Segmentation of small bowel tumor tissue in capsule endoscopy images by using the MAP algorithm.
State of the art algorithms for diagnosis of the small bowel by using capsule endoscopic images usually rely on the processing of the whole frame, hence no segmentation is usually required. However, some specific applications such as three-dimensional reconstruction of the digestive wall, detection of small substructures such as polyps and ulcers or training of young medical staff require robust segmentation. Current state of the art algorithms for robust segmentation are mainly based on Markov Random Fields (MRF) requiring prohibitive computational resources not compatible with applications that generate a great amount of data as is the case of capsule endoscopy. However context information given by MRF is not the only way to improve robustness. Alternatives could come from a more effective use of the color information. This paper proposes a Maximum A Posteriori (MAP) based approach for lesion segmentation based on pixel intensities read simultaneously in the three color channels. Usually tumor regions are characterized by higher intensity than normal regions, where the intensity can be measured as the vectorial sum of the 3 color channels. The exception occurs when the capsule is positioned perpendicularly and too close to the small bowel wall. In this case a hipper intense tissue region appears at the middle of the image, which in case of being normal tissue, will be segmented as tumor tissue. This paper also proposes a Maximum Likelihood (ML) based approach to deal with this situation. Experimental results show that tumor segmentation becomes more effective in the HSV than in the RGB color space where diagonal covariance matrices have similar effectiveness than full covariance matrices.


5-Lipoxygenase: a target for antiinflammatory drugs revisited.
Arachidonate 5-lipoxygenase is the key enzyme in leukotriene biosynthesis and catalyzes the initial steps in the conversion of arachidonic acid to biologically active leukotrienes. Leukotrienes are considered as potent potent mediators of inflammatory and allergic reactions which are locally released by leukocytes and other 5-LO expressing cells and exert their effects via binding to specific membrane receptors and, as suggested recently, the nuclear receptor PPARa. Because of the proinflammatory profile of leukotrienes it was assumed that leukotriene biosynthesis inhibitors and leukotriene receptor antagonists have a therapeutical potential in a variety of inflammatory diseases. Clinical studies confirmed the therapeutic value of the antileukotriene therapy in asthma but the results with leukotriene biosynthesis inhibitors in psoriasis, arthritis and inflammatory bowel disease were more or less disappointing. This review summarizes the biochemistry of the 5-lipoxygenase pathway, the pharmacology of FLAP and 5 lipoxygenase inhibitors and discusses possible criteria for the development of these drugs.


Pathology and Pathogenesis of Eurasian Blackbirds (Turdus merula) Naturally Infected with Usutu Virus.
The Usutu virus (USUV) is a mosquito-borne zoonotic flavivirus. Despite its continuous circulation in Europe, knowledge on the pathology, cellular and tissue tropism and pathogenetic potential of different circulating viral lineages is still fragmentary. Here, macroscopic and microscopic evaluations are performed in association with the study of cell and tissue tropism and comparison of lesion severity of two circulating virus lineages (Europe 3; Africa 3) in 160 Eurasian blackbirds (Turdus merula) in the Netherlands. Results confirm hepatosplenomegaly, coagulative necrosis and lymphoplasmacytic inflammation as major patterns of lesions and, for the first time, vasculitis as a novel virus-associated lesion. A USUV and Plasmodium spp. co-infection was commonly identified. The virus was associated with lesions by immunohistochemistry and was reported most commonly in endothelial cells and blood circulating and tissue mononucleated cells, suggesting them as a major route of entry and spread. A tropism for mononuclear phagocytes cells was further supported by viral labeling in multinucleated giant cells. The involvement of ganglionic neurons and epithelial cells of the gastrointestinal tract suggests a possible role of oral transmission, while the involvement of feather follicle shafts and bulbs suggests their use as a diagnostic sample for live bird testing. Finally, results suggest similar pathogenicity for the two circulating lineages.


Triplet electron transfer and spin polarization in a palladium porphyrin-fullerene conjugate.
Transient electron paramagnetic resonance (TREPR) spectroscopy is used to investigate the pathway and dynamics of electron transfer in a palladium porphyrin-fullerene donor-acceptor conjugate. The heavy Pd atom in the porphyrin greatly enhances the rate of intersystem crossing and as a result, electron transfer from the porphyrin to fullerene occurs via the porphyrin triplet state. The sign of the polarization pattern of the radical pair generated by the electron transfer is opposite in benzonitrile and the liquid crystal 5CB. This difference is the result of a change in sign of the spin-spin coupling, which allows the values of the dipolar and exchange couplings between the electrons in the charge-separated state to be estimated. In addition to the radical pair, signals from the fullerene triplet state are also observed. The polarization of the fullerene triplet state inverts with time, while the radical pair signal decays to a multiplet pattern that persists for times longer than the spin-lattice relaxation time. A kinetic model, developed to explain these effects, reveals that forward and reverse electron transfer between the charge-separated state and the fullerene takes place. This process, combined with singlet recombination of the radical pair accounts for the inversion of the fullerene triplet state polarization and the long-lived multiplet polarization of the radical pair.


A Rhodnius prolixus Insulin Receptor and Its Conserved Intracellular Signaling Pathway and Regulation of Metabolism.
The insulin signaling pathway is a modulator of metabolism in insects and can regulate functions associated with growth and development, as well as lipid and carbohydrate balance. We have previously reported the presence of an insulin-like peptide and an insulin-like growth factor in Rhodnius prolixus, which are involved in the homeostasis of lipids and carbohydrates in post-feeding and non-feeding periods. In the present study, we have characterized the first insulin receptor (IR) to be discovered in R. prolixus, Rhopr-IR, and investigated its intracellular signaling cascade and its role in nutrient control. We identified a candidate protein sequence within R. prolixus putative peptidome and predicted its conserved features using bioinformatics. Tissue-specific expression analyses indicated that the Rhopr-IR transcript is differentially-expressed in all tissues tested, with the highest values observed in the central nervous system (CNS). Treatment of insects with the IR kinase activator BpV(phen), glucose, or porcine insulin resulted in the activation of protein phosphorylation in the fat body, and stimulated the phosphorylation of protein kinase Akt, an evolutionarily conserved key regulator of the intracellular insulin signaling cascade. We also observed activation of Akt and phosphorylation of its downstream targets glycogen synthase kinase 3 β (GSK3β) and the transcription factor FOXO for several days following a blood meal. We used dsRNA to knockdown transcript expression and examined the resulting effects on metabolism and intracellular signaling. Furthermore, knockdown of the Rhopr-IR transcript increased lipid levels in the hemolymph, while reducing lipid content in the fat body. Interestingly, the levels of carbohydrates in the hemolymph and in the fat body did not show any alterations. The activation of Akt and phosphorylation of FOXO were also reduced in knockdown insects, while the phosphorylation pattern of GSK3β did not change. Our results support the identification of the first IR in R. prolixus and suggest that Rhopr-IR signaling is involved in hemolymph nutrient homeostasis and fat body storage both in post-feeding and in non-feeding stages. These metabolic effects are likely regulated by the activation of Akt and downstream cascades similar to mammalian insulin signaling pathways.


A single-blinded, single-centre, controlled study in healthy adult smokers to identify the effects of a reduced toxicant prototype cigarette on biomarkers of exposure and of biological effect versus commercial cigarettes.
Despite universal acceptance that smoking is harmful, a substantial number of adults continue to smoke. The development of potential reduced exposure products (more recently termed modified risk tobacco products) has been suggested as a way to reduce the risks of tobacco smoking. This trial is designed to investigate whether changes in toxicant exposure after switching from a commercial to reduced toxicant prototype (RTP) cigarette (7 mg International Organisation for Standardisation (ISO) tar yield) can be assessed by measurement of biomarkers and other factors. The primary objective is to descriptively assess changes in selected biomarkers of exposure (BoE) and biomarkers of biological effect (BoBE) within participants and within and between groups after switching. Secondary objectives are to assess similarly changes in other biomarkers, quality of life, smoking behaviours, physiological measures, mouth-level exposure to toxicants and sensory perception. This trial will assess current smokers, ex-smokers and never-smokers in a single-centre single-blind, controlled clinical trial with a forced-switching design and in-clinic (residential) and ambulatory (non-residential) periods. Smokers will be aged 23-55 years (minimum legal smoking age plus 5 years) and non-smokers 28-55 years (minimum legal smoking age plus 5 years, plus minimum 5 years since last smoked). Smokers will be allowed to smoke freely at all times. We will assess changes in selected BoE and BoBE and effective dose in urine and blood after switching. Creatinine concentrations in serum, creatinine clearance in urine, cotinine concentration in saliva, diaries and collection of spent cigarette filters will be used to assess compliance with the study protocol. Mouth-level exposure to toxins will be assessed by filter analysis. Data from this study are expected to improve scientific understanding of the effects of RTP cigarettes on BoE and BoBE, and give insights into study design for clinical assessment of potential MRTPs. The study was registered in the Current Controlled Trials database under the reference ISRCTN81286286.


Characteristic SD-OCT findings in preeclampsia.
High-resolution spectral-domain optical coherence tomography of a patient affected by acute macular edema secondary to preeclampsia is described. The particular optical coherence tomography pattern was characterized by bilateral macular edema with a tent-shaped organization, associated with massive neurosensorial retinal detachment. Many hyperreflective irregular dots were evident in the context of a subfoveal clear cystic lesion. A different hyperreflective irregularity was detected in the retinal pigment epithelium. The central role of spectral-domain optical coherence tomography among instrumental imaging procedures and for final successful diagnosis in this particular macular edema is emphasized.


Statins and the myocardium.
Cardiac hypertrophy and heart failure are leading causes of morbidity and mortality worldwide. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, have been shown to inhibit cardiac hypertrophy and improve symptoms of heart failure by cholesterol-independent mechanisms. Statins block the isoprenylation and function of members of the Rho GTPase family, such as Rac1 and RhoA. Because Rac1 is a requisite component of NADPH oxidase, which is a major source of reactive oxygen species in cardiovascular cells, the ability of statins to inhibit Rac1-mediated oxidative stress contributes importantly to their inhibitory effects on cardiac hypertrophy. Furthermore, inhibition of RhoA by statins leads to the activation of protein kinase B/Akt and upregulation of Type 3 nitric oxide synthase in the endothelium and the heart. This activation and upregulation results in increased angiogenesis and myocardial perfusion, decreased myocardial apoptosis, and improvement in endothelial and cardiac function. Because these effects of statins occur independent of cholesterol lowering, statins may have therapeutic benefits in nonhyperlipidemic patients with cardiac hypertrophy and heart failure.


