific era that ultimately will link metabolic needs with food preferences, hedonics and healthy nutrition.


Stress selectively increases fos protein in dopamine neurons innervating the prefrontal cortex.
Stress-induced alterations in expression of c-fos protein (Fos) in mesencephalic dopamine (DA) neurons of the rat were examined in order to discern which midbrain DA neurons are metabolically activated by stress. Restraint stress for 30 min increased the number of DA neurons exhibiting Fos-like immunoreactivity in the ventral tegmental area (VTA), but not in the substantia nigra or retrorubral field. Stress elicited an increase in the number of DA neurons expressing Fos in specific nuclei within the VTA. Administration of the anxiogenic beta-carboline FG 7142 also increased the total number of VTA DA neurons expressing Fos protein, whereas pretreatment with an anxiolytic benzodiazepine (diazepam) partially prevented the stress-induced increase in Fos expression. Restraint stress for 30 min increased concentrations of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens and striatum, as well as in the prefrontal cortex. Retrograde tracer studies revealed that stress increased Fos protein expression in a distinct subset of DA neurons projecting to the prefrontal cortex. In contrast, Fos expression was not increased in any DA neurons projecting to the nucleus accumbens. The present data indicate that there are at least two functionally distinct DA systems embedded within the prefrontal cortex of the rat.


THE LOSS OF RESISTANCE TO MURINE TYPHUS INFECTION RESULTING FROM RIBOFLAVIN DEFICIENCY IN RATS.
Riboflavin deficiency, even in a relatively early stage, greatly lowers the resistance of the rat to endemic typhus, thereby resulting in a fatal disease. Not only the serosal cells, but also the endothelial cells in several organs, notably the Kupfer cells of the liver, become greatly distended with rickettsiae under these conditions. Preliminary experiments strongly suggest that advanced vitamin A deficiency, even when making animals markedly cachetic, does not have a comparable effect. Riboflavin deficient animals remain alive for several weeks with an abnormal intracellular metabolism. This type of deficiency is worthy of further study as a possible method of approach in the investigation of other intracellular parasites and filtrable viruses. Speculation regarding the mechanism concerned also suggests the desirability of a study of the effects of this deficiency upon the production of immune bodies in general.


Atorvastatin reduces long pentraxin 3 expression in vascular cells by inhibiting protein geranylgeranylation.
The long pentraxin PTX3 is an acute-phase multi-functional protein that might play both positive and detrimental effects under different pathophysiological conditions. We previously showed that statins down-regulate the release of PTX3 in human endothelial cells (ECs). The present study investigated the mechanism mediating this effect, its occurrence in other cells involved in atherogenesis, and whether it takes place in experimental atherosclerosis. We found that atorvastatin (1-5 μmol/L) decreased the production and release of PTX3 in human ECs through a post-transcriptional effect. Co-incubation with mevalonate or geranylgeranyl pyrophosphate prevented this effect. Direct blockade of geranylgeranyl transferase I by GGTI-286, treatment with the Rac inhibitor NSC23766 or silencing of the geranylgeranylated GTPase Rac2 by siRNA closely mimicked the action of atorvastatin. In contrast, inactivation of other geranylgeranylated proteins such as RhoA, RhoB, and RhoC or Rac1 did not affect PTX3 release. In addition, we found that atorvastatin also decreased PTX3 secretion in aortic SMCs through a mechanism likely dependent on protein geranylgeranylation, while no effect was observed in monocytes. Finally, we found that atherosclerotic lesions from cholesterol-fed rabbits treated with atorvastatin (2.5 mg/kg/day for 8 weeks) showed less immunoreactive PTX3 than lesions from control animals. Results suggest that statins may interfere with PTX3 expression in vascular cells via inhibition of protein geranylgeranylation. Since PTX3 is increasingly regarded as an important mediator of the inflammatory response underlying atherosclerosis and its complications, these results highlight the need for further studies of the role of PTX3 and its potential pharmacological modulation in cardiovascular disease.


Revisions in the International System for Staging Lung Cancer.
Revisions in stage grouping of the TNM subsets (T=primary tumor, N=regional lymph nodes, M=distant metastasis) in the International System for Staging Lung Cancer have been adopted by the American Joint Committee on Cancer and the Union Internationale Contre le Cancer. These revisions were made to provide greater specificity for identifying patient groups with similar prognoses and treatment options with the least disruption of the present classification: T1N0M0, stage IA; T2N0M0, stage IB; T1N1M0, stage IIA; T2N1M0 and T3N0M0, stage IIB; and T3N1M0, T1N2M0, T2N2M0, T3N2M0, stage IIIA. The TNM subsets in stage IIIB-T4 any N M0, any T N3M0, and in stage IV-any T any N M1, remain the same. Analysis of a collected database representing all clinical, surgical-pathologic, and follow-up information for 5,319 patients treated for primary lung cancer confirmed the validity of the TNM and stage grouping classification schema.


Hybrid Elastic Organic Crystals that Respond to Aerial Humidity.
Reshaping of elongated organic crystals that can be used as semiconductors, waveguides or soft robotic grippers by application of force or light is now a commonplace, however mechanical response of organic crystals to changes in humidity has not been accomplished yet. Here, we report a universal approach to instigating a humidity response into elastically bendable organic crystals that elicits controllable deformation with linear response to aerial humidity while retaining their physical integrity entirely intact. Hygroresponsive bilayer elements are designed by mechanically coupling a humidity-responsive polymer with elastic molecular crystals that have been mechanically reinforced by a polymer coating. As an illustration of the application of these cladded crystalline actuators, they are tested as active optical transducers of visible light where the position of light output can be precisely controlled by variations in aerial humidity. Within a broader context, the approach described here provides access to a vast range of mechanically robust, lightweight hybrid hygroresponsive crystalline materials.


A Privacy and Energy-Aware Federated Framework for Human Activity Recognition.
Human activity recognition (HAR) using wearable sensors enables continuous monitoring for healthcare applications. However, the conventional centralised training of deep learning models on sensor data poses challenges related to privacy, communication costs, and on-device efficiency. This paper proposes a federated learning framework integrating spiking neural networks (SNNs) with long short-term memory (LSTM) networks for energy-efficient and privacy-preserving HAR. The hybrid spiking-LSTM (S-LSTM) model synergistically combines the event-driven efficiency of SNNs and the sequence modelling capability of LSTMs. The model is trained using surrogate gradient learning and backpropagation through time, enabling fully supervised end-to-end learning. Extensive evaluations of two public datasets demonstrate that the proposed approach outperforms LSTM, CNN, and S-CNN models in accuracy and energy efficiency. For instance, the proposed S-LSTM achieved an accuracy of 97.36% and 89.69% for indoor and outdoor scenarios, respectively. Furthermore, the results also showed a significant improvement in energy efficiency of 32.30%, compared to simple LSTM. Additionally, we highlight the significance of personalisation in HAR, where fine-tuning with local data enhances model accuracy by up to 9% for individual users.


Nudix proteins affecting microbial pathogenesis.
Nudix proteins catalyse hydrolysis of pyrophosphate bonds in a variety of substrates and are ubiquitous in all domains of life. Their widespread presence and broad substrate specificity suggest that they have important cellular functions. In this review, we summarize the state of knowledge on microbial Nudix proteins involved in pathogenesis.


