Non-suicidal self-injury among adult males in a correctional setting.
Non-suicidal self-injury (NSSI) was thought to be a predominantly female malady and adult males who engage in NSSI in a correctional setting have not yet been well-researched. This study is, therefore, one of a few that explores the phenomenon of NSSI among males who engage in this behavior in a correctional setting. The purpose of this article is to present the demographic and motivational factors of adult males who engage in NSSI in a correctional setting. The sample consisted of 42 adult males incarcerated in three New Mexico Prisons who had a history of NSSI. Of the participants, 40% were Hispanic and 60% were non-Hispanic. Three measures were used in this study: the Deliberate Self-Harm Inventory (DSHI), the Self-Injury Motivational Scale-II (SIMS-II), and a researcher-created demographic questionnaire. The DSHI was used to examine the types of self-harm, as well as the frequency, severity, and duration of each behavior. The SIMS-II explored 36 potential types of motivations or reasons for self-injurious behavior. Fifteen of the 16 forms of NSSI were endorsed by at least one of the participants. The most predominant type of NSSI reported was cutting (93%), followed by head banging (78%), and sticking oneself with sharp objects (71.4%). Ninety-three percent of the participants required medical attention or hospitalization due to NSSI behaviors. Motivational factors associated with cutting were predominantly mood dysregulation, communication, and addictive qualities.


Therapy of allergic bronchial asthma with omalizumab - an anti-IgE monoclonal antibody.
The immunoglobulin E (IgE) antibody plays a central role in the allergic immune responses, such as those which characterise allergic bronchial asthma. The ability to reduce circulating IgE by using anti-IgE antibodies represents a novel therapeutic approach for IgE-mediated allergic diseases. Omalizumab (rhuMAb-E25/Xolair Genentech, USA/Tanox, Inc., USA/Novartis Pharma AG, Switzerland) is a non-anaphylactogen humanised murine monoclonal antibody which binds to circulating IgE. Therapeutic use of an anti-IgE antibody in the treatment of asthma was first suggested in preliminary studies in which omalizumab demonstrated efficacy in attenuating both the early- and late-phase bronchial responses to inhaled allergens in atopic subjects. Treatment with omalizumab has demonstrated both a significant beneficial effect on a number of measures, and a favourable safety profile. It reduces the frequency of asthma exacerbations and the need for inhaled corticosteroids (ICSs), and improves asthma symptoms, lung function and quality of life. The anti-IgE approach to asthma treatment has a number of further potential advantages, such as the treatment of other concomitant atopic diseases (allergic conjunctivitis and rhinitis, atopic dermatitis and food allergy), regardless of the type of allergic sensitisation (seasonal or perennial). On the basis of several studies, omalizumab is likely to provide a new strategy for treating atopic asthma.


Impulsivity and compulsivity in gambling disorder and bulimic spectrum eating disorders: Analysis of neuropsychological profiles and sex differences.
Gambling disorder (GD) and bulimic spectrum eating disorders (BSDs) not only share numerous psychopathological, neurobiological, and comorbidity features but also are distinguished by the presence of inappropriate behaviours related to impulsivity and compulsivity. This study aimed to emphasise the differences and similarities in the main impulsivity and compulsivity features between GD and BSD patients, and to analyse the potential influence of sex in these domains. Using self-reported and neurocognitive measures, we assessed different impulsive-compulsive components in a sample of 218 female and male patients (59 with BSD and 159 with GD) and 150 healthy controls. We observed that GD and BSDs exhibited elevated levels of impulsivity and compulsivity in all the dimensions compared to healthy controls. Moreover, these disorders showed differences in several personality traits, such as high novelty seeking in GD, and low persistence and high harm avoidance in BSDs. In addition, patients with BSDs also displayed a trend towards greater impulsive choice than GD patients. Regarding sex effects, GD women presented higher overall impulsivity and compulsivity than GD men. Nevertheless, no sex differences were found in BSDs. Clinical interventions should consider these deficits to enhance their effectiveness, including adjunctive treatment to target these difficulties. Our findings also provide support to the relevance of sex in GD, which should also be considered in clinical interventions.


Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers.
Although the majority of colorectal cancers exhibit chromosome instability (CIN), only a few genes that might cause this phenotype have been identified and no general mechanism underlying their function has emerged. To systematically identify somatic mutations in potential CIN genes in colorectal cancers, we determined the sequence of 102 human homologues of 96 yeast CIN genes known to function in various aspects of chromosome transmission fidelity. We identified 11 somatic mutations distributed among five genes in a panel that included 132 colorectal cancers. Remarkably, all but one of these 11 mutations were in the homologs of yeast genes that regulate sister chromatid cohesion. We then demonstrated that down-regulation of such homologs resulted in chromosomal instability and chromatid cohesion defects in human cells. Finally, we showed that down-regulation or genetic disruption of the two major candidate CIN genes identified in previous studies (MRE11A and CDC4) also resulted in abnormal sister chromatid cohesion in human cells. These results suggest that defective sister chromatid cohesion as a result of somatic mutations may represent a major cause of chromosome instability in human cancers.


A nonpathogenic GAAGGA repeat in the Friedreich gene: implications for pathogenesis.
An individual with late-onset ataxia was found to be heterozygous for an unusual (GAAGGA)65 sequence and a normal GAA repeat in the frataxin gene. No frataxin point mutation was present, excluding a form of Friedreich ataxia. (GAAGGA)65 did not have the inhibitory effect on gene expression in transfected cells shown by pathogenic GAA repeats of similar length. GAA repeats, but not (GAAGGA)65, adopt a triple helical conformation in vitro. We suggest that such a triplex structure is essential for suppression of gene expression.


An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010.
In 2010, an outbreak of coxsackievirus A6 (CA6) hand, foot and mouth disease (HFMD) occurred in Taiwan and some patients presented with onychomadesis and desquamation following HFMD. Therefore, we performed an epidemiological and molecular investigation to elucidate the characteristics of this outbreak. Patients who had HFMD with positive enterovirus isolation results were enrolled. We performed a telephone interview with enrolled patients or their caregivers to collect information concerning symptoms, treatments, the presence of desquamation, and the presence of nail abnormalities. The serotypes of the enterovirus isolates were determined using indirect immunofluorescence assays. The VP1 gene was sequenced and the phylogenetic tree for the current CA6 strains in 2010, 52 previous CA6 strains isolated in Taiwan from 1998 through 2009, along with 8 reference sequences from other countries was constructed using the neighbor-joining command in MEGA software. Of the 130 patients with laboratory-confirmed CA6 infection, some patients with CA6 infection also had eruptions around the perioral area (28, 22%), the trunk and/or the neck (39, 30%) and generalized skin eruptions (6, 5%) in addition to the typical presentation of skin eruptions on the hands, feet, and mouths. Sixty-six (51%) CA6 patients experienced desquamation of palms and soles after the infection episode and 48 (37%) CA6 patients developed onychomadesis, which only occurred in 7 (5%) of 145 cases with non-CA6 enterovirus infection (p < 0.001). The sequences of viral protein 1 of CA6 in 2010 differ from those found in Taiwan before 2010, but are similar to those found in patients in Finland in 2008. HFMD patients with CA6 infection experienced symptoms targeting a broader spectrum of skin sites and more profound tissue destruction, i.e., desquamation and nail abnormalities.


Parenteral nutrition: never say never.
This review emphasizes the benefits of parenteral nutrition (PN) in critically ill patients, when prescribed for relevant indications, in adequate quantities, and in due time. Critically ill patients are at risk of energy deficit during their ICU stay, a condition which leads to unfavorable outcomes, due to hypercatabolism secondary to the stress response and the difficulty to optimize feeding. Indirect calorimetry is recommended to define the energy target, since no single predictive equation accurately estimates energy expenditure. Energy metabolism is intimately associated with protein metabolism. Recent evidence calls for adequate protein provision, but there is no accurate method to estimate the protein requirements, and recommendations are probably suboptimal. Enteral nutrition (EN) is the preferred route of feeding, but gastrointestinal intolerance limits its efficacy and PN allows for full coverage of energy needs. Seven recent articles concerning PN for critically ill patients were identified and carefully reviewed for the clinical and scientific relevance of their conclusions. One article addressed the unfavorable effects of early PN, although this result should be more correctly regarded as a consequence of glucose load and hypercaloric feeding. The six other articles were either in favor of PN or concluded that there was no difference in the outcome compared with EN. Hypercaloric feeding was not observed in these studies. Hypocaloric feeding led to unfavorable outcomes. This further demonstrates the beneficial effects of an early and adequate feeding with full EN, or in case of failure of EN with exclusive or supplemental PN. EN is the first choice for critically ill patients, but difficulties providing optimal nutrition through exclusive EN are frequently encountered. In cases of insufficient EN, individualized supplemental PN should be administered to reduce the infection rate and the duration of mechanical ventilation. PN is a safe therapeutic option as long as sufficient attention is given to avoid hypercaloric feeding.


Immunofluorescent localization of urease in the cotyledons of jack bean, Canavalia ensiformis.
Urease has been localized in sections of cotyledons from germinating seeds of jack bean, using FITC-labelled immunoglobulin prepared from urease antiserum raised in rabbits. The complication of lectin binding to the immunoglobulins was resolved by treatment of the sections with specific glycosides. Urease is localized in 2 sites: within the cytoplasm of storage parenchyma cells in spherical granules up to 3 micrometer in diameter, and within the intercellular spaces in spherical granules. Although similar in size, the latter are distinguished from the cytoplasmic granules by the presence of beta-lectin and appear to function as an extracellular lytic compartment or lysosome.


[Transfer of bacterial genes for proline synthesis in plants and their expression by various plant promotors].
Accumulation of free proline (Pro) by bacteria and plants serves as a mechanism protecting these organisms from abiotic stress. We introduced two E. coli genes, proBosm, encoding a mutant variant of the first enzyme of the Pro biosynthetic pathway, gamma-glutamyl kinase, and proA, encoding the second enzyme of the Pro pathway, glutamyl-gamma-semialdehyde dehydrogenase, into tobacco plants. The spontaneous proBosm mutation was selected for Pro overproduction and mapped to the N-terminus of a polypeptide chain; it was found to result from one amino-acid substitution. Two E. coli genes were simultaneously introduced into tobacco plants, each under the control of a strong constitutive CaMV 35S promoter, which contained a duplicated sequence of enhancer, or the root-specific Pmas promoter sequence. Transgenic plants were characterized by Pro overproduction, increased resistance to L-azetidine-2-carboxylic acid (a toxic analog of Pro), and tolerance to salt stress.


