Coordination of care for multimorbid patients from the perspective of general practitioners - a qualitative study.
In Germany, a decreasing number of general practitioners (GPs) face a growing number of patients with multimorbidity. Whilst care for patients with multimorbidity involves various healthcare providers, the coordination of this care is one of the many responsibilities of GPs. The aims of this study are to identify the barriers to the successful coordination of multimorbid patient care and these patients' complex needs, and to explore the support needed by GPs in the care of multimorbid patients. Interviewees were asked for their opinion on concepts which involve the support by additional employees within the practice or, alternatively, external health care professionals, providing patient navigation. Thirty-two semi-structured, qualitative interviews were conducted with 16 GPs and 16 medical practice assistants (MPAs) from 16 different practices in Berlin. A MPA is a qualified non-physician practice employee. He or she undergoes a three years vocational training which qualifies him or her to provide administrative and clinical support. The interviews were digitally recorded, transcribed and analysed using the framework analysis methodology. The results of this paper predominantly focus on GPs' perspectives of coordination within and external to general practice. Coordination in the context of care for multimorbid patients consists of a wide range of different tasks. Organisational and administrative obstacles under the regulatory framework of the German healthcare system, and insufficient communication with other healthcare providers constitute barriers described by the interviewed GPs and MPAs. In order to ensure optimal care for patients with multimorbidity, GPs may have to delegate responsibilities associated with coordinating tasks. GPs consider the deployment of an additional specifically qualified employee inside the general practice to take on coordinative and social and legal duties to be a viable option. The cross-sectoral cooperation between all involved key players working within the healthcare system, as well as the coordination of the whole care process, is seemingly challenging for GPs within the complex care system of multimorbid patients. GPs are generally open to the assignment of a person to support them in coordination tasks, preferably situated within the practice team.


Effects of paradoxical sleep deprivation on two-way avoidance acquisition.
Immediately following 72 hrs of paradoxical sleep (PS) deprivation, Wistar rats were given a shuttle-box avoidance task consisting of 50 trials. At an interval of 6 days retention was assessed through a reacquisition session of 20 trials. In a first experiment, the pendulum technique was employed for PS deprivation and its effects were compared with those produced by the conventional watertank technique. The first technique consists of arousing animals from sleep before PS can arise, by swinging their cages in a way that produces postural imbalance at regular intervals. A moving pendulum just not causing imbalance in the animals served as control for this technique. As control for the watertank technique the large platform was chosen. Shuttle-box avoidance was greatly impaired during the second half of the acquisition session in both platform conditions as compared to both pendulum conditions. A relatively small deficit was found toward the end of the session in both PS deprivation conditions as compared to both control conditions. No differences in avoidance were established during retention testing, suggesting that performance rather than learning deficits occurred during acquisition. In a second experiment, the multiple platform was used for PS deprivation. This modified version of the watertank technique also disrupted performance during shuttle-box avoidance acquisition. However, this effect appeared to be less pronounced than the effect found in the classical platform condition of Experiment 1. It is concluded that the performance deficit induced by both the classical and the multiple platform condition was mainly due to nonspecific effects.


Isolation of lymphocytes from clotted blood.
A problem often faced in clinical cell-mediated immunology research is to obtain peripheral blood lymphocytes (PBLs) in sufficient numbers to carry out cellular immune assays. Obtaining sufficient amounts of blood for serum is usually more practical than for PBLs. Blood is usually drawn easily for serum, but obtaining PBLs from clotted blood has not been very practical. In this report we describe a procedure whereby PBLs can be recovered from clotted blood and used in functional immune assays. Using the enzyme streptokinase (SK) blood clots were dissolved and viable PBLs recovered up to 24 h post clotting. Concentrations of SK from 250 to 500 SK U/ml gave maximum recovery of PBLs.


Advances in the allostery of angiotensin II type 1 receptor.
Angiotensin II type 1 receptor (AT1R) is a promising therapeutic target for cardiovascular diseases. Compared with orthosteric ligands, allosteric modulators attract considerable attention for drug development due to their unique advantages of high selectivity and safety. However, no allosteric modulators of AT1R have been applied in clinical trials up to now. Except for the classical allosteric modulators of AT1R such as antibody, peptides and amino acids, cholesterol and biased allosteric modulators, there are non-classical allosteric modes including the ligand-independent allosteric mode, and allosteric mode of biased agonists and dimers. In addition, finding the allosteric pockets based on AT1R conformational change and interaction interface of dimers are the future of drug design. In this review, we summarize the different allosteric mode of AT1R, with a view to contribute to the development and utilization of drugs targeting AT1R allostery.


Lack of Association between IL-10 Gene Promoter Polymorphisms and Susceptible to Tuberculosis in Thai Patients.
Cytokines play a major role in defense against Mycobacterium tuberculosis infection. Polymorphisms in the genes encoding various cytokines have been associated with tuberculosis susceptibility. Polymorphisms of the regulatoy cytokine gene, the interleukin (IL)-10 is associated with the risk of tuberculosis (TB) in different populations. However IL-10 gene polymorphism and susceptibility to TB in Thai is still unknown. The purpose of this study was to evaluate whether the common IL-10 promoter gene polymorphisms are associated with TB in Thai population. Forty-eight patients with newly diagnosed pulmonary tuberculosis were studied. DNA samples were extracted from leukocytes and used to investigate -1087A/G -819C/T -252C/A (rs1800896, rs1800871, rs1800872) in IL-10 gene using restriction fragment length polymorphism (PCR-RFLP) methods. In this study, the genotype and allele frequencies of IL-10-1087A/G, -819C/T -252C/A polymorphism did not significantly different between TB patients and healthy controls ((genotype: p = 0.38, p = 0.92,p = 1; allele: p = 0.57, p = 0.77, p = 0.89, respectively). The lack of association between common IL-10 promoter polymorphisms and TB susceptibility in this study may provide clue for better understanding of IL-10-1087A/G -819C/T -252C/A polymorphism and TB susceptibility in Thai population, which might facilitate the rationale design of vaccines. However further studies in large scales population are required for confirmation.


The State of Clinical Trials in Pediatric Inflammatory Bowel Disease.
The gap between available biologic and small molecule therapy for inflammatory bowel disease for children and adults remains large. At present only 2 anti-TNF agents are licensed for pediatric use compared with multiple other agents with different mechanisms of action being used in adults. The reasons are many but largely revolve around the inadequate acceptance of adult efficacy data to children, and the reluctance of industry to commit to early pediatric drug development for fear of inadequate return on investment. We suggest common sense steps that need to be taken to improve this situation.


Purification and characterization of moderately thermostable raw-starch digesting α-amylase from endophytic Streptomyces mobaraensis DB13 associated with Costus speciosus.
Endophytic actinobacteria are known to produce various enzymes with potential industrial applications. Alpha-amylase is an important class of industrial enzyme with a multi-dimensional utility. The present experiment was designed to characterize a moderately thermostable α-amylase producing endophytic Streptomyces mobaraensis DB13 isolated from Costus speciosus (J. Koenig) Sm. The enzyme was purified using 60% ammonium sulphate precipitation, dialysis, and Sephadex G-100 column chromatography. Based on 12% SDS-PAGE, the molecular weight of the purified α-amylase was estimated to be 55 kDa. The maximum α-amylase activity was achieved at pH 7.0, 50°C and it retained 80% of its activity at both pH 7.0 and 8.0 after incubation for 2 h. The α-mylase activity is strongly enhanced by Ca2+, Mg2+, and inhibited by Ba2+. The activity remains stable in the presence of Tween-80, SDS, PMSF, and Triton X-100; however, β-mercaptoethanol, EDTA, and H2O2 reduced the activity. The kinetic parameters Km and Vmax values for this α-amylase were calculated as 2.53 mM and 29.42 U/mL respectively. The α-amylase had the ability to digest various raw starches at a concentration of 10 mg/mL at pH 7.0, 50°C, where maize and rice are the preferred substrates. The digestion starts after 4 h of incubation, which reaches maximum after 48 h of incubation. These results suggest that S. mobaraensis DB13 is a potential source of moderately thermostable α-amylase enzyme, that effciently hydrolyzes raw starch. It suggesting that this α-amylase is a promising candidate to be use for industrial purposes.


The superior ophthalmic vein and tumours of the sellar area.
The venous drainage dynamics of the cavernous sinus were studied by means of 50 carotid angiograms and 18 orbital phlebographies performed on 47 patients with various tumours of the sellar area. Normal blood flow direction in the superior ophthalmic vein (SOV) (from the facial veins into the cavernous sinus) was seen in supra- and small intrasellar tumours, but not in parasellar tumours. In bigger intrasellar tumours and in parasellar tumours the reversed blood flow direction visible in the SOV (from the cavernous sinus into the facial veins) indicated infiltration or compression of the cavernous sinus by tumour. The sign of reversed flow together with CT findings is useful in differential diagnosis and in planning surgical treatment for tumours of the sellar area.


New approach for reduction of diesel consumption by comparing different mining haulage configurations.
The mining operations of loading and haulage have an energy source that is highly dependent on fossil fuels. In mining companies that select trucks for haulage, this input is the main component of mining costs. How can the impact of the operational aspects on the diesel consumption of haulage operations in surface mines be assessed? There are many studies relating the consumption of fuel trucks to several variables, but a methodology that prioritizes higher-impact variables under each specific condition is not available. Generic models may not apply to all operational settings presented in the mining industry. This study aims to create a method of analysis, identification, and prioritization of variables related to fuel consumption of haul trucks in open pit mines. For this purpose, statistical analysis techniques and mathematical modelling tools using multiple linear regressions will be applied. The model is shown to be suitable because the results generate a good description of the fuel consumption behaviour. In the practical application of the method, the reduction of diesel consumption reached 10%. The implementation requires no large-scale investments or very long deadlines and can be applied to mining haulage operations in other settings.


The Role of Cardiac PET in Diagnosis and Prognosis of Ischemic Heart Disease: Optimal Modality Across Different Patient Populations.
Despite single-photon emission computerized tomography (SPECT) being the most used nuclear imaging technique for diagnosis of coronary artery disease (CAD), many now consider positron emission tomography (PET) as a superior modality. This review will focus on the advances of cardiac PET in recent years and its advantages compared to SPECT in diagnosis and prognosis of CAD. PET's higher resolution and enhanced diagnostic accuracy, as well as lower radiation exposure, all help explain the rationale for its wider spread and use. PET also allows for measurement of myocardial blood flow (MBF) and myocardial flow reserve (MFR), which aids in several different clinical scenarios, such as diagnosing multivessel disease or identifying non-responders. PET has also been shown to be useful in diagnosing CAD in various specific populations, such as patients with prior COVID-19 infection, cardiac transplant, and other comorbidities.


