Mechanisms facilitating the uptake of carboxyl-polythene glycol-functionalized gold nanoparticles into multicellular spheroids.
Nanomedicines represent theragnostic alternatives to traditional candidate drugs, with increased targeting and delivery potential due to their size and functional tailorability. Biological activity typically relies on nanomaterials permeating into the intracellular environment, necessitating characterization of uptake and intracellular trafficking pathways. Spheroids' three-dimensional architecture and heterogenous cellular distribution offer an in-vivo-representative platform to assess the biological activity of nanoparticles (NPs). This study aimed to develop an A549 alveolar carcinoma spheroid model as a NP uptake assessment platform for carboxyl-polythene glycol-functionalized gold NPs affording further biological characterization opportunities in nanomedicine. A549 spheroids were generated via the liquid overlay method, and their morphology and viability were assessed for 21 days. Cytotoxicity was assessed via lactate dehydrogenase release. NP uptake was elucidated using uptake pathway inhibition, combined with CytoViva hyperspectral imaging of sectioned spheroids to count internalized NPs. Cytotoxicity was absent for all exposure groups. Clathrin-mediated endocytosis was the primary endocytic mechanism (33.5-54.8% of uptake), which may precede lysosomal degradation. Lysosomal membrane permeabilization appears to be a potential downstream application. Low penetration into spheroids (4.5 μm) suggests the failure of NPs to traverse cellular layers in the spheroid. Although poor uptake was observed, a multicellular spheroid model of A549 alveolar carcinoma cells was established, allowing for similar future uptake assessment of various NPs.


Feature Selection for Varying Coefficient Models With Ultrahigh Dimensional Covariates.
This paper is concerned with feature screening and variable selection for varying coefficient models with ultrahigh dimensional covariates. We propose a new feature screening procedure for these models based on conditional correlation coefficient. We systematically study the theoretical properties of the proposed procedure, and establish their sure screening property and the ranking consistency. To enhance the finite sample performance of the proposed procedure, we further develop an iterative feature screening procedure. Monte Carlo simulation studies were conducted to examine the performance of the proposed procedures. In practice, we advocate a two-stage approach for varying coefficient models. The two stage approach consists of (a) reducing the ultrahigh dimensionality by using the proposed procedure and (b) applying regularization methods for dimension-reduced varying coefficient models to make statistical inferences on the coefficient functions. We illustrate the proposed two-stage approach by a real data example.


Lysosomal membrane dynamics: structure and interorganellar movement of a major lysosomal membrane glycoprotein.
The biochemistry and intracellular transit of an integral membrane glycoprotein of chicken fibroblast lysosomes were studied with monoclonal antibody techniques. The glycoprotein had an apparent molecular weight of 95,000-105,000. Structural analysis involving metabolic labeling with [35S]methionine and cleavage with glycosidases revealed the presence of numerous oligosaccharide chains N-linked to a core polypeptide of apparent molecular weight 48,000. A primary localization of the glycoprotein to lysosomes was demonstrated by the coincidence of antibody binding sites with regions of acridine orange uptake, electron immunocytochemical labeling on the inner surface of lysosome-like vacuolar membranes, and preferential association of the glycoprotein with lysosome-enriched subcellular fractions from Percoll gradients. In addition, small quantities of the glycoprotein were detected on endocytic vesicle and plasma membranes. To study the intracellular pathway of the glycoprotein, we used a monoclonal antibody whose binding to the glycoprotein at the cell surface had no effect on the number or subcellular distribution of antigen molecules. Incubation of chicken fibroblasts with monoclonal antibody at 37 degrees C led to the rapid uptake and subsequent delivery of antibody to lysosomes, where antibody was degraded. This process continued undiminished for many hours on cells continuously exposed to the antibody and was not blocked by the addition of cycloheximide. The rate at which antigen sites were replenished in the plasma membrane of cells prelabeled with antibody (t1/2 = 2 min) was essentially equivalent to the rate of internalization of antibody bound to cell surfaces. These results suggest that there is a continuous and rapid exchange of this glycoprotein between plasma membrane and the membranes of endosomes and/or lysosomes.


Finding the evidence: resources and skills for locating information on clinical effectiveness.
Limited time and lack of knowledge about where and how to search for information often present barriers to practitioners who want to locate current best evidence for treating their patients. There is as yet no single place they can go to get an answer to all their questions. High quality clinical studies are difficult to filter out from the mass of information on large databases, and secondary resources of evaluated information are dispersed over hundreds of Internet sites worldwide. This overview presents a practical guide for the busy practitioner who searches only occasionally and needs to maximise the time spent. Major collections of secondary resources are identified and their individual features described briefly. Following this, several services using PubMed are outlined that automatically apply filters for studies with high quality research design. Further sources of information and assistance are listed for those who wish to learn more.


Selecting the right tool for the job.
There are competing ethical concerns when it comes to designing any clinical research study. Clinical trials of possible treatments for Ebola virus are no exception. If anything, the competing ethical concerns are exacerbated in trying to find answers to a deadly, rapidly spreading, infectious disease. The primary goal of current research is to identify experimental therapies that can cure Ebola or cure it with reasonable probability in infected individuals. Pursuit of that goal must be methodologically sound, practical and consistent with prevailing norms governing human subjects research. Some maintain that only randomized controlled trials (RCTs) with a placebo or standard-of-care arm can meet these conditions. We maintain that there are alternative trial designs that can do so as well and that sometimes these are preferable to RCTs.


Impact of Different Exercise Modalities on the Human Gut Microbiome.
In this study we examined changes to the human gut microbiome resulting from an eight-week intervention of either cardiorespiratory exercise (CRE) or resistance training exercise (RTE). Twenty-eight subjects (21 F; aged 18-26) were recruited for our CRE study and 28 subjects (17 F; aged 18-33) were recruited for our RTE study. Fecal samples for gut microbiome profiling were collected twice weekly during the pre-intervention phase (three weeks), intervention phase (eight weeks), and post-intervention phase (three weeks). Pre/post VO2max, three repetition maximum (3RM), and body composition measurements were conducted. Heart rate ranges for CRE were determined by subjects' initial VO2max test. RTE weight ranges were established by subjects' initial 3RM testing for squat, bench press, and bent-over row. Gut microbiota were profiled using 16S rRNA gene sequencing. Microbiome sequence data were analyzed with QIIME 2. CRE resulted in initial changes to the gut microbiome which were not sustained through or after the intervention period, while RTE resulted in no detectable changes to the gut microbiota. For both CRE and RTE, we observe some evidence that the baseline microbiome composition may be predictive of exercise gains. This work suggests that the human gut microbiome can change in response to a new exercise program, but the type of exercise likely impacts whether a change occurs. The changes observed in our CRE intervention resemble a disturbance to the microbiome, where an initial shift is observed followed by a return to the baseline state. More work is needed to understand how sustained changes to the microbiome occur, resulting in differences that have been reported in cross sectional studies of athletes and non-athletes.


Brain metabolism modulates neuronal excitability in a mouse model of pyruvate dehydrogenase deficiency.
Glucose is the ultimate substrate for most brain activities that use carbon, including synthesis of the neurotransmitters glutamate and γ-aminobutyric acid via mitochondrial tricarboxylic acid (TCA) cycle. Brain metabolism and neuronal excitability are thus interdependent. However, the principles that govern their relationship are not always intuitive because heritable defects of brain glucose metabolism are associated with the paradoxical coexistence, in the same individual, of episodic neuronal hyperexcitation (seizures) with reduced basal cerebral electrical activity. One such prototypic disorder is pyruvate dehydrogenase (PDH) deficiency (PDHD). PDH is central to metabolism because it steers most of the glucose-derived flux into the TCA cycle. To better understand the pathophysiology of PDHD, we generated mice with brain-specific reduced PDH activity that paralleled salient human disease features, including cerebral hypotrophy, decreased amplitude electroencephalogram (EEG), and epilepsy. The mice exhibited reductions in cerebral TCA cycle flux, glutamate content, spontaneous, and electrically evoked in vivo cortical field potentials and gamma EEG oscillation amplitude. Episodic decreases in gamma oscillations preceded most epileptiform discharges, facilitating their prediction. Fast-spiking neuron excitability was decreased in brain slices, contributing to in vivo action potential burst prolongation after whisker pad stimulation. These features were partially reversed after systemic administration of acetate, which augmented cerebral TCA cycle flux, glutamate-dependent synaptic transmission, inhibition and gamma oscillations, and reduced epileptiform discharge duration. Thus, our results suggest that dysfunctional excitability in PDHD is consequent to reduced oxidative flux, which leads to decreased neuronal activation and impaired inhibition, and can be mitigated by an alternative metabolic substrate.


Tmc1 is necessary for normal functional maturation and survival of inner and outer hair cells in the mouse cochlea.
The deafness (dn) and Beethoven (Bth) mutant mice are models for profound congenital deafness (DFNB7/B11) and progressive hearing loss (DFNA36), respectively, caused by recessive and dominant mutations of transmembrane cochlear-expressed gene 1 (TMC1), which encodes a transmembrane protein of unknown function. In the mouse cochlea Tmc1 is expressed in both outer (OHCs) and inner (IHCs) hair cells from early stages of development. Immature hair cells of mutant mice seem normal in appearance and biophysical properties. From around P8 for OHCs and P12 for IHCs, mutants fail to acquire (dn/dn) or show reduced expression (Bth/Bth and, to a lesser extent Bth/+) of the K+ currents which contribute to their normal functional maturation (the BK-type current IK,f in IHCs, and the delayed rectifier IK,n in both cell types). Moreover, the exocytotic machinery in mutant IHCs does not develop normally as judged by the persistence of immature features of the Ca2+ current and exocytosis into adulthood. Mutant mice exhibited progressive hair cell damage and loss. The compound action potential (CAP) thresholds of Bth/+ mice were raised and correlated with the degree of hair cell loss. Homozygous mutants (dn/dn and Bth/Bth) never showed CAP responses, even at ages where many hair cells were still present in the apex of the cochlea, suggesting their hair cells never function normally. We propose that Tmc1 is involved in trafficking of molecules to the plasma membrane or serves as an intracellular regulatory signal for differentiation of immature hair cells into fully functional auditory receptors.


