COMPARE CPM-RMI Trial: Intramyocardial Transplantation of Autologous Bone Marrow-Derived CD133+ Cells and MNCs during CABG in Patients with Recent MI: A Phase II/III, Multicenter, Placebo-Controlled, Randomized, Double-Blind Clinical Trial.
The regenerative potential of bone marrow-derived mononuclear cells (MNCs) and CD133+ stem cells in the heart varies in terms of their pro-angiogenic effects. This phase II/III, multicenter and double-blind trial is designed to compare the functional effects of intramyocardial autologous transplantation of both cell types and placebo in patients with recent myocardial infarction (RMI) post-coronary artery bypass graft. This was a phase II/III, randomized, double-blind, placebo-controlled trial COMPARE CPM-RMI (CD133, Placebo, MNCs - recent myocardial infarction) conducted in accordance with the Declaration of Helsinki that assessed the safety and efficacy of CD133 and MNCs compared to placebo in patients with RMI. We randomly assigned 77 eligible RMI patients selected from 5 hospitals to receive CD133+ cells, MNC, or a placebo. Patients underwent gated single photon emission computed tomography assessments at 6 and 18 months post-intramyocardial transplantation. We tested the normally distributed efficacy outcomes with a mixed analysis of variance model that used the entire data set of baseline and between-group comparisons as well as within subject (time) and group×time interaction terms. There were no related serious adverse events reported. The intramyocardial transplantation of both cell types increased left ventricular ejection fraction by 9% [95% confidence intervals (CI): 2.14% to 15.78%, P=0.01] and improved decreased systolic wall thickening by -3.7 (95% CI: -7.07 to -0.42, P=0.03). The CD133 group showed significantly decreased non-viable segments by 75% (P=0.001) compared to the placebo and 60% (P=0.01) compared to the MNC group. We observed this improvement at both the 6- and 18-month time points. Intramyocardial injections of CD133+ cells or MNCs appeared to be safe and efficient with superiority of CD133+ cells for patients with RMI. Although the sample size precluded a definitive statement about clinical outcomes, these results have provided the basis for larger studies to confirm definitive evidence about the efficacy of these cell types (Registration Number: NCT01167751).


Chronic low-sodium diet in rats: responses to severe heat exposure.
To determine the effects of sodium (Na+) deficiency on the responses to severe heat stress (35.5 degrees C), immature (mean wt 150.4 g) male rats (n = 21) were fed a low-Na+ diet for 71 days. Rates of weight gain and food consumption were significantly (P less than 0.001) reduced in the low-Na+ group, whereas water consumption was unaffected. Prior to heat exposure circulating Na+ levels were unaffected by dietary Na+ restriction, but both circulating potassium (K+) and hematocrit levels were significantly (P less than 0.001) increased. After 24-h exposure to severe heat stress, circulating Na+ levels did manifest a significant (P less than 0.001) decrement in the low-Na+ group. K+ levels increased significantly (P less than 0.01) in the control group after 6 h of heat exposure but remained depressed in comparison with the low-Na+ group after 48 and 72 h. Although plasma renin activity (PRA) was not increased by chronic consumption of the low-Na+ diet or by severe heat exposure in the control group, severe heat stress in the low-Na+ group did elicit significant (P less than 0.005) increments in PRA after 24 h of exposure. Alternatively, plasma aldosterone levels were significantly (P less than 0.001) elevated by both the low-Na+ diet and heat stress. We concluded from these studies that chronic consumption of the low-Na+ diet had severe effects on hematologic, endocrinological, and thermoregulatory variables as well as thermal sensitivity to prolonged and sedentary exposure to severe heat stress.


[New insights into ways of determining cortisol exposure in patients with bipolar disorder].
Previous research has shown a relationship between the stress hormone cortisol and bipolar disorder. The level of cortisol exposure is usually examined by means of measurements that provide a snapshot of cortisol exposure or by means of dynamic testing. Recently, a new technique has been introduced which can measure, retrospectively, the cortisol level in scalp hair over longer periods of time. To provide insight into various methods used in psychiatry for measuring the hypothalamus-pituitary-adrenal (HPA)-axis activity and also to highlight recent research into measurements of cortisol in scalp hair of patients with bipolar disorder. We give a brief overview of the literature relating to HPA-axis testing in psychiatric patients. As a result of our recent studies with 100 patients suffering from bipolar disorder, we are now able to determine the levels of cortisol in scalp hair. Tests that measure hpa activity can be divided into three categories: point measurements, stimulation tests and inhibition tests. In our recent study of bipolar patients we found that a raised level of cortisol in scalp hair was related to a later onset of bipolar disorder (in patients over 30) or to multiple psychiatric diagnoses. Lower levels of cortisol level in scalp hair of bipolar patients were observed in bipolar patients with comorbid panic disorder. The use of hair analysis to measure mean cortisol levels over long periods seems to give added value to the hpa-axis tests currently used for measuring cortisol exposure. The technique may make it easier to differentiate between various subtypes of bipolar disorder.


The application of particle filters in single trial event-related potential estimation.
In this paper, an approach for the estimation of single trial event-related potentials (ST-ERPs) using particle filters (PFs) is presented. The method is based on recursive Bayesian mean square estimation of ERP wavelet coefficients using their previous estimates as prior information. To enable a performance evaluation of the approach in the Gaussian and non-Gaussian distributed noise conditions, we added Gaussian white noise (GWN) and real electroencephalogram (EEG) signals recorded during rest to the simulated ERPs. The results were compared to that of the Kalman filtering (KF) approach demonstrating the robustness of the PF over the KF to the added GWN noise. The proposed method also outperforms the KF when the assumption about the Gaussianity of the noise is violated. We also applied this technique to real EEG potentials recorded in an odd-ball paradigm and investigated the correlation between the amplitude and the latency of the estimated ERP components. Unlike the KF method, for the PF there was a statistically significant negative correlation between amplitude and latency of the estimated ERPs, matching previous neurophysiological findings.


X-ray structure of the arenavirus glycoprotein GP2 in its postfusion hairpin conformation.
Arenaviruses are important agents of zoonotic disease worldwide. The virions expose a tripartite envelope glycoprotein complex at their surface, formed by the glycoprotein subunits GP1, GP2 and the stable signal peptide. This complex is responsible for binding to target cells and for the subsequent fusion of viral and host-cell membranes for entry. During this process, the acidic environment of the endosome triggers a fusogenic conformational change in the transmembrane GP2 subunit of the complex. We report here the crystal structure of the recombinant GP2 ectodomain of the lymphocytic choriomeningitis virus, the arenavirus type species, at 1.8-Å resolution. The structure shows the characteristic trimeric coiled coil present in class I viral fusion proteins, with a central stutter that allows a close structural alignment with most of the available structures of class I and III viral fusion proteins. The structure further shows a number of intrachain salt bridges stabilizing the postfusion hairpin conformation, one of which involves an aspartic acid that appears released from a critical interaction with the stable signal peptide upon low pH activation.


Independent movements of the digits in grasping.
Reaching out for an object is often considered to consist of the control of two components: transporting the hand to the object's position, and scaling the grip to the object's size. We recently proposed an alternative view. According to this view, grasping consists of controlling the digits, not the hypothetical transport and grip. This alternative view assumes that the opening of the hand emerges from the trajectories of the digits. We therefore studied the movements of the digits in grasping. We asked subjects to grasp disks (diameters ranging from 5 to 8 cm) at marked positions with two digits. The positions were at opposite sides of the disk, at the same distance from the starting position, so that the orientation of the surface was the same for both digits. The subjects grasped the disks either with the index finger and thumb of the dominant hand, with the same digits of the non-dominant hand, or bimanually with both index fingers. Our predictions are: that the well-known relation between object size and grip aperture holds for each digit; that the same relation holds if the object is grasped with two hands instead of with the thumb and finger of one hand; that maximum deviation, variability and duration of the digit movements are related; and that variations in the timing of the maximum deviation of one digit are independent of those in the other digit. In accordance with our predictions, we found that the maximum deviation of both digits increased with 0.75 times the object radius, independent of the hand(s) used. The movements of the thumb were more variable than those of the index finger, which was reflected by a larger deviation earlier in the movement. The timing of the maximum deviation of the two digits was independent. These results on the digits' movements are consistent with our view that grasping can be understood as the largely independent movements of the digits. The results are not in conflict with the hypothesis that the grip is controlled during grasping, but can only be explained by extending that hypothesis post hoc.


Anti-oxidative stress regulator NF-E2-related factor 2 mediates the adaptive induction of antioxidant and detoxifying enzymes by lipid peroxidation metabolite 4-hydroxynonenal.
NF-E2-related factor 2 (NRF2) regulates a battery of antioxidative and phase II drug metabolizing/detoxifying genes through binding to the antioxidant response elements (ARE). NRF2-ARE signaling plays a central role in protecting cells from a wide spectrum of reactive toxic species including reactive oxygen/nitrogen species (RONS). 4-hydroxylnonenal (4-HNE) is a major end product from lipid peroxidation of omega-6 polyunsaturated fatty acids (PUFA) induced by oxidative stress, and it is highly reactive to nucleophilic sites in DNA and proteins, causing cytotoxicity and genotoxicity. In this study, we examined the role of NRF2 in regulating the 4-HNE induced gene expression of antioxidant and detoxifying enzymes. When HeLa cells were treated with 4-HNE, NRF2 rapidly transloated into the nucleus, as determined by the distribution of NRF2 tagged with the enhanced green fluorescent protein (EGFP) and increased NRF2 protein in the nuclear fraction. Transcriptional activity of ARE-luciferase was significantly induced by 0.01-10 μM of 4-HNE in a dose-dependent manner, and the induction could be blocked by pretreatment with glutathione (GSH). 4-HNE induced transcriptional expression of glutathione S-transferase (GST) A4, aldoketone reductase (AKR) 1C1 and heme oxygenase-1 (HO-1), and the induction was attenuated by knocking down NRF2 using small interfering RNA. NRF2 is critical in mediating 4-HNE induced expression of antioxidant and detoxifying genes. This may account for one of the major cellular defense mechanisms against reactive metabolites of lipids peroxidation induced by oxidative stress and protect cells from cytotoxicity.


