Prenatal exposure to titanium dioxide nanoparticles increases dopamine levels in the prefrontal cortex and neostriatum of mice.
Titanium dioxide (TiO(2)) nanoparticles are widely used in cosmetics, sunscreen and as a photocatalyst. However, little is known about the biological effect of TiO(2) nanoparticles in humans and other animals. Here, we investigated whether prenatal exposure to TiO(2) nanoparticles impacted the central nervous system in mice. We measured the levels of dopamine (DA) and its metabolites in several regions of the brain in mice using high performance liquid chromatography (HPLC). HPLC analysis showed that DA and its metabolites were increased in the prefrontal cortex and the neostriatum following prenatal exposure to TiO(2) nanoparticles. The present study highlights the possibility that maternal exposure to TiO(2) nanoparticles might influence the development of the central dopaminergic system in offspring.


Auras and experiential responses arising in the temporal lobe.
Complex partial seizures and the auras that precede them are often manifestations of localized temporal lobe activity. Auras, unlike complex partial seizures, are reportable, since memory for them is retained. Similar experiences can be elicited by local electrical stimulation of mesial or lateral temporal cortex. Auras and "experiential phenomena" arising in the temporal lobe reflect dissociation of human experience into perceptual, mnemonic, and affective components, which in some cases can be specifically localized. Auras often persist following medial temporal lobe surgery, even when patients are rendered seizure-free. This suggests that these auras, like formed memories, are widely distributed and may eventually become consolidated in the neocortex.


Psychoactive substances in seriously injured drivers in Denmark.
This study assesses the presence of a number of psychoactive substances, including alcohol, based on blood samples from 840 seriously injured drivers admitted to five selected hospitals located in five different regions of Denmark. The study was a part of the EU 6th framework program DRUID (Driving Under the Influence of Drugs, Alcohol and Medicines). Blood samples were screened for 30 illegal and legal psychoactive substances and metabolites as well as ethanol. Danish legal limits were used to evaluate the frequency of drivers violating the Danish legislation while limit of quantification (LOQ) was used for monitoring positive drivers. Tramadol is not included in the Danish legislation therefore the general cut off, as decided in the DRUID project was used. Overall, ethanol (18%) was the most frequently identified compound (alone or in combination with other drugs) exceeding the legal limit, which is 0.53g/l in Denmark. The percentage of seriously injured drivers testing positive for medicinal drugs at levels above the Danish legal limit was 6.8%. Benzodiazepines and Z-drugs (6.4%) comprised the majority of this group. One or more illegal drugs (primarily amphetamines and cannabis) were found to be above the Danish legal limit in 4.9% of injured drivers. Young men (median age 31 years) were over-represented among injured drivers who violated Danish law for alcohol and drugs. Diazepam (4.4%), tramadol (3.2%), and clonazepam (3.0%) were the medicinal drugs most frequently detected at levels above LOQ, whereas amphetamines (5.4%) (amphetamine [5.2%] and methamphetamine [1.5%]), tetrahydrocannabinol (3.7%), and cocaine (3.3%), including the metabolite benzoylecgonine, were the most frequently detected illegal drugs. A driver could be positive for more than one substance; therefore, percentages are not mutually exclusive. Poly-drug use was observed in 112 (13%) seriously injured drivers. Tramadol was detected above DRUID cutoffs in 2.1% of seriously injured drivers. This is 3.5 times that observed in a Danish survey of randomly selected drivers. Moreover, illegal and medicinal drug levels above the Danish legal limit were present more than 10 times as frequently as in injured drivers, whereas ethanol was present more than 30 times as frequently than in randomly selected drivers. The results indicate that there is an increased risk in traffic when driving under the influence of psychoactive drugs, especially alcohol in young male drivers.