Spatial transcriptomics reveals novel genes during the remodelling of the embryonic human arterial valves.
Abnormalities of the arterial valves, including bicuspid aortic valve (BAV) are amongst the most common congenital defects and are a significant cause of morbidity as well as predisposition to disease in later life. Despite this, and compounded by their small size and relative inaccessibility, there is still much to understand about how the arterial valves form and remodel during embryogenesis, both at the morphological and genetic level. Here we set out to address this in human embryos, using Spatial Transcriptomics (ST). We show that ST can be used to investigate the transcriptome of the developing arterial valves, circumventing the problems of accurately dissecting out these tiny structures from the developing embryo. We show that the transcriptome of CS16 and CS19 arterial valves overlap considerably, despite being several days apart in terms of human gestation, and that expression data confirm that the great majority of the most differentially expressed genes are valve-specific. Moreover, we show that the transcriptome of the human arterial valves overlaps with that of mouse atrioventricular valves from a range of gestations, validating our dataset but also highlighting novel genes, including four that are not found in the mouse genome and have not previously been linked to valve development. Importantly, our data suggests that valve transcriptomes are under-represented when using commonly used databases to filter for genes important in cardiac development; this means that causative variants in valve-related genes may be excluded during filtering for genomic data analyses for, for example, BAV. Finally, we highlight "novel" pathways that likely play important roles in arterial valve development, showing that mouse knockouts of RBP1 have arterial valve defects. Thus, this study has confirmed the utility of ST for studies of the developing heart valves and broadens our knowledge of the genes and signalling pathways important in human valve development.


Divergence of mitochondrial dna is not corroborated by nuclear dna, morphology, or behavior in Drosophila simulans.
We ask whether the observed mitochondrial DNA (mtDNA) population subdivision of Drosophila simulans is indicative of organismal structure or of specific processes acting on the mitochondrial genome. Factors either intrinsic or extrinsic to the host genome may influence the evolutionary dynamics of mtDNA. Potential intrinsic factors include adaptation of the mitochondrial genome and of nucleomitochondrial gene complexes specific to the local environment. An extrinsic force that has been shown to influence mtDNA evolution in invertebrates is the bacterial endosymbiont Wolbachia. Evidence presented in this study suggests that mtDNA is not a good indicator of organismal subdivision in D. simulans. Furthermore, there is no evidence to suggest that Wolbachia causes any reduction in nuclear gene flow in this species. The observed differentiation in mtDNA is not corroborated by data from NADH: ubiquinone reductase 75kD subunit precursor or the Alcohol dehydrogenase-related loci, from the shape or size of the male genital arch, or from assortative premating behavior. We discuss these results in relation to a mitochondrial genetic species concept and the potential for Wolbachia-induced incompatibility to be a mechanism of speciation in insects. We conclude with an iterated appeal to include phylogenetic and statistical tests of neutrality as a supplement to phylogenetic and population genetic analyses when using mtDNA as an evolutionary marker.


Encapsulation of core-satellite silicon in carbon for rational balance of the void space and capacity.
The void space is widely used in anode materials for relieving the volume expansion during lithium insertion and extraction processes. Generally, the void is randomly generated or exceeded the expansion to ensure the structural stability, which thus sacrifices the capacity and energy density. In this research, a core-satellite architecture was constructed with an elaborate structural design to obtain a rational balance of the void space and capacity. Such well fabricated silicon@porous silicon@carbon (Si@pSi@C) core-satellite nanoparticles with a precise void space present a satisfactory capacity of 1002 mA h g-1 over 100 cycles at a current of 100 mA g-1. This delicate core-satellite architecture could promote the use of the structural design in high-energy density lithium-ion batteries.


Investigation into La(Fe/Mn)O3 Perovskites Formation over Time during Molten Salt Synthesis.
Molten salt synthesis (MSS) of complex oxides is generally investigated by characterization of the product phases with no insight into evolution of particle morphology. In this work, LaFeO3 and LaMnO3 MSS was investigated in KF-KCl and LiCl-KCl at 850 °C using a "feeding-and-sampling" procedure. By feeding the oxide reagents into a molten salt, the reaction starting point was clearly defined, while subsequent sampling of the melt provided means for tracking the phase composition along with the shape and size of product particles during MSS. Samples taken just after 1 min contained perovskite particles along with reagents and intermediates, which were consumed over time to yield a pure product within 10-30 min. The shape and size of perovskite particles sampled at different times during MSS were virtually unchanged, revealing a lack of notable growth. The observed fast MSS along with prevailing nucleation provided means to control perovskite particle size by varying the extent of reagent dissolution. Thus, increasing the salt/reagent ratio (from 10:1 to 25:1) strikingly reduced the duration required to obtain a pure product, along with decreasing the size of product particles (from 0.5-1.5 μm to 80-200 nm). Furthermore, performing MSS in KF-KCl, which exhibits greater oxide solubility compared to LiCl-KCl, resulted in a shorter duration and smaller perovskite particles (80-200 nm and 0.6-2.0 μm, respectively). This insight into perovskite formation and growth during MSS and its kinetics provides valuable guidelines for tuning MSS conditions to better control synthesis duration and particle size.


Australian Group on Antimicrobial Resistance (AGAR) Australian Enterococcal Sepsis Outcome Programme(AESOP) Annual Report 2015.
From 1st January to 31st December 2015, 31 Australian institutions participated in the Australian Enterococcal Sepsis Outcome Programme (AESOP). The aim of AESOP 2015 was to determine the proportion of enterococcal bacteraemia isolates in Australia that were antimicrobial resistant, and to characterise the molecular epidemiology of the Enterococcus faecium isolates. Of the 1,009 unique episodes of bacteraemia investigated, 95.4% were caused by either E. faecalis (55.7%) or E. faecium (39.6%). Ampicillin resistance was detected in 0.2% of E. faecalis and in 86.0% of E. faecium. Vancomycin non-susceptibility was reported in 0.4% and 50.1% of E. faecalis and E. faecium respectively. Overall 56.2% of E. faecium harboured vanA or vanB genes. For the vanA/B positive E. faecium isolates, 61.0% harboured vanB genes and 36.8% vanA genes. The percentage of E. faecium bacteraemia isolates resistant to vancomycin in Australia is significantly higher than that seen in most European countries. E. faecium consisted of 49 multilocus sequence types (STs) of which 85.6% of isolates were classified into 11 major STs containing five or more isolates. All major STs belong to clonal cluster 17, a major hospital-adapted polyclonal E. faecium cluster. Four of the five predominant STs (ST796, ST555, ST203, and ST80) were found across most regions of Australia. The second most predominant clone was non-typable by multilocus sequence typing and found only in NSW and the ACT. Overall 73.9% of isolates belonging to the five predominant STs harboured vanA or vanB genes. In conclusion, the AESOP 2015 has shown enterococcal bacteraemias in Australia are frequently caused by polyclonal ampicillin-resistant high-level gentamicin resistant vanA or vanB E. faecium which have limited treatment options.


Factors Related to Average Concentric Velocity of Four Barbell Exercises at Various Loads.
Fahs, CA, Blumkaitis, JC, and Rossow, LM. Factors related to average concentric velocity of four barbell exercises at various loads. J Strength Cond Res 33(3): 597-605, 2019-The resistance exercise load is the primarily determinant of the average concentric velocity (ACV) during a repetition. It is unknown whether individual factors such as training experience or anthropometrics also influence the ACV. Previous research has shown the ACV during the 1 repetition maximum (1RM) varies between exercises, but it is not clear whether ACV is different between exercises at various percentages of the 1RM. This information could provide practical guidelines for trainees using ACV to select training loads. Therefore, the purpose of this study was to determine whether training age, current training frequency, limb length, height, and relative strength are related to ACV at loads between 35 and 100% of the 1RM for the squat, bench press, deadlift, and overhead press. A secondary purpose was to compare the ACV values between the 4 lifts at each relative load. Fifty-one (18 women and 33 men) completed 2 testing sessions in which the squat, bench press, deadlift, and overhead press ACV were measured during a modified 1RM protocol. Average concentric velocity values were significantly different among the 4 lifts (p < 0.05) at all relative loads between 35 and 100% 1RM except for 55% 1RM (p = 0.112). Generally, compared at the same relative loads, the overhead press exhibited the greatest ACV followed by the squat, bench press, and deadlift (in order). In addition, relative strength level was inversely related to ACV at maximal loads (≥95% 1RM) for the squat, bench press, and deadlift while height was positively related to ACV at moderate loads (55% 1RM) for all lifts (p < 0.05). These results suggest that the load-velocity profile is unique for each of these exercises, and that velocity ranges used for exercise prescription should be specific to the exercise. A trainee's relative strength and height may be a primary influence on the ACV.


3,4-Dihydroxybenzalacetone (DBL) Prevents Aging-Induced Myocardial Changes in Senescence-Accelerated Mouse-Prone 8 (SAMP8) Mice.
Aging is a predominant risk factor for the development and progression of cardiovascular complications. Physiologically and anatomically, the heart undergoes numerous changes that result in poor cardiac function in the elderly population. Recently, several studies have provided promising results, confirming the ability of the senescence-accelerated mouse-prone 8 (SAMP8) model to accurately model age-related cardiovascular alterations. In this study, using a murine model of senescence, SAMP8, we aimed to investigate the effect of 3,4-dihydroxybenzalacetone (DBL), a catechol-containing phenylpropanoid derivative isolated from Inonotusobliquus (Chaga), on cardiac aging. DBL was administered at the doses of 10 mg/kg and 20 mg/kg by oral gavage to SAMP8 mice to examine aging-mediated cardiac changes, such as oxidative DNA damage, oxygen radical antioxidant capacity (ORAC) value, fibrosis, inflammation, and apoptosis. The treatment with DBL at both doses significantly reduced aging-mediated oxidative DNA damage, and simultaneously increased the ORAC value in the SAMP8 assay. Cardiac fibrosis was assessed with Azan-Mallory staining, and the number of cardiac remodeling markers was found to be significantly reduced after the treatment with DBL. We also observed a decrease in cardiomyocyte apoptosis as measured by the terminal transferase-mediated dUTP nick end labeling (TUNEL) staining method and the caspase-3 levels in SAMP8 mice compared with senescence-resistant control (SAMR1) mice. The findings from this study suggest that DBL has a potentially beneficial effect on aging-mediated myocardial alterations. Further studies are warranted to confirm the promising potential of this catechol compound against aging-associated myocardial dysfunction.


