[Acute bronchospasm due to periwinkle alkaloid and mitomycin association].
We report six cases in which patients presented with acute dyspnoea following injections of either vindesine or vinorelbin. These patients were receiving chemotherapy in association with cisplatin, mitomycin, and vindesine or vinorelbin, for inoperable bronchial cancer. Three of the patients had evidence of airflow obstruction before these incidents. The clinical picture suggested bronchospasm and appeared in the two hours following an injection of the vinca alkaloid and a significant time away from the administration of the mitomycin. Additional respiratory support was necessary in one patient, the bronchial spasm stopped spontaneously in three cases, and following bronchodilator in two. The respiratory toxicity of vinca alkaloids (vindesine, vinblastin) was observed in 4% of the cases, uniquely when they were associated with mitomycin. Vinorelbin seems to possess the same respiratory toxicity. The bronchospasm, sometimes very severe, seems to occur in the two hours following the injection in the case of the cytotoxics and some time after the administration of mitomycin. The recurrence of the bronchospasm is a constant feature when the vinca alkaloid is readministered. This side effect is different to the pulmonary fibrosis due to mitomycin. Clinical follow up and spirometry is thus necessary in those patients receiving chemotherapy in which vinca alkaloids and mitomycin are associated and the regime should be followed after each administration of a vinca derivative. After the first episode of dyspnoea, it is probably wise to stop the administration of these anti-mitotics to prevent any further respiratory side-effects which could be more severe.


miR-34a mediates oxaliplatin resistance of colorectal cancer cells by inhibiting macroautophagy via transforming growth factor-β/Smad4 pathway.
To investigate whether microRNA (miR)-34a mediates oxaliplatin (OXA) resistance of colorectal cancer (CRC) cells by inhibiting macroautophagy via the transforming growth factor (TGF)-β/Smad4 pathway. miR-34a expression levels were detected in CRC tissues and CRC cell lines by quantitative real-time polymerase chain reaction. Computational search, functional luciferase assay and western blotting were used to demonstrate the downstream target of miR-34a in CRC cells. Cell viability was measured with Cell Counting Kit-8. Apoptosis and macroautophagy of CRC cells were analyzed by flow cytometry and transmission electron microscopy, and expression of beclin I and LC3-II was detected by western blotting. Expression of miR-34a was significantly reduced while expression of TGF-β and Smad4 was increased in CRC patients treated with OXA-based chemotherapy. OXA treatment also resulted in decreased miR-34a levels and increased TGF-β and Smad4 levels in both parental cells and the OXA-resistant CRC cells. Activation of macroautophagy contributed to OXA resistance in CRC cells. Expression levels of Smad4 and miR-34a in CRC patients had a significant inverse correlation and overexpressing miR-34a inhibited macroautophagy activation by directly targeting Smad4 through the TGF-β/Smad4 pathway. OXA-induced downregulation of miR-34a and increased drug resistance by activating macroautophagy in CRC cells. miR-34a mediates OXA resistance of CRC by inhibiting macroautophagy via the TGF-β/Smad4 pathway.


Helicobacter pylori infection in Turkish children with gastrointestinal symptoms and evaluation of serology.
Helicobacter pylori infection is a common etiopathogenetic factor in children with gastrointestinal symptoms in the developing world. Although serology offers an easy noninvasive method of diagnosis, its sensitivity and specificity are reported to be low among children. In this prospective study, we investigated the frequency and endoscopical and morphological findings of H. pylori infection in 180 Turkish children who underwent upper gastrointestinal endoscopy either for peptic symptoms or on a routine basis and in asymptomatic pediatric patients who underwent endoscopy for other reasons, and then evaluated the diagnostic accuracy of serology in our population. Overall H. pylori infection was diagnosed in 77 of the 180 patients (42.7%) by histology and urease test. The sensitivity of H. pylori specific IgG antibody assay by ELISA was determined to be 100%, while the specificity was 98%, the positive predictive value 97.4%, the negative predictive value 100%. Frequency of H. pylori infection is high in Turkish pediatric patients without gastrointestinal symptoms as well as in children with gastrointestinal complaints. H. pylori specific antibody assay is a noninvasive and sensitive method for the diagnosis of H. pylori infection in the Turkish pediatric population.


Hexose phosphorylation and the putative calcium channel component Mid1p are required for the hexose-induced transient elevation of cytosolic calcium response in Saccharomyces cerevisiae.
Saccharomyces cerevisiae responds to environ-mental stimuli such as an exposure to pheromone or to hexoses after carbon source limitation with a transient elevation of cytosolic calcium (TECC) response. In this study, we examined whether hexose transport and phosphorylation are necessary for the TECC response. We found that a mutant strain lacking most of the known hexose transporters was unable to carry out the TECC response when exposed to glucose. A mutant strain that lacked the ability to phosphorylate glucose was unable to respond to glucose addition, but displayed a normal TECC response after the addition of galactose. These results indicate that hexose uptake and phosphorylation are required to trigger the hexose-induced TECC response. We also found that the TECC response was significantly smaller than normal when the level of environmental calcium was reduced, and was abolished in a mid1 mutant that lacked a subunit of the high-affinity calcium channel of the yeast plasma membrane. These results indicate that most or all of the TECC response is mediated by an influx of calcium from the extracellular space. Our results indicate that this transient increase in plasma membrane calcium permeability may be linked to the accumulation of Glc-1-P (or a related glucose metabolite) in yeast.


Transthyretin mutation (serine 84) associated with familial amyloid polyneuropathy in a Hungarian family.
A Hungarian family with familial amyloid polyneuropathy (FAP) was studied. The disease presented in two individuals with carpal tunnel syndrome in the fourth and fifth decades of life. The proband subsequently developed vitreous opacities requiring vitrectomy and now has evidence of cardiomyopathy. Single strand conformation polymorphism analysis and direct DNA sequencing revealed a variant AGC (serine) codon at amino acid position 84 of the amyloid precursor protein, transthyretin (TTR). The same single amino acid substitution in TTR was detected in an Indiana kindred with Swiss/German origin. Six individuals of the 11 tested being at risk for FAP proved to have the mutation in the present Hungarian kindred. This is the first description of this TTR gene mutation in Europe. Despite TTR gene haplotype analysis which suggests that the Hungarian and Indiana kindreds may have a common origin, no genealogical link has been identified between the families living in Indiana and Hungary.


Granular cell tumour (choristoma) of the neurohypophysis--a report of two cases.
Granular cell tumours of the neurohypophysis are uncommon and only 30 cases are documented in the literature till 1994. In this communication, the salient clinical and histomorphological features in two patients with granular-cell tumour of the neurohypophysis are described.


Presence of cobalamin analogues in animal tissues.
Cobalamin (Cbl, vitamin B-12) has been extracted and isolated from a number of animal tissues by using (i) reverse-affinity chromatography on R protein-Sepharose followed by adsorption to and elution from charcoal-coated agarose and (ii) paper chromatography. Radioisotope dilution assays showed that only 75-97% of the Cbl chromatographed in the position of crystalline Cbl. The remaining 3-25% was present in a number of slower and faster moving fractions. This suggested that Cbl analogues are present in animal tissues because appropriate controls ruled out the possibility that this material was artifactually derived from Cbl during the extraction and purification procedures. With a large-scale isolation from rabbit kidney, the material in five such fractions contained cobalt and had absorption spectra that were similar to but different from the spectrum of Cbl, indicating that they were Cbl analogues. Compared to Cbl, these Cbl analogues had decreased but definite affinities for Cbl-binding proteins with the following order of strength of binding: R protein > transcobalamin II > intrinsic factor. Compared to Cbl, they also had decreased but definite growth-promoting activity for two microorganisms, Euglena gracilis and Lactobacillus leichmannii, which require Cbl for growth. These Cbl analogues differed from each other and from 18 synthetic Cbl analogues, including the most common Cbl analogues synthesized by microorganisms, in at least one of the above features. These studies indicate that animal tissues contain a number of Cbl analogues whose origins, structures, and biologic activities remain to be determined.


Vitamin D-Binding Protein (Gc-Globulin) in Acute Liver Failure in Children.
This study aimed to analyse vitamin d-binding protein (Gc-globulin) serum levels in acute liver failure (ALF) in children in relation to disease outcomes and correlations with other known markers used to evaluate the severity of ALF. Our study included 34 children (mean age 4.87 ± 5.30 years) with ALF of different causes (metabolic, 26.47%; autoimmune, 23.53%; toxic, 20.59%; infection, 17.65%; unknown, 11.76%) and 30 children without any liver injury (mean age 6.11 ± 4.26 years). The outcome was poor in 14 patients (41.18%), including one child with liver transplantation (2.94%). Serum Gc-globulin levels were significantly lower in ALF patients compared to the control group (151.57 ± 171.8 mg/L vs. 498.63 ± 252.50 mg/L; p < 0.000001), with an optimum cut-off of 163.5 mg/L (Area Under the Curve, AUC, 0.8921; sensitivity, 76.50%; specificity, 100%). Levels were also lower in patients with poor outcomes compared to survivors (59.34 ± 33.73 mg/L vs. 216.12 ± 199.69 mg/L; p < 0.0001), with an optimum cut-off 115 mg/L (AUC, 0.7642; sensitivity, 100%; specificity, 50%). Gc-globulin serum levels were variable according to ALF aetiology, i.e., lower in metabolic, infectious, or unknown causes compared to autoimmune and toxic causes. Gc-globulin serum levels were decreased in children with ALF and lower in those with poor outcomes compared with survivors. Gc-globulin serum levels were correlated with other known parameters used to evaluate the severity of ALF and could help to identify patients at high risk for poor outcomes.