SOCS3 is required to temporally fine-tune photoreceptor cell differentiation.
Suppressor of cytokine signaling 3 (SOCS3) is an intracellular, ligand-induced negative feedback modulator of STAT3 activation that acts during inflammation. Here, we demonstrate that SOCS3 expression is important for normal retinal development in the perinatal period. STAT3 is highly activated in the late-embryonic retina, then downregulated at postnatal day 0 (P0), presumably by the depletion of upstream ligands. We found that SOCS3 was required after P0 to shut down the residual STAT3 activation; this loss of activated STAT3 leads to Rhodopsin expression and rod photoreceptor cell differentiation. SOCS3 deficiency failed to terminate STAT3 activation, thereby delaying expression of Rhodopsin and its upstream transcription factor, crx. Development subsequently continued, but its course was temporally erratic, probably because of faulty compensation. Interestingly, SOCS3 protein expression was first detected postnatally, after STAT3 activation was mostly downregulated. It initially appeared in some of the presumptive photoreceptor cells and gradually spread. SOCS3 mRNA level was constant from the late-embryonic to early-postnatal period. Post-transcriptional inhibition of SOCS3 protein expression maintains a high STAT3 activation during late embryogenesis, and after P0, releasing from the inhibition promptly terminates STAT3 activation. Thus, SOCS3 can act as a temporal fine-tuner of STAT3 activation during photoreceptor cell differentiation.


Evolution of NAFLD and Its Management.
The global prevalence of nonalcoholic fatty liver disease (NAFLD) is estimated to be 25% and continues to rise worldwide in the setting of the obesity epidemic. This increase is especially concerning because NAFLD is often a progressive disease that can be associated with significant complications such as liver cirrhosis, hepatocellular carcinoma, and an increase in liver-related and overall mortality. Because of the devastating complications and comorbidities, NAFLD is a very costly disease for the healthcare system, with estimated annual direct medical costs exceeding $100 billion in the United States alone. Given this progressive course, it is imperative to make the diagnosis in patients with risk factors (metabolic syndrome, weight gain, and insulin resistance/diabetes). Once the diagnosis is made, the focus should shift to treatment and monitoring for the development of associated complications. Given that currently no pharmaceutical intervention is approved for the treatment of NAFLD, focus shifts instead to mitigation of risk factors through avoidance of foods that are rich in red meat, trans fats, refined carbohydrates, and high-fructose corn syrup; are low fiber; and have high energy density. The landmark of treatment, however, continues to be weight loss and improvement of insulin resistance, often through a multimodality approach. The current manuscript reviews the clinical phenotypes of NAFLD, its risk factors, and pathogenesis, as well as treatment options including lifestyle modifications and dietary interventions, medical therapies, endoscopic bariatric interventions, and bariatric surgery.


A toxicologic and dermatologic assessment of cinnamyl phenylpropyl materials when used as fragrance ingredients.
The cinnamyl phenylpropyl fragrance ingredients are a diverse group of chemical structures that have similar metabolic and toxicity profiles. A toxicological and dermatological review of these fragrance ingredients is presented. The common characteristic structural element of cinnamyl phenylpropyl materials is an aryl substituted primary alcohol/aldehyde/ester. For high end users, calculated maximum dermal exposures vary from 0.14% to 0.72%; systemic exposures vary from 0.0002 to 0.0280 mg/kg/day. Human dermatological studies show that these materials are not generally irritants or sensitizers at lower exposures from consumer products. Reactions (0.9%) in fragrance sensitive patients were observed with 3-phenyl-1-propanol at 5% in petrolatum. The cinnamyl phenylpropyl materials had low acute toxicity and no significant toxicity in repeat dose oral or dermal toxicity studies. No mutagenic or genotoxic activity in bacteria and mammalian cell line assays was observed. The cinnamyl phenylpropyl alcohol materials participate in the same beta oxidation pathways as their parent cinnamic acid derivatives, including common routes of absorption, distribution, and metabolic detoxification, and exhibit similar toxicological endpoints. Based on the review of available data, it is concluded that these materials would not present a safety concern at current levels of use as fragrance ingredients.


Low Iliofemoral Calcium Score May Predict Higher Survival after EVAR and FEVAR.
Abdominal aortic aneurysm is associated with an increased mortality, mostly cardiovascular events. Moreover, aortoiliac calcification is associated with increased mortality in patients with peripheral occlusive disease. The aim of this study is to assess the potential association between iliofemoral calcification, assessed by calcium score, in patients undergoing infrarenal (endovascular aneurysm repair [EVAR]) or fenestrated endovascular aortic repair (FEVAR) and long-term mortality, particularly caused by cardiac events. All patients with preoperative noncontrast-enhanced computed tomographic scans who underwent infrarenal EVAR and FEVAR of nonruptured abdominal aortic aneurysm between 2004 and 2012 at a single tertiary center were screened for inclusion. Agatston calcium score was measured from the aortic bifurcation to common femoral arteries using a dedicated postprocessing software. The values are presented as median and interquartile range. About 404 (62.05%) of 651 patients who underwent EVAR and FEVAR had sufficient imaging quality to be included. There was no difference in survival between included and excluded patients (P = 0.33). Nine patients (2.2%) died within 30 days of the operation, whereas the remaining were followed up for 6.3 (4.7-8.4) years. The iliofemoral calcium score was 8348 (3830-14,179). Estimated overall survival at 5 years was 73 ± 2%. Patients within the lowest quartile of iliofemoral calcium score had significantly higher overall survival (5 years: 79 ± 4% vs. 71 ± 3%; P = 0.01) and cardiac event-free survival (5 years: 95 ± 2% vs. 91 ± 2%; P = 0.033) when compared with the remaining ones. Calcium score was associated with neither univariate regression analysis with survival (odds ratio, 1.016 [0.988-1.045]; P = 0.268) nor cardiac event-free survival (odds ratio, 1.024 [0.986-1.063]; P = 0.222). Low iliofemoral calcium score may be associated with lower incidence of fatal cardiac events and all-cause long-term mortality after EVAR and FEVAR. This may be partially a reflection of aging and cardiovascular comorbidity but needs to be studied further.


A data-driven approach to optimising the encoding for multi-shell diffusion MRI with application to neonatal imaging.
Diffusion MRI has the potential to provide important information about the connectivity and microstructure of the human brain during normal and abnormal development, noninvasively and in vivo. Recent developments in MRI hardware and reconstruction methods now permit the acquisition of large amounts of data within relatively short scan times. This makes it possible to acquire more informative multi-shell data, with diffusion sensitisation applied along many directions over multiple b-value shells. Such schemes are characterised by the number of shells acquired, and the specific b-value and number of directions sampled for each shell. However, there is currently no clear consensus as to how to optimise these parameters. In this work, we propose a means of optimising multi-shell acquisition schemes by estimating the information content of the diffusion MRI signal, and optimising the acquisition parameters for sensitivity to the observed effects, in a manner agnostic to any particular diffusion analysis method that might subsequently be applied to the data. This method was used to design the acquisition scheme for the neonatal diffusion MRI sequence used in the developing Human Connectome Project (dHCP), which aims to acquire high quality data and make it freely available to the research community. The final protocol selected by the algorithm, and currently in use within the dHCP, consists of 20 b=0 images and diffusion-weighted images at b = 400, 1000 and 2600 s/mm2 with 64, 88 and 128 directions per shell, respectively.


Molecular detection and identification of zygomycetes species from paraffin-embedded tissues in a murine model of disseminated zygomycosis: a collaborative European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG) evaluation.
The present study was performed to assess the interlaboratory reproducibility of the molecular detection and identification of species of Zygomycetes from formalin-fixed paraffin-embedded kidney and brain tissues obtained from experimentally infected mice. Animals were infected with one of five species (Rhizopus oryzae, Rhizopus microsporus, Lichtheimia corymbifera, Rhizomucor pusillus, and Mucor circinelloides). Samples with 1, 10, or 30 slide cuts of the tissues were prepared from each paraffin block, the sample identities were blinded for analysis, and the samples were mailed to each of seven laboratories for the assessment of sensitivity. A protocol describing the extraction method and the PCR amplification procedure was provided. The internal transcribed spacer 1 (ITS1) region was amplified by PCR with the fungal universal primers ITS1 and ITS2 and sequenced. As negative results were obtained for 93% of the tissue specimens infected by M. circinelloides, the data for this species were excluded from the analysis. Positive PCR results were obtained for 93% (52/56), 89% (50/56), and 27% (15/56) of the samples with 30, 10, and 1 slide cuts, respectively. There were minor differences, depending on the organ tissue, fungal species, and laboratory. Correct species identification was possible for 100% (30 cuts), 98% (10 cuts), and 93% (1 cut) of the cases. With the protocol used in the present study, the interlaboratory reproducibility of ITS sequencing for the identification of major Zygomycetes species from formalin-fixed paraffin-embedded tissues can reach 100%, when enough material is available.


The TREC 2004 genomics track categorization task: classifying full text biomedical documents.
The TREC 2004 Genomics Track focused on applying information retrieval and text mining techniques to improve the use of genomic information in biomedicine. The Genomics Track consisted of two main tasks, ad hoc retrieval and document categorization. In this paper, we describe the categorization task, which focused on the classification of full-text documents, simulating the task of curators of the Mouse Genome Informatics (MGI) system and consisting of three subtasks. One subtask of the categorization task required the triage of articles likely to have experimental evidence warranting the assignment of GO terms, while the other two subtasks were concerned with the assignment of the three top-level GO categories to each paper containing evidence for these categories. The track had 33 participating groups. The mean and maximum utility measure for the triage subtask was 0.3303, with a top score of 0.6512. No system was able to substantially improve results over simply using the MeSH term Mice. Analysis of significant feature overlap between the training and test sets was found to be less than expected. Sample coverage of GO terms assigned to papers in the collection was very sparse. Determining papers containing GO term evidence will likely need to be treated as separate tasks for each concept represented in GO, and therefore require much denser sampling than was available in the data sets. The annotation subtask had a mean F-measure of 0.3824, with a top score of 0.5611. The mean F-measure for the annotation plus evidence codes subtask was 0.3676, with a top score of 0.4224. Gene name recognition was found to be of benefit for this task. Automated classification of documents for GO annotation is a challenging task, as was the automated extraction of GO code hierarchies and evidence codes. However, automating these tasks would provide substantial benefit to biomedical curation, and therefore work in this area must continue. Additional experience will allow comparison and further analysis about which algorithmic features are most useful in biomedical document classification, and better understanding of the task characteristics that make automated classification feasible and useful for biomedical document curation. The TREC Genomics Track will be continuing in 2005 focusing on a wider range of triage tasks and improving results from 2004.