Crypts are the site of intestinal fluid and electrolyte secretion.
The site of adenosine 3',5'-monophosphate-mediated fluid and electrolyte secretion across mammalian large intestine was found to be the crypts of Lieberkühn by means of two techniques. First, the formation of fluid droplets was visualized on the oil-covered mucosal surface directly over crypt duct openings when secretion was stimulated. Second, microelectrode impalement of individual surface and crypt cells revealed that only crypts cells produced a pattern of secretagogue induced alterations in membrane potential and resistance that was characteristic of secretory epithelia.


Cholesterol and risk of coronary heart disease and mortality in men.
Extensive data implicate cholesterol in the atherosclerotic process responsible for coronary disease. Of the atherosclerotic disease outcomes, serum cholesterol is most strongly related to coronary disease. A significant relationship of serum cholesterol to all clinical manifestations of coronary heart disease has been demonstrated in the Framingham Study, after adjusting for coexistent risk factors. Cholesterol and blood pressure exert similar influences on the occurrence of coronary heart disease. Risk of coronary heart disease associated with serum cholesterol is continuous, graded, and strong, with ideal values for cholesterol probably in the 130-190 mg/dL range. The impact of serum cholesterol diminishes with advancing age, but the predictive value of cholesterol is restored when fractionated into its atherogenic LDL and protective HDL components. The predictive value of total cholesterol in serum at all concentrations, including values less than 200 mg/dL, can be enhanced by taking HDL cholesterol into account. The total/HDL cholesterol ratio is a practical, efficient means for evaluating the joint effect of the two-way cholesterol traffic. Other cardiovascular risk factors such as blood pressure, glucose, cigarette smoking, fibrinogen, and left ventricular hypertrophy markedly influence the risk associated with measured concentrations of serum cholesterol. In correcting hypertension or diabetes, lipid values are an important consideration in determining the urgency, type, and efficacy of treatment used. In contrast to coronary mortality, rates of overall mortality show a quadratic relationship to total cholesterol in serum, with excessive mortality at concentrations greater than 160 mg/dL.


Calix[4]arenes as molecular platforms for magnetic resonance imaging (MRI) contrast agents.
The novel amphipilic conjugate of a calix[4]arene with four Gd-1,4,7,10- tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DOTA) chelates has potential as a magnetic resonance imaging contrast agent, both in its monomeric and in its micellar form. The system, illustrated here with its nuclear magnetic relaxation profile, shows good relaxivities, thanks to its high rigidity.An amphiphilic conjugate 1 of a calix[4]arene with four Gd-DOTA chelates (DOTA=1,4,7,10-tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane) was prepared and the properties relevant to its application as a magnetic resonance imaging (MRI) contrast agent were investigated by NMR, dynamic light scattering (DLS), and cryo-electron microscopy (cryo-TEM). The compound aggregates in water; its critical micelle concentration (cmc) is 0.21 mM (or 0.84 mM for Gd) at 37 degrees C. The relaxivity of the aggregates at 37 degrees C and 20 MHz (18.3 s(-1) per mM Gd or 73.2 s(-1) per mM 1) is about twice that of the monomer. Nuclear magnetic relaxation dispersion (NMRD) profiles show the relaxivity of the monomer to be almost independent of the magnetic field strength up to 60 MHz. At higher concentrations, the NMRD profiles exhibit a maximum at about 20 MHz, which is typical for high molecular volumes. The average water residence lifetime is 1.20 mus at 298 K as determined by (17)O NMR. The rotational correlation time of the monomer (390 ns at 37 degrees C) is very close to the optimal value predicted for high-field contrast agents. Monomer as well as micelles are very rigid systems with negligible local contributions to the overall rotational dynamics. The binding to human serum albumin (HSA) is significant (K(A)=1.2x10(3) M(-1)) and the relaxivity of the HSA adduct at 20 MHz is 24.6 s(-1) per mM Gd or 98.5 s(-1) per mM 1.


On the Difference Between Necessary and Unnecessary Glances Away From the Forward Roadway: An Occlusion Study on the Motorway.
The present study strove to distinguish traffic-related glances away from the forward roadway from non-traffic-related glances while assessing the minimum amount of visual information intake necessary for safe driving in particular scenarios. Published gaze-based distraction detection algorithms and guidelines for distraction prevention essentially measure the time spent looking away from the forward roadway, without incorporating situation-based attentional requirements. Incorporating situation-based attentional requirements would entail an approach that not only considers the time spent looking elsewhere but also checks whether all necessary information has been sampled. We assess the visual sampling requirements for the forward view based on 25 experienced drivers' self-paced visual occlusion in real motorway traffic, dependent on a combination of situational factors, and compare these with their corresponding glance behavior in baseline driving. Occlusion durations were on average 3 times longer than glances away from the forward roadway, and they varied substantially depending on particular maneuvers and on the proximity of other traffic, showing that interactions with nearby traffic increase perceived uncertainty. The frequency of glances away from the forward roadway was relatively stable across proximity levels and maneuvers, being very similar to what has been found in naturalistic driving. Glances away from the forward roadway proved qualitatively different from occlusions in both their duration and when they occur. Our findings indicate that glancing away from the forward roadway for driving purposes is not the same as glancing away for other purposes, and that neither is necessarily equivalent to distraction.


Co-creation of a student-implemented allied health service in a First Nations remote community of East Arnhem Land, Australia.
To co-create a culturally responsive student-implemented allied health service in a First Nations remote community and to determine the feasibility and acceptability of the service. Co-creation involved a pragmatic iterative process, based on participatory action research approaches. Feasibility and acceptability were determined using a mixed-method pre/postdesign. The service was in Nhulunbuy, Yirrkala and surrounding remote First Nations communities of East Arnhem Land, Northern Territory, Australia. Co-creation of the service was facilitated by the Northern Australia Research Network, guided by Indigenous Allied Health Australia leadership, with East Arnhem local community organisations and community members. Co-creation of the day-to-day service model involved local cultural consultants, service users and their families, staff of community organisations, students, supervisors, placement coordinators and a site administrator. A reciprocal learning service model was co-created in which culturally responsive practice was embedded. The service was feasible and acceptable: it was delivered as intended; resources were adequate; the service management system was workable; and the service was acceptable. Health outcome measures, however, were not appropriate to demonstrate impact, particularly through the lens of the people of East Arnhem. Recommendations for the service included: continuing the reciprocal learning service model in the long term; expanding to include all age groups; and connecting with visiting and community-based services. The co-created service was feasible and acceptable. To demonstrate the impact of the service, measures of health service impact that are important to First Nations people living in remote communities of northern Australia are required.


Immunosuppressive properties of tissues obtained from eyes with experimentally manipulated corneas.
To use explants of cornea and iris and ciliary body (I/CB) of experimentally manipulated eyes to determine whether loss of the capacity to suppress T-cell activation in vitro correlates with other consequences of manipulation, i.e., the migration of Langerhans cells into the central corneal epithelium, the leakiness of stromal neovessels, and the presence of axons in the cornea. Mouse eyes were subjected to cautery of central corneal surface, suture-induced neovascularization, circumferential or criss-crossed corneal surface wounds, and orthotopic corneal grafting. Corneas and I/CB were excised, explanted in vitro, and assayed for capacity to suppress mixed lymphocyte reaction. Integrity of suture-induced corneal neovessels was assessed with high molecular weight dextran, Langerhans cells were enumerated in corneal epithelium, nerve axons were evaluated in corneal stroma, and capacity of manipulated eyes to support anterior chamber-associated immune deviation (ACAID) induction after anterior chamber injection of bovine serum albumin were assessed. Experimental manipulations that abolished ACAID included cautery, neovascularization, and keratoplasty, whereas criss-crossed corneal excision wounds did not. Loss of ACAID correlated variably with loss of ability of corneal explants to secrete immunosuppressive factors in vitro, presence of Langerhans cells within the central corneal epithelium, leakiness of corneal neovessels, loss of axons in corneal stroma, and loss of ability of I/CB after keratoplasty to secrete immunosuppressive factors. The cornea plays an active role in ocular immune privilege and ACAID by creating a local immunosuppressive microenvironment, providing neural afferent stimuli that affect immunosuppressive properties of I/CB, and preventing neovascularization and infiltration with Langerhans cells.


Biodiversity loss along a gradient of deforestation in Amazonian agricultural landscapes.
Assessing how much management of agricultural landscapes, in addition to protected areas, can offset biodiversity erosion in the tropics is a central issue for conservation that still requires cross-taxonomic and landscape-scale studies. We measured the effects of Amazonia deforestation and subsequent land-use intensification in 6 agricultural areas (landscape scale), where we sampled plants and 4 animal groups (birds, earthworms, fruit flies, and moths). We assessed land-use intensification with a synthetic index based on landscape metrics (total area and relative percentages of land uses, edge density, mean patch density and diversity, and fractal structures at 5 dates from 1990 to 2007). Species richness decreased consistently as agricultural intensification increased despite slight differences in the responses of sampled groups. Globally, in moderately deforested landscapes species richness was relatively stable, and there was a clear threshold in biodiversity loss midway along the intensification gradient, mainly linked to a drop in forest cover and quality. Our results suggest anthropogenic landscapes with high-quality forest covering >40 % of the surface area may prevent biodiversity loss in Amazonia.