Next-Generation Sequencing as an Auxiliary Tool in Pediatric Laryngeal Lymphoma Diagnosis.
Lymphomatous involvement of the larynx is a rare entity. We present a case of atypical laryngotracheitis as the initial manifestation of non-Hodgkin's lymphoma in a pediatric patient. The diagnosis was aided through the use of microbial cell-free DNA (mcfDNA) testing, which detected the presence of Epstein-Barr virus in the patient's plasma. This enabled the consideration of an Epstein-Barr virus-related lymphoproliferative process, leading to additional workup and the final diagnosis of lymphoma. To our knowledge, this is the first case of mcfDNA testing leading not simply to an infectious organism, but further to a new oncologic diagnosis. Plasma mcfDNA testing has the potential to inform clinical practice beyond classic infectious disease manifestations. In this article, we review both the possible future applications and the areas of further investigation that remain.


Use of autofluorescence and fluorescent probes as a potential diagnostic tool for oral cancer: A systematic review.
The prognosis of patients with Oral squamous cell carcinoma (OSCC) are directly related to the stage of development of the tumor at the time of diagnosis, but it is estimated an average delay in diagnosis of 2-5 months. New non-invasive techniques for the early diagnosis of OSCC are being developed, such as methodologies to detect spectral changes of tumor cells. We conducted a systematic review to analyze the potential use of autofluorescence and/or fluorescent probes for OSCC diagnosis. Four databases (PubMed, Scopus, Embase and Web of Science) were used as research sources. Protocol was registered with PROSPERO. It was included studies that evaluated tissue autofluorescence and/or used fluorescent probes as a method of diagnosing and/or treatment of oral cancer in humans. Forty-five studies were selected for this systematic review, of which 28 dealt only with autofluorescence, 18 on fluorescent probes and 1 evaluated both methods. The VELscope® was the most used device for autofluorescence, exhibiting sensitivity (33%-100%) and specificity (12%-88.6%). 5-Aminolevulinic acid (5-ALA) was the most used fluorescent probe, exhibiting high sensitivity (90%-100%) and specificity (51.3%-96%). Hypericin, rhodamine 6 G, rhodamine 610, porphyrin and γ-glutamyl hydroxymethyl rhodamine green have also been reported. Thus, the autofluorescence and fluorescent probes can provide an accurate diagnosis of oral cancer, assisting the dentist during daily clinical activity, but it is not yet possible to suggest that this method may replace histopathological examination.


Characterization of the key odorants and their content variation in Niulanshan Baijiu with different storage years using flavor sensory omics analysis.
Niulanshan Baijiu (NLS) is a light-flavor Baijiu (LFB) with a long history. The aroma-active compounds in six NLSs with different storage years were analyzed using gas chromatography-olfactometry-mass spectrometry (GC-O-MS), coupled with Osme and aroma extraction dilution analysis (AEDA). A total of 59 odorants were identified, 5 odorants of them were, for the first time, identified as aroma-active compounds of LFB. After quantifying and calculating their odorant activity values (OAVs), 34 compounds had OAVs > 1, and the recombination and omission experiments further confirmed that ethyl acetate, ethyl acrylate, ethyl 2-methylbutyrate, γ-nonalactone, ethyl isovalerate, ethyl butyrate, isoamyl acetate, ethyl caprylate, ethyl valerate, 3-methylbutanal, β-damascenone, and geosmin have important contributions to the aroma of NLS. One-way ANOVA analysis further found that the contents of key odorants in NLS stored for four to five years were relatively stable. This study provides an important reference for product quality control in NLS.


Regions upstream from the core promoter of the rat ribosomal gene are required for the formation of a stable transcription initiation complex by RNA polymerase I in vitro.
The sites required for the formation of a stable transcription initiation complex and for the initiation of transcription of rat rDNA in vitro were examined. A series of 5' deletion mutants of the rat transcription initiation region (-167 through +638) were constructed. These mutants were examined for their ability to support the faithful initiation of transcription in vitro. Mutants which contain less than 31 nucleotides upstream of the initiation site (+1) were unable to support detectable initiation of transcription. In this transcription system a series of deletion mutants from -167 to -31 were transcribed with equal efficiency when assayed individually. On the other hand, when the wild-type and mutant templates were compared in order-of-addition assays, they were found to be unequal. The incubation of an extract with a wild-type template, prior to the addition of nucleotides, precluded transcription of any second template added after the preincubation step. However, the preincubation of extract with mutants of the region upstream of the core promoter, from -122 to -31, did not preclude transcription of a wild-type template added after the preincubation step. Formation of the stable preinitiation complex was found to require the region between and -167.


Vanadium accelerates polymerase chain reaction and expands the applicability of forensic DNA testing.
Polymerase chain reaction (PCR) has been rapidly established as one of the most widely used techniques in molecular biology. Because most DNA analysis is PCR-based, the analysis of unamplifiable DNA of poor quality or low quantity is nearly impossible. However, we observed that if an appropriate concentration of vanadium chloride is added to the standard reaction mixture, the enzymatic amplification of DNA could be enhanced. Using multiplex PCR with the addition of vanadium, DNA typing was possible from even trace amounts of DNA that we were unable to amplify using normal reaction conditions. This method might be an effective tool for not only criminal investigations and ancient DNA analysis, but also for nearly all fields using DNA technology.


Neonatal gastric perforation: report of 15 cases and review of the literature.
Gastric perforation among neonates is a rare but frequently fatal condition of uncertain etiology. The aim of this study was to review the clinical course of neonatal gastric perforation and to evaluate possible prognostic factors. We retrospectively analyzed the medical records of 15 patients with neonatal gastric perforation over a 19-year period. Another 97 patients described in the medical literature, for whom the gestational ages and birth weights were clearly stated, were also reviewed. In our series, there were three girls and 12 boys, nine of whom were full-term infants and six preterm infants. The most common initial manifestations were poor activity, abdominal distension, and respiratory distress. The overall mortality was 47% (7/15). Prematurity was the only statistically significant risk factor; 83% (5/6) of premature infants died compared with 22% (2/9) of term babies (p < 0.05). Combining our series with the patients reported in the literature, there were a total of 50 premature infants and 62 term infants. Gastric perforation occurred on postnatal days 2-7 and presented with nonspecific manifestations. The mortality was significantly higher in premature than in term infants (31/50, 62% vs. 16/62, 26%; p < 0.001). A trend towards higher mortality in infants with lower birth weights was observed (>2500 g, 28%; 1501-2500 g, 52%; 1000-1500 g, 60%; <1000 g, 100%). Infants with birth weights <2500 g had a significantly higher mortality than infants with birth weights >2500 g (32/58, 55% vs. 15/54, 28%; p<0.05). Neonatal gastric perforation is associated with high mortality, particularly in premature infants. There is also a trend towards higher mortality in lower-birth-weight infants.


The effects of cholinergic blockade on the growth hormone and prolactin response to insulin hypoglycaemia.
The effect of cholinergic blockade on growth hormone (GH) and prolactin (PRL) secretion during insulin-induced hypoglycaemia was assessed in six normal male volunteers (mean age 23, age range 21-25). Each subject underwent two insulin tolerance tests with and without atropine. GH responses were significantly lower 45 min after insulin administration with atropine (17.5 +/- 2.5 mU/l (mean +/- SEM) than with placebo (37.6 +/- 3.6 mU/l, P less than 0.0006). In contrast PRL responses were higher (P less than 0.01) at 45 and 90 min after insulin during treatment with atropine. These data demonstrate that cholinergic mechanisms are involved in stimulatory and inhibitory pathways in the medication of the respective GH and PRL responses to insulin induced hypoglycaemia in man.


Left main bronchial-esophageal fistula: a complication of bronchial artery embolization.
Left bronchial-esophageal fistula is a rare complication of bronchial artery embolization. A case is presented with pathologic correlation. The pathophysiology of this complication is discussed as well as recommendations on how it may possibly be avoided.


Neural circuit mechanisms linking courtship and reward in Drosophila males.
Courtship has evolved to achieve reproductive success in animal species. However, whether courtship itself has a positive value remains unclear. In the present work, we report that courtship is innately rewarding and can induce the expression of appetitive short-term memory (STM) and long-term memory (LTM) in Drosophila melanogaster males. Activation of male-specific P1 neurons is sufficient to mimic courtship-induced preference and memory performance. Surprisingly, P1 neurons functionally connect to a large proportion of dopaminergic neurons (DANs) in the protocerebral anterior medial (PAM) cluster. The acquisition of STM and LTM depends on two distinct subsets of PAM DANs that convey the courtship-reward signal to the restricted regions of the mushroom body (MB) γ and α/β lobes through two dopamine receptors, D1-like Dop1R1 and D2-like Dop2R. Furthermore, the retrieval of STM stored in the MB α'/β' lobes and LTM stored in the MB α/β lobe relies on two distinct MB output neurons. Finally, LTM consolidation requires two subsets of PAM DANs projecting to the MB α/β lobe and corresponding MB output neurons. Taken together, our findings demonstrate that courtship is a potent rewarding stimulus and reveal the underlying neural circuit mechanisms linking courtship and reward in Drosophila males.


Solar UV Exposure and Mortality from Skin Tumors: An Update.
Solar UV exposure is critical and complex in the etiology and prognosis of skin cancer, particularly cutaneous malignant melanoma. Sun exposure and one of its "derivatives," vitamin D, have been implicated in protection against mortality from melanoma. However, the relationships are inconsistent. At this time, it is not possible to make clear recommendations for or against sun exposure in relationship to melanoma prognosis. However, this relationship deserves continued exploration.


Percutaneous saphenous vein graft intervention with sequential embolic protection devices: complementing lesion anatomy with embolic protection device.
Saphenous vein graft (SVG) percutaneous coronary intervention (PCI) carries unique technical challenges requiring the utilization of embolic protection devices (EPDs) to reduce the adverse events associated with distal embolization. Distal embolization is a common and almost ubiquitous consequence of SVG PCI due to the soft and friable nature of the SVG lesions. We describe a case of revascularizing a SVG with tandem stenoses employing the use of two different EPDs that complemented their respective lesion's location within the SVG.