Multiple testing in high-throughput sequence data: experiences from Group 8 of Genetic Analysis Workshop 17.
The use of high-throughput sequence data in genetic epidemiology allows the investigation of common and rare variants in the entire genome, thus increasing the amount of information and the potential number of statistical tests performed within one study. As a consequence, the problem of multiple testing may become even more pressing than in previous studies. As an important challenge, the exact number of statistical tests depends on the actual statistical method used. Furthermore, many statistical approaches for the analysis of sequence data require permutation. Thus it may be difficult to also use permutation to estimate correct type I error levels as in genome-wide association studies. In view of this, a separate group at Genetic Analysis Workshop 17 was formed with a focus on multiple testing. Here, we present the approaches used for the workshop. Apart from tackling the multiple testing problem, the new group focused on different issues. Some contributors developed and investigated modifications of existing collapsing methods. Others aimed at improving the identification of functional variants through a reduction and analysis of the underlying data dimensions. Two research groups investigated the overall accumulation of rare variation across the genome and its value in predicting phenotypes. Finally, other investigators left the path of traditional statistical analyses by reversing null and alternative hypotheses and by proposing a novel resampling method. We describe and discuss all these approaches.


Knee pain and joint loading in subjects with osteoarthritis of the knee.
Although treatments for osteoarthritis of the knee are often directed at relieving pain, pain may cause patients to alter how they perform activities to decrease the loads on the joints. The knee-adduction moment is a major determinant of the load distribution between the medial and lateral plateaus. Therefore, the interrelationship between pain and the external knee-adduction moment during walking may be especially important for understanding mechanical factors related to the progression of medial tibiofemoral osteoarthritis. Fifty-three subjects with symptomatic radiographic evidence of osteoarthritis of the knee were studied. These subjects were a subset of those enrolled in a double-blind study in which gait analysis and radiographic and clinical evaluations were performed after a 2-week washout of anti-inflammatory and analgesic treatment. The subjects then took a nonsteroidal anti-inflammatory drug, acetaminophen, or placebo for 2 weeks, and the gait and clinical evaluations were repeated. The change in the peak external adduction moment between the two evaluations was inversely correlated with the change in pain (R = 0.48, p < 0.001) and was significantly different between those whose pain increased (n = 7), decreased (n = 18), or remained unchanged (n = 28) (p = 0.009). Those with increased pain had a significant decrease in the peak external adduction (p = 0.005) and flexion moments (p = 0.023). In contrast, the subjects with decreased pain tended to have an increase in the peak external adduction moment (p = 0.095) and had a significant increase in the peak external extension moment (p = 0.017). The subjects whose pain was unchanged had no significant change in the peak external adduction (p = 0.757), flexion (p = 0.234), or extension (p = 0.465) moments. Thus, decreases in pain among patients with medial tibiofemoral osteoarthritis were related to increased loading of the degenerative portion of the joints. Additional long-term prospective studies are needed to determine whether increased loading during walking actually results in accelerated progression of the disease.


Olive mill wastewater phenolic concentrate as natural antioxidant against lipid-protein oxidative deterioration in chicken meat during storage.
Considering that many plant-derived substances show antioxidant and antimicrobial properties, natural antioxidant administered through feed in livestock animals could increase the shelf life of meat and meat products. The aim of this work was to study the effect of olive oil by-products on chicken meat lipid and protein oxidation and oxidative stability during storage. Two hundred and ninety-seven 22-day-old fast growing (Ross 308) female chicks were randomly assigned to three experimental grower-finisher diets: i) a basal control diet (CTR), ii) CTR diet supplemented with a low dosage (4.8%) of olive mill wastewater extract (L-OW) and iii) CTR diet supplemented with a high dosage (9.9%) of olive mill wastewater extract (H-OW). Breast meat of animals belonging to each experimental group was sliced, overwrapped with oxygen-permeable packaging and analysed at three different storage times (zero, three and seven days). At the three sampling times considered, for all samples, colour coordinates (a*), saturation index, Hue angle, peroxide value, thiobarbituric reactive substance, carbonyl assay and the oxygen radical absorbance capacity determinations were performed. No differences in colour were detected among the groups in all the sampling times considered. In conclusion, the supplementation of chicken diet with olive mill wastewater extract (OW) affected oxidation of meat, retarding lipid and protein oxidation and improving antioxidant activity during storage.


Perioperative management of massive pulmonary hemorrhage after pulmonary endarterectomy.
This study aims to evaluate our approaches and outcomes in patients who developed hemoptysis following pulmonary endarterectomy. Pulmonary endarterectomy was performed in 460 patients at Kartal Koşuyolu Training and Research Hospital between March 2011 and September 2017. Clinical characteristics, perioperative management and postoperative outcomes of 10 patients (2.1%) (4 males, 6 females; mean age 48.3±16.5 years; range 21 to 76 years) with massive pulmonary hemorrhage following pulmonary endarterectomy were evaluated. Mean period of diagnosis for chronic thromboembolic pulmonary hypertension was 17±13.6 months. All patients were New York Heart Association functional class II (n=2), III (n=5) or IV (n=3). For the treatment of massive pulmonary hemorrhage, intraoperative extracorporeal membrane oxygenation was used in six patients (60%), while conservative treatments were used in four patients (40%). In-hospital mortality rate was 50% (n=5); the causes for mortality were septic shock in two patients, multiple organ failure in two patients and intracranial hemorrhage in one patient. Survival was achieved in two patients on extracorporeal membrane oxygenation and three patients receiving conservative treatment. Functional and hemodynamic improvement was observed in all surviving patients. Despite the relatively low incidence of massive pulmonary hemorrhage after pulmonary endarterectomy, it is a potentially fatal complication. Our approach focuses on early diagnosis with a multidisciplinary team and management with bronchoscopy, bronchial blockers and use of extracorporeal membrane oxygenation. The choice of treatment depends on the site and origin of the hemorrhage, the availability of equipment and expertise, and the potential short- and long-term advantages and disadvantages.


Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease.
Nearly all human genetic disorders result from a limited repertoire of mutations in an associated gene or its regulatory elements. We recently described an individual with an inherited form of anemia (alpha-thalassemia) who has a deletion that results in a truncated, widely expressed gene (LUC7L) becoming juxtaposed to a structurally normal alpha-globin gene (HBA2). Although it retains all of its local and remote cis-regulatory elements, expression of HBA2 is silenced and its CpG island becomes completely methylated early during development. Here we show that in the affected individual, in a transgenic model and in differentiating embryonic stem cells, transcription of antisense RNA mediates silencing and methylation of the associated CpG island. These findings identify a new mechanism underlying human genetic disease.


Emerging strategies in the treatment of advanced hepatocellular carcinoma: the role of targeted therapies.
Hepatocellular cancer (HCC) is the fifth most common cause of cancer worldwide and its incidence is increasing as a result of the dissemination of hepatitis B and C virus infection. Surgical resection and liver transplantation are considered the only cures for HCC, but benefit approximately 10-15% of patients. In addition, radiofrequency ablation may is potentially curative for patients' with small HCC. Some patients with unresectable disease confined to the liver may benefit from embolisation or chemoembolisation. In the presence of disease not amenable to loco-regional therapy, median survival is only a few months. Current systemic therapy with cytotoxic chemotherapy induces relatively few responses and has no clear survival benefit. Current interest is focussed on the potential role of targeted therapies based on the key aspects of molecular pathogenesis of HCC, most notably sorafenib, an oral multikinase inhibitor. Recent developments discussed in this article demonstrate the potential benefits of this drug which seems destined to become first-line therapy for advanced HCC.


Endotoxin-induced growth hormone resistance in skeletal muscle.
Inflammation-induced skeletal muscle wasting is a serious clinical problem and arises in part because of resistance to GH-stimulated IGF-I expression. Although it is established that in the liver, resistance develops because of impaired signaling through the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) transduction pathway, together with a more distal defect in STAT5 DNA-binding activity, the situation in skeletal muscle is unclear. Accordingly, we set out to characterize the mechanisms behind the skeletal muscle resistance to GH in rats with acute inflammation induced by endotoxin. Endotoxin caused significant declines in GH-stimulated STAT5a/b phosphorylation and IGF-I gene expression, and this occurred despite a lack of change in signaling protein levels or phosphorylation of JAK2. In whole muscle, GH-stimulated phospho-STAT5a/b levels were reduced by half, and in the nucleus, phospho-STAT5b levels were similarly reduced. Furthermore, the binding of phosphorylated STAT5b to DNA was reduced and to a similar extent to the reduction in nuclear phosphorylated STAT5b. Interestingly, GH-induced androgen receptor gene expression was also suppressed. Thus, it appears that skeletal muscle resistance to GH-stimulated IGF-I expression in acute endotoxemia arises from a defect in STAT5b signaling, with a proportionate reduction in STAT5b DNA binding. Finally, it appears that resistance to GH-induced androgen receptor expression also develops and, together with the attenuated GH-induced IGF-I expression, likely plays an important role in the muscle wasting that arises in endotoxin-induced inflammation.