Potassium channel-based optogenetic silencing.
Optogenetics enables manipulation of biological processes with light at high spatio-temporal resolution to control the behavior of cells, networks, or even whole animals. In contrast to the performance of excitatory rhodopsins, the effectiveness of inhibitory optogenetic tools is still insufficient. Here we report a two-component optical silencer system comprising photoactivated adenylyl cyclases (PACs) and the small cyclic nucleotide-gated potassium channel SthK. Activation of this 'PAC-K' silencer by brief pulses of low-intensity blue light causes robust and reversible silencing of cardiomyocyte excitation and neuronal firing. In vivo expression of PAC-K in mouse and zebrafish neurons is well tolerated, where blue light inhibits neuronal activity and blocks motor responses. In combination with red-light absorbing channelrhodopsins, the distinct action spectra of PACs allow independent bimodal control of neuronal activity. PAC-K represents a reliable optogenetic silencer with intrinsic amplification for sustained potassium-mediated hyperpolarization, conferring high operational light sensitivity to the cells of interest.


High affinity binding of ramiprilat on isolated human glomeruli.
Evidence for angiotensin-converting enzyme (ACE) on isolated human glomeruli was furnished by specific binding of tritium-labeled ramiprilat, a potent inhibitor of ACE. 3H-ramiprilat bound to isolated glomeruli, depending on time and temperature displaying a KD of 3.8 nmol/l and a Bmax of 853 fmol/mg protein. Specific binding represented more than 90% of total binding. Dissociation occurred rapidly after dilution of the sample with incubation buffer or after addition of an excess of unlabeled inhibitor. Binding of 3H-ramiprilat was also inhibited by increasing concentrations of enalaprilat, another ACE-inhibitor or by preincubation of the glomeruli with polyclonal antibodies against ACE. ACE is a zinc-containing enzyme. Addition of EGTA to the assay, which chelates zinc ions, completely inhibited binding. This inhibitory effect of EGTA was reversed by divalent Zn2+ and Ca2+ ions but not by magnesium. Binding of 3H-ramiprilat to isolated glomeruli was maximal when the pH of the assay medium was brought to pH 8. In conclusion, the binding of 3H-ramiprilat to isolated human glomeruli is specific and resembles the characteristics which have been found earlier for enzyme activity of ACE. Thus, binding of 3H-ramiprilat to isolated glomeruli can be assumed to be directed to ACE.


Ablation of placental REST deregulates fetal brain metabolism and impacts gene expression of the offspring brain at the postnatal and adult stages.
In this study, the transcriptional repressor REST (Repressor Element 1 Silencing Transcription factor) was ablated in the mouse placenta to investigate molecular and cellular impacts on the offspring brain at different life stages. Ablation of placental REST deregulated several brain metabolites, including glucose and lactate that fuel brain energy, vitamin C (ascorbic acid) that functions in the epigenetic programming of the brain during postnatal development, and glutamate and creatine that help the brain to respond to stress conditions during adult life. Bulk RNA-seq analysis showed that a lack of placental REST persistently altered multiple transport genes, including those related to oxygen transportation in the offspring brain. While metabolic genes were impacted in the postnatal brain, different stress response genes were activated in the adult brain. DNA methylation was also impacted in the adult brain due to the loss of placental REST, but in a sex-biased manner. Single-nuclei RNA-seq analysis showed that specific cell types of the brain, particularly those of the choroid plexus and ependyma, which play critical roles in producing cerebrospinal fluid and maintaining metabolic homeostasis, were significantly impacted due to the loss of placental REST. These cells showed significant differential expression of genes associated with the metabotropic (G coupled protein) and ionotropic (ligand-gated ion channel) glutamate receptors, suggesting an impact of ablation of placental REST on the glutamatergic signaling of the offspring brain. The study expands our understanding of placental influences on the offspring brain.


Objective functional assessment using the "Timed Up and Go" test in patients with lumbar spinal stenosis.
OBJECTIVEPatient-reported outcome measures (PROMs) are standard of care for the assessment of functional impairment. Subjective outcome measures are increasingly complemented by objective ones, such as the "Timed Up and Go" (TUG) test. Currently, only a few studies report pre- and postoperative TUG test assessments in patients with lumbar spinal stenosis (LSS).METHODSA prospective two-center database was reviewed to identify patients with LSS who underwent lumbar decompression with or without fusion. The subjective functional status was estimated using PROMs for pain (visual analog scale [VAS]), disability (Roland-Morris Disability Index [RMDI] and Oswestry Disability Index [ODI]), and health-related quality of life (HRQoL; 12-Item Short-Form Physical Component Summary [SF-12 PCS] and the EQ-5D) preoperatively, as well as on postoperative day 3 (D3) and week 6 (W6). Objective functional impairment (OFI) was measured using age- and sex-standardized TUG test results.RESULTSSixty-four patients (n = 32 [50%] male, mean age 66.8 ± 11.7 years) were included. Preoperatively, they reported a mean VAS back pain score of 4.1 ± 2.7, VAS leg pain score of 5.4 ± 2.7, RMDI of 10.4 ± 5.3, ODI of 41.9 ± 16.2, SF-12 PCS score of 32.7 ± 8.3, and an EQ-5D index of 0.517 ± 0.226. The preoperative rates of severe, moderate, and mild OFI were 4.7% (n = 3), 12.5% (n = 8), and 7.8% (n = 5), respectively, and the mean OFI T-score was 116.3 ± 23.7. At W6, 60 (93.8%) of 64 patients had a TUG test result within the normal population range (no OFI); 3 patients (4.7%) had mild and 1 patient (1.6%) severe OFI. The mean W6 OFI T-score was significantly decreased (103.1 ± 13.6; p < 0.001). Correspondingly, the PROMs showed a decrease in subjective VAS back pain (1.6 ± 1.7, p < 0.001) and leg pain (1.0 ± 1.8, p < 0.001) scores, disability (RMDI 5.3 ± 4.7, p < 0.001; ODI 21.3 ± 16.1, p < 0.001), and increase in HRQoL (SF-12 PCS 40.1 ± 8.3, p < 0.001; EQ-5D 0.737 ± 0.192, p < 0.001) at W6. The W6 responder status (clinically meaningful improvement) ranged between 81.3% (VAS leg pain) and 29.7% (EQ-5D index) of patients.CONCLUSIONSThe TUG test is a quick and easily applicable tool that reliably measures OFI in patients with LSS. Objective tests incorporating longer walking time should be considered if OFI is suspected but fails to be proven by the TUG test, taking into account that neurogenic claudication may not clinically manifest during the brief TUG examination. Objective tests do not replace the subjective PROM-based assessment, but add valuable information to a comprehensive patient evaluation.


Perceptions of bed days for individuals with chronic illness in extended care facilities.
We explored perceptions of bed days (defined as staying in bed for 1 or more days per week) in 46 patients receiving extended in-patient services for chronic illness management. Illness onset or exacerbation (35%), limited mobility (22%), and tiredness (15%) were the most prevalent reasons for initiating bed days. Tiredness (44%), limited mobility (26%), pain (24%), bowel treatment (22), and conserving energy for future activities (20%) were the most prevalent current reasons. Most participants (74%) noted having been involved in decisions concerning bed days and preferred to continue bed days. The results suggest patients schedule bed days to manage several health related symptoms. Based on our findings, nurses could help patients to alternate daily upright activity with rest to mitigate the known consequences of bed days.


Motivation for change as a predictor of treatment response for dysthymia.
Dysthymia constitutes a chronic, mild affective disorder characterized by heterogeneous treatment effects. Several predictors of clinical response and attendance have been postulated, although research on the role of the psychological variables involved in this mental disorder is still scarce. Fifty-four adult patients, who met criteria for dysthymia completed an ongoing naturalistic treatment based on the brief interpersonal psychotherapy (IPT-B), which was delivered bimonthly over 16 months. As potential predictor variables, the therapeutic alliance, coping strategies, perceived self-efficacy, and motivation for change were measured at baseline. Outcome variables were response to treatment (Clinical Global Impression and Beck's Depression Inventory) and treatment attendance. Stepwise multiple linear regression analyses revealed that higher motivation for change predicted better response to treatment. Moreover, higher motivation for change also predicted treatment attendance. Therapeutic alliance was not a predictor variable of neither clinical response nor treatment attendance. These preliminary findings support the adjunctive use of motivational interviewing (MI) techniques in the treatment of dysthymia. Further research with larger sample size and follow-up assessment is warranted.