Intratumor heterogeneity in colorectal cancer: Distribution of tumor suppressor gene variants with regard to patient lymph node status.
Intratumor heterogeneity (ITH) results from accumulation of somatic mutations in the fractions of successive cancer cell generations. We aimed to use deep sequencing to investigate ITH in colorectal tumors with particular emphasis on variants in oncogenes (ONC) and tumor suppressor genes (TSG). Samples were collected from 16 patients with colorectal cancer and negative or positive lymph node status (n = 8 each). We deep-sequenced a panel of 56 cancer-related genes in the central and peripheral locations of T3 size primary tumors and healthy mucosa. The central region of T3 tumors has a different frequency profile and composition of genetic variants. This mutation profile is capable of independently discriminating patients with different lymph node status (p = 0.028) in the central region. We noted an increasing number of mutations outside of the central region of the tumor and a higher number of mutations in tumors from node-positive patients. Unexpectedly, in the healthy mucosa, we identified somatic mutations with variant allele frequencies, characteristic not only of heterozygotes and homozygotes but also of other discrete peaks (e.g., around 10%, 20%), suggestive of clonal expansion of certain mutant alleles. We found differences in the distribution of variant allele frequencies in TSGs when comparing node-negative and node-positive tumors (p = 0.029), as well as central and peripheral regions (p = 0.00399). TSGs may play an important role in the escape of the tumor toward metastatic colonization.


Synaptic loss and retention of different classic cadherins with LTP-associated synaptic structural remodeling in vivo.
Cadherins are synaptic cell adhesion molecules that contribute to persistently enhanced synaptic strength characteristic of long-term potentiation (LTP). What is relatively unexplored is how synaptic activity of the kind that induces LTP-associated remodeling of synapse structure affects localization of cadherins, particularly in mature animals in vivo, details which could offer insight into how different cadherins contribute to synaptic plasticity. Here, we use a well-described in vivo LTP induction protocol that produces robust synaptic morphological remodeling in dentate gyrus of adult rats in combination with confocal and immunogold electron microscopy to localize cadherin-8 and N-cadherin at remodeled synapses. We find that the density and size of cadherin-8 puncta are significantly diminished in the potentiated middle molecular layer (MML) while concurrently, N-cadherin remains tightly clustered at remodeled synapses. These changes are specific to the potentiated MML, and occur without any change in density or size of synaptophysin puncta. Thus, the loss of cadherin-8 probably represents selective removal from synapses rather than overall loss of synaptic junctions. Together, these findings suggest that activity-regulated loss and retention of different synaptic cadherins could contribute to dual demands of both flexibility and stability in synapse structure that may be important for synaptic morphological remodeling that accompanies long-lasting plasticity.


Immunochemical studies on Shigella dysenteriae type 10 bacterial polysaccharide.
On graded hydrolysis and Smith degradation, the O-somatic polysaccharide isolated from Shigella dysenteriae type 10 bacteria yielded four oligosaccharides which were characterized by methylation studies. Immunochemical studies using constituent monosaccharides and the oligosaccharides indicated that the sugar grouping leads to 3)-ManNAc-(1 leads to 3)-Rha-(1 leads to 4)-GlcNAc-(1 leads to was the immunodominant part in the polysaccharide molecule, and that 2-acetamido-2-deoxy-D-mannose contributed maximally to the immunological specificity of the macromolecule.


Incidence of Strabismus and Amblyopia Among Children Initially Diagnosed With Pseudostrabismus Using the Optum Data Set.
To determine the frequency of strabismus among children initially diagnosed with pseudostrabismus using big data. Population-based retrospective cohort study. Setting: Population-based retrospective cohort study using claims data. StudyPopulation: 17,885 children diagnosed with pseudostrabismus at age ≤3 years who were later diagnosed with strabismus using the Optum deidentified Clinformatics Data Mart Database (2003-2016). We excluded patients diagnosed with strabismus before the diagnosis of pseudostrabismus or diagnosed simultaneously with strabismus and pseudostrabismus. We assessed age, refractive error, and presence of amblyopia. Patients with pseudostrabismus were compared to a group of patients from the Optum data set diagnosed with esotropia, exotropia, and unspecified heterotropia who had not been previously diagnosed with pseudostrabismus. MainOutcomeMeasures: Incidence of strabismus, among patients initially diagnosed with pseudostrabismus vs those without an initial diagnosis of pseudostrabismus. Strabismus was diagnosed in 9.6% (n = 1,725) of children initially diagnosed with pseudostrabismus at a median age of 1.65 years (IQR: 1.17-2.46) compared to 1.7% (136,047 of 7,787,743) of children in the control group (P < .001). Strabismus was diagnosed more than a year later in the pseudostrabismus group (3.32 years; IQR: 2.28-4.74) compared with the control group (2.28 years, IQR: 1.43-3.16) (P < .001). Esotropia was the most common type of strabismus in both groups (pseudostrabismus, 69.7%; control, 62.1%). A total of 377 children (21.9%) in the pseudostrabismus group underwent strabismus surgery compared with 12.1% of children in the control group (P < .001). Young children diagnosed with pseudostrabismus are at increased risk of developing strabismus and undergoing strabismus surgery.


MEOX2 Regulates the Growth and Survival of Glioblastoma Stem Cells by Modulating Genes of the Glycolytic Pathway and Response to Hypoxia.
The most widely accepted hypothesis for the development of glioblastoma suggests that glioblastoma stem-like cells (GSCs) are crucially involved in tumor initiation and recurrence as well as in the occurrence of chemo- and radio-resistance. Mesenchyme homeobox 2 (MEOX2) is a transcription factor overexpressed in glioblastoma, whose expression is negatively correlated with patient survival. Starting from our observation that MEOX2 expression is strongly enhanced in six GSC lines, we performed shRNA-mediated knock-down experiments in two different GSC lines and found that MEOX2 depletion resulted in the inhibition of cell growth and sphere-forming ability and an increase in apoptotic cell death. By a deep transcriptome analysis, we identified a core group of genes modulated in response to MEOX2 knock-down. Among these genes, the repressed ones are largely enriched in genes involved in the hypoxic response and glycolytic pathway, two strictly related pathways that contribute to the resistance of high-grade gliomas to therapies. An in silico study of the regulatory regions of genes differentially expressed by MEOX2 knock-down revealed that they mainly consisted of GC-rich regions enriched for Sp1 and Klf4 binding motifs, two main regulators of metabolism in glioblastoma. Our results show, for the first time, the involvement of MEOX2 in the regulation of genes of GSC metabolism, which is essential for the survival and growth of these cells.


Genes offering the potential for designing yield-related traits in rice.
Breeding of high-yielding rice is crucial for meeting the food demand of the increasing world population. New technologies have facilitated identification of genes involved in quantitative traits, and many genes underpinning quantitative trait loci involved in rice crop yield have been isolated. Meanwhile, various kinds of mutants have been intensively studied, leading to characterization of many genes related to yield traits. A combination of quantitative trait locus analysis and studies of such mutants has made it possible to compile a list of genes available for breeding rice with higher yield.


The neural and hormonal bases of human parental care.
As parents in modern western societies face increasing pressures that strain their ability to provide quality childcare, it is important to consider the neural and hormonal bases of sensitive and nurturing parenting. The topic has been explored systematically in non-human animals, and these studies have yielded a rich source of hypotheses for human studies. Considerable evidence links oxytocin (OT) with sensitive caregiving in both men and women, and with stimulatory infant contact in men and affectionate infant contact in women. Testosterone, on the other hand, decreases in men who become involved fathers, and testosterone may interfere with aspects of paternal care. In neuroimaging studies, exposing parents to child stimuli activates neural systems involved in understanding others' facial expressions (the putative mirror neuron system), others' feelings (anterior insula and thalamocingulate regions) and others' thoughts (dorsomedial prefrontal cortex), as well as reward systems involved in approach-related motivation (ventral tegmental area, substantia nigra, ventral striatum and medial orbitofrontal cortex), and systems involved with emotion regulation (lateral prefrontal cortex). There is some evidence that this activity can be attenuated in mothers who do not breastfeed, and mothers with post-partum depression, perhaps due in part to lower levels of OT exposure. On the other hand, there is evidence suggesting that high levels of oxytocin (OT) may enhance activation in some of these systems. For example, OT may stimulate dopamine release in the ventral striatum, rendering child stimuli more rewarding. A few recent studies have gone beyond merely describing neural correlates to establishing the functional significance of activation patterns by linking them with observed maternal behavior outside the scanner. The results of these studies suggest that there may be an optimal range of activation within certain neural systems, neither too high nor too low, that supports appropriate parenting. There is also mounting evidence that the very structure of the human brain is altered by the cognitive challenges inherent in learning how to parent. Given that human mothers typically receive help with childrearing, it will be important to begin studying the neural and hormonal bases of alloparental care, with a particular emphasis on fathers due to their increasing involvement in childcare in modern western societies.


Determination of pyraclostrobin dynamic residual distribution in tilapia tissues by UPLC-MS/MS under acute toxicity conditions.
As a lipophilic fungicide, pyraclostrobin is highly toxic to aquatic organisms, especially to fish. In recent years, research has mainly focused on the pyraclostrobin residue in fish tissues under chronic toxicity, but less is known about its distribution in fish tissues under acute toxicity conditions. In this study, the distribution of pyraclostrobin in fish tissues (blood, liver, muscle and gill) was determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The purification effects of different purification materials [1) mixtures of PSA, C18 and MgSO4; 2) QuEChERS-PC; and 3) Oasis HLB SPE] were compared for the detection of pyraclostrobin in fish tissues. Finally, the quick and easy clean-up tool of the Oasis HLB SPE procedure was selected. Under optimum conditions, the linearities had a good relationship (determination coefficient R2 > 0.999). The mean recoveries of the analyte for all tested concentrations ranged from 86.94% to 108.81% with RSDs of 0.7%-4.9%. The pyraclostrobin residue amount was much different in fish tissues. Furthermore, the pyraclostrobin residue in different fish tissues increased initially and then decreased gradually. The concentrations in each tissue were initially ranked before 120 min in the following order: gill > liver > blood > muscle. These phenomena may be attributed to the stress response of fish under acute poisoning. This is the first study to document the distribution of pyraclostrobin in fish tissues under acute toxicity conditions, and it provides reference for the management of agrochemicals in terms of aquatic ecological risks.


Addition of Novel Biomarkers for Predicting All-Cause and Cardiovascular Mortality in Prevalent Hemodialysis Patients.
Novel biomarkers might improve the prediction of mortality in hemodialysis (HD) patients. We simultaneously measured the levels of conventional and novel biomarkers [serum N-terminal pro-brain natriuretic peptide (NT-proBNP), intact fibroblast growth factor-23 (FGF23), β2-microglobulin (β2MG), cystatin C, and high-sensitivity C-reactive protein (hsCRP)] in 307 prevalent Japanese HD patients. There were 66 all-cause deaths, and 25 cardiovascular (CV) deaths during 2 years, which were assessed using Cox models and concordance (C)-statistics. The addition of NT-proBNP alone (P < 0.05) or NT-proBNP, hsCRP, and β2MG as a panel (C-statistics: 0.834 vs. 0.776, P < 0.01) to a conventional risk model composed of age, diabetes, and the serum albumin level significantly improved the prediction of 2-year all-cause mortality, and the addition of NT-proBNP and hsCRP as a panel to a conventional risk model composed of age significantly improved the prediction of 2-year CV mortality (P < 0.05) in Japanese prevalent HD patients. Neither FGF23 nor cystatin C improved mortality prediction.