Cumulative live birth rates and number of oocytes retrieved in women of advanced age. A single centre analysis including 4500 women ≥38 years old.
Is there any relationship between the number of oocytes retrieved and cumulative live birth rates (CLBRs) in women of advanced age? CLBRs increase with the number of oocytes retrieved in women of advanced reproductive age up to 41 years old, the added value is minimal in women more than 41 years and futile in women 44 years or older. CLBR is actually the most relevant outcome of IVF from patients' perspective. There are several studies that have analysed CLBR's but some of them have included several stimulation cycles, others have not included the frozen embryo transfers (FETs) in their analysis and none has focused on women of advanced reproductive age. We aimed to assess CLBR in women ≥38 years after a single stimulation cycle plus the subsequent frozen embryo transfers. This is a retrospective analysis carried out in a University-affiliated tertiary centre between January 2000 and December 2013. Overall, 4570 infertile women aged ≥38 years who underwent their first cycle in our centre were included. Patients were categorized in four age-groups: 38-39 years (G1 = 1875 cycles), 40-41 years (G2 = 1380 cycles), 42-43 years (G3 = 833 cycles) and ≥44 years (G4 = 482 cycles). CLBR's were evaluated by adding the pregnancies and live births achieved in the FET's to the ones obtained in the fresh cycle. In order to find out the actual effect of the number of oocytes retrieved in these patients, a predictive model of CLBR according to age and oocyte yield was built. CLBRs significantly decrease with increasing age among women ≥38 years of age, with the most prominent and clinically relevant decline observed at 42-43 years old, and clear evidence for futility in women aged ≥44 years (25.9% at 38-39 years, 16.4% at 40-41 years, 7% at 42-43 years and 1.2% from 44 years onwards). The higher the number of oocytes retrieved, the higher the CLBR; however, this is more evident up to 41 years old and no clear benefit is observed from 44 years and beyond. Limitations are related to the retrospective nature of the study; however, no significant differences were observed in the treatment protocols used. Other potential limitations could be the fact that embryo cryopreservation was carried out with slow freezing in 80% of cases and that a small proportion of patients still have frozen embryos; nevertheless, we do not expect a relevant impact of these issues as slow freezing showed excellent results that did not differ significantly compared to vitrification and, on the other hand, the extra benefit coming from the FETs was very limited. The number of oocytes retrieved is significantly associated with CLBR also in women of advanced reproductive age. However, the added benefit appears to be restricted mainly in women up to 41 years old. Women over 43 do not experience any benefit in CLBR irrespective of the number of oocytes retrieved, and thus should be discouraged from doing an IVF cycle with their own oocytes; for the other age-groups, recommendations should be given considering the age and the expected ovarian response. None. NA.


Intestinal dysbiosis in children with short bowel syndrome is associated with impaired outcome.
The composition of the intestinal microbiota seems to be an important factor in determining the clinical outcome in children with short bowel syndrome (SBS). Alterations in the microbiota may result in serious complications such as small bowel bacterial overgrowth (SBBO) and intestinal mucosal inflammation that lead to prolonged parenteral nutrition (PN) dependency with subsequently increased risk of liver failure and sepsis. To date, there are no reported mappings of the intestinal microbiome in children with SBS. Here, we present the first report on the intestinal microbial community profile in children with SBS. The study includes children diagnosed with SBS in the neonatal period. Healthy siblings served as controls. Fecal samples were collected, and microbial profiles were analyzed by using 16S rRNA gene sequencing on the Illumina MiSeq platform. We observed a pronounced microbial dysbiosis in children with SBS on PN treatment with an increased and totally dominating relative abundance of Enterobacteriacae in four out of five children compared to children with SBS weaned from PN and healthy siblings. The overall decreased bacterial diversity in children with SBS is consistent with intestinal microbiome mappings in inflammatory bowel diseases such as Crohn's disease and necrotizing enterocolitis in preterm infants. Our findings indicate that intestinal dysbiosis in children with SBS is associated with prolonged PN dependency.


'In the picture': perspectives on living and working with cancer.
We explored working and living with cancer at a large research-intensive National Health Service hospital breast cancer service and adjoining non-governmental organisation (NGO). The project had three elements that were largely autonomous in practice but conceptually integrated through a focus on personalised cancer medicine. Di Sherlock held conversations with staff and patients from which she produced a collection of poems, Written Portraits At the same time, we conducted interviews and observation in the hospital, and hosted a public series of science cafés in the NGO. The trajectory of this project was not predetermined, but we found that the poetry residency provided a context for viewing participation in experimental cancer care and vice versa. Taking themes from the poetry practice, we show how they revealed categories of relevance to participants and illuminated others that circulated in the hospital and NGO. Reciprocally, turning to findings from long-term ethnographic research with patients, we show that their observations were not only representations but also tools for navigating life in waiting with cancer. The categories that we discovered and assembled about living and working with cancer do not readily combine into an encompassing picture, we argue, but instead provide alternating perspectives. Through analysis of different forms of research participation, we hope to contribute to an understanding of how categories are made, recognised and inhabited through situated comparisons. In personalised medicine, category-making is enabled if not dependent on increasingly intensive computation and so the practices seem far removed from mundane processes of interaction. Yet, we emphasise connections with everyday practices, in which people categorise themselves and others routinely according to what they like and resemble.


Impact of a methadone maintenance program on an Aboriginal community: a qualitative study.
Methadone maintenance treatment programs implemented in Aboriginal communities have proven to be beneficial for the control of opioid addiction and its associated consequences, but the perceptions and opinions of different community members about these programs remain elusive. The goal of this study was to determine the perceptions of members of a First Nation community in New Brunswick, Canada, on the implementation of a methadone maintenance treatment program and its effects on the community. We conducted a qualitative study using semistructured focus group discussions with 3 distinct groups composed of health care professionals and influential community members, patients in the methadone maintenance treatment program and community members at large. Thematic analysis of discussion transcripts was performed. A total of 22 partipants were included in the 3 focus groups. All groups of participants expressed that patients in the program are stigmatized and marginalized. Discussions also revealed widespread misconceptions about the program. Participants associated the program with improvements in community-level outcomes and in parenting abilities of patients, but also with difficulties preserving family unity. Despite being culturally adapted to the community, elements surrounding the methadone maintenance treatment program in this First Nation community appear to be misunderstood and stigmatized. It may be beneficial to provide community education on these programs to assure community buy-in for the successful implementation of harm reduction programs in Aboriginal communities.


Transcriptome analysis of pigeon milk production - role of cornification and triglyceride synthesis genes.
The pigeon crop is specially adapted to produce milk that is fed to newly hatched young. The process of pigeon milk production begins when the germinal cell layer of the crop rapidly proliferates in response to prolactin, which results in a mass of epithelial cells that are sloughed from the crop and regurgitated to the young. We proposed that the evolution of pigeon milk built upon the ability of avian keratinocytes to accumulate intracellular neutral lipids during the cornification of the epidermis. However, this cornification process in the pigeon crop has not been characterised. We identified the epidermal differentiation complex in the draft pigeon genome scaffold and found that, like the chicken, it contained beta-keratin genes. These beta-keratin genes can be classified, based on sequence similarity, into several clusters including feather, scale and claw keratins. The cornified cells of the pigeon crop express several cornification-associated genes including cornulin, S100-A9 and A16-like, transglutaminase 6-like and the pigeon 'lactating' crop-specific annexin cp35. Beta-keratins play an important role in 'lactating' crop, with several claw and scale keratins up-regulated. Additionally, transglutaminase 5 and differential splice variants of transglutaminase 4 are up-regulated along with S100-A10. This study of global gene expression in the crop has expanded our knowledge of pigeon milk production, in particular, the mechanism of cornification and lipid production. It is a highly specialised process that utilises the normal keratinocyte cellular processes to produce a targeted nutrient solution for the young at a very high turnover.


Additive effect of latanoprost and dorzolamide in patients with elevated intraocular pressure.
To evaluate the additive ocular hypotensive effect of latanoprost and dorzolamide in combination, on intraocular pressure reduction in patients with elevated intraocular pressure (IOP). Thirty patients with ocular hypertension or early capsular or primary open-angle glaucoma and elevated IOP were randomly assigned to two parallel treatment groups. The treatment period was twenty days. Fifteen patients (Group 1) received latanoprost once daily during the first ten days and, in addition, dorzolamide three times daily during the second ten days. Fifteen patients (Group 2) received dorzolamide three times daily during the first ten days and, in addition latanoprost, once daily during the second ten days. IOP was measured and conjunctival hyperemia was evaluated. In Group 1, the mean IOP on day 0 was 26.8 mm Hg; on day 10, 18.7 mm Hg; and on day 20, 15.9 mm Hg. In Group 2, the mean IOP on day 0 was 26.3 mm Hg; on day 10, 21.2 mm Hg; and on day 20, 16.1 mm Hg. Both groups had clinically significant IOP-lowering effect on day 10 as compared with baseline day (30.2% and 19.4% respectively) (p<0.01). When dorzolamide was added to latanoprost, the additional IOP reduction was 2.8 mm Hg (15%) (p<0.01) compared with 5.1 mm Hg (24.1%) (p<0.01) when latanoprost was added to dorzolamide. No local serious adverse reactions were observed. A mild but statistically significant increase in conjunctival hyperemia was seen in latanoprost applied patients. The results showed that latanoprost and dorzolamide can be combined successfully to reduce IOP with their additive effects.


Patient profiling in heart failure for tailoring medical therapy. A consensus document of the Heart Failure Association of the European Society of Cardiology.
Despite guideline recommendations and available evidence, implementation of treatment in heart failure (HF) is poor. The majority of patients are not prescribed drugs at target doses that have been proven to positively impact morbidity and mortality. Among others, tolerability issues related to low blood pressure, heart rate, impaired renal function or hyperkalaemia are responsible. Chronic kidney disease plays an important role as it affects up to 50% of patients with HF. Also, dynamic changes in estimated glomerular filtration rate may occur during the course of HF, resulting in inappropriate dose reduction or even discontinuation of decongestive or neurohormonal modulating therapy in clinical practice. As patients with HF are rarely naïve to pharmacologic therapies, the challenge is to adequately prioritize or select the most appropriate up-titration schedule according to patient profile. In this consensus document, we identified nine patient profiles that may be relevant for treatment implementation in HF patients with a reduced ejection fraction. These profiles take into account heart rate (<60 bpm or >70 bpm), the presence of atrial fibrillation, symptomatic low blood pressure, estimated glomerular filtration rate (<30 or >30 mL/min/1.73 m2 ) or hyperkalaemia. The pre-discharge patient, frequently still congestive, is also addressed. A personalized approach, adjusting guideline-directed medical therapy to patient profile, may allow to achieve a better and more comprehensive therapy for each individual patient than the more traditional, forced titration of each drug class before initiating treatment with the next.