Phenotypic assessment of pulmonary hypertension using high-resolution echocardiography is feasible in neonatal mice with experimental bronchopulmonary dysplasia and pulmonary hypertension: a step toward preventing chronic obstructive pulmonary disease.
Bronchopulmonary dysplasia (BPD) and chronic obstructive pulmonary disease (COPD) are chronic lung diseases of human infants and adults, respectively, that are characterized by alveolar simplification. One-third of the infants with severe BPD develop pulmonary hypertension (PH). More importantly, PH increases morbidity and mortality in BPD patients. Additionally, COPD is a common respiratory morbidity in former BPD patients. The lack of an appropriate small animal model wherein echocardiography (Echo) can demonstrate PH is one of the major barriers to understand the molecular mechanisms of the disease and, thereby, develop rational therapies to prevent and/or treat PH in BPD patients. Thus, the goal of this study was to establish a model of experimental BPD and PH and investigate the feasibility of Echo to diagnose PH in neonatal mice. Since hyperoxia-induced oxidative stress and inflammation contributes to the development of BPD with PH, we tested the hypothesis that exposure of newborn C57BL/6J mice to 70% O2 (hyperoxia) for 14 days leads to lung oxidative stress, inflammation, alveolar and pulmonary vascular simplification, pulmonary vascular remodeling, and Echo evidence of PH. Hyperoxia exposure caused lung oxidative stress and inflammation as evident by increased malondialdehyde adducts and inducible nitric oxide synthase, respectively. Additionally, hyperoxia exposure caused growth restriction, alveolar and pulmonary vascular simplification, and pulmonary vascular remodeling. At 14 days of age, Echo of these mice demonstrated that hyperoxia exposure decreased pulmonary acceleration time (PAT) and PAT/ejection time ratio and increased right ventricular free wall thickness, which are indicators of significant PH. Thus, we have demonstrated the feasibility of Echo to phenotype PH in neonatal mice with experimental BPD with PH, which can aid in discovery of therapies to prevent and/or treat BPD with PH and its sequelae such as COPD in humans.


The contribution of proteomics to understanding epididymal maturation of mammalian spermatozoa.
The acquisition of the ability of the male gamete to fertilize an ovum is the result of numerous and sequential steps of differentiation of spermatozoa that occur as they transit from the testis to the end of the epididymal tubule. The post gonadal sperm modifications are mostly related to motility, egg binding, and penetration processes. As the activity of the epididymis and its luminal fluid composition are believed to be directly related to 'sperm maturation', a review on epididymal proteins is presented. Comparative studies have shown that the epididymal activities are species specific. Nevertheless, for all mammalian species studied, similarities exist in the sequential proteomic changes of the luminal composition of the epididymal tubule and proteins on the sperm surface. The potential roles of these modifications are discussed.


Apelin: A putative novel predictive biomarker for bevacizumab response in colorectal cancer.
Bevacizumab (bvz) is currently employed as an anti-angiogenic therapy across several cancer indications. Bvz response heterogeneity has been well documented, with only 10-15% of colorectal cancer (CRC) patients benefitting in general. For other patients, clinical efficacy is limited and side effects are significant. This reinforces the need for a robust predictive biomarker of response. To identify such a biomarker, we performed a DNA microarray-based transcriptional profiling screen with primary endothelial cells (ECs) isolated from normal and tumour colon tissues. Thirteen separate populations of tumour-associated ECs and 10 of normal ECs were isolated using fluorescence-activated cell sorting. We hypothesised that VEGF-induced genes were overexpressed in tumour ECs; these genes could relate to bvz response and serve as potential predictive biomarkers. Transcriptional profiling revealed a total of 2,610 differentially expressed genes when tumour and normal ECs were compared. To explore their relation to bvz response, the mRNA expression levels of top-ranked genes were examined using quantitative PCR in 30 independent tumour tissues from CRC patients that received bvz in the adjuvant setting. These analyses revealed that the expression of MMP12 and APLN mRNA was significantly higher in bvz non-responders compared to responders. At the protein level, high APLN expression was correlated with poor progression-free survival in bvz-treated patients. Thus, high APLN expression may represent a novel predictive biomarker for bvz unresponsiveness.


Cultural differences and shame in an expressive writing alcohol intervention.
The present study evaluates the relationships between shame, culture, and drinking behavior in predicting drinking intentions in the context of an expressive writing intervention. Theory and empirical findings have generally found that shame is maladaptive and can lead to anxiety, depression, and problematic alcohol use. However, research on cultural differences suggests that shame may be differentially damaging to individuals of collectivist, Asian cultures. Previous research evaluating expressive writing as a brief alcohol intervention has shown promising results such as reduced drinking intentions and increased readiness to change drinking behavior. The present study tested the hypothesis that feelings of shame after writing about a negative heavy drinking event would be associated with greater alcohol use generally and that this effect would differ for Caucasian compared to Asian individuals. We also explored whether this differed for light and heavy drinkers. Two hundred sixty-four undergraduates (74% female) who drank at least one alcoholic beverage in the past month completed measures of demographics, baseline drinking, event-related shame and guilt, pre- and postwriting affect, and drinking intentions. Results revealed that, independent of affect, social desirability, and event-related guilt, shame was generally negatively associated with drinking intentions for Caucasians and light drinking Asians. However, for heavy drinking Asians, shame was associated with increased drinking intentions. Results suggest that interventions that elicit shame are differentially effective and should be targeted accordingly.


Critical physiological factors influencing the outcome of antimicrobial testing according to ISO 22196 / JIS Z 2801.
Bactericidal materials gained interest in the health care sector as they are capable of preventing material surfaces from microbial colonization and subsequent spread of infections. However, commercialization of antimicrobial materials requires proof of their efficacy, which is usually done using in vitro methods. The ISO 22196 standard (Japanese test method JIS Z 2801) is a method for measuring the antibacterial activity of daily goods. As it was found reliable for testing the biocidal activity of antimicrobially active materials and surface coatings most of the laboratories participating in this study used this protocol. Therefore, a round robin test for evaluating antimicrobially active biomaterials had to be established. To our knowledge, this is the first report on inaugurating a round robin test for the ISO 22196 / JIS Z 2801. The first round of testing showed that analyses in the different laboratories yielded different results, especially for materials with intermediate antibacterial effects distinctly different efficacies were noted. Scrutinizing the protocols used by the different participants and identifying the factors influencing the test outcomes the approach was unified. Four critical factors influencing the outcome of antibacterial testing were identified in a series of experiments: (1) incubation time, (2) bacteria starting concentration, (3) physiological state of bacteria (stationary or exponential phase of growth), and (4) nutrient concentration. To our knowledge, this is the first time these parameters have been analyzed for their effect on the outcome of testing according to ISO 22196 / JIS Z 2801. In conclusion, to enable assessment of the results obtained it is necessary to evaluate these single parameters in the test protocol carefully. Furthermore, uniform and robust definitions of the terms antibacterial efficacy / activity, bacteriostatic effects, and bactericidal action need to be agreed upon to simplify communication of results and also regulate expectations regarding antimicrobial tests, outcomes, and materials.


Transient receptor potential vanilloid 1 mediates hyperalgesia and is up-regulated in rats with chronic pancreatitis.
The neurobiologic basis of pancreatic hyperalgesia in chronic pancreatitis (CP) is understood poorly and there is a need to identify novel therapeutic targets. Our aim was to study the role of the transient receptor potential vanilloid 1 (TRPV1), a key integrator of noxious stimuli, in the pathogenesis of pancreatic pain in a rat model of CP. CP was induced in rats by intraductal injection of trinitrobenzene sulfonic acid. TRPV1 currents in pancreas-specific DRG neurons were measured using perforated patch-clamp techniques. Reverse-transcription polymerase chain reaction was used to measure mRNA expression of TRPV1 in these neurons after laser capture microdissection. Immunofluorescence and Western blot analysis, using TRPV1-specific antibodies, also were performed. Pancreatic hyperalgesia was assessed by rat's nocifensive behavior to electrical stimulation of the pancreas. CP was associated with a 4-fold increase in capsaicin-induced current density (P < .02), along with an increase in the proportion of pancreas-specific DRG neurons that responded to capsaicin (52.9% in controls vs 79.0% in CP; P < .05). CP also was associated with a significant increase in TRPV1 expression both at the messenger RNA and protein level in whole thoracic DRGs and pancreas-specific sensory neurons. Systemic administration of the TRPV1 antagonist SB-366791 markedly reduced both visceral pain behavior and referred somatic hyperalgesia in rats with CP, but not in control animals. TRPV1 up-regulation and sensitization is a specific molecular mechanism contributing to hyperalgesia in CP and represents a useful target for treating pancreatic hyperalgesia caused by inflammation.


Temporal Processing Capacity in High-Level Visual Cortex Is Domain Specific.
Prevailing hierarchical models propose that temporal processing capacity--the amount of information that a brain region processes in a unit time--decreases at higher stages in the ventral stream regardless of domain. However, it is unknown if temporal processing capacities are domain general or domain specific in human high-level visual cortex. Using a novel fMRI paradigm, we measured temporal capacities of functional regions in high-level visual cortex. Contrary to hierarchical models, our data reveal domain-specific processing capacities as follows: (1) regions processing information from different domains have differential temporal capacities within each stage of the visual hierarchy and (2) domain-specific regions display the same temporal capacity regardless of their position in the processing hierarchy. In general, character-selective regions have the lowest capacity, face- and place-selective regions have an intermediate capacity, and body-selective regions have the highest capacity. Notably, domain-specific temporal processing capacities are not apparent in V1 and have perceptual implications. Behavioral testing revealed that the encoding capacity of body images is higher than that of characters, faces, and places, and there is a correspondence between peak encoding rates and cortical capacities for characters and bodies. The present evidence supports a model in which the natural statistics of temporal information in the visual world may affect domain-specific temporal processing and encoding capacities. These findings suggest that the functional organization of high-level visual cortex may be constrained by temporal characteristics of stimuli in the natural world, and this temporal capacity is a characteristic of domain-specific networks in high-level visual cortex. Significance statement: Visual stimuli bombard us at different rates every day. For example, words and scenes are typically stationary and vary at slow rates. In contrast, bodies are dynamic and typically change at faster rates. Using a novel fMRI paradigm, we measured temporal processing capacities of functional regions in human high-level visual cortex. Contrary to prevailing theories, we find that different regions have different processing capacities, which have behavioral implications. In general, character-selective regions have the lowest capacity, face- and place-selective regions have an intermediate capacity, and body-selective regions have the highest capacity. These results suggest that temporal processing capacity is a characteristic of domain-specific networks in high-level visual cortex and contributes to the segregation of cortical regions.