Central inflammatory response to experimental stroke is inhibited by a neuroprotective dose of dietary soy.
Dietary soy and soy isoflavones are neuroprotective in experimental cerebral ischemia. Because the isoflavones in soy that are responsible for this neuroprotective effect act as phytoestrogens, we hypothesized that they would mimic the beneficial effects of estrogens on the innate inflammatory response to cerebral ischemia. Ovariectomized Sprague-Dawley rats were fed a soy free diet or a diet containing high dietary levels of soy for 5 weeks, after which they were subjected to transient middle cerebral artery occlusion (tMCAO) for 90min. Dietary soy was associated with a reduced inflammatory response in the cerebral cortex during the acute innate period 4 and 24h after tMCAO, including significant (>2-fold) reductions in interleukins 1 beta, 2, and 13, and the chemokine CXCL1. However, there was no effect of soy on tumor necrosis factor-alpha or interferon-gamma. Dietary soy was also associated with a 40 percent reduction in the nuclear translocation of p65 nuclear factor kappa B despite an increase in the expression of p65 RELA mRNA. In support of an early effect on the innate immune response to stroke, soy-fed rats had 44 percent fewer activated microglia in the infarct core than soy free rats. Interestingly, despite increased expression following injury, the steady state mRNA levels of inflammatory factors were not altered in soy-fed rats even though inflammatory proteins were. These data suggest that dietary soy isoflavones, like estrogens, inhibit of the innate immune response to injury. However, post-transcriptional mechanisms may play an important role in the mechanism of this action. Coupled with previously published data, these results support an early and rapid effect of dietary soy on the evolution of brain injury following stroke.


Apoptotic and genomic effects of corilagin on SKOV3 ovarian cancer cell line.
Corilagin is a member of the tannin family and has been isolated from traditional Chinese medicinal plants, such as Phyllanthus spp. Corilagin has anti-inflammatory, antioxidative, antiatherogenic, and antihypertensive effects in various experimental models. In this research, we aimed to investigate for the first time whether corilagin had apoptotic and genomic effects in ovarian cancer treatment in the same study. The potential apoptotic of corilagin was investigated using a WST1 cell proliferation test, caspase 3, and mitochondrial membrane potential JC1 assays in a time- and dose-dependent manner. Genomic changes in expression levels against corilagin treatment were measured using an Illumina human HT-12V4 BeadChip microarray. Bioinformatic data analyses were performed using GenomeStudio and Ingenuity Pathway Analysis software. The data of our study demonstrated that there were statistically significant time- and dose-dependent increases in caspase 3 enzymatic activity and loss of mitochondrial membrane potential in line with decreases in cancer cell proliferation. According to gene-ontology analysis, we found that adherens junctions, antigen processing and presentation, and the phosphatidylinositol signaling system were the most statistically significant networks in response to corilagin treatment on SKOV3 cells, in a time- and dose-dependent manner. The apoptotic and genome-wide effects of corilagin on ovarian cancer cells were examined in detail for the first time in the literature. The results of our study suggest that corilagin might have the potential to be used as a new treatment option for epithelial ovarian cancer.


Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations.
Formation and homeostasis of the vascular system requires several coordinated cellular functions, but their precise interplay during development and their relative importance for vascular pathologies remain poorly understood. Here, we investigated the endothelial functions regulated by Cdc42 and their in vivo relevance during angiogenic sprouting and vascular morphogenesis in the postnatal mouse retina. We found that Cdc42 is required for endothelial tip cell selection, directed cell migration and filopodia formation, but dispensable for cell proliferation or apoptosis. Although the loss of Cdc42 seems generally compatible with apical-basal polarization and lumen formation in retinal blood vessels, it leads to defective endothelial axial polarization and to the formation of severe vascular malformations in capillaries and veins. Tracking of Cdc42-depleted endothelial cells in mosaic retinas suggests that these capillary-venous malformations arise as a consequence of defective cell migration, when endothelial cells that proliferate at normal rates are unable to re-distribute within the vascular network.


British Transplantation Society guidelines on abdominal organ transplantation from deceased donors after circulatory death.
The British Transplantation Society (BTS) 'Guideline on transplantation from deceased donors after circulatory death' has recently been updated and this manuscript summarises the relevant recommendations in abdominal organ transplantation from Donation after Circulatory Death (DCD) donors, encompassing the chapters on liver, kidney, pancreas and islet cell transplantation.


Dual functionality of pyrimidine and flavone in targeting genomic variants of EGFR and ER receptors to influence the differential survival rates in breast cancer patients.
Breast cancer ranks as one of the most prevalent forms of cancer and stands as the primary global cause of mortality among women. Overexpression of EGFR and ER receptors or their genomic alterations leads to malignant transformation, disease aggression and is linked to poor patient survival outcomes. The clinical breast cancer patient's genomic expression, survival analysis, and computational drug-targeting approaches were used to identify best-hit phytochemicals for therapeutic purposes. Breast cancer patients have genomic alterations in EGFR (4%, n = 5699) and ER (9%, n = 8461), with the highest proportion being missense mutations. No statistically significant difference was observed in the patient survival rates between the altered and unaltered ER groups, unlike EGFR, with the lowest survival rates in the altered group. Computational screening of natural compound libraries (7711) against each EGFR (3POZ) and ER (3ERT) receptor shortlists the best-hit 3 compounds with minimum docking score (ΔG = -7.9 to -10.8), MMGBSA (-40.16 to -51.91 kcal/mol), strong intermolecular H-bonding, drug-like properties with least kd, and ki. MD simulation studies display stable RMSD, RMSF, and good residual correlation of best-hit common compounds (PubChem ID: 5281672 and 5280863) targeting both EGFR and ER receptors. In vitro, studies revealed that these common drugs exhibited a high anti-proliferative effect on MCF-7 and MDA-MB-231 breast cancer cells, with effective IC50 values (15-40 μM) and lower free energy, kd, and ki (5281672 > 5280863 > 5330286) much affecting HEK-293 non-cancerous cells, indicating the safety profile. The experimental and computational correlation studies suggest that the highly expressed EGFR and ER receptors in breast cancer patients having poor survival rates can be effectively targeted with best-hit common potent drugs with a multi-target therapeutic approach. Insight Box: The findings of this study provide valuable insights into the genomic/proteomic data, breast cancer patient's survival analysis, and EGFR and ER receptor variants structural analysis. The genetic alterations analysis of EGFR and ER/ESR1 in breast cancer patients reveals the high frequency of mutation types, which affect patient's survival rate and targeted therapies. The common best-hit compounds affect the cell survival patterns with effective IC50, drug-like properties having lower equilibrium and dissociation constants demonstrating the anti-proliferative effects. This work integrates altered receptor structural analysis, molecular interaction-based simulations, and ADMET properties to illuminate the identified best hits phytochemicals potential efficacy targeting both EGFR and ER receptors, demonstrating a multi-target therapeutic approach.


Effectiveness of traveller screening for emerging pathogens is shaped by epidemiology and natural history of infection.
During outbreaks of high-consequence pathogens, airport screening programs have been deployed to curtail geographic spread of infection. The effectiveness of screening depends on several factors, including pathogen natural history and epidemiology, human behavior, and characteristics of the source epidemic. We developed a mathematical model to understand how these factors combine to influence screening outcomes. We analyzed screening programs for six emerging pathogens in the early and late stages of an epidemic. We show that the effectiveness of different screening tools depends strongly on pathogen natural history and epidemiological features, as well as human factors in implementation and compliance. For pathogens with longer incubation periods, exposure risk detection dominates in growing epidemics, while fever becomes a better target in stable or declining epidemics. For pathogens with short incubation, fever screening drives detection in any epidemic stage. However, even in the most optimistic scenario arrival screening will miss the majority of cases.


Neurobehavioral effects of cyclohexane in rat and human.
The neurobehavioral effects of inhaled cyclohexane in rats and humans are investigated to define relationships between internal doses and acute central nervous system effects. Rats are exposed for 3 consecutive days at target concentrations of 0, 1.4, 8, and 28 g/m(3), 8 h/d. Measurements include standardized observational measures, spontaneous motor activity assessments, and learned visual discrimination performance. Cyclohexane concentrations in blood and brain are measured to assess internal exposure. Human volunteers are exposed for 4 hours to 86 or 860 mg/m(3) in 2 test sessions. Neurobehavioral effects are measured using a computerized neurobehavioral test battery. In rats, there are slight reductions in psychomotor speed in the high-exposure group but minimal central nervous system effects. In humans, there are no significant treatment-related effects at the levels tested.


Does the sequential addition of accelerometer-based navigation and sensor-guided ligament balancing improve outcomes in TKA?
A significant percentage of patients remain dissatisfied after total knee arthroplasty (TKA). The aim of this study was to determine whether the sequential addition of accelerometer-based navigation for femoral component preparation and sensor-guided ligament balancing improved complication rates, radiological alignment, or patient-reported outcomes (PROMs) compared with a historical control group using conventional instrumentation. This retrospective cohort study included 371 TKAs performed by a single surgeon sequentially. A historical control group, with the use of intramedullary guides for distal femoral resection and surgeon-guided ligament balancing, was compared with a group using accelerometer-based navigation for distal femoral resection and surgeon-guided balancing (group 1), and one using navigated femoral resection and sensor-guided balancing (group 2). Primary outcome measures were Patient-Reported Outcomes Measurement Information System (PROMIS) and Knee injury and Osteoarthritis Outcome (KOOS) scores measured preoperatively and at six weeks and 12 months postoperatively. The position of the components and the mechanical axis of the limb were measured postoperatively. The postoperative range of motion (ROM), haematocrit change, and complications were also recorded. There were 194 patients in the control group, 103 in group 1, and 74 in group 2. There were no significant differences in baseline demographics between the groups. Patients in group 2 had significantly higher baseline mental health subscores than control and group 1 patients (53.2 vs 50.2 vs 50.2, p = 0.041). There were no significant differences in any PROMs at six weeks or 12 months postoperatively (p > 0.05). There was no difference in the rate of manipulation under anaesthesia (MUA), complication rates, postoperative ROM, or blood loss. There were fewer mechanical axis outliers in groups 1 and 2 (25.2%, 14.9% respectively) versus control (28.4%), but this was not statistically significant (p = 0.10). The sequential addition of navigation of the distal femoral cut and sensor-guided ligament balancing did not improve short-term PROMs, radiological outcomes, or complication rates compared with conventional techniques. The costs of these added technologies may not be justified. Cite this article: Bone Joint J 2020;102-B(6 Supple A):24-30.


Cuspal coverage with resin-bonded metal onlays.
The use of resin-bonded onlays as a means of cuspal coverage is described with reference to two clinical cases. One distinct feature of this technique is the minimal tooth preparation required compared with that needed for a conventional crown or onlay. Conservation of the already compromised tooth tissue is thus achieved.