Olfactory Orientation and Navigation in Humans.
Although predicted by theory, there is no direct evidence that an animal can define an arbitrary location in space as a coordinate location on an odor grid. Here we show that humans can do so. Using a spatial match-to-sample procedure, humans were led to a random location within a room diffused with two odors. After brief sampling and spatial disorientation, they had to return to this location. Over three conditions, participants had access to different sensory stimuli: olfactory only, visual only, and a final control condition with no olfactory, visual, or auditory stimuli. Humans located the target with higher accuracy in the olfaction-only condition than in the control condition and showed higher accuracy than chance. Thus a mechanism long proposed for the homing pigeon, the ability to define a location on a map constructed from chemical stimuli, may also be a navigational mechanism used by humans.


Evaluation of "point of care" devices in the measurement of low blood glucose in neonatal practice.
Low blood glucose in newborns is difficult to detect clinically. Hence a reliable "point of care" device (glucometer) for early detection and treatment of low glucose is needed. To evaluate the performance of five readily available glucometers for the detection of low blood glucose in newborn infants. Glucostix measurements were taken for newborns with risk factors using a Reflolux S (Boehringer) glucometer. If the initial reading was low (< 2.6 mmol/l), further measurements were taken with two other glucometers (phase I, Advantage and Glucotrend (Roche); phase II, Elite XL (Bayer) and Precision (Abbott)), and plasma glucose was measured in the laboratory (Aeroset; Abbott). Over 10 months, 101 specimens were collected from 71 newborns (57 in phase I; 44 in phase II). The Advantage glucometer usually overestimated blood glucose with a mean difference of 1.07 mmol/l (p < 0.01) at all low glucose ranges. The Glucotrend, Precision, and Elite XL glucometers performed better; the mean differences were not significantly different from the laboratory measured value (0.17 mmol/l (p = 0.37); -0.12 mmol/l (p = 0.13), and 0.24 mmol/l (p = 0.13) respectively). For detection of glucose concentrations < 2.6 mmol/l, the Precision glucometer had the highest sensitivity (96.4%) and negative predictive value (90%). For lower glucose concentrations (< 2.0 mmol/l), the Glucotrend glucometer performed even better (sensitivity 92.3%, negative predictive value 96.3%). Point of care devices should have good precision in the low glucose concentration range, sensitivity, and accuracy for early detection of neonatal hypoglycaemia. None of the five glucometers was satisfactory as the sole measuring device. The Glucotrend and Precision glucometers have the greatest sensitivity and negative predictive value. However, confirmation with laboratory measurements of plasma glucose and clinical assessment are still of the utmost importance.


Chemical Space Expansion of Bromodomain Ligands Guided by in Silico Virtual Couplings (AutoCouple).
Expanding the chemical space and simultaneously ensuring synthetic accessibility is of upmost importance, not only for the discovery of effective binders for novel protein classes but, more importantly, for the development of compounds against hard-to-drug proteins. Here, we present AutoCouple, a de novo approach to computational ligand design focused on the diversity-oriented generation of chemical entities via virtual couplings. In a benchmark application, chemically diverse compounds with low-nanomolar potency for the CBP bromodomain and high selectivity against the BRD4(1) bromodomain were achieved by the synthesis of about 50 derivatives of the original fragment. The binding mode was confirmed by X-ray crystallography, target engagement in cells was demonstrated, and antiproliferative activity was showcased in three cancer cell lines. These results reveal AutoCouple as a useful in silico coupling method to expand the chemical space in hit optimization campaigns resulting in potent, selective, and cell permeable bromodomain ligands.


Does really previous stenting affect graft patency following CABG? A 5-year follow-up: The effect of PCI on graft survival.
The aim of this study was to compare the graft patency rates among patients who had a previous history of percutaneous coronary intervention (PCI) followed by coronary artery bypass grafting surgery (CABG) with the patients who had experienced CABG surgery alone. The 69 patients who were included in the study had a history of bare metal stent implantation prior to CABG (group 1). The coronary angiography results were compared with 69 patients who had a previous history of CABG (group 2). Graft patency rates of the left anterior descending artery and circumflex anastomoses are statistically significant for both groups, whereas the right coronary artery anastomoses are not statistically significant (p = 0.008; 0.009; 0.2). Graft patency rate of LIMA-LAD anastomoses was 43.9 ± 10.8 % in group 1 and 86.2 ± 6 % in group 2 for means of 60 months (p = 0.0001) and circumflex coronary artery anastomosis is 28.9 ± 0.9 % in group 1, 65.7 ± 10.8 % in group 2 (p = 0.0001) and the right coronary artery anastomosis is 37.2 ± 13.6 % in group 1, 56.4 ± 8.9 % in group 2 (p = 0.0001). The graft patency rates of coronary arteries without previous stent implantation were higher than the patients with previous stent implantation and experienced CABG. The results suggest that prior PCI may induce atherosclerotic events in the vessel that can adversely affect graft patency after surgery.


Effects of hydrostatic pressure on the structure and biological activity of infectious bursal disease virus.
The effects of high hydrostatic pressure on the structure and biological activity of infectious bursal disease virus (IBDV), a commercially important pathogen of chickens, were investigated. IBDV was completely dissociated into subunits at a pressure of 240 MPa and 0 degrees C revealed by the change in intrinsic fluorescence spectrum and light scattering. The dissociation of IBDV showed abnormal concentration dependence as observed for some other viruses. Electron microscopy study showed that morphology of IBDV had an obvious change after pressure treatment at 0 degrees C. It was found that elevating pressure destroyed the infectivity of IBDV, and a completely pressure-inactivated IBDV could be obtained under proper conditions. The pressure-inactivated IBDV retained the original immunogenic properties and could elicit high titers of virus neutralizing antibodies. These results indicate that hydrostatic pressure provides a potential physical means to prepare antiviral vaccine.


Tick survey and detection of Crimean-Congo hemorrhagic fever virus in tick species from a non-endemic area, South Marmara region, Turkey.
Crimean-Congo hemorrhagic fever (CCHF) is an increasing health concern in Turkey since 2002. There were also some recent human cases from the South Marmara region of Turkey; thus, a tick survey was performed, and possible vector tick species for the CCHF virus were determined in the region. A total of 740 adult ticks were collected from infested livestock from five locations: Çanakkale-Biga, Bursa-Orhaneli, Bursa-Keles, Balıkesir and Bilecik. Total of 11 tick species from the genera Hyalomma, Rhipicephalus, Dermacentor, Ixodes and Haemaphysalis were identified. Rhipicephalus ticks were dominant in the region; the most frequently observed tick species was R. turanicus, (53.1 %), and only 15.4 % of the identified ticks were H. marginatum. The occurrence of H. rufipes infestation in the region fort he first time. A total of 73 pools of adult ticks were tested with both an antigen-detecting ELISA and RT real-time PCR (RT rt PCR). The presence of the CCHF virus was demonstrated in 9 (12.3 %) of the tested tick pools. Although seven of the tick pools were positive for the CCHF virus with both of the methods, one pool was positive only with RT rt PCR and the other pool was only positive with the ELISA. Positive results were obtained from ticks collected from cattle, sheep and goats from two locations, Bursa-Orhaneli and Bilecik. The CCHF virus was detected in R. turanicus (n = 3), R. bursa (n = 2), H. marginatum (n = 2) and D. marginatus (n = 2) ticks. The results of this study confirm the presence of the CCHF virus and present preliminary data on the vector tick species in the southern Marmara region of Turkey.