Second primary malignancy after Hodgkin's disease, ovarian cancer and cancer of the testis: a population-based cohort study.
The risk of second primary malignancy was assessed in a population-based cohort study of all persons registered with Hodgkin's disease (n = 2,970), ovarian cancer (n = 11,802) and testicular cancer (n = 2,013) in the South Thames Cancer Registry during the period 1961-80, to identify for further study those second malignancies which might be treatment-related. A total of 244 second malignancies was observed. After adjustment for age, sex and calendar period, the relative risk of any second malignancy was 1.4 (90% confidence interval (CI) 1.1-1.7) after Hodgkin's disease, 1.1 (90% CI 1.0-1.2) after ovarian cancer and 0.7 (90% CI 0.5-1.0) after testicular cancer. In particular, the relative risk for leukaemia was 11.9 after Hodgkin's disease, 3.7 after ovarian cancer and 2.5 after testicular cancer. Excess risks were also observed for cancers of the cervix and lung after Hodgkin's disease, for cancers of the breast, lung and rectum after ovarian cancer, and for contralateral testicular cancer. Confounding by social class or smoking does not explain these observations. The excess risks of leukaemia and of second cancer were higher in patients first diagnosed with Hodgkin's disease and ovarian cancer in the 1970s than for those first diagnosed in the 1960s. Increased use of multiple-agent chemotherapy regimes for these tumours in the 1970s may have contributed to these increases in excess risk.


The ductus and the coarctation.
After Robert E. Gross' historic ligation of a persistent ductus arteriosus in August 1938, it took 6 years before the first coarctation was operated on. Gross initiated experimental procedures directed at repair of coarctation even before the ductal operation had been performed. He had the desire, the drive, and the determination. Why the delay that allowed Clarence Crafoord to perform the first coarctation repair in October 1944?


Monoclonal antibodies derived during graft-versus-host reaction. II. Antibodies detect unique determinants common to many MCF viruses.
Hybridoma cell lines were recovered from the spleens of 6-week-old (B6 X D2)F1 mice undergoing graft-versus-host reaction induced by the transfer of 5-week-old B6 parental spleen cells. These cell lines produced antibodies reactive with envelope polypeptides of a variety of MuLV. The viral specificity assessed by membrane immunofluorescence and virus-binding radioimmunoassay indicated that the reactivity of these antibodies was distinctly different from monoclonal antibodies recovered from (B6 X D2)F1 recipients of D2 spleen cells reported previously (Portis et al., Virology 118, 181-190, 1982). Ten out of 17 monoclonal antibodies in the current study reacted exclusively with MCF viruses and three of these antibodies detected envelope determinants which were shared by a broad panel of MCF viruses of diverse origin. These common MCF determinants were expressed by the gp70 molecule as determined by Western blot analysis. The production of these antibodies by young mice in the absence of exogenous virus inoculation suggests that these antigens may be encoded by endogenous MCF-like sequences.


Comparison of the clinical efficacy of standard and mucoadhesive-based nasal decongestants.
To compare two xylometazoline 0.1% preparations: reference commercial solution (RS) and test mucoadhesive solution (TS). Twenty subjects with perennial allergic rhinitis (age range 18-69 years, 5 atopic, 7 men) applied randomly in turn TS and RS for 5 days in a double-blind crossover clinical trial. Nasal airflow resistance (NAR), nasal symptoms (6 grade scoring), frequency of application (times/day), and side-effects were recorded. Mean ratio TS/RS of areas under the resistance/time curves for NAR +/- 90% CI: 3.56 +/- 0.92; mean TS-RS differences +/- 95% CI: for congestion: -1.12 +/- 0.59, for frequency of application: -1.10 +/- 0.20. Subjects experienced fewer side-effects with TS. A mucoadhesive solution with a decongestant had a greater and longer lasting effect on nasal congestion in subjects with perennial allergic rhinitis than the commercially available decongestant solution. It also caused fewer side effects.


Singlet oxygen induces frank strand breaks as well as alkali- and piperidine-labile sites in supercoiled plasmid DNA.
A covalently closed, circular, supercoiled plasmid was exposed to singlet oxygen by a separated-surface sensitizer. For each exposure, the quantity of single oxygen entering the DNA target solution was estimated by its oxidation of histidine. After singlet oxygen exposure, some DNA samples were treated to disclose occult lesions. Agarose gel electrophoresis was then used to resolve the unrelaxed supercoils from the relaxed circular and linear species, and all bands were quantitated fluorometrically. Exposure of supercoiled plasmid DNA to singlet oxygen induced frank DNA strand breaks, alkali-labile sites (pH 12.5, 90 degrees C, 30 min), and piperidine-labile sites (0.4 M, 60 degrees C, 30 min), all in a dose-dependent manner. Yields of alkali-labile and piperidine-labile sites ranged from one to four times the frank strand break yield. Replacement of buffered H2O by buffered D2O as the DNA solvent for singlet oxygen exposures increased DNA lesion yields by a factor of 2.6 (averaged over lesion classes). Our data for the detection of frank strand breaks is at variance with published results from studies in which singlet oxygen was derived from a thermolabile endoperoxide dissolved in the DNA solution.


Titania-coated fibrous silica (TiO2/KCC-1) core-shell microspheres based solid-phase extraction in clam (Corbicula fluminea) using hydrophilic interaction liquid chromatography and mass spectrometry.
Clam (Corbicula fluminea) contains significant amount of phospholipids, and the profile of phospholipids could be used as an index for nutrition evaluation. In this study, a titania-coated fibrous silica (TiO2/KCC-1) core-shell microsphere based solid-phase extraction (SPE) and hydrophilic interaction liquid chromatography mass spectrometry (HILIC-MS) method was developed to study the phospholipids in clam. The structure and morphology of TiO2/KCC-1 were characterized by transmission electron microscopy (TEM), scanning electron microscope (SEM), X-ray diffraction (XRD), and ultraviolet-visible diffuse reflectance spectroscopy (UV-vis DRS). The analytical results indicated that the phospholipid molecular species (PMS) could be extracted in a cleaner manner after TiO2/KCC-1 SPE, benefiting from the enhanced signals and decreased MS noise of phospholipids. Based on the principal component analysis (PCA) and partial least squares regression discriminant analysis (PLS-DA) models, the PMS with the most obvious beneficiaries of TiO2/KCC-1 SPE were identified, e.g. PC 16:0/20:5 (m/z 824.6), PC 16:0/22:6 (m/z 850.6), PE 18:1/18:2 (m/z 740.4), and PE 18:0/22:6 (m/z 790.5). Finally, the proposed method was validated to be sensitive and precise. This study provides an efficient tool to analyze the phospholipids in clam and the prospect to use this method for future applications in various samples.


Antibody levels to Malassezia pachydermatis and Staphylococcus pseudintermedius in atopic dogs and their relationship with lesion scores.
Elevated immunoglobulin E (IgE) levels to Malassezia or Staphylococcus species in human atopic dermatitis are related to the skin severity index; a similar association has not been reported in atopic dogs. To investigate serum levels of allergen-specific IgE, total specific IgG and IgG subclasses (IgG1 and IgG2) for M. pachydermatis and S. pseudintermedius, and to correlate them with the severity of dermatitis in dogs. Serum samples were collected from dogs categorized by age and disease status. Groups 1 and 2: <3-year-old healthy (n = 9) and atopic dogs (n = 9), respectively; and groups 3 and 4: ≥3-year-old healthy (n = 11) and atopic dogs (n = 14), respectively. Antibody levels were measured by ELISA. The Canine Atopic Dermatitis Lesion Index (CADLI) was analyzed in relation to antibody levels. Specific IgE and total IgG against M. pachydermatis and S. pseudintermedius were significantly increased in atopic dogs of all ages. Although differences between atopic and healthy dogs, with regard to specific IgG1 and IgG2 levels to each microbe, varied in significance within age groups. No significant relationships were found between the CADLI and any specific immunoglobulin levels for both microbe types. In dog skin, microbes may act as allergens triggering inflammatory responses via IgE- and IgG-dependent pathway(s). The affinity of the IgG subclass produced may vary according to antigen type. Specific IgE levels may be related to clinical disease in dogs and not to skin lesion severity.


Common feature learning for brain tumor MRI synthesis by context-aware generative adversarial network.
Multi-modal structural Magnetic Resonance Image (MRI) provides complementary information and has been used widely for diagnosis and treatment planning of gliomas. While machine learning is popularly adopted to process and analyze MRI images, most existing tools are based on complete sets of multi-modality images that are costly and sometimes impossible to acquire in real clinical scenarios. In this work, we address the challenge of multi-modality glioma MRI synthesis often with incomplete MRI modalities. We propose 3D Common-feature learning-based Context-aware Generative Adversarial Network (CoCa-GAN) for this purpose. In particular, our proposed CoCa-GAN method adopts the encoder-decoder architecture to map the input modalities into a common feature space by the encoder, from which (1) the missing target modality(-ies) can be synthesized by the decoder, and also (2) the jointly conducted segmentation of the gliomas can help the synthesis task to better focus on the tumor regions. The synthesis and segmentation tasks share the same common feature space, while multi-task learning boosts both their performances. In particular, for the encoder to derive the common feature space, we propose and validate two different models, i.e., (1) early-fusion CoCa-GAN (eCoCa-GAN) and (2) intermediate-fusion CoCa-GAN (iCoCa-GAN). The experimental results demonstrate that the proposed iCoCa-GAN outperforms other state-of-the-art methods in synthesis of missing image modalities. Moreover, our method is flexible to handle the arbitrary combination of input/output image modalities, which makes it feasible to process brain tumor MRI data in real clinical circumstances.


Expression of caveolar components in primary desminopathy.
Myofibrillar myopathies (MFM) involve accumulation of various proteins in the muscle cytoplasm. In myopathy with a heterozygous A337P mutation of the desmin gene, electron-micrographs showed aggregates of vesicular and tubular structures. Positive cytoplasmic reaction for caveolin-3 immunohistochemistry and cholera toxin B binding suggested that caveolae comprised some of the aggregates. As caveolae occur in the Golgi complex and are transported to the cell surface, the results suggest inhibition of their trafficking to the sarcolemma. Alternatively, they could be trapped during internalization. We hypothesize that the accumulation of multiple proteins in MFM could be partially due to inhibited intracellular trafficking.