Mindfulness training targets neurocognitive mechanisms of addiction at the attention-appraisal-emotion interface.
Prominent neuroscience models suggest that addictive behavior occurs when environmental stressors and drug-relevant cues activate a cycle of cognitive, affective, and psychophysiological mechanisms, including dysregulated interactions between bottom-up and top-down neural processes, that compel the user to seek out and use drugs. Mindfulness-based interventions (MBIs) target pathogenic mechanisms of the risk chain linking stress and addiction. This review describes how MBIs may target neurocognitive mechanisms of addiction at the attention-appraisal-emotion interface. Empirical evidence is presented suggesting that MBIs ameliorate addiction by enhancing cognitive regulation of a number of key processes, including: clarifying cognitive appraisal and modulating negative emotions to reduce perseverative cognition and emotional arousal; enhancing metacognitive awareness to regulate drug-use action schema and decrease addiction attentional bias; promoting extinction learning to uncouple drug-use triggers from conditioned appetitive responses; reducing cue-reactivity and increasing cognitive control over craving; attenuating physiological stress reactivity through parasympathetic activation; and increasing savoring to restore natural reward processing. Treatment and research implications of our neurocognitive framework are presented. We conclude by offering a temporally sequenced description of neurocognitive processes targeted by MBIs through a hypothetical case study. Our neurocognitive framework has implications for the optimization of addiction treatment with MBIs.


[Phonophoretic permeation of procaine hydrochloride through an MDCK cell monolayer].
With the aid of permanent cultured MDCK (Madin Darby Canine Kidney) epithelial cell a model for investigations dealing with phonophoresis effects was developed. The permeation of procaine hydrochloride through cell monolayers was examined while applying therapeutical ultrasound simultaneously. It could be shown that this permeation follows Higuchi kinetics. A comparison of the velocity factors, using a continuous irradiation of 1.0 W/cm2, shows about a 4.8 fold increase. Single Ultrasound pulses, however, result in a short-time enhancement of the permeation. The conclusion can be drawn that extent and velocity of the permeation of the permeation of procaine hydrochloride through MDCK monolayer can be controlled by phonophoresis.


Cell surface immunoglobulin. XVI. Polypeptide chain structure of mouse IgM and IgD-like molecule.
125I-membrane IgM, 125I-membrane IgD-like molecules, and their constituent chains from iodinated murine splenocytes were characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The apparent m.w. of the heavy chains decreased as the acrylamide concentration was raised. The membrane mu-chain had a slower mobility than did mu-chain from secreted IgM. Unreduced IgM and IgD-like molecules had mobilities consistent with an H2L2 structure. Intact IgD-like molecules were replaced after overnight dialysis by molecules with the properties of HL. Unreduced surface IgM had a slower mobility than that of monomeric IgM obtained by partial reduction of secreted IgM.


In vivo studies of nanostructure-based photosensitizers for photodynamic cancer therapy.
Animal models, particularly rodents, are major translational models for evaluating novel anticancer therapeutics. In this review, different types of nanostructure-based photosensitizers that have advanced into the in vivo evaluation stage for the photodynamic therapy (PDT) of cancer are described. This article focuses on the in vivo efficacies of the nanostructures as delivery agents and as energy transducers for photosensitizers in animal models. These materials are useful in overcoming solubility issues, lack of tumor specificity, and access to tumors deep in healthy tissue. At the end of this article, the opportunities made possible by these multiplexed nanostructure-based systems are summarized, as well as the considerable challenges associated with obtaining regulatory approval for such materials. The following questions are also addressed: (1) Is there a pressing demand for more nanoparticle materials? (2) What is the prognosis for regulatory approval of nanoparticles to be used in the clinic?


Carboplatin plus oral etoposide in elderly patients with advanced non small cell lung cancer. A phase II study.
More than 30% of lung cancers arise in patients over 70 years old. Elderly patients are not considered to tolerate chemotherapy, are generally excluded from clinical trials, and are not considered eligible for aggressive cisplatinbased chemotherapy in clinical practice. The aims of the present study were to test the activity and toxicity of a combination of carboplatin and oral etoposide in patients over 70 years old with advanced non small cell lung cancer. Carboplatin was given at a dose of 300 mg/m2, i.v., at day 1, and oral etoposide (50 mg capsules) at a total dose of 100 mg/die from day 1 to day 7, recycled every 4 weeks. Fourteen patients entered the study. Median age was 73 years (range 70-77), 42.9% of patients had at least one concomitant illness. The trial, according to the Gehan design, was terminated earlier because no objective response was observed among the first 14 patients. We reported, according to intent to treat analysis, 2 stable and 12 progressive diseases. Median time to progression was 2 months and median survival 6 months. Remarkable hematological toxicity was recorded. Finally, we do not recommend the combination of carboplatin and oral etoposide, at the doses and schedule used in the present study, in the treatment of elderly patients with advanced NSCLC. The combination might be reconsidered using a different etoposide schedule with chronic administration (21 days).


Polyamine synthesis from proline in the developing porcine placenta.
Polyamines (putrescine, spermidine, and spermine) are essential for placental growth and angiogenesis. However, little is known about polyamine synthesis in the porcine placenta during conceptus development. The present study was conducted to test the hypothesis that arginine and proline are the major sources of ornithine for placental polyamine production in pigs. Placentae, amniotic fluid, and allantoic fluid were obtained from gilts on Days 20, 30, 35, 40, 45, 50, 60, 90, and 110 of the 114-day gestation (n = 6 per day). Placentae as well as amniotic and allantoic fluids were analyzed for arginase, proline oxidase, ornithine aminotransferase (OAT), ornithine decarboxylase (ODC), proline transport, concentrations of amino acids and polyamines, and polyamine synthesis using established radiochemical and chromatographic methods. Neither arginase activity nor conversion of arginine into polyamines was detected in the porcine placenta. In contrast, both proline and ornithine were converted into putrescine, spermidine, and spermine in placental tissue throughout pregnancy. The activities of proline oxidase, OAT, and ODC as well as proline transport, polyamine synthesis from proline, and polyamine concentrations increased markedly between Days 20 and 40 of gestation, declined between Days 40 and 90 of gestation, and remained at the reduced level through Day 110 of gestation. Proline oxidase and OAT, but not arginase, were present in allantoic and amniotic fluids for the production of ornithine (the immediate substrate for polyamine synthesis). The activities of these two enzymes as well as the concentrations of ornithine and total polyamines in fetal fluids were highest at Day 40 but lowest at Days 20, 90, and 110 of gestation. These results indicate that proline is the major amino acid for polyamine synthesis in the porcine placenta and that the activity of this synthetic pathway is maximal during early pregnancy, when placental growth is most rapid. Our novel findings provide a new base of information for future studies to define the role of proline in fetoplacental growth and development.


Implementation and validation of time-of-flight PET image reconstruction module for listmode and sinogram projection data in the STIR library.
In this paper, we describe the implementation of support for time-of-flight (TOF) positron emission tomography (PET) for both listmode and sinogram data in the open source software for tomographic image reconstruction (STIR). We provide validation and performance characterization using simulated data from the open source GATE Monte Carlo toolbox, with TOF configurations spanning from 81.2 to 209.6 ps. The coincidence detector resolution was corrected for the timing resolution deterioration due to the contribution of the crystal length. Comparison between the reconstruction of listmode and sinogram data demonstrated good agreement in both TOF and non-TOF cases in terms of relative absolute error. To reduce the reconstruction time, we assessed the truncation of the TOF kernel along lines-of-response (LOR). Rejection of LOR elements beyond four times the TOF standard deviation provides significant acceleration of [Formula: see text] [Formula: see text] without compromising the image quality. Further narrowing of the kernel can provide extra time reduction but with the gradual introduction of error in the reconstructed images. As expected, TOF reconstruction performs better than non-TOF in terms of both contrast-recovery-coefficient (CRC) and signal-to-noise ratio (SNR). CRC achieves convergence faster with TOF, at lower noise levels. SNR with TOF was superior for early iterations, but with quick deterioration. Higher timing resolution further improved reconstruction performance, while TOF bin mashing was shown to have only a small impact on reconstructed images.


Diagnostic Performance of Serial High-Sensitivity Cardiac Troponin Measurements in the Emergency Setting.
Serial high-sensitivity cardiac troponin (hsTn) testing in the emergency department (ED) and the intensive cardiac care unit may assist physicians in ruling out or ruling in acute myocardial infarction (MI). There are three major algorithms proposed for high-sensitivity cardiac troponin I (hsTnI) using serial measurements while incorporating absolute concentration changes for MI or death following ED presentation. We sought to determine the diagnostic estimates of these three algorithms and if one was superior in two different Canadian ED patient cohorts with serial hsTnI measurements. An undifferentiated ED population (Cohort-1) and an ED population with symptoms suggestive of acute coronary syndrome (ACS; Cohort-2) were clinically managed with non-hsTn testing with the hsTnI testing performed in real-time with physicians blinded to these results (i.e., hsTnI not reported). The three algorithms evaluated were the European Society of Cardiology (ESC), the High-STEACS pathway, and the COMPASS-MI algorithm. The diagnostic estimates were derived for each algorithm for the 30-day MI/death outcome for the rule-out and rule-in arm in each cohort and compared to proposed diagnostic benchmarks (i.e., sensitivity ≥ 99.0% and specificity ≥ 90.0%) with 95% confidence intervals (CI). In Cohort-1 (n = 2966 patients, 15.3% had outcome) and Cohort-2 (n = 935 patients, 15.6% had outcome), the algorithm that obtained the highest sensitivity (97.8%; 95% CI: 96.0-98.9 and 98.6%; 95% CI: 95.1-99.8, respectively) in both cohorts was COMPASS-MI. Only Cohort-2 with both the ESC and COMPASS-MI algorithms exceeded the specificity benchmark (97.0%; 95% CI: 95.5-98.0 and 96.7%; 95% CI: 95.2-97.8, respectively). Patient selection for serial hsTnI testing will affect specificity estimates, with no algorithm achieving a sensitivity ≥ 99% for 30-day MI or death.