Neural and Behavioral Outcomes Differ Following Equivalent Bouts of Motor Imagery or Physical Practice.
Despite its reported effectiveness for the acquisition of motor skills, we know little about how motor imagery (MI)-based brain activation and performance evolves when MI (the imagined performance of a motor task) is used to learn a complex motor skill compared to physical practice (PP). The current study examined changes in MI-related brain activity and performance driven by an equivalent bout of MI- or PP-based training. Participants engaged in 5 days of either MI or PP of a dart-throwing task. Brain activity (via fMRI) and performance-related outcomes were obtained using a pre/post/retention design. Relative to PP, MI-based training did not drive robust changes in brain activation and was inferior for realizing improvements in performance: Greater activation in regions critical to refining the motor program was observed in the PP versus MI group posttraining, and relative to those driven via PP, MI led only to marginal improvements in performance. Findings indicate that the modality of practice (i.e., MI vs. PP) used to learn a complex motor skill manifests as differences in both resultant patterns of brain activity and performance. Ultimately, by directly comparing brain activity and behavioral outcomes after equivalent training through MI versus PP, this work provides unique knowledge regarding the neural mechanisms underlying learning through MI.


Ea-GANs: Edge-Aware Generative Adversarial Networks for Cross-Modality MR Image Synthesis.
Magnetic resonance (MR) imaging is a widely used medical imaging protocol that can be configured to provide different contrasts between the tissues in human body. By setting different scanning parameters, each MR imaging modality reflects the unique visual characteristic of scanned body part, benefiting the subsequent analysis from multiple perspectives. To utilize the complementary information from multiple imaging modalities, cross-modality MR image synthesis has aroused increasing research interest recently. However, most existing methods only focus on minimizing pixel/voxel-wise intensity difference but ignore the textural details of image content structure, which affects the quality of synthesized images. In this paper, we propose edge-aware generative adversarial networks (Ea-GANs) for cross-modality MR image synthesis. Specifically, we integrate edge information, which reflects the textural structure of image content and depicts the boundaries of different objects in images, to reduce this gap. Corresponding to different learning strategies, two frameworks are proposed, i.e., a generator-induced Ea-GAN (gEa-GAN) and a discriminator-induced Ea-GAN (dEa-GAN). The gEa-GAN incorporates the edge information via its generator, while the dEa-GAN further does this from both the generator and the discriminator so that the edge similarity is also adversarially learned. In addition, the proposed Ea-GANs are 3D-based and utilize hierarchical features to capture contextual information. The experimental results demonstrate that the proposed Ea-GANs, especially the dEa-GAN, outperform multiple state-of-the-art methods for cross-modality MR image synthesis in both qualitative and quantitative measures. Moreover, the dEa-GAN also shows excellent generality to generic image synthesis tasks on benchmark datasets about facades, maps, and cityscapes.


Feature Screening via Distance Correlation Learning.
This paper is concerned with screening features in ultrahigh dimensional data analysis, which has become increasingly important in diverse scientific fields. We develop a sure independence screening procedure based on the distance correlation (DC-SIS, for short). The DC-SIS can be implemented as easily as the sure independence screening procedure based on the Pearson correlation (SIS, for short) proposed by Fan and Lv (2008). However, the DC-SIS can significantly improve the SIS. Fan and Lv (2008) established the sure screening property for the SIS based on linear models, but the sure screening property is valid for the DC-SIS under more general settings including linear models. Furthermore, the implementation of the DC-SIS does not require model specification (e.g., linear model or generalized linear model) for responses or predictors. This is a very appealing property in ultrahigh dimensional data analysis. Moreover, the DC-SIS can be used directly to screen grouped predictor variables and for multivariate response variables. We establish the sure screening property for the DC-SIS, and conduct simulations to examine its finite sample performance. Numerical comparison indicates that the DC-SIS performs much better than the SIS in various models. We also illustrate the DC-SIS through a real data example.


Crafting Compliance Regime under COVID-19: Using Taiwan's Quarantine Policy as a Case Study.
One year after the World Health Organization declared COVID-19 a global pandemic, governments around the world adopt similar practices in containing the COVID-19 spread. Nevertheless, variation exists in the level of policy compliance, which directly contribute to policy success/failure across countries. As the pandemic continues, pandemic fatigue also decreases the public's willingness to comply. Increasing policy compliance during the remainder of pandemic has become a transnational concern. Using Taiwan's quarantine policy as an example, this article illustrates three aspects to craft an effective compliance regime to fight public health crises like COVID-19: (1) a comprehensive policy mix to reduce heterogeneous compliance barriers that impact different social groups; (2) constant and various policy communication with heterogeneous target audiences; and (3) leveraging and integrating street-level bureaucrats in the policy implementation stages. Taiwan's case provides several policy lessons for other countries: compliance regime is not driven by top-down enforcement but through the integration of policy design and implementation that remove all barriers for compliance. Taiwan's street level bureaucrats are the glue of the compliance regime. This article bears policy implications for policy makers around the world when aiming for increasing policy compliance.


Collective music listening: Movement energy is enhanced by groove and visual social cues.
The regularity of musical beat makes it a powerful stimulus promoting movement synchrony among people. Synchrony can increase interpersonal trust, affiliation, and cooperation. Musical pieces can be classified according to the quality of groove; the higher the groove, the more it induces the desire to move. We investigated questions related to collective music-listening among 33 participants in an experiment conducted in a naturalistic yet acoustically controlled setting of a research concert hall with motion tracking. First, does higher groove music induce (1) movement with more energy and (2) higher interpersonal movement coordination? Second, does visual social information manipulated by having eyes open or eyes closed also affect energy and coordination? Participants listened to pieces from four categories formed by crossing groove (high, low) with tempo (higher, lower). Their upper body movement was recorded via head markers. Self-reported ratings of grooviness, emotional valence, emotional intensity, and familiarity were collected after each song. A biomechanically motivated measure of movement energy increased with high-groove songs and was positively correlated with grooviness ratings, confirming the theoretically implied but less tested motor response to groove. Participants' ratings of emotional valence and emotional intensity correlated positively with movement energy, suggesting that movement energy relates to emotional engagement with music. Movement energy was higher in eyes-open trials, suggesting that seeing each other enhanced participants' responses, consistent with social facilitation or contagion. Furthermore, interpersonal coordination was higher both for the high-groove and eyes-open conditions, indicating that the social situation of collective music listening affects how music is experienced.


Optimisation of intact cell MALDI method for fingerprinting of methicillin-resistant Staphylococcus aureus.
The use of matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry on intact cell microorganisms, Intact Cell MALDI (ICM), has been shown by numerous workers to yield effective species level identification. Early work highlighted the significant effect that variation in culture media, incubation conditions and length of incubation had on the spectra produced. Therefore, in order to achieve reliable and reproducible species level identification and sub-typing of microorganisms from ICM fingerprints, it has been essential to develop standardised methods. For methicillin-resistant Staphylococcus aureus (MRSA), a major nosocomial pathogen, we have developed such a standardised method. In this paper we present the experimental parameters, namely, the incubation period, the number of passages required from lyophilised or stored isolates, the method of deposition of the bacterial cells, the concentration of matrix solution, the drying time of bacterial cells prior to the addition of the matrix solution, the time between preparation of the bacterial/matrix sample and analysis and the MALDI pulsed extraction setting, which were considered during the development of defined methods.


Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis.
Safety of individual probiotic strains approved under Investigational New Drug (IND) policies in cirrhosis with minimal hepatic encephalopathy (MHE) is not clear. The primary aim of this phase I study was to evaluate the safety, tolerability of probiotic Lactobacillus GG (LGG) compared to placebo, while secondary ones were to explore its mechanism of action using cognitive, microbiome, metabolome and endotoxin analysis in MHE patients. Cirrhotic patients with MHE patients were randomised 1:1 into LGG or placebo BID after being prescribed a standard diet and multi-vitamin regimen and were followed up for 8 weeks. Serum, urine and stool samples were collected at baseline and study end. Safety was assessed at Weeks 4 and 8. Endotoxin and systemic inflammation, microbiome using multi-tagged pyrosequencing, serum/urine metabolome were analysed between groups using correlation networks. Thirty MHE patients (14 LGG and 16 placebo) completed the study without any differences in serious adverse events. However, self-limited diarrhoea was more frequent in LGG patients. A standard diet was maintained and LGG batches were comparable throughout. Only in the LGG-randomised group, endotoxemia and TNF-α decreased, microbiome changed (reduced Enterobacteriaceae and increased Clostridiales Incertae Sedis XIV and Lachnospiraceae relative abundance) with changes in metabolite/microbiome correlations pertaining to amino acid, vitamin and secondary BA metabolism. No change in cognition was found. In this phase I study, Lactobacillus GG is safe and well-tolerated in cirrhosis and is associated with a reduction in endotoxemia and dysbiosis.