Gender perspective in medicine: a vital part of medical scientific rationality. A useful model for comprehending structures and hierarchies within medical science.
During the past few decades, research has reported gender bias in various areas of clinical and academic medicine. To prevent such bias, a gender perspective in medicine has been requested, but difficulties and resistance have been reported from implementation attempts. Our study aimed at analysing this resistance in relation to what is considered good medical research. We used a theoretical model, based on scientific competition, to understand the structures of scientific medicine and how they might influence the resistance to a gender perspective in medicine. The model was originally introduced to discuss how pluralism improves rationality in the social sciences. The model provided a way to conceptualise different fields of research in medicine: basic research, applied research, medical philosophy, and 'empowering' research. It clarified how various research approaches within medicine relate to each other, and how they differ and compete. It also indicated why there might be conflicts between them: basic and applied research performed within the biomedical framework have higher status than gender research and other research approaches that are performed within divergent research paradigms. This hierarchy within medical research contributes to the resistance to a gender perspective, causing gender bias and making medical scientific rationality suboptimal. We recommend that the theoretical model can be applied in a wider medical context when different and hierarchically arranged research traditions are in conflict. In this way, the model might contribute to shape a medical community where scientific pluralism is acknowledged to enlarge, not to disturb, the scientific rationality of medicine.


The viability of hearing protection device fit-testing at navy and marine corps accession points.
The viability of hearing protection device (HPD) verification (i.e., fit-testing) on a large scale was investigated to address this gap in a military accession environment. Personal Attenuation Ratings (PARs) following self-fitted (SELF-Fit) HPDs were acquired from 320 US Marine Corps training recruits (87.5% male, 12.5% female) across four test protocols (1-, 3-, 5-, and 7- frequency). SELF-Fit failures received follow-up to assess potential causes. Follow-up PARs were acquired (Experimenter fit [EXP-Fit], followed by Subject re-fit [SUB Re-Fit]). EXP-Fit was intended to provide a perception (dubbed "ear canal muscle memory") of what a correctly fitted HPD should feel like. SUB Re-Fit was completed following EXP-Fit to determine whether a training recruit could duplicate EXP-Fit on her/his own without assistance. A one-way analysis of variance (ANOVA) (N = 320) showed that SELF-Fit means differed significantly between protocols (P < 0.001). Post-hoc analyses showed that the 1-freq SELF-Fit mean was significantly lower than all other protocols (P < 0.03) by 5.6 dB or more. No difference was found between the multi-frequency protocols. For recruits who were followed up with EXP-Fit (n = 79), across all protocols, a significant (P < 0.001) mean improvement of 25.68 dB (10.99) was found, but PARs did not differ (P = 0.99) between EXP-Fit protocols. For recruits in the 3-freq and 5-freq protocol groups who experienced all three PAR test methods (n = 33), PAR methods differed (P < 0.001) but no method by protocol interaction was found (P = 0.46). Post hoc tests showed that both EXP-Fit and SUB Re-Fit had significantly better attenuation than SELF-Fit (P < 0.001), but no difference was found between EXPFit and SUB Re-Fit (P = 0.59). For SELF-Fit, the 1-freq protocol resulted in a 35% pass rate, whereas the 3-, 5-, and 7-freq protocols resulted in >60% pass rates. Results showed that once recruits experienced how HPDs should feel when inserted correctly, they were able to properly replicate the procedure with similar results to the expert fit suggesting "ear canal muscle memory" may be a viable training strategy concomitant with HPD verification. Fit-test duration was also measured to examine the tradeoff between results accuracy and time required to complete each protocol. Results from this study showed the critical importance of initial selection and fitting of HPDs followed by verification (i.e., fit-testing) at Navy and Marine Corps accession points. Achieving adequate protection from an HPD is fundamentally dependent on obtaining proper fit of the issued HPD as well as the quality of training recruits receive regarding HPD use.


[Clinical analysis of surgically resected multiple primary lung cancer].
Synchronous and metachronous lung cancer is occasionally encountered. Frequency of the occurrence is increasing because of recent progress of imaging technique such as high resolution CT and CT based annual lung survey. We analyzed clinical characteristics of both synchronous and metachronous lung cancer treated surgically in our facility. There were 20 cases of multiple lung cancer cases, which is consisted of 12 synchronous multiple lung cancer cases and 8 metachronous lung cancer cases. Mean age was 62 years old and there were 14 male and 6 female cases. Among synchronous group, 8 cases have multiple shadow in ipsilateral hemithorax and 4 cases in both side. Surgery was carried out according to the extent of the disease and lung reserve. Associated cancer was diagnosed stage IA or IB in all cases. Five-year survival was 58.9%. Meanwhile, as regards to metachronous group, mean interval between first cancer and second cancer was 73 months. Seven cases have contralateral second primary lung cancer and one case has ipsilateral second primary lung cancer. In 3 cases, histology of the first and the second disease were different and in 5 cases that were the same. The first procedures were complete resection with systemic mediastinal LN dissection. The second procedures were determined based on the lung reserve. Pathological stage of the second disease were either stage IA or IB. There were no operative mortality and 5 years survival was 75%. Since there is no operative mortality and the outcome seems satisfactory when the patient has enough lung reserve, aggressive surgical resection should be considered in the case of multiple primary lung cancer. There is an increasing chance of synchronous multiple primary lung cancer because of improvement of imaging system. We have to prepare new therapeutic strategy for those patients.


Cloning and expression of ADAM-related metalloproteases in equine laminitis.
Equine laminitis is a debilitating disease affecting the digital laminae that suspend the distal phalanx within the hoof. While the clinical progression of the disease has been well documented, the molecular events associated with its pathogenesis remain largely unknown. Using real time quantitative PCR (RT-qPCR), we have investigated the expression of genes coding for proteins containing a Disintegrin and Metalloprotease domain (ADAM), as well as genes encoding the natural inhibitors of these enzymes (tissue inhibitor of metalloprotease; TIMP) in horses with naturally-acquired (acute, chronic and aggravated chronic clinical cases) or experimentally-induced (black walnut extract (BWE) and starch gruel models) laminitis. Changes in expression of these enzymes and regulators may underlie the pathologic remodeling of lamellar tissue in laminitis. Genes encoding ADAMs involved in inflammation (ADAM-10 and ADAM-17), as well as those implicated in arthritis (ADAMTS-1, ADAMTS-4 and ADAMTS-5) were cloned, and the sequences used to generate specific oligonucleotide primers for the RT-qPCR experiments. Our results show that genes encoding ADAM-10 and ADAM-17 were not induced in most laminitic animals, whereas ADAMTS-4 gene expression was strongly upregulated in nearly all horses with experimentally-induced and naturally-acquired laminitis. The expression of matrix metalloproteases (MMP)-9 and ADAMTS-5 was also increased in many of the laminitic horses. In addition, TIMP-2 gene expression was decreased in most laminitic horses, whereas expression of genes encoding other TIMPs, namely TIMP-1 and TIMP-3, was randomly increased or decreased in the various models. We conclude that increased expression of lamellar ADAMTS-4 is a common feature of laminitis consistent with a central role of the gene product in the pathophysiology of the disease.


GAGA Regulates Border Cell Migration in Drosophila.
Collective cell migration is a complex process that happens during normal development of many multicellular organisms, as well as during oncological transformations. In Drosophila oogenesis, a small set of follicle cells originally located at the anterior tip of each egg chamber become motile and migrate as a cluster through nurse cells toward the oocyte. These specialized cells are referred to as border cells (BCs) and provide a simple and convenient model system to study collective cell migration. The process is known to be complexly regulated at different levels and the product of the slow border cells (slbo) gene, the C/EBP transcription factor, is one of the key elements in this process. However, little is known about the regulation of slbo expression. On the other hand, the ubiquitously expressed transcription factor GAGA, which is encoded by the Trithorax-like (Trl) gene was previously demonstrated to be important for Drosophila oogenesis. Here, we found that Trl mutations cause substantial defects in BC migration. Partially, these defects are explained by the reduced level of slbo expression in BCs. Additionally, a strong genetic interaction between Trl and slbo mutants, along with the presence of putative GAGA binding sites within the slbo promoter and enhancer, suggests the direct regulation of this gene by GAGA. This idea is supported by the reduction in the slbo-Gal4-driven GFP expression within BC clusters in Trl mutant background. However, the inability of slbo overexpression to compensate defects in BC migration caused by Trl mutations suggests that there are other GAGA target genes contributing to this process. Taken together, the results define GAGA as another important regulator of BC migration in Drosophila oogenesis.


Insights into culturally appropriate latent tuberculosis infection (LTBI) screening in NSW: perspectives of Indian and Pakistani migrants.
Latent tuberculosis (LTBI) case-finding and treatment are a focus of TB elimination in Australia. We sought the perspectives of migrants from two high-burden countries likely to be targeted by this strategy. To understand perceptions of migrant groups in Australia on LTBI screening, 28 in-depth interviews were conducted with Indian and Pakistani community members recruited purposively through local organisations in the Illawarra region, New South Wales. Drawing on local TB policy, data collected qualitatively was analysed using framework methodologies. Australia's immigration system prioritises migrants of higher socioeconomic status. Participants supported elimination but perceived TB as a disease of the poor and not relevant to them. Lack of understanding of LTBI and sensitivity to being 'targeted' are further barriers to screening participation. Information provision and targeting rationale are an essential preamble to LTBI screening. Migration appears to modify cultural attitudes to TB, but not significantly. Despite less stigma surrounding TB in Australian contexts, testing privacy and confidentiality, and limiting public identification of specific groups remain important to program acceptability. Implications for public health: Progress towards TB elimination can be enhanced by consulting with targeted communities, using existing networks for communication and service provision; emphasising prevention benefits.