[Not Available].
A sensitive and selective method using high-performance liquid chromatography in combination with atmospheric pressure chemical ionization tandem mass spetrometry (LC-APCI-MS/MS) has been developed for the determination of Deoxynivalenol (DON) in trace levels. The extract was purified with a MultiSep™ column followed by the Vicam™ DON immunoaffinity column. Quantification is based on an external standard method using positive Multiple Reaction Monitoring (MRM). The limit of detection was 5 μg/kg with a signal to noise ratio of 3:1.


Removing a well-fixed femoral sleeve during revision total knee arthroplasty.
The following surgical technique describes a case of a 51-year-old man with severe juvenile rheumatoid arthritis that required a 2-stage revision of an infected revision total knee implant. The patient had previously been implanted with a revision rotating platform, constrained condylar device which gained excellent fixation through the use of diaphyseal-engaging stems, and a well-ingrown, fully porous-coated femoral metaphyseal sleeve. To avoid intraoperative complications while removing the femoral sleeve, a novel technique for femoral sleeve extraction was used. Using this technique, the femoral sleeve was successfully removed without intraoperative fracture or substantial bone loss.


An a posteriori method based on photo-acoustic cell information to correct for lidar transmitter spectral shift: application to atmospheric CO(2) differential absorption lidar measurements.
An a posteriori corrective method based on photo-acoustic cell (PAC) information is proposed to correct for laser transmitter spectral shift during atmospheric CO(2) measurements by 2 microm heterodyne differential absorption lidar (HDIAL) technique. The method for using the PAC signal to retrieve the actual atmospheric CO(2) absorption is presented in detail. This issue is tackled using a weighting function. The performance of the proposed corrective method is discussed and the various sources of error associated with the PAC signal are investigated. For 300 shots averaged and a frequency shift (from the CO(2) absorption line center) lower than the CO(2) absorption line half-width, the relative error on HDIAL CO(2) mixing ratio measurements is lower than 1.3%. The corrective method is validated in absolute value by comparison between HDIAL and in situ sensor measurements of CO(2).


Sutureless closure of the renal wound surface by extracorporeal renal surgery on dogs.
The authors have elaborated a sutureless method of closing the wound surface in order to preserve the renal parenchyma. They have used oxydized cellulose net (Surgicel) and tissue adhesive (Histoacryl-N-blau) to hold together the cut surface of the kidney at renal hypothermy (bench surgery) on dogs.


A new spider of the genus Scotinella Banks, 1911 (Araneae: Phrurolithidae) from Mexico and new combinations in Phrurolithidae.
A new phrurolithid species, Scotinella elpotosi sp. nov., is described from San Luis Potos, Mexico. Males of this new species are characterized by the long and filiform embolus, and females by the W-shaped copulatory ducts. Additionally, based on delimitation of the genus Phrurolithus C. L. Koch, 1839 made by previous authors, we propose the transfer of all Mexican Phrurolithus to Scotinella Banks, 1911: S. adjacens (Gertsch Davis, 1940) comb. nov., S. approximatus (Gertsch Davis, 1940) comb. nov., S. coahuilanus (Gertsch Davis, 1940) comb. nov., S. debilis (Gertsch Davis, 1940) comb. nov., S. diversus (Gertsch Davis, 1940) comb. nov., S. tamaulipanus (Gertsch Davis, 1940) comb. nov., and S. tepejicanus (Gertsch Davis, 1940) comb. nov.


Ellipsoid Zone Mapping Parameters In Retinal Venous Occlusive Disease With Associated Macular Edema.
To evaluate the association of baseline ellipsoid zone (EZ) parameters on optical coherence tomography (OCT) as calculated by a semi-automated computer algorithm with baseline visual acuity in eyes with retinal vein occlusion (RVO). Retrospective consecutive case series. Patients affected by RVO presenting from January 2011 to December 2014. Baseline demographics, clinical characteristics, and SD-OCT data at presentation were collected. Macular cube scans were exported into a retinal layer analysis software platform and outer retinal parameters were evaluated. Outer retinal/EZ parameters included EZ-retinal pigment epithelium (RPE) volume, central foveal EZ-RPE area, EZ-RPE central subfield thickness (CST), and EZ-RPE central foveal thickness (CFT). In addition, en face EZ mapping features were extracted including percent area with EZ attenuation (i.e., EZ-RPE thickness < 20 μm) and percent area with total EZ loss (i.e., EZ-RPE thickness = 0 μm). Correlation of EZ parameters and baseline visual acuity (VA). Secondary outcome measures: Correlation of EZ parameters with other clinical characteristics and OCT measures of cube volume, cube average thickness, central subfield thickness. One hundred and twelve eyes were included in this analysis. Mean baseline VA was 56.53 ±17.68 ETDRS letters and was inversely associated with total EZ loss and EZ-RPE attenuation (r= - 0.33 and -0.38 respectively, p<0.001). VA was directly associated with all other EZ parameters (r=0.37 to 0.45, p<0.001). The presence of subretinal fluid was strongly linked to central parameters of central foveal EZ-RPE, EZ-RPE-CST, and EZ-RPE-CFT (Kruskal-Wallis test). Conventional OCT parameters (central subfield retinal thickness, cube volume and cube average thickness) did not have significant correlations with EZ measures (-0.3<R<0.3 and/or P>0.05). Baseline EZ integrity is closely linked to presenting visual acuity in eyes with RVO and macular edema. EZ mapping provides an additional metric for evaluating RVO impact on retinal anatomy and potential function.


Intravenous cholangiography in the CT era.
With the availability of computed tomography (CT), ultrasonography (US), percutaneous transhepatic cholangiography (PTC), and endoscopic retrograde cholangiopancreatography (ERCP), the use of intravenous cholangiography (IVC) has waned. A retrospective study of 69 intravenous cholangiograms performed from 1979 through 1982 assessed the utility of intravenous cholangiography, as well as its effect on patient management, at an institution where CT was highly developed. In no case after normal findings on CT and/or ultrasound examination did IVC make a positive pathologic diagnosis. After abnormal results on CT and/or US examinations, in no case did IVC add to the diagnosis. Finally, after technically suboptimal results of CT and/or US examinations, IVC made only 1 positive pathologic diagnosis. Overall, IVC correctly demonstrated only 5 of 9 cases of common duct stones or strictures. Of the 26 cases with anatomical correlation there were a total of 7 false-positive and -negative IVC examinations. In this series, IVC was rarely useful in the diagnosis of biliary tract disease. Given the high inaccuracy rate of IVC in this study, its use for the exclusion of biliary tract disease is discouraged.


Identification of the fitness determinants of budding yeast on a natural substrate.
The budding yeasts are prime models in genomics and cell biology, but the ecological factors that determine their success in non-human-associated habitats is poorly understood. In North America Saccharomyces yeasts are present on the bark of deciduous trees, where they feed on bark and sap exudates. In the North East, Saccharomyces paradoxus is found on maples, which makes maple sap a natural substrate for this species. We measured growth rates of S. paradoxus natural isolates on maple sap and found variation along a geographical gradient not explained by the inherent variation observed under optimal laboratory conditions. We used a functional genomic screen to reveal the ecologically relevant genes and conditions required for optimal growth in this substrate. We found that the allantoin degradation pathway is required for optimal growth in maple sap, in particular genes necessary for allantoate utilization, which we demonstrate is the major nitrogen source available to yeast in this environment. Growth with allantoin or allantoate as the sole nitrogen source recapitulated the variation in growth rates in maple sap among strains. We also show that two lineages of S. paradoxus display different life-history traits on allantoin and allantoate media, highlighting the ecological relevance of this pathway.


Initial experience with the freestyle stentless aortic bioprosthesis.
We report our initial experience with the Freestyle aortic bioprosthesis. This prosthesis was implanted in 40 patients between February 1993 and December 1998. Operative indications were aortic stenosis in 32 patients (80%), aortic regurgitation in seven patients (18%) and a combined lesion in one (3%). The mean patient age was 71.4+/-9.7 (SD) years, with 29 (72%) females. Pre-operative New York Heart Association (NYHA) class was III or IV in 28 (70%). Left ventricular systolic function was impaired in four (10%). Six (15%) patients had undergone previous cardiac surgery. Concomitant procedures were carried out in 21 patients (53%). Early mortality was zero. Early morbidity included three re-operations for bleeding, one cerebrovascular event, one haemorrhagic complication and one case of valve dysfunction. At follow up (range 4.6 to 75.6 months, mean 29.5+/-25.5) there has been one (3%) late death which was non valve related, one (3%) episode of study-valve endocarditis, and three (8%) thromboembolic episodes. NYHA Class was I or II in all but one survivor. Echocardiographic follow-up has shown no further instances of valve dysfunction with satisfactory haemodynamic parameters at 24-months post-operation, and a significant and sustained regression of left ventricular mass. The initial experience with the Freestyle valve is that it results in good clinical and haemodynamic performance, suggesting it as an ideal bioprosthesis for this patient group.


[The video impression--a CAD procedure for manufacture of ceramic inlays].
Study was provided, creating a CAD/CAM technique for automated producing of ceramic inlays based on a optical topographic scanning procedure.


A fluorescent chemosensor for cobalt ions based on a multi-substituted phenol-ruthenium(II) tris(bipyridine) complex.
An amide-linked 2,6-bis{[(2-hydroxy-5-tert-butylbenzyl)(pyridyl-2-methyl)-amino]-methyl}-4-methylphenol-ruthenium(II) tris(bipyridine) 2PF6- complex, 1, was first used to recognize Co(II) in EtOH/H(2)O (1:1, v/v) solution, with the ruthenium(II) tris(bipyridine) moiety selected as a fluorophore and the multi-substituted phenol unit chosen as a receptor. The fluorescence quenching of 1 was attributed to the formation of an inclusion complex between multi-substituted phenol unit and Co(II) by 1:1 complex ratio (K=2.5 x 10(5)), which has been utilized as the basis of the fabrication of the Co(II)-sensitive fluorescent chemosensor. The analytical performance characteristics of the proposed Co(II)-sensitive chemosensor were investigated. The sensor can be applied to the quantification of Co(II) with a linear range covering from 1.0 x 10(-7) to 5.0 x 10(-5) M and a detection limit of 5 x 10(-8) M. The experiment results show that the response behavior of 1 to Co(II) is pH-independent in medium condition (pH 4.5-9.5) and show excellent selectivity for Co(II) over transition metal cations except Cu(II). The chemosensor has been used for determination of Co(II) in water samples.