Methods of mapping from phase to sine amplitude in direct digital synthesis.
There are many methods for performing functional mapping from phase to sine amplitude (e.g., ROM look-up, coarse/fine segmentation into multiple ROM's, Taylor series, CORDIC algorithm). The spectral purity of the conventional direct digital synthesizer (DDS) is also determined by the resolution of the values stored in the sine table ROM. Therefore, it is desirable to increase the resolution of the ROM. Unfortunately, larger ROM storage means higher power consumption, lower reliability, lower speed, and greatly increased costs. Different memory compression and algorithmic techniques and their effect on distortion and trade-offs are investigated in detail. A computer program has been created to simulate the effects of the memory compression and algorithmic techniques on the output spectrum of the DDS. For each memory compression and algorithmic technique, the worst case spurious response is calculated using the computer program.


[Clinical inertia in the management of patients with type 2 diabetes: how to solve it?].
Although strict glucose control can prevent or delay the onset of complications in patients with diabetes, optimal control frequently is not achieved. A partial explanation for this phenomenon can be attributed to so-called clinical inertia of physicians, defined as "recognition of the problem but failure to act". Such therapeutic inertia may result from patient's reluctance, difficulties inherent to available treatments and physician's attitudes. Clinical inertia may be present at each successive step in the management of type 2 diabetes. This article describes some solutions to help physicians reducing therapeutic inertia and improving patient care.


Double Vascularized Fibula Proximal Growth Plate Transplantation: Novel Technique for the Radial Longitudinal Deficiency (RLD) Grade IV Reconstruction.
Radial absence or severe hypoplasia in radial longitudinal deficiency (RLD) is most commonly treated through stabilization of the carpus on the ulna (centralization or radialization) with or without preliminary distraction. Alternative methods include bone transfer to replace the absent or deficient radius using the proximal fibula, vascularized or nonvascularized, and more recently the transfer of a vascularized second metatarsophalangeal joint. There is paucity of articles suggesting vascularized fibula growth plate transfer for RLD grade III where proximal part of radius can be found and none about double fibular growth plate transplantation. We developed new technique a bilateral growth plate transplantation for the pediatric patient with unilateral RLD stage IV (Bayne and Klug). Totally 2 patients were operated using new technique. No vascular problems occurred and no peroneal nerve damage were observed at the follow-ups. Annual growth was determined on x-rays at the 1 and 2-year follow-ups measuring 0.75 to 0.9 cm with open growth plates. The x-rays also show no changes that can harm the long-term growth potential in the forearm, demonstrating this technique's capacity to achieve better results for forearm length and functionality in comparison to the Vilkki procedure or radialization operation and there is no need to sacrifice second toe. Thumb reconstruction can be done at age 3 or 4 years using pollicization or toe-to hand transplantation techniques. The patients and parents are satisfied with functional and esthetic outcomes. We believe the double fibular growth plate transplantation is a promising method to use to reconstruct unilateral RLD grade IV.


[Choroidal miliary tuberculosis: fluoroangiographic study (author's transl)].
The authors have followed the evolution of disseminated choroidal tuberculosis during a period of 16 months. At the beginning of the disease, fluorescein angiography showed an early 'screen effect' and later a 'focus effect'. During the later stage of the disease, the pigmented epithelium was seen to be involved as well, as demonstrated by (1) the presence of advanced pigmented chorioretinitis at the sites where the tubercles were observed at the beginning of the disease and (2) the presence of fluorescent areas early during fluorescein angiography.


Implementing Family Health Nursing in Tajikistan: from policy to practice in primary health care reform.
The health systems of former Soviet Union countries are undergoing reform away from the highly centralised, resource-intensive, specialised and hierarchical Soviet system, towards a more generalist, efficient health service with greater focus on primary health care. Family Health Nursing is a new model designed by WHO Europe in which skilled generalist community nurses deliver primary health care to local communities. This paper presents a qualitative evaluation of the implementation of Family Health Nursing in Tajikistan. Using Stufflebeam's 'Context, Input, Process, and Product' model, the paper aims to evaluate the progress of this reform, and to understand the factors that help or hinder its implementation. A four-phase research design investigates the development of the Family Health Nurse role over time. In 5 rural areas, 6 focus groups and 18 interviews with Family Health Nurses, 4 observations of their practice, 7 interviews with families and 9 interviews with physicians were carried out. Data were analysed according to the components of Stufflebeam's model. Although the legacy of the Soviet health system did not set a precedent for a nurse who is capable of decision-making and who works in partnership with the physician, Family Health Nurses were successfully implementing new practices. Crucial to their ability to do so were the co-operation of physicians and families. Physicians were impressed by the nurses' development of knowledge, and families were impressed that the nurses could offer real solutions to their problems. However, failure to pay the nurses regular salaries had led to serious attrition of the workforce. We conclude that the success of the Family Health Nurse role in other countries will depend upon its position in relation to the historical health care system.


Ca2+-activated K+ channels modulate membrane potential in the human parathyroid cell: Possible role in exocytosis.
The relationships between parathyroid hormone (PTH) secretion and parathyroid cell membrane potential, including the identities and roles of K+ channels that regulate and/or modulate membrane potential are not well defined. Here we have used Western blot/immunohistochemistry as well as patch-clamp and perifusion techniques to identify and localize specific K+ channels in parathyroid cells and to investigate their roles in the control of membrane potential and PTH secretion. We also re-investigated the relationship between membrane potential and exocytosis. We showed that in single human parathyroid cells K+ current is dependent on at least two types of Ca2+-activated K+ channels: a small-conductance Ca2+-activated K+ channel (KSK) and a large-conductance voltage and Ca2+-activated K+ channel (KBK). These channels were sensitive to specific peptide blocking toxins including apamin, charybdotoxin, and iberiotoxin. These channels confer sensitivity of the membrane potential in single cells to high extracellular K+, TEA, and peptide toxins. Blocking of KBK potently inhibited K+ channel current, and KBK was shown to be expressed in the plasma membrane of parathyroid cells. In addition, when using the capacitance technique as an indicator of exocytosis, clamping the parathyroid cell at -60 mV prevented exocytosis, whereas holding the membrane potential at 0 mV facilitated it. Taken together, the results show that human parathyroid cells have functional KBK and KSK channels but the data presented herein suggest that KBK/KSK channels likely contribute to the maintenance of the membrane potential, and that membrane potential, per se, modulates exocytosis independently of [Ca2+]i.


Surgical treatment and histopathological analysis of proptosis.
Inflammations and tumors of the orbit and para-orbital regions may present as proptosis. Management depends on clinical, radiological, histo-pathological and biochemical evaluation. To analyze the clinical and histopathological profile of the lesions causing proptosis and to report the outcome of their surgical management. In a retrospective study, 25 cases of proptosis due to orbital and paraorbital tumours were analyzed in relation to their age, sex, and clinical and histopathological profiles. CT Scan was considered as the first line investigation modality. According to location and type of tumour, different surgical options like anterior orbitotomy, lateral orbitotomy and medial orbitotomy were considered. The majority of the patients were of the age group 50-59 years (28%). Primary orbital tumors were encountered in 15 cases (60%) and para-orbital in 10 (40%). Of 15 primary orbital tumors, 7 (46.66%) were excised by lateral orbitotomy, another 7 (46.66%) were approached via anterior orbitotomy, whereas 1 (6.67%) was removed by medial orbitotomy. Pediatric orbital tumors were quite common {7 (46.66%)}. Three cases of rhabdomyosarcoma, 3 cases of dermoid cyst and 1 case each of optic nerve glioma were found in pediatric age group. The most common benign adult tumor found in our study was pleomorphic adenoma of the lacrimal gland {3 (20%)}. The majority of the patients with proptosis are of the age group 50-59 years. Proptosis due to primary orbital tumors is more common than para-orbital tumors. Early diagnosis and timely surgical intervention provide good functional and cosmetic results.