Allium ursinum and Allium oschaninii against Klebsiella pneumoniae and Candida albicans Mono- and Polymicrobic Biofilms in In Vitro Static and Dynamic Models.
The present study assesses the in vitro antibiofilm potential activity of extracts of wild Allium ursinum and Allium oschaninii. The active ingredients of the extracts were obtained with a technique named Naviglio (rapid solid-liquid dynamic extraction, RSLDE) which is based on an innovative and green solid-liquid extraction methodology. The extracts were tested against models of mono- and polymicrobial biofilm structures of clinically antibiotic-resistant pathogens, Klebsiella pneumoniae ATCC 10031 and Candida albicans ATCC 90028. Biofilms were studied using a static and a dynamic model (microtiter plates and a CDC reactor) on three different surfaces reproducing what happens on implantable medical devices. Antimicrobic activities were determined through minimum inhibitory concentration (MIC), while antibiofilm activity was assessed by minimum biofilm eradication concentration (MBEC) using a crystal violet (CV) biofilm assay and colony forming unit (CFU) counts. Results showed that both Allium extracts eradicated biofilms of the tested microorganisms well; biofilms on Teflon were more susceptible to extracts than those on polypropylene and polycarbonate, suggesting that when grown on a complex substrate, biofilms may be more tolerant to antibiotics. Our data provide significant advances on antibiotic susceptibility testing of biofilms grown on biologically relevant materials for future in vitro and in vivo applications.


[Influence of computer tomography diagnostics on the treatment in state health care system].
The presented paper is a continuation of the widely debated topic on the role of radiation technologies, including computed tomography (CT), in municipal medicine, which has been earlier raised on the pages of the Vestnik. The main objective of the paper is that by using the results obtained from the use of CT in a near-Moscow health care facility that is typical of Russia's municipal health care service, the author attempted to provide evidence that it is necessary to extensively introduce this technique into the most mass link of Russian public health care--municipal medicine. As an evidence basis, the author analyzed changes occurring in the organization of a therapeutic-and-diagnostic process the municipal health care facility from a great variety of organ and system pathology that is particularly important from the practical point of view. The data obtained before and after introduction of CT into the municipal diagnostic algorithms on specific, the most critical clinical situations are compared. Moreover, objective analytical data are confirmed by a battery of brilliant diagnostic images. The author elucidates the readiness of municipal clinicians for virtually complete use of CT data for their purposes. By using several nosological entities, he shows the CT-induced transfer of some therapeutic procedures from the regional to municipal area of practice. In addition, arguments are advanced in favor of the thesis that some therapeutic technologies now in use are not up to world standards and municipal health care cannot be in compliance with civilized standards without its effective diagnostic support. Prominent in the paper is the description of changes in the continuity of diagnostic medicine at the municipal and regional levels after inclusion CT into the day-to-day activities of a municipal facility. It is concluded that the population needs for CT: one 24-slice unit per 50,000 dwellers of an area under service of a municipal facility.


Efficacy of Intravenous, Endotracheal, or Nasal Adrenaline Administration During Resuscitation of Near-Term Asphyxiated Lambs.
Objectives: Neonatal resuscitation guidelines recommend administering intravenous (IV) adrenaline if bradycardia persists despite adequate ventilation and chest compressions (CC). Rapid IV access is challenging, but little evidence exists for other routes of administration. We compared IV, endotracheal (ET), and intranasal routes for adrenaline administration during resuscitation of asphyxiated newborn lambs. Study design: Near-term lambs (n = 22) were delivered by caesarean section. Severe asphyxia was induced by clamping the umbilical cord while delaying ET ventilation until blood flow in the carotid artery ceased. Following a 30 s sustained inflation and ventilation for 30 s, we commenced uncoordinated CC at 90/min. We randomized four groups receiving repeated treatment doses (Tds) every 3rd min of (i) IV-Adrenaline (50 μg), (ii) ET-Adrenaline (500 μg), (iii) Nasal-Adrenaline via an atomizer (500 μg), and (iv) IV-saline. If return of spontaneous circulation (ROSC) was not achieved after three Tds by the assigned route, up to two rescue doses (Rds) of IV adrenaline were administered. Main outcome measures were achievement of ROSC and time from start of CC to ROSC, defined as heart rate >100/min, and mean carotid arterial pressure >30 mmHg. Results: In the IV-Adrenaline group, 5/6 lambs achieved ROSC after the first Td, whereas 1 lamb required two Tds before achieving ROSC. In the ET-Adrenaline group, 1/5 lambs required one Td, 1 lamb required three Tds, 2 lambs required 2 Rds, and 1 did not achieve ROSC. In the Nasal-Adrenaline group, 1/6 lambs required one Td, 2 required two Tds, whereas 3 lambs required either one (2 lambs) or two (1 lamb) Rds of adrenaline to achieve ROSC. In the IV-saline group, no lambs achieved ROSC until adrenaline Rds; 4/5 lambs required one Rd and 1 lamb required two Rds. Time to ROSC was shorter using IV-Adrenaline (2.4 ± 0.4 min) compared with ET-Adrenaline (10.3 ± 2.4 min), Nasal-Adrenaline (9.2 ± 2.2 min), and IV-saline (11.2 ± 1.2 min). Conclusion: IV adrenaline had superior efficacy compared with nasal or ET administration. Nasal administration had a similar effect as ET administration and is an easier route for early application. Nasal high-dose adrenaline administration for neonatal resuscitation merits further investigation.


An explicit quantum chemical method for modeling large solvation shells applied to aminocoumarin C151.
The absorption spectra of aminocoumarin C151 in water and n-hexane solution are investigated by an explicit quantum chemical solvent model. We improved the efficiency of the frozen-density embedding scheme, as used in a former study on solvatochromism (J. Chem. Phys. 2005, 122, 094115) to describe very large solvent shells. The computer time used in this new implementation scales approximately linearly (with a low prefactor) with the number of solvent molecules. We test the ability of the frozen-density embedding to describe specific solvent effects due to hydrogen bonding for a small example system, as well as the convergence of the excitation energy with the number of solvent molecules considered in the solvation shell. Calculations with up to 500 water molecules (1500 atoms) in the solvent system are carried out. The absorption spectra are studied for C151 in aqueous or n-hexane solution for direct comparison with experimental data. To obtain snapshots of the dye molecule in solution, for which subsequent excitation energies are calculated, we use a classical molecular dynamics (MD) simulation with a force field adapted to first-principles calculations. In the calculation of solvatochromic shifts between solvents of different polarity, the vertical excitation energy obtained at the equilibrium structure of the isolated chromophore is sometimes taken as a guess for the excitation energy in a nonpolar solvent. Our results show that this is, in general, not an appropriate assumption. This is mainly due to the fact that the solute dynamics is neglected. The experimental shift between n-hexane and water as solvents is qualitatively reproduced, even by the simplest embedding approximation, and the results can be improved by a partial polarization of the frozen density. It is shown that the shift is mainly due to the electronic effect of the water molecules, and the structural effects are similar in n-hexane and water. By including water molecules, which might be directly involved in the excitation, in the embedded region, an agreement with experimental values within 0.05 eV is achieved.


Electrochemical Detection of Solution Phase Hybridization Related to Single Nucleotide Mutation by Carbon Nanofibers Enriched Electrodes.
In the present study, a sensitive and selective impedimetric detection of solution-phase nucleic acid hybridization related to Factor V Leiden (FV Leiden) mutation was performed by carbon nanofibers (CNF) modified screen printed electrodes (SPE). The microscopic and electrochemical characterization of CNF-SPEs was explored in comparison to the unmodified electrodes. Since the FV Leiden mutation is a widespread inherited risk factor predisposing to venous thromboembolism, this study herein aimed to perform the impedimetric detection of FV Leiden mutation by a zip nucleic acid (ZNA) probe-based assay in combination with CNF-SPEs. The selectivity of the assay was then examined against the mutation-free DNA sequences as well as the synthetic PCR samples.


Independent polarisation control of multiple optical traps.
We present a system which uses a single spatial light modulator to control the spin angular momentum of multiple optical traps. These traps may be independently controlled both in terms of spatial location and in terms of their spin angular momentum content. The system relies on a spatial light modulator used in a "split-screen" configuration to generate beams of orthogonal polarisation states which are subsequently combined at a polarising beam splitter. Defining the phase difference between the beams with the spatial light modulator enables control of the polarisation state of the light. We demonstrate the functionality of the system by controlling the rotation and orientation of birefringent vaterite crystals within holographic optical tweezers.


Associations of health-related quality of life with sociodemographic characteristics, health, pain, and lifestyle factors, and motivation for changing lifestyle in adults living with chronic pain: a cross-sectional exploratory study.
We investigated the associations between health-related quality of life (HRQoL) and health, pain and lifestyle factors, as well as motivation for lifestyle changes, in adults living with chronic pain referred to a Danish pain centre. A total of 144 outpatients completed a questionnaire on HRQoL (EQ-5D-5L), health, pain, lifestyle factors (Body Mass Index [BMI], physical activity, smoking, alcohol, physical fitness, eating, sleep and stress) and motivation for lifestyle changes. We used multiple linear regression analyses to assess associations between HRQoL and the independent variables. The participants (age mean 50 years, 81% females) had ≥2 body pain sites (93%), BMI≥25 (64%), sedentary lifestyle (43%) and multiple (n≥2) elevated metabolic risk factors (58%). Most considered lifestyle important for HRQoL (72%) and expressed moderate to very high motivation for changing lifestyle (92%). Poorer HRQoL in the study population was significantly associated with higher pain intensity in the most painful body site (β=-0.316, p=0.001) and very poor sleep quality (β=-0.410, p=0.024). Serious-to-extreme problems in usual activities were associated with significantly poorer health (β=-0.328, p=0.030). Adults living with chronic pain participating in this survey had significantly lower self-evaluated HRQoL than the general population. Lower HRQoL was significantly associated with greater pain intensity and poor sleep quality. Serious-to-extreme problems in usual activities, such as work, study, housework, family and leisure, were associated with poorer self-evaluated health. We observed high frequencies of overweight, obesity, sedentary lifestyle, pain in multiple body sites and multiple lifestyle-related risk factors in the study population. Most participants felt motivated for changing lifestyle. Further interventions addressing pain alleviation, sleep quality, prevention of problems in usual activities and promotion of healthy lifestyle, e.g. physical activity and healthy eating, are needed to estimate the effect of a lifestyle-oriented approach on health and quality of life in people living with chronic pain. The results of this study will inform the research project reg. SJ-703, the Danish the Research Ethics Committee for Region Zealand, Denmark.