The social gradient in work and health: a cross-sectional study exploring the relationship between working conditions and health inequalities.
Social inequalities in health are widely examined. But the reasons behind this phenomenon still remain unclear in parts. It is undisputed that the work environment plays a crucial role in this regard. However, the contribution of psychosocial factors at work is unclear and inconsistent, and most studies are limited with regard to work factors and health outcomes. This study, therefore, aimed to explore the role and contribution of various physical and psychosocial working conditions to explaining social inequalities in different self-reported health outcomes. Data from a postal survey among the workforces of four medium-sized and large companies from diverse industries of the secondary sector in Switzerland were used and analysed. The study sample covered 1,846 employees aged 20 and 64 and included significant proportions of unskilled manual workers and highly qualified non-manual workers. Cross tabulations and logistic regression analyses were performed to study multiple associations between social status, work factors and health outcomes. Combinations of educational level and occupational position wee used as a measure of social status or class. Clear social gradients were observed for almost all adverse working conditions and poor health outcomes studied, but in different directions. While physical workloads and other typical blue-collar job characteristics not suprisingly, were found to be much more common among the lower classes, most psychosocial work demands and job resources were more prevalent in the higher classes. Furthermore, workers in lower classes, i.e. with lower educational and occupational status, were more likely to report poor self-rated health, limited physical functioning and long sickness absence, but at the same time were less likely to experience increased stress feelings and burnout symptoms showing a reversed health gradient. Finally, blue-collar job characteristics contributed substantially to the social gradient found in general and physical health outcomes. In contrast, white-collar job characteristics made no contribution to explaining the gradient in these health outcomes, but instead largely explained the reversed social gradient observed for the mental health outcomes. The findings suggest a more differentiated pattern of the commonly found social gradient in health and the differential role of work in this respect.


Routine antenatal anti-D prophylaxis in women who are Rh(D) negative: meta-analyses adjusted for differences in study design and quality.
To estimate the effectiveness of routine antenatal anti-D prophylaxis for preventing sensitisation in pregnant Rhesus negative women, and to explore whether this depends on the treatment regimen adopted. Ten studies identified in a previous systematic literature search were included. Potential sources of bias were systematically identified using bias checklists, and their impact and uncertainty were quantified using expert opinion. Study results were adjusted for biases and combined, first in a random-effects meta-analysis and then in a random-effects meta-regression analysis. In a conventional meta-analysis, the pooled odds ratio for sensitisation was estimated as 0.25 (95% CI 0.18, 0.36), comparing routine antenatal anti-D prophylaxis to control, with some heterogeneity (I² = 19%). However, this naïve analysis ignores substantial differences in study quality and design. After adjusting for these, the pooled odds ratio for sensitisation was estimated as 0.31 (95% CI 0.17, 0.56), with no evidence of heterogeneity (I² = 0%). A meta-regression analysis was performed, which used the data available from the ten anti-D prophylaxis studies to inform us about the relative effectiveness of three licensed treatments. This gave an 83% probability that a dose of 1250 IU at 28 and 34 weeks is most effective and a 76% probability that a single dose of 1500 IU at 28-30 weeks is least effective. There is strong evidence for the effectiveness of routine antenatal anti-D prophylaxis for prevention of sensitisation, in support of the policy of offering routine prophylaxis to all non-sensitised pregnant Rhesus negative women. All three licensed dose regimens are expected to be effective.


Association between high serum total IgE levels and D11S97 on chromosome 11q13 in Japanese subjects.
The genetic linkage of atopy to chromosome 11q13 through maternally derived alleles has been previously reported. Linkage analysis in Japanese families did not confirm the existence of a major gene for atopy at this locus under the model of autosomal dominant inheritance. However, we observed a significant association between serum total IgE levels and genetic markers at this locus both in 14 Japanese atopic families and in 120 unrelated Japanese subjects. We detected eight alleles at the D11S97 locus and eight alleles in the CA/GT repeat region in the fifth intron of the Fc epsilon RI beta gene. A significantly increased frequency of the D11S97/PstI 0.96 kb allele was observed in the chromosomes of the subjects with high serum total IgE levels both in the family study (p < 0.001) and in the population study (p < 0.05). However, multipoint linkage analysis again did not show any evidence for the existence of a major gene regulating atopy on chromosome 11q13 with location scores to -35 under the model of maternal inheritance. Evidence against linkage was confirmed by the non-parametric linkage analysis, using the affected pedigree member method. Also, there was no substitution of isoleucine for leucine in the fourth transmembrane domain of Fc epsilon RI beta (Leu181), which was reported to be responsible for a subset of atopy in the British population. Therefore, the association of serum total IgE levels with chromosome 11q13 indicates that a gene or genes at this locus may contribute to the expression of high IgE levels in the Japanese population as well as in the British population, but the heterogeneity of the genetic regulation of serum total IgE levels is evident between the two populations.


Licochalcone A Upregulates Nrf2 Antioxidant Pathway and Thereby Alleviates Acetaminophen-Induced Hepatotoxicity.
Acetaminophen (APAP) overdose-induced fatal hepatotoxicity is majorly characterized by overwhelmingly increased oxidative stress while enhanced nuclear factor-erythroid 2-related factor 2 (Nrf2) is involved in prevention of hepatotoxicity. Although Licochalcone A (Lico A) upregulates Nrf2 signaling pathway against oxidative stress-triggered cell injury, whether it could protect from APAP-induced hepatotoxicity by directly inducing Nrf2 activation is still poorly elucidated. This study aims to explore the protective effect of Lico A against APAP-induced hepatotoxicity and its underlying molecular mechanisms. Our findings indicated that Lico A effectively decreased tert-butyl hydroperoxide (t-BHP)- and APAP-stimulated cell apoptosis, mitochondrial dysfunction and reactive oxygen species generation and increased various anti-oxidative enzymes expression, which is largely dependent on upregulating Nrf2 nuclear translocation, reducing the Keap1 protein expression, and strengthening the antioxidant response element promoter activity. Meanwhile, Lico A dramatically protected against APAP-induced acute liver failure by lessening the lethality; alleviating histopathological liver changes; decreasing the alanine transaminase and aspartate aminotransferase levels, malondialdehyde formation, myeloperoxidase level and superoxide dismutase depletion, and increasing the GSH-to-GSSG ratio. Furthermore, Lico A not only significantly modulated apoptosis-related protein by increasing Bcl-2 expression, and decreasing Bax and caspase-3 cleavage expression, but also efficiently alleviated mitochondrial dysfunction by reducing c-jun N-terminal kinase phosphorylation and translocation, inhibiting Bax mitochondrial translocation, apoptosis-inducing factor and cytochrome c release. However, Lico A-inhibited APAP-induced the lethality, histopathological changes, hepatic apoptosis, and mitochondrial dysfunction in WT mice were evidently abrogated in Nrf2-/- mice. These investigations firstly implicated that Lico A has protective potential against APAP-induced hepatotoxicity which may be strongly associated with the Nrf2-mediated defense mechanisms.


Functional Validation of Osteoporosis Genetic Findings Using Small Fish Models.
The advancement of human genomics has revolutionized our understanding of the genetic architecture of many skeletal diseases, including osteoporosis. However, interpreting results from human association studies remains a challenge, since index variants often reside in non-coding regions of the genome and do not possess an obvious regulatory function. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary, such as the one offered by animal models. These models enable us to identify causal mechanisms, clarify the underlying biology, and apply interventions. Over the past several decades, small teleost fishes, mostly zebrafish and medaka, have emerged as powerful systems for modeling the genetics of human diseases. Due to their amenability to genetic intervention and the highly conserved genetic and physiological features, fish have become indispensable for skeletal genomic studies. The goal of this review is to summarize the evidence supporting the utility of Zebrafish (Danio rerio) for accelerating our understanding of human skeletal genomics and outlining the remaining gaps in knowledge. We provide an overview of zebrafish skeletal morphophysiology and gene homology, shedding light on the advantages of human skeletal genomic exploration and validation. Knowledge of the biology underlying osteoporosis through animal models will lead to the translation into new, better and more effective therapeutic approaches.


Charging and discharging at the nanoscale: Fermi level equilibration of metallic nanoparticles.
The redox properties of metallic nanoparticles are discussed, in particular the relationships between excess charge, size and the Fermi level of the electrons. The redox potentials are derived using simple electrostatic models to provide a straightforward understanding of the basic phenomena. The different techniques used to measure the variation of Fermi level are presented. Finally, redox aspects of processes such as toxicity, electrochromicity and surface plasmon spectroscopy are discussed.


Nanodiamond for Sample Preparation in Proteomics.
Protein analysis of potential disease markers in blood is complicated by the fact that proteins in plasma show very different abundances. As a result, high-abundance proteins dominate the analysis, which often render the analysis of low-abundance proteins impossible. Depleting high-abundance proteins is one strategy to solve this problem. Here, we present, for the first time, a very simple approach based on selective binding of serum proteins to the surface of nanodiamonds. In our first proof-of-principle experiments, we were able to detect, on average, eight proteins that are present at a concentration of 1 ng/mL (instead of 0.5 ng/mL in the control without sample preparation). Remarkably, we detect proteins down to a concentration of 400 pg/mL after only one simple depletion step. Among the proteins we could analyze are also numerous disease biomarkers, including markers for multiple cancer forms, cardiovascular diseases, or Alzheimer's disease. Remarkably, many of the biomarkers we find also could not be detected with a state-of-the-art ultrahigh-performance liquid chromatography column (which depletes the 64 most-abundant serum proteins).


Sex hormones in alcohol consumption: a systematic review of evidence.
Sex hormones play an important role in establishing sex-distinctive brain structural and functional variations that could contribute to the sex differences in alcohol consumption behavior. Here, we systematically reviewed articles that studied sex hormone impacts on alcohol consumption and alcohol use disorder (AUD). An extensive literature search conducted in MEDLINE, PubMed, Scopus and CINAHL databases identified 776 articles, which were then evaluated for pre-specified criteria for relevance and quality assurance. A total of 50 articles, including 19 human studies and 31 animal studies, were selected for this review. Existing evidence supports the association of increased testosterone level and increased risk for alcohol use and AUD in males but results are inconclusive in females. In contrast, the evidence supports the association of increased estrogen level and increased alcohol use in females, with mixed findings reported in males. Much less is known about the impact of progestins on alcohol use and misuse in human subjects. Future observational and experimental studies conducted in both sexes with a comprehensive hormone panel are needed to elucidate the impact of the interplay between various sex hormone levels during various developmental stages on alcohol use-related phenotypes and AUD.