MYB oncogene amplification in hereditary BRCA1 breast cancer.
Comparative genomic hybridization analysis has demonstrated that breast tumors from BRCA1 and BRCA2 germ-line mutation carriers contain a large number of chromosomal copy number gains and losses. A high regional copy number gain at 6q22-q24 was observed in one BRCA1 tumor, and fluorescence in situ hybridization analysis indicated a strong amplification of the MYB oncogene (15 copies of MYB compared with 1 copy of chromosome 6 centromere). Fluorescence in situ hybridization analysis revealed amplification of MYB in 5 (29%) of 17 BRCA1 breast tumors, whereas none of 8 BRCA2 tumors and 13 breast cancer cell lines, and only 2 of 100 sporadic breast tumors exhibited altered MYB copy numbers. Gene amplification resulted in mRNA overexpression as determined by Northern blot and cDNA microarray analysis, and protein overexpression by immunohistochemical staining. We conclude that MYB amplification is infrequent in sporadic breast cancer but common in breast tumors from BRCA1 mutation carriers, suggesting a role of this cell cycle regulator and transcription factor in the progression of some BRCA1 tumors. However, we cannot rule out the significance of other genes in the 6q22-q24 amplicon.


Role of collagen in acute myocardial infarct expansion.
We sought to determine if damage to the myocardial collagen network was the cause of infarct expansion. Using polarized light microscopy, we examined sections from rat hearts obtained at 1, 2, 3, and 4 days after permanent coronary artery occlusion. Three features of the collagen network likely to be important in resisting infarct expansion were assessed: collagen quality, collagen quantity, and collagen organization. We observed a decrease in the number of normally birefringent collagen fibers in the infarct as early as 1 day after infarction. This decrease correlated significantly with time (r = -0.989, p less than 0.001). In addition, we found that the fewer normally birefringent collagen fibers present, the greater the degree of infarct expansion (assessed by measurement of total left ventricular cross-sectional area). At 4 days after infarction, we noted a loss of intermyocyte collagen struts and loss of interstitial space. These changes coincided with the onset of pronounced infarct expansion. The loss of collagen struts is consistent with the concept that expansion proceeds via slippage of myocytes previously tethered by the struts. The loss of interstitial space may represent the resolution of interstitial edema, which could further weaken the ventricular wall. The correlation of infarct expansion with collagen damage and the loss of support provided by collagen struts suggest that collagen is important in maintaining structural integrity after acute myocardial infarction.


Parasitoid-specific induction of plant responses to parasitized herbivores affects colonization by subsequent herbivores.
Plants are exposed to a suite of herbivorous attackers that often arrive sequentially. Herbivory affects interactions between the host plants and subsequently attacking herbivores. Moreover, plants may respond to herbivory by emitting volatile organic compounds (VOCs) that attract carnivorous natural enemies of the herbivores. However, information borne by VOCs is ubiquitous and may attract carnivores, such as parasitoids, that differ in their effectiveness at releasing the plant from its herbivorous attackers. Furthermore, the development of parasitoids within their herbivorous hosts, attacking a given host plant, may influence the elicitation of defensive reactions in the host plant. This may, in turn, affect the behavior of subsequent herbivores attacking the host plant. Here, we show that the species identity of a parasitoid had a more significant effect on defense responses of Brassica oleracea plants than the species identity of the herbivorous hosts of the parasitoids. Consequently, B. oleracea plants that were damaged by caterpillars (Pieris spp.) parasitized by different parasitoid species varied in the degree to which diamondback moths (Plutella xylostella) selected the plants for oviposition. Attracting parasitoids in general benefitted the plants by reducing diamondback moth colonization. However, the species of parasitoid that parasitized the herbivore significantly affected the magnitude of this benefit by its species-specific effect on herbivore-plant interactions mediated by caterpillar regurgitant. Our findings show that information-mediated indirect defense may lead to unpredictable consequences for plants when considering trait-mediated effects of parasitized caterpillars on the host plant and their consequences because of community-wide responses to induced plants.


Dynamics and asymmetry in the dimer of the norovirus major capsid protein.
Noroviruses are the major cause of non-bacterial acute gastroenteritis in humans and livestock worldwide, despite being physically among the simplest animal viruses. The icosahedral capsid encasing the norovirus RNA genome is made of 90 dimers of a single ca 60-kDa polypeptide chain, VP1, arranged with T = 3 icosahedral symmetry. Here we study the conformational dynamics of this main building block of the norovirus capsid. We use molecular modeling and all-atom molecular dynamics simulations of the VP1 dimer for two genogroups with 50% sequence identity. We focus on the two points of flexibility in VP1 known from the crystal structure of the genogroup I (GI, human) capsid and from subsequent cryo-electron microscopy work on the GII capsid (also human). First, with a homology model of the GIII (bovine) VP1 dimer subjected to simulated annealing then classical molecular dynamics simulations, we show that the N-terminal arm conformation seen in the GI crystal structure is also favored in GIII VP1 but depends on the protonation state of critical residues. Second, simulations of the GI dimer show that the VP1 spike domain will not keep the position found in the GII electron microscopy work. Our main finding is a consistent propensity of the VP1 dimer to assume prominently asymmetric conformations. In order to probe this result, we obtain new SAXS data on GI VP1 dimers. These data are not interpretable as a population of symmetric dimers, but readily modeled by a highly asymmetric dimer. We go on to discuss possible implications of spontaneously asymmetric conformations in the successive steps of norovirus capsid assembly. Our work brings new lights on the surprising conformational range encoded in the norovirus major capsid protein.


Ameliorating effect of Klotho on endoplasmic reticulum stress and renal fibrosis induced by unilateral ureteral obstruction.
Expression of Klotho is decreased and endoplasmic reticulum (ER) stress is activated in patients with chronic kidney disease. This study aimed to investigate the effect of Klotho protein on ER stress-related apoptosis and renal fibrosis in rates with unilateral ureteral obstruction (UUO). Twenty-four rats were divided into the sham, UUO, and Klotho treatment groups. Renal interstitial fibrosis model was induced by UUO in the rats of the latter two groups. Soluble Klotho protein was injected into the abdominal cavity. Serum and kidney samples were collected 14 days after the UUO surgery for examination of renal injury and renal interstitial fibrosis using hematoxylin-eosin and Masson trichrome staining methods. The level of apoptotic cells was assessed by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Expression of 3 ER stress-related proteins including glucose-regulated protein 78, CCAAT/enhancer-binding protein homologous protein, and caspase-12 were measured. Kidney dysfunction, increased renal injury index, and aggravated renal fibrosis were documented in the UUO group. Expression of Klotho in the UUO rats was remarkably decreased (P < .05) and expression of all three ER stress-related proteins were significantly upregulated, accompanied by increasing numbers of apoptotic cells (P < .05). Soluble Klotho administration improved kidney function, ameliorated pathological changes, decreased expressions of ER-stress related-proteins, and reduced the number of apoptotic cells. Unilateral ureteral obstruction decreased Klotho expression and activated ER stress and related apoptosis. Klotho administration ameliorated UUO-induced ER stress, inhibited apoptotic process, and attenuated renal fibrosis.


[Wood smoke condensate had weak proliferation and strong necrotic effects on human airway smooth muscle cells].
To investigate the effect of wood smoke condensate (WSC) on proliferation and necrosis of human airway smooth muscle cells (HASMCs). Primary cultured HASMCs between passage 2 and 8 were divided into 3 groups: a control group, a WSC group and a cigarette smoke condensate (CSC) group. The viability of cells was examined by the CCK8 assays. The ratio of cellular proliferative stage (S phase) and cell cycle index were examined by fluorescent-labeled thymidine analogue uptake assays and flow cytometry. The expression of cyclin D1 was detected by quantitative reverse transcriptase polymerase chain reaction (Q-PCR) and Western blot. Cell apoptosis and necrosis were observed by the annexin-V and PI staining. Statistical analysis was performed by using the One-way ANOVA and LSD-t test. Cell viability reached peak at WSC 1 mg/L[(126 ± 12)%] and at CSC 10 mg/L exposure level [(142 ± 11) %] respectively. While at WSC 10 mg/L and CSC 60 mg/L exposure levels, cell viability decreased significantly to 86% and 76%, respectively, as compared with that of the blank control group[(100 ± 0)%] (q = 3.63- 9.33, P < 0.05). In the WSC 1 mg/L group, the cell proliferation ratio and the expression of cyclin D1 protein were (124 ± 20)% and 1.31 ± 0.64, respectively, the differences being significant as compared with the blank control group [(100 ± 0)%, 1.0 ± 0.0] (q = 5.85, 5.91, P < 0.05), while the expression of cyclin D1 mRNA and the percentage of S+G2M phase were 1.18 ± 0.21 and (103 ± 4)%, respectively, not significantly different as compared to the control group [(100 ± 0)%, 1.0 ± 0.0], (q = 1.16, 2.05, P > 0.05). In the CSC 10 mg/L group, the above-mentioned values were (204 ± 45)%, 1.80 ± 0.25, (140 ± 6)%, 1.48 ± 0.2, respectively, which were significantly higher than those in the blank control group (q = 5.38-16.51, P < 0.05) and in the WSC group (q = 3.33-15.35, P < 0.05). However, when HASMCs were exposed to WSC 10 mg/L, the cell death ratio was (13.39 ± 0.15)%, higher than that of the blank control group [(1.57 ± 0.41)%] and the CSC group [(6.61 ± 1.91)%] (q = 18.03, 10.34, P < 0.05). Apoptosis ratio in the CSC 40 mg/L group was [(61.8 ± 10.6)%], higher than that of the blank control group [(0.0 ± 0.0)%] and the WSC group [(1.7 ± 0.4)%] (q = 17.44, 16.95, P < 0.05). Exposure to WSC caused a weak proliferation of HASMCs, but resulted in cell necrosis instead of apoptosis at high doses. There was a slight difference in cell effects between the WSC group and the CSC group.


The role of Bayesian Networks in the diagnosis of pulmonary embolism.
Pulmonary embolism (PE) is a life-threatening condition and, despite advances in diagnostic technology, it remains an elusive diagnosis. The rich variety of possible clinical presentations make it particularly difficult to represent the diagnostic process as a 'decision tree'. However, Bayesian networks offer the opportunity of a compact representation of the domain underlying the decision process: once the network portrays the natural history of the disease, the utility of investigations can be quantitatively evaluated. We developed a network for the diagnosis of PE, including 72 variables to represent both the risk factors and the pathophysiological consequences of the disease. Its structure has been specified by discussing which causal relationships explain the manifestations of the disease. The quantitative measures of associations were retrieved from the medical literature, through a critical review of available studies and agreement on the assumptions made to cope with the lack of published information. Six examples are presented to illustrate the appropriateness of 'entropy reduction' as a measure of the utility of investigation, once the set of examinations to be evaluated is bounded on the grounds of their cost and the patient's current risk. The network, which has been given the acronym 'BayPAD' (Bayesian network for Pulmonary embolism Assisted Diagnosis), appears to be able to detect which observations make others irrelevant, so that decisions can be tailored to single cases.