Cyclic AMP stimulates the synthesis and function of the low-density lipoprotein receptor in human vascular smooth-muscle cells and fibroblasts.
1. Cyclic AMP-elevating agents stimulate low-density lipoprotein (LDL) receptor activity in human vascular smooth-muscle cells by increasing the rate of receptor protein synthesis. The stimulation is not secondary to the decrease in the regulatory pool of free cholesterol, since it is unaffected, or even enhanced, by inhibition of cholesterol synthesis and esterification, or inhibition of the conversion of cholesterol into its repressor metabolites. The cyclic AMP-mediated up-regulation of the receptor is maintained at low concentrations of inhibitory sterols, but is eventually over-ridden at high concentrations of these sterols. 2. Cyclic AMP-elevating agents also stimulate the hydrolysis of lysosomal cholesterol esters, thus increasing the cellular cholesterol pool and repressing the expression of the LDL receptor. This cholesterol-mediated repressive effect of cyclic AMP can be prevented by chloroquine, which inhibits lysosomal actions, or by ketoconazole, which inhibits conversion of free cholesterol into its repressor metabolite. Thus the cyclic AMP stimulation of the LDL receptor can be masked by the rapid mobilization of free cholesterol from existing cholesterol esters within cultured cells. 3. We have observed that elevated cyclic AMP concentrations will up-regulate the LDL receptor in cholesterol-depleted human vascular smooth-muscle cells, skin fibroblasts and foetal-lung fibroblasts. We propose that our results are evidence for a cyclic AMP-stimulated, sterol-independent, control of LDL-receptor synthesis which is of widespread occurrence in human cells.


Carbon-layer-protected cuprous oxide nanowire arrays for efficient water reduction.
In this work, we propose a solution-based carbon precursor coating and subsequent carbonization strategy to form a thin protective carbon layer on unstable semiconductor nanostructures as a solution to the commonly occurring photocorrosion problem of many semiconductors. A proof-of-concept is provided by using glucose as the carbon precursor to form a protective carbon coating onto cuprous oxide (Cu₂O) nanowire arrays which were synthesized from copper mesh. The carbon-layer-protected Cu₂O nanowire arrays exhibited remarkably improved photostability as well as considerably enhanced photocurrent density. The Cu₂O nanowire arrays coated with a carbon layer of 20 nm thickness were found to give an optimal water splitting performance, producing a photocurrent density of -3.95 mA cm⁻² and an optimal photocathode efficiency of 0.56% under illumination of AM 1.5G (100 mW cm⁻²). This is the highest value ever reported for a Cu₂O-based electrode coated with a metal/co-catalyst-free protective layer. The photostability, measured as the percentage of the photocurrent density at the end of 20 min measurement period relative to that at the beginning of the measurement, improved from 12.6% on the bare, nonprotected Cu₂O nanowire arrays to 80.7% on the continuous carbon coating protected ones, more than a 6-fold increase. We believe that the facile strategy presented in this work is a general approach that can address the stability issue of many nonstable photoelectrodes and thus has the potential to make a meaningful contribution in the general field of energy conversion.


[Control of onchocerciasis with ivermectin: results of a mass campaign in northern Cameroon].
A mass chemotherapy campaign to treat onchocerciasis with ivermectin was carried out in northern Cameroon, in the North Vina valley, a savanna area that is part of the extended Vina-Pendé-Longone focus. More than 20,000 people aged five years and over were treated at least once and more than 30,000 treatments were distributed. One to four treatments were given at intervals of six months or one year. Clinical and parasitological examinations of representative samples of the treated population and full ophthalmological examinations of males aged 15 to 35 years were carried out before each treatment to assess the efficacy of the different protocols of treatment. Secondary effects were recorded daily during the week after administration of ivermectin in the whole population treated. The evolution of arterial blood pressure was monitored over seven days in about 300 adults living in the hyperendemic region. The impact of mass treatment on natural transmission of the disease was evaluated by daily capture and dissection of blackflies during the month before and the two months after treatment. All levels of onchocerciasis endemicity were represented in the study area (maximum community microfilarial load (CMFL), 300 microfilariae per biopsy). Six months and one year after the first treatment, loads were down by more than 90% and more than 60% respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Exploring the personal and professional impact of reflective practice groups: a survey of 18 cohorts from a UK clinical psychology training course.
Given the importance of reflective practice within clinical psychology and a lack of empirical research, this study aimed to investigate the personal and professional impact of reflective practice groups (RPGs) for former trainees. This study followed an analytic survey design utilizing a convenience sample of qualified clinical psychologists from a UK training programme. A RPG questionnaire (RPGQ) was developed for the purposes of the study. Following initial pilot work, 297 qualified psychologists were invited to complete the RPGQ. One hundred and twenty-four psychologists (42%) completed the RPGQ. Factor analysis yielded two underlying constructs labelled 'value' and 'distress'. The RPGQ demonstrated significant internal and test-retest reliability. The majority rated the RPGs as valuable for personal and professional development and learning about group processes. Just under half however reported distress as a result of the groups. Whilst some trainees, who reported distress, were able to view the challenges positively, one-sixth were not. Potency of facilitation and group size significantly predicted levels of perceived value and distress. In view of the ethical issues raised by compulsory RPGs, recommendations were made to keep group sizes within an average of 10-13, utilize facilitators with sufficient training in group processes and ensure additional methods of reflective practice development are available. Further suggestions and recommendations for future research in relation to coping and personal learning style were also made.


Glutathione sulfinamide serves as a selective, endogenous biomarker for nitroxyl after exposure to therapeutic levels of donors.
Nitroxyl (HNO) donors exhibit promising pharmacological characteristics for treatment of cardiovascular disorders, cancer, and alcoholism. However, whether HNO also serves as an endogenous signaling agent is currently unknown, largely because of the inability to selectively and sensitively detect HNO in a cellular environment. Although a number of methods to detect HNO have been developed recently, sensitivity and selectivity against other nitrogen oxides or biological reductants remain problematic. To improve selectivity, the electrophilic nature of HNO has been harnessed to generate modifications of thiols and phosphines that are unique to HNO, especially compared to nitric oxide (NO). Given high bioavailability, glutathione (GSH) is expected to be a major target of HNO. As a result, the putative selective product glutathione sulfinamide (GS(O)NH2) may serve as a high-yield biomarker of HNO production. In this work, the formation of GS(O)NH2 after exposure to HNO donors was investigated. Fluorescent labeling followed by separation and detection using capillary zone electrophoresis with laser-induced fluorescence allowed quantitation of GS(O)NH2 with nanomolar sensitivity, even in the presence of GSH and derivatives. Formation of GS(O)NH2 was found to occur exclusively upon exposure of GSH to HNO donors, thus confirming selectivity. GS(O)NH2 was detected in the lysate of cells treated with low-micromolar concentrations of HNO donors, verifying that this species has sufficient stability to server as a biomarker of HNO. Additionally, the concentration-dependent formation of GS(O)NH2 in cells treated with an HNO donor suggests that the concentration of GS(O)NH2 can be correlated to intracellular levels of HNO.


[PCR test systems for genetic identification of enterohemorrhagic Escherichia coli].
The analysis of modern data on the development of amplification test systems for the gene indication of enterohemorrhagic E. coli (EHEC) is presented. In this work the emphasis is laid on the importance of using specific primers whose nucleotide sequence is closely linked with genes controlling the key factors of EHEC pathogenicity; these factors include the determinants of the synthesis of adhesins and invasins (bfp, eae, tir), shiga-like toxins (stx1, stx2), enterohemolysin (ehx), serine protease (epsA) and specific LPS of O-antigen (rfb). The problem of using primers whose sequence is not linked with virulence genes, but which may also be used for the gene indication of E. coli O157:H7 (uid, fliC) is discussed.