The relationship between fibromyalgia and interstitial cystitis.
Interstitial cystitis (IC) is a relatively uncommon and enigmatic disorder characterized by pain in the bladder and pelvic region, typically accompanied by urinary urgency and frequency. Fibromyalgia is a more common disorder, with the prominent symptoms being diffuse musculoskeletal pain and fatigue, and it has been well established that there is substantial clinical overlap between fibromyalgia and chronic fatigue syndrome (CFS). Although genitourinary and musculoskeletal symptoms predominate in IC and fibromyalgia respectively, both disorders share a number of features, including similar demographics, "allied conditions" (e.g. irritable bowel syndrome, headaches, etc.), natural history, aggravating factors, and efficacious therapy. We hypothesized that there was substantial clinical overlap between fibromyalgia and IC, and examined cohorts of individuals with these two disorders in parallel, to compare the spectrum of symptomatology. Sixty fibromyalgia patients, 30 IC patients, and 30 age-matched healthy controls were questioned regarding current symptomatology. A dolorimeter examination was also performed in the three groups to assess peripheral nociception. We found that the frequency of current symptoms was very similar for the fibromyalgia and IC groups. Both the fibromyalgia and IC patients displayed increased pain sensitivity when compared to healthy individuals, at both tender and control points. These data suggest that IC and fibromyalgia have significant overlap in symptomatology, and that IC patients display diffusely increased peripheral nociception, as is seen in fibromyalgia. Although central mechanisms have been suspected to contribute to the pathogenesis of fibromyalgia for some time, we speculate that these same types of mechanisms may be operative in IC, which has traditionally been felt to be a bladder disorder.


[Incidence of malignant mesothelioma in Piedmont, 1990-2001].
age-, period-, and cohort-models allowed the prediction ofan increase in mortality from malignant mesotheliomas (MM) in Western Europe, expected to peak between 2015 and 2025 in different Countries, and around 2020 in Italy. Recently, however, a deceleration in the increase has been reported. we updated to 31 december 2001 previous estimates ofMM incidence among residents in the Piedmont region (Italy) and assessed time-trends in incidence. the Registry of Malignant Mesotheliomas actively searches cases in hospital wards and pathology units' records since 1990; since 1996 the database of hospital admissions and discharges is also used. Cases are registered when eligible for inclusion in the National Mesothelioma Registry. the average yearly incidence of pleural MM, computed across four consecutive three-year calendar periods, from 1990-1992 to 1999-2001, increased in both sexes, for histologically confirmed as well as for all cases. No changes were observed in peritoneal MM incidence. the rise in incidence might be due to increased diagnostic awareness for MM. An analysis by birth-cohort, however, revealed a cohort-effect, therefore it is unlikely that diagnostic bias alone could explain the observed trend. Among men residing at diagnosis in the province of Turin, but not among women nor in both sexes outside Turin province, the increase in incidence has levelled off in the most recent calendar period; for them exposures stopped on average seven years earlier than those of residents in other areas of Piedmont.


Orbital exenteration: one size does not fit all.
To evaluate the clinical indications for orbital exenteration in a tertiary referral center and to compare clinicopathologic correlation and cosmetic outcome with previously reported data. Retrospective, nonrandomized, consecutive case series. Review of Electronic Medical Record system, Orbital Clinic, Jules Stein Eye Institute, between January 1999 and December 2003. main outcome measures: Surgery type, clear margins histologically, survival, and wearing an eye patch. Thirty-four patients (mean age 67 years) underwent orbital exenteration; mean follow-up 1.2 +/- 1.5 years (6 months to 6 years). Diagnosis included orbital, ocular, and adnexal malignancies, with squamous and basal cell carcinoma being the most common. Twenty-one patients (62%) underwent total or extended orbital exenteration, and 13 patients (38%) underwent subtotal exenteration including tissue reconstruction. Clear surgical margins were obtained in 23 cases (68%), whereas positive margins were left in 11 cases (32%). Many of the patients preferred an eye patch to cover the surgical region regardless of surgical reconstruction. Only 4 patients (11.8%) who underwent subtotal exenteration with orbital prosthesis did not use a patch. During follow-up period 3 patients expired, only 1 of which was tumor-related. Clinical indications for orbital exenteration remain similar over the last four decades with a higher prevalence of squamous cell carcinoma in our institute. Orbital exenteration is considered curative in cases of basal or squamous cell carcinoma but not in cases of malignant infiltrative processes such as adenoid cystic carcinoma of the lacrimal gland. Patients are likely to wear an eye patch regardless of any attempt at surgical reconstruction.


Unanswered Questions in Contemporary Heart Failure.
The epidemiology of heart failure (HF) is changing. This study aimed to describe questions that arise during the routine care of HF patients that are unanswered by the current literature and describe how the type and focus of these questions has changed over time. Investigators from the National Heart, Lung, and Blood Institute-sponsored Heart Failure Apprentice Network collected and categorized questions from 5 academic hospitals over 12 months. A total of 174 unanswered questions were collected and analyzed. Compared with 2004, there were more unanswered questions about "whether" to use therapies and fewer about "how" to use therapies. There were fewer questions about what therapeutic targets, therapy adjustment, and combination therapies. There were more questions about whether or how to stop therapies and how to add therapies back. Newly prominent topics, not observed in 2004, including novel therapeutics, refractory ventricular tachycardia, right heart failure, and nutrition/frailty, accounted for 24% of questions. Compared with 2004, there are fewer unanswered questions about how to use, adjust, and combine therapies. There were more unanswered questions about whether and how to stop therapies. Almost 25% of unanswered questions dealt with topics indicative of more advanced disease which were not observed in 2004.


Planetary radio astronomy observations from voyager 2 near saturn.
Planetary radio astronomy measurements obtained by Voyager 2 near Saturn have added further evidence that Saturnian kilometric radiation is emitted by a strong dayside source at auroral latitudes in the northern hemisphere and by a weaker source at complementary latitudes in the southern hemisphere. These emissions are variable because of Saturn's rotation and, on longer time scales, probably because of influences of the solar wind and Dione. The electrostatic discharge bursts first discovered by Voyager 1 and attributed to emissions from the B ring were again observed with the same broadband spectral properties and an episodic recurrence period of about 10 hours, but their occurrence frequency was only about 30 percent of that detected by Voyager 1. While crossing the ring plane at a distance of 2.88 Saturn radii, the spacecraft detected an intense noise event extending to above 1 megahertz and lasting about 150 seconds. The event is interpreted to be a consequence of the impact, vaporization, and ionization of charged, micrometer-size G ring particles distributed over a vertical thickness of about 1500 kilometers.


Diffraction of homogeneous and inhomogeneous plane waves by a planar junction between perfectly conducting and impedance half-planes.
The problem of diffraction of homogeneous and inhomogeneous plane waves at the discontinuity formed by perfectly conducting and impedance half-planes is examined by the method of modified theory of physical optics (MTPO). The MTPO integral of the reflected scattered waves by the perfectly conducting half-plane is reconstructed in order to include the effect of the diffracted wave coming from the edge of the impedance half-plane. The integrals are evaluated by a uniform asymptotic method. The results are plotted numerically and compared with the literature.


miR-181a is associated with poor clinical outcome in patients with colorectal cancer treated with EGFR inhibitor.
miR-181a expression is frequently altered in different types of cancer. Members of the Wnt/β-catenin signalling pathway, which is commonly altered in colorectal cancer (CRC), have been reported as molecular interaction partners of miR-181. However, the role of miR-181a expression in CRC and its ability to predict survival and response to agents targeting the epidermal growth factor receptor (EGFR) have not been explored yet. In this study, we analysed 80 patients with wild type KRAS CRC undergoing treatment with the EGFR-targeting monoclonal antibodies cetuximab and panitumumab for metastatic CRC. The KRAS mutational status was determined by pyrosequencing and miR-181a expression was measured by quantitative RT-PCR in CRC tumour tissue and corresponding non-neoplastic colon tissue. The microRNA expression levels were correlated with clinicopathological characteristics. Cancer-specific survival was calculated by univariate and multivariate analyses, and progression-free survival (PFS) during treatment with EGFR-targeting agents was also evaluated. A low miR-181a expression level was associated with poor differentiation of CRC (p=0.04). A Kaplan-Meier curve showed a decreased survival time for patients with low miR-181a expression (p=0.019). Low miR-181a expression was furthermore associated with poor PFS (p=0.015). In conclusion, our data suggest that the miR-181a expression level is associated with poor survival in patients with CRC. Furthermore, miR-181a expression might predict PFS in EGFR-targeted therapy.


A phylogenetic re-evaluation of Arthrinium.
Although the genus Arthrinium (sexual morph Apiospora) is commonly isolated as an endophyte from a range of substrates, and is extremely interesting for the pharmaceutical industry, its molecular phylogeny has never been resolved. Based on morphology and DNA sequence data of the large subunit nuclear ribosomal RNA gene (LSU, 28S) and the internal transcribed spacers (ITS) and 5.8S rRNA gene of the nrDNA operon, the genus Arthrinium is shown to belong to Apiosporaceae in Xylariales. Arthrinium is morphologically and phylogenetically circumscribed, and the sexual genus Apiospora treated as synonym on the basis that Arthinium is older, more commonly encountered, and more frequently used in literature. An epitype is designated for Arthrinium pterospermum, and several well-known species are redefined based on their morphology and sequence data of the translation elongation factor 1-alpha (TEF), beta-tubulin (TUB) and internal transcribed spacer (ITS1, 5.8S, ITS2) gene regions. Newly described are A. hydei on Bambusa tuldoides from Hong Kong, A. kogelbergense on dead culms of Restionaceae from South Africa, A. malaysianum on Macaranga hullettii from Malaysia, A. ovatum on Arundinaria hindsii from Hong Kong, A. phragmites on Phragmites australis from Italy, A. pseudospegazzinii on Macaranga hullettii from Malaysia, A. pseudosinense on bamboo from The Netherlands, and A. xenocordella from soil in Zimbabwe. Furthermore, the genera Pteroconium and Cordella are also reduced to synonymy, rejecting spore shape and the presence of setae as characters of generic significance separating them from Arthrinium.


