California physician's professional image of therapists.
The purpose of this study was to identify the attitudes of California physicians toward the professional image of physical therapists and to determine the influence of several independent variables on that image. A three-part questionnaire was used to survey the sample of physicians. The first two sections contained attitudinal statements based on criteria representing degrees of professionalism; the third section contained questions on demographic variables. The results indicated that, although the majority of responding physicians viewed physical therapists as possessing all of the criteria denoting professionalism, there was relatively less agreement with the two criteria representing the highest degrees of professionalism-evaluative skills and autonomy of judgment. None of the independent variables influenced physicians' professional image of physical therapists except physician specialty area, in which family practitioners held a significantly higher professional image of physical therapists than did neurosurgeons and orthopedists. The authors suggest further study of other factors that may affect physicians' professional image of physical therapists as well as recommend steps that may be taken to improve the professional image of physical therapists.


A Review of Scientific Evidence for THC:CBD Oromucosal Spray (Nabiximols) in the Management of Chronic Pain.
The 20% prevalence of chronic pain in the general population is a major health concern given the often profound associated impairment of daily activities, employment status, and health-related quality of life in sufferers. Resource utilization associated with chronic pain represents an enormous burden for healthcare systems. Although analgesia based on the World Health Organization's pain ladder continues to be the mainstay of chronic pain management, aside from chronic cancer pain or end-of-life care, prolonged use of non-steroidal anti-inflammatory drugs or opioids to manage chronic pain is rarely sustainable. As the endocannabinoid system is known to control pain at peripheral, spinal, and supraspinal levels, interest in medical use of cannabis is growing. A proprietary blend of cannabis plant extracts containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) as the principal cannabinoids is formulated as an oromucosal spray (USAN name: nabiximols) and standardized to ensure quality, consistency and stability. This review examines evidence for THC:CBD oromucosal spray (nabiximols) in the management of chronic pain conditions. Cumulative evidence from clinical trials and an exploratory analysis of the German Pain e-Registry suggests that add-on THC:CBD oromucosal spray (nabiximols) may have a role in managing chronic neuropathic pain, although further precise clinical trials are required to draw definitive conclusions.


The music of morality and logic.
Musical theory has built on the premise that musical structures can refer to something different from themselves (Nattiez and Abbate, 1990). The aim of this work is to statistically corroborate the intuitions of musical thinkers and practitioners starting at least with Plato, that music can express complex human concepts beyond merely "happy" and "sad" (Mattheson and Lenneberg, 1958). To do so, we ask whether musical improvisations can be used to classify the semantic category of the word that triggers them. We investigated two specific domains of semantics: morality and logic. While morality has been historically associated with music, logic concepts, which involve more abstract forms of thought, are more rarely associated with music. We examined musical improvisations inspired by positive and negative morality (e.g., good and evil) and logic concepts (true and false), analyzing the associations between these words and their musical representations in terms of acoustic and perceptual features. We found that music conveys information about valence (good and true vs. evil and false) with remarkable consistency across individuals. This information is carried by several musical dimensions which act in synergy to achieve very high classification accuracy. Positive concepts are represented by music with more ordered pitch structure and lower harmonic and sensorial dissonance than negative concepts. Music also conveys information indicating whether the word which triggered it belongs to the domains of logic or morality (true vs. good), principally through musical articulation. In summary, improvisations consistently map logic and morality information to specific musical dimensions, testifying the capacity of music to accurately convey semantic information in domains related to abstract forms of thought.


Shaped by asymmetrical interdependence: a qualitative case study of the external influences on international non-governmental organizations' implementation of equity principles in HIV/AIDS work.
Addressing inequities is a key role for international non-governmental organizations (INGOs) working in health and development. Yet, putting equity principles into practice can prove challenging. In-depth empirical research examining what influences INGOs' implementation of equity principles is limited. This study examined the influences on one INGO's implementation of equity principles in its HIV/AIDS programs. This research employed a case study with nested components (an INGO operating in Kenya, with offices in North America). We used multiple data collection methods, including document reviews, interviews (with staff, partners and clients of the INGO in Kenya), and participant observation (with Kenyan INGO staff). Participant observation was conducted with 10 people over three months. Forty-one interviews were completed, and 127 documents analyzed. Data analysis followed Auerbach and Silverstein's analytic process (2003), with qualitative coding conducted in multiple stages, using descriptive matrices, visual displays and networks (Miles and Huberman, 1994). There was a gap between the INGO's intent to implement equity principles and actual practice due to multiple influences from various players, including donors and country governments. The INGO was reliant on donor funding and needed permission from the Kenyan government to work in-country. Major influences included donor agendas and funding, donor country policies, and Southern country government priorities and legislation. The INGO privileged particular vulnerable populations (based on its reputation, its history, and the priorities of the Kenyan government and the donors). To balance its equity commitment with the influences from other players, the INGO aligned with the system as well as pushed back incrementally on the donors and the Kenyan government to influence these organizations' equity agendas. By moving its equity agenda forward incrementally and using its reputational advantage, the INGO avoided potential negative repercussions that might result from pushing too fast or working outside the system. The INGO aligned the implementation of equity principles in its HIV/AIDS initiatives by working within a system characterized by asymmetrical interdependence. Influences from the donors and Kenyan government contributed to an implementation gap between what the INGO intended to accomplish in implementing equity principles in HIV/AIDS work and actual practice.


An optical fiber sensor for remote pH sensing and imaging.
A fiber-optical probe for pH sensing and real-time imaging is successfully fabricated by connecting a polymer imaging fiber and a gradient index (GRIN) lens rod which was modified with a sensing film. By employing an improved metallographic microscope, an optical system is designed to cooperate with the probe. This novel technique has high-quality imaging capabilities for observing remote samples while measuring pH. The linear range of the probe is pH 1.2-3.5. This technique overcomes the difficulty that high-quality images cannot be obtained when directly using conventional imaging bundles for pH sensing and imaging. As preliminary applications, the corrosion behavior of an iron screw and the reaction process of rust were investigated in buffer solutions of pH 2.0 and 2.9, respectively. The experiment demonstrated that the pH values of the analytes' surface were higher than that of buffer solutions due to the chemical reaction. It provides great potential for applications in optical multifunctional detection, especially in chemical sensing and biosensing.


Complications, failure to rescue, and mortality with major inpatient surgery in medicare patients.
We sought to determine whether hospital variations in surgical mortality were due to differences in complication rates or failure to rescue rates (ie, case-fatality rates in patients with a complication). Wide variations in mortality after major surgery are becoming increasingly apparent. The clinical mechanisms underling these variations are largely unexplored. We studied all Medicare beneficiaries undergoing 6 major operations in 2005 to 2006: pancreatectomy, esophagectomy, abdominal aortic aneurysm repair, coronary artery bypass grafting, aortic valve replacement, and mitral valve replacement. We ranked hospitals according to risk-adjusted mortality and divided them into 5 equal groups. We then compared the incidence of complications and rates of failure to rescue between the top 20% of hospitals ("best") and bottom 20% of hospitals ("worst"). Analyses were conducted for all operations combined and for each individual procedure. For all 6 operations combined, the worst hospitals had mortality rates 2.5-fold higher than the best hospitals (8.0% vs. 3.0%). However, complication rates were similar at worst and best hospitals (36.4% vs. 32.7%). In contrast, failure to rescue rates were much higher at the worst compared with the best hospitals (16.7% vs. 6.8%). These findings persisted in analyses with individual operations and specific complications. Reducing variations in mortality will require strategies to improve the ability of high-mortality hospitals to manage postoperative complications.


Homeodomain Proteins SIX3 and SIX6 Regulate Gonadotrope-specific Genes During Pituitary Development.
Sine oculis-related homeobox 3 (SIX3) and SIX6, 2 closely related homeodomain transcription factors, are involved in development of the mammalian neuroendocrine system and mutations of Six6 adversely affect fertility in mice. We show that both small interfering RNA knockdown in gonadotrope cell lines and knockout of Six6 in both embryonic and adult male mice (Six6 knockout) support roles for SIX3 and SIX6 in transcriptional regulation in gonadotrope gene expression and that SIX3 and SIX6 can functionally compensate for each other. Six3 and Six6 expression patterns in gonadotrope cell lines reflect the timing of the expression of pituitary markers they regulate. Six3 is expressed in an immature gonadotrope cell line and represses transcription of the early lineage-specific pituitary genes, GnRH receptor (GnRHR) and the common α-subunit (Cga), whereas Six6 is expressed in a mature gonadotrope cell line and represses the specific β-subunits of LH and FSH (LHb and FSHb) that are expressed later in development. We show that SIX6 repression requires interaction with transducin-like enhancer of split corepressor proteins and competition for DNA-binding sites with the transcriptional activator pituitary homeobox 1. Our studies also suggest that estradiol and circadian rhythm regulate pituitary expression of Six6 and Six3 in adult females but not in males. In summary, SIX3 and SIX6 play distinct but compensatory roles in regulating transcription of gonadotrope-specific genes as gonadotrope cells differentiate.


Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure.
Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterised by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognised to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in dynein axonemal heavy chain 11 (DNAH11). To test further for mutant DNAH11 as a cause of PCD, DNAH11 was sequenced in patients with a PCD clinical phenotype, but no known genetic aetiology. 82 exons and intron/exon junctions in DNAH11 were sequenced in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer and/or inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, DNAH11 was sequenced in 13 subjects with isolated situs abnormalities to see if mutant DNAH11 could cause situs defects without respiratory disease. Of the 58 unrelated patients with PCD with normal ultrastructure, 13 (22%) had two (biallelic) mutations in DNAH11; and two patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in DNAH11. Of the 35 identified mutant alleles, 24 (69%) were nonsense, insertion/deletion or loss-of-function splice-site mutations. Mutations in DNAH11 are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients.