[Experiences with 'optical' biopsies of leukoplakia of the vocal folds].
It is often difficult to distinguish leucoplakia from carcinoma or chronic laryngitis. In this study, we examined if color texture optical biopsies are able to detect leukoplakia reliably and to distinguish this from normal vocal fold tissue. 25 images from patients with a normal larynx and 25 images from patients with leucoplakia were analysed retrospectively. The images were recorded with a rigid 90 degrees -laryngoscope (Wolf Typ 4450.571) during a clinical setting and were recorded by a S-VHS-videorecorder. With a software program (InSegT), regions with leucoplakia, normal tissue and suspicious tissue were manually marked. Within each marked region, the use of color texture analysis numeric features were calculated to characterize the surface in texture and color. Color histogramms (HST), Sum- and Difference histogramms (S/D), Statistical Geometric Features (SGF) and Grey-Value-Dependent-Matrix (GLDM) were used. 29 women and 21 men (age 18 to 81 years, average of 53 years), who were examined in our clinic from 10/1999 - 8/2003, took part in this study. The automatized classification for color texture analysis resulted in 71 % for leucoplakia and 97 % for normal tissue. Optical biopsies can contribute to find the correct diagnosis. However, classification results must still get better when optical biopsies should be used in clinical practice.


Clinical, quality of life, and economic value of acromegaly disease control.
Although acromegaly is a rare disease, the clinical, economic and health-related quality of life (HRQoL) burden is considerable due to the broad spectrum of comorbidities as well as the need for lifelong management. We performed a comprehensive literature review of the past 12 years (1998-2010) to determine the benefit of disease control (defined as a growth hormone [GH] concentration <2.5 μg/l and insulin-like growth factor [IGF]-1 normal for age) on clinical, HRQoL, and economic outcomes. Increased GH and IGF-1 levels and low frequency of somatostatin analogue use directly predicted increased mortality risk. Clinical outcome measures that may improve with disease control include joint articular cartilage thickness, vertebral fractures, left ventricular function, exercise capacity and endurance, lipid profile, and obstructive apnea events. Some evidence suggests an association between controlled disease and improved HRQoL. Total direct treatment costs were higher for patients with uncontrolled compared to controlled disease. Costs incurred for management of comorbidities, and indirect cost could further add to treatment costs. Optimizing disease control in patients with acromegaly appears to improve outcomes. Future studies need to evaluate clinical outcomes, as well as HRQoL and comprehensive economic outcomes achieved with controlled disease.


Measurement of bone mineral using multiple-energy x-ray absorptiometry.
Our laboratory has previously reported a method of determining the amount of bone mineral using triple-energy absorptiometry with a continuous x-ray spectrum. In the present study, the experimental properties of the technique were examined. The accuracy, the influence of fat content and body thickness and the in vitro and in vivo precision were analysed. The results found in this investigation showed that despite the complexity of the technique, the amount of bone mineral can be accurately determined. The in vivo precision was determined to be 3.4%, expressed as the coefficient of variation (CV), for different skeletal parts. The in vitro precision was found to be 2.1% (CV). Neither the fat content nor the body thickness had any effect on the measured bone mineral values. Excellent linearity and a close correlation were found between the true and the measured bone mineral values.


A new targeting agent for the selective drug delivery of nanocarriers for treating neuroblastoma.
Novel targeting agents against neuroblastoma based on the meta-iodobenzylguanidine (MIBG) moiety were synthesized and biologically evaluated for nanocarrier vectorization. These compounds have been anchored on the surface of drug loaded mesoporous silica nanocarriers, resulting in the improved cellular uptake in tumoral cells. Neuroblastoma (NB) is the most frequent extracranial pediatric tumor. Advanced forms of the disease (metastatic and/or refractory) have a dismal prognosis despite the combination of chemotherapy, radiotherapy, surgery and bone narrow transplants. These treatments carry severe side effects and, in some cases, compromise the life of the patient. MIBG has been widely applied in the medical diagnosis of NB due to its affinity for tumor cells through the norepinephrine transporter (NET), which is expressed in 90% of NB tumors. The exclusive accumulation of MIBG in neuroblastoma has been widely studied; however, its properties have been never exploited as a targeting agent in nanocarrier drug delivery systems. Several structural analogues of MIBG have been prepared and attached on the surface of nanocarriers. Their selective internalization has been tested against human neuroblastoma cells, which show, in the best case, cellular uptake four times higher than that of the naked nanosystem. Furthermore, in vivo experiments showed preferential and selective accumulation and retention of the targeted nanosystem comparing with the naked and only PEGylated counterpart systems. This novel nanosystem could be easily applicable to all kinds of drug delivery nanocarriers, providing a universal tool for neuroblastoma chemotherapies that is superior to classical approaches through a novel nanosystem exclusively designed to target this terrible malignancy.


The obesity paradox in multiple myeloma: A report from Multiple Myeloma Research Foundation (MMRF) dataset.
Obesity is a risk factor for multiple myeloma (MM). However, we still lack knowledge on the clinical course of obese MM patients in a broad view. Here, we reviewed 568 MM patients recorded in the Multiple Myeloma Research Foundation (MMRF) coMMpass dataset. Patients were divided into the normal and obese groups according body mass index (BMI) at diagnosis, and then the baseline characteristics, cytogenetic abnormalities, treatment variability, and survival outcomes were evaluated in the obese cohort. We found no differences in the characteristics when comparing normal and obese MM patients other than more male in the obese part (50.4% vs. 59.9%, p = 0.024). Compared with the normal BMI patients, median overall survival (OS) was shorter for obese MM patients but without significant meaning (82.3 vs. 95.3 months, p = 0.25). However, in the subgroup analysis, obese MM patients younger than 65 years had significantly inferior OS than that in the normal category (p = 0.047). We also found obese MM patients had a higher overall response rate (ORR) compared with normal BMI patients (92.7% vs. 88.6%, p = 0.037). Additionally, obese patients seemed to achieve faster best response during first-line therapy. Obesity assumes a paradoxical function in the clinical trajectory of myeloma.


IL-6 indirectly modulates the induction of glyceroneogenic enzymes in adipose tissue during exercise.
Glyceroneogenesis is an important step in the control of fatty acid re-esterification with PEPCK and PDK4 being identified as key enzymes in this process. We have previously shown that glyceroneogenic enzymes such as PDK4 are rapidly induced in white adipose tissue during exercise. Recent studies have suggested that IL-6 regulates adipose tissue metabolism and gene expression during exercise. Interestingly, IL-6 has been reported to directly decrease PEPCK expression. The purpose of this investigation was to determine the role of IL-6 in modulating the effects of exercise on the expression of glyceroneogenic enzymes in mouse adipose tissue. We hypothesized that the exercise-mediated induction of PDK4 and PEPCK would be greater in adipose tissue from IL-6 deficient mice compared to wild type controls. Treatment of cultured epididymal adipose tissue (eWAT) with IL-6 (150 ng/ml) increased the phosphorylation of AMPK, ACC and STAT3 and induced SOCS3 mRNA levels while decreasing PEPCK and PDK4 mRNA. AICAR decreased the expression of PDK4 and PEPCK. The activation of AMPK by IL-6 was independent of increases in lipolysis. An acute bout of treadmill running (15 meters/minute, 5% incline, 90 minutes) did not induce SOCS3 or increase phosphorylation of STAT3 in eWAT, indicating that IL-6 signalling was not activated. Exercise-induced increases in PEPCK and PDK4 mRNA expression were attenuated in eWAT from IL-6(-/-) mice in parallel with a greater relative increase in AMPK phosphorylation compared to exercised WT mice. These changes occurred independent of alterations in beta-adrenergic signalling in adipose tissue from IL-6(-/-) mice. Our findings question the role of IL-6 signalling in adipose tissue during exercise and suggest an indirect effect of this cytokine in the regulation of adipose tissue gene expression during exercise.


Identification of WNT16 as a Predictable Biomarker for Accelerated Osteogenic Differentiation of Tonsil-Derived Mesenchymal Stem Cells In Vitro.
The application of mesenchymal stem cells (MSCs) for treating bone-related diseases shows promising outcomes in preclinical studies. However, cells that are isolated and defined as MSCs comprise a heterogeneous population of progenitors. This heterogeneity can produce variations in the performance of MSCs, especially in applications that require differentiation potential in vivo, such as the treatment of osteoporosis. Here, we aimed to identify genetic markers in tonsil-derived MSCs (T-MSCs) that can predict osteogenic potential. Using a single-cell cloning method, we isolated and established several lines of nondifferentiating (ND) or osteoblast-prone (OP) clones. Next, we performed transcriptome sequencing of three ND and three OP clones that maintained the characteristics of MSCs and determined the top six genes that were upregulated in OP clones. Upregulation of WNT16 and DCLK1 expression was confirmed by real-time quantitative PCR, but only WNT16 expression was correlated with the osteogenic differentiation of T-MSCs from 10 different donors. Collectively, our findings suggest that WNT16 is a putative genetic marker that predicts the osteogenic potential of T-MSCs. Thus, examination of WNT16 expression as a selection criterion prior to the clinical application of MSCs may enhance the therapeutic efficacy of stem cell therapy for bone-related complications, including osteoporosis.


Cyclic hardening in bundled actin networks.
Nonlinear deformations can irreversibly alter the mechanical properties of materials. Most soft materials, such as rubber and living tissues, display pronounced softening when cyclically deformed. Here we show that, in contrast, reconstituted networks of crosslinked, bundled actin filaments harden when subject to cyclical shear. As a consequence, they exhibit a mechano-memory where a significant stress barrier is generated at the maximum of the cyclic shear strain. This unique response is crucially determined by the network architecture: at lower crosslinker concentrations networks do not harden, but soften showing the classic Mullins effect known from rubber-like materials. By simultaneously performing macrorheology and confocal microscopy, we show that cyclic shearing results in structural reorganization of the network constituents such that the maximum applied strain is encoded into the network architecture.