The different use dependences of tocainide and benzocaine are correlated with different effects on sodium channel inactivation.
To study the mechanism of use dependence, we investigated the influence of 0.5 mM tocainide on the amplitude of sodium currents elicited by membrane depolarizations with standard test pulses in voltage-clamped human myoballs. For comparison, the experiments were also conducted with 1 mM benzocaine, a drug with almost no use dependence. These concentrations were so chosen that without stimulation and at a holding potential of -135 mV, either drug blocked about 50% of the channels (tonic block). With repetitive stimulation at 1 Hz, tocainide blocked about 75% of the channels that had remained open in the rested state (phasic block), while benzocaine had little such effect. The potential dependence of steady-state inactivation (h infinity curves) of the sodium channels in these myoballs depended on the duration of the prepotential indicating that they possess at least two states of inactivation: fast and intermediate. The two drugs differed in their effects on these two states. Benzocaine always produced a left-shift of the h infinity curve, no matter whether the duration of the conditioning pulse was short (8 ms) or long (512 ms) indicating that it can bind when the channel is in the state of fast inactivation. Tocainide shifted the h infinity curve only with long prepulses, i.e. when the sodium channels were in the state of intermediate inactivation. The recovery from inactivation, a process governed by two time constants in the absence of drugs, was also differently influenced by the two drugs. In the presence of tocainide, the channels mainly recovered with the slow time constant and this time constant was significantly increased, whereas benzocaine did not substantially modify this biphasic process.(ABSTRACT TRUNCATED AT 250 WORDS)


Reduced Hedonic Capacity/Approach Motivation Relates to Blunted Responsivity to Gain and Loss Feedback in Children.
Adolescents and adults with major depressive disorder or elevated depressive symptoms show reduced reward responses and tend to show enhanced responses to negative stimuli. However, reward-related behaviors and adaptive responses to negative feedback undergo dramatic changes across puberty. Thus, key questions remain regarding how altered incentive processing relates to depressive and anhedonic symptoms in prepubertal child populations. Twenty-four nonclinical prepubertal children 7-10 years of age (15 male; 16 Caucasian) completed two signal detection tasks that assessed behavioral responsivity to candy gain and loss feedback, respectively. These tasks were based on Pizzagalli's probabilistic reward task where asymmetric feedback leads to greater bias toward the more frequently rewarded response in more hedonic or nondepressed adults. We further modified the task to create a version where incorrect responses could result in losses from an original allotment of candy. Children and parents/guardians also completed individual difference questionnaires to assess the child's depressive symptoms, general affect, and hedonic capacity/approach motivation. Regressions indicated a relation between hedonic capacity/approach motivation (child self-report) and response bias in both gain and loss tasks. No significant relations were observed between depressive (child self-report), internalizing (parent report), or externalizing symptoms (parent report) and bias in either the gain or loss task in this small sample. These results suggest that reduced hedonic capacity/approach motivation is associated with blunted responses to both gain and loss feedback in prepubertal children.


Prognostic indicators for intracranial metastases from pancreatic cancer: a population-based retrospective Surveillance, Epidemiology, and End Results database analysis.
The natural history, treatment options, and clinical outcomes of pancreatic metastases to the brain remain largely unknown. Here, we seek to investigate characteristics that influence OS in pancreatic metastases to the brain. This is a population-based retrospective study of OS in 508 patients with pancreatic metastases to the brain using the SEER database. Univariate and multivariate Cox regression analyses were utilized, and a predictive nomogram was developed. There were 508 patients identified for this study, with a median OS of two months. In the univariate analysis, patients older than 65 years had significantly reduced OS (p<0.001). Patients with liver metastases (p<0.001) and liver and lung metastases (p<0.001) exhibited significantly reduced OS. Treatment of the primary tumor with chemotherapy only (p<0.001), radiation only (p=0.01), radiation and chemotherapy (p<0.001), and surgery only (p=0.01) were associated with increased OS. Resection of a distant metastasis site (p=0.009) and of a brain metastasis (p=0.03) were associated with increased OS. In the multivariable analysis, factors that remained significant included patient age (p=0.01), liver metastases (p<0.001), liver and lung metastases (p<0.001), treatment with chemotherapy (p<0.001), treatment with radiation and chemotherapy (p<0.001), and treatment with surgery and chemotherapy (p<0.001). The nomogram had a C-index of 0.766, suggesting congruence between the findings on the nomogram and the results in the internal verification. Median OS is influenced by age, multiorgan metastases, and treatment of the primary tumor. These data highlight the marginal benefit of treatment, yet improved quality of life remains to be elucidated.


Physiological Basis of Noise-Induced Hearing Loss in a Tympanal Ear.
Acoustic overexposure, such as listening to loud music too often, results in noise-induced hearing loss. The pathologies of this prevalent sensory disorder begin within the ear at synapses of the primary auditory receptors, their postsynaptic partners and their supporting cells. The extent of noise-induced damage, however, is determined by overstimulation of primary auditory receptors, upstream of where the pathologies manifest. A systematic characterization of the electrophysiological function of the upstream primary auditory receptors is warranted to understand how noise exposure impacts on downstream targets, where the pathologies of hearing loss begin. Here, we used the experimentally-accessible locust ear (male, Schistocerca gregaria) to characterize a decrease in the auditory receptor's ability to respond to sound after noise exposure. Surprisingly, after noise exposure, the electrophysiological properties of the auditory receptors remain unchanged, despite a decrease in the ability to transduce sound. This auditory deficit stems from changes in a specialized receptor lymph that bathes the auditory receptors, revealing striking parallels with the mammalian auditory system.SIGNIFICANCE STATEMENT Noise exposure is the largest preventable cause of hearing loss. It is the auditory receptors that bear the initial brunt of excessive acoustic stimulation, because they must convert excessive sound-induced movements into electrical signals, but remain functional afterward. Here we use the accessible ear of an invertebrate to, for the first time in any animal, characterize changes in auditory receptors after noise overexposure. We find that their decreased ability to transduce sound into electrical signals is, most probably, due to changes in supporting (scolopale) cells that maintain the ionic composition of the ear. An emerging doctrine in hearing research is that vertebrate primary auditory receptors are surprisingly robust, something that we show rings true for invertebrate ears too.


The Human Papillomavirus E6 Oncoprotein Targets USP15 and TRIM25 To Suppress RIG-I-Mediated Innate Immune Signaling.
Retinoic acid-inducible gene I (RIG-I) is a key pattern recognition receptor that senses viral RNA and interacts with the mitochondrial adaptor MAVS, triggering a signaling cascade that results in the production of type I interferons (IFNs). This signaling axis is initiated by K63-linked ubiquitination of RIG-I mediated by the E3 ubiquitin ligase TRIM25, which promotes the interaction of RIG-I with MAVS. USP15 was recently identified as an upstream regulator of TRIM25, stabilizing the enzyme through removal of degradative K48-linked polyubiquitin, ultimately promoting RIG-I-dependent cytokine responses. Here, we show that the E6 oncoprotein of human papillomavirus type 16 (HPV16) as well as of other HPV types form a complex with TRIM25 and USP15 in human cells. In the presence of E6, the K48-linked ubiquitination of TRIM25 was markedly increased, and in line with this, TRIM25 degradation was enhanced. Our results further showed that E6 inhibited the TRIM25-mediated K63-linked ubiquitination of RIG-I and its CARD-dependent interaction with MAVS. HPV16 E6, but not E7, suppressed the RIG-I-mediated induction of IFN-β, chemokines, and IFN-stimulated genes (ISGs). Finally, CRISPR-Cas9 gene targeting in human keratinocytes showed that the TRIM25-RIG-I-MAVS triad is important for eliciting an antiviral immune response to HPV16 infection. Our study thus identifies a novel immune escape mechanism that is conserved among different HPV strains and further indicates that the RIG-I signaling pathway plays an important role in the innate immune response to HPV infection.IMPORTANCE Persistent infection and tumorigenesis by HPVs are known to require viral manipulation of a variety of cellular processes, including those involved in innate immune responses. Here, we show that the HPV E6 oncoprotein antagonizes the activation of the cytoplasmic innate immune sensor RIG-I by targeting its upstream regulatory enzymes TRIM25 and USP15. We further show that the RIG-I signaling cascade is important for an antiviral innate immune response to HPV16 infection, providing evidence that RIG-I, whose role in sensing RNA virus infections has been well characterized, also plays a crucial role in the antiviral host response to small DNA viruses of the Papillomaviridae family.


DMSP synthesis genes distinguish two types of DMSP producer phenotypes.
Dimethylsulfoniopropionate (DMSP) is an important organic carbon and sulfur source in the surface ocean that fuels microbial activity and significantly impacts Earth's climate. After three decades of research, the cellular role(s) of DMSP and environmental drivers of production remain enigmatic. Recent work suggests that cellular DMSP concentrations, and changes in these concentrations in response to environmental stressors, define two major groups of DMSP producers: high DMSP producers that contain ≥ 50 mM intracellular DMSP and low DMSP producers that contain < 50 mM. Here we show that two recently described DMSP synthesis genes (DSYB and TpMT2) may differentiate these two DMSP phenotypes. A survey of prokaryotic and eukaryotic isolates found a significant correlation between the presence of DSYB and TpMT2 genes and previous measurements of high and low DMSP concentrations, respectively. Phylogenetic analysis demonstrated that DSYB and TpMT2 form two distinct clades. DSYB and TpMT2 were also found to be globally abundant in in situ surface communities, and their taxonomic annotations were similar to those observed for isolates. The strong correlation of the DSYB and TpMT2 synthesis genes with high and low producer phenotypes establishes a foundation for direct quantification of DMSP producers, enabling significantly improved predictions of DMSP in situ.