Thrombus formation in deep venous thrombosis. A clinical approach to diagnosis and control of lysis efficacy.
The efficacy of fibrinolysis in deep venous thrombosis (DVT) depends on the age and organization of the thrombus as well as its localization. Up to now, indication for lysis therapy is defined according to the duration of clinical symptoms (less than 7 days). Our lysis results in urokinase therapy (n = 87) with high-dose and long-term regimen (mean 7.8 days), however, have shown no correlation between the duration of clinical symptoms (up to six weeks) and lysis efficacy (p less than 0.05). Therefore phlebographic criteria were established to allow the differentiation of fibrinolytic therapy depending on the site of the thrombus, its localization and the formation of collateral veins. In order to determine the state of thrombus organization, we used a new ultrasound Duplex system device (ARTIS, 7.5 Mhz, Picker International). In vivo experiments with induced thrombosis in human vena saphena magna demonstrate that echodensity of thrombi in ultrasound starts at the 11th-15th day. These findings are in good agreement with pathological studies of thrombus formation. Recent results of 24 patients with DVT indicate that echodensity of thrombus in ultrasound correlates with the course of organization and the efficacy of later lysis therapy.


Room-Temperature Potassium-Sulfur Batteries Enabled by Microporous Carbon Stabilized Small-Molecule Sulfur Cathodes.
Potassium-sulfur (K-S) batteries are a promising alternative to lithium ion batteries for large-area energy storage applications, owing to their high capacity and inexpensiveness, but they have been seldom investigated. Here we report room-temperature K-S batteries utilizing a microporous carbon-confined small-molecule sulfur composite cathode. The synergetic effects of the strong confinement of microporous carbon matrix and the small-molecule sulfur structure can effectually eliminate the formation of soluble polysulfides and ensure a reversible capacity of 1198.3 mA h g-1 and retain 72.5% after 150 cycles with a Coulombic efficiency of ∼97%. The potassium-storage mechanism was investigated by X-ray photoelectron spectroscopy analysis and theoretical calculations. The results suggest that K2S is the final potassiation product along with the reaction of 2K + S ↔ K2S, giving a theoretical capacity of 1675 mA h g-1. Our findings not only provide an effective strategy to fabricate high-performance room-temperature K-S batteries but also offer a basic comprehension of the potassium storage mechanism of sulfur cathode materials.


Evaluation of Regional Economic Innovation Ability Based on Neural Network.
In order to further improve regional economic innovation capability and governance level and solve the problems of lack of attention to evaluation indicators in traditional evaluation methods of regional economic innovation capability and easy to be affected by subjective factors, an evaluation model based on neural network algorithm is proposed. Through re-analysis of regional economic innovation capability evaluation indexes, the model defines the most reasonable combination of characteristics by combining information gain characteristic selection strategy and finally builds a scientific evaluation index system. By testing the prediction accuracy of the experimental discovery model and evaluation index, the neural network model improves by 41% compared with the traditional subjective evaluation method, and the accuracy increases by 20% compared with the GA-BP neural network model. The experiment proves the stability and good convergence effect of the evaluation model.


A combinatorial approach to the restriction of a mouse genome.
A fragmentation of genomic DNA by restriction digestion is a popular step in many applications. Usually attention is paid to the expected average size of the DNA fragments. Another important parameter, randomness of restriction, is regularly implied but rarely verified. This parameter is crucial to the expectation, that either all fragments made by restriction will be suitable for the method of choice, or only a fraction of those will be effectively used by the method. If only a fraction of the fragments are used, we often should know whether the used fragments are representative of the whole genome. With a modern knowledge of mouse, human and many other genomes, frequencies and distributions of restriction sites and sizes of corresponding DNA fragments can be analyzed in silico. In this manuscript, the mouse genome was systematically scanned for frequencies of complementary 4-base long palindromes. The study revealed substantial heterogeneity in distribution of those sites genome-wide. Only few palindromes showed close to random pattern of distribution. Overall, the distribution of frequencies for most palindromes is much wider than expected by random occurrence. In practical terms, accessibility of genome upon restriction can be improved by a selective combination of restrictases using a few combinatorial rules. It is recommended to mix at least 3 restrictases, their recognition sequences (palindrome) should be the least similar to each other. Principles of the optimization and optimal combinations of restrictases are provided.


A review of nutrition in human immunodeficiency virus infection in the era of highly active antiretroviral therapy.
Nutrition complications of HIV infection, including wasting syndrome, nutrient deficiencies, and metabolic complications, have been well documented over the last 25 years. A systematic review of the literature was performed using the keywords HIV; nutrition; nutrition support; vitamins A, B, C, and E; selenium; zinc; and glutamine through MEDLINE using Medscape and PubMed. Although no accurate prediction equations exist for determining energy needs in patients with HIV/acquired immunodeficiency syndrome (AIDS), the Harris-Benedict equation with a 1.3 stress factor has been used for weight maintenance. Some experts recommend protein requirements of 1.0 to 1.4 g/kg for maintenance and 1.5 to 2.0 g/kg for anabolism. There is a general consensus that all individuals with HIV benefit from a daily multivitamin and mineral supplement at levels of 100% of the US recommended daily intake (RDI). Nutrition therapy for HIV wasting is similar to that for other chronic diseases and begins with nutrition counseling. For persistent weight loss, standard oral supplements may be useful. The benefit of specialized supplements has yet to be proven. Enteral and parenteral nutrition support has produced positive outcomes related to mortality and quality of life in patients with HIV. Although the benefit of providing adequate amounts of calories, protein, and micronutrients for persons with HIV is well accepted, the exact amounts of nutrients and optimal feeding modalities are less clear. Long-term clinical trials are needed to provide more conclusive data on nutrition intervention in HIV infection, particularly related to supplementation of specific nutrients.


Training Improves Vibrotactile Spatial Acuity and Intensity Discrimination on the Lower Back Using Coin Motors.
Tactile vision substitution devices are assistive technologies for the blind that redirect visual information to the tactile sense. They typically include a tactile display that conveys visual information to the skin. Two important parameters that determine the maximum information bandwidth of tactile displays are the spatial acuity of the skin, and the ability of the user to discriminate between stimulus intensities. These two parameters were investigated by determining the two-point discrimination (TPD) threshold and the just-noticeable intensity difference (JND) using coin motors on the lower back. Coin motors are eccentric rotating-mass motors that are affordable, energy-efficient, and easy to implement. The lower back was chosen because it is a discreet place to wear assistive technology. It is generally available for use, as it is usually not critically involved in activities of daily living. Rehabilitation with sensory substitution devices often requires training by professional occupational therapists, because the user needs to extract visual information from sparse information presented through an alternative channel such as the skin. In this study they determined whether short, automated training sessions of 5 min each could improve the TPD threshold and JND. It was found that 10 min of computer-assisted training improved the vibrotactile TPD threshold on the lower back by 36%, and that 18 min of training improved the just-noticeable intensity difference (JND) by 44%. It was concluded that short, automated training sessions could provide a fast and inexpensive means to improve people's basic spatial acuity and intensity discrimination skills with coin motors.


Effect of 3 lactobacilli on immunoregulation and intestinal microbiota in a β-lactoglobulin-induced allergic mouse model.
Milk is one of the earliest and most common allergen sources in the world, with β-lactoglobulin representing a major allergen protein. Numerous studies have reported that probiotics exert antiallergic and anti-inflammatory effects. Here, we examined the effects of 3 strains of Lactobacillus on immunomodulatory functions, intestinal barrier functions, and intestinal microbiota through a β-lactoglobulin-induced allergic mouse model. We found that the oral administration of Lactobacillus plantarum ZDY2013 and Lactobacillus rhamnosus GG suppressed allergic response, attenuating serum IgE and relieving anaphylaxis symptoms. The 3 strains of Lactobacillus could induce T helper (Th) 1 or T regulatory cells to differentiate to inhibit the Th2-biased response for regulating Th1/Th2 immune balance. Furthermore, L. plantarum ZDY2013 and L. rhamnosus GG enhanced intestinal barrier function through the regulation of tight junction. We also found that L. plantarum ZDY2013 and L. plantarum WLPL04 could regulate alterations in intestinal microbiota caused by allergies. In particular, Rikenella, Ruminiclostridium, and Lachnospiraceae UCG-006 were considerably reduced after treatment with L. plantarum ZDY2013 and L. plantarum WLPL04. These results suggested that 3 Lactobacillus strains may serve as an effective tool for the treatment of food allergies by regulating immune and gut microbiota.


Development and Validation of the Nursing Care and Religious Diversity Scale (NCRDS).
(1) Background: In response to the impact of religious intervention on health outcomes and the importance of documenting how nurses experience the spiritual need of 392 hospitalized patients, it is vital to provide the nursing profession with instruments to evaluate these spiritual aspects. This study describes the development and validation of the Nursing Care and Religious Diversity Scale (NCRDS); (2) Methods: A two-step design was used for NCRDS translation and psychometric validation. The tool design was developed in the first step, while the psychometric characteristics were tested in the second step. An inductive study was conducted to test the validity and reliability of the NCRDS tool. The overall sample consisted of 317 nurses; (3) Results: The final instrument comprised 25 items in five dimensions. The construct validity indicated five dimensions. The face and content validity were adequate. Test-retest reliability displayed good stability, and internal consistency (Cronbach's α) was acceptable (0.83); (4) Conclusions: Initial testing of the NCRDS suggested that it is a valid and reliable instrument to evaluate individuals in religious diversity, with five dimensions for evaluating the meaning of spirituality and individual belief, the religious healthcare environment, educational adequacy, spiritual and religious needs, and religious plurality.


Cost-effectiveness of RAS screening before monoclonal antibodies therapy in metastatic colorectal cancer based on FIRE3 Study.
The surprising results published by FIRE-3 revealed that the overall survival (OS) of RAS wild-type metastatic colorectal cancer (mCRC) patients treated with Cetuximab(Cmab) and FOLFIRI combination was prolonged to 33.1 months. The substantial increase in testing and treatment costs, however, impose a considerable health burden on patients and society. Hence the study was aimed to assess the cost-effectiveness of RAS screening before monoclonal antibodies (mAbs) therapy based on FIRE-3 study. Four groups were analyzed: group 1, patients with KRAS testing treated with Cmab and FOLFIRI; group 2, patients with RAS testing treated with Cmab and FOLFIRI; group 3, patients with KRAS testing treated with bevacizumab(Bmab) and FOLFIRI; group 4, patients with RAS testing treated with Bmab and FOLFIRI. A Markov model comprising 3 health states (progression-free survival, progressive disease and death) was built. The costs were calculated from a Chinese payer perspective, and survival was reported in quality-adjusted life-months (QALMs). Average total lifetime costs ranged from $104,682.44 (RAS-Bmab) to $136,867.44 (RAS-Cmab), while the survival gained varied from 16.88 QALMs in RAS-Bmab to 21.85 QALMs in RAS-Cmab. The cost per QALM was $6,263.86 for RAS-Cmab, $6,145.84 for KRAS-Bmab, $6,201.57 for RAS-Bmab and $6,960.70 for KRAS-Cmab respectively. The KRAS-Cmab strategy was dominated by the other 3 groups. The first-treatment cost of RAS-Cmab was the most influential one to the model. In all, the RAS screening prior to Cmab treatment in mCRC seems to be a cost-effective strategy in the time of monoclonal antibodies (mAbs) therapy with the most gained QALMs.