Association of Obesity, Metabolic Syndrome, and Diabetes With Urinary Incontinence and Chronic Kidney Disease: Analysis of the National Health and Nutrition Examination Survey, 2003-2020.
Diabetes and obesity, components of the metabolic syndrome (MetS), are risk factors for urinary incontinence (UI) and chronic kidney disease (CKD). We interrogated US population-based data to explore independent, sex-specific associations between nondiabetic MetS, with and without obesity, and UI and/or CKD. We analyzed data from 8586 males and 8420 females ≥20 years from the National Health and Nutrition Examination Survey. Multivariable logistic regression models were used to examine associations of UI or CKD with diabetes and 4 nondiabetic obesity/metabolic phenotypes: non-MetS/nonobese, MetS/nonobese, non-MetS/obese, and MetS/obese. Multinominal logistic regression models were used to assess associations of co-occurring UI/CKD with obesity/metabolic phenotypes. Male MetS/obese participants had increased odds of any UI (1.25; 95% CI 1.00-1.57) and urgency UI (1.36; 1.03-1.80), compared with non-MetS/nonobese participants. Female MetS/obese participants had increased odds of any UI (2.16; 95% CI 1.76-2.66), stress UI (1.51; 1.21-1.87), and mixed UI (1.66; 1.31-2.11) compared with non-MetS/nonobese participants. The odds of co-occurring UI/CKD were increased relative to either condition alone in persons with diabetes, and in males with MetS/obese phenotypes and females with MetS phenotypes as compared to same sex participants with neither obesity nor MetS. We found novel associations between MetS/obese and urgency UI in males without diabetes, and between SUI and both MetS and obesity in females without diabetes. Odds estimates for UI/CKD were increased by existing obesity or MetS as compared to those for UI or CKD alone. Improved understanding of modifiable factors associated with UI will inform prevention and treatment opportunities.


The potential role of SOCS-3 in the interleukin-1beta-induced desensitization of insulin signaling in pancreatic beta-cells.
Defects in insulin secretion, resulting from loss of function or destruction of pancreatic beta-cells, trigger diabetes. Interleukin (IL)-1beta is a proinflammatory cytokine that is involved in type 1 and type 2 diabetes development and impairs beta-cell survival and function. Because effective insulin signaling is required for the optimal beta-cell function, we assessed the effect of IL-1beta on the insulin pathway in a rat pancreatic beta-cell line. We show that IL-1beta decreases insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS) proteins as well as phosphatidylinositol 3-kinase (PI3K) activation, and that this action is not due to the IL-1beta-dependent nitric oxide (NO) production in RINm5F cells. We next analyzed if suppressor of cytokine signaling (SOCS)-3, which can be induced by multiple cytokines and which we identified as an insulin action inhibitor, was implicated in the IL-1beta inhibitory effect on insulin signaling in these cells. We show that IL-1beta increases SOCS-3 expression and induces SOCS-3/IR complex formation in RINm5F cells. Moreover, we find that ectopically expressed SOCS-3 associates with the IR and reduces insulin-dependent IR autophosphorylation and IRS/PI3K pathway in a way comparable to IL-1beta treatment in RINm5F cells. We propose that IL-1beta decreases insulin action in beta-cells through the induction of SOCS-3 expression, and that this effect potentially alters insulin-induced beta-cell survival.


The capacity of various non-esterified fatty acids to suppress lipid transfer inhibitor protein activity is related to their perturbation of the lipoprotein surface.
Lipid transfer inhibitor protein (LTIP) regulates cholesteryl ester transfer protein (CETP) activity by selectively impeding lipid transfer events involving low density lipoproteins (LDLs). We previously demonstrated that LTIP activity is suppressed in a dose-dependent manner by sodium oleate and that its activity can be blocked by physiological levels of free fatty acids [R.E. Morton, D. J. Greene, Arterioscler. Thromb. Vasc. Biol. 17 (1997)]. These data further suggested that palmitate has greater LTIP suppressive activity than oleate. In this report we define the ability of the major non-esterified fatty acids (NEFAs) in plasma to modulate LTIP activity. The greater suppression of LTIP activity by palmitate compared to oleate noted above was also seen in lipid transfer assays with various lipoprotein substrates and in the presence of albumin, showing that the relative effects of these two NEFAs are independent of assay conditions. To assess the effect of other NEFAs on LTIP activity, pure NEFAs were added to assays containing (3)H-cholesteryl ester labeled LDLs, unlabeled high density lipoproteins (HDLs) and CETP+/-LTIP. Whereas myristate, palmitate, stearate, oleate and linoleate stimulated CETP activity to varying extents, all NEFAs suppressed LTIP activity. Among these NEFAs, LTIP suppressive activity was greatest for the long-chain saturated and monounsaturated NEFAs. In contrast, linoleate and myristate were poor inhibitors of LTIP activity. The effects of increasing amounts of a given NEFA on LTIP activity correlated well with the increase in LDL negative charge induced by that NEFA, yet this relationship was unique for each NEFA, especially stearate. Notably, as measured by fluorescence anisotropy, the suppression of LTIP was highly and negatively correlated with the decreased order in the molecular packing of lipoprotein surface phospholipids caused by all NEFAs. Long-chain, saturated and monounsaturated NEFAs appear to be most effective in this regard partly because of their preferential association with LDLs where LTIP inhibition likely takes place. We hypothesize that NEFAs suppress LTIP activity by perturbing the surface properties of LDLs and counteracting the heightened molecular packing normally caused by LTIP. Diets rich in long-chain saturated and monounsaturated fatty acids may lead to a greater suppression of LTIP activity in vivo, which would allow LDLs to participate more actively in CETP-mediated lipid transfer reactions.


Initial experience with the AbioCor implantable replacement heart at the University of Louisville.
Potential benefits of heart transplantation are limited by the severe donor organ shortage. The AbioCor implantable replacement heart has been developed as a potential alternative to heart transplantation. We report our initial experience with the AbioCor in a bovine model. A right thoracotomy was performed for access to the heart and great vessels. After initiation of cardiopulmonary bypass, excision of the native ventricles was followed by orthotopic placement of the IRH and complete implantation of the transcutaneous energy transfer coil, controller, and battery pack. Invasive monitoring of IVC, SVC, carotid artery, pulmonary artery, and left atrial (LA) pressures was performed in all animals. Twelve calves have undergone implantation of the AbioCor. There were three early deaths, one from bleeding, one from respiratory failure, and one from neurodysfunction from low flow during CPB. Nine animals have had a normal recovery and survived a mean of 24.5 days (range, 4-48 days). All the animals have demonstrated excellent hemodynamics with the maintenance of normal pressures in the LA, SVC, IVC, pulmonary artery, and aorta. Adjustment of the right-sided internal hydraulic fluid shunt has allowed for control of right-left balance and, thereby, manipulation of left and right side filling pressures. Late morbidity has consisted of neck wound infection and sepsis, pneumonia, and bleeding. Successful orthotopic implantation of all components of the AbioCor has been achieved in a bovine model. This device has demonstrated restoration of normal hemodynamics and excellent function of the atrial hydraulic shunt to achieve right-left balance.