Effect of health education program on promoting physical activity among diabetic women in Mashhad, Iran: applying social cognitive theory.
Physical activity regularly is one of the important aspects of healthy lifestyle, which has an essential role in reducing the burden of disease and death. Diabetes is a typical general health problem. The aim of this study to determine the effect of education based on social cognitive theory on promoting physical activity among women with diabetes II in Iran. In this randomized control study, 82 diabetic females were randomly selected then were assigned into two groups: intervention (n=41) and control (n=41). Educational intervention was planned then performed during 7 sessions of 60-min in accordance with social-cognitive theory (SCT). The participants were asked to fill in the questionnaires in educational evaluation before and immediately after intervention and the follow up (10 weeks later). The data were analyzed through Repeated Measures ANOVA, Friedman, independence t and Mann-Whitney tests. The mean age among the participants was 48.37±5.67 yr also the body mass index was 28.69±3.95. In the intervention group, light physical activity and sedentary behavior reduced from 56.1% (23 individuals) to 14.6% (6 individuals) in the following up stage. There was significant improvement across time in the mean of minute's physical activity (P=0.042). There were significant differences in the mean's constructs of the Social-cognitive theory (SCT) (P<0.05). Design and execution of training program based on social cognitive theory can lead to promote physical activity among women with diabetes II through changes in the theoretical constructs.


Spatiotemporal characterization of single-order high harmonic pulses from time-compensated toroidal-grating monochromator.
Extreme ultraviolet (XUV) single-order high harmonic pulses with 10(6) photons/pulse were separated from multiple harmonic orders by a time-compensated toroidal-grating monochromator consisting of a pair of toroidal gratings. The first grating separates the harmonic order and the second one compensates for the pulse-front tilt. The center photon energies were tunable between 42 and 23 eV. The separated single harmonic pulses were spatially and temporally characterized as having a spot size of 58 +/- 3 microm at the focus, with a shortest pulse duration of 47 +/- 2 fs. The developed XUV light source is versatile for application to time- and space-resolved spectroscopy.


Clinical benefit for patients with non-small cell lung cancer enrolled in phase I trials.
To analyze the clinical features and outcomes of advanced non-small cell lung cancer (NSCLC) patients treated in phase I trials. The clinical characteristics, efficacy and toxicity data of 70 pretreated NSCLC patients enrolled in 17 phase I trials between January 2005 and June 2010 were analyzed at our institution. The histological types were: adenocarcinoma (79%), squamous cell carcinoma (13%), and others. Patients received a median number of 3 prior lines of treatment before inclusion. 1 complete response (CR), 11 (16%) partial responses (PRs), and 29 (41%) stable diseases (SDs) were observed (according to Response Evaluation Criteria in Solid Tumors (RECIST)). The median overall survival (OS) time was 18 months and the median progression-free survival (PFS) time was 4.1 months. The median PFS of these patients within their prior therapy line before phase I inclusion was 4.3 months. A performance status score of 0 and the number of prior lines of treatment were significant for OS and PFS in multivariate analysis, respectively. Grade 3/4 toxicities were observed in 20 (27%) patients, and there was 1 treatment-related death. Patients in good general condition and with limited pretreatment derived an improved benefit, suggesting that phase I studies may be a valid option for pretreated NSCLC patients.


Analysis of family satisfaction in intensive care unit.
To know the needs and level of family members' satisfaction is an essential part of the care provided to critically ill patients in intensive care units. The objective of this study was to identify the level of family members' satisfaction in an intensive care unit. A descriptive survey was carried out in the general adult intensive care unit of the Hospital Português (Salvador - BA) from November 2007 to January 2008. Jonhson's 14-question modified version of the Critical Care Family Needs Inventory was used to evaluate satisfaction of family members. Fifty three family members were included, mean age was 44 years and 68% were female. The median of family members satisfaction level was 11 (IQI = 9-13). Critical Care Family Need Inventory, questions with higher percentiles of satisfaction were those stating that family members felt that the patient was receiving the best possible care (96%) and that the information provided was honest (96%). The questions with lower percentiles of satisfaction were those stating that family members believed that someone in the intensive care unit had shown interest in their feelings (45%) and that a healthcare professional had explained how the intensive care unit equipment was used (41%). Most family members positively evaluated the intensive care unit professionals in the questions related to communication, attitude and patient care. However, there was a lower level of satisfaction in the questions related to the intensive care unit professionals' ability to comfort family members.


Current topics in signal transduction in bacteria.
Among the signal transfer systems in bacteria two types predominate: two-component regulatory systems and quorum sensing systems. Both types of system can mediate signal transfer across the bacterial cell envelope; however, the signalling molecule typically is not taken up into the cells in the former type of system, whereas it usually is in the latter. The Two-component systems include the recently described (eukaryotic) phosphorelay systems; quorum sensing systems can be based upon autoinducers of the N-acylated homoserine lactones, and on autoinducers of a peptidic nature. A single bacterial cell contains many signalling modules that primarily operate in parallel. This may give rise to neural-network behaviour. Recently, however, for both types of basic signal transfer modules, it has been demonstrated that they also can be organised in series (i.e. in a hierarchical order). Besides their hierarchical position in the signal transduction network of the cell, the spatial distribution of individual signalling modules may also be an important factor in their efficiency in signal transfer. Many challenges lie hidden in future work to understand these signal transfer processes in more detail. These are discussed here, with emphasis on the mutual interactions between different signal transfer processes. Successful contributions to this work will require rigorous mathematical modelling of the performance of signal transduction components, and -networks, as well as studies on light-sensing signal transduction systems, because of the unsurpassed time resolution obtainable in those latter systems, the opportunity to apply repeated reproducible stimuli, etc. The increased understanding of bacterial behaviour that already has resulted--and may further result--from these studies, can be used to fine-tune the beneficial activities of bacteria and/or more efficiently inhibit their deleterious ones.


Coping with divided attention: the advantage of familiarity.
The ability of an animal to perform a task successfully is limited by the amount of attention being simultaneously focused on other activities. One way in which individuals might reduce the cost of divided attention is by preferentially focusing on the most beneficial tasks. In territorial animals where aggression is lower among familiar individuals, the decision to associate preferentially with familiar conspecifics may therefore confer advantages by allowing attention to be switched from aggression to predator vigilance and feeding. Wild juvenile brown trout were used to test the prediction that familiar fishes respond more quickly than unfamiliar fishes to a simulated predator attack. Our results confirm this prediction by demonstrating that familiar trout respond 14% faster than unfamiliar individuals to a predator attack. The results also show that familiar fishes consume a greater number of food items, foraging at more than twice the rate of unfamiliar conspecifics. To the best of our knowledge, these results provide the first evidence that familiarity-biased association confers advantages through the immediate fitness benefits afforded by faster predator-evasion responses and the long-term benefits provided by increased feeding opportunities.


Hyperammonemia and proteostasis in cirrhosis.
Skeletal muscle loss or sarcopenia is a frequent complication of cirrhosis that adversely affects clinical outcomes. As skeletal muscle is the largest store of proteins in the body, proteostasis or protein homeostasis is required for maintenance of muscle mass. This review will focus on disordered skeletal muscle proteostasis in liver disease. Increased skeletal muscle uptake of ammonia initiates responses that result in disordered proteostasis including impaired protein synthesis and increased autophagy. The cellular response to the stress of hyperammonemia (hyperammonemic stress response, HASR) involves the coordinated action of diverse signaling pathways targeting the molecular mechanisms of regulation of protein synthesis. Transcriptional upregulation of myostatin, a TGFβ superfamily member, results in impaired mTORC1 signaling. Phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) also relates to decreased global protein synthesis rates and mTORC1 signaling. Ammonia also causes mitochondrial and bioenergetic dysfunction because of cataplerosis of α-ketoglutarate. Lowering ammonia, targeting components of HASR and regulating cellular amino acid levels can potentially restore proteostasis. Signaling via myostatin and eIF2α phosphorylation causes decreases in protein synthesis and mTORC1 activity with a parallel mitochondrial dysfunction and increased autophagy contributing to proteostasis perturbations during skeletal muscle hyperammonemia of liver disease.


Effects of ileal digesta collection time on standardized ileal digestibility of amino acids in corn, soybean meal, and distiller's dried grains with solubles fed to growing pigs.
The objective of this experiment was to determine the minimum collection time needed to obtain representative samples of ileal digesta from pigs fed different types of diets. Eight barrows with an initial BW of 34.6 kg (SD 2.1) were individually fitted with a T-cannula in the distal ileum and randomly allotted to a replicated 4 × 4 Latin square design with 4 diets and 4 periods per square. Three diets contained corn, soybean meal (SBM), or distiller's dried grains with solubles (DDGS) as the sole source of CP. An N-free diet was also prepared. All diets contained 0.5% chromic oxide as an indigestible marker. Equal meals were provided at 0800 and 2000 h. Ileal digesta samples were collected in 2-h intervals from 0800 to 2000 h during the last 3 d of each 7-d period. When pigs were fed the corn diet, the standardized ileal digestibility (SID) of most indispensable AA and dispensable AA increased and then decreased (quadratic, < 0.05) during each of the six 2-h periods. The SID of most AA were less ( < 0.05) if the ileal digesta samples were collected from 1800 to 2000 h or from 1600 to 2000 h compared with the SID values from the ileal samples collected over the entire 12-h period. When pigs were fed the SBM diet, the SID of Ile, Leu, Thr, Trp, Val, Ala, and Cys increased and then decreased (quadratic, < 0.05) but the SID of all other AA linearly decreased ( < 0.05) during the six 2-h periods. The SID of almost all AA were greater ( < 0.05) if the ileal samples were collected from 0800 to 1000 h, from 0800 to 1200 h, from 1000 to 1400 h, or from 0800 to 1400 h but less ( < 0.05) if collected from 1600 to 1800 h, from 1800 to 2000 h, from 1600 to 2000 h, or from 1400 to 2000 h compared with the SID values from the ileal samples collected over the entire 12-h period. When pigs were fed the DDGS-based diet, the SID of Ile, Leu, Lys, Phe, Trp, Val, and Tyr increased and then decreased (quadratic, < 0.05) during the six 2-h periods. The SID of most AA were less ( < 0.05) if the ileal samples were collected from 1800 to 2000 h compared with the SID values from the ileal samples collected over the entire 12-h period. In conclusion, diurnal variations in SID of AA in pigs indicate that 6 h of ileal sample collection starting 4 or 6 h after feeding may provide representative samples of ileal digesta from pigs fed different types of diets.