Retinal Angiomatous Proliferation in a Patient with Retinitis Pigmentosa.
Retinal angiomatous proliferation (RAP) and other types of choroidal neovascularization (CNV) are very rarely reported in patients with retinitis pigmentosa (RP). We present a case report of a 91-year-old patient with an obvious RP phenotype, who presented with a sudden onset of vision worsening and metamorphopsia in the left eye. Genetic testing on the UK inherited retinal disease panel did not identify a pathogenic variant. Multimodal imaging comprising optical coherence tomography (OCT), OCT angiography, and fluorescein and indocyanine green angiography showed a RAP lesion in the left macula. The patient received three treatments of monthly injections of aflibercept, with excellent morphological and functional outcomes. Taking into account the patient's age at presentation of the RAP lesion, it is not clear whether the RAP was associated or coincidental with RP. This case report highlights the importance of possessing an awareness that RAP lesions can occur in RP. Moreover, due to a good response and potential safety concerns with continuous anti-VEGF injections in RP patients, a pro re nata (PRN) regimen might be the safest option.


Slow Water Dynamics near a Glass Transition or a Solid Interface: A Common Rationale.
Performing molecular dynamics simulations, we investigate the enormous slowdowns of water dynamics when approaching a glass transition or a solid interface. We show that both effects can be described on common grounds within a theoretical framework, which was recently proposed by Schweizer et al. and considers coupled local hopping and elastic distortion. For confined water, we correctly describe the variation of the α-relaxation time, τα, as a function of both temperature and position with respect to the interface. Exploiting our knowledge of a cooperative length scale ξ(T) from the confinement studies, we quantitatively rationalize the glassy slowdown, τα(T), and the Stokes-Einstein breakdown of bulk water. For both confined and bulk liquid, variations of the α-relaxation time are intimately related to changes of the cage-rattling amplitude.


Acromegaly caused by ectopic growth hormone-releasing hormone production from a bronchial carcinoid tumor.
Acromegaly is usually caused by a growth hormone (GH)-secreting pituitary adenoma. In rare cases, however, it is caused by the ectopic production of growth hormone-releasing hormone (GHRH). We report a case of acromegaly due to ectopic production of GHRH from a bronchial carcinoid in a 42-year-old female. The carcinoid tumor was successfully treated with bilobectomy.


Visual deficits related to dopamine deficiency in experimental animals and Parkinson's disease patients.
In patients affected by Parkinson's disease, and in the monkey model of this disease, visual defects have been shown using psychophysical and electrophysiological measures of spatial and temporal contrast sensitivity. These studies imply an essential role for dopamine in primate vision. There is electrophysiological and neurochemical evidence to suggest that at least part of the problem is impaired retinal processing caused by systemic dopaminergic deficiency. Some of the deficits that have been demonstrated, consistent with physiological studies, suggest that center-surround interaction of neurons may suffer as a consequence of dopaminergic deficiency. The role of the regulation of retinal dopamine (D1 and D2) receptors in primate vision and of the balance of these receptors in presynaptic dopaminergic deficiency is not yet determined. Using sinusoidal grating stimuli in cognitively loaded tasks may increase understanding of the behavioral consequences of visual deficits seen in dopamine deficiency syndromes.


The Ste20-like kinase - a Jack of all trades?
Over the past 20 years, the Ste20-like kinase (SLK; also known as STK2) has emerged as a central regulator of cytoskeletal dynamics. Reorganization of the cytoskeleton is necessary for a plethora of biological processes including apoptosis, proliferation, migration, tissue repair and signaling. Several studies have also uncovered a role for SLK in disease progression and cancer. Here, we review the recent findings in the SLK field and summarize the various roles of SLK in different animal models and discuss the biochemical mechanisms regulating SLK activity. Together, these studies have revealed multiple roles for SLK in coupling cytoskeletal dynamics to cell growth, in muscle repair and in negative-feedback loops critical for cancer progression. Furthermore, the ability of SLK to regulate some systems appears to be kinase activity independent, suggesting that it may be an important scaffold for signal transduction pathways. These various findings reveal highly complex functions and regulation patterns of SLK in development and disease, making it a potential therapeutic target.


Trace and contextual fear conditioning require neural activity and NMDA receptor-dependent transmission in the medial prefrontal cortex.
The contribution of the medial prefrontal cortex (mPFC) to the formation of memory is a subject of considerable recent interest. Notably, the mechanisms supporting memory acquisition in this structure are poorly understood. The mPFC has been implicated in the acquisition of trace fear conditioning, a task that requires the association of a conditional stimulus (CS) and an aversive unconditional stimulus (UCS) across a temporal gap. In both rat and human subjects, frontal regions show increased activity during the trace interval separating the CS and UCS. We investigated the contribution of prefrontal neural activity in the rat to the acquisition of trace fear conditioning using microinfusions of the gamma-aminobutyric acid type A (GABA(A)) receptor agonist muscimol. We also investigated the role of prefrontal N-methyl-d-aspartate (NMDA) receptor-mediated signaling in trace fear conditioning using the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV). Temporary inactivation of prefrontal activity with muscimol or blockade of NMDA receptor-dependent transmission in mPFC impaired the acquisition of trace, but not delay, conditional fear responses. Simultaneously acquired contextual fear responses were also impaired in drug-treated rats exposed to trace or delay, but not unpaired, training protocols. Our results support the idea that synaptic plasticity within the mPFC is critical for the long-term storage of memory in trace fear conditioning.


Effect of overexpression of progesterone receptor A on endogenous progestin-sensitive endpoints in breast cancer cells.
The human progesterone receptor (PR) is expressed as two isoforms, PRA and PRB, which differ in the N-terminal region and exhibit different activities in vitro, with PRA demonstrating dominant negative inhibitory effects on the activity of PRB and other nuclear receptors. PRA and PRB are expressed in target tissues at comparable levels although cells expressing a predominance of one isoform can be identified. In breast cancers, PRA is expressed at high levels in some tumors, and this may be associated with features of poorer prognosis. To investigate the role of PRA overexpression in PR-positive target cells, the effect of PRA induction on cell proliferation and expression of endogenous progestin-sensitive genes, SOX4 and fatty acid synthetase (FAS), was examined using PR-positive T-47D cell lines, which express a predominance of PRB, in which PRA could be increased 2- to 20-fold over basal levels. No effect of PRA induction was noted on cell proliferation, but marked changes in morphology, consistent with loss of adherent properties, were observed. Increases up to 4-fold in the relative PRA levels augmented progestin induction of SOX4 mRNA expression, and RU486 treatment revealed a progestin agonist effect. There was no consistent effect of PRA induction on progestin-mediated increases in FAS mRNA levels under these conditions. Clones with PRA:PRB ratios greater than 15 were associated with diminished progestin responses on both SOX4 and FAS mRNA expression. These data show that PRA overexpression is associated with alteration in adhesive properties in breast cancer cells and effects on endogenous progestin targets that were dependent on the cellular ratio of PRA:PRB. The results of this study are consistent with the view that PRA expression can fluctuate within a broad range in target cells without influencing the nature of progestin action on downstream targets, but that overexpression of PRA, such as is seen in a proportion of breast cancers, may be associated with inhibition of progestin action and features of poor prognosis.


Case Report: 'Z' osteotomy - a novel technique of treatment in Blount's disease.
Blount's disease is a progressive form of genu varum due to asymmetrical inhibition of the postero medial portion of the proximal tibial epiphysis. The surgical treatments involved in correction of Blount's disease are often technically demanding, complicated procedures. These procedures can lead to prolonged recovery times and poor patient compliance. In such a context we are suggesting "fibulectomy with Z osteotomy" of the proximal tibia, a relatively simple and highly effective technique. This technique is based on correcting the mechanical axis of the lower limb thereby restoring growth from the medial physis of proximal tibia. We have used a new surgical technique, which includes fibulectomy followed by a Z-shaped osteotomy. We have used this simple technique in a 5 year-old boy with unilateral Blount's disease. The femoro-tibial angle was corrected from 18.2° of varus to 4.2° of valgus. The angular correction obtained after operation was 22°. There were no postoperative complications. This technique has the advantages of correcting both angular and rotational deformities simultaneously. The purpose of this case study is to introduce a new surgical technique in the treatment of Blount's disease.


Non-Invasive detection of respiratory effort-related arousals (REras) by a nasal cannula/pressure transducer system.
The published AASM guidelines approve use of a nasal cannula/pressure transducer to detect apneas/hypopneas, but require esophageal manometry for Respiratory Effort-Related Arousals (RERAs). However, esophageal manometry may be poorly tolerated by many subjects. We have shown that the shape of the inspiratory flow signal from a nasal cannula identifies flow limitation and elevated upper-airway resistance. This study tests the hypothesis that detection of flow limitation events using the nasal cannula provides a non-invasive means to identify RERAs. N/A. N/A. 10 UARS/OSAS and 5 normal subjects N/A. All subjects underwent full NPSG. Two scorers identified events from the nasal cannula signal as apneas, hypopneas, and flow limitation events. Two additional scorers identified events from esophageal manometry. Arousals were scored in a separate pass. Interscorer reliability and intersignal agreement were assessed both without and with regard to arousal. The total number of respiratory events identified by the two scorers of the nasal cannula was similar with an Intraclass Correlation (ICC) =0.96, and was essentially identical to the agreement for the two scorers of esophageal manometry (ICC=0.96). There was good agreement between the number of events detected by the two techniques with a slight bias towards the nasal cannula (4.5 events/hr). There was no statistically significant difference (bias 0.9/hr, 95%CI -0.3-2.0) between the number of nasal cannula flow limitation events terminated by arousal and manometry events terminated by arousal (RERAs). The nasal cannula/pressure transducer provides a non-invasive reproducible detector of all events in sleep disordered breathing; in particular, it detects the same events as esophageal manometry (RERAs).


Local elastic constants in thin films of an fcc crystal.
In this work we present a formalism for the calculation of the local elastic constants in inhomogeneous systems based on a method of planes. Unlike previous work, this formalism does not require the partitioning of the system into a set of finite volumes over which average elastic constants are calculated. Results for the calculation of the local elastic constants of a nearest-neighbor Lennard-Jones fcc crystal in the bulk and in a thin film are presented. The local constants are calculated at exact planes of the (001) face of the crystal. The average elastic constants of the bulk system are also computed and are consistent with the local constants. Additionally we present the local stress profiles in the thin film when a small uniaxial strain is applied. The resulting stress profile compares favorably with the stress profile predicted via the local elastic constants. The surface melting of a model for argon for which experimental and simulation data are available is also studied within the framework of this formalism.