Extensive sequence and structural evolution of Arginase 2 inhibitory antibodies enabled by an unbiased approach to affinity maturation.
Affinity maturation is a powerful technique in antibody engineering for the in vitro evolution of antigen binding interactions. Key to the success of this process is the expansion of sequence and combinatorial diversity to increase the structural repertoire from which superior binding variants may be selected. However, conventional strategies are often restrictive and only focus on small regions of the antibody at a time. In this study, we used a method that combined antibody chain shuffling and a staggered-extension process to produce unbiased libraries, which recombined beneficial mutations from all six complementarity-determining regions (CDRs) in the affinity maturation of an inhibitory antibody to Arginase 2 (ARG2). We made use of the vast display capacity of ribosome display to accommodate the sequence space required for the diverse library builds. Further diversity was introduced through pool maturation to optimize seven leads of interest simultaneously. This resulted in antibodies with substantial improvements in binding properties and inhibition potency. The extensive sequence changes resulting from this approach were translated into striking structural changes for parent and affinity-matured antibodies bound to ARG2, with a large reorientation of the binding paratope facilitating increases in contact surface and shape complementarity to the antigen. The considerable gains in therapeutic properties seen from extensive sequence and structural evolution of the parent ARG2 inhibitory antibody clearly illustrate the advantages of the unbiased approach developed, which was key to the identification of high-affinity antibodies with the desired inhibitory potency and specificity.


Post-traumatic growth: a qualitative analysis of experiences regarding positive psychological changes among Iranian women with breast cancer.
Cancer diagnosis is an extremely stressful experience that has a profound impact on a patient's life. Cancer related perceived stress and complications may lead to the experience of positive psychological changes and post-traumatic growth (PTG). Since there is lack of qualitative research assessing the experience of PTG in Iranian women with breast cancer, this study aims to investigate experiences relating to PTG of Iranian women. A qualitative phenomenological approach was selected to explore the experiences of Iranian women with PTG. Data were gathered using semi-structured, in-depth interviews with 18 eligible patients, which were then transcribed and analyzed using Van Manen's thematic analysis approach. Data gathering and analyses were conducted simultaneously. In addition, MAXQDA software was used for data management. In this study, the participants were 18 Iranian women between the ages of 31 and 65 years. Four prominent themes were extracted from the participant's statements that demonstrated the Iranian women's experiences with breast cancer-induced psychological growth and maturity: 1) appreciate of life, 2) stability, 3) spiritual prosperity, and 4) effective interaction. Health care professionals are strongly recommended to design robust and timely intervention programs to improving PTG among breast cancer survivors and reduce their perceived distress resulting from cancer diagnosis.


The Dynamics Underlying the Rise of Star Performers.
Across different domains, there are 'star performers' who are able to generate disproportionate levels of performance output. To date, little is known about the model principles underlying the rise of star performers. Here, we propose that star performers' abilities develop according to a multi-dimensional, multiplicative and dynamical process. Based on existing literature, we defined a dynamic network model, including different parameters functioning as enhancers or inhibitors of star performance. The enhancers were multiplicity of productivity, monopolistic productivity, job autonomy, and job complexity, whereas productivity ceiling was an inhibitor. These enhancers and inhibitors were expected to influence the tail-heaviness of the performance distribution. We therefore simulated several samples of performers, thereby including the assumed enhancers and inhibitors in the dynamic networks and compared their tail-heaviness. Results showed that the dynamic network model resulted in heavier and lighter tail distributions, when including the enhancer- and inhibitor-parameters, respectively. Together, these results provide novel insights into the dynamical principles that give rise to star performers in the population.


Fatigue with epidermal growth factor receptor tyrosine kinase inhibitors in cancer patients: A meta-analysis of randomized controlled trials.
We conducted this systematic review to fully investigate the fatigue of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in cancer patients. The approved and clinical used EGFR-TKIs were selected for the present meta-analysis. The relevant studies of the randomized controlled trials (RCTs) in cancer patients treated with EGFR-TKIs were retrieved and the systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published till July 2017. Eighteen randomized controlled trials and 14088 patients were included. The current analysis suggested that the use of EGFR-TKIs increased the risk of all-grade fatigue (1.26;95%CI, 1.17-1.36;p < 0.00001) and high-grade (≥grade 3) fatigue (1.47;95%CI, 1.22-1.78;p < 0.0001). On subgroup analysis, the RR of high-grade fatigue varies significantly according to drug type, cancer type, treatment line, and treatment duration. The available data suggested that the use of EGFR-TKIs is associated with a significantly increased risk of fatigue in cancer patients.


Think of the Children: A Discussion of the Rationale for and Implications of the Perspective Used for EQ-5D-Y Health State Valuation.
The recently published EQ-5D-Y valuation protocol prescribes the general public values EQ-5D-Y health states for a 10-year-old child. This child perspective differs from the individual perspective applied for valuation of adult EQ-5D instruments. This article discusses the rationale for and implications of applying a child perspective for EQ-5D-Y health state valuation. This article was informed by an exploration of the normative and empirical literature on health state valuation. We identified and summarized key discussion points in a narrative review. Although valuing EQ-5D-Y health states from an individual perspective is feasible, it may be problematic for several reasons. The use of a child perspective implies that-rather than valuing one's own health-someone else's health is valued. This may require the projection of one's own beliefs, expectations, and preferences on others, which could change the decision processes underlying the elicited preferences. Furthermore, because preferences are obtained for a 10-year-old child, it is unclear if this given age as well as other (missing) information on the described child beneficiary (should) affect valuation of EQ-5D-Y health states. The change from an individual to a child perspective in the valuation of EQ-5D-Y will likely lead to differences in utilities. This has implications for the estimation of incremental health-related quality-of-life gains in economic evaluations of health technologies for children and adolescents and therefore might affect reimbursement decisions. Further research is necessary for gaining insight into the extent to which this impact is normatively and empirically justified.


Differential associations of specific depressive and anxiety disorders with somatic symptoms.
Previous studies have shown that depressive and anxiety disorders are strongly related to somatic symptoms, but much is unclear about the specificity of this association. This study examines the associations of specific depressive and anxiety disorders with somatic symptoms, and whether these associations are independent of comorbid depressive and anxiety disorders. Cross-sectional data were derived from The Netherlands Study of Depression and Anxiety (NESDA). A total of 2008 persons (mean age: 41.6 years, 64.9% women) were included, consisting of 1367 patients with a past-month DSM-diagnosis (established with the Composite International Diagnostic Interview [CIDI]) of depressive disorder (major depressive disorder, dysthymic disorder) and/or anxiety disorder (generalized anxiety disorder, social phobia, panic disorder, agoraphobia), and 641 controls. Somatic symptoms were assessed with the somatization scale of the Four-Dimensional Symptom Questionnaire (4DSQ), and included cardiopulmonary, musculoskeletal, gastrointestinal, and general symptoms. Analyses were adjusted for covariates such as chronic somatic diseases, sociodemographics, and lifestyle factors. All clusters of somatic symptoms were more prevalent in patients with depressive and/or anxiety disorders than in controls (all p<.001). Multivariable logistic regression analyses showed that all types of depressive and anxiety disorders were independently related to somatic symptoms, except for dysthymic disorder. Major depressive disorder showed the strongest associations. Associations remained similar after adjustment for covariates. This study demonstrated that depressive and anxiety disorders show strong and partly differential associations with somatic symptoms. Future research should investigate whether an adequate consideration and treatment of somatic symptoms in depressed and/or anxious patients improve treatment outcomes.


Quantitative mapping of cocaine-induced ΔFosB expression in the striatum of male and female rats.
ΔFosB plays a critical role in drug-induced long-term changes in the brain. In the current study, we evaluated locomotor activity in male and female rats treated with saline or cocaine for 2 weeks and quantitatively mapped ΔFosB expression in the dorsal striatum and nucleus accumbens of each animal by using an anti-FosB antibody that recognizes ΔFosB isoforms preferentially. Behavioral analysis showed that while there was little difference between males and females that sensitized to cocaine, nonsensitizing rats showed a large sex difference. Nonsensitizing males showed low behavioral activation in response to cocaine on the first day of treatment, and their activity remained low. In contrast, nonsensitizing females showed high activation on the first day of treatment and their activity remained high. Western blot and immunohistochemical analyses indicated that basal levels of ΔFosB were higher in the nucleus accumbens than the dorsal striatum, but that the effect of cocaine on ΔFosB was greater in the dorsal striatum. Immunostaining showed that the effect of cocaine in both the dorsal striatum and nucleus accumbens was primarily to increase the intensity of ΔFosB immunoreactivity in individual neurons, rather than to increase the number of cells that express ΔFosB. Detailed mapping of ΔFosB-labeled nuclei showed that basal ΔFosB levels were highest in the medial portion of the dorsal striatum and dorsomedial accumbens, particularly adjacent to the lateral ventricle, whereas the cocaine-induced increase in ΔFosB was most pronounced in the lateral dorsal striatum, where basal ΔFosB expression was lowest. Sex differences in ΔFosB expression were small and independent of cocaine treatment. We discuss implications of the sex difference in locomotor activation and regionally-specific ΔFosB induction by cocaine.