Lateral epicondylitis in general practice: course and prognostic indicators of outcome.
To investigate the course of lateral epicondylitis and identify prognostic indicators associated with short- and longterm outcome of pain intensity. We prospectively followed patients (n = 349) from 2 randomized controlled trials investigating conservative interventions for lateral epicondylitis in primary care. Uni- and multivariate linear regression analyses were used to investigate the association between potential prognostic indicators and pain intensity (0-100 point scale) measured at 1, 6, and 12 months after randomization. Potential prognostic factors were duration of elbow complaints, concomitant neck pain, concomitant shoulder pain, previous elbow complaints, baseline pain scores, age, gender, involvement of dominant side, social class, and work status. The variables "study" and "treatment" were included as covariates in all models. Pain scores at 1 month followup were higher in patients with severe pain, a long duration of elbow complaints, and concomitant shoulder pain. At 12 month followup, the only different prognostic indicator for poor outcome was concomitant neck pain, in place of shoulder pain. Patients from higher social classes reported lower pain scores at 12 month followup than patients from lower social classes. Lateral epicondylitis seems to be a self-limiting condition in most patients. Long duration of elbow complaints, concomitant neck pain, and severe pain at presentation are associated with poor outcome at 12 months. Our results will help care providers give patients accurate information regarding their prognosis and assist in medical decision-making.


Silymarin efficacy against influenza A virus replication.
The anti-influenza A/PR/8/34 virus activity of silymarin was evaluated in MDCK cells and investigated the effect of silymarin on synthesis of viral mRNAs. Silymarin was investigated for its antiviral activity against influenza A/PR virus using a cytopathic effect (CPE) reduction method. Silymarin exhibited anti-influenza A/PR/8/34 virus activity of 98% with no cytotoxicity at the concentration of 100 μg/ml reducing the formation of a visible CPE. Oseltamivir also did show moderate antiviral activity of about 52% against influenza A/PR/8/34 virus at the concentration of 100 μg/ml. Furthermore, the mechanism of anti-influenza virus action in the inhibition of viral mRNA synthesis was analyzed by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR), and the data indicated an inhibitory effect in late viral RNA synthesis compared with oseltamivir in the presence of 100 μg/ml of silymarin. Therefore, the potential of silymarin for use in treating influenza virus infection merits greater attention.


Neuronal correlates of cognitive reappraisal in borderline patients with affective instability.
Borderline personality disorder has been characterized by enhanced emotional reactivity and deficient emotion regulation in behavioral and functional imaging studies. We aimed to validate patients' difficulties in the cognitive regulation of negative emotions and investigated if emotion regulation deficits are restricted to the decrease of negative emotions. A cognitive reappraisal paradigm was used and hence a regulation strategy that is typically applied in cognitive-behavioral therapy. Fifteen unmedicated female borderline patients with affective instability and 15 healthy female control subjects underwent functional magnetic resonance imaging during a delayed reappraisal paradigm. Hemodynamic responses were measured in response to aversive pictures in an initial viewing phase and a subsequent reappraisal phase with three different conditions: decreasing, increasing, and maintaining the initial emotional reaction. Patients demonstrated enhanced activation of left amygdala and right insula during the initial viewing of aversive stimuli. During attempting to decrease the initial emotional reaction, patients showed attenuated activation of the left orbitofrontal cortex and increased activation of the bilateral insula. The attempt to increase negative emotions resulted in enhanced activity in amygdala and insula, whereas no group differences were found. The results point to the role of two distinguishable processes of emotional difficulties in borderline personality disorder: enhanced emotional reactivity as well as deficits of voluntarily decreasing aversive emotions by means of cognitive reappraisal. The results suggest the neuronal substrate of deficits in explicit emotion regulation in the orbitofrontal cortex, which is in line with previous findings of a dysfunctional prefrontal network in borderline personality disorder.


Challenging diagnosis: adult respiratory distress syndrome.
ARDS patients require nursing care on all levels. Basic care such as turning and prevention of fatigue, as well as nursing care necessitated by mechanical ventilation and hemodynamic monitoring, is needed. Because nurses are the only professionals at the bedside around the clock, we are in the unique position to make a difference for ARDS patients. There is no cure yet for ARDS; therefore, appropriate supportive nursing care is of paramount importance.


Antimicrobial properties, antioxidant activity and bioactive compounds from six wild edible mushrooms of western ghats of Karnataka, India.
Methanolic extracts of 6 wild edible mushrooms isolated from the Western Ghats of Karnataka were used in this study. Among the isolates (Lycoperdon perlatum, Cantharellus cibarius, Clavaria vermiculris, Ramaria formosa, Marasmius oreades, Pleurotus pulmonarius), only 4 showed satisfactory results. Quantitative analysis of bioactive components revealed that total phenols are the major bioactive component found in extracts of isolates expressed as mg of GAE per gram of fruit body, which ranged from 3.20 ± 0.05 mg/mL to 6.25 ± 0.08 mg/mL. Average concentration of flavonoid ranged from 0.40 ± 0.052 mg/mL to 2.54 ± 0.08 mg/mL; followed by very small concentration of ascorbic acid (range, 0.06 ± 0.01 mg/mL to 0.16 ± 0.01 mg/mL) in all the isolates. All the isolates showed high phenol and flavonoid content, but ascorbic acid content was found in traces. Antioxidant efficiency by inhibitory concentration on 1,1-Diphenly-2-picrylhydrazyl (DPPH) was found significant when compared to standard antioxidant like Buthylated hydroxyanisol (BHA). The concentration (IC(50)) ranged from 0.94 ± 0.27 mg/mL to 7.57 ± 0.21 mg/mL. Determination of antimicrobial activity profile of all the isolates tested against a panel of standard pathogenic bacteria and fungi indicated that the concentrations of bioactive components directly influence the antimicrobial capability of the isolates. Agar diffusion assay showed considerable activity against all bacteria. Minimum inhibitory concentration values of the extracts of 4 isolates showed that they are also active even in least concentrations. These results are discussed in relation to therapeutic value of the studied mushrooms.


Frontline health workers as brokers: provider perceptions, experiences and mitigating strategies to improve access to essential medicines in South Africa.
Front-line health providers have a unique role as brokers (patient advocates) between the health system and patients in ensuring access to medicines (ATM). ATM is a fundamental component of health systems. This paper examines in a South African context supply- and demand- ATM barriers from the provider perspective using a five dimensional framework: availability (fit between existing resources and clients' needs); accessibility (fit between physical location of healthcare and location of clients); accommodation (fit between the organisation of services and clients' practical circumstances); acceptability (fit between clients' and providers' mutual expectations and appropriateness of care) and affordability (fit between cost of care and ability to pay). This cross-sectional, qualitative study uses semi-structured interviews with nurses, pharmacy personnel and doctors. Thirty-six providers were purposively recruited from six public sector Community Health Centres in two districts in the Eastern Cape Province representing both rural and urban settings. Content analysis combined structured coding and grounded theory approaches. Finally, the five dimensional framework was applied to illustrate the interconnected facets of the issue. Factors perceived to affect ATM were identified. Availability of medicines was hampered by logistical bottlenecks in the medicines supply chain; poor public transport networks affected accessibility. Organization of disease programmes meshed poorly with the needs of patients with comorbidities and circular migrants who move between provinces searching for economic opportunities, proximity to services such as social grants and shopping centres influenced where patients obtain medicines. Acceptability was affected by, for example, HIV related stigma leading patients to seek distant services. Travel costs exacerbated by the interplay of several ATM barriers influenced affordability. Providers play a brokerage role by adopting flexible prescribing and dispensing for 'stable' patients and aligning clinic and social grant appointments to minimise clients' routine costs. Occasionally they reported assisting patients with transport money. All five ATM barriers are important and they interact in complex ways. Context-sensitive responses which minimise treatment interruption are needed. While broad-based changes encompassing all disease programmes to improve ATM are needed, a beginning could be to assess the appropriateness, feasibility and sustainability of existing brokerage mechanisms.


Relationship between pregame concentrations of free testosterone and outcome in rugby union.
To assess the measures of salivary free testosterone and cortisol concentrations across selected rugby union matches according to game outcome. Twenty-two professional male rugby union players were studied across 6 games (3 wins and 3 losses). Hormone samples were taken 40 min before the game and 15 min after. The hormonal data were grouped and compared against competition outcomes. These competition outcomes included wins and losses and a game-ranked performance score (1-6). Across the entire team, pregame testosterone concentrations were significantly higher during winning games than losses (P = 5.8 × 10-5). Analysis by playing position further revealed that, for the backs, pregame testosterone concentrations (P = 3.6 × 10-5) and the testosterone-to-cortisol ratio T:C (P = .038) were significantly greater before a win than a loss. Game-ranked performance score correlated to the team's pregame testosterone concentrations (r = .81, P = .049). In backs, pregame testosterone (r = .91, P = .011) and T:C (r = .81, P = .05) also correlated to game-ranked performance. Analysis of the forwards' hormone concentrations did not distinguish between game outcomes, nor did it correlate with game-ranked performance. Game venue (home vs away) only affected postgame concentrations of testosterone (P = .018) and cortisol (P = 2.58 × 10-4). Monitoring game-day concentrations of salivary free testosterone may help identify competitive readiness in rugby union matches. The link between pregame T:C and rugby players in the back position suggests that monitoring weekly training loads and enhancing recovery modalities between games may also assist with favorable performance and outcome in rugby union matches.