Iranian Children With ADHD and Mental Health of Their Mothers: The Role of Stress.
Attention deficit/hyperactivity disorder (ADHD) is a psychiatric disorder that can result in stress for the mother, resulting in poor health. The current study, conducted in 2012, aims to assess stress among forty-six Iranian mothers of ADHD children (Group 1) who were admitted to a psychiatric center in Tehran with forty-six Iranian mothers of normal children (Group 2) in 2012. The Child Symptom Inventory-4 (CSI-4), the child behavior checklist (CBCL) and the parental stress index-short form (PSI/SF) were completed. Data was analyzed using the Levene test and the independent t-test in SPSS Version 18. With the exception of mood, ADHD children had more problems in attention compared with normal children. As a result, mothers of ADHD children had more stress compared with the controls. ADHD can impair a mother's mental health by inducing stress. Specific diagnostic and treatment programs should be designed and tailored for the mothers of ADHD children in order to decrease stress.


College students' expectations of the results of drinking.
Social drinkers, when drinking, are expected to feel better and to be kinder, more fun to be with and more energetic and active than they would be if they were not drinking; inebriated alcoholics are expected to be meaner, less fun to be with and more lethargic than they would be if they were not inebriated.


HPV vaccination coverage within 3 years of program launching (2008-2011) at Geneva State, Switzerland.
The objective of this study is to assess the HPV vaccination coverage of 11-19-year-old girls during a state-coordinated HPV vaccination program in Geneva, Switzerland, from September 2008 to June 2011. State Medical Office coordinated the HPV vaccination program. Each service provider transmitted the list of the persons who had received their first, second, or third shot. The global coverage rates, 3 years after the program had been launched, were 63.72% for one dose, 63.22% for two doses, and 61.40% for three doses of the HPV vaccine. This study shows that it is possible to obtain a good coverage rates after 3 years of a state-coordinated HPV vaccination program.


A safe and simple technique for nasogastric tube insertion in patients with thoracic esophageal cancer surgery.
Risk factors for anastomotic leakage include local factors such as excessive tension across anastomosis and increased intraluminal pressure on the gastric conduit; therefore, we consider the placement of a nasogastric tube to be essential in reducing anastomotic leakage. In this study, we devised a safe and simple technique to place an NGT during an end-to-side, automatic circular-stapled esophagogastrostomy. First, a 4-0 nylon thread is fixed in the narrow groove between the plastic and metal parts of the tip of the anvil head. After dissecting the esophagus, the tip of the NGT is guided out of the lumen of the cervical esophageal stump. The connecting nylon thread is applied to the anvil head with the tip of the NGT. The anvil head is inserted into the cervical esophageal stump, and a purse-string suture is performed on the esophageal stump to complete the anvil head placement. The main unit of the automated stapler is inserted through the tip of a reconstructed gastric conduit, and the stapler is subsequently fired and an end-to-side esophagogastrostomy is achieved. The main unit of the automated stapler is then pulled out from the gastric conduit, and the NGT comes out with the anvil head from the tip of the reconstructed gastric conduit. Subsequently, the nylon thread is cut. After creating an α-loop with the NGT outside of the lumen, the tip of the NGT is inserted into the gastric conduit along the lesser curvature toward the caudal side. Finally, the inlet of the automated stapler on the tip of the gastric conduit is closed with an automated linear stapler, and the esophagogastrostomy is completed. We utilized this technique in seven patients who underwent esophagectomy for esophageal cancer; smooth and safe placement of the NGT was accomplished in all cases. Our technique of NGT placement is simple, safe, and feasible.


Results of a single-arm pilot study of 32P microparticles in unresectable locally advanced pancreatic adenocarcinoma with gemcitabine/nab-paclitaxel or FOLFIRINOX chemotherapy.
Unresectable locally advanced pancreatic cancer (LAPC) is generally managed with chemotherapy or chemoradiotherapy, but prognosis is poor with a median survival of ∼13 months (or up to 19 months in some studies). We assessed a novel brachytherapy device, using phosphorous-32 (32P) microparticles, combined with standard-of-care chemotherapy. In this international, multicentre, single-arm, open-label pilot study, adult patients with histologically or cytologically proven unresectable LAPC received 32P microparticles, via endoscopic ultrasound-guided fine-needle implantation, planned for week 4 of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) or gemcitabine/nab-paclitaxel chemotherapy, per investigator's choice. The primary endpoint was safety and tolerability measured using Common Terminology Criteria for Adverse Events version 4.0. The lead efficacy endpoint was local disease control rate at 16 weeks. Fifty patients were enrolled and received chemotherapy [intention-to-treat (ITT) population]. Forty-two patients received 32P microparticle implantation [per protocol (PP) population]. A total of 1102 treatment-emergent adverse events (TEAEs) were reported in the ITT/safety population (956 PP), of which 167 (139 PP) were grade ≥3. In the PP population, 41 TEAEs in 16 (38.1%) patients were possibly or probably related to 32P microparticles or implantation procedure, including 8 grade ≥3 in 3 (7.1%) patients, compared with 609 TEAEs in 42 (100%) patients attributed to chemotherapy, including 67 grade ≥3 in 28 patients (66.7%). The local disease control rate at 16 weeks was 82.0% (95% confidence interval: 68.6% to 90.9%) (ITT) and 90.5% (95% confidence interval: 77.4% to 97.3%) (PP). Tumour volume, carbohydrate antigen 19-9 levels, and metabolic tumour response at week 12 improved significantly. Ten patients (20.0% ITT; 23.8% PP) had surgical resection and median overall survival was 15.2 and 15.5 months for ITT and PP populations, respectively. Endoscopic ultrasound-guided 32P microparticle implantation has an acceptable safety profile. This study also suggests clinically relevant benefits of combining 32P microparticles with standard-of-care systemic chemotherapy for patients with unresectable LAPC.


When More Is Less: Dual Phosphorylation Protects Signaling Off State against Overexpression.
Kinases in signaling pathways are commonly activated by multisite phosphorylation. For example, the mitogen-activated protein kinase Erk is activated by its kinase Mek by two consecutive phosphorylations within its activation loop. In this article, we use kinetic models to study how the activation of Erk is coupled to its abundance. Intuitively, Erk activity should rise with increasing amounts of Erk protein. However, a mathematical model shows that the signaling off state is robust to increasing amounts of Erk, and Erk activity may even decline with increasing amounts of Erk. This counterintuitive, bell-shaped response of Erk activity to increasing amounts of Erk arises from the competition of the unmodified and single phosphorylated form of Erk for access to its kinase Mek. This shows that phosphorylation cycles can contain an intrinsic robustness mechanism that protects signaling from aberrant activation e.g., by gene expression noise or kinase overexpression after gene duplication events in diseases like cancer.


Cost-effectiveness analysis of aprepitant-based anti-emetic regimen for children receiving highly emetogenic chemotherapy: Individual patient data analysis of a randomized trial.
Aprepitant has been shown to reduce chemotherapy-induced nausea and vomiting in children receiving highly emetogenic chemotherapy (HEC). In this study, we assessed the cost-effectiveness of aprepitant for children receiving HEC in India, United Kingdom, and the United States. We utilized individual patient-level outcome data from a pediatric randomized trial, which demonstrated the superiority of an aprepitant-based anti-emetic prophylaxis over standard ondansetron and dexamethasone for HEC. Health state for each day of follow-up was analyzed and quality-adjusted life years (QALYs) were estimated. The incremental cost-utility ratio (ICUR), incremental cost-effectiveness ratio (ICER), and net monetary benefit (NMB) for each country were estimated. Sensitivity analyses by varying cost of aprepitant, hospitalization, and health state utility values by ±25% were conducted. Use of the aprepitant-based regimen resulted in gain of 0.0019 QALY per chemotherapy cycle along with cost savings of $22.25, $1335.52, and $6612.10 for India, United Kingdom, and the United States, respectively. The cost savings per QALY was estimated to be $12,355.84 for India, $734,282.90 for the United Kingdom, and $3,567,564.11 for the United States. The cost savings for 50% gain in the percentage of days without grade 3 vomiting was $124.18 for India, $7451.63 for the United Kingdom, and $36,892.76 for the United States. The NMB for gain in QALY was $33.62, $1418.60, and $6727.01 for India, United Kingdom, and the United States, respectively. The estimates remained cost-effective across all scenarios of the sensitivity analyses. Aprepitant-based anti-emetic regimen is cost-effective for children receiving HEC. It results in overall cost savings and reduced healthcare-resource utilization.


[Use of blood products in patients treated surgically for stage I non-small cell lung cancer].
Retrospective study on the relation between the use of blood products and survival rates in patients treated surgically for stage I non-small cell lung cancer (NSCLC). The study included 856 patients who underwent surgical resection from 1969 to 2000 for stage I NSCLC, classified histologically according to the current guidelines of the Spanish Society of Pulmonary and Thoracic Surgery (SEPAR). Patients who died in the postoperative period were excluded from the study. A series of clinicopathological variables were recorded, including the perioperative use or not of blood products. Descriptive, univariate, and multivariate statistical analyses were performed. Follow up concluded in December of 2003. One hundred twenty-five patients (14.6%) underwent a perioperative transfusion. A significant association was found between the use of blood products and tumor size (P<.001), pneumectomy (P<.001), and cell type (P<.05). The respective 2, 5, and 10-year survival rates were 78%, 63%, and 54% for the nontransfusion group, and 73%, 59%, and 46% for the transfusion group. Both survival curves were compared and no significant differences were found (P=.23). Multivariate regression analysis included tumor size, patient age, and histologic cell type (squamous cell carcinoma or not); no relation between transfusion and survival was found. In our series, we found no difference in survival rates for patients with stage I NSCLC after perioperative blood transfusion.


Functional Reuniens and Rhomboid Nuclei Are Required for Proper Acquisition and Expression of Cued and Contextual Fear in Trace Fear Conditioning.
The reuniens (Re) and rhomboid (Rh) nuclei (ReRh) of the midline thalamus interconnect the hippocampus and the medial prefrontal cortex. The hippocampus and medial prefrontal cortex are both involved in the acquisition of trace fear conditioning, in which a conditioned stimulus (tone) and an aversive unconditioned stimulus (footshock) are paired but separated in time with a trace interval. Earlier, we demonstrated that ReRh inactivation during trace conditioning impaired the acquisition of cued fear. In contrast, ReRh inactivation during both conditioning and test resulted in heightened fear to tones during retrieval. Because there was a generalized contextual fear on top of heightened fear to tones in the latter experiment, here we aimed to examine the specific importance of the functional ReRh in cued fear and contextual fear through introducing prolonged contextual exposure. The ReRh were pharmacologically inactivated with muscimol (or saline as controls) before each experimental session. We showed that although ReRh inactivation before trace fear conditioning impaired the acquisition of cued fear, the animals still acquired a certain level of fear to the tones. However, without the functional ReRh throughout the entire behavioral sessions, these animals showed heightened contextual fear that did not decline much with the passage of time, which generalized to the other context, and fear to tones reoccurred when the tones were presented. Our results suggested that functional ReRh are important for proper acquisition and expression of fear to context and tones acquired under trace procedure.