Treatment recommendations following 3-day masked continuous glucose monitoring (CGM) in youth with type 1 diabetes.
Glycemic control remains suboptimal in youth with type 1 diabetes. Retrospective continuous glucose monitoring (CGM) has demonstrated utility in fine-tuning diabetes management by detecting postprandial hyperglycemia and hypoglycemia. In this study, we explored the process of 3-day masked CGM use, subsequent treatment recommendations, and impact on A1c in a clinic-based sample of youth with type 1 diabetes. Over 2 years, 122 youth were referred for masked CGM. Patients/families completed a diary of blood glucose levels, insulin doses, food intake, and exercise during CGM use. A1c was assessed pre- and 2-3 months post-CGM. Treatment recommendations were formulated using data from CGM reports and diaries. Mean age was 14.3 ± 3.9 years, diabetes duration was 7.5 ± 4.7 years, and A1c was 8.5 ± 1.1% (69 ± 12 mmol/mol); 61% were pump-treated. Patients received an average of 3.1 ± 1.1 treatment recommendations following review of the CGM report. Most (80%) received reinforcement of the importance of preprandial bolusing; 37% received a recommendation regarding advanced insulin management (use of combination boluses/attend to active insulin). Receipt of the latter recommendation was related to A1c improvement ≥0.5% (OR: 4.0, P < .001). Masked CGM offers opportunities to guide advanced insulin management (by injection or pump), which may yield A1c improvements in youth with type 1 diabetes.


Efficacy of saccharomyces boulardii with antibiotics in acute amoebiasis.
To compare the efficacy of antibiotics therapy alone with antibiotics and saccharomyces boulardii in treatment of acute amebiasis. In a double blind, random clinical trial on patients with acute intestinal amoebiasis, 57 adult patients with acute amoebiasis, diagnosed with clinical manifestations (acute mucous bloody diarrhea) and amebic trophozoites engulfing RBCs found in stool were enrolled in the study. Regimen 1 included metronidazole (750 mg Tid) and iodoquinol (630 mg Tid) for 10 days. Regimen 2 contained capsules of lyophilized saccharomyces boulardii (250 mg Tid) orally in addition to regimen 1. Patients were re-examined at two and four weeks after the treatment, and stool examination was performed at the end of week 4. Student's t-test, chi(2) and McNemar's tests were used for statistical analysis. Three patients refused to participate. The other 54 patients were randomized to receive either regimen 1 or regimen 2 (Groups 1 and 2 respectively, each with 27 patients). The two groups were similar regarding their age, sex and clinical manifestations. In Group 1, diarrhea lasted 48.0+/-18.5 hours and in Group 2, 12.0+/-3.7 hours (P<0.0001). In Group 1, the durations of fever and abdominal pain were 24.0+/-8.8 and 24.0+/-7.3 hours and in Group 2 they were 12.0+/-5.3 and 12.0+/-3.2 hours, respectively (P<0.001). Duration of headache was similar in both groups. At week 4, amebic cysts were detected in 5 cases (18.5 %) of Group 1 but in none of the Group 2 (P<0.02). Adding saccharomyces boulardii to antibiotics in the treatment of acute amebiasis seems to decrease the duration of clinical symptoms and cyst passage.


Rotational Transitions in the N2 + Ion Induced by Collisions with Helium Atoms in Cold Helium Plasmas. A Quasiclassical Trajectory Study.
Cross-sections of state-to-state rotational transitions in electronically ground-state 14 N 2 + ${{\rm{N}}_2^ + }$ (X2 Σ g + ${{\Sigma }_{g}^{+}}$ ) ions induced by collisions with 4 He atoms have been calculated using a quasiclassical trajectory method and a set of artificial neural networks representing the N 2 + ${{\rm{N}}_2^ + }$ /He potential energy surface. The training points for the neural networks have been calculated at a MCSCF (multi-configuration self-consistent field)/aug-cc-pVQZ level. A broad range of the N 2 + ${{\rm{N}}_2^ + }$ /He collision energy has been considered ( E c o l l ≤ 100 ${{E}_{{\rm c}{\rm o}{\rm l}{\rm l}}\le 100}$ eV) and the efficiency of vibrational transitions in the N 2 + ${{\rm{N}}_2^ + }$ ion has also been analyzed. It has been found that vibrational transitions are negligible with respect to rotational transitions up to E c o l l ≈ 10 ${{E}_{{\rm c}{\rm o}{\rm l}{\rm l}}\approx 10}$ eV and that above this energy, both rotational and vibrational transitions in N 2 + ${{\rm{N}}_2^ + }$ are marginal in the N 2 + ${{\rm{N}}_2^ + }$ /He collisions.


Chlorhexidine concentration in saliva after topical treatment with an antibacterial dental varnish.
To evaluate the salivary levels of chlorhexidine (CHX) after a single professional treatment with an antibacterial dental varnish (Cervitec) containing 1% CHX and 1% thymol. Unstimulated whole saliva from 21 healthy young adults was collected at baseline and up to 24 hours after treatment at designated time intervals and the CHX levels in saliva were quantified with high-performance liquid chromatography. Post-treatment saliva samples were added to suspensions of mutans streptococci and supragingival dental plaque for a growth inhibition. CHX concentration in saliva showed a peak value (76.5 microg/ml) after 5 minutes followed by a slow decrease with time. The elevation was statistically significant (P < 0.05) up to 4 hours after the application of the varnish and the recorded values were back to baseline levels after 24 hours. The 2- and 4-hour post-treatment saliva samples inhibited growth of mutans streptococci by 46% and 33%, respectively.


Examining the Relationship between Older Adults' Readiness for Discharge after Surgery and Satisfaction with Nursing Care and the Associated Factors.
This study aimed to examine the relationship between older adults' readiness for discharge after surgery and satisfaction with nursing care and effects factors, using a descriptive, cross-sectional design that included 204 older adults. Examining the state of readiness for the discharge of older adults who underwent surgery in terms of the expected support sub-dimension of patients revealed that the presence of someone to support home care, the existence of health insurance, living with someone, undergoing emergency surgery, and being illiterate were statistically significant predictors. Thought of improvement in terms of nursing care between prior hospitalization and the latest hospitalization, use of intensive care unit, male, nursing care satisfaction, and the existence of health insurance were statistically significant predictors of the readiness for discharge in older adults after surgery in terms of personal status sub-dimension. Accordingly, an individual approach that takes these characteristics/variables into account is recommended when planning discharge.


Nerve growth factor and its high-affinity receptor in chronic pancreatitis.
To study the mechanisms that are involved in nerve growth and contribute to pain generation in chronic pancreatitis (CP). Chronic pancreatitis is a painful disease associated with characteristic nerve changes, including an increase in nerve number and diameter. The mechanisms that influence nerve growth are not known. Nerve growth factor (NGF) and its high-affinity tyrosine kinase receptor A (TrkA) are involved in neural development and survival and growth of central and peripheral nerves. Nerve growth factor and TrkA were investigated by Northern blot analysis, in situ hybridization, and immunohistochemical staining in the pancreases of 24 patients with CP, and the findings were correlated with clinical parameters. By Northern blot analysis, NGF and TrkA mRNA expression were increased in 42% (13.1-fold) and 54% (5.5-fold) of the CP samples (p < 0.01), respectively. In situ hybridization revealed that in CP, enhanced NGF mRNA expression was present in metaplastic ductal cells, in degenerating acinar cells, and in acinar cells dedifferentiating into tubular structures. TrkA mRNA was intensely present in the perineurium. Further, enhanced NGF and TrkA mRNA signals were also present in intrapancreatic ganglia cells in CP samples. Immunohistochemistry confirmed the in situ hybridization findings. Analysis of the molecular findings with clinical parameters revealed a significant relation (p < 0.05) between NGF mRNA levels and pancreatic fibrosis (r = 0.64) and acinar cell damage (r = 0.74) and between TrkA mRNA and pain intensity (r = 0.84). Activation of the NGF/TrkA pathway occurs in CP. It might influence neural morphologic changes and the pain syndrome in this disorder.