Discovery of the novel candidate phylum "Poribacteria" in marine sponges.
Marine sponges (Porifera) harbor large amounts of commensal microbial communities within the sponge mesohyl. We employed 16S rRNA gene library construction using specific PCR primers to provide insights into the phylogenetic identity of an abundant sponge-associated bacterium that is morphologically characterized by the presence of a membrane-bound nucleoid. In this study, we report the presence of a previously unrecognized evolutionary lineage branching deeply in the domain Bacteria that is moderately related to the Planctomycetes, Verrucomicrobia, and Chlamydia lines of decent. Because members of this lineage showed <75% 16S rRNA gene sequence similarity to known bacterial phyla, we suggest the status of a new candidate phylum, named "Poribacteria", to acknowledge the affiliation of the new bacterium with sponges. The affiliation of the morphologically conspicuous sponge bacterium with the novel phylogenetic lineage was confirmed by fluorescence in situ hybridization with newly designed probes targeting different sites of the poribacterial 16S rRNA. Consistent with electron microscopic observations of cell compartmentalization, the fluorescence signals appeared in a ring-shaped manner. PCR screening with "Poribacteria"-specific primers gave positive results for several other sponge species, while samples taken from the environment (seawater, sediments, and a filter-feeding tunicate) were PCR negative. In addition to a report for Planctomycetes, this is the second report of cell compartmentalization, a feature that was considered exclusive to the eukaryotic domain, in prokaryotes.


Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1.
HER4 expression in human breast cancers correlates with a positive prognosis. While heregulin inhibits the growth of HER4-positive breast cancer cells, it does so by undefined mechanisms. We demonstrate that heregulin-induced HER4 activity inhibits cell proliferation and delays G(2)/M progression of breast cancer cells. While investigating pathways of G(2)/M delay, we noted that heregulin increased the expression of BRCA1 in a HER4-dependent, HER2-independent manner. Induction of BRCA1 by HER4 occurred independently of the cell cycle. Moreover, BRCA1 expression was elevated in HER4-postive human breast cancer specimens. Heregulin stimulated c-Jun N-terminal kinase (JNK), and pharmacologic inhibition of JNK impaired heregulin-enhanced expression of BRCA1 and mitotic delay; inhibition of Erk1/2 did not. Knockdown of BRCA1 with small interfering RNA in a human breast cancer cell line interfered with HER4-mediated mitotic delay. Heregulin/HER4-dependent mitotic delay was examined further with an isogenic pair of mouse mammary epithelial cells (MECs) derived from mice harboring homozygous LoxP sites flanking exon 11 of BRCA1, such that one cell line expressed BRCA1 while the other cell line, after Cre-mediated excision, did not. BRCA1-positive MECs displayed heregulin-dependent mitotic delay; however, the isogenic BRCA1-negative MECs did not. These results suggest that heregulin-mediated growth inhibition in HER4-postive breast cancer cells requires BRCA1.


The antibody response in human autoimmune thyroid disease.
1. The analysis of the antibody response in autoimmune thyroid disease has followed several historical trends. It was the investigation of thyroid-reactive antibody that allowed the initial characterization of the three principle thyroid autoantigens, thyroglobulin, thyroid peroxidase and the thyroid stimulating hormone receptor. 2. Analysis can be grouped under two broad areas: analysis of the physiological and pathological effects of the antibody, and analysis of the structure of the antibodies themselves. This review will focus on the latter. 3. Within recent years there has been a great increase in knowledge of thyroid-reactive antibody structure, principally through the adoption of phage display combinatorial library methodologies. While this latter technique has established some general principles for antibodies to thyroglobin and especially thyroid peroxidase, there is still a substantial gap in our knowledge of the antibody response to the thyroid stimulating hormone receptor. 4. Thyroid peroxidase antibodies have a relatively restricted V-region usage, and there is a correlation between the V-regions used and the epitope on thyroid peroxidase bound. In particular the V kappa light chain V kappa I(O12), is associated with reactivity to one epitope. 5. The purpose of this review is to bring together the latest results concerning the molecular analysis of the antibody response in autoimmune thyroid disease, to highlight areas of ignorance and conflict, and to discuss the methods adopted to circumvent the problems associated with analysis of the antibody response.


The Role of Monocytes and Macrophages in Autoimmune Diseases: A Comprehensive Review.
Monocytes (Mo) and macrophages (Mϕ) are key components of the innate immune system and are involved in regulation of the initiation, development, and resolution of many inflammatory disorders. In addition, these cells also play important immunoregulatory and tissue-repairing roles to decrease immune reactions and promote tissue regeneration. Several lines of evidence have suggested a causal link between the presence or activation of these cells and the development of autoimmune diseases. In addition, Mo or Mϕ infiltration in diseased tissues is a hallmark of several autoimmune diseases. However, the detailed contributions of these cells, whether they actually initiate disease or perpetuate disease progression, and whether their phenotype and functional alteration are merely epiphenomena are still unclear in many autoimmune diseases. Additionally, little is known about their heterogeneous populations in different autoimmune diseases. Elucidating the relevance of Mo and Mϕ in autoimmune diseases and the associated mechanisms could lead to the identification of more effective therapeutic strategies in the future.


Pacemaker technology: an overview.
Cardiac pacing has evolved considerably over the past 30 years. Early pacemakers were nonprogrammable asynchronous devices which prevented asystole, syncope, and death. The current generation of implantable devices is much more sophisticated. With multiprogrammable features, these devices are intended not only to save life but also to improve the quality of life. This chapter reviews the pacemaker mode-code, indications, electronic circuitry, power sources, and programmable/telemetry features of current devices.


Identifying subtypes of dual alcohol and marijuana users: a methodological approach using cluster analysis.
Alcohol is the most common psychoactive substance used with marijuana. However, little is known about the potential impact of different levels of use of both alcohol and marijuana and their influence on risky behaviors, injuries and psychosocial functioning. A systematic approach to identifying patterns of alcohol and marijuana use associated with increased risks has not yet been identified in the literature. We report on the secondary analysis of data collected from a RCT conducted in a busy urban emergency department. Cluster analysis was performed on the patterns of past 30-day alcohol and marijuana use in two random subsamples N₁=210 and N₂=217. Four distinct subtypes of those who use both alcohol and marijuana were identified: (1) Daily Marijuana and Weekly Alcohol users; (2) Weekly Alcohol and Weekly Marijuana users; (3) Daily Alcohol and Daily Marijuana users; and (4) Daily Alcohol, Weekly Marijuana users. The four subtypes were replicated in both subsamples and examination of the external validity using ANOVA to determine cluster differences on psychosocial and behavioral variables confirmed the theoretical relevance of different patterns of alcohol and marijuana use. There were significantly different psychosocial negative consequences and related risky behaviors among subtypes. We found that Daily Alcohol and Daily Marijuana users are at the highest risk to experience more negative consequences and engage in a broader spectrum of risky behaviors related to both substances, than the other three types of alcohol and marijuana users.


Uncertainty and variability in models of the cardiac action potential: Can we build trustworthy models?
Cardiac electrophysiology models have been developed for over 50years, and now include detailed descriptions of individual ion currents and sub-cellular calcium handling. It is commonly accepted that there are many uncertainties in these systems, with quantities such as ion channel kinetics or expression levels being difficult to measure or variable between samples. Until recently, the original approach of describing model parameters using single values has been retained, and consequently the majority of mathematical models in use today provide point predictions, with no associated uncertainty. In recent years, statistical techniques have been developed and applied in many scientific areas to capture uncertainties in the quantities that determine model behaviour, and to provide a distribution of predictions which accounts for this uncertainty. In this paper we discuss this concept, which is termed uncertainty quantification, and consider how it might be applied to cardiac electrophysiology models. We present two case studies in which probability distributions, instead of individual numbers, are inferred from data to describe quantities such as maximal current densities. Then we show how these probabilistic representations of model parameters enable probabilities to be placed on predicted behaviours. We demonstrate how changes in these probability distributions across data sets offer insight into which currents cause beat-to-beat variability in canine APs. We conclude with a discussion of the challenges that this approach entails, and how it provides opportunities to improve our understanding of electrophysiology.


Quality and bioactive compounds of blends of Arabica and Robusta spray-dried coffee.
The objective of this study was to develop both a possible process and a spray-dried coffee product with a balanced content of bioactive compounds. Spray-dried coffees were prepared by mixing different ratios of medium-roasted Coffea canephora (R) with green Coffea arabica (A) beans. Overall, quality characteristics of spray-dried coffees were not different. The dominant signals of 1D 1H NMR were identified as trigonelline, caffeine and chlorogenic and organic acids. Principal component analysis explained 81.8% of the total variance. Roasted Robusta spray-dried coffee was clearly distinguished from blended coffees. Forty-two volatile compounds were identified. An increase in green Arabica mixed with roasted Robusta in the blends resulted in an increase in 5-caffeoylquinic acid but a decrease in caffeine contents. Spray-dried coffee prepared from a A35:R65 showed greater total phenolic content and antioxidant activity due to a balance in bioactive compounds. In addition, its coffee brew obtained the highest overall liking score.


FOCUS 1: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia.
Ceftaroline, the active form of the prodrug ceftaroline fosamil, is a novel cephalosporin with bactericidal activity against important pathogens associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and common Gram-negative pathogens. FOCUS 1 is a randomized, double-blinded, Phase III study that was conducted to evaluate the efficacy and safety of ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) ≥ -10%] in clinical cure rates achieved with ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations. Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Patients also received two 500 mg doses of oral clarithromycin every 12 h administered on day 1. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 1 registration number NCT00621504 (http://clinicaltrials.gov/ct2/show/NCT00621504). Of 613 enrolled patients, 298 received ceftaroline fosamil and 308 received ceftriaxone. Baseline characteristics between treatment groups were comparable. Clinical cure rates were as follows: CE population, 86.6% (194/224) for ceftaroline fosamil and 78.2% (183/234) for ceftriaxone [difference (95% CI), 8.4% (1.4, 15.4)]; and MITTE population, 83.8% (244/291) for ceftaroline fosamil and 77.7% (233/300) for ceftriaxone [difference (95% CI), 6.2% (-0.2, 12.6)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE population were 88.9% (24/27) and 66.7% (20/30) for ceftaroline fosamil and ceftriaxone, respectively. Both agents were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations because of an AE. The most common AEs for ceftaroline fosamil-treated patients were diarrhoea, headache, insomnia and nausea, and the most common AEs for ceftriaxone-treated patients were hypokalaemia, hypertension, nausea and diarrhoea. Ceftaroline fosamil demonstrated high clinical cure and microbiological response rates in hospitalized patients with CAP of PORT risk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile similar to that of ceftriaxone and consistent with the cephalosporin class. In this study, ceftaroline fosamil was an effective and well-tolerated treatment option for CAP.