Vasodilator-stimulated phosphoprotein (VASP) is phosphorylated on Ser157 by protein kinase C-dependent and -independent mechanisms in thrombin-stimulated human platelets.
VASP (vasodilator-stimulated phosphoprotein) is an actin- and profilin-binding protein that is expressed in platelets at high levels and plays a major role in negatively regulating secretory and adhesive events in these cells. VASP is a major substrate for cAMP- and cGMP-regulated protein kinases and it has been shown to be directly phosphorylated on Ser157 by PKC (protein kinase C). In the present paper, we show that, in human platelets, VASP is phosphorylated by PKC on Ser157, but not Ser239, in response to phorbol ester stimulation, in a manner blocked by the PKC inhibitor BIM I (bisindolylmaleimide I). In response to thrombin, VASP was also phosphorylated on Ser157, but this response was only partially inhibited by BIM I, indicating PKC-dependent and -independent pathways to VASP phosphorylation by thrombin. Using inhibitors, we have ruled out the possibility that the PKC-independent pathway acts through guanylate cyclase generation of cGMP, or through a phosphoinositide 3-kinase-dependent kinase. Inhibition of Rho kinase, however, substantially reduced Ser157 VASP phosphorylation, and its effects were additive with BIM I. This implicates Rho kinase and PKC as the major kinases that phosphorylate VASP Ser157 in response to thrombin in platelets.


Ontogeny of hepatocyte growth factor (HGF) and its receptor (c-met) in human placenta: reduced HGF expression in intrauterine growth restriction.
Severe intrauterine growth restriction (IUGR) is characterized by abnormal placentation. Mouse gene knockout studies show that an absence of either hepatocyte growth factor (HGF) or its receptor, c-met, leads to intrauterine death secondary to severe IUGR with deficient placentation. In this study, immunocytochemistry localized HGF protein throughout placental villi across gestation, whereas c-met protein was localized only to the perivillous trophoblast and vascular endothelium. Within the IUGR placentae, a reduction in HGF immunostaining within the villous stroma was observed. HGF mRNA was strongly expressed in the perivascular tissue around the stem villous arteries throughout gestation, with weaker expression within the villous stroma and the terminal villi. c-met mRNA expression was limited to the perivillous trophoblast, particularly in the first trimester, with only a faint hybridization signal from the villous stroma. Placental mRNA expression was examined quantitatively using a ribonuclease protection assay: HGF and c-met mRNA expression increased from the first to the second trimester, reaching a zenith before decreasing again through the third trimester to term. HGF mRNA levels were significantly reduced in the IUGR placentae (P = 0.036), whereas c-met mRNA expression was within the normal range for gestation. These findings suggest that HGF derived from the perivascular tissue of stem villous arteries may play an important role in controlling normal villous development. Whereas reduced expression of HGF within IUGR placentae does not prove a causative link with abnormal villous development, the association lends support to this possibility.


Predicting adult occupational environments from gender and childhood personality traits.
To test aspects of a theory of the role of personality and gender on the development of vocational interests and their subsequent effects on adult occupational choices, the authors of this study examined associations among childhood personality traits, gender, and occupational environments more than 40 years later. Participants (N = 587) were assessed on the Big Five by their teachers when the participants were between 6 and 12 years old. In middle-age (late 40s), the participants reported their occupation. Holland's (1997) RIASEC vocational types (Realistic, Investigative, Artistic, Social, Enterprising, Conventional) were used to characterize the job environments of reported occupations. Childhood Openness/Intellect and Conscientiousness, but no other Big Five traits, were associated with occupational environments. For the most strongly sex-typed work environments, associations with Openness/Intellect were moderated by gender. These findings suggest that the roots of the strongest gender-stereotyping effects in occupations may be found not only in the social factors associated with gender but also in the individual differences of children related to Openness/Intellect.


Experience of Psychotropic Medication -An Interview Study of Persons with Psychosis.
Psychotropic drugs, particularly antipsychotic types, are a cornerstone of the treatment of people with psychosis. Despite numerous studies showing that drug treatment with psychotropic drugs initially alleviates psychiatric symptoms, the proportion of people with mental health problems and symptoms that do not follow doctors' prescriptions, thus exhibiting so-called non-adherence, is considerable. Non-adherence is predominantly seen as a clinical feature and as a patient characteristic that is especially due to patients' poor understanding that they are ill. There is also a widespread notion that non-adherence is of great disadvantage to the patient. This article is based on interviews with 19 persons diagnosed with psychosis. It challenges the notion of patients being either adherent or non-adherent to the doctor's orders. The findings show that persons with psychosis are active agents when it comes to adjusting medication. The interviewees created their own strategies to gain power over treatment with psychotropic drugs. The most common strategies were to adjust the doses or take breaks of varying lengths from the medication. These deviations from prescriptions were important to conceal, not only from their own psychiatrists, but from all psychiatric staff.