Mechanism of E2F1-induced apoptosis in primary vascular smooth muscle cells.
The transcription factor E2F1 serves as a major regulator of the cell-cycle by controlling G1-S phase transition. However, apart from its proliferative function high levels of deregulated E2F1 are capable of inducing apoptosis depending on the cellular context. In particular the tumor suppressor p53 and its homologue p73 are implicated in this proapoptotic function. Here, we investigated the mechanistic basis for E2F1-mediated apoptosis in vascular smooth muscle cells (VSMCs) which have previously been shown to be E2F1-responsive. Interestingly, E2F1-expression in these cells induced clear signs of apoptosis in the absence of any proliferative activity. Although cell-cycle regulated genes such as CCNE1 and CDC25A were activated, BrdU-staining revealed no S-phase entry. Instead, a rapid loss of cell viability by induction of apoptosis was observed. Using a transactivation-defective E2F1-mutant, we show that apoptosis induction is independent of the transactivation function and therefore independent of ARF and p73. However, this mutant retains its ability to stabilize and phosphorylate p53, suggesting that p53 is sufficient for the effect of E2F1. VSMCs therefore represent a cellular system in which the transactivation-independent, proapoptotic activity of E2F1 is the primary cellular function. Ectopic expression of E2F1 might therefore be a suitable therapy to prevent VSMC hyperproliferation.


Time-course expression of CNS inflammatory, neurodegenerative tissue repair markers and metallothioneins during experimental autoimmune encephalomyelitis.
Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS). EAE and MS are characterized by CNS inflammation, demyelination and neurodegeneration. The inflammatory response occurring within the CNS leads to glial activation, dysfunction and death, as well as axonal damage and neurological deficit. Although the pathogenic mechanisms involved in EAE/MS are not well understood, accumulating data suggest that oxidative stress plays a major role in lesion development, and contributes to axonal dysfunction and degeneration. Metallothionein-I and -II are anti-inflammatory, neuroprotective, antioxidant proteins expressed during EAE and MS, in which they might play a protective role. The present study aimed to describe the expression profile of a group of inflammatory, neurodegenerative and tissue repair markers as well as metallothioneins during proteolipid protein-induced EAE, and to establish the time-relationships these molecules had during EAE. Interestingly, we found two marker expression profiles. In the first, marker expression increased as clinical signs worsened and reverted to baseline expression during recovery; in the second, marker expression increased at a later point during relapse, peaked at highest clinical score, and remained elevated throughout recovery. Of note, metallothionein expression was found to be related to the second profile, which would suggest that metallothionein proteins are implicated in the clinical recovery of EAE and perhaps these antioxidant proteins may provide therapeutic benefits in MS.


Mutagenic and clastogenic activity of direct-acting components from air pollutants of the Silesian industrial region.
Sequential elution solvent chromatography (SESC) developed by Farcasiu for characterization of coal liquids was used for the fractionation of benzene extracts of airborne particulate pollutants. Mutagenic and clastogenic activity of SESC fractions was determined by the Salmonella/microsome test and the assay for V79 cell chromosomal aberrations (CAs), respectively. Five out of 8 obtained fractions showed differentiated, direct and indirect mutagenic activity. Selected 'direct' fractions, examined by the rodent cell chromosome aberration test, also gave a clastogenic response that increased with prolonged treatment time. The SESC system combined with 2 biological assays, the Ames test and the CAs test, seems to be a useful method for examination of genotoxic components of environmental pollutants.


Simple device to determine the pressure applied by pressure clips for the treatment of earlobe keloids.
Keloids of the ear are common problems. Various treatment modalities are available for the treatment of ear keloids. Surgical excision with intralesional steroid injection along with compression therapy has the least recurrence rate. Various types of devices are available for pressure therapy. Pressure applied by these devices is uncontrolled and is associated with the risk of pressure necrosis. We describe here a simple and easy to use device to measure pressure applied by these clips for better outcome. To devise a simple method to measure the pressure applied by various pressure clips used in ear keloid pressure therapy. By using a force sensitive resistor (FSR), the pressure applied gets converted into voltage using electrical wires, resistors, capacitors, converter, amplifier, diode, nine-volt (9V) cadmium battery and the voltage is measured using a multimeter. The measured voltage is then converted into pressure using pressure voltage graph that depicts the actual pressure applied by the pressure clip. The pressure applied by different clips was variable. The spring clips were adjustable by slight variation in the design whereas the pressure applied by binder clips and magnet discs was not adjustable. The uncontrolled/suboptimal pressure applied by certain pressure clips can be monitored to provide optimal pressure therapy in ear keloid for better outcome.


Radioimmunoassay for subunit B in isoenzymes CK-MB and CK-BB of creatine phosphokinase.
We report the development of a double-antibody system for radioimmunoassay of CK-B subunit in isoenzymes CK-MB and CK-BB of creatine phosphokinase. With our method, 4.1 ng/ml of isoenzyme CK-BB can be detected. Within-run and between-run coefficients of variation are respectively 5.3% and 19.6% Analytical recovery of added antigen is 98.9 +/- 14.7%. The CK-B concentration in sera from 20 healthy adults was less than 75 ng/ml. In sera from 25 patients with a rise in CK-total activity, but without CK-MB or CK-BB activity tested with the previous reported immunological methods, we found CK-B concentrations in the range 0--86 ng/ml. In contrast, in 23 sera from patients with acute myocardial infarction within the last 48 hours CK-B concentration was in the range 104--225 ng/ml.


Effects of adjuvants on bovine humoral and cellular responses to hypodermin A.
Hypodermin A, a serine protease of the first-instar larva of the common cattle grub, Hypoderma lineatum (Villers), when formulated with complete Freund's adjuvant and administered to naive calves, will elicit protective immunity defined by an increase in in vivo larval mortality. This study evaluated two veterinary acceptable adjuvants, alhydrogel and amphigen (alone and in combination), for suitability as an adjuvant for hypodermin A. Complete Freund's adjuvant (CFA) is not an acceptable adjuvant for use because of adverse reactions at the injection site. The veterinary acceptable adjuvants were not as effective as CFA in inducing an antibody response as detected in the peripheral circulation. Of the adjuvants evaluated, the mixture of alhydrogel and amphigen induced the highest serum antibody response to hypodermin A. All adjuvants evaluated induced comparable immediate-type skin test responses, and the mixture of alhydrogel and amphigen was most comparable with CFA in terms of delayed-type skin reaction and resultant cellular infiltration at the reaction site. Although the mixture of alhydrogel and amphigen, when compared with CFA, did not elicit comparable levels of responsiveness in all parameters tested, the overall performance of the mixture suggests it to be worthy of further efficacy investigation in a vaccine formulation with hypodermin A.


Optimizing sampling designs for volume measurements of components of human brain using a stereological method.
Measurements of the cerebral cortical volume used to be very laborious, due to the 3-D complexity of the gyral pattern. Using stereological methods, which allow the quantification of 3-D structures from measurements on 2-D cross-sections, the difficulties have been overcome. In thirty formalin-fixed normal human brains the total volumes were measured by saline displacement. The brains were serially sliced in coronal sections and the fractional areas of the cortex, white matter, central grey structures and ventricles were determined by point-counting. Using Cavaliéri's principle the volumes of these structures were calculated. The average cortical fixed volume was 549 ml (SD +/- 107) corresponding to 54% of the total volume of the hemispheres. The coefficient of error of the cortical volume determinations was 2.6%. The efficiency of the design and the possibilities for optimizing the design are discussed. This point-counting method was preferred to the use of an automatic image analyser, being precise, easy to handle and not interfering with further tissue processing for histological preparation.


Peptide capillary zone electrophoresis mass spectrometry of recombinant human erythropoietin: an evaluation of the analytical method.
An evaluation of capillary zone electrophoresis-mass spectrometry (CZE-MS) as an analytical methodology for the separation and characterization of complex glycopeptides and nonglycopeptide structures has been performed. The evaluation employed endoproteinase V8 digested recombinant human erythropoietin (rHuEPO) that was further fractionated by reverse phase chromatography. The peptides were subjected to sequence analysis and evaluated by capillary electrophoresis, with or without mass detection, for peptide purity. The peptide mass determined from the sequence was then compared to the mass obtained from CZE-MS. Glycosylation sites and carbohydrate branch patterns were easily determined, site specific microheterogeneity (either O-acetylation of N-acetylneuraminic acids or lactosamine extensions of the carbohydrate chain length) was assessed directly, glycosylation site occupancy was evaluated qualitatively, and nonglycopeptides were resolved and analyzed on-line with ease. Incomplete peptide digestion products were detected and identified by CZE-MS. Protein sequence coverage by CZE-MS was 98.2 percent complete from a single map. Off-line evaluation of peptide purity by CZE greatly aided the interpretation of multiple sequence analysis and, in validating that, the CZE-MS was detecting all peptides present. All off-line CZE and on-line CZE-MS experiments employed a capillary that was dynamically coated with Polybrene in the presence of polyethylene glycol; separations were conducted in 0.67 M formic acid.


Predictors of family focused practice: organisation, profession, or the role as child responsible personnel?
Health professionals in Norway are required by law to help safeguard information and follow-up with children of parents with mental or physical illness, or who have substance abuse problems, to reduce their higher risk of psychosocial problems. Knowledge is lacking regarding whether organisation and/or worker-related factors can explain the differences in health professionals' ability to support the families when patients are parents. Employing a translated, generic version of the Family Focused Mental Health Practice Questionnaire (FFPQ), this cross-sectional study examines family focused practice (FFP) differences in relation to health professionals' background and role (N = 280) along with exploring predictors of parent, child, and family support. While most health professions had begun to have conversations with parents on children's needs, under one-third have had conversations with children. There were significant differences between nurses, social workers, psychologists, physicians, and others on seven of the FFP subscales, with physicians scoring lowest on five subscales and psychologists providing the least family support. Controlling for confounders, there were significant differences between child responsible personnel (CRP) and other clinicians (C), with CRP scoring significantly higher on knowledge and skills, confidence, and referrals. Predictors of FFP varied between less complex practices (talking with parents) and more complex practices (family support and referrals). The type of profession was a key predictor of delivering family support, suggesting that social workers have more undergraduate training to support families, followed by nurses; alternately, the results could suggest that that social workers and nurses have been more willing or able than physicians and psychologists to follow the new legal requirements. The findings highlight the importance of multidisciplinary teams and of tailoring training strategies to health professionals' needs in order to strengthen their ability to better support children and families when a parent is ill.