Assessment and predictive ability of the absolute neutrophil count in peripheral blood for in vivo CAR T cells expansion and CRS.
Chimeric antigen receptor (CAR) T cell therapy is an advanced and effective immunotherapy for relapsed or refractory B-cell malignancies. High expansion of CAR T cells in vivo and durable antitumor activity indicate a persistent therapeutic response. However, this treatment is linked to a high frequency of adverse events, such as cytokine release syndrome (CRS), which affects its efficacy and can even be life-threatening. At present, a variety of markers associated with clinical response and treatment toxicity after CAR T cells infusion have been reported. Although these biomarkers can act as effective indicators reflecting CAR T cells expansion as well as CRS, they fail to predict the expansion rate of CAR T cells. Hence, further investigation is urgent to find a new biomarker to fill this void. We analyzed the association between the absolute neutrophil count (ANC) and CAR expansion and CRS in 45 patients with B-cell malignancies from two clinical trials. We proposed that ANC could be a practical biomarker for CAR T cells expansion and CRS, and conducted a feasibility analysis on its predictive ability. In this study, 17 B-cell hematological malignancy patients with anti-B-cell maturation antigen CAR-treated and 28 with CAR19/22 T-cell-treated were enrolled and divided into an ANC-absence group and an ANC-presence group. The results showed that ANC absence correlated positively with CAR expansion and the expansion rate. The ANC can be used as a predictive marker for CAR T cells expansion. Moreover, the patients with ANC absence experienced a more severe CRS, and ANC performed a predictive ability for CRS. In addition, the peak serum concentration of several cytokines involved in CRS was higher in patients with ANC absence. Thus, we suggest ANC as an evaluative and predictive biomarker for CAR expansion and CRS during CAR T cell therapy, which can help to maximize clinical efficacy, reduce treatment-related toxicity and prolong survival.


Treatments and outcomes of advanced/recurrent non-small cell lung cancer harboring the EGFR T790M mutation: a retrospective observational study of 141 patients in Japan.
The epidermal growth factor receptor (EGFR) T790M mutation is considered the major mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations. Although chemotherapy is commonly used for those patients under the condition without T790M-targeted therapy, the clinical outcomes are poorly defined. Therefore, we aimed to reveal the treatment patterns and clinical outcomes in patients with T790M-positive NSCLC. We conducted a retrospective observational study at 23 sites in Japan, and 141 patients with T790M-positive advanced/recurrent NSCLC were identified from January 2008 to December 2014. Their records were studied to understand treatment patterns after detection of a T790M mutation and to assess the objective response rate (ORR) and median survival time (MST) to specific treatment modalities. Of 141 patients, 24 had de novo T790M-positive tumors and 117 had acquired T790M-positive tumors, with MSTs (95% CI) of 21.4 (12.4-36.7) and 9.1 (6.4-13.9) months, respectively. The most common regimen was platinum-based doublet chemotherapy ± bevacizumab, which was associated with an ORR/MST of 25.0%/29.1 months, respectively, in patients with de novo T790M mutations, and 22.2%/15.3 months, respectively, in patients with acquired T790M mutations. This study reveals the treatment patterns and outcomes of NSCLC patients in Japan after detection of the T790M mutation. The most common treatment following detection of the T790M mutation was platinum-based doublet chemotherapy ± bevacizumab. Platinum-based doublet chemotherapy ± bevacizumab was moderately effective, indicating the need for targeted therapies for patients with T790M mutation-positive NSCLC.


A patient with an allergy emergency.
Anaphylaxis is a severe life-threatening systemic reaction that otolaryngologists may come in contact with through emergency cases, or in their offices when delivering allergy immunotherapy. Rapid recognition of the entity should be followed by epinephrine administration. Anaphylaxis causes, including a hypothetical scenario, are described. Various risk factors for anaphylaxis, such as β-blocker use, are discussed. The differential diagnosis of anaphylaxis and adjunct treatment are explained.


The effect of Medicaid payment generosity on access and use among beneficiaries.
This study examines the effects of Medicaid payment generosity on access and care for adult and child Medicaid beneficiaries. Three years of the National Surveys of America's Families (1997, 1999, 2002) are linked to the Urban Institute Medicaid capitation rate surveys, the Area Resource File, and the American Hospital Association survey files. In order to identify the effect of payment generosity apart from unmeasured differences across areas, we compare the experiences of Medicaid beneficiaries with groups that should not be affected by Medicaid payment policies. To assure that these groups are comparable to Medicaid beneficiaries, we reweight the data using propensity score methods. We use a difference-in-differences model to assess the effects of Medicaid payment generosity on four categories of access and use measures (continuity of care, preventive care, visits, and perceptions of provider communication and quality of care). Higher payments increase the probability of having a usual source of care and the probability of having at least one visit to a doctor and other health professional for Medicaid adults, and produce more positive assessments of the health care received by adults and children. However, payment generosity has no effect on the other measures that we examined, such as the probability of receiving preventive care or the probability of having unmet needs. Higher payment rates can improve some aspects of access and use for Medicaid beneficiaries, but the effects are not dramatic.


Empowering Voice through the Creation of a Safe space: An experience of Aboriginal Women in Regional Queensland.
Sharing stories creates a space for respectful conversation and contributes to both knowledge and a sense of fellowship. This paper reflects on the experience of the research team in supporting a group of Aboriginal women to create safe spaces and to share their stories of healing, social and emotional wellbeing. Secondary data of a study exploring community perceptions about cancer were analysed using the holistic model of Indigenous Wellbeing developed by the Rumbalara Aboriginal Cooperative (2008). Qualitative data were collected during yarning sessions with a group of Aboriginal women while creating a quilt. Four elements of the Indigenous Wellbeing model were identified: connectedness, sense of control, threats and relationship with the mainstream. The yarning sessions promoted dialogue, identified needs and supported the voices of the participants. A duality of forces (positive and negative) influencing community wellbeing was identified. This project highlights the need for spaces that support people and the community to express concerns, identify needs, propose solutions and begin a dialogue that encourages empowerment. Community-driven conversation and the identification of safe and empowering spaces can serve to empower social and emotional wellbeing.


Novel Time-of-Flight Residual Gas Analyzer (TOF-RGA) for in situ Real-time Process Monitoring.
Sensitive gas analyses, in particular in industrial processes, are nowadays performed either via spectroscopy or using quadrupole mass spectrometers; the first method provides a fast but indirect measurement, whereas the second provides in situ measurements of only one species at a time. In this article, we present a novel time-of-flight residual gas analyzer (TOF-RGA) built by the Swiss company Spacetek Technology AG, and show the results of measurements such as the characterization of the FC5311 calibration compound, the detection of naturally abundant noble gases in air, the measurement of a noble gas mixture in the ultra-high vacuum facilities of CERN, and measurements acquired in a X-ray Photoelectron Spectroscopy facility in Germany, to demonstrate the capability of this new TOF-RGA to compete with already existing techniques for the monitoring of the composition of gases in real time (10 times per second), at high resolution (m/?m = 1 200 measured at m/z 132), and with a high sensitivity at ppb level.


Syndrome of inappropriate antidiuretic hormone secretion concurrent with liver disease in a dog.
A 5-year-old female Chihuahua was presented for acute collapse. Laboratory examinations showed markedly elevated levels of hepatobiliary enzymes. Empiric antibiotic therapy for bacterial infection of the liver was ineffective. The clinical signs worsened with the development of hyponatremia with hypoosmolality and elevated urine sodium levels. The dog was suspected of having acute cholangiohepatitis associated with an immune-mediated disease. Subsequently, it was diagnosed with syndrome of inappropriate antidiuretic hormone secretion (SIADH) on the basis of the specific disease criteria. Further tests showed normal function of the adrenal and thyroid glands, and MRI and cerebrospinal fluid (CSF) analysis did not show any intracranial diseases. Immunosuppressive therapy and water restriction resolved the clinical signs and improved the SIADH in this dog. This case indicates that SIADH can occur concurrently with suspected immune-mediated liver disease in dogs.


Maintenance of spermatogenesis requires TAF4b, a gonad-specific subunit of TFIID.
The establishment and maintenance of spermatogenesis in mammals requires specialized networks of gene expression programs in the testis. The gonad-specific TAF4b component of TFIID (formerly TAF(II)105) is a transcriptional regulator enriched in the mouse testis. Herein we show that TAF4b is required for maintenance of spermatogenesis in the mouse. While young Taf4b-null males are initially fertile, Taf4b-null males become infertile by 3 mo of age and eventually exhibit seminiferous tubules devoid of germ cells. At birth, testes of Taf4b-null males appear histologically normal; however, at post-natal day 3 gonocyte proliferation is impaired and expression of spermatogonial stem cell markers c-Ret, Plzf, and Stra8 is reduced. Together, these data indicate that TAF4b is required for the precise expression of gene products essential for germ cell proliferation and suggest that TAF4b may be required for the regulation of spermatogonial stem cell specification and proliferation that is obligatory for normal spermatogenic maintenance in the adult.


Development of extraction procedures for the analysis of polycyclic aromatic hydrocarbons and organochlorine pesticides in municipal sewage sludge.
Land application of sludge as fertilizers is a way of disposal and recycling of sludge. However, public concern has arisen due to the fact that organic contaminants in sludge may ultimately enter the food chain. Hence the need arises to analyse the organic contaminants such as PAHs and OCPs in sludge. In this study, Soxhlet was utilised as the extraction method and the extracts subjected to extensive cleanup via either silica columns or solid phase extraction cartridges prior to analysis using gas chromatography or high performance liquid chromatography. Sludge samples were collected from the drying beds of oxidation ponds in three locations in South Johore. OCPs such as heptachlor, dieldrin and pp-DDT were detected in low amounts (52-159 mg/kg) whereas PAHs such as naphthalene, phenanthrene, fluoranthene and benzo(a)pyrene were detected in the range of 0.2-5.5 mg/kg dry mass. Subcritical water extraction (SWE) recovery studies of PAHs were also performed from spiked sludge samples. Although a recovery range of 41-68% was obtained using the SWE method, the results indicated the usefulness of the technique as an alternative to Soxhlet extraction for the analysis of PAHs in sludge samples.