FLIGHTLESSNESS IN GREBES (AVES, PODICIPEDIDAE): ITS INDEPENDENT EVOLUTION IN THREE GENERA.
The morphological bases of flightlessness in three genera of grebes were studied using 790 study skins, 322 skeletons, myological data from 40 anatomical specimens studied by Sanders (1967), and ancillary data on wing-loadings. Three species, Rollandia microptera, Podilymbus gigas, and Podiceps taczanowskii, are considered to be flightless; each is endemic to a high-altitude, neotropical lake or lake system. Compared to their flighted (capable of flight) sister-species, the three flightless species shared several broadly convergent characters: larger body mass and skeletal dimensions (exclusive of the sternal carina), reductions in relative lengths of wing, tail, and primary remiges, and reduction in the relative size of breast muscles. Rollandia microptera exhibited the greatest morphological differences from its flighted sister-species; these differences were comparable to intergeneric morphometric differences in magnitude and involved a tripling of body mass, a modal loss of one primary remex in each wing, absolute reduction of the sternal carina, flattening of proximal wing elements, a large morphometric shift in skeletal dimensions, an increase in the scapulocoracoid angle, and six qualitative differences in the pectoral musculature. Morphological differences between Podilymbus gigas and its flighted congener were comparatively minor; flightlessness in this species, if genuine, evidently results from an allometric increase in size combined with a large decrease in relative bulk of breast musculature and shift of alar muscle mass. Podiceps taczanowskii was intermediate in degree of anatomical difference from its flighted relatives, but was unique in its slight reduction in absolute length of the wings and decrease in absolute widths of the skeletal wing elements. Multivariate differences in external characters associated with flightlessness were strongly convergent in the three genera, but multivariate differences in skeletal proportions differed substantially among genera in detail. An estimate of wing-loading indicated that Podilymbus gigas and, especially, Podiceps taczanowskii may be only "flight-impaired" rather than flightless. Relative wing lengths and conformation of sterna in Rollandia microptera and Podiceps taczanowskii indicate that morphological changes associated with flightlessness are paedomorphic; intraspecific allometry in Rollandia indicates that the underlying ontogenetic change may involve a delay in the start of pectoral-alar development (postdisplacement). Flightlessness in grebes, a family typified by moderately heavy wing-loadings and relatively small pectoral muscles, is related in all three instances to the year-round residency afforded by large lakes at low latitudes. The primary selective advantages of morphological changes leading to flightlessness probably are related to the thermodynamic advantages of increased body sizes, feeding specialization associated with enlargement of the bill, and reduction of intraspecific niche overlap through increased sexual dimorphism; the changes are also possibly related to economy of pectoral-alar development.


From colorectal cancer pattern to the characterization of individuals at risk: Picture for genetic research in Latin America.
Colorectal cancer (CRC) is one of the most common cancers in Latin America and the Caribbean, with the highest rates reported for Uruguay, Brazil and Argentina. We provide a global snapshot of the CRC patterns, how screening is performed, and compared/contrasted to the genetic profile of Lynch syndrome (LS) in the region. From the literature, we find that only nine (20%) of the Latin America and the Caribbean countries have developed guidelines for early detection of CRC, and also with a low adherence. We describe a genetic profile of LS, including a total of 2,685 suspected families, where confirmed LS ranged from 8% in Uruguay and Argentina to 60% in Peru. Among confirmed LS, path_MLH1 variants were most commonly identified in Peru (82%), Mexico (80%), Chile (60%), and path_MSH2/EPCAM variants were most frequently identified in Colombia (80%) and Argentina (47%). Path_MSH6 and path_PMS2 variants were less common, but they showed important presence in Brazil (15%) and Chile (10%), respectively. Important differences exist at identifying LS families in Latin American countries, where the spectrum of path_MLH1 and path_MSH2 variants are those most frequently identified. Our findings have an impact on the evaluation of the patients and their relatives at risk for LS, derived from the gene affected. Although the awareness of hereditary cancer and genetic testing has improved in the last decade, it is remains deficient, with 39%-80% of the families not being identified for LS among those who actually met both the clinical criteria for LS and showed MMR deficiency.


CHANGES IN MAIN VEIN CHARACTERISTICS OF COSMONAUT'S LOWER EXTREMITIES IN THE COURSE OF YEAR-LONG SPACE MISSIONS.
Leg venous measurements were performed in two cosmonauts during the 379-d "Mir" mission (K-1 and 340-d ISS mission (K-2). The paper presents individual changes in venous capacity, distention and filling rate in the legs of these two cosmonauts, and 23 cosmonauts on 6-mos. missions as controls. In the first half of the year-long missions, changes in venous characteristics showed similar trends though had different dimensions. For instance, in K-1 increases in capacity and distention were more pronounced than in K-2. In the second half of the missions, the cosmonauts again displayed different changes in venous characteristics. In K-1 they all were unstable with episodes of simultaneous increases in venous capacity, distention and filling rate that were unfavorable for orthostatic stability (OS). Changes in the K-2 leg veins were less dramatic and detrimental to OS. Recovery of the pre-flight status of leg veins following the year-long missions took a longer time as compared with 6-mos. missions; the process was still incomplete by day 8 after landing. We surmise that in future one-year and longer missions the majority of cosmonauts are likely to have favorable changes in leg veins; however, untoward venous developments and consequent OS impairment must not be excluded.


Clinical significance of isolated fetal pericardial effusion.
Prenatal sonographic identification of a small rim of pericardial fluid, measuring less than 2 mm in thickness, is a normal finding. Pericardial fluid 2 mm or greater in thickness may be associated with structural anomalies or hydrops, but its clinical significance in the absence of these associated findings has not been evaluated. We assessed the outcome in fetuses with isolated pericardial effusions of at least 2 mm thick. Our study population included 52 fetuses with effusions ranging from 2 to 7 mm in thickness. We compared rates of preterm delivery, cesarean section, intrauterine growth retardation, perinatal complications, Apgar scores, and length of neonatal hospital stay in these 52 cases to the overall hospital rates and found no statistically significant difference. We conclude that in the absence of other sonographic abnormalities, the finding of a fetal pericardial fluid collection 2 to 7 mm in thickness is not associated with adverse outcome.


[Elimination of haloperidol from erythrocytes surfaces supernatant and blood plasma].
The aim of the study was to investigate the adsorption rate of haloperidol on erythrocytes surfaces. The pharmacokinetic and pharmacodynamic parameters of haloperidol were monitored in the experiment. The neuroleptic was administered to 12 adult dogs and the blood samples were collected for further analysis following 20, 30, 60, 180, 240, 360, 420 and 480 minutes after the injection. The groups of samples (blood plasma and supernatant) were monitored during this period. The differences between haloperidol concentration in the supernatant and blood plasma were compared. Our data have shown that dynamics of the elimination of intact and acidified forms of haloperidol from the supernatant and the blood serum are not the same. Intact and acidified forms are differently regulated by plasma. albumines and globulines. The process of redistribution of haloperidol between the both substrates takes place, while the supernatant has a donor function for the free form of haloperidol and represents the acceptor of the haloperidol's metabolites. This provides the possibility to develop multidiscipline approach to the optimization to the prescription of haloperidol.


Ionizing radiation causes greater DNA base damage in radiation-sensitive mutant M10 cells than in parent mouse lymphoma L5178Y cells.
DNA base damage in radiation-sensitive mutant M10 cells and parent mouse lymphoma L5178Y cells was studied. Cells were exposed to ionizing radiation in the dose range of 48 to 400 Gy. Chromatin was isolated from cells and analyzed by gas chromatography-mass spectrometry. Ten DNA base products were identified and quantified. A dose-dependent formation of the products was observed. The yields of products in M10 cells were up to threefold greater than in L5178Y cells. Of the products measured, formamidopyrimidines had the highest difference in their yields between the two cell lines. The greater initial DNA base damage in M10 cells may play a role in their hypersensitivity to ionizing radiation.


Gene expression profiles in HPV-infected head and neck cancer.
Epidemiological and laboratory evidence indicate that, in addition to tobacco and alcohol, human papillomaviruses (HPV) play an important aetiological role in a subset of head and neck squamous cell carcinoma (HNSCC). To evaluate the molecular pathogenesis of HPV-infected HNSCC, we compared gene expression patterns between HPV-positive and -negative HNSCC tumours using cDNA microarrays. Tumour tissue was collected from 42 histologically confirmed HNSCC patients from an inner-city area of New York. Total DNA and RNA were extracted and purified from frozen tumour samples and gene expression levels were compared to a universal human reference RNA standard using a 27 323 cDNA microarray chip. HPV detection and genotyping were performed using an MY09/11-PCR system and RT-PCR. HPV was detected in 29% of HNSCC tumours. Most harboured only HPV16 and expressed the HPV16-E6 oncogene. HPV prevalence was highest in pharyngeal tumours (45%). Gene expression patterns that differentiated HPV-positive from negative tumours were compared by supervised classification analysis, and a multiple-gene signature was found to predict HPV16 prevalence in primary HNSCC with a false discovery rate < 0.2. Focusing on never-smokers, we further identified a distinct subset of 123 genes that were specifically dysregulated in HPV16-positive HNSCC. Overexpressed genes in HPV-positive HNSCC tumours included the retinoblastoma-binding protein (p18), replication factor-C gene, and an E2F-dimerization partner transcription factor (TFDP2) that have also been found to be overexpressed in cervical cancer. An additional subset of genes involved in viral defence and immune response, including interleukins and interferon-induced proteins, was found to be down-regulated in HPV-positive tumours, supporting a characteristic and unique transcriptional profile in HPV-induced HNSCC.


Immunohistochemistry in bone marrow pathology: a useful adjunct for morphologic diagnosis.
Pathomorphological examination of trephine biopsies of the bone marrow (BM) represents a standard method for the diagnosis and staging of hematologic neoplasms and other disorders involving the BM. The increasing knowledge about the genetic basis and biology of hematologic neoplasms, as well as the recently proposed WHO classification system, provide the framework for an accurate diagnosis. Although conventional morphology remains the gold standard for paraffin-embedded BM trephines, immunohistochemical stainings have become an integral part of the diagnostic workup. Antibodies suitable for paraffin sections are generally applicable to BM trephines, but modifications of staining protocols may be necessary due to the alternative fixatives and decalcification procedures used for BM biopsies. The indications for immunostainings range from confirmation and classification of lymphoma involvement, subclassification of acute leukemias, and estimating blast counts in myelodysplastic and myeloproliferative syndromes to characterization of BM involvement in nonhematologic neoplasms. Although subtyping of NHL in the BM is more difficult from the point of morphology, classification of the entities that frequently involve the BM, especially the small B-cell lymphomas, can easily be achieved with the help of immunohistochemistry. In this review, we try to summarize the current state of the art in BM immunohistochemistry for the diagnosis of hematologic disorders. Moreover, diagnostic algorithms and useful antibody panels are proposed for a rational and cost-effective approach.