More Than Spikes: On the Added Value of Non-linear Intracranial EEG Analysis for Surgery Planning in Temporal Lobe Epilepsy.
Epilepsy surgery can be a very effective therapy in medication refractory patients. During patient evaluation intracranial EEG is analyzed by clinical experts to identify the brain tissue generating epileptiform events. Quantitative EEG analysis increasingly complements this approach in research settings, but not yet in clinical routine. We investigate the correspondence between epileptiform events and a specific quantitative EEG marker. We analyzed 99 preictal epochs of multichannel intracranial EEG of 40 patients with mixed etiologies. Time and channel of occurrence of epileptiform events (spikes, slow waves, sharp waves, fast oscillations) were annotated by a human expert and non-linear excess interrelations were calculated as a quantitative EEG marker. We assessed whether the visually identified preictal events predicted channels that belonged to the seizure onset zone, that were later resected or that showed strong non-linear interrelations. We also investigated whether the seizure onset zone or the resection were predicted by channels with strong non-linear interrelations. In patients with temporal lobe epilepsy (32 of 40), epileptic spikes and the seizure onset zone predicted the resected brain tissue much better in patients with favorable seizure control after surgery than in unfavorable outcomes. Beyond that, our analysis did not reveal any significant associations with epileptiform EEG events. Specifically, none of the epileptiform event types did predict non-linear interrelations. In contrast, channels with strong non-linear excess EEG interrelations predicted the resected channels better in patients with temporal lobe epilepsy and favorable outcome. Also in the small number of patients with seizure onset in the frontal and parietal lobes, no association between epileptiform events and channels with strong non-linear excess EEG interrelations was detectable. In contrast to patients with temporal seizure onset, EEG channels with strong non-linear excess interrelations did neither predict the seizure onset zone nor the resection of these patients or allow separation between patients with favorable and unfavorable seizure control. Our study indicates that non-linear excess EEG interrelations are not strictly associated with epileptiform events, which are one key concept of current clinical EEG assessment. Rather, they may provide information relevant for surgery planning in temporal lobe epilepsy. Our study suggests to incorporate quantitative EEG analysis in the workup of clinical cases. We make the EEG epochs and expert annotations publicly available in anonymized form to foster similar analyses for other quantitative EEG methods.


Guidance for Structuring a Pediatric Intermediate Care Unit.
The purpose of this policy statement is to update the 2004 American Academy of Pediatrics clinical report and provide enhanced guidance for institutions, administrators, and providers in the development and operation of a pediatric intermediate care unit (IMCU). Since 2004, there have been significant advances in pediatric medical, surgical, and critical care that have resulted in an evolution in the acuity and complexity of children potentially requiring IMCU admission. A group of 9 clinical experts in pediatric critical care, hospital medicine, intermediate care, and surgery developed a consensus on priority topics requiring updates, reviewed the relevant evidence, and, through a series of virtual meetings, developed the document. The intended audience of this policy statement is broad and includes pediatric critical care professionals, pediatric hospitalists, pediatric surgeons, other pediatric medical and surgical subspecialists, general pediatricians, nurses, social workers, care coordinators, hospital administrators, health care funders, and policymakers, primarily in resource-rich settings. Key priority topics were delineation of core principles for an IMCU, clarification of target populations, staffing recommendations, and payment.


Characterizing microbial communities and processes in a modern stromatolite (Shark Bay) using lipid biomarkers and two-dimensional distributions of porewater solutes.
Modern microbial mats are highly complex and dynamic ecosystems. Diffusive equilibration in thin films (DET) and diffusive gradients in thin films (DGT) samplers were deployed in a modern smooth microbial mat from Shark Bay in order to observe, for the first time, two-dimensional distributions of porewater solutes during day and night time. Two-dimensional sulfide and alkalinity distributions revealed a strong spatial heterogeneity and a minor contribution of sulfide to alkalinity. Phosphate distributions were also very heterogeneous, while iron(II) distributions were quite similar during day and night with a few hotspots of mobilization. Lipid biomarkers from the three successive layers of the mat were also analysed in order to characterize the microbial communities regulating analyte distributions. The major hydrocarbon products detected in all layers included n-alkanes and isoprenoids, whilst other important biomarkers included hopanoids. Phospholipid fatty acid profiles revealed a decrease in cyanobacterial markers with depth, whereas sulfate-reducing bacteria markers increased in abundance in accordance with rising sulfide concentrations with depth. Despite the general depth trends in community structure and physiochemical conditions within the mat, two-dimensional solute distributions showed considerable small-scale lateral variability, indicating that the distributions and activities of the microbial communities regulating these solute distributions were equally heterogeneous and complex.


[Ultrasound-assisted low-density solvent dispersive liquid-liquid microextraction for the determination of eight drugs in biological samples by gas chromatography-triple quadrupole mass spectrometry].
A novel microextraction technique based on ultrasound-assisted low-density solvent dispersive liquid-liquid microextraction (UA-LDS-DLLME) has been developed for the determination of multiple drugs of abuse in biological samples by gas chromatography-triple quadrupole mass spectrometry (GC-QQQ-MS). A total of 100 µL of toluene as extraction solvent was dropped into the sample solution. Then the mixture was sonicated drastically in an ultrasonic bath for 3 min with occasional manual shaking to form a cloudy suspension. After centrifugation at 10,000 r/min for 3 min, the upper layer of low-density extractant was withdrawn and injected into the GC-QQQ-MS for analysis. The parameters affecting extraction efficiency have been investigated and optimized. Under the optimum conditions, good linearities were observed for all analytes with the correlation coefficients ranging from 0. 998 4 to 0. 999 4. The recoveries of 79.3%-100.3% with RSDs < 5.7% were obtained. The LODs (S/N = 3) were in the range from 0.05 to 0.40 µg/L. UA-LDS-DLLME technique has the advantages of less extraction time, suitable for batches of sample pretreatment simultaneously, and higher extraction efficiency. It was successfully applied to the analysis of amphetamines in real human urine samples.


New drugs in treatment of asthma.
Therapy for bronchial asthma should be preventive when possible. Around-the-clock treatment with theophylline is a new way of using an old drug. Beta2-adrenergic receptor stimulators, cromolyn sodium, and steroids in aerosol form are new drugs that are useful in treatment of asthma. The good news with respect to drug treatment of asthma is that in addition to the old reliable medications which have provided good relief-including epinephrine, ephedrine, isoproterenol, aminophylline, and steroids given orally and parenterally-new drugs are available which have been extremely helpful in controlling symptoms in many patients. The bad news is that none of the new agents is a panacea and that many of them have significant undesirable side effects. It is the physician's responsibility to be wary of the new drugs for asthma and to use them appropriately.


Association of parainfluenza-3 virus with bovine macrophages and blood cells: an in vitro study.
Bovine blood cells and peritoneal and lung macrophages were exposed in vitro to parainfluenza-3 (PI-3) virus. Residual nonadsorbed PI-3 virus (expressed in percentage of input virus) in the supernate of the various cell fractions 1 hour after incubation at 37 C was as follows: lung macrophages, 11%; peritoneal macrophages, 59%; monocytes, 26%; RBC, 14%; lymphocytes, 28%; and polymorphonuclear cells (PMN), 63%. Lung macrophages, monocytes, lymphocytes, and PMN were monitored over a 72-hour period for hemadsorption of chicken RBC. Hemadsorption increased for lung macrophages and monocytes, whereas it decreased for lymphocytes and PMN. Infective virus could not be recovered from PMN, RBC, lymphocytes, or monocytes for more than 24 hours after PI-3 infection. Recovery of infective PI-3 virus from infected peritoneal and lung macrophages extended over 4 to 8 days, respectively.


Manganese superoxide dismutase: guardian of the powerhouse.
The mitochondrion is vital for many metabolic pathways in the cell, contributing all or important constituent enzymes for diverse functions such as β-oxidation of fatty acids, the urea cycle, the citric acid cycle, and ATP synthesis. The mitochondrion is also a major site of reactive oxygen species (ROS) production in the cell. Aberrant production of mitochondrial ROS can have dramatic effects on cellular function, in part, due to oxidative modification of key metabolic proteins localized in the mitochondrion. The cell is equipped with myriad antioxidant enzyme systems to combat deleterious ROS production in mitochondria, with the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) acting as the chief ROS scavenging enzyme in the cell. Factors that affect the expression and/or the activity of MnSOD, resulting in diminished antioxidant capacity of the cell, can have extraordinary consequences on the overall health of the cell by altering mitochondrial metabolic function, leading to the development and progression of numerous diseases. A better understanding of the mechanisms by which MnSOD protects cells from the harmful effects of overproduction of ROS, in particular, the effects of ROS on mitochondrial metabolic enzymes, may contribute to the development of novel treatments for various diseases in which ROS are an important component.


Serum Lipids prior to Starting Androgen Deprivation Therapy and Risk of Castration Resistant Prostate Cancer and Metastasis: Results from the SEARCH Database.
We tested the association of serum lipid levels prior to androgen deprivation therapy with the risk of castration resistant prostate cancer and metastasis. We identified 302 men in the SEARCH (Shared Equal Access Regional Cancer Hospital) database who received androgen deprivation therapy after radical prostatectomy for nonmetastatic disease, had never received statins before androgen deprivation therapy and had available serum lipid data within 2 years prior to androgen deprivation therapy. Cox proportional hazards models were used to test associations between total cholesterol (less than 200 vs 200 mg/dl or greater), low density lipoprotein (less than 130 vs 130 mg/dl or greater), high density lipoprotein (40 or greater vs less than 40 mg/dl) and triglycerides (less than 150 vs 150 mg/dl or greater) and the risk of castration resistant prostate cancer and metastasis after androgen deprivation therapy while adjusting for potential confounders. Subanalyses were restricted to men who remained statin nonusers after androgen deprivation therapy. Median followup after androgen deprivation therapy was 67 months. Castration resistant prostate cancer and metastasis developed in 42 and 44 men, respectively. Men with elevated cholesterol received androgen deprivation therapy in an earlier year and had longer followup and a higher rate of statin use after androgen deprivation therapy. On multivariable analysis total cholesterol and low density lipoprotein were unrelated to castration resistant prostate cancer. Low high density lipoprotein (less than 40 vs 40 mg/dl or greater) was suggestively linked to an increased risk of castration resistant prostate cancer (HR 1.86, 95% CI 0.99-3.48). The association was stronger in men who remained statin nonusers after androgen deprivation therapy (HR 3.64, 95% CI 1.45-9.17). Results for metastasis were similar to those for castration resistant prostate cancer. Among men with nonmetastatic prostate cancer who started androgen deprivation therapy serum cholesterol was unrelated to castration resistant prostate cancer or metastasis. Low high density lipoprotein was suggestively associated with risks of increased castration resistant prostate cancer and metastasis, particularly in statin never users. Further studies are needed to explore a potential role for lipids in prostate cancer progression after androgen deprivation therapy.