Staphylococcus aureus isolates from Eurasian Beavers (Castor fiber) carry a novel phage-borne bicomponent leukocidin related to the Panton-Valentine leukocidin.
Staphylococcus aureus can be a harmless coloniser, but it can also cause severe infections in humans, livestock and wildlife. Regarding the latter, only few studies have been performed and knowledge on virulence factors is insufficient. The aim of the present study was to study S. aureus isolates from deceased wild beavers (Castor fiber). Seventeen isolates from eleven beavers, found in Germany and Austria, were investigated. Antimicrobial and biocide susceptibility tests were performed. Isolates were characterised using S. aureus-specific DNA microarrays, spa typing and whole-genome sequencing. From two isolates, prophages were induced by mitomycin C and studied by transmission electron microscopy. Four isolates belonged to clonal complex (CC) 8, CC12, and CC398. Twelve isolates belonged to CC1956 and one isolate was CC49. The CC49 and CC1956 isolates carried distinct lukF/S genes related to the Panton-Valentine leukocidin (PVL) from human isolates of S. aureus. These genes were located on related, but not identical, Siphovirus prophages. The beavers, from which those isolates originated, suffered from abscesses, purulent organ lesions and necrotising pneumonia, i.e., clinical manifestations resembling symptoms of severe PVL-associated disease in humans. It might thus be assumed that the "Beaver Leukocidin (BVL, lukF/S-BV)"-positive strains are beaver-specific pathogens, and further studies on their clinical role as well as on a possible transmissibility to other species, including humans, are warranted.


Ventilation and perfusion imaging by electrical impedance tomography: a comparison with radionuclide scanning.
Electrical impedance tomography (EIT) is a technique that makes it possible to measure ventilation and pulmonary perfusion in a volume that approximates to a 2D plane. The possibility of using EIT for measuring the left-right division of ventilation and perfusion was compared with that of radionuclide imaging. Following routine ventilation (81mKr) and perfusion scanning (99mTc-MAA), EIT measurements were performed at the third and the sixth intercostal level in 14 patients with lung cancer. A correlation (r = 0.98, p < 0.005) between the left-right division for the ventilation measured with EIT and that with 81mKr was found. For the left-right division of pulmonary perfusion a correlation of 0.95 (p < 0.005) was found between the two methods. The reliability coefficient (RC) was calculated for estimating the left-right division with EIT. The RC for the ventilation measurements was 94% and 96% for the perfusion measurements. The correlation analysis for reproducibility of the EIT measurements was 0.95 (p < 0.001) for the ventilation and 0.93 (p < 0.001) for the perfusion measurements. In conclusion, EIT can be regarded as a promising technique to estimate the left-right division of pulmonary perfusion and ventilation.


Surgical timing for cervical and upper thoracic injuries in patients with polytrauma.
OBJECTIVE Few studies have investigated the advantages of early spinal stabilization in the patient with polytrauma in terms of reduction of morbidity and mortality. Previous analyses have shown that early stabilization may reduce ICU stay, with no effect on complication rates. METHODS The authors prospectively observed 340 polytrauma patients with an Injury Severity Score (ISS) of greater than 16 at a single Level 1 trauma center who were treated in accordance with a protocol termed "early appropriate care," which emphasizes operative treatment of various fractures within 36 hours of injury. Of these patients, 46 had upper thoracic and/or cervical spine injuries. The authors retrospectively compared patients treated according to protocol versus those who were not. Continuous variables were compared using independent t-tests and categorical variables using Fisher's exact test. Logistic regression analysis was performed to account for baseline confounding factors. RESULTS Fourteen of 46 patients (30%) did not undergo surgery within 36 hours. These patients were significantly more likely to be older than those in the protocol group (53 vs 38 years, p = 0.008) and have greater body mass index (BMI; 33 vs 27, p = 0.02), and they were less likely to have a spinal cord injury (SCI) (82% did not have an SCI vs 44% in the protocol group, p = 0.04). In terms of outcomes, patients in the protocol-breach group had significantly more total ventilator days (13 vs 6 days, p = 0.02) and total ICU days (16 vs 9 days, p = 0.03). Infection rates were 14% in the protocol-breach group and 3% in the protocol group (p = 0.2) Total complications trended toward being statistically significantly more common in the protocol-breach group (57% vs 31%). After controlling for potential confounding variables by logistic regression (including age, sex, BMI, race, and SCI), total complications were significantly (p < 0.05) greater in the protocol-breach group (OR 29, 95% CI 1.9-1828). This indicates that the odds of developing "any complication" were 29 times greater if treatment was delayed more than 36 hours. CONCLUSIONS Early surgical stabilization in the polytrauma patient with a cervical or upper thoracic spine injury is associated with fewer complications and improved outcomes. Hospitals may consider the benefit of protocols that promote early stabilization in this patient population.


Calluna vulgaris (L.) Hull: chemical characterization, evaluation of its bioactive properties and effect on the vaginal microbiota.
The inflorescences of Calluna vulgaris were nutritionally and chemically characterized. Furthermore, different organic and aqueous extracts were prepared for the evaluation of their bioactive properties. From the obtained results, carbohydrates were the major compounds, followed by protein, lipid and ashes. It was possible to identify the sugars fructose and glucose, five organic acids, 26 individual fatty acids and the four tocopherol isoforms. Concerning the extract composition, 12 phenolic compounds were identified, with myricetin-3-O-glucoside and myricetin-O-rhamnoside predominating. Concerning the bioactive effects, the more polar extracts showed not only the highest amount in phenolic compounds, but also the strongest antioxidant and antibacterial activities. In contrast, for the anti-inflammatory and cytotoxic potential, the most effective extracts were the n-hexane and the ethyl acetate extracts, respectively. C. vulgaris presented a wide range of biological effects, highlighting their capacity to inhibit pathogenic bacteria without affecting beneficial microflora, corroborating their use in traditional medicine.


Hyperpolarized 13C MRI of the pulmonary vasculature and parenchyma.
The study of lung perfusion in normal and diseased subjects is of great interest to physiologists and physicians. In this work we demonstrate the application of a liquid-phase hyperpolarized (HP) carbon-13 ((13)C) tracer to magnetic resonance imaging (MRI) of the pulmonary vasculature and pulmonary perfusion in a porcine model. Our results show that high spatial and temporal resolution images of pulmonary perfusion can be obtained with this contrast technique. Traditionally, pulmonary perfusion measurement techniques have been challenging because of insufficient signal for quantitative functional assessments. The use of polarized (13)C in MRI overcomes this limitation and may lead to a viable clinical method for studying the pulmonary vasculature and perfusion.


Respiratory mechanics during sevoflurane anesthesia in children with and without asthma.
We studied lung function in children with and without asthma receiving anesthesia with sevoflurane. Fifty-two children had anesthesia induced with sevoflurane (up to 8%) in a mixture of 50% nitrous oxide in oxygen and then maintained at 3% with children breathing spontaneously via face mask and Jackson-Rees modification of the T-piece. Airway opening pressure and flow were then measured. After insertion of an oral endotracheal tube under 5% sevoflurane, measurements were repeated at 3%, as well as after increasing to 4.2%. Respiratory system resistance (Rrs) and compliance during expiration were calculated using multilinear regression analysis of airway opening pressure and flow, assuming a single-compartment model. Data from 44 children were analyzed (22 asthmatics and 22 normal children). The two groups were comparable with respect to age, weight, ventilation variables, and baseline respiratory mechanics. Intubation was associated with a significant increase in Rrs in asthmatics (17% +/- 49%), whereas in normal children, Rrs slightly decreased (-4% +/- 39%). At 4.2%, Rrs decreased slightly in both groups with almost no change in compliance system resistance. We concluded that in children with mild to moderate asthma, endotracheal intubation during sevoflurane anesthesia was associated with increase in Rrs that was not seen in nonasthmatic children. Tracheal intubation using sevoflurane as sole anesthetic is possible and its frequency is increasing. When comparing children with and without asthma, tracheal intubation under sevoflurane was associated with an increase in respiratory system resistance in asthmatic children. However, no apparent clinical adverse event was observed.


HPV vaccine recommendation profiles among a national network of pediatric practitioners: understanding contributors to parental vaccine hesitancy and acceptance.
Background: Practitioner communication is one of the most important influences and predictors of HPV vaccination uptake. The objective of this study was to conduct a latent class analysis characterizing pediatric practitioner HPV recommendation patterns. Methods: Pediatric practitioners of the American Academy of Pediatrics' (AAP) Pediatric Research in Office Settings (PROS) national network completed an online survey where they were presented with 5 hypothetical vignettes of well child visits and responded to questions. Questions asked about their use of communication strategies, assessments about the adolescent patient becoming sexually active in the next 2 years for decision-making about HPV vaccine recommendation, and peer norms. Latent class analysis characterized practitioner subgroups based on their response patterns to 10 survey questions. Multinomial logistic regression examined practitioner characteristics associated with each profile. Results: Among 470 respondents, we identified three distinct practitioner HPV vaccine recommendation profiles: (1) Engagers (52%) followed national age-based guidelines, strongly recommended HPV vaccination, and perceived peers as strongly recommending; (2) Protocol Followers (20%) also strongly recommended HPV vaccination, but were less likely to engage families in a discussion about benefits; and (3) Ambivalent HPV Vaccine Recommenders (28%) delayed or did not recommend HPV vaccination and were more likely to use judgment about whether adolescents will become sexually active in the next two years. Practicing in a suburban setting was associated with twice the odds of being an Ambivalent Recommender relative to being an Engager (OR = 2.2; 95% CI:1.1-4.1). Conclusions: Findings underscore the importance of continued efforts to bolster practitioner adoption of evidence-based approaches to HPV vaccine recommendation especially among Ambivalent Recommenders.


Use of denaturing gradient gel electrophoresis to detect Actinobacteria associated with the human faecal microbiota.
With the exceptions of the bifidobacteria, propionibacteria and coriobacteria, the Actinobacteria associated with the human gastrointestinal tract have received little attention. This has been due to the seeming absence of these bacteria from most clone libraries. In addition, many of these bacteria have fastidious growth and atmospheric requirements. A recent cultivation-based study has shown that the Actinobacteria of the human gut may be more diverse than previously thought. The aim of this study was to develop a denaturing gradient gel electrophoresis (DGGE) approach for characterizing Actinobacteria present in faecal samples. Amount of DNA added to the Actinobacteria-specific PCR used to generate strong PCR products of equal intensity from faecal samples of five infants, nine adults and eight elderly adults was anti-correlated with counts of bacteria obtained using fluorescence in situ hybridization probe HGC69A. A nested PCR using Actinobacteria-specific and universal PCR-DGGE primers was used to generate profiles for the Actinobacteria. Cloning of sequences from the DGGE bands confirmed the specificity of the Actinobacteria-specific primers. In addition to members of the genus Bifidobacterium, species belonging to the genera Propionibacterium, Microbacterium, Brevibacterium, Actinomyces and Corynebacterium were found to be part of the faecal microbiota of healthy humans.