Modelling the growth of ZnO thin films by PVD methods and the effects of post-annealing.
Results are presented for modelling of the evaporation and magnetron sputter deposition of Zn(x)O(y) onto an O-terminated ZnO (0001¯) wurtzite surface. Growth was simulated through a combination of molecular dynamics (MD) and an on-the-fly kinetic Monte Carlo (otf-KMC) method, which finds diffusion pathways and barriers without prior knowledge of transitions. We examine the effects of varying experimental parameters, such as substrate bias, distribution of the deposition species and annealing temperature. It was found when comparing evaporation and sputtering growth that the latter process results in a denser and more crystalline structure, due to the higher deposition energy of the arriving species. The evaporation growth also exhibits more stacking faults than the sputtered growth. Post-annealing at 770 K did not allow complete recrystallization, resulting in films which still had stacking faults where monolayers formed in the zinc blende phase, whereas annealing at 920 K enabled the complete recrystallization of some films to the wurtzite structure. At the latter temperature atoms could also sometimes be locked in the zinc blende phase after annealing. When full recrystallization did not take place, both wurtzite and zinc blende phases were seen in the same layer, resulting in a phase boundary. Investigation of the various distributions of deposition species showed that, during evaporation, the best quality film resulted from a stoichiometric distribution where only ZnO clusters were deposited. During sputtering, however, the best quality film resulted from a slightly O rich distribution. Two stoichiometric distributions, one involving mainly ZnO clusters and the other involving mainly single species, showed that the distribution of deposition species makes a huge impact on the grown film. The deposition of predominantly single species causes many more O atoms at the surface to be sputtered or reflected, resulting in an O deficiency of up to 18% in the deposited film and therefore resulting in more stacking faults and phase boundaries. The methods used allow analysis of key mechanisms that occur during the growth process and give hints as to the optimum conditions under which complete crystalline layers can form.


Avoidance behavior of Hyalella azteca in response to three common-use insecticides.
Non-target organisms in aquatic environments may experience lethal or sublethal effects following exposure to contaminants. Most protocols and regulations, however, are designed to provide protection from lethal effects and are thus based on conventional estimates of population lethality. The relative lack of reliable behavioral endpoints makes it challenging to implement regulations that are similarly protective against sublethal toxicity. The objective of this study was to quantify the avoidance behavior of Hyalella azteca when exposed to three insecticides-bifenthrin (B), chlorpyrifos (C), and permethrin (P)-at a range of estimated lethal concentrations. A two-choice behavioral arena was used for each chemical to quantify H. azteca activity and time spent in either uncontaminated sediment or sediment spiked at concentrations reflecting estimated 48-h lethal concentrations (LC50, LC25, and LC10). For all three insecticides, naïve H. azteca demonstrated a preference for the uncontaminated sediment over the contaminated sediment at the LC50 (B: 312 ng/gOC; C: 1265 ng/gOC; P: 5042 ng/gOC) and LC25 (B: 230 ng/gOC; C: 859 ng/gOC; P: 3817 ng/gOC), spending significantly more time in the uncontaminated side of the arena. H. azteca did not avoid sediment at LC10 (B: 204 ng/gOC; C: 609 ng/gOC; P: 1515 ng/gOC) levels, indicating the existence of a potential threshold of detection. Despite the lack of substrate preference at this exposure level, H. azteca were nevertheless more active (i.e., increased zone-switching) when exposed to bifenthrin at the LC10, suggesting a possible irritation response (e.g., movement after exposure) to this chemical. Our results provide evidence that H. azteca exhibit innate avoidance responses to sediments contaminated with common insecticides at concentrations below those represented by traditional toxicological endpoints (e.g., LC50). The sensitivity and ease with which this behavioral endpoint can be assayed demonstrates the potential utility of behavioral endpoints in toxicological assessments using model organisms.


Localization of myo-inositol-1-phosphate synthase to the endosperm in developing seeds of Arabidopsis.
Expression and localization of myo-inositol-1-phosphate synthase (MIPS) in developing seeds of Arabidopsis thaliana was investigated. MIPS is an essential enzyme for production of inositol and inositol phosphates via its circularization of glucose-6-phosphate as the initial step. myo-inositol-6-phosphate (InsP(6) or phytic acid) is the predominant form of phosphorus found in seeds and accumulates as a consequence of MIPS action. Three MIPS genes have been identified in Arabidopsis, all of which were expressed not only in siliques but in both leaves and roots. Immunoelectron microscopy using a MIPS antibody showed that MIPS localizes to the cytosol primarily in the endosperm during seed development and not in the embryo. This is consistent with results obtained using fluorescent microscopy and western blot analysis that showed a similar pattern of localization. However, InsP(6), which is the final product of inositol phosphate metabolism, was present mainly in the embryo. This suggests that a complex interaction between the endosperm and embryo occurs during the synthesis and subsequent accumulation of InsP(6) in developing seeds of Arabidopsis.


Two-dimensional Vlasov solution for a collisionless plasma jet across transverse magnetic field lines with a sheared bulk velocity.
We consider a two-dimensional (2D) stationary stream of a collisionless plasma injected across an external stationary magnetic field and a background stagnant plasma. The solution is found by solving the Vlasov equation for each species (electrons and protons), the Maxwell-Ampere equation for the magnetic vector potential, and the equation of plasma quasineutrality for the electrostatic potential. The solution of the stationary Vlasov equation is given in terms of two constants of motion and one adiabatic invariant. The partial charge and current densities are given by analytical expressions of the moments of the velocity distribution functions for each particle species. The 2D distribution of the plasma bulk velocity, Vx (y,z), is roughly uniform inside the jet. There is no plasma bulk flow in the direction of the magnetic field. Inside the boundary layer interfacing the jet and the stagnant plasma, the bulk velocity has gradients (i.e., shears) in the direction parallel as well perpendicular to the magnetic field. The parallel component of this gradient, inverted Delta parallel) inverted Delta perpendicular, produces a nonzero electric field component parallel to the magnetic field lines, E.B not equal to 0. The parallel electric field within the transition layer is a basic element allowing plasma elements to be transported across magnetic field lines in astrophysical systems as well as in laboratory experiments where plasmoids are injected across magnetic fields.


Increasing School Success Through Partnership-Based Family Competency Training: Experimental Study of Long-Term Outcomes.
An expanding body of research suggests an important role for parent or family competency training in children's social-emotional learning and related school success. This article summarizes a test of a longitudinal model examining partnership-based family competency training effects on academic success in a general population. Specifically, it examines indirect effects of the Iowa Strengthening Families Program (ISFP) on school engagement in 8th grade and academic success in the 12th grade, through direct ISFP effects on intervention-targeted outcomes-parenting competencies and student substance-related risk-in 6th grade. Twenty-two rural schools were randomly assigned to either ISFP or a minimal-contact control group; data were collected from 445 families. Following examination of the equivalence of the measurement model across group and time, a structural equation modeling approach was used to test the hypothesized model and corresponding hypothesized structural paths. Significant effects of the ISFP were found on proximal intervention outcomes, intermediate school engagement, and the academic success of high school seniors.


Tonsillar solitary fibrous tumour: A interesting rare case.
A solitary fibrous tumour (SFT) is a rare mesenchymal tumour that frequently originates in the mesothelium-covered surfaces, such as the pleura and peritoneum. It may develop in various body parts, including the head and neck. These tumours may arise in several different patterns, which results in difficulties in diagnosing them. This case is a solitary tumour developing from the palatine tonsil in a 17-year-old male patient; it is the second case in the literature. The tumour has the histopathological characteristics of a patternless pattern, a slight pleomorphism, and a composition of hypercellular and hypocellular sites. Immunohistochemically, the tumour cells showed a strong positive staining with CD34, Bcl-2, and vimentin. No recurrence developed in the patient's approximately 18-month-long follow-up period.


Occurrence of human leukocyte antigen B51-related ankylosing spondylitis in a family: Two case reports.
Ankylosing spondylitis (AS) is strongly associated with the human leukocyte antigen (HLA) B27 haplotype. In regions where conventional polymerase chain reaction for HLA typing is available for antigens such as HLA B27 or HLA B51, it is common to perform the HLA B27 test for evaluation of AS. While HLA B27-associated clustered occurrences of AS have been reported in families, we report the first case series of HLA B51-related occurrences of AS in a family. A father and his daughters were diagnosed with AS and did not have the HLA B27 haplotype. Although they were positive for HLA B51, they exhibited no signs of Behçet's disease (BD). Of the five daughters, one had AS, and three, including the daughter with AS, were positive for HLA B51. The two daughters with the HLA B51 haplotype (excluding the daughter with AS) exhibited bilateral grade 1 sacroiliitis, whereas the daughters without the HLA B51 haplotype did not have sacroiliitis. Thus, this Korean family exhibited a strong association with the HLA B51 haplotype and clinical sacroiliitis, irrespective of the symptoms of BD. It is advisable to check for HLA B51 positivity in patients with AS/spondyloarthropathy who test negative for HLA B27.


Molecular analysis of the ramRA locus in clinical Klebsiella pneumoniae isolates with reduced susceptibility to tigecycline.
Mutations in ramR, a negative regulator of ramA which stimulates transcription of acrA/-B encoding the multidrug efflux pump AcrAB-TolC, were recently shown to result in reduced susceptibility to tigecycline in Klebsiella pneumoniae. We analysed six non-duplicate K. pneumoniae isolates with elevated MICs to tigecycline. All isolates showed transcriptional up-regulation of ramA and acrB as demonstrated by Northern blot and quantitative real-time PCR. Sequencing of the ramR gene revealed deletions in five of the isolates and a premature stop codon in one isolate. Transformation of the wild-type ramR gene but not of any of the detected mutant ramR genes into a ramR-mutant K. pneumoniae strain restored tigecycline susceptibility and repressed ramA and acrB transcription to wild type levels. Thus, our study confirms the role of inactivating mutations in the ramR gene in tigecycline resistance.