Strong plasmonic confinement and optical force in phosphorene pairs.
The plasmonic responses in the spatially separated phosphorene (single-layer black phosphorus) pairs are investigated, mainly containing the field enhancement, light confinement, and optical force. It is found that the strong anisotropic dispersion of black phosphorus gives rise to the direction-dependent symmetric and anti-symmetric plasmonic modes. Our results demonstrate that the symmetrical modes possess stronger field enhancement, higher light confinement, and larger optical force than the anti-symmetric modes in the nanoscale structures. Especially, the light confinement ratio and optical force for the symmetric mode along the armchair direction of black phosphorus can reach as high as >90% and >3000 pN/mW, respectively. These results may open a new door for the light manipulation at nanoscale and the design of black phosphorus based photonic devices.


Anthropometric methods in evaluation of chronic obstructive pulmonary disease.
Chronic Obstructive Pulmonary Disease (COPD) is mainly expressed by weight loss with especially fat-free mass (FFM) depletion and a low body weight correlates with increased mortality and a poor prognosis. We investigated whether anthropometric body composition equations could be used for evaluation of the body composition in COPD. Thirty clinically stable patients with COPD and 13 healthy age matched control subjects underwent the skinfolds and circumference measurements in addition to body mass index (BMI) calculations. Body fat mass (BFM) and FFM were determined by using anthropometric equations. The percent BFM, predicted from body density either using Siri's or Brozek's equations was determined lower than that of calculated with equations by using BMI, age and gender. The values of BFM and body weight were reduced in patients with FEV1 < % predicted compared to other participants. The FFM values also dropped depending on the severity of COPD. BMI was not statistically different among the participants while FFM index (FFMI) reflected the nutritional status of the disorders. Anthropometric equations easily and cost effectively applied for prediction of % BFM, FFM, and FFMI in patients with COPD. In addition, the FFMI can be possibly used for expressing COPD severity.


FRS2-dependent SRC activation is required for fibroblast growth factor receptor-induced phosphorylation of Sprouty and suppression of ERK activity.
Activation of signalling by fibroblast growth factor receptor leads to phosphorylation of the signalling attenuator human Sprouty 2 (hSpry2) on residue Y55. This event requires the presence of the signalling adaptor fibroblast growth factor receptor substrate 2 (FRS2). The phosphorylation of hSpry2 is therefore mediated by an intermediate kinase. Using a SRC family kinase-specific inhibitor and mutant cells, we show that hSpry2 is a direct substrate for SRC family kinases, including SRC itself. Activation of SRC via fibroblast growth factor signalling is dependent upon FRS2 and fibroblast growth factor receptor kinase activity. SRC forms a complex with hSpry2 and this interaction is enhanced by hSpry2 phosphorylation. Phosphorylation of hSpry2 is required for hSpry2 to inhibit activation of the extracellular signal-regulated kinase pathway. These results show that recruitment of SRC to FRS2 leads to activation of signal attenuation pathways.


Theoretical foundations guiding culture change: The work of the Partnerships in Dementia Care Alliance.
Longstanding concerns about quality care provision, specifically in the area of long-term care, have prompted calls for changing the culture of care to reflect more client-driven and relationship-centred models. Despite an increase in culture change initiatives in both Canada and the United States, there is insufficient information about the theories and approaches that guide culture change. The purpose of this paper is to describe a culture change initiative currently underway in Canada, the Partnerships in Dementia Care Alliance, and the theoretical foundations informing our work. More specifically, we describe how the theoretical and philosophical underpinnings of the Alzheimer Disease and Related Dementias framework, the authentic partnership approach, participatory action research and Appreciative Inquiry have been integrated to guide a culture change process that encourages working collaboratively, thinking and doing differently and re-imagining new possibilities for changing the culture of dementia care.


Work done on a single-particle gas during an adiabatic compression and expansion process.
We compute the average work done by an external agent, driving a piston at constant speed, over a single-particle gas going through an adiabatic compression and expansion process. To do so, we get the analytical expression relating the number of collisions between the piston and the particle with the position of the piston during the process. The ergodicity breaking of the system during the process is identified as the source of its irreversibility. In addition, we observe that by using particular initial distributions for the state of the particle, it is possible to preclude the possibility of a net energy transfer from the agent to the particle during the process.


Evaluation of the Personal Impact Health Assessment Questionnaire (PI HAQ) to capture the impact of disability in osteoarthritis.
Measuring facts about disability may not reflect their personal impact. An individualized values instrument has been used to weight difficulty in performing activities of daily living in rheumatoid arthritis, and calculate personal impact (Personal Impact Health Assessment Questionnaire; PI HAQ). This study aimed to evaluate the PI HAQ in osteoarthritis (OA). Study 1: 51 people with OA completed short and long versions of the value instrument at 0 and 1 week. Study 2: 116 people with OA completed the short value instrument, disability and psychological measures at 0 and 4 weeks. Study 1: The eight-category and 20-item value instruments correlated well (r = 0.85) and scores differed by just 2.7%. The eight-category instrument showed good internal consistency reliability (Cronbach's alpha = 0.85) and moderate one-week test-retest reliability (r = 0.68, Wilcoxon signed-rank test p = 0.16, intra-class correlation coefficient [ICC] 0.62). Study 2: Values for disability were not associated with disability severity or clinical status. After weighting disability by value, the resulting PI HAQ scores were significantly associated with dissatisfaction with disability, perceived increase in disability, poor clinical status and life dissatisfaction, and differed significantly between people with high and low clinical status (convergent and discriminant construct validity). There was moderate association with the disease repercussion profile disability subscale (r = 0.511; p < 0.001) (criterion validity). The PI HAQ was stable over four weeks (ICC 0.81). These studies provide an initial evaluation of an instrument to measure the personal impact of disability in people with OA, setting disability within a personal context. Further studies, including sensitivity to change, are required.


Convergence and parameter choice for Monte-Carlo simulations of diffusion MRI.
This paper describes a general and flexible Monte- Carlo simulation framework for diffusing spins that generates realistic synthetic data for diffusion magnetic resonance imaging. Similar systems in the literature consider only simple substrates and their authors do not consider convergence and parameter optimization. We show how to run Monte-Carlo simulations within complex irregular substrates. We compare the results of the Monte-Carlo simulation to an analytical model of restricted diffusion to assess precision and accuracy of the generated results. We obtain an optimal combination of spins and updates for a given run time by trading off number of updates in favor of number of spins such that precision and accuracy of sythesized data are both optimized. Further experiments demonstrate the system using a tissue environment that current analytic models cannot capture. This tissue model incorporates swelling, abutting, and deformation. Swelling-induced restriction in the extracellular space due to the effects of abutting cylinders leads to large departures from the predictions of the analytical model, which does not capture these effects. This swelling-induced restriction may be an important mechanism in explaining the changes in apparent diffusion constant observed in the aftermath of acute ischemic stroke.


High trapping forces for high-refractive index particles trapped in dynamic arrays of counterpropagating optical tweezers.
We demonstrate the simultaneous trapping of multiple high-refractive index (n > 2) particles in a dynamic array of counterpropagating optical tweezers in which the destabilizing scattering forces are canceled. These particles cannot be trapped in single-beam optical tweezers. The combined use of two opposing high-numerical aperture objectives and micrometer-sized high-index titania particles yields an at least threefold increase in both axial and radial trap stiffness compared to silica particles under the same conditions. The stiffness in the radial direction is obtained from measured power spectra; calculations are given for both the radial and the axial force components, taking spherical aberrations into account. A pair of acousto-optic deflectors allows for fast, computer-controlled manipulation of the individual trapping positions in a plane, while the method used to create the patterns ensures the possibility of arbitrarily chosen configurations. The manipulation of high-index particles finds its application in, e.g., creating defects in colloidal photonic crystals and in exerting high forces with low laser power in, for example, biophysical experiments.


Caco-2 cells and Biopharmaceutics Classification System (BCS) for prediction of transepithelial transport of xenobiotics (model drug: caffeine).
The Caco-2 cell monolayer model is widely used as a standard screening tool for studying the mechanisms of cellular drug transport. Caffeine was chosen as a model drug and is supposed to be class I of the Biopharmaceutics Classification System (BCS). Our study was conducted 1) to characterize the mechanisms of caffeine transport across the intestinal barrier, 2) to classify caffeine according to BCS, 3) to predict drugs intestinal absorption in humans. Caffeine transport (0.1, 0.3, 1 and 10 mmol/l) was studied in Caco-2 cell monolayer in apical to basolateral (AP-BL) and basolateral to apical (BL-AP) direction, under iso-pH 7.4 and pH-gradient (6/7.4) conditions. The relative contribution of the paracellular route was estimated using Ca2+- free transport medium (opening tight junctions). The caffeine transport was linear with time, transport direction and pH independent, displaying non-saturable (first-order) kinetics, with high permeability coefficient (Papp): in AP-BL direction Papp = 46.3-53.5 x 10-6 cm/s; in BL-AP direction Papp = 45.6-49.4 x 10-6 cm/s. Thus, the transport seems to be transcellular mediated by passive diffusion. Using Ca2+- free transport medium tight junctions were opened (confirmed by increased Papp of mannitol) but the caffeine Papp was not changed. Thus, the paracellular route is only a minor way of caffeine transport. High solubility and high permeability of caffeine rank it among class I of BCS and well absorbed compounds.