Patulous eustachian tube syndrome: the relationship with sensorineural hearing loss. Treatment by eustachian tube diathermy.
The patulous Eustachian tube syndrome has previously been regarded as a troublesome but benign condition. Nine out of 13 patients reported here had evidence of cochlear damage similar to that caused by acoustic trauma. These patients also had vestibular symptoms which improved with treatment of the patulous tube. It is postulated that abnormal patency of the Eustachian tube may allow excessive middle ear pressure changes to occur which may be transmitted by abnormal ossicular movement to the cochlea. Eustachian tube diathermy using a ureteric diathermy probe is a safe and effective method of treating this condition.


The importance of age groups in estimates of alcohol-attributable mortality: impact on trends in Switzerland between 1997 and 2011.
Monitoring trends of alcohol-attributable mortality is an integral part of the global strategy to reduce the harmful use of alcohol. However, mortality estimates based on different age ranges come to different conclusions. This study examined the impact of including different age ranges in terms of directions of trends of alcohol-attributable mortality during 14 years in Switzerland. Alcohol-attributable mortality was estimated at four time-points between 1997 and 2011 using the Global Burden of Disease 2010 methodology. Estimates were obtained for two age groups: 15-64 years and the total adult population (15 years and older). Alcohol-attributable mortality among 15-64-year-olds decreased [1997: 1334 deaths, confidence interval (CI) = 1237-1432; 2011: 1019 deaths, CI = 964-1073; trend per year odds ratio (OR) = 0.99, P < 0.001]. In contrast, alcohol-attributable mortality among those 65 and older increased in the same time-period (1997: 581 deaths, CI = -196 to 1357; 2011: 1664 deaths, CI = 957-2372; OR = 1.07, P< 0.001), resulting in an overall increase of alcohol-attributable mortality for 15+ year-olds (1997: 1915 deaths, CI = 1133-2697; 2011: 2683, CI = 1973-3393; OR = 1.02, P < 0.001). The main shift in trends was due to changes in the mixture (e.g. hypertension, ischaemic heart disease) of cardiovascular diseases over time among those 65+ years old. Trends in alcohol-attributable mortality may yield qualitatively different results based on the upper age limit for deaths set for these estimates. Global trends of alcohol-attributable mortality between 1997 and 2011 were influenced heavily by changes in the mixture of deaths across cardiovascular diseases. Trends for alcohol-attributable mortality and cross-country comparisons should be reported separately for 15-64 and 65+ year-olds.


[Accelerated method of determining the antiviral activity of interferon inducers in experimental infection].
By the example of trials of two typical interferon inducers: a double-stranded complex of synthetic polyribonucleotides poly (I).poly (C) and polyacrylic acid the use of the proposed rapid method for the determination of the antiviral activity of interferon inducers in an experimental infection of mice with an alphavirus is described. The method permits to perform a statistically treated evaluation of the antiviral effect of a group of preparations within 96 hours. The mean standard error of the method is +/- 0,333 1g PFU per 1 ml of 10% brain suspension.


Spontaneous rupture of an infected renal cyst and external drainage through a lumbar surgical scar in a male patient with cervical spinal cord injury: a case report.
The spontaneous rupture of an infected renal cyst is a rare event. Spontaneous rupture with drainage to the exterior through a surgical scar has not been reported previously. A 49-year-old male with tetraplegia had undergone extended right pyelolithotomy in 1999. Deroofing and marsupialisation of a cyst in the upper pole of the right kidney was performed in 2003. Subsequently there was recurrence of a thick-walled cystic space-occupying lesion in the upper pole of the right kidney. Thick pus was aspirated from the renal cyst on six occasions between September 2003 and November 2004. In March 2006, ultrasound examination revealed a cyst measuring 6.2 cm in diameter in the upper pole of the right kidney. Aspiration was planned when the renal cyst reached 7.5 cm in diameter. However, 11 months later, the cyst ruptured spontaneously and drained through the previous surgical scar in the flank, while the patient was recovering from a severe chest infection in the spinal unit. Ultrasound examination showed a fistulous tract running between the renal cyst and the abdominal wall. Repeated minor trauma sustained during turning, hoisting and chest physiotherapy all may have contributed to the rupture of the infected renal cyst and drainage through a weak spot in the abdominal wall. In hindsight, we might have prevented rupture of the renal cyst had we considered aspiration of the renal cyst before it reached 7.5 cm in diameter, although this 7.5 cm diameter, as the threshold for percutaneous aspiration, is an arbitrary setting. This patient could have been advised to wear an abdominal corset to protect the right flank from pressure applied unintentionally during turning, hoisting or assisted coughing.


'(m6)A' stands for 'autoimmunity': reading, writing, and erasing RNA modifications during inflammation.
Covalent RNA modifications that regulate gene expression post transcriptionally, in particular N6-methyladenosine (m6A), are emerging as important regulators of autoimmune responses. Here, we highlight new findings describing the functional diversity and specificity of m6A modifications and their regulation in the context of autoimmunity.


Evaluation of contaminated drinking water and male breast cancer at Marine Corps Base Camp Lejeune, North Carolina: a case control study.
Solvents contaminated drinking water supplies at Marine Corps Base Camp Lejeune during 1950s-1985. We conducted a case-control study among Marines to evaluate associations between residential exposure to contaminated drinking water at Camp Lejeune and male breast cancer risk. The study included 71 male breast cancer cases and 373 controls identified from the Department of Veteran's Affairs (VA) cancer registry whose military personnel records were available. Controls were selected from cancers not known to be associated with solvent exposure and included 270 skin cancers, 71 mesotheliomas, and 32 bone cancers. Base assignment and risk factor information came from military personnel and VA records. Groundwater contaminant fate/transport and distribution system models provided monthly estimated residential contaminant levels. We conducted exact logistic regression using the 50th percentile level among exposed controls to create low and high exposure categories. We calculated 95% confidence intervals (CIs) to indicate precision of effect estimates. Exploratory analyses used proportional hazards methods to evaluate associations between exposures and age at diagnosis. After adjusting for age at diagnosis, race, and service in Vietnam, the odds ratio (OR) for ever stationed at Camp Lejeune was 1.14 (95% CI: 0.65, 1.97). Adjusted ORs for high residential cumulative exposures to tetrachloroethylene (PCE), t-1,2 dichloroethylene (DCE), and vinyl chloride were 1.20 [95% CI: 0.16-5.89], 1.50 [95% CI: 0.30-6.11], 1.19 [95% CI: 0.16-5.89], respectively, with a monotonic exposure response relationship for PCE only. However these results were based on two or three cases in the high cumulative exposure categories. Ever stationed at Camp Lejeune and high cumulative exposures to trichloroethylene (TCE), PCE, DCE and vinyl chloride were associated with earlier age at onset for male breast cancer; hazard ratios ranged from 1.4-2.7 with wide confidence intervals for cumulative exposure variables. Findings suggested possible associations between male breast cancer and being stationed at Camp Lejeune and cumulative exposure to PCE, DCE, and vinyl chloride. TCE, PCE, DCE and vinyl chloride cumulative exposures showed possible associations with earlier age at onset of male breast cancer. However, this study was limited by small numbers of cases in high exposure categories.


Novel Schiff base scaffolds derived from 4-aminoantipyrine and 2-hydroxy-3-methoxy-5-(phenyldiazenyl)benzaldehyde: Synthesis, antibacterial, antioxidant and anti-inflammatory.
The synthesis of four new azo-Schiff base ligands from 2-hydroxy-3-methoxy-5-(phenyldiazenyl)benzaldehyde and 4-aminoantipyrine is described in this study. The molecular structures of all the scaffolds were confirmed using NMR spectroscopies such as 1 H and 13 C, as well as FT-IR and Mass spectroscopy. After successful synthesis and characterization of all the ligands, their in vitro antibacterial, antioxidant and anti-inflammatory activities were carried out by using standard protocols. Results revealed that all the four ligands (L1-L4) possessed excellent biological potency.


Extracts from Erythronium japonicum and Corylopsis coreana Uyeki reduce 1,3-dichloro-2-propanol-mediated oxidative stress in human hepatic cells.
In this study, it was demonstrated that 1,3-dichloro-2-propanol (1,3-DCP) induced oxidative stress and cell death in HuH7, human hepatocytes. The protective effects of Erythronium japonicum (E. japonicum) and Corylopsis coreana Uyeki (C. coreana Uyeki) extracts against 1,3-DCP-treated cells were also investigated. First, the activities of superoxide dismutase (SOD) and catalase (CAT) were diminished by the treatment of 1,3-DCP. Moreover, 1,3-DCP stimulated the expression and catalytic activity of cytochrome P450 2E1 (CYP2E1), an enzyme that generates reactive oxygen species in the liver. In contrast, co-treatment of 1,3-DCP with the extracts significantly decreased ROS generation and inhibited CYP2E1 activity without affecting its expression. The co-administration of extracts also restored the activities of SOD and CAT reduced by 1,3-DCP and protected against 1,3-DCP-mediated cell death. In conclusion, these results suggest that 1,3-DCP induces oxidative stress through the elevated CYP2E1 level, which is inhibited by the extracts, protecting cells against the effects of 1,3-DCP.


The rational application of liquid biopsy based on next-generation sequencing in advanced non-small cell lung cancer.
Plasma and tissue biopsy have both used for targeting actionable driver gene mutations in lung cancer, whose concordance is imperfect. A reliable method to predict the concordance is urgently needed to ease clinical application. A total of 1012 plasma samples, including 519 with paired-tissue biopsy samples, derived from lung adenocarcinoma patients were retrospectively enrolled. We assessed the associations of several clinicopathological characteristics and serum tumor markers with the concordance between plasma and tissue biopsies. When carcinoembryonic antigen (CEA) levels were higher than thresholds of 15.01 ng/ml and 51.15 ng/ml, the positive predictive value of concordance reached 90% and 95%, respectively. When CEA levels were lower than thresholds of 5.19 ng/ml and 3.26 ng/mL, the negative predictive value of concordance reached 45% and 50%. The performance of CYFRA21-1 in predicting concordance was similar but inferior to CEA (AUC: 0.727 vs. 0.741, p = 0.633). The performance of CEA combined with CYFRA21-1 in predicting the concordance was similar to that of the combination of independent factors derived from the LASSO regression model (AUC: 0.796 vs. 0.818, p = 0.067). CEA (r = 0.47, p < 0.01) and CYFRA21-1 levels (r = 0.45, p < 0.05) were significantly correlated with the maximum variant allele frequency, respectively. CEA combined with CYFRA21-1 could effectively predict the concordance between plasma and tissue biopsies, which could be used for evaluating the priority of plasma and tissue biopsies for gene testing to timely guide clinical applications in advanced lung adenocarcinoma patients.