LINE Insertion Polymorphisms are Abundant but at Low Frequencies across Populations of Anolis carolinensis.
Vertebrate genomes differ considerably in size and structure. Among the features that show the most variation is the abundance of Long Interspersed Nuclear Elements (LINEs). Mammalian genomes contain 100,000s LINEs that belong to a single clade, L1, and in most species a single family is usually active at a time. In contrast, non-mammalian vertebrates (fish, amphibians and reptiles) contain multiple active families, belonging to several clades, but each of them is represented by a small number of recently inserted copies. It is unclear why vertebrate genomes harbor such drastic differences in LINE composition. To address this issue, we conducted whole genome resequencing to investigate the population genomics of LINEs across 13 genomes of the lizard Anolis carolinensis sampled from two geographically and genetically distinct populations in the Eastern Florida and the Gulf Atlantic regions of the United States. We used the Mobile Element Locator Tool to identify and genotype polymorphic insertions from five major clades of LINEs (CR1, L1, L2, RTE and R4) and the 41 subfamilies that constitute them. Across these groups we found large variation in the frequency of polymorphic insertions and the observed length distributions of these insertions, suggesting these groups vary in their activity and how frequently they successfully generate full-length, potentially active copies. Though we found an abundance of polymorphic insertions (over 45,000) most of these were observed at low frequencies and typically appeared as singletons. Site frequency spectra for most LINEs showed a significant shift toward low frequency alleles compared to the spectra observed for total genomic single nucleotide polymorphisms. Using Tajima's D, FST and the mean number of pairwise differences in LINE insertion polymorphisms, we found evidence that negative selection is acting on LINE families in a length-dependent manner, its effects being stronger in the larger Eastern Florida population. Our results suggest that a large effective population size and negative selection limit the expansion of polymorphic LINE insertions across these populations and that the probability of LINE polymorphisms reaching fixation is extremely low.


Participation and social networks of school-age children with complex communication needs: a descriptive study.
Social participation becomes particularly important in middle childhood, as it contributes towards the acquisition and development of critical life skills such as developing friendships and a sense of belonging. However, only limited literature is available on the impact of communication difficulties on social participation in middle childhood. This study compared the participation patterns of school-age children with and without physical disabilities and complex communication needs in extracurricular activities. Participants included five children between 6-9 years of age with moderate-severe physical disability and complex communication needs, and five matched peers. Findings showed that children with physical disability and complex communication needs engaged in activities with reduced variety, lower frequency, fewer partners and in limited venues, but reported higher levels of enjoyment and preference for activity participation, than their matched peers. These children also had fewer same-aged friends, but more paid workers in their social circle. This small-scale descriptive study provides some preliminary evidence about the impact of severe communication difficulties on participation and socialization.


A student nurse experience of an intervention that addresses the perioperative nursing shortage.
Registered nurses are the largest group of professionals in the global healthcare system. The number of nurses is estimated to be 19.3 million throughout the world (Flinkman et al 2013). In the United States the need for registered nurses is growing. It has been predicted that 260,000 positions for registered nurses will remain unfilled by the year 2025 (Harris et al 2014) with a shortage of registered nurses projected to spread across the United States between 2009 and 2030 (Juraschek et al 2012). Compounding the projected nursing shortage is the increased attrition rate, which is as high as 61% within the first year (Pine & Tart 2007). There are several reasons for this shortage including supply and demand issues, projected changes to healthcare and the aging population. Additionally, the number of college graduates who have majored in nursing has not met the demand (Dunn 2014).


Consensus Statement for Protocols of Factorial Randomized Trials: Extension of the SPIRIT 2013 Statement.
Trial protocols outline a trial's objectives as well as the methods (design, conduct, and analysis) that will be used to meet those objectives, and transparent reporting of trial protocols ensures objectives are clear and facilitates appraisal regarding the suitability of study methods. Factorial trials, in which 2 or more interventions are assessed in the same set of participants, have unique methodological considerations. However, no extension of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement, which provides guidance on reporting of trial protocols, for factorial trials is available. To develop a consensus-based extension to the SPIRIT 2013 Statement for factorial trials. The SPIRIT extension for factorial trials was developed using the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework. First, a list of reporting recommendations was generated using a scoping review of methodological articles identified using a MEDLINE search (inception to May 2019), which was supplemented with relevant articles from the personal collections of the authors. Second, a 3-round Delphi survey (January to June 2022, completed by 104 panelists from 14 countries) was conducted to assess the importance of items and identify additional recommendations. Third, a hybrid consensus meeting was held, attended by 15 panelists to finalize selection and wording of the checklist. This SPIRIT extension for factorial trials modified 9 of the 33 items in the SPIRIT 2013 checklist. Key reporting recommendations were that the rationale for using a factorial design should be provided, including whether an interaction is hypothesized; the treatment groups that will form the main comparisons should be identified; and statistical methods for each main comparison should be provided, including how interactions will be assessed. In this consensus statement, 9 factorial-specific items were provided that should be addressed in all protocols of factorial trials to increase the trial's utility and transparency.


Suppressor of Zeste 12 homolog RNA interference inhibits retinoblastoma cell invasion.
Suppressor of Zeste 12 homolog (SUZ12) is known to regulate tumor phenotype through altering gene expression, with an important regulatory role in tumor genesis and development. SUZ12 has been widely investigated; however, no studies regarding the role of the SUZ12 gene in retinoblastoma (RB) have been conducted. In this study, SUZ12 small interfering (si)RNA was transfected into SO-RB50 human RB cells. The influence of SUZ siRNA on RB cell invasion was detected using a soft agar colony forming assay and a Transwell cabin model. The effect of the SUZ12 siRNA on the expression levels of the associated proteins, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-9 and MMP-2, was detected by western blotting. The number of cell clones was found to be reduced by the siRNA in a dose-dependent manner, and the number of cells that had permeated through the filter membrane was reduced following transfection with the siRNA. SUZ12 inhibition resulted in a marked reduction in VEGF, MMP-2 and MMP-9 expression levels (0.26±0.04, 0.16±0.02 and 0.12±0.02, respectively) compared with the levels in the non-transfected group (0.80±0.10, 0.94±0.16 and 1.15±0.18, respectively) (P<0.01). In conclusion, SUZ12 siRNA inhibited cell invasion and the expression of VEGF, MMP-2 and MMP-9 in SO-RB50 retinoblastoma cells.


Selection bias in a population survey with registry linkage: potential effect on socioeconomic gradient in cardiovascular risk.
Non-participation in population studies is likely to be a source of bias in many types of epidemiologic studies, including those describing social disparities in health. The objective of this paper is to present a non-attendance analysis evaluating the possible impact of selection bias, when investigating the association between education level and cardiovascular risk factors. Data from the INTERGENE research programme including 3,610 randomly selected individuals aged 25-74 (1,908 women and 1,702 men), in West Sweden were used. Only 42% of the invited population participated. Non-attendance analyses were done by comparing data from official registries (Statistics Sweden) covering the entire invited study population. This analysis revealed that participants were more likely to be women, have university education, high income, be married and of Nordic origin compared to non-participants. Among participants, all health behaviours studied were significantly related to education. Physical activity, alcohol use and breakfast consumption were higher in the more educated group, while there were more smokers in the less educated group. Central obesity, obesity and hypertension were also significantly associated with lower education level. Weaker associations were observed for blood lipids, diabetes, high plasma glucose level and perceived stress. The socio-demographic differences between participants and non-participants indicated by the register analysis imply potential biases in epidemiological research. For instance, the positive association between education level and frequent alcohol consumption, may, in part be explained by participation bias. For other risk factors studied, an underestimation of the importance of low socioeconomic status may be more likely.


A report of six surgically treated cases.
Six cases of brain-stem hematoma are described. The clinical presentation in these cases was extremely variable. Operative evacuation of the hematoma resulted in immediate improvement in all cases, and a full or nearly full recovery in five. Untreated brain-stem hematoma is probably always fatal, whereas surgical evacuation is effective and safe. The diagnosis of brain-stem hematoma should be considered in any case of brain-stem lesion.