Cleavage of human high molecular weight kininogen markedly enhances its coagulant activity. Evidence that this molecule exists as a procofactor.
High molecular weight kininogen (HMW)-kininogen, the cofactor of contact-activated blood coagulation, accelerates the activation of Factor XII, prekallikrein, and Factor XI on a negatively charged surface. Although prekallikrein and Factor XI circulate as a complex with HMW-kininogen, no physical association has been demonstrated between Factor XII and HMW-kininogen, nor has the order of adsorption to surfaces of these proteins been fully clarified. In this report we explore the requirements for adsorption of HMW-kininogen to a clot-promoting surface (kaolin), in purified systems, as well as in normal plasma and plasma genetically deficient in each of the proteins of the contact system. The fraction of each coagulant protein associated with the kaolin pellet was determined by measuring the difference in coagulant activity between the initial sample and supernatants after incubation with kaolin, or by directly quantifying the amount of 125I-HMW-kininogen that was associated with the kaolin pellet. In normal plasma, the adsorption of HMW-kininogen to kaolin increased as the quantity of kaolin was increased in the incubation mixture. However, the HMW-kininogen in Factor XII-deficient plasma did not absorb appreciably to kaolin. Furthermore, the quantity of HMW-kininogen from prekallikrein-deficient plasma that adsorbed to kaolin was decreased as compared with normal plasma. These observations suggested that HMW-kininogen in plasma must be altered by a reaction involving both Factor XII and prekallikrein in order for HMW-kininogen to adsorb to kaolin, and to express its coagulant activity. Subsequently, the consequence of the inability of HMW-kininogen to associate with a negatively charged surface results in decreased surface activation. This assessment was derived from the further observation of the lack of prekallikrein adsorption and the diminished Factor XI adsorption in both Factor XII-deficient and HMW-kininogen-deficient plasmas, since these two zymogens (prekallikrein and Factor XI) are transported to a negatively charged surface in complex with HMW-kininogen. The percentage of HMW-kininogen coagulant activity that adsorbed to kaolin closely correlated (r = 0.98, slope = 0.97) with the amount of 125I-HMW-kininogen adsorbed, suggesting that adsorption of HMW-kininogen results in the expression of its coagulant activity. Since kallikrein, which is known to cleave HMW-kininogen, is generated when kaolin is added to plasma, we tested the hypothesis that proteolysis by kallikrein was responsible for the enhanced adsorption of HMW-kininogen to kaolin. When purified HMW-kininogen was incubated with purified kallikrein, its ability to absorb to kaolin increased with time of digestion until a maximum was reached. Moreover, (125)I-HMW-kininogen, after cleavage by kallikrein, had markedly increased affinity for kaolin than the uncleaved starting material. Furthermore, fibrinogen, at plasma concentration (3 mg/ml), markedly curtailed the adsorption of a mixture of cleaved and uncleaved HMW-kininogen to kaolin, but was unable to prevent fully cleaved HMW-kininogen from adsorbing to the kaolin. Addition of purified kallikrein to Factor XII-deficient plasma, which bypasses Factor XII-dependent contact-activation amplified the ability of its HMW-kininogen to adsorb to kaolin. These observations indicate that HMW-kininogen is a procofactor that is activated by kallikrein, a product of a reaction which it accelerates. This cleavage, which enhances its association with a clot-promoting surface in a plasma environment, is an event that is necessary for expression of its cofactor activity. These interactions would allow coordination of HMW-kininogen adsorption with the adsorption of Factor XII, which adsorbs independently of cleavage, to the same negatively charged surface.


Population-specific responses to an invasive species.
Predicting the impacts of non-native species remains a challenge. As populations of a species are genetically and phenotypically variable, the impact of non-native species on local taxa could crucially depend on population-specific traits and adaptations of both native and non-native species. Bitterling fishes are brood parasites of unionid mussels and unionid mussels produce larvae that parasitize fishes. We used common garden experiments to measure three key elements in the bitterling-mussel association among two populations of an invasive mussel (Anodonta woodiana) and four populations of European bitterling (Rhodeus amarus). The impact of the invasive mussel varied between geographically distinct R. amarus lineages and between local populations within lineages. The capacity of parasitic larvae of the invasive mussel to exploit R. amarus was higher in a Danubian than in a Baltic R. amarus lineage and in allopatric than in sympatric R. amarus populations. Maladaptive oviposition by R. amarus into A. woodiana varied among populations, with significant population-specific consequences for R. amarus recruitment. We suggest that variation in coevolutionary states may predispose different populations to divergent responses. Given that coevolutionary relationships are ubiquitous, population-specific attributes of invasive and native populations may play a critical role in the outcome of invasion. We argue for a shift from a species-centred to population-centred perspective of the impacts of invasions.


Natural sources and heavy metals.
PTS, PM10 and PM2.5 samples have been collected at a rural site of south-east Italy (40 degrees 20' 13" N; 18 degrees 6' 47" E) from June to October, 2004 to investigate natural and anthropogenic contributions on particulate matter and heavy metal mass concentrations. It is shown that sharp-peak particulate-matter concentrations have been recorded during most African dust outbreaks occurred over south-east Italy. In particular, PM10 concentrations exceeding the 24-hour limit value of 50 microg/m3 have been monitored during dust events. Al, Cd, Cr, Cu, Fe, Mn, V, Ni, Pb, and Zn metal concentrations have been evaluated by an inductively coupled plasma atomic emission spectrometer and Al mass concentrations >500 ng/m3 have been observed in PTS and PM10 samples during the advection of African dust particles. Accordingly to geochemical calculations Al, Fe, and Mn, have a significant crustal origin while, Cd, Cu, Pb, and Zn are of anthropogenic origin. Moreover, Fe resulted predominant in the coarse particle fraction, while Ni, Pb, V, and Zn were predominant in the fine particle fraction. It is also shown that Cd, Mn, Ni, Pb, and V concentrations never exceeded guide and/or limit values recommended by the World Health Organization and the European Council Directives.


Nonopsonic phagocytosis of group C Neisseria meningitidis by human neutrophils.
Although complement-mediated bactericidal activity in serum has long been known to be very important in host defense against Neisseria meningitidis, recent studies have shown that opsonic phagocytosis by neutrophils is also important. The purpose of this study was to determine if endemic group C N. meningitidis strains were susceptible to nonopsonic (complement- and antibody-independent) phagocytosis by human neutrophils, which is a well-described phenomenon for Neisseria gonorrhoeae. Gonococci that possess one or more of a group of heat-modifiable outer membrane proteins (called opacity-associated [Opa] proteins) are phagocytosed by neutrophils in the absence of serum. We found that four serogroup C meningococcal strains bearing the lacto-N-neotetraose (LNnT) structure on lipooligosaccharide (LOS) were phagocytosed by neutrophils in the absence of antibody and active complement. Confocal microscopy confirmed that the organisms were internalized by neutrophils. This susceptibility was not restricted to carrier isolates, since two of the strains were cultured from blood or cerebrospinal fluid. All four strains expressed Opa protein and had relatively less endogenous LOS and capsule sialylation compared to six strains that were resistant to this type of phagocytosis. Nonopsonic phagocytosis of two of the four strains was inhibited by exogenous sialylation of LOS LNnT and the binding of monoclonal antibody to LNnT. However, an isogenic mutant that lacked the LNnT structure was fully susceptible to nonopsonic phagocytosis. We conclude that group C meningococci can be phagocytosed by neutrophils in the absence of antibody and active complement possibly by two different mechanisms. Expression of Opa protein and downregulation of endogenous surface sialic acids analogous to what is seen for N. gonorrhoeae might be necessary for N. meningitidis as well.


[Role of fleas, the principal and secondary plague vectors, in the circulation of the causative agent in Siberian natural foci].
The paper reviews data on the role of fleas as the principal and secondary vectors of infection in the Siberian natural foci of plague. The role of Citellophilus tesquorum as the principal plague vectors in the Transbaikalian and Tuvinian natural foci is shown to be determined by their ecological characteristics (the degree of specificity to the main host, numbers, and natural infection) to a greater extent and by the rate of block formation to a lesser extent. The significance of principal and secondary vectors is estimated in the circulation of the causative agent in the monovectoral (Transbaikalian and Tuvinian) and multivectoral (Gorno-Altai) foci of plagues. It is suggested that the "microfocal" form (phenotype) of the agent's existence is characteristic of the Siberian natural foci where the rate of block formation does not generally show high indices. This phenomenon might be a basis for the long circulation of the plague microbe in the mountain (Tuva and Gorno-Altai) foci where protracted interepizootic periods have not been registered.