[New regulations concerning EHEC/VTEC].
New regulations concerning EHEC/VTEC Hemolytic Uremic Syndrome (HUS) is the most severe complication to an infection with EHEC (enterohemorrhagic E. coli), also called VTEC (verocytotoxin-producing E. coli). Risk of severe complications such as HUS is an important reason why the Swedish Communicable Diseases Act (Smittskyddslag. 2004:168) includes infection with EHEC. With very few exceptions, only EHEC with the stx2 gene is associated with HUS. According to the law, persons working with unpackaged foods, infants or severely immunocompromised patients, and children attending preschool can be suspended awaiting negative test results for EHEC. Symptom free carriers of EHEC-infection only harbouring the stx1 gene and without an epidemiological association to HUS need not be suspended from work or preschool.


Physical literacy assessment in adults: A systematic review.
Physical literacy is a multidimensional construct that has been defined and interpreted in various ways, one of the most common being "the motivation, confidence, physical competence, knowledge and understanding to maintain physical activity throughout the life course". Although its improvement can positively affect many behavioral, psychological, social, and physical variables, debate remains over an appropriate method of collecting empirical physical literacy data. This systematic review sought to identify and critically evaluate all primary studies (published and unpublished, regardless of design or language) that assessed physical literacy in adults or have proposed measurement criteria. Relevant studies were identified by searching four databases (Pubmed, SportDiscus, APA PsycINFO, Web of Science), scanning reference lists of included articles, and manual cross-referencing of bibliographies cited in prior reviews. The final search was concluded on July 15, 2022. Thirty-one studies, published from 2016 to 2022, were analyzed. We found seven instruments measuring physical literacy in adults, of which six were questionnaires. The Perceived Physical Literacy Instrument was the first developed for adults and the most adopted. The included studies approached physical literacy definition in two ways: by pre-defining domains and assessing them discretely (through pre-validated or self-constructed instruments) and by defining domains as sub-scales after factorial analyses. We found a fair use of objective and subjective measures to assess different domains. The wide use of instruments developed for other purposes in combined assessments suggests the need for further instrument development and the potential oversimplification of the holistic concept, which may not result in a better understanding of physical literacy. Quality and usability characteristics of measurements were generally insufficiently reported. This lack of data makes it impossible to compare and make robust conclusions. We could not identify if any of the existing physical literacy assessments for adults is appropriate for large-scale/epidemiological studies.


Molecular cloning of CoA Synthase. The missing link in CoA biosynthesis.
Coenzyme A functions as a carrier of acetyl and acyl groups in living cells and is essential for numerous biosynthetic, energy-yielding, and degradative metabolic pathways. There are five enzymatic steps in CoA biosynthesis. To date, molecular cloning of enzymes involved in the CoA biosynthetic pathway in mammals has been only reported for pantothenate kinase. In this study, we present cDNA cloning and functional characterization of CoA synthase. It has an open reading frame of 563 aa and encodes a protein of approximately 60 kDa. Sequence alignments suggested that the protein possesses both phosphopantetheine adenylyltransferase and dephospho-CoA kinase domains. Biochemical assays using wild type recombinant protein confirmed the gene product indeed contained both these enzymatic activities. The presence of intrinsic phosphopantetheine adenylyltransferase activity was further confirmed by site-directed mutagenesis. Therefore, this study describes the first cloning and characterization of a mammalian CoA synthase and confirms this is a bifunctional enzyme containing the last two components of CoA biosynthesis.


Early emphysema in patients with anorexia nervosa.
Postmortem studies of patients who died in the Warsaw Ghetto during World War II suggested that death from starvation was associated with pulmonary emphysema. This study re-examines this hypothesis in patients who are chronically malnourished because of anorexia nervosa. Age, smoking history, body mass index, and pulmonary function were measured in 21 subjects with anorexia nervosa and 16 control subjects. Computed tomography (CT) scans were obtained from three regions of the lung (at the level of the aortic arch, the carina, and the posterior position of the eighth rib) using a multislice scanner. The CT measurements of lung density, emphysema, and surface area-to-volume ratio were obtained using the X-ray attenuation values. CT measurements of emphysema were greater in the group that was anorexic than in historical control subjects (p < 0.001). Furthermore, there were significant correlations between the body mass index and the CT measures of emphysema for all the patients and between diffusing capacity and the CT measurements in the patients who were anorexic. A multiple linear regression analysis showed the diffusing capacity was predicted best by the percentage of lung voxels within the large emphysematous changes category. These data demonstrate that emphysema-like changes are present in the lungs of patients who are chronically malnourished.


Noninterruptive Clinical Decision Support Decreases Ordering of Respiratory Viral Panels during Influenza Season.
A growing body of evidence suggests that testing for influenza virus alone is more appropriate than multiplex respiratory viral panel (RVP) testing for general populations of patients with respiratory tract infections. We aimed to decrease the proportion of RVPs out of total respiratory viral testing ordered during influenza season. We implemented two consecutive interventions: reflex testing for RVPs only after a negative influenza test, and noninterruptive clinical decision support (CDS) including modifications of the computerized physician order entry search behavior and cost display. We conducted an interrupted time series of RVPs and influenza polymerase chain reaction tests pre- and postintervention, and performed a mixed-effects logistic regression analysis with a primary outcome of proportion of RVPs out of total respiratory viral tests. The primary predictor was the intervention period, and covariates included the provider, clinical setting, associated diagnoses, and influenza incidence. From March 2013 to April 2019, there were 24,294 RVPs and 26,012 influenza tests (n = 50,306). Odds of ordering an RVP decreased during the reflex testing period (odds ratio: 0.432, 95% confidence interval: 0.397-0.469), and decreased more dramatically during the noninterruptive CDS period (odds ratio: 0.291, 95% confidence interval: 0.259-0.327). The odds of ordering an RVP were 71% less with the noninterruptive CDS intervention, which projected 4,773 fewer RVPs compared with baseline. Assuming a cost equal to Medicare reimbursement rates for RVPs and influenza tests, this would generate an estimated averted cost of $1,259,474 per year. Noninterruptive CDS interventions are effective in reducing unnecessary and expensive testing, and avoid typical pitfalls such as alert fatigue.


Focusing on the relation: fewer exemplars facilitate children's initial verb learning and extension.
One of the most prominent theories for why children struggle to learn verbs is that verb learning requires the abstraction of relations between an object and its action (Gentner, 2003). Two hypotheses suggest how children extract relations to extend a novel verb: (1) seeing many different exemplars allows children to detect the invariant relation between actions in different contexts (Gentner, 2003), and (2) repetition of fewer exemplars allows children to move beyond the entities involved to extract the relation (Kersten & Smith, 2002). We tested 2 1/2- and 3-year-olds' ability to extend a novel verb after viewing the repetition of one novel actor compared to four different actors performing a novel action. Both ages were better at learning and extending a novel verb to a novel actor when shown only one actor rather than four different actors. These results indicate that during initial verb learning less information is more effective.


[Rationale for equipment of the functional diagnosis department].
The paper discusses the problems in the equipping of diagnostic sections for various therapeutical-and-prophylactic facilities. It proposes a list of the minimum set of tools used in the examination at various structural levels of functional diagnostic service.


Bacillus subtilis HemY is a peripheral membrane protein essential for protoheme IX synthesis which can oxidize coproporphyrinogen III and protoporphyrinogen IX.
The hemY gene of the Bacillus subtilis hemEHY operon is essential for protoheme IX biosynthesis. Two previously isolated hemY mutations were sequenced. Both mutations are deletions affecting the hemY reading frame, and they cause the accumulation of coproporphyrinogen III or coproporphyrin III in the growth medium and the accumulation of trace amounts of other porphyrinogens or porphyrins intracellularly. HemY was found to be a 53-kDa peripheral membrane-bound protein. In agreement with recent findings by Dailey et al. (J. Biol. Chem. 269:813-815, 1994) B. subtilis HemY protein synthesized in Escherichia coli oxidized coproporphyrinogen III and protoporphyrinogen IX to coproporphyrin and protoporphyrin, respectively. The protein is not a general porphyrinogen oxidase since it did not oxidize uroporphyrinogen III. The apparent specificity constant, kcat/Km, for HemY was found to be about 12-fold higher with coproporphyrinogen III as a substrate compared with protoporphyrinogen IX as a substrate. The protoporphyrinogen IX oxidase activity is consistent with the function of HemY in a late step of protoheme IX biosynthesis, i.e., HemY catalyzes the penultimate step of the pathway. However, the efficient coproporphyrinogen III to coproporphyrin oxidase activity is unexplained in the current view of protoheme IX biosynthesis.


Lead-207 NMR spectroscopy at 1.4 T: Application of benchtop instrumentation to a challenging I = ½ nucleus.
The practicality of obtaining liquid- and solid-state 207 Pb nuclear magnetic resonance (NMR) spectra with a low permanent-field magnet is investigated. Obtaining 207 Pb NMR spectra of salts in solution is shown to be viable for samples as dilute as 0.05 M. The concentration dependence of the 207 Pb chemical shifts for lead nitrate was investigated; the results are comparable with those obtained with high-field instruments. Likewise, the isotope effect of substituting D2 O for H2 O as the solvent was investigated and found to be comparable with those reported previously. Obtaining solid-state 207 Pb NMR spectra is challenging, but we demonstrate the ability to obtain such spectra for three unique solid samples. An axially symmetric 207 Pb powder pattern for lead nitrate and the powder pattern expected for lead chloride reveal linewidths dominated by shielding anisotropy, while 207 Pb-35/37 Cl J-coupling dominates in the methylammonium lead chloride perovskite material. Finally, recent innovations and the future potential of the instruments are considered.


Stanford type A aortic dissection after urgent prosthetic valve replacement: case reports.
Occurrence of acute aortic dissection after aortic valve replacement is rare, however, it is associated with high mortality and morbidity rates. We report two Asian cases in which acute aortic dissection occurred after urgent aortic valve replacement for infective endocarditis. Successful graft replacement was carried out with preservation of the prosthetic valves in both cases. Our experience with these cases suggests that, even in urgent or emergent situations, surgical intervention for associated aortic dilatation should be considered when aortic valve replacement is performed.