Outcomes associated with postoperative delirium after cardiac surgery.
Delirium after surgery is a common condition that leads to poor outcomes. Few studies have examined the effect of postoperative delirium on outcomes after cardiac surgery. To assess the relationship between delirium after cardiac surgery and the following outcomes: length of stay after surgery, prevalence of falls, discharge to a nursing facility, discharge to home with home health services, and use of inpatient physical therapy. Electronic medical records of 656 cardiac surgery patients were reviewed retrospectively. Postoperative delirium occurred in 161 patients (24.5%). Patients with postoperative delirium had significantly longer stays (P < .001) and greater prevalence of falls (P < .001) than did patients without delirium. Patients with delirium also had a significantly greater likelihood for discharge to a nursing facility (P < .001) and need for home health services if discharged to home (P < .001) and a significantly higher need for inpatient physical therapy (P < .001). Compared with patients without postoperative delirium, patients who had this complication were more likely to have received zolpidem and benzodiazepines postoperatively and to have a history of arrhythmias, renal disease, and congestive heart failure. Patients who have delirium after cardiac surgery have poorer outcomes than do similar patients without this complication. Development and implementation of an extensive care plan to address postoperative delirium is necessary for cardiac surgery patients who are at risk for or have delirium after the surgery.


The role of antioxidant micronutrients in the prevention of diabetic complications.
Diabetes mellitus is associated with an increased production of reactive oxygen species and a reduction in antioxidant defenses. This leads to oxidative stress, which is partly responsible for diabetic complications. Tight glycemic control is the most effective way of preventing or decreasing these complications. Nevertheless, antioxidant micronutrients can be proposed as adjunctive therapy in patients with diabetes. Indeed, some minerals and vitamins are able to indirectly participate in the reduction of oxidative stress in diabetic patients by improving glycemic control and/or are able to exert antioxidant activity. This article reviews the use of minerals (vanadium, chromium, magnesium, zinc, selenium, copper) and vitamins or cofactors (tocopherol [vitamin E], ascorbic acid [vitamin C], ubidecarenone [ubiquinone; coenzyme Q], nicotinamide, riboflavin, thioctic acid [lipoic acid], flavonoids) in diabetes, with a particular focus on the prevention of diabetic complications. Results show that dietary supplementation with micronutrients may be a complement to classical therapies for preventing and treating diabetic complications. Supplementation is expected to be more effective when a deficiency in these micronutrients exists. Nevertheless, many clinical studies have reported beneficial effects in individuals without deficiencies, although several of these studies were short term and had small sample sizes. However, a randomized, double-blind, placebo-controlled, multicenter trial showed that thioctic acid at an oral dosage of 800 mg/day for 4 months significantly improved cardiac autonomic neuropathy in type 2 diabetic patients. Above all, individuals with diabetes should be educated about the importance of consuming adequate amounts of vitamins and minerals from natural food sources, within the constraints of recommended sugar and carbohydrate intake.


Masculine Gender Ideologies, Intimate Partner Violence, and Alcohol Use Increase Risk for Genital Tract Infections Among Men.
Masculine gender ideologies are thought to underlie alcohol use, intimate partner violence (IPV) perpetration, and sexual risk of HIV and other sexually transmitted infections (STIs). We extend on studies in the Indian context by examining the roles of masculine gender ideologies, alcohol use, and IPV on three outcomes of HIV risk (condom use, genital tract infection [GTI] symptoms, and GTI diagnosis). We applied logistic regression models to cross-sectional data of men and their wives in rural Maharashtra, India (n = 1,080 couples). We found that men with less masculine gender ideologies demonstrated greater odds of condom use (i.e., lower odds no condom use, odds ratio [OR] = 0.96, 95% confidence interval [CI] = [0.93, 0.98]). IPV perpetration was associated with increased odds of reporting ≥1 GTI symptom (adjusted OR [AOR] = 1.56, 95% CI = [1.07, 2.26]) and decreased GTI diagnosis (AOR = 0.28, 95% CI = [0.08, 0.97]). Moderate alcohol consumption was associated with increased odds of reporting ≥1 GTI symptom (AOR = 1.51, 95% CI = [1.01, 2.25]). Our findings have direct implications for men's and women's health in rural India, including targeted GTI diagnosis and treatment, integrated violence prevention in STI clinics, and targeted intervention on masculine gender ideologies.


Insights into the mechanisms of vertical transmission of HIV-1. BIOMED2 Working Group on the in utero transmission of HIV-1.
This paper is a summary of three oral presentations, as well as the ensuing discussion, at the Rijeka/Opatija 3rd Alps Adria Immunology meeting by three members of the European Biomed group on vertical transmission of HIV (G. Chaouat, F. Barre-Sinoussi, G. Scarlatti). This group also involves the laboratories of D. Dormont (CEA, Fontenay aux roses, France), P. Gounon (Electron Microscopy, the Pasteur Institute, France; Irène Athanassakis, University of Crete, Greece; Eva Maria Fenyö, Karolinska Institute, Sweden; and Larry Guilbert, Canada). As such, this paper intends to be neither a review, nor an original article, but rather is an opinion paper discussing the working hypothesis of this network, as well as some of their recent results, which were presented at this meeting. The paper was issued at the request of the organizers of the meeting.


Holistic and biomedical concepts of health: a study of health notions among Swedish occupational therapists and a suggestion for developing an instrument for comparative studies.
The objectives of this study were to inquire into notions of health among a group of 439 Swedish occupational therapists and to test a model derived from a qualitative study by Björklund & Svensson with a representative sample of occupational therapists in Sweden. The data were collected through a questionnaire and were analyzed using descriptive statistics, cluster analysis, and confirmatory factor analysis. The means and ranking of the health notions showed that Swedish occupational therapists most frequently hold holistic notions of health, and to a lesser extent biostatistical ones. Most Swedish occupational therapists indicate that being clearly conscious of one's health notions is important both to themselves and to their profession. The test of the model provides a step towards developing an instrument for measuring notions of health that clearly distinguishes between holistic and biomedical ones and that could possibly be used for comparative studies.


Outpatient management of oral anticoagulation therapy in patients with nonvalvular atrial fibrillation.
Due to heightened risk for thromboembolic complications, nonvalvular atrial fibrillation (NVAF) presents an absolute indication for long-term oral anticoagulation therapy. This was an observational, analytical, randomised, one-year clinical study, conducted in the Blood Transfusion Institute Sarajevo, Bosnia & Herzegovina. The aim of this study was to present the oral anticoagulation treatment in terms of International normalised ratio (INR) monitoring and warfarin/acenocoumarol dose titration in 117 patients with NVAF. INR values, the doses of warfarin and acenocoumarol, as well as the tendency and adequacy of their changes were monitored. Percentages of the therapeutic INR values were 51,77% and 53,62%, subtherapeutic 42,84% and 35,86%, and supratherapeutic 5,39% and 10,53% for the warfarin and acenocoumarol treatment, respectively. The average total weekly doses (TWD) which most frequently achieved the therapeutic INR values were 27,89+/-12,34 mg and 20,44+/-9,94 mg, for warfarin and acenocoumarol, respectively. The dose changes with the INR values 1,7 or lower/3,3 or higher were omitted in 13,46% and 15,63%, and with the INR values 1,8-3,2 were noted in 8,62% and 13,48% of all the check-up visits in the warfarin and acenocoumarol group, respectively. The annual dose changes were noted in 24,65% and 31,41%, and the daily dose changes in 74,43% and 73,36% of all the check-up visits of warfarin and acenocoumarol group, respectively. We can conclude that the management of the oral anticoagulation treatment in our country is in accordance with the relevant recommendations, but with the present tendency toward underdosing and unnecessary frequent dose changing.


Knowledge about and experience of sexually transmissible infections in a representative sample of adults: the Second Australian Study of Health and Relationships.
Background Sexually transmissible infections (STIs) present a substantial public health burden, and are related to modifiable sexual behaviours. Computer-assisted telephone interviews were completed by a population-representative sample of 20 094 men and women aged 16-69 years. The overall participation rate among eligible people was 66.2%. Respondents were asked questions regarding their knowledge about, self-reported history of, and testing for STIs. STI knowledge was better in women, the young, people of higher socioeconomic status, those with a variety of indicators of being at high STI risk and those with a history of receiving sex education in school. Approximately one in six men and women reported a lifetime history of an STI. A history of STI testing in the last year was reported by ~one in six (17%) women and one in eight men (13%) and higher rates of testing in women were reported in most high-risk groups. The highest rates of STI testing (61%) and HIV testing (89%) were reported in homosexual men. Knowledge of STI-related health consequences and transmission is improving in Australians, and rates of STI testing were relatively high but were higher in women than in men. Further increases in testing rates in both sexes will be required to facilitate the early diagnosis and treatment of STIs, which is a cornerstone of STI control.


Transient expression of the intermediate filament nestin during skeletal muscle development.
It has previously been established that skeletal muscle development is accompanied by changes in the composition of intermediate filaments: vimentin is expressed predominantly in myoblasts and desmin in adult myotubes. We show that the intermediate filament transitions during muscle development are more complex, and involve a transient expression of the recently discovered intermediate filament nestin. Nestin RNA is expressed predominantly early, in a biphasic pattern, and is markedly downregulated in adult rat muscle, whereas desmin RNA becomes more abundant throughout development. Nestin protein was found up to the postnatal myotube stage, where it colocalized with desmin in Z bands. The intracellular distribution of nestin, vimentin and desmin was analysed in the human myogenic cell line G6 before and after in vitro differentiation. Despite its more distant evolutionary and structural relationship to the other two intermediate filaments, nestin formed a cytoplasmic filamentous network indistinguishable from that of desmin and vimentin, both in undifferentiated myoblasts and after differentiation to multinuclear myotubes. In conclusion, our data suggest that nestin is an integrated component of the dynamic intermediate filament network during muscle development and that nestin copolymerizes with desmin and vimentin at stages of coexpression.