Applying modern pain neuroscience in clinical practice: criteria for the classification of central sensitization pain.
The awareness is growing that central sensitization is of prime importance for the assessment and management of chronic pain, but its classification is challenging clinically since no gold standard method of assessment exists. Designing the first set of classification criteria for the classification of central sensitization pain. A body of evidence from original research papers was used by 18 pain experts from 7 different countries to design the first classification criteria for central sensitization pain. It is proposed that the classification of central sensitization pain entails 2 major steps: the exclusion of neuropathic pain and the differential classification of nociceptive versus central sensitization pain. For the former, the International Association for the Study of Pain diagnostic criteria are available for diagnosing or excluding neuropathic pain. For the latter, clinicians are advised to screen their patients for 3 major classification criteria, and use them to complete the classification algorithm for each individual patient with chronic pain. The first and obligatory criterion entails disproportionate pain, implying that the severity of pain and related reported or perceived disability are disproportionate to the nature and extent of injury or pathology (i.e., tissue damage or structural impairments). The 2 remaining criteria are 1) the presence of diffuse pain distribution, allodynia, and hyperalgesia; and 2) hypersensitivity of senses unrelated to the musculoskeletal system (defined as a score of at least 40 on the Central Sensitization Inventory). Although based on direct and indirect research findings, the classification algorithm requires experimental testing in future studies. Clinicians can use the proposed classification algorithm for differentiating neuropathic, nociceptive, and central sensitization pain.


Dynamic Control of Nanocavities with Tunable Metal Oxides.
Fabry-Pérot metal-insulator-metal (MIM) nanocavities are widely used in nanophotonic applications due to their extraordinary electromagnetic properties and deeply subwavelength dimensions. However, the spectral response of nanocavities is usually controlled by the spatial separation between the two reflecting mirrors and the spacer's refractive index. Here, we demonstrate static and dynamic control of Fabry-Pérot nanocavities by inserting a plasmonic metasurface, as a passive element, and a gallium doped-zinc oxide (Ga:ZnO) layer as a dynamically tunable component within the nanocavities' spacer. Specifically, by changing the design of the silver (Ag) metasurface one can "statically" tailor the nanocavity response, tuning the resonance up to 200 nm. To achieve the dynamic tuning, we utilize the large nonlinear response of the Ga:ZnO layer near the epsilon near zero wavelength to enable effective subpicosecond (<400 fs) optical modulation (80%) at reasonably low pump fluence levels (9 mJ/cm2). We demonstrate a 15 nm red shift of a near-infrared Fabry-Pérot resonance (λ ≅ 1.16 μm) by using a degenerate pump probe technique. We also study the carrier dynamics of Ga:ZnO under intraband photoexcitation via the electronic band structure calculated from first-principles density functional method. This work provides a versatile approach to design metal nanocavities by utilizing both the phase variation with plasmonic metasurfaces and the strong nonlinear response of metal oxides. Tailorable and dynamically controlled nanocavities could pave the way to the development of the next generation of ultrafast nanophotonic devices.


Using FTIR spectroscopy to model alkaline pretreatment and enzymatic saccharification of six lignocellulosic biomasses.
Fourier transform infrared, attenuated total reflectance (FTIR-ATR) spectroscopy, combined with partial least squares (PLS) regression, accurately predicted solubilization of plant cell wall constituents and NaOH consumption through pretreatment, and overall sugar productions from combined pretreatment and enzymatic hydrolysis. PLS regression models were constructed by correlating FTIR spectra of six raw biomasses (two switchgrass cultivars, big bluestem grass, a low-impact, high-diversity mixture of prairie biomasses, mixed hardwood, and corn stover), plus alkali loading in pretreatment, to nine dependent variables: glucose, xylose, lignin, and total solids solubilized in pretreatment; NaOH consumed in pretreatment; and overall glucose and xylose conversions and yields from combined pretreatment and enzymatic hydrolysis. PLS models predicted the dependent variables with the following values of coefficient of determination for cross-validation (Q²): 0.86 for glucose, 0.90 for xylose, 0.79 for lignin, and 0.85 for total solids solubilized in pretreatment; 0.83 for alkali consumption; 0.93 for glucose conversion, 0.94 for xylose conversion, and 0.88 for glucose and xylose yields. The sugar yield models are noteworthy for their ability to predict overall saccharification through combined pretreatment and enzymatic hydrolysis per mass dry untreated solids without a priori knowledge of the composition of solids. All wavenumbers with significant variable-important-for-projection (VIP) scores have been attributed to chemical features of lignocellulose, demonstrating the models were based on real chemical information. These models suggest that PLS regression can be applied to FTIR-ATR spectra of raw biomasses to rapidly predict effects of pretreatment on solids and on subsequent enzymatic hydrolysis.


The Origin and Activities of IgA1-Containing Immune Complexes in IgA Nephropathy.
IgA nephropathy (IgAN) is the most common primary glomerulonephritis, frequently leading to end-stage renal disease, as there is no disease-specific therapy. IgAN is diagnosed from pathological assessment of a renal biopsy specimen based on predominant or codominant IgA-containing immunodeposits, usually with complement C3 co-deposits and with variable presence of IgG and/or IgM. The IgA in these renal deposits is galactose-deficient IgA1, with less than a full complement of galactose residues on the O-glycans in the hinge region of the heavy chains. Research from the past decade led to the definition of IgAN as an autoimmune disease with a multi-hit pathogenetic process with contributing genetic and environmental components. In this process, circulating galactose-deficient IgA1 (autoantigen) is bound by antiglycan IgG or IgA (autoantibodies) to form immune complexes. Some of these circulating complexes deposit in glomeruli, and thereby activate mesangial cells and induce renal injury through cellular proliferation and overproduction of extracellular matrix components and cytokines/chemokines. Glycosylation pathways associated with production of the autoantigen and the unique characteristics of the corresponding autoantibodies in patients with IgAN have been uncovered. Complement likely plays a significant role in the formation and the nephritogenic activities of these complexes. Complement activation is mediated through the alternative and lectin pathways and probably occurs systemically on IgA1-containing circulating immune complexes as well as locally in glomeruli. Incidence of IgAN varies greatly by geographical location; the disease is rare in central Africa but accounts for up to 40% of native-kidney biopsies in eastern Asia. Some of this variation may be explained by genetically determined influences on the pathogenesis of the disease. Genome-wide association studies to date have identified several loci associated with IgAN. Some of these loci are associated with the increased prevalence of IgAN, whereas others, such as deletion of complement factor H-related genes 1 and 3, are protective against the disease. Understanding the molecular mechanisms and genetic and biochemical factors involved in formation and activities of pathogenic IgA1-containing immune complexes will enable the development of future disease-specific therapies as well as identification of non-invasive disease-specific biomarkers.


Fecal occult blood testing as a diagnostic test in symptomatic patients is not useful: a retrospective chart review.
The fecal occult blood test (FOBT) is a screening tool designed for the early detection of colorectal cancer in primary care. Although not validated for use in hospitalized patients, it is often used by hospital physicians for reasons other than asymptomatic screening. To profile the in-hospital use of the FOBT and assess its impact on patient care. Patient charts were retrospectively reviewed for all FOBTs conducted over a three-month period in 2011 by the central laboratory supporting the three acute care campuses of Hamilton Health Sciences (Hamilton, Ontario). A total of 229 patients underwent 351 tests; 52% were female and the mean age was 49 years (range one to 104 years). A total of 80 (34.9%) patients had at least one positive test. The most common indications for testing were anemia (51.0%) and overt gastrointestinal bleeding (19.2%). Only one patient had testing performed for asymptomatic colorectal cancer screening. In only 20 (8.7%) cases medications were modified before testing and diet was modified in only 21 (9.2%) cases. Most patients (85.2%) were taking one or more medications that could result in a false-positive result. Only 18 (7.9%) patients had a digital rectal examinations documented, of which seven were positive. All patients with a positive digital rectal examination underwent endoscopic procedures that revealed a source of bleeding. Among 44 patients with overt gastrointestinal bleeding, 12 (27.3%) had endoscopic investigations delayed to await results of the FOBT. Four patients were referred despite a negative FOBT due to a high degree of suspicion of gastrointestinal bleeding. The FOBT is often used inappropriately in the hospital setting. Confounding factors, such as diet and medication use, which may lead to false positives, are often ignored. Use of the FOBT in-hospital may lead to inappropriate management of patients, increased length of stay and increased direct medical costs. Use of the FOBT should be limited to validated indications only.


Awareness in Alzheimer's disease and associated dementias: theoretical framework and clinical implications.
Awareness can be defined as a reasonable or realistic perception or appraisal of a given aspect of one's situation, functioning or performance, or of the resulting implications, expressed explicitly or implicitly. Disturbances of awareness have significant implications for people with dementia and their caregivers. The construction of awareness has been extensively studied in dementia, but a lack of conceptual and methodological clarity in this area means that few clear findings have emerged. This article presents a framework for conceptualizing awareness in people with Alzheimer's disease and associated dementias that can guide research and influence practice. This article begins by considering the general concept of awareness and the ways in which neurological damage can place constraints on awareness. Within an integrative biopsychosocial model that acknowledges the influence of neurocognitive, psychological, and social variables on awareness, challenges for empirical research on awareness in dementia are addressed, and a 'levels of awareness' framework is presented within which awareness operates at four levels of increasing complexity, providing a means of differentiating among awareness phenomena. Approaches to mapping awareness phenomena are discussed, and directions for future research and clinical practice are outlined. The levels of awareness framework should act as a stimulus to further research in this area, resulting in a more coherent understanding of the nature of awareness deficits, the implications of these for people with dementia and their caregivers, and the possibilities for targeted and effective interventions.