Hard and soft tissue responses to three different implant materials in a dog model.
The aim of this study was to assess hard and soft tissue responses using three dental implants made of different materials. Implants made of titanium (Ti), yttria-stabilized tetragonal zirconia polycrystals (Y-TZP) and ceria partially stabilized zirconia/alumina nanocomposite (Ce-TZP/Al2O3) were used in a dog model. Five male beagles were sacrificed at three months after implantation, and harvested mandible were observed and analyzed. Histological observations were similar in all groups. There were no significant differences in any histomorphometric parameters. Our results suggested the possibility of Ce-TZP/Al2O3 as a dental implant material, similar to Ti and Y-TZP.


Characterization of a novel tektin member, TEKT5, in mouse sperm.
Tektins are important components of flagella. Alterations in the expression of or mutations in mouse tektins are correlated with defective sperm motility, a cause of male infertility. Our proteomic studies of flagellar accessory structures previously identified a novel tektin, TEKT5, whose function is unknown. To understand the role of TEKT5 in mouse sperm, we characterized the expression of the mouse Tekt5 gene and the presence of TEKT5 in spermatogenic cells and spermatozoa. A complete cDNA encoding the Tekt5 transcript was assembled following reverse transcription-polymerase chain reaction (RT-PCR) and 3'-rapid amplification of cDNA ends and predicted that TEKT5 is a 62 730-dalton protein with an unusual, long C-terminus. Tekt5 mRNA was highly expressed during late stages of spermiogenesis. Among examined tissues, Tekt5 mRNA was present only in testis and brain, and quantitative RT-PCR showed that the expression level of mRNA in testis was 6.8-fold higher than that in brain. At the protein level, TEKT5 was present in sperm and was enriched in the accessory structures of flagella. Immunofluorescence confirmed that TEKT5 was localized throughout the sperm tail in flagellar accessory structures. The expression pattern suggests that TEKT5 plays an important role in flagella formation during spermiogenesis as well as being implicated in sperm motility.


Functional Fixedness in Creative Thinking Tasks Depends on Stimulus Modality.
Pictorial examples during creative thinking tasks can lead participants to fixate on these examples and reproduce their elements even when yielding suboptimal creative products. Semantic memory research may illuminate the cognitive processes underlying this effect. Here, we examined whether pictures and words differentially influence access to semantic knowledge for object concepts depending on whether the task is close- or open-ended. Participants viewed either names or pictures of everyday objects, or a combination of the two, and generated common, secondary, or ad hoc uses for them. Stimulus modality effects were assessed quantitatively through reaction times and qualitatively through a novel coding system, which classifies creative output on a continuum from top-down-driven to bottom-up-driven responses. Both analyses revealed differences across tasks. Importantly, for ad hoc uses, participants exposed to pictures generated more top-down-driven responses than those exposed to object names. These findings have implications for accounts of functional fixedness in creative thinking, as well as theories of semantic memory for object concepts.


The cyclical behavior of hospital utilization and staffing.
Aggregate monthly data on hospital utilization and staffing are examined to assess the hospital industry's ability to adjust staffing levels to regular monthly cycles in demand. Graphical analysis and linear regression are used to assess the relationship between monthly trends in utilization and full-time-equivalent hospital personnel. We show that although regular seasonal patterns exist in both utilization and staffing levels, these series are largely independent of each other. The staffing level response to cycles in admissions and patient-days is, in fact, small relative to those observed for other industries that face predictable and regular fluctuations in product demand. Staffing levels appear to be more closely related to bed levels than to actual utilization levels. For a typical hospital which does not face effective incentives to control costs, smoother patterns of seasonal utilization probably will not result in lower staffing levels and reduced costs unless accompanied by a slowdown in the rate of increase in hospital bed size.


Biotinylated phosphoproteins from kinase-catalyzed biotinylation are stable to phosphatases: implications for phosphoproteomics.
Kinase-catalyzed protein phosphorylation is involved in a wide variety of cellular events. Development of methods to monitor phosphorylation is critical to understand cell biology. Our lab recently discovered kinase-catalyzed biotinylation, where ATP-biotin is utilized by kinases to label phosphopeptides or phosphoproteins with a biotin tag. To exploit kinase-catalyzed biotinylation for phosphoprotein purification and identification in a cellular context, the susceptibility of the biotin tag to phosphatases was characterized. We found that the phosphorylbiotin group on peptide and protein substrates was relatively insensitive to protein phosphatases. To understand how phosphatase stability would impact phosphoproteomics research applications, kinase-catalyzed biotinylation of cell lysates was performed in the presence of kinase or phosphatase inhibitors. We found that biotinylation with ATP-biotin was sensitive to inhibitors, although with variable effects compared to ATP phosphorylation. The results suggest that kinase-catalyzed biotinylation is well suited for phosphoproteomics studies, with particular utility towards monitoring low-abundance phosphoproteins or characterizing the influence of inhibitor drugs on protein phosphorylation.


Plant Sterol Esters in Extruded Food Model Inhibits Colon Carcinogenesis by Suppressing Inflammation and Stimulating Apoptosis.
Plant sterols in their free forms are known to inhibit colon cancer. Whether these activities persist when compounds are incorporated into processed food is not reported yet. This study aimed to test the ability of plant sterol esters (PSE) incorporated into a nonpuffed extruded food (NPE) model to inhibit colon carcinogenesis. PSE was added into NPE at four concentrations (0.0%, 0.7%, 1.4%, and 2.1%). PSE-NPE activity was tested in azoxymethane/dextran sodium sulfate-induced Balb/c mice. The groups given PSE-NPE did not show any colon tumor formation. Immunohistochemistry results revealed that the group fed with 1.4% PSE had the lowest histoscore for cyclooxygenase-2 expression and the highest histoscore for cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9expressions. The results of this study indicated that even after incorporation into a food system, which is processed using high pressure and temperature, PSE retained its chemopreventive activity. The proposed mechanisms are by suppressing inflammation and inducing apoptosis.


Quantitative analysis of phytopathogenic ascomycota on leaves of pedunculate oaks (Quercus robur L.) by real-time PCR.
Leaves of oak trees are often infected by various pathogenic fungi. As it is difficult to remove such organisms quantitatively from the leaf surface and as it is often impossible to grow these organisms independently from their host, there are almost no molecular data available from these oak leaf specific pathogens. For the quantitative removal of the microorganisms a procedure was developed combining a wax and microorganism freezing method with a DNA extraction technique. For the development of a species specific detection, DNA of pathogenic filamentous fungi was isolated from hyphae of the upper leaf surface of Quercus robur. Three different species could be identified as (i) Cladosporium sp., (ii) Ramularia sp. and (iii) Microsphaera alphitoides by amplifying and sequencing an 18S-28S segment of their rDNA. For the final quantification a real-time PCR protocol was established allowing the species specific quantification of the three pathogenic filamentous fungi. The whole procedure was successfully applied to quantify the amount of the three species on oak leaves collected in autumn.


The Building Blocks of Implementation Frameworks and Models in Primary Care: A Narrative Review.
Background: Our aim is to identify the core building blocks of existing implementation frameworks and models, which can be used as a basis to further develop a framework for the implementation of complex interventions within primary care practices. Within the field of implementation science, various frameworks, and models exist to support the uptake of research findings and evidence-based practices. However, these frameworks and models often are not sufficiently actionable or targeted for use by intervention designers. The objective of this research is to map the similarities and differences of various frameworks and models, in order to find key constructs that form the foundation of an implementation framework or model that is to be developed. Methods: A narrative review was conducted, searching for papers that describe a framework or model for implementation by means of various search terms, and a snowball approach. The core phases, components, or other elements of each framework or model are extracted and listed. We analyze the similarities and differences between the frameworks and models and elaborate on their core building blocks. These core building blocks form the basis of an overarching model that we will develop based upon this review and put into practice. Results: A total of 28 implementation frameworks and models are included in our analysis. Throughout 15 process models, a total of 67 phases, steps or requirements are extracted and throughout 17 determinant frameworks a total of 90 components, constructs, or elements are extracted and listed into an Excel file. They are bundled and categorized using NVivo 12© and synthesized into three core phases and three core components of an implementation process as common elements of most implementation frameworks or models. The core phases are a development phase, a translation phase, and a sustainment phase. The core components are the intended change, the context, and implementation strategies. Discussion: We have identified the core building blocks of an implementation framework or model, which can be synthesized in three core phases and three core components. These will be the foundation for further research that aims to develop a new model that will guide and support intervention designers to develop and implement complex interventions, while taking account contextual factors.


The relationship between blood gastrin levels and gastric secretion in conscious dogs.
1. In conscious dogs with gastric fistulae and Heidenhain pouches, acid and pepsin secretion, immunoreactive plasma pancreatic polypeptide (PP) and gastrin were measured following intravenously administered pentagastrin, cholinomimetics, and intragastric administration of milk. 2. Pentagastrin did not raise endogenous plasma gastrin. There was a significant positive dose-response relationship between pentagastrin and acid and fistula pepsin secretions, but not between plasma gastrin of endogenous origin and gastric secretion. 3. Carbachol raised plasma gastrin immunoreactivity; but in no instance was there a significant relationship between gastric secretion and plasma gastrin immunoreactivity. Gastric acid secretion faded, but plasma gastrin concentrations did not. 4. PP plasma immunoreactivity was elevated by methacholine and carbachol. Its levels correlated significantly with gastric acid secretion. Pentagastrin did not raise PP and its levels did not, therefore, correlate with gastric acid secretion. 5. Intragastric milk raised plasma gastrin immunoreactivity, but the acid secretion per pg of plasma gastrin was much smaller than with the cholinomimetics. Ganglionic blocking agents depressed both plasma gastrin and acid and pepsin secretion. 6. The results suggest that cholinomimetics sensitize parietal cells to the stimulating action of gastrin.