Cholesterol-Lowering Effect of Beta Glucan Extracted from Saccharomyces cerevisiae in Rats.
Glucans are present in fungi, plants, algae, and bacteria. β-Glucan, one of the major cell wall components of Saccharomyces cerevisiae, has been found to enhance immune functions. Glucans are glucose polymers with an α- or β-type glycosidic chain. The role of (1→3)-β-D-glucan is in the maintenance of yeast cell wall shape and rigidity. Studies reveal that soluble glucans can lower total cholesterol and LDL levels in patients with hypercholesterolemia. The important benefit of β-glucan is to improve the immune system and to decrease cholesterol levels in the blood. Several studies have reported the benefits of β-glucan as: antiseptic, antioxidant, anti-aging, immune system activators, protection against radiation, anti-inflammatory, anti-diabetic, anti-cholesterol etc. In this research S. cerevisiae was cultured in yeast extract-peptone-glucose (YPG) broth medium to produce beta-glucan. Cells were harvested at the stationary phase, washed, and disrupted by means of sonication method. The obtained cell walls were used to prepare alkali-soluble β-glucan (glucan-S1). In this regard, 2% sodium hydroxide (NaOH) and 3% acetic acid were used in alkaline-acid extraction, respectively. Potential use of beta-glucan extract as an anticholesterol agent was tested using Sprague dawley strain rats. The experiments were divided into eight groups with four replicates: Group I (normal control), group II (fed with cholesterol without beta-glucan), group III (fed with cholesterol + atorvastatin), group IV (fed with cholesterol + β-glucan standard), group V-VIII (fed of cholesterol + β-glucan of S. cerevisiae with each dose of 10, 20, 30, and 40 mg / BW. Rats were fed with cholesterol for 14 days, except for group I. Analysis of blood was carried out to determine total cholesterol, triglycerides, and malondialdehyde. The results showed that beta-glucan crude obtained from S. cerevisiae cultures was 6.890g.L(-1). Βeta-glucan extract of S. cerevisiae can reduce total cholesterol approaching normal values at doses of 10 mg of 32.79 % (blood plasma) and 33.71 % (in the liver). The extract was capable of reducing triglyceride levels in a dose of 10 mg of beta-glucan 64.43 % (blood plasma) and at a dose 30 mg of beta-glucan 19.45 % (liver). Beta-glucan treatment at a dose of 40 mg can reduce MDA levels of 45.22 % (blood plasma) and 42.64 % (liver).


CannibiSenS: an on-demand rapid screen for THC in human saliva.
Management of substances that possess high potential for abuse requires a comprehensive understanding of the temporal effects of a corresponding volume of intake. Cannabis is deemed as one of the most widely used drugs in the United States and studies related to the primary psychoactive compound present in it, Δ-9-tetrahydrocannabinol (THC), have revealed that it causes adverse health effects. In this study, we present a field-deployable electrochemical sensing system that can detect THC at the 5 ng mL-1 cut-off level with a dynamic range of 0.1-100 ng mL-1 in human saliva. Considering the complexity of the human saliva matrix, the specificity study demonstrated selectivity towards THC with minimum interactions with ethanol and cannabidiol (CBD). Surface Plasmon Resonance (SPR) has been implemented to visualize and validate the capture probe as a means for THC detection. A robust, compatible binary classifier model has been shown in this work to effectively group samples into THC+ (high) and THC- (low) groups from human saliva with an accuracy greater than 90% considering a limited dataset. Hence, we demonstrate the potential of an innovative end-to-end system to effectively regulate cannabis use and prevent substance abuse in our surroundings.


Perceived family support among older persons in diabetes mellitus self-management.
The aging process has functional consequences for older persons, such as degenerative processes of the pancreas resulting in diabetes mellitus. The increasing age of the population will eventually lead to increasing health problems of older persons, including diabetes mellitus. Diabetes mellitus is a chronic disease that requires long-term care through self-management. Diabetes self-management in older persons is influenced by family support as the main support system. This study aimed to explore perceived family support by older persons in diabetes mellitus self-management. This study applied descriptive phenomenology method. The data were collected through in-depth interviews. There were nine older persons with diabetes mellitus as participants. Data consisted of in-depth interview recordings and field notes. Data were transcribed and analyzed using Colaizzi's method. The results identified that family support as perceived by older persons included daily activity assistance, assistance with obtaining health services, food preparation, financial support, attention, guidance, and problem solving. The response to family support was pleasure as expressed by the older persons. Physical and economic limitations were a significant hindrance to self-management of diabetes mellitus in older persons; therefore, they require family support to optimize their independence. The results of this study highlight the importance of family support in diabetes mellitus self-management in older persons.


Chimera: a Bioconductor package for secondary analysis of fusion products.
Chimera is a Bioconductor package that organizes, annotates, analyses and validates fusions reported by different fusion detection tools; current implementation can deal with output from bellerophontes, chimeraScan, deFuse, fusionCatcher, FusionFinder, FusionHunter, FusionMap, mapSplice, Rsubread, tophat-fusion and STAR. The core of Chimera is a fusion data structure that can store fusion events detected with any of the aforementioned tools. Fusions are then easily manipulated with standard R functions or through the set of functionalities specifically developed in Chimera with the aim of supporting the user in managing fusions and discriminating false-positive results.


Intraepithelial lymphocytes in celiac disease immunopathology.
Celiac disease is a T cell-mediated immune disorder induced by dietary gluten that is characterized by the development of an inflammatory anti-gluten CD4 T cell response, anti-gluten antibodies, and autoantibodies against tissue transglutaminase 2 and the activation of intraepithelial lymphocytes (IELs) leading to the destruction of the intestinal epithelium. Intraepithelial lymphocytes represent a heterogeneous population of T cells composed mainly of cytotoxic CD8 T cells residing within the epithelial layer, whose main role is to maintain the integrity of the epithelium by eliminating infected cells and promoting epithelial repair. Dysregulated activation of IELs is a hallmark of CD and is critically involved in epithelial cell destruction and the subsequent development of villous atrophy. In this review, we compare and contrast the phenotype and function of human and mouse small intestinal IELs under physiological conditions. Furthermore, we discuss how conditions of epithelial distress associated with overexpression of IL-15 and non-classical MHC class I molecules induce cytotoxic IELs to become licensed killer cells that upregulate activating NKG2D and CD94/NKG2C natural killer receptors, acquiring lymphokine killer activity. Pathways leading to dysregulated IEL activation could eventually be targeted to prevent villous atrophy and treat patients who respond poorly to gluten-free diet.


Determination of microbial phenolic acids in human faeces by UPLC-ESI-TQ MS.
The aim of the present work was to develop a reproducible, sensitive, and rapid UPLC-ESI-TQ MS analytical method for determination of microbial phenolic acids and other related compounds in faeces. A total of 47 phenolic compounds including hydroxyphenylpropionic, hydroxyphenylacetic, hydroxycinnamic, hydroxybenzoic, and hydroxymandelic acids and simple phenols were considered. To prepare an optimum pool standard solution, analytes were classified in 5 different groups with different starting concentrations according to their MS response. The developed UPLC method allowed a high resolution of the pool standard solution within an 18 min injection run time. The LOD of phenolic compounds ranged from 0.001 to 0.107 μg/mL and LOQ from 0.003 to 0.233 μg/mL. The method precision met acceptance criteria (<15% RSD) for all analytes, and accuracy was >80%. The method was applied to faecal samples collected before and after the intake of a flavan-3-ol supplement by a healthy volunteer. Both external and internal calibration methods were considered for quantification purposes, using 4-hydroxybenzoic-2,3,4,5-d4 acid as internal standard. For most analytes and samples, the level of microbial phenolic acids did not differ by using one or another calibration method. The results revealed an increase in protocatechuic, syringic, benzoic, p-coumaric, phenylpropionic, 3-hydroxyphenylacetic, and 3-hydroxyphenylpropionic acids, although differences due to the intake were only significant for the latter compound. In conclusion, the UPLC-DAD-ESI-TQ MS method developed is suitable for targeted analysis of microbial-derived phenolic metabolites in faecal samples from human intervention or in vitro fermentation studies, which requires high sensitivity and throughput.


Prophylactic salpingectomy and delayed oophorectomy as an alternative for BRCA mutation carriers.
Prophylactic bilateral salpingo-oophorectomy is advised for women with BRCA mutations, but there are adverse consequences of premature menopause. The majority of BRCA-associated ovarian cancers appear to arise in the fallopian tube; therefore, salpingectomy may be an alternative to bilateral salpingo-oophorectomy. We compared the costs and benefits of salpingectomy with bilateral salpingo-oophorectomy among BRCA mutation carriers. We developed a Markov Monte Carlo simulation model to compare three strategies for risk reduction in women with BRCA mutations: 1) bilateral salpingo-oophorectomy; 2) bilateral salpingectomy; and 3) bilateral salpingectomy with delayed oophorectomy. Net health benefits were measured in years-of-life expectancy and quality-adjusted life-year expectancy, and the primary outcome was the incremental cost-effectiveness ratio. The model estimated the number of future breast and ovarian cancers and cardiovascular deaths attributed to premature menopause with each strategy. Bilateral salpingo-oophorectomy was associated with the lowest cost and highest life expectancy compared with the other two strategies. When quality-of-life measures were included, salpingectomy followed by delayed oophorectomy yielded the highest quality-adjusted life expectancy with incremental cost-effectiveness ratios of $37,805 and $89,680 per quality-adjusted life-year for BRCA1 and BRCA2, respectively, relative to salpingectomy alone. Bilateral salpingo-oophorectomy yielded the lowest number of future breast and ovarian cancers compared with the other two strategies. Bilateral salpingo-oophorectomy offers the greatest risk reduction for breast and ovarian cancer among BRCA mutation carriers. However, when considering quality-adjusted life expectancy, bilateral salpingectomy with delayed oophorectomy is a cost-effective strategy and may be an acceptable alternative for those unwilling to undergo bilateral salpingo-oophorectomy.


Anticancer sulfonamide hybrids that inhibit bladder cancer cells growth and migration as tubulin polymerisation inhibitors.
Novel sulfonamide-dithiocarbamate hybrids were designed and synthesised via the molecular hybridisation strategy. Among them, compound 13d displayed a potent activity with IC50 values of 0.9, 0.7, 1.9 and 2.6 µM against UM-UC-3, RT-112, RT4 and T24. Compound 13d inhibited the migration and regulated the migration-related markers (E-cadherin, N-cadherin, Vimentin, Snail and Slung) against RT-112 cells in a concentration dependent manner. By the tubulin polymerisation assay in vitro and immunostaining assay, compound 13d was identified as a novel tubulin polymerisation inhibitor. Intragastric administration of compound 13d could inhibit the growth of RT-112 cells in vivo in a xenograft mouse model with the low toxicity, indicating that it may be a leading candidate with antitumor properties to treat bladder cancer.