Functional T cells in rabbits gut mucosal lymphocytes.
Functional studies of Peyer's patch and gut mucosa lymphocytes were performed in mixed lymphocyte culture reaction (MLC), an in vitro measure of the capacity of T cells to recognize and respond to cell surface alloantigens. The data demonstrate the functional effectiveness of both these mucosal lymphocyte populations in one-way MLC, both as responding as well as stimulating cells. Both the responding and stimulating capacities of these cells in MLC were almost the same as observed for lymphocytes obtained from either spleen or thymus. We conclude that functional T cells exist in both rabbit gut lamina propria and Peyer's patches with approximately the same quantitative capacity to respond in the MLC.


Surgical site infection rate and risk factors among obstetric cases of jimma university specialized hospital, southwest ethiopia.
Surgical Site infections are the second most frequently reported infections of all nosocomial infections among hospital patients. Among surgical patients in obstetrics, Surgical Site Infections were the most common nosocomial infections and the rate is higher in sub-Saharan Africa. There has not been a study which documented the extent of the problem in the study area; hence the objective of this study was to determine the surgical site infection rate among women having surgery for delivery in obstetrics of Jimma University Specialized Hospital (JUSH) from April 1, 2009 to March 31, 2010. A prospective descriptive study design was conducted with the aim of determining the surgical site infection rate on all 770 women who had surgery for delivery from April 1, 2009 to March 31, 2010 in obstetric ward of the Hospital. Data on history of the patient, patient specific demographic information on potential risk factors and the occurrence of Surgical Site infections in the first 30 days following surgery were collected using pretested data collection form. In addition, relevant data were also abstracted from the operation logbook of the cases. Then data were cleaned, edited and fed to computer and analyzed using SPSS for window version 16.0. Finally Statistical test for significance was employed using chi-squared (X (2)) where appropriate at 5% level of significance. The mean (±SD) of the subjects' age was 26(±7) years and the majority of the women were from the rural areas (72.7%). The overall surgical site infection rate was 11.4%. Of those who had surgical site infections, 64.8% had clean-contaminated wound and 35.2% had contaminated /dirty wounds. Wound class at time of surgery has a statistically significant association with Surgical Site infections (p <0.001).The Surgical Site infections rate was similar for cesarean section and abdominal hysterectomy but higher for destructive delivery under direct vision. Majority of the operations were made for emergency Obstetric conditions (96.6%) and the Surgical Site Infections rate was two times higher compared to that of elective surgery. Chorioamnionitis, presence of meconium, large intraoperative blood loss and Perioperative blood transfusion were associated with increased severity of SSIs with p < 0.001. Absence of antenatal care follow up was also associated with increased severity of Surgical Site Infections. It has been revealed that Surgical Site Infections rates are higher than acceptable standards indicating the need for improving Antenatal care, increasing the number of skilled birth attendants at the local clinics, increasing basic and comprehensive emergency obstetric care services, applying improved surgical techniques and improving infection prevention practices to decrease infection rate to acceptable standard.


Genetic parameters, reciprocal cross differences, and age-related heterosis of egg-laying performance in chickens.
Egg-laying performance is economically important in poultry breeding programs. Crossbreeding between indigenous and elite commercial lines to exploit heterosis has been an upward trend in traditional layer breeding for niche markets. The objective of this study was to analyse the genetic background and to estimate the heterosis of longitudinal egg-laying traits in reciprocal crosses between an indigenous Beijing-You and an elite commercial White Leghorn layer line. Egg weights were measured for the first three eggs, monthly from 28 to 76 weeks of age, and at 86 and 100 weeks of age. Egg quality traits were measured at 32, 54, 72, 86, and 100 weeks of age. Egg production traits were measured from the start of lay until 43, 72, and 100 weeks of age. Heritabilities and phenotypic and genetic correlations were estimated. Heterosis was estimated as the percentage difference of performance of a crossbred from that of the parental average. Reciprocal cross differences were estimated as the difference between the reciprocal crossbreds as a percentage of the parental average. Estimates of heritability of egg weights ranged from 0.29 to 0.75. Estimates of genetic correlations between egg weights at different ages ranged from 0.72 to 1.00. Estimates of heritability for cumulative egg numbers until 43, 72, and 100 weeks of age were around 0.15. Estimates of heterosis for egg weight and cumulative egg number increased with age, ranging from 1.0 to 9.0% and from 1.4 to 11.6%, respectively. From 72 to 100 weeks of age, crossbreds produced more eggs per week than the superior parent White Leghorn (3.5 eggs for White Leghorn, 3.8 and 3.9 eggs for crossbreds). Heterosis for eggshell thickness ranged from 2.7 to 6.6% when using Beijing-You as the sire breed. No significant difference between reciprocal crosses was observed for the investigated traits, except for eggshell strength at 54 weeks of age. The heterosis was substantial for egg weight and cumulative egg number, and increased with age, suggesting that non-additive genetic effects are important in crossbreds between the indigenous and elite breeds. Generally, the crossbreds performed similar to or even outperformed the commercial White Leghorns for egg production persistency.


High speed phase shifting interferometry using injection locking of the laser frequency to the resonant modes of a confocal Fabry-Perot cavity.
We present a high speed phase shifting interferometer which utilizes the self injection locking of a frequency tunable laser diode. By using a confocal Fabry-Perot cavity made of ultra low expansion glass, and linearly modulating the laser diode current, the laser frequency could be injection locked to the resonant modes of the Fabry-Perot cavity consecutively. It provided equal phase steps to the interferograms which are ideal to be analyzed by the Carré algorithm. The phase step error was evaluated to be about 3 MHz which corresponds to 0.2 nm in length measurement. With this technique, profile measurements are insensitive to external vibration since four 640x480 pixels images can be acquired within 4 ms. Difference of two profile measurements, each made with and without vibration isolation, respectively, was evaluated to be 0.5 nm (rms).


Improving health-related quality of life in middle-age children with cerebral palsy following selective percutaneous myofascial lengthening and functional physiotherapy.
Children with cerebral palsy (CP) experience decreased health-related quality of life (HRQOL). This study aimed to assess the HRQOL of children with CP before versus after a combined program of minimally invasive selective percutaneous myofascial lengthening (SPML) and functional physiotherapy. A single-group pre-posttest design was used. Twenty-six middle childhood children with spastic CP, aged 5-7 years, with Gross Motor Function Classification System levels II-IV underwent SPML surgery and 9 months of postoperative functional strength training therapy. The proxy version of the DISABKIDS-Smiley questionnaire was completed by one parent of each child. Dependent t-tests were used to compare mean pre- and post-measurement scores. After the 9-month intervention, the children with CP had significantly higher quality of life scores (mean difference, 11.06 ± 9.05; 95% confidence interval [CI], 7.40-14.71; p < 0.001). This study demonstrated that children with CP had better HRQOL after a combined program of minimally invasive SPML surgery and functional physiotherapy (ACTRN12618001535268).


Murine cytomegalovirus particle types in relation to sources of virus and pathogenicity.
Murine cytomegalovirus (MCMV) preparations from mouse embryo fibroblasts and from infected salivary glands were purified on potassium tartrate density gradients and examined by electron microscopy. The cell culture virus contained multicapsid enveloped virions which are ruptured easily and account for the excess number of free capsids in these preparations. Salivary gland virus consisted of single-capsid enveloped virus and equal numbers of free capsids. Particle types were imperfectly separated on density gradients, but successful separation was achieved by filtration through 220 and 450 nm Millipore membrane filters. Naked capsids were not infectious and could not be rendered infectious by centrifugal adsorption, showing that centrifugal enhancement of MCMV infectivity is not mediated through this mechanism. Although present in excess number in (avirulent) cell culture virus preparations, naked capsids did not interfere with the action of (virulent) salivary gland virus in newborn mice.


Pericytes in the myovascular niche promote post-natal myofiber growth and satellite cell quiescence.
The satellite cells, which serve as adult muscle stem cells, are both located beneath myofiber basement membranes and closely associated with capillary endothelial cells. We observed that 90% of capillaries were associated with pericytes in adult mouse and human muscle. During post-natal growth, newly formed vessels with their neuroglial 2 proteoglycan (NG2)-positive pericytes became progressively associated with the post-natal muscle stem cells, as myofibers increased in size and satellite cells entered into quiescence. In vitro, human muscle-derived pericytes promoted myogenic cell differentiation through insulin-like growth factor 1 (IGF1) and myogenic cell quiescence through angiopoietin 1 (ANGPT1). Diphtheria toxin-induced ablation of muscle pericytes in growing mice led both to myofiber hypotrophy and to impaired establishment of stem cells quiescence. Similar effects were observed following conditional in vivo deletion of pericyte Igf1 and Angpt1 genes, respectively. Our data therefore demonstrate that, by promoting post-natal myogenesis and stem cell quiescence, pericytes play a key role in the microvascular niche of satellite cells.


Modulation of mitochondrial complex I activity by reversible Ca2+ and NADH mediated superoxide anion dependent inhibition.
Complex I, a key component of the mitochondrial respiratory chain, exhibits diminished activity as a result of cardiac ischemia/reperfusion. Cardiac ischemia/reperfusion is associated with increases in the levels of mitochondrial Ca(2+) and pro-oxidants. In the current in vitro study, we sought evidence for a mechanistic link between Ca(2+), pro-oxidants, and inhibition of complex I utilizing mitochondria isolated from rat heart. Our results indicate that addition of Ca(2+) to solubilized mitochondria results in loss in complex I activity. Ca(2+) induced a maximum decrease in complex I activity of approximately 35% at low micromolar concentrations over a narrow physiologically relevant pH range. Loss in activity required reducing equivalents in the form of NADH and was not reversed upon addition of EGTA. The antioxidants N-acetylcysteine and superoxide dismutase, but not catalase, prevented inhibition, indicating the involvement of superoxide anion (O2(*-)) in the inactivation process. Importantly, the sulfhydryl reducing agent DTT was capable of fully restoring complex I activity implicating the formation of sulfenic acid and/or disulfide derivatives of cysteine in the inactivation process. Finally, complex I can reactivate endogenously upon Ca(2+) removal if NADH is present and the enzyme is allowed to turnover catalytically. Thus, the present study provides a mechanistic link between three alterations known to occur during cardiac ischemia/reperfusion, mitochondrial Ca(2+) accumulation, free radical production, and complex I inhibition. The reversibility of these processes suggests redox regulation of Ca(2+) handling.