[Studies on aerobic granular sludge cultivated under selective pressure].
As inoculum sludge from a conventional COD removal activated sludge wastewater treatment plant was used, aerobic granular sludge was cultured in sequencing batch reactor (SBR) fed with glucose as carbon substrate. The SBR was operated with decreasing sedimentation time and increasing COD loading rate resulting in the selective pressure to enhance the formation of granular sludge. According to morphology change of sludge, the generation of granule could be divided into three stage. Granules started to appear after 67 days operation. After increasing COD loading rate to 4.8 kg/(m3.d), and superficial gas velocity to 0.0175 m/s, granules were the dominant sludge forms with diameter about 6-9 mm, the minimal settling velocity of 32.7 m/h, and the MLSS of 7800 mg/L. Aerobic granular sludge demonstrates high activity and ability to withstand high COD loading rate. The properties of aerobic granular sludges and the effect of different operational conditions on the formation of these aerobic granules were also analyzed preliminarily.


Comorbidity between reading disability and math disability: concurrent psychopathology, functional impairment, and neuropsychological functioning.
Reading disability (RD) and math disability (MD) frequently co-occur, but the etiology of this comorbidity is not well understood. Groups with RD only (N = 241), MD only (N = 183), and RD + MD (N = 188) and a control group with neither disorder (N = 411) completed a battery of measures of internalizing and externalizing psychopathology, social and academic functioning, and 10 neuropsychological processes. Groups with RD only, MD only, and RD + MD were significantly impaired versus the control group on nearly all measures, and the group with RD + MD was more impaired than the groups with MD and RD alone on measures of internalizing psychopathology, academic functioning, and 7 of 10 neuropsychological constructs. Multiple regression analyses of the neuropsychological measures indicated that deficits in reading and math were associated with shared weaknesses in working memory, processing speed, and verbal comprehension. In contrast, reading difficulties were uniquely associated with weaknesses in phoneme awareness and naming speed, and math deficits were uniquely associated with weaknesses in set shifting. These results support multiple-deficit neuropsychological models of RD and MD and suggest that RD and MD are distinct but related disorders that co-occur because of shared neuropsychological weaknesses in working memory, processing speed, and verbal comprehension.


First Approval of Improved Medical Device Conditional on Use-Result Survey in Japan - Regulatory Review of Polymer-Free Drug-Coated BioFreedom Coronary Stent.
A prospective randomized clinical trial showed that the BioFreedom stent (Biosensors International), which is a polymer-free and carrier-free drug-coated stent, was significantly superior to a bare-metal stent (BMS) in patients at high bleeding risk who were receiving a 1-month course of dual antiplatelet therapy (DAPT). However, the stent thrombosis rate (2.01% for BioFreedom vs. 2.20% for BMS) was 4-6-fold higher than that of approved drug-eluting stents based on real-world data in Japan. Furthermore, the frequency of stent thrombosis at more than 1 month with the BioFreedom stent was slightly higher than that at less than 1 month. This result suggested that it would not be acceptable to stop DAPT universally at 1 month. Thus, the target patients for the BioFreedom stent are unspecified patients at high bleeding risk needing to continue DAPT for as long as necessary in Japan. Therefore, based on the pre- and post-marketing balance of medical devices regulations, regulatory approval was given for unspecified patients conditionally upon real-world data collection of 2,000 patients with a Use-Results Survey, instead of conducting additional pre-marketing clinical trial(s). The Use-Results Survey System is part of a strategy to expedite patients' access to innovative medical devices and to accelerate the development of medical devices.


New Oral Anaticoagulant Prescribing Decisions amongst General Practitioners: Handle with Care.
Background: Prescribing oral anticoagulants for atrial fibrillation patients is becoming more challenging as more alternatives enter the market. While warfarin has dominated the market it is a challenging medicine to use owing to its narrow therapeutic range, increased bleeding risk and requirement for continuous monitoring. The introduction of new oral anticoagulants (NOACs) offers a wider choice but they are more costly and their use also brings additional pharmacological considerations. Objective: This paper investigates if the identified risk factors (renal impairment, hepatic impairment, other co-morbidities & drug interactions) influence GPs' NOAC prescribing decisions, using a multivariate probit model, while controlling for other GP characteristics. Methods: Employing primary data, collected using a dedicated survey of Irish GPs in November 2015, a multivariate probit is employed. This measures the joint decision making process of prescribing a NOAC based on four risk factors - renal impairment, hepatic impairment, other comorbidities and drug interactions. Results: Younger GPs are more likely to consider 'other co-morbidities' and 'renal impairment' as important when making NOAC prescribing decisions. Male GPs are more likely to consider 'other co-morbidities' and 'drug interactions' as important when prescribing NOACs compared to female GPs. Prescribers who have initiated NOACs are more likely to consider 'renal impairment' as important compared with non-initiators. Conclusions: Our study highlights the importance for general practitioners prescribing NOACs and caring for patients on oral anticoagulants, of adequate education, of appropriate patient selection and of appropriate monitoring of such patients. While warfarin prescribing remains predominant, NOAC prescribing is increasing. Incorporating the risk factors into prescribing decisions signals responsible prescribing for atrial fibrillation patients. Existing prescribing guidelines/toolkits need to be used in an effective manner.


Ecdysteroids and oocyte development in the black fly Simulium vittatum.
Oocyte development was studied in the autogenous black fly, Simulium vittatum (Diptera, Nematocera), a vector of Onchocerca volvulus, the causative agent of onchocerciasis. Oocyte growth was nearly linear between adult eclosion and was complete by 72 hours at 21 degrees C. The oocyte became opaque at 14 hours after eclosion indicating the initiation of protein yolk deposition. The accumulation of vitellogenin was measured using SDS-PAGE. The density of the yolk protein bands at about 200 and 65 kDa increased during the first and second days after eclosion. The amount of protein in the 200 kDa band of vitellogenin, determined using densitometry, rapidly increased between 12 and 25 hours after eclosion. Ecdysteroid levels were measured using a competitive ELISA. Ecdysteroid levels increased rapidly and subsequently declined during the first day after eclosion. These data show a correlation between the appearance of vitellogenin in the oocyte, and the rise in ecdysteroids. A possible relationship to molting of the nematode, Onchocerca volvulus, is discussed.


Effect of single intralesional treatment of surgically induced equine superficial digital flexor tendon core lesions with adipose-derived mesenchymal stromal cells: a controlled experimental trial.
Adipose tissue is a promising source of mesenchymal stromal cells (MSCs) for the treatment of tendon disease. The goal of this study was to assess the effect of a single intralesional implantation of adipose tissue-derived mesenchymal stromal cells (AT-MSCs) on artificial lesions in equine superficial digital flexor tendons (SDFTs). During this randomized, controlled, blinded experimental study, either autologous cultured AT-MSCs suspended in autologous inactivated serum (AT-MSC-serum) or autologous inactivated serum (serum) were injected intralesionally 2 weeks after surgical creation of centrally located SDFT lesions in both forelimbs of nine horses. Healing was assessed clinically and with ultrasound (standard B-mode and ultrasound tissue characterization) at regular intervals over 24 weeks. After euthanasia of the horses the SDFTs were examined histologically, biochemically and by means of biomechanical testing. AT-MSC implantation did not substantially influence clinical and ultrasonographic parameters. Histology, biochemical and biomechanical characteristics of the repair tissue did not differ significantly between treatment modalities after 24 weeks. Compared with macroscopically normal tendon tissue, the content of the mature collagen crosslink hydroxylysylpyridinoline did not differ after AT-MSC-serum treatment (p = 0.074) while it was significantly lower (p = 0.027) in lesions treated with serum alone. Stress at failure (p = 0.048) and the modulus of elasticity (p = 0.001) were significantly lower after AT-MSC-serum treatment than in normal tendon tissue. The effect of a single intralesional injection of cultured AT-MSCs suspended in autologous inactivated serum was not superior to treatment of surgically created SDFT lesions with autologous inactivated serum alone in a surgical model of tendinopathy over an observation period of 22 weeks. AT-MSC treatment might have a positive influence on collagen crosslinking of remodelling scar tissue. Controlled long-term studies including naturally occurring tendinopathies are necessary to verify the effects of AT-MSCs on tendon disease.


Oncologists' recommendations for adjuvant therapy in hormone receptor-positive breast cancer patients of varying age and health status.
Currently, evidence supports the use of adjuvant endocrine therapy with aromatase inhibitors in post-menopausal patients with hormone receptor (HR)-positive breast cancer. The goal of the current study is to understand the effect of patient age and health status on oncologists' decision to recommend adjuvant treatment (endocrine therapy and chemotherapy) in older women with HR-positive breast cancer. An online survey was conducted, with questions related to a hypothetical patient of varying age and health status with a T2 N2 HR-positive, HER2-negative breast cancer. Treatment options included chemotherapy and endocrine therapy, endocrine therapy alone, or no therapy. Respondents (n = 151) were further asked to specify use of either tamoxifen or aromatase inhibitors. A generalized linear mixed-effects model was used to determine the effect of age and health status on recommendations. As the hypothetical patient's age increased or health status deteriorated, oncologists (n = 151) were less likely to recommend a combination of chemotherapy and endocrine therapy (P < .0001 for both). In contrast, oncologists were more likely to recommend endocrine therapy alone with advanced age and deteriorating health status (P < .0001 for both). Oncologists were more likely to choose treatment with aromatase inhibitors as opposed to tamoxifen (P < .01), irrespective of age or health status. With increasing age and declining health status, oncologists were more likely to recommend endocrine therapy alone as opposed to chemotherapy with endocrine therapy. Oncologists were most likely to recommend aromatase inhibitors, irrespective of age or health status.


The uropygiols: identification of the unsaponifiable constituent of a diester wax from chicken preen glands.
The chief lipid fraction in the uropygial gland excretion of the domestic hen is a diester wax. The saponifiable fraction of this wax consists of saturated normal C(10)-C(20) fatty acids. The unsaponifiable fraction consists of a series of three homologous compounds, which have been named the uropygiols and identified by mass spectrometry, gas-liquid chromatography, and periodate cleavage as 2,3-n-alkanediols containing 22-24 carbon atoms. The native diols were shown to consist of about equal amounts of the threo and erythro isomers. Records of analyses of the natural products as well as related synthetic compounds are shown.