Objective Measurement of Ball-Handling Proficiency in Wheelchair Sports: A Systematic Review.
In Paralympic sports, classification of athletes based on the impact of impairments on the ability to perform is needed, to prevent a one-sided and predictable outcome of the competition in which the least impaired athlete has the best chance to win. Classification is developing from expert opinion based to evidence based. In wheelchair court sports, there is evidence to support the impact of impairment on wheeled mobility, but not on ball handling. To assess the impact of impairment on the ability to perform ball-handling activities, standardised tests for ball handling are needed. To assess if reliable and valid standardised tests for the measurement of ball-handling proficiency in a wheelchair or able-bodied court sports exist; to assist in the development of Evidence-Based Classification (EBC) in wheelchair court sports according to the guidelines of the International Paralympic Committee (IPC). The review was conducted according to the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) statement. Search terms used were "wheelchair," "ball," "ball sports," "test," and "performance." Databases searched were Medline, Embase, PubMed, and Sport Discus. Study quality was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology checklist. Twenty-two articles were included. Foundational Movement Skills in ball-handling proficiency were assessed. Tests for throwing maximal distance showed sufficient reliability and validity. Precision in throwing showed low-to-moderate reliability and conflicting results in validity. Throwing techniques differed between studies. Dribbling the ball showed high reliability, but conflicting results in validity. Tests for throwing maximal distance, throwing precision, and dribbling the ball can be used in standardised tests for activity limitation in wheelchair court sports. However, tests need to be adapted and standardised and then reassessed for reliability and validity in athletes with and without arm impairment.


Red cell alloimmunization is associated with development of autoantibodies and increased red cell transfusion requirements in myelodysplastic syndrome.
Up to 90% of patients with a myelodysplastic syndrome require red blood cell transfusion; nevertheless, comprehensive data on red cell alloimmunization in such patients are limited. This study evaluates the incidence and clinical impact of red cell alloimmunization in a large cohort of patients with myelodysplastic syndrome registered in the statewide South Australian-MDS registry. The median age of the 817 patients studied was 73 years, and 66% were male. The cumulative incidence of alloimmunization was 11%. Disease-modifying therapy was associated with a lower risk of alloimmunization while alloimmunization was significantly higher in patients with a revised International Prognostic Scoring System classification of Very Low, Low or Intermediate risk compared to those with a High or Very High risk (P=0.03). Alloantibodies were most commonly directed against antigens in the Rh (54%) and Kell (24%) systems. Multiple alloantibodies were present in 49% of alloimmunized patients. Although 73% of alloimmunized patients developed alloantibodies during the period in which they received their first 20 red cell units, the total number of units transfused was significantly higher in alloimmunized patients than in non-alloimmunized patients (90±100 versus 30±52; P<0.0001). In individual patients, red cell transfusion intensity increased significantly following alloimmunization (2.8±1.3 versus 4.1±2.0; P<0.0001). A significantly higher proportion of alloimmunized patients than non-alloimmunized patients had detectable autoantibodies (65% versus 18%; P<0.0001) and the majority of autoantibodies were detected within a short period of alloimmunization. In conclusion, this study characterizes alloimmunization in a large cohort of patients with myelodysplastic syndrome and demonstrates a signficant increase in red cell transfusion requirements following alloimmunization, most probably due to development of additional alloantibodies and autoantibodies, resulting in subclinical/clinical hemolysis. Strategies to mitigate alloimmunization risk are critical for optimizing red cell transfusion support.


Factors influencing the accuracy of beam range estimation in proton therapy using prompt gamma emission.
In-vivo imaging is a strategy to monitor the range of protons inside the patient during radiation treatment. A possible method of in-vivo imaging is detection of secondary 'prompt' gamma (PG) photons outside the body, which are produced by inelastic proton-nuclear interactions inside the patient. In this paper, important parameters influencing the relationship between the PG profile and percentage depth dose (PDD) in a uniform cylindrical phantom are explored. Monte Carlo simulations are performed with the new Geant4 based code TOPAS for mono-energetic proton pencil beams (range: 100-250 MeV) and an idealized PG detector. PG depth profiles are evaluated using the inflection point on a sigmoid fit in the fall-off region of the profile. A strong correlation between the inflection point and the proton range determined from the PDD is found for all conditions. Variations between 1.5 mm and 2.7 mm in the distance between the proton range and the inflection point are found when either the mass density, phantom diameter, or detector acceptance angle is changed. A change in cut-off energy of the detector could induce a range difference of maximum 4 mm. Applying time-of-flight discrimination during detection, changing the primary energy of the beam or changing the elemental composition of the tissue affects the accuracy of the range prediction by less than 1 mm. The results indicate that the PG signal is rather robust to many parameter variations, but millimetre accurate range monitoring requires all medium and detector properties to be carefully taken into account.


Longitudinal stability of asthma characteristics and biomarkers from the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study.
Asthma is a biologically heterogeneous disease and development of novel therapeutics requires understanding of pathophysiologic phenotypes. There is uncertainty regarding the stability of clinical characteristics and biomarkers in asthma over time. This report presents the longitudinal stability over 12 months of clinical characteristics and clinically accessible biomarkers from ADEPT. Mild, moderate, and severe asthma subjects were assessed at 5 visits over 12 months. Assessments included patient questionnaires, spirometry, bronchodilator reversibility, fractional exhaled nitric oxide (FENO), and biomarkers measured in induced sputum. Mild (n = 52), moderate (n = 55), and severe (n = 51) asthma cohorts were enrolled from North America and Western Europe. For all clinical characteristics and biomarkers, group mean data showed no significant change from visit to visit. However, individual data showed considerable variability. FEV1/FVC ratio showed excellent reproducibility while pre-bronchodilator FEV1 and FVC were only moderately reproducible. Of note bronchodilator FEV1 reversibility showed low reproducibility, with the nonreversible phenotype much more reproducible than the reversible phenotype. The 7-item asthma control questionnaire (ACQ7) demonstrated moderate reproducibility for the combined asthma cohorts, but the uncontrolled asthma phenotype (ACQ7 > 1.5) was inconstant in mild and moderate asthma but stable in severe asthma. FENO demonstrated good reproducibility, with the FENO-low phenotype (FENO < 35 ppb) more stable than the FENO-high phenotype (FENO ≥ 35 ppb). Induced sputum inflammatory phenotypes showed marked variability across the 3 sputum samples taken over 6 months. The ADEPT cohort showed group stability, individual stability in some parameters e.g. low FEV1/FVC ratio, and low FENO, but marked individual variability in other clinical characteristics and biomarkers e.g. type-2 biomarkers over 12 months. This variability is possibly related to seasonal variations in climate and allergen exposure, medication changes and acute exacerbations. The implications for patient selection strategies based on clinical biomarkers may be considerable.


[Erectile dysfunction caused by neurapraxia of the pudendal nerve after the use of a traction table for the treatment of traumatic fractures. Report of a case and review of the literature].
To describe a case of erectile dysfunction as a result of traction on the fracture table. We report on a 39-year-old man who developed erctile dysfunction postoperatively and for several months thereafter, following intramedullary nailing with the Grosse-Kept bolt type fixation system. The patient spontaneously recovered erectile function six months after orthopaedic treatment. Erectile dysfunction induced by orthopaedic fracture table is a complication that should be taken into account. There are many procedures available to reduce the risk of this complication.


Risk Management of Dairy Product Losses as a Tool to Improve the Environment and Food Rescue.
"Food loss", defined as food produced for human consumption, which for various reasons leaves the supply chain, can be assigned to a group of new risks. Irrational use of food constitutes a risk to the environment. Moreover, food losses represent a missed opportunity to improve global food security. The aim of this study was to develop a risk management model for dairy product losses using the example of ripening cheese. The necessary data to develop the model were derived from a survey that was conducted in five dairies located in Poland. Total losses for nine products amounted to 1.1% of the average annual production, which accounted for more than 5635 t per annum. The studies that were conducted allowed the identification of three management methods of food loss in dairies: reprocessing, hand over for feed, and disposal. The level of risk was defined as "high" with two suggested courses of action: prevention and tolerance. Risks must be prevented by eliminating any errors that may result in a product of inadequate quality. Another solution is to redistribute or sell products at a reduced price, which despite their reduced quality, are nevertheless suitable for consumption. To some extent, this risk must be tolerated.


PTHrP regulates angiogenesis and bone resorption via VEGF expression.
Parathyroid hormone-related protein (PTHrP) is a key regulator of osteolytic metastasis of breast cancer (BC) cells, but its targets and mechanisms of action are not fully understood. This study investigated whether/how PTHrP (1-34) signaling regulates expression of vascular endothelial growth factor (VEGF) produced by BC cells. A mouse model of bone metastasis was prepared by inoculating mice with tumour cell suspensions of the human BC cell line MDA-MB-231 via the left cardiac ventricle. VEGF expression was examined by Western blot and real-time RT-PCR analysis, as well as by confocal microscopy in the bone microenvironment. PTHrP was expressed in cancer cells producing PTH/PTHrP receptor and VEGF that had invaded the bone marrow, and PTHrP was up-regulated VEGF in MDA-MB-231 in vitro. The culture medium conditioned by PTHrP-treated MDA-MB-231 cells stimulated angiogenesis and osteoclastogenesis compared with control medium, giving a response that was inhibited by VEGF-neutralizing antibody treatment. Inhibition of protein kinase C (PKC) prevented PTHrP-induced extracellular signal-regulated kinase (ERK1/2) and p38 activation, and PTHrP-induced VEGF expression. PTHrP plays an important role in modulating the angiogenic and bone osteolytic actions of VEGF through PKC-dependent activation of an ERK1/2 and p38 signaling pathway during bone metastasis by breast cancer cells.


Stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomics study of a thyroid hormone-regulated secretome in human hepatoma cells.
The thyroid hormone, 3, 3',5-triiodo-l-thyronine (T(3)), regulates cell growth, development, differentiation, and metabolism via interactions with thyroid hormone receptors (TRs). However, the secreted proteins that are regulated by T(3) are yet to be characterized. In this study, we used the quantitative proteomic approach of stable isotope labeling with amino acids in cell culture coupled with nano-liquid chromatography-tandem MS performed on a LTQ-Orbitrap instrument to identify and characterize the T(3)-regulated proteins secreted in human hepatocellular carcinoma cell lines overexpressing TRα1 (HepG2-TRα1). In total, 1742 and 1714 proteins were identified and quantified, respectively, in three independent experiments. Among these, 61 up-regulated twofold and 11 down-regulated twofold proteins were identified. Eight proteins displaying increased expression and one with decreased expression in conditioned media were validated using Western blotting. Real-time quantitative RT-PCR further disclosed induction of plasminogen activator inhibitor-1 (PAI-1), a T(3) target, in a time-course and dose-dependent manner. Serial deletions of the PAI-1 promoter region and subsequent chromatin immunoprecipitation assays revealed that the thyroid hormone response element on the promoter is localized at positions -327/-312. PAI-1 overexpression enhanced tumor growth and migration in a manner similar to what was seen when T(3) induced PAI-1 expression in J7-TRα1 cells, both in vitro and in vivo. An in vitro neutralizing assay further supported a crucial role of secreted PAI-1 in T(3)/TR-regulated cell migration. To our knowledge, these results demonstrate for the first time that proteins involved in the urokinase plasminogen activator system, including PAI-1, uPAR, and BSSP4, are augmented in the extra- and intracellular space of T(3)-treated HepG2-TRα1 cells. The T(3)-regulated secretome generated in the current study may provide an opportunity to establish the mechanisms underlying T(3)-associated tumor progression and prognosis.


Characterization of protease cleavage sites involved in the formation of the envelope glycoprotein and three non-structural proteins of dengue virus type 2, New Guinea C strain.
Amino terminal sequences of the envelope protein E and the three largest nonstructural proteins NS1, NS3, and NS5 of the New Guinea C strain of dengue virus type 2 (DEN-2) were obtained by nucleotide and protein sequencing. Clones were prepared containing cDNA of DEN-2 virus in the plasmid pUC8. The nucleotide sequences of viral cDNA inserts were determined and the cDNA of each clone positioned on the flavivirus genomic map by comparison of the deduced amino acid sequence with that of yellow fever virus. Radiolabelled E, NS1, NS3 and NS5 were purified by lectin affinity chromatography and preparative gel electrophoresis. Purified proteins were subsequently analysed by Edman degradation to establish the origins of the amino termini of these proteins in the deduced DEN-2 amino acid sequence. Thus the amino acid sequences surrounding the likely proteolytic cleavage sites used in the formation of these four proteins were determined. Of particular interest was the sequence containing the amino terminus of NS3, namely Lys-Lys-Gln-Arg-Ala-Gly where Ala is the first amino acid of NS3. Cleavage following one basic residue in the flavivirus polyprotein has not been reported previously.


MR angiography with sensitivity encoding (SENSE) for suspected pulmonary embolism: comparison with MDCT and ventilation-perfusion scintigraphy.
The aim of our study was to determine the utility of time-resolved contrast-enhanced MR angiography combined with sensitivity encoding (SENSE) for patients with pulmonary embolism. SUBJECTS AND METHODS. Forty-eight consecutive patients (26 men and 22 women; age range, 27-73 years; mean age, 55 years) with suspected pulmonary embolism underwent chest radiography, contrast-enhanced MDCT, MR angiography with SENSE, ventilation-perfusion scintigraphy, and pulmonary angiography. MR angiography with SENSE was performed using IV administration of gadolinium contrast medium with a 3D turbo field-echo pulse sequence (TR/TE, 4.0/1.2; flip angle, 30 degrees ) on a 1.5-T scanner. Capabilities of diagnosing pulmonary embolism using MR angiography (data set A), contrast-enhanced MDCT (data set B), contrast-enhanced MDCT with MR angiography (data set C), ventilation-perfusion scintigraphy (data set D), and contrast-enhanced MDCT with ventilation-perfusion scintigraphy (data set E) were determined by receiver operating characteristic analysis, using the results of pulmonary angiography as the reference standard. The diagnostic capability of each data set was analyzed on a per-vascular zone and a per-patient basis with the McNemar test. Sensitivity and specificity of data set A were 83% and 97%, respectively, on a per-vascular zone basis and 92% and 94%, respectively, on a per-patient basis. Specificity and accuracy of data set A were significantly higher than those of data set D on a per-patient basis (p < 0.05). Time-resolved MR angiography with SENSE is effective for the diagnosis of pulmonary embolism.


An experimental model of chronic rhinosinusitis in rabbits without bacterial inoculation.
Evaluate and compare two different experimental techniques of maxillary sinus ostium occlusion using N-butyl cyanoacrylate in developing chronic histological findings without the inoculation of pathogenic bacteria among rabbits. In a randomized study, sixteen New Zealand rabbits were assigned for occlusion of the right maxillary sinus through a transmaxillary approach or through the roof of the nasal cavity. The contralateral sinus served as a control. After 12 weeks, the animals were sacrificed for blinded histopathological analysis of the maxillary sinus mucosa. Histopathological changes consistent with CRS were found in eight (100%) of the maxillary sinuses approached transmaxillary and three of those through the roof of the nasal cavity (37.5%), p 0.008 and 0.250, respectively, comparing with the control side. Chronic mucosal changes were significantly better induced using the transmaxillary approach (p 0.026). It is possible to induce a model of chronic sinusitis among rabbits with transmaxillary sinus occlusion without bacterial inoculation. This model can be replicated for future cellular studies.


Genomic landscape of transcriptional and epigenetic dysregulation in early onset polyglutamine disease.
Transcriptional dysregulation is an important early feature of polyglutamine diseases. One of its proposed causes is defective neuronal histone acetylation, but important aspects of this hypothesis, such as the precise genomic topography of acetylation deficits and the relationship between transcriptional and acetylation alterations at the whole-genome level, remain unknown. The new techniques for the mapping of histone post-translational modifications at genomic scale enable such global analyses and are challenging some assumptions about the role of specific histone modifications in gene expression. We examined here the genome-wide correlation of histone acetylation and gene expression defects in a mouse model of early onset Huntington's disease. Our analyses identified hundreds of loci that were hypoacetylated for H3K9,14 and H4K12 in the chromatin of these mice. Surprisingly, few genes with altered transcript levels in mutant mice showed significant changes in these acetylation marks and vice versa. Our screen, however, identified a subset of genes in which H3K9,14 deacetylation and transcriptional dysregulation concur. Genes in this group were consistently affected in different brain areas, mouse models, and tissue from patients, which suggests a role in the etiology of this pathology. Overall, the combination of histone acetylation and gene expression screenings demonstrates that histone deacetylation and transcriptional dysregulation are two early, largely independent, manifestations of polyglutamine disease and suggests that additional epigenetic marks or mechanisms are required for explaining the full range of transcriptional alterations associated with this disorder.


In vivo ultrathin Descemet stripping automated endothelial keratoplasty with a low-energy and high-frequency femtosecond laser.
This case report describes the production of an ultrathin endothelial donor corneal lamella using a femtosecond laser with low energy and a high frequency. In addition, we report its use in vivo in an eye with pseudophakic bullous keratopathy. The outcomes were observed 3 months after surgery in terms of the change in endothelial donor lamella and full cornea thickness (including pachymetric mapping), visual acuity, and endothelial cell count.


Factors influencing the deaggregation of chymotrypsin-treated human platelets aggregated by fibrinogen.
Washed human platelets aggregated by ADP can be deaggregated by EDTA or PGE1, provided the release reaction does not occur; when the release reaction occurs platelets deaggregate less readily. Platelets treated with chymotrypsin are aggregated by fibrinogen indicating that fibrinogen receptors may be permanently exposed by this treatment. Fibrinogen-induced aggregation of chymotrypsin-treated platelets provides another method of bringing platelets into close contact with each other. Although EDTA deaggregated chymotrypsin-treated platelets aggregated by fibrinogen in a medium containing a physiological concentration of Ca2+, EDTA did not deaggregate these platelets if they were in a medium without calcium in which the release reaction occurs. In this medium, when ASA was added to prevent the release reaction, EDTA caused deaggregation. More fibrinogen associated with platelets in the medium without calcium than in the calcium-containing medium. In both media, EDTA displaced approximately half of the fibrinogen indicating that deaggregation is not solely dependent on dissociation of fibrinogen from its receptors. Thus when platelets undergo the release reaction, a form of platelet-to-platelet adhesion occurs that is not disrupted by chelation of divalent cations and is therefore not likely to involve only fibrinogen or thrombospondin and fibrinogen since the association of fibrinogen with its receptor requires Ca2+ and the binding of thrombospondin to platelets that have undergone the release reaction is also dependent on Ca2+.


Biological Therapy in Pediatric Inflammatory Bowel Disease: A Systematic Review.
The incidence of inflammatory bowel disease (IBD) has increased steadily worldwide, both in adult and in children; approximately 25% of IBD patients are diagnosed before the age of 18. The natural history of IBD is usually more severe in children than in adults, and can be associated with linear growth impairment, delayed puberty onset, reduced bone mass index, malnutrition, and the need for surgery. Biological therapies, especially blocking tumor necrosis factor-α (TNFα), have radically modified the treatment strategies and disease course of IBD in children. In particular, drugs such as Infliximab and Adalimumab are routinely used in the treatment of pediatric IBD. The role of Infliximab and Adalimumab in the management of pediatric IBD has been recently updated in the Consensus guidelines of ECCO/ESPGHAN. Data regarding short-term and long-term efficacy and safety of these drugs in children, and the effects of "top-down" and "step-up" strategies, are lacking. In this paper, the authors will review current indications, efficacy, and safety of biological therapy in pediatric IBD patients, evaluating all articles published after ECCO/ESPGHAN guidelines publication. The authors carried out a systematic search through MEDLINE through PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) Embase, CINAHL, Cochrane Library, and gray literature, from January 2013 to January 2016. Anti-TNFα has been shown to be effective and safe to maintain remission and to achieve mucosal healing. Multicenter trials based on large sample size cohorts are needed to better clarify long-term efficacy of anti-TNFα and the real incidence of treatment-related complications in pediatric IBD.