2011 Compendium of Physical Activities: a second update of codes and MET values.
The Compendium of Physical Activities was developed to enhance the comparability of results across studies using self-report physical activity (PA) and is used to quantify the energy cost of a wide variety of PA. We provide the second update of the Compendium, called the 2011 Compendium. The 2011 Compendium retains the previous coding scheme to identify the major category headings and specific PA by their rate of energy expenditure in MET. Modifications in the 2011 Compendium include cataloging measured MET values and their source references, when available; addition of new codes and specific activities; an update of the Compendium tracking guide that links information in the 1993, 2000, and 2011 compendia versions; and the creation of a Web site to facilitate easy access and downloading of Compendium documents. Measured MET values were obtained from a systematic search of databases using defined key words. The 2011 Compendium contains 821 codes for specific activities. Two hundred seventeen new codes were added, 68% (561/821) of which have measured MET values. Approximately half (317/604) of the codes from the 2000 Compendium were modified to improve the definitions and/or to consolidate specific activities and to update estimated MET values where measured values did not exist. Updated MET values accounted for 73% of all code changes. The Compendium is used globally to quantify the energy cost of PA in adults for surveillance activities, research studies, and, in clinical settings, to write PA recommendations and to assess energy expenditure in individuals. The 2011 Compendium is an update of a system for quantifying the energy cost of adult human PA and is a living document that is moving in the direction of being 100% evidence based.


Vitamin D(3) attenuates 6-hydroxydopamine-induced neurotoxicity in rats.
Previous reports have demonstrated that exogeneous administration of glial cell line-derived neurotrophic factor (GDNF) reduces ventral mesencephalic (VM) dopaminergic (DA) neuron damage induced by 6-hydroxydopamine (6-OHDA) lesioning in rats. Recent studies have shown that 1,25-dihydroxyvitamin D(3) (D3) enhances endogenous GDNF expression in vitro and in vivo. The purpose of present study was to investigate if administration of D3 in vivo and in vitro would protect against 6-OHDA-induced DA neuron injury. Adult male Sprague-Dawley rats were injected daily with D3 or with saline for 8 days and then lesioned unilaterally with 6-OHDA into the medial forebrain bundle. Locomotor activity was measured using automated activity chambers. We found that unilateral 6-OHDA lesioning reduced locomotor activity in saline-pretreated animals. Pretreatment with D3 for 8 days significantly restored locomotor activity in the lesioned animals. All animals were sacrificed for neurochemical analysis 6 weeks after lesioning. We found that 6-OHDA administration significantly reduced dopamine (DA), 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanilic acid (HVA) levels in the substantia nigra (SN) on the lesioned side in the saline-treated rats. D3 pretreatment protected against 6-OHDA-mediated depletion of DA and its metabolites in SN. Using primary cultures obtained from the VM of rat embryos, we found that 6-OHDA or H(2)O(2) alone caused significant cell death. Pretreatment with D3 (10(-10) M) protected VM neurons against 6-OHDA- or H(2)O(2)-induced cell death in vitro. Taken together, our data indicate that D3 pretreatment attenuates the hypokinesia and DA neuronal toxicity induced by 6-OHDA. Since both H(2)O(2) and 6-OHDA may injure cells via free radical and reactive oxygen species, the neuroprotection seen here may operate via a reversal of such a toxic mechanism.


The health effects of vitamin C supplementation: a review.
A comprehensive review of the literature indicates that populations with long-term consumption of higher than RDA levels of vitamin C (> or = 60 mg/day) from foods and/or supplements have reduced risks of cancer at several sites, cardiovascular disease, and cataracts. The safety of higher than RDA intakes of vitamin C is confirmed in eight placebo-controlled, double-blind studies and six non-placebo clinical trials in which up to 10,000 mg of vitamin C was consumed daily for up to 3 years. There are no clinical data which suggest that vitamin C's enhancement of non-heme iron absorption in individuals with low iron status could be a critical factor in the possible increased risk of heterozygous hemochromatosis-related cardiovascular disease. In fact, the cumulative data do not confirm that iron status is related to risk of cardiovascular disease. Moreover, higher than RDA intakes of vitamin C have been associated with several indices of lowered cardiovascular disease risk including increases in HDL, and decreases in LDL oxidation, blood pressure and cardiovascular mortality.


Big effects of small RNAs: a review of microRNAs in anxiety.
Epigenetic and regulatory elements provide an additional layer of complexity to the heterogeneity of anxiety disorders. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that have recently drawn interest as epigenetic modulators of gene expression in psychiatric disorders. miRNAs elicit their effects by binding to target messenger RNAs (mRNAs) and hindering translation or accelerating degradation. Considering their role in neuronal differentiation and synaptic plasticity, miRNAs have opened up new investigative avenues in the aetiology and treatment of anxiety disorders. In this review, we provide a thorough analysis of miRNAs, their targets and their functions in the central nervous system (CNS), focusing on their role in anxiety disorders. The involvement of miRNAs in CNS functions (such as neurogenesis, neurite outgrowth, synaptogenesis and synaptic and neural plasticity) and their intricate regulatory role under stressful conditions strongly support their importance in the aetiology of anxiety disorders. Furthermore, miRNAs could provide new avenues for the development of therapeutic targets in anxiety disorders.


Physiological consequences of hypohydration: exercise performance and thermoregulation.
During exercise in the heat, sweat output often exceeds water intake, which results in a body water deficit or hypohydration. This water deficit occurs from both the intracellular and extracellular fluid compartments, and causes a hypertonic-hypovolemia of the blood. Aerobic exercise tasks are likely to be adversely affected by hypohydration; and the warmer the environment the greater the potential for performance decrements. Hypohydration causes greater heat storage and reduces one's ability to tolerate heat strain. The greater heat storage is mediated by reduced sweating rate (evaporative heat loss) and reduced skin blood flow (dry heat loss) for a given core temperature. Reductions of sweating rate and skin blood flow are most tightly coupled to blood hypertonicity and hypovolemia, respectively. In addition, hypovolemia and the displacement of blood to the skin make it difficult to maintain central venous pressure and thus an adequate cardiac output to simultaneously support metabolism and thermoregulation during exercise-heat stress.


Predictors of individual player match performance in junior Australian football.
Player match statistics in junior Australian football (AF) are not well documented, and contributors to success are poorly understood. A clearer understanding of the relationships between fitness and skill in younger players participating at the foundation level of the performance pathway in AF has implications for the development of coaching priorities (eg, physical or technical). To investigate the relationships between indices of fitness (speed, power, and endurance) and skill (coach rating) on player performance (disposals and effective disposals) in junior AF. Junior male AF players (N = 156, 10-15 y old) were recruited from 12 teams of a single amateur recreational AF club located in metropolitan Victoria. All players were tested for fitness (20-m sprint, vertical jump, 20-m shuttle run) and rated by their coach on a 6-point Likert scale for skill (within a team in comparison with their teammates). Player performance was assessed during a single match in which disposals and their effectiveness were coded from a video recording. Coach rating of skill displayed the strongest correlations and, combined with 20-m shuttle test, showed a good ability to predict the number of both disposals and effective disposals. None of the skill or fitness attributes adequately explained the percentage of effective disposals. The influence of team did not meaningfully contribute to the performance of any of the models. Skill development should be considered a high priority by coaches in junior AF.


Maternal request for caesarean section: an ethical consideration.
Caesarean section (CS) is a method of delivering a baby through a surgical incision into the abdominal wall. Until recently in the UK, it was preserved as a procedure which was only carried out in certain circumstances. These included if the fetus lay in a breech position or was showing signs of distress leading to a requirement for rapid delivery. CS is perceived as a safe method of delivery due to the recommendation by the National Institute for Health and Care Excellence (NICE) in these situations. As a result, the opportunity for maternal request for CS arose, whereby the mother requests the operation despite no medical indication. There are risks associated with CS, as with all surgery, however, these risks in current and future pregnancies may not be fully understood by the mother. The ethics of exposing mothers to these risks, as well as performing surgery on what is otherwise a healthy patient, become entangled with the demand for patient choice, as well as the increasing financial strain on our healthcare system. The main question to be examined in this essay is whether it is ethical to allow women to choose a CS in the absence of obstetric indication, taking into account the increased risk to the mother and her future offspring in order to potentially decrease the risk to the current baby. Alongside a case report, this analysis will apply Beauchamp and Childress' four principles of biomedical ethics and an exploration of the scientific literature.


MYOD-1 in normal colonic mucosa--role as a putative biomarker?
DNA methylation of promoter-associated CpG islands of certain genes may play a role in the development of colorectal cancer. The MYOD-1 gene which is a muscle differentiation gene has been showed to be significantly methylated in colorectal cancer which, is an age related event. However the role of this gene in the colonic mucosa is not understood and whether methylation occurs in subjects without colon cancer. In this study, we have determined the frequency of methylation of the MYOD-1 gene in normal colonic mucosa and investigated to see if this is associated with established colorectal cancer risk factors primarily ageing. We analysed colonic mucosal biopsies in 218 normal individuals and demonstrated that in most individuals promoter hypermethylation was not quantified for MYOD-1. However, promoter hypermethylation increased significantly with age (p<0.001 using regression analysis) and this was gender independent. We also showed that gene promoter methylation increased positively with an increase in waist to hip (WHR) ratio - the latter is also a known risk factor for colon cancer development. Our study suggests that promoter gene hypermethylation of the MYOD-1 gene increases significantly with age in normal individuals and thus may offer potential as a putative biomarker for colorectal cancer.


Partially connected feedforward neural networks structured by input types.
This paper proposes a new method to model partially connected feedforward neural networks (PCFNNs) from the identified input type (IT) which refers to whether each input is coupled with or uncoupled from other inputs in generating output. The identification is done by analyzing input sensitivity changes as amplifying the magnitude of inputs. The sensitivity changes of the uncoupled inputs are not correlated with the variation on any other input, while those of the coupled inputs are correlated with the variation on any one of the coupled inputs. According to the identified ITs, a PCFNN can be structured. Each uncoupled input does not share the neurons in the hidden layer with other inputs in order to contribute to output in an independent manner, while the coupled inputs share the neurons with one another. After deriving the mathematical input sensitivity analysis for each IT, several experiments, as well as a real example (blood pressure (BP) estimation), are described to demonstrate how well our method works.