[Free choice of doctors - an international comparison].
The focus of this international comparison concerning the issue of free choice among primary care physicians and specialists is to learn from experiences in other countries. Two different types of health care systems are analysed: state-administered health systems such as in Finland and Great Britain or competition-based systems such as in Switzerland and the USA. In the countries outlined mentioned and other OECD nations (Organisation for Economic Co-Operation and Development) not described in this study, several restrictions of free choice among physicians can be observed. Restrictions are to be found when changing the general practitioner as well as in first contact to specialists. Both limitations do not seem to have a significant effect on the level of satisfaction of the population with health care in general. From an international perspective free choice of doctors seems to be an exception in health systems.


Glide Mechanisms in Experimentally Deformed Minerals.
A method for study of mechanisms of twin and translation gliding in minerals in rocks has been devised by which slip markings produced experimentally on polished surfaces are related to crystallographic planes by universal stage measurements of the crystal orientations. In specimens strained 5 to 10 percent at 5 to 7 kilobars confining pressure and 700 degrees to 850 degrees C, the glide plane and glide direction for slip and twinning have been determined in olivine, enstatite, kyanite, and diopside. Slip occurs in closest-packed directions, in which also lies the shortest Burgers vector of a unit edge dislocation in the slip plane.


Posterior uveitis and primary cerebral reticulum cell sarcoma.
Primary cerebral reticulum cell sarcoma appeared as unexplained posterior uveitis. A retrospective review of 19 cases of cerebral reticulum cell sarcoma seen at Massachusetts General Hospital has not confirmed the previously described high incidence of ocular involvement in patients with this tumor. The presence of posterior uveitis remote from a definite cerebral mass should suggest the possible diagnosis of primary cerebral reticulum cell sarcoma.


A rare HBV subgenotype D4 with unique genomic signatures identified in north-eastern India--an emerging clinical challenge?
HBV has been classified into ten genotypes (A-J) and multiple subgenotypes, some of which strongly influence disease outcome and their distribution also correlate with human migration. HBV infection is highly prevalent in India and its diverse population provides an excellent opportunity to study the distinctiveness of HBV, its evolution and disease biology in variegated ethnic groups. The North-East India, having international frontiers on three sides, is one of the most ethnically and linguistically diverse region of the country. Given the paucity of information on molecular epidemiology of HBV in this region, the study aimed to carry out an in-depth genetic characterization of HBV prevailing in North-East state of Tripura. From sera of chronically HBV infected patients biochemical/serological tests, HBV DNA quantification, PCR-amplification, sequencing of PreS/S or full-length HBV genomes were done. HBV genotype/subgenotype determination and sequence variability were assessed by MEGA5-software. The evolutionary divergence times of different HBV subgenotypes were estimated by DNAMLK/PHYLIP program while jpHMM method was used to detect any recombination event in HBV genomes. HBV genotypes D (89.5%), C (6.6%) and A (3.9%) were detected among chronic carriers. While all HBV/A and HBV/C isolates belonged to subgenotype-A1 and C1 respectively, five subgenotypes of HBV/D (D1-D5) were identified including the first detection of rare D4. These non-recombinant Indian D4 (IndD4) formed a distinct phylogenetic clade, had 2.7% nucleotide divergence and recent evolutionary radiation than other global D4. Ten unique amino acids and 9 novel nucleotide substitutions were identified as IndD4 signatures. All IndD4 carried T120 and R129 in ORF-S that may cause immune/vaccine/diagnostic escape and N128 in ORF-P, implicated as compensatory Lamivudine resistance mutation. IndD4 has potential to undermine vaccination programs or anti-viral therapy and its introduction to North-East India is believed to be linked with the settlement of ancient Tibeto-Burman migrants from East-Asia.


Biologic characterization of H4, H6, and H9 type low pathogenicity avian influenza viruses from wild birds in chickens and turkeys.
The pathogenesis, virus shedding, and serologic response in specific-pathogen-free (SPF) chickens and commercial turkeys against H4, H6, and H9 type low pathogenic avian influenza viruses (LPAI) from wild birds was examined. Four-week-old chickens and three-week-old turkeys were given 1 x 10(6) EID50 of LPAI per bird, intrachoanally, and examined for clinical signs for 3 wk. Oropharyngeal and cloacal swabs, and fecal samples, were collected at 2, 4, and 7 days postinoculation (PI) for virus detection by real-time RT-PCR. Serum was collected at 7, 14, and 21 days PI and examined for antibodies against avian influenza virus (AIV) by the enzyme-linked immunosorbant assay (ELISA) and hemagglutination inhibition tests. Tissue samples for histopathology were collected from three birds per group at 3 days PI. The hemagglutinin genes of the viruses were sequenced, and phylogenetic analysis was conducted. Clinical signs ranged from no clinical signs to moderate depression, decreased activity, and decreased food and water consumption. Based on virus detection results, SPF chickens were generally found to be shedding more virus from both the oropharynx and cloaca than were commercial turkeys. Microscopic lesion results in both species showed the predominance of lesions in the respiratory and gastrointestinal tract, which is consistent with the fact that these viruses are of low pathogenicity. In chickens and turkeys, oropharyngeal shedding strongly correlated with the lesions found in the upper respiratory tract. Turkeys had fewer lesions in the respiratory tract and more lesions in the gastrointestinal tract compared to chickens. Thirteen LPAI viruses caused seroconversion in commercial turkeys, whereas only 6 LPAI viruses caused seroconversion in SPF chickens. Phylogenetic analysis of the HA genes showed that the H4, H6, and H9 viruses evaluated here represented the full genetic diversity of North American AIVs of their respective subtypes. This data is important for surveillance and control because some of the LPAI viruses (of wild bird origin and examined in this study) that can infect and be shed by chickens and turkeys would be difficult to detect in commercial poultry. Specifically, detection is difficult because these viruses did not cause overt clinical disease or mortality, but only induced mild microscopic lesions and exhibited poor seroconversion.


Do general practitioner hospitals reduce the utilisation of general hospital beds? Evidence from Finnmark county in north Norway.
To assess whether populations with access to general practitioner hospitals (GP hospitals) utilise general hospitals less than populations without such access. Observational study comparing the total rates of admissions and of occupied bed days in general hospitals between populations with and without access to GP hospitals. Comparisons were also made separately for diagnoses commonly encountered in GP hospitals. Two general hospitals serving the population of Finnmark county in north Norway. 35,435 admissions based on five years' routine recordings from the two hospitals. The total rate of admission to general hospitals was lower in peripheral municipalities with a GP hospital than in central municipalities without this kind of institution, 26% and 28% lower for men and women respectively. The corresponding differences were 38% and 52%, when analysed for occupied bed days. The differences were most pronounced for patients with respiratory diseases, cardiac failure, and cancer who are primarily or intermediately treated or cared for in GP hospitals, and for patients with stroke and fractures, who are regularly transferred from general hospitals to GP hospitals for longer term follow up care. GP hospitals seem to reduce the utilisation of general hospitals with respect to admissions as well as occupied bed days.


Prognostic value of Delphian lymph node in T1b glottic carcinoma.
The published papers concerning Delphian lymph node (DN) involvement in laryngeal tumours generally consider advanced laryngeal and hypopharyngeal cancer. We investigated the role of DN in a selected group of patients with T1b glottic squamous cell carcinoma. The study involved 53 patients with T1b glottic squamous cell carcinoma who underwent horizontal glottectomy. DN was isolated in 46 (86.8%). Histological evaluation of the isolated nodes revealed the presence of metastases in three cases (6.5%). Forty-six of the 53 patients (86.8%) are still alive and disease-free; four (7.5%) died because of their disease and three (5.7%) because of unrelated causes. The 3- and 5-year overall survival was, respectively, 94.3% and 90.6%. Both the 3- and 5-year disease-free survival was 92.5%. Two of the three patients with a metastatic DN died because of a recurrence: laterocervical lymph node metastases in one case and parastomal recurrence in the other. The frequency of local relapse was at the threshold of significance in the patients with a positive DN (p = 0.0540). Of the four patients who died of their disease, two were DN-positive. Mortality was statistically higher in the DN-positive patients (p = 0.0166). The presence of DN metastases was statistically associated with recurrence and overall survival in T1b glottic cancer.


Continuous Online Sequence Learning with an Unsupervised Neural Network Model.
The ability to recognize and predict temporal sequences of sensory inputs is vital for survival in natural environments. Based on many known properties of cortical neurons, hierarchical temporal memory (HTM) sequence memory recently has been proposed as a theoretical framework for sequence learning in the cortex. In this letter, we analyze properties of HTM sequence memory and apply it to sequence learning and prediction problems with streaming data. We show the model is able to continuously learn a large number of variable order temporal sequences using an unsupervised Hebbian-like learning rule. The sparse temporal codes formed by the model can robustly handle branching temporal sequences by maintaining multiple predictions until there is sufficient disambiguating evidence. We compare the HTM sequence memory with other sequence learning algorithms, including statistical methods-autoregressive integrated moving average; feedforward neural networks-time delay neural network and online sequential extreme learning machine; and recurrent neural networks-long short-term memory and echo-state networks on sequence prediction problems with both artificial and real-world data. The HTM model achieves comparable accuracy to other state-of-the-art algorithms. The model also exhibits properties that are critical for sequence learning, including continuous online learning, the ability to handle multiple predictions and branching sequences with high-order statistics, robustness to sensor noise and fault tolerance, and good performance without task-specific hyperparameter tuning. Therefore, the HTM sequence memory not only advances our understanding of how the brain may solve the sequence learning problem but is also applicable to real-world sequence learning problems from continuous data streams.