A pivotal role for CXCL12 signaling in HPV-mediated transformation of keratinocytes: clues to understanding HPV-pathogenesis in WHIM syndrome.
The WHIM syndrome, which features high susceptibility to human papillomavirus (HPV) infection, is a rare immunodeficiency associated with autosomal dominant heterozygous mutations of the CXCR4 chemokine receptor. CXCL12 and its receptors, CXCR4 and CXCR7, are linked to tumorigenesis, and we reported that abnormal expression of CXCL12 in epidermal keratinocytes correlates with HPV infection. However, the HPV-related pathologies observed in WHIM patients remain mechanistically unexplained. We show that keratinocytes immortalized by oncogenic HPV16 or HPV18 upregulate CXCL12 and its receptors in a manner dependent upon expression of the viral proteins E6 and E7. Autocrine signaling activated by CXCL12-engagement of its receptors controls motility and survival of the infected cells. Strikingly, expression of a WHIM syndrome-related gain-of-function CXCR4 mutant confers transforming capacity to HPV18-immortalized keratinocytes. These results establish a pivotal role for CXCL12 signaling in HPV-mediated transformation and provide a mechanistic basis for understanding HPV pathogenesis in WHIM syndrome.


Environmental Stressors Suffered by Women with Gynecological Cancers in the Aftermath of Hurricanes Irma and María in Puerto Rico.
Hurricanes are the immediate ways that people experience climate impacts in the Caribbean. These events affect socio-ecological systems and lead to major disruptions in the healthcare system, having effects on health outcomes. In September 2017, Puerto Rico (PR) and the United States Virgin Islands (USVI) experienced one of the most catastrophic hurricane seasons in recent history (Hurricane Irma was a Category 5 and Hurricane María was a Category 4 when they hit PR). This study examines environmental stressors experienced by women with gynecologic (GYN) cancers from PR and USVI who received oncologic cancer care in PR, in the aftermath of the hurricanes. A descriptive qualitative study design was used to obtain rich information for understanding the context, barriers, knowledge, perspectives, risks, vulnerabilities, and attitudes associated to these hurricanes. We performed focus groups among GYN cancer patients (n = 24) and key-informant interviews (n = 21) among health-care providers and administrators. Interviews were conducted from December 2018-April 2019. Environmental health stressors such as lack of water, heat and uncomfortable temperatures, air pollution (air quality), noise pollution, mosquitos, and rats ranked in the top concerns among cancer patients and key-informants. These findings are relevant to cancer patients, decision-makers, and health providers facing extreme events and disasters in the Caribbean. Identifying environmental secondary stressors and the most relevant cascading effects is useful for decision-makers so that they may address and mitigate the effects of hurricanes on public health and cancer care.


Analysis of engraftment, graft-versus-host disease, and immune recovery following unrelated donor cord blood transplantation.
Unrelated cord blood (UCB) is being used as a source of alternative hematopoietic stem cells for transplantation with increasing frequency. From November 1994 to February 1999, 30 UCB transplant procedures were performed for both malignant and nonmalignant diseases in 27 children, aged 0.4 to 17.1 years. Patients received either HLA-matched (n = 3) or 1- or 2-antigen-mismatched (n = 27) UCB following 1 of 2 standardized preparative and graft-versus-host disease regimens (hyperfractionated total body irradiation, cyclophosphamide, and antithymocyte globulin [ATG] with cyclosporine A and methotrexate; or busulfan, melphalan, and ATG with cyclosporine A and prednisone). The median time to neutrophil and platelet engraftment was 27 days (12-60 days) and 75 days (33-158 days) posttransplantation, respectively. No correlation was noted between neutrophil and platelet engraftment and nucleated cells per kilogram, CD34(+) cells per kilogram infused, or cytomegalovirus status of recipient. The cumulative probability of acute grade 2 or greater graft-versus-host disease (GVHD) was 37.2%, and of grade 3 or greater GVHD was 8.8%. No patients developed chronic GVHD. CD4, CD19, and natural killer cell recovery was achieved at a median of 12, 6, and 2 months, respectively. CD8 recovery was delayed at a median of 9 months. Normal mitogen response was achieved at 6 to 9 months. The probability of survival, disease-free survival, and event-free survival at 1 year was 52.3% (34.1%-70.5%), 54.7% (34.5%-74.9 %) and 49.6% (29.9%-69.4%), respectively. This series of 30 UCB transplants suggests that although CD8 cell recovery is delayed, the pattern of immune reconstitution with UCB is similar to that reported for other stem cell sources. (Blood. 2000;96:2703-2711)


Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.
Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.


Primary mixed adenocarcinoma and small cell carcinoma of the appendix: a clinicopathologic, immunohistochemical, and molecular study of a hitherto unreported tumor.
Appendiceal carcinoids range from well-differentiated endocrine tumor to well-differentiated endocrine carcinoma, while poorly differentiated (small cell) carcinoma has not been described in this site. We report herein a case of mixed intestinal-type adenocarcinoma associated with a small cell carcinoma arisen in a 35-year-old woman and clinically presenting as an appendiceal abscess. The resected tumor histologically appeared as a biphasic lesion composed of a nonmucinous adenocarcinoma closely juxtaposed with a poorly differentiated (small cell) endocrine carcinoma. The subsequent right hemicolectomy was unremarkable, but one pericolic lymph node showed a metastatic deposit consisting of the adenocarcinoma only. The patient thus underwent a chemotherapeutic protocol for colorectal cancer, and she is alive and well at the 65-month follow-up. Immunohistochemically, the adenocarcinoma strongly stained for cytokeratin 20 and carcinoembryonic antigen, while the endocrine component displayed a dot-like positivity for pan-cytokeratins and chromogranin. Of note, both components did not stain with CDX2 and p53. At genotypic analysis by microsatellite instability, both components shared many microsatellite alterations as well as a normal p53 gene setup, although small cell carcinoma harbored additional alterations. Clinical and molecular findings led us to consider this lesion as a clonal tumor in which the endocrine component seems to derive from a progressive differentiation of the adenocarcinoma following a glandular-to-endocrine sequence.


Association between Loneliness and Depression among Community-Dwelling Older Women Living Alone in South Korea: The Mediating Effects of Subjective Physical Health, Resilience, and Social Support.
Social isolation and loneliness are the key risk factors for depression in late life. Older adults living alone and socially isolated are at greater risk for physical and mental health. This study aims to examine the mediating effects of subjective physical health, resilience, and social support on the association between loneliness and depression among the elderly female population living alone in South Korea. We included a total of 308 older women aged 60 years or older who live alone in a medium-sized city in South Korea. The survey data was collected using the validated survey instruments between November 2015 and April 2016. A parallel mediation model was performed to investigate whether physical health, resilience, and social support had mediating effects on the association of loneliness with depression. The findings of this study showed that loneliness was directly and indirectly associated with depression through its association with the subjective physical health, resilience, and social support among the older female population living alone. Our results suggest the importance of supporting community-based programs to improve physical and mental health of the elderly people as a way to minimize the level of loneliness and prevent depression.


Assessment of CD39 expression in regulatory T-cell subsets by disease severity in adult and juvenile COVID-19 cases.
COVID-19 is a disease characterized by acute respiratory failure and is a major health problem worldwide. Here, we aimed to investigate the role of CD39 expression in Treg cell subsets in COVID-19 immunopathogenesis and its relationship to disease severity. One hundred and ninety COVID-19 patients (juveniles, adults) and 43 volunteers as healthy controls were enrolled in our study. Flow cytometric analysis was performed using a 10-color monoclonal antibody panel from peripheral blood samples. In adult patients, CD39+ Tregs increased with disease severity. In contrast, CD39+ Tregs were decreased in juvenile patients in an age-dependent manner. Overall, our study reveals an interesting profile of CD39-expressing Tregs in adult and juvenile cases of COVID-19. Our results provide a better understanding of the possible role of Tregs in the mechanism of immune response in COVID-19 cases.


Long-term use of sertraline leads to alterations in contractility of rat isolated vas deferens.
Previous experiments with rat isolated vas deferens have shown that sertraline pretreatment inhibits contractile responses to noradrenaline, KCl, serotonin and electrical field stimulation. In the present study, the aim was to investigate the effects of long-term use of sertraline on contractile responses of rat isolated vas deferens. Fifteen Sprague-Dawley rats were given long-term (21 days) sertraline treatment, while another 15 were used as control. Both vas deferens were excised. Epididymal and prostatic segments of each underwent electrical field and chemical stimulation (noradrenaline, serotonin, acetylcholine, adenosine-triphosphate). Epididymal and prostatic segments had different contraction characteristics. Long-term sertraline treatment inhibited contractile responses of vas deferens segments to electrical field stimulation. The responses to noradrenaline were amplified with a left shift on both segments. Responses to serotonin had only a left shift on epididymal segments, while no contractile responses were observed on prostatic segments of the groups. Long-term treatment with sertraline had peripheral effects on rat vas deferens contractility, and some of the effects may be through mechanisms other than the inhibition of serotonin re-uptake.


The C-Terminal Domains SnRK2 Box and ABA Box Have a Role in Sugarcane SnRK2s Auto-Activation and Activity.
Resistance to drought stress is fundamental to plant survival and development. Abscisic acid (ABA) is one of the major hormones involved in different types of abiotic and biotic stress responses. ABA intracellular signaling has been extensively explored in Arabidopsis thaliana and occurs via a phosphorylation cascade mediated by three related protein kinases, denominated SnRK2s (SNF1-related protein kinases). However, the role of ABA signaling and the biochemistry of SnRK2 in crop plants remains underexplored. Considering the importance of the ABA hormone in abiotic stress tolerance, here we investigated the regulatory mechanism of sugarcane SnRK2s-known as stress/ABA-activated protein kinases (SAPKs). The crystal structure of ScSAPK10 revealed the characteristic SnRK2 family architecture, in which the regulatory SnRK2 box interacts with the kinase domain αC helix. To study sugarcane SnRK2 regulation, we produced a series of mutants for the protein regulatory domains SnRK2 box and ABA box. Mutations in ScSAPK8 SnRK2 box aimed at perturbing its interaction with the protein kinase domain reduced protein kinase activity in vitro. On the other hand, mutations to ScSAPK ABA box did not impact protein kinase activity but did alter the protein autophosphorylation pattern. Taken together, our results demonstrate that both SnRK2 and ABA boxes might play a role in sugarcane SnRK2 function.


Molecular aspects of avian oogenesis and fertilisation.
In this paper, we summarise studies which have been carried out on the metabolism of nucleic acids (maternal RNA, DNA, nucleolytic enzymes) in avian oocytes and embryos (Japanese quail, Coturnix coturnix japonica ) within the last 10 years in the Institute of Genetics and Animal Breeding of the Polish Academy of Sciences. The accumulation of maternal RNA in the quail oocyte during oogenesis is shown and discussed. Several individual transcripts were identified in RNA from the germinal disc and some also in extraembryonic RNA under the perivitelline membrane. The presence of the transcript encoding chick zona pellucida C protein (chZPC) points to the possibility of ZPC synthesis by the oocyte itself. The transcript encoding AA-NAT (arylalkylamine N-acetyltransferase, the penultimate enzyme in melatonin synthesis) was present in 2 forms (with and without an intron) and the ratio of the two forms changes during oogenesis. Melatonin and the two enzymes engaged in its synthesis (AA-NAT and HIOMT) have been found in the egg yolk; their transcripts and the transcripts of the melatonin receptors mel-1a,b and c are present in RNA from the germinal discs. This suggests a possible role for melatonin in early avian development. DNases I and II activity has been detected in the germinal disc and the cytoplasmic layer under the perivitelline membrane. We propose that they participate in degradation of supernumerary sperm entering avian oocytes during polyspermic fertilisation. A hypothesis to explain the selection of a single sperm participating in the formation of the zygotic nucleus is discussed; we propose that sperm entry into the centre of the germinal disc is the essential event underlying the selection mechanism.


Thirty-Day Outcomes of Transcatheter Mitral Valve Replacement for Degenerated Mitral Bioprostheses (Valve-in-Valve), Failed Surgical Rings (Valve-in-Ring), and Native Valve With Severe Mitral Annular Calcification (Valve-in-Mitral Annular Calcification) in the United States: Data From the Society of Thoracic Surgeons/American College of Cardiology/Transcatheter Valve Therapy Registry.
Transcatheter mitral valve replacement using aortic transcatheter heart valves has recently become an alternative for patients with degenerated mitral bioprostheses, failed surgical repairs with annuloplasty rings or severe mitral annular calcification who are poor surgical candidates. Outcomes of these procedures are collected in the Society of Thoracic Surgeons/American College of Cardiology/Transcatheter Valve Therapy Registry. A comprehensive analysis of mitral valve-in-valve (MViV), mitral valve-in-ring (MViR), and valve-in-mitral annular calcification (ViMAC) outcomes has not been performed. We sought to evaluate short-term outcomes of early experience with MViV, MViR, and ViMAC in the United States. Retrospective analysis of data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. Nine hundred three high-risk patients (median Society of Thoracic Surgeons score 10%) underwent MViV (n=680), MViR (n=123), or ViMAC (n=100) between March 2013 and June 2017 at 172 hospitals. Median age was 75 years, 59.2% female. Technical and procedural success were higher in MViV. Left ventricular outflow tract obstruction occurred more frequently with ViMAC (ViMAC=10%, MViR=4.9%, MViV=0.7%; P<0.001). In-hospital mortality (MViV=6.3%, MViR=9%, ViMAC=18%; P=0.004) and 30-day mortality (MViV=8.1%, MViR=11.5%, ViMAC=21.8%; P=0.003) were higher in ViMAC. At 30-day follow-up, median mean mitral valve gradient was 7 mm Hg, most patients (96.7%) had mitral regurgitation grade ≤1 (+) and were in New York Heart Association class I to II (81.7%). MViV using aortic balloon-expandable transcatheter heart valves is associated with a low complication rate, a 30-day mortality lower than predicted by the Society of Thoracic Surgeons score, and superior short-term outcomes than MViR and ViMAC. At 30 days, patients in all groups experienced improvement of symptoms, and valve performance remained stable. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02245763.


Novel Application of Steroid Eluting Stent in Petrous Apex Cholesterol Granuloma.
Objective This study describes the safety and efficacy of mometasone furoate eluting stents in the management of petrous apex cholesterol granuloma approached through an endonasal endoscopic route and assesses the restenosis rate. Methods Consecutive patients undergoing endoscopic endonasal marsupialization of a petrous apex cholesterol granuloma at a tertiary referral center who had a mometasone furoate eluting stent placed intraoperatively were reviewed in a retrospective fashion. Postoperative endoscopy was used to determine success of surgery and stenting. Results Five patients were included in the study, three were primary cases and two patients had revision surgeries performed. The steroid eluting stent was placed successfully and safely in all patients with no dural or vascular injuries. The average follow-up duration was 10.6 months. There was no restenosis in three patients and one patient had an immediate restenosis that was debrided in clinic (revision case). This was patent at the 16 months follow-up. One patient also developed stenosis, 4 months after surgery due to sphenoid sinusitis. Conclusion Mometasone furoate eluting stents are safe and effective in the primary management of petrous apex cholesterol granuloma. Further studies are needed to assess their efficacy in revision cases and for long term results.


Too much to handle? Interference from distractors with similar affordances on target selection for handled objects.
The existence of handle affordances has been classically demonstrated using the Stimulus-Response Compatibility paradigm, with shorter response times when the orientation of the object handle and the response hand are compatible in comparison to incompatible. Yet the activation of handle affordances from visual objects has been investigated in very simple situations involving single stimulus and motor response. As natural perceptual scenes are usually composed of multiple objects that could activate multiple affordances, the consequence of multiple affordance activation on the perception and processing of a given object of the scene requires more investigation. The aim of this study was to determine the impact of distractor affordances on the processing of a target object in situations involving several familiar graspable objects. In two online experiments, 229 participants had to select a target object (the kitchen utensil or the tool) in a visual scene displaying a pair of objects. They performed left key presses when the target was on the left and right key presses when the target was on the right. Target handle orientation and response side could be compatible or incompatible. Critically, target and distractor objects had similar or dissimilar handle affordances, with handles oriented for left- or right-hand grasps. Results from the two experiments showed slower response times when target and distractor objects had similar handle affordances in comparison to dissimilar affordances, when participants performed right hand responses and when target orientation and response were compatible. Thus, affordance similarity between objects may interfere rather than facilitate object processing and slow down target selection. These findings are in line with models of affordance and object selection assuming automatic inhibition of distractors' affordances for appropriate object interaction.


Genotyping and surveillance for scrapie in Finnish sheep.
The progression of scrapie is known to be influenced by the amino acid polymorphisms of the host prion protein (PrP) gene. There is no breeding programme for TSE resistance in sheep in Finland, but a scrapie control programme has been in place since 1995. In this study we have analysed PrP genotypes of total of 928 purebred and crossbred sheep together with the data of scrapie survey carried out in Finland during 2002-2008 in order to gain knowledge of the genotype distribution and scrapie prevalence in Finnish sheep. The ARQ/ARQ genotype was the most common genotype in all breeds studied. ARR allele frequency was less than 12% in purebred Finnish sheep and in most genotypes heterozygous for ARR, the second allele was ARQ. The VRQ allele was not detected in the Grey race sheep of Kainuu or in the Aland sheep, and it was present in less than 6% of the Finnish Landrace sheep. Leucine was the most prominent amino acid found in codon 141. In addition, one novel prion dimorphisms of Q220L was detected. During the scrapie survey of over 15 000 sheep in 2002-2008, no classical scrapie cases and only five atypical scrapie cases were detected. The results indicate that the Finnish sheep populations have genetically little resistance to classical scrapie, but no classical scrapie was detected during an extensive survey in 2002-2008. However, five atypical scrapie cases emerged; thus, the disease is present in the Finnish sheep population at a low level.


Adaptive response of the archaeon Sulfolobus acidocaldarius BC65 to phosphate starvation.
The adaptive response of the archaeon Sulfolobus acidocaldarius BC65 to phosphate starvation was studied. When cells were subjected to phosphate limitation, their growth was affected. In addition, the levels of synthesis and/or the degree of phosphorylation of several proteins changed, as detected by two-dimensional nonequilibrium pH gradient electrophoresis of cells labelled in vivo with [35S]methionine and [35S]cysteine, or H3 32PO4. After another growth-restricting treatment, a heat shock, a general inhibition of protein synthesis was observed. Under phosphate starvation conditions, a 36 kDa protein became phosphorylated without its synthesis being significantly modified, suggesting a probable regulatory role during adaptation of the cell to the change in the external environment. In Southern blot analysis with specific probes from very conserved regions of the phoR and phoB genes from Escherichia coli, a positive hybridization with S. acidocaldarius BC65 chromosomal DNA fragments was found. This suggested the presence in S. acidocaldarius BC65 of genes related to the E. coli genes involved in the phosphate starvation response system. This appears to be the first evidence of the possible existence of a two-component sensory system in a micro-organism from the archaeal kingdom Crenarchaeota.


Developing Healthy Lifestyle Behaviors in Early Age-An Intervention Study in Kindergartens.
Childhood obesity prevention is a leading public health challenge requiring the adoption of healthy lifestyles at an early age. We examined how the kindergarten environment can promote eating sensibly, drinking water and becoming physically active. The effects of an intervention program among 42 Israeli kindergartens (1048 children, aged 4-6) whose teachers participated in a health education training program were compared to 32 kindergartens (842 children) whose teachers did not undergo this training program. An eight-month intervention program focused on knowledge/mathematical/logical/critical thinking, self-regulation/control acquisition, and sensible decision-making abilities. We hypothesized that nutrition and physical-exercise-oriented intervention programs, combining knowledge/mathematical logical thinking, would positively impact the quality of children's mid-morning snack and water consumption, their ability to express feelings following physical exercise, and the adoption of healthy lifestyles at home. The quality of mid-morning snacks and water consumption were observed in both groups pre- and post-intervention. Qualitative interviews documented children's subjective feelings following physical exercise. A significant improvement (p < 0.001) was observed in the mid-morning snacks composition and in water drinking habits in the intervention group; 80% of children offered a physiological explanation regarding energy expenditure processes following intense physical exercise. In conclusion, kindergarten interventions implemented by trained teachers can promote adoption of health behaviors necessary for obesity prevention.