Effect of prior exercise on the partitioning of an intestinal glucose load between splanchnic bed and skeletal muscle.
Exercise leads to marked increases in muscle insulin sensitivity and glucose effectiveness. Oral glucose tolerance immediately after exercise is generally not improved. The hypothesis tested by these experiments is that after exercise the increased muscle glucose uptake during an intestinal glucose load is counterbalanced by an increase in the efficiency with which glucose enters the circulation and that this occurs due to an increase in intestinal glucose absorption or decrease in hepatic glucose disposal. For this purpose, sampling (artery and portal, hepatic, and femoral veins) and infusion (vena cava, duodenum) catheters and Doppler flow probes (portal vein, hepatic artery, external iliac artery) were implanted 17 d before study. Overnightfasted dogs were studied after 150 min of moderate treadmill exercise or an equal duration rest period. Glucose ([14C]glucose labeled) was infused in the duodenum at 8 mg/kg x min for 150 min beginning 30 min after exercise or rest periods. Values, depending on the specific variable, are the mean +/- SE for six to eight dogs. Measurements are from the last 60 min of the intraduodenal glucose infusion. In response to intraduodenal glucose, arterial plasma glucose rose more in exercised (103 +/- 4 to 154 +/- 6 mg/dl) compared with rested (104 +/- 2 to 139 +/- 3 mg/dl) dogs. The greater increase in glucose occurred even though net limb glucose uptake was elevated after exercise (35 +/- 5 vs. 20 +/- 2 mg/min) as net splanchnic glucose output (5.1 +/- 0.8 vs. 2.1 +/- 0.6 mg/kg x min) and systemic appearance of intraduodenal glucose (8.1 +/- 0.6 vs. 6.3 +/- 0.7 mg/kg x min) were also increased due to a higher net gut glucose output (6.1 +/- 0.7 vs. 3.6 +/- 0.9 mg/kg x min). Adaptations at the muscle led to increased net glycogen deposition after exercise [1.4 +/- 0.3 vs. 0.5 +/- 0.1 mg/(gram of tissue x 150 min)], while no such increase in glycogen storage was seen in liver [3.9 +/- 1.0 vs. 4.1 +/- 1.1 mg/(gram of tissue x 150 min) in exercised and sedentary animals, respectively]. These experiments show that the increase in the ability of previously working muscle to store glycogen is not solely a result of changes at the muscle itself, but is also a result of changes in the splanchnic bed that increase the efficiency with which oral glucose is made available in the systemic circulation.


Catalytic hydroacetylenation of carbodiimides with homoleptic alkaline earth hexamethyldisilazides.
The homoleptic alkaline earth hexamethyldisilazides, [M{N(SiMe3)2}2(THF)2] (M = Mg 1a; Ca 1b; Sr 1c), have been shown to act as efficient precatalysts for the hydroacetylenation of organic carbodiimides with alkyl- and arylacetylenes. Catalytic activity was observed to increase with the size of the group 2 metal centre employed and to be strongly influenced by the steric properties of the carbodiimide substrate. The intermediate dimeric calcium and strontium bis(amidinate) complexes, [{PhC≡CC(N(i)Pr)2}2M]2 (M = Ca 2b, Sr 2c), have been isolated and crystallographically characterised. Kinetic studies using the strontium precursor, 1c, provided a reaction rate law independent of [acetylene] but proportional to [carbodiimide](2) and inversely proportional to the concentration of the amidine product in solution.


Myofascial Trigger Points Then and Now: A Historical and Scientific Perspective.
The intent of this article is to discuss the evolving role of the myofascial trigger point (MTrP) in myofascial pain syndrome (MPS) from both a historical and scientific perspective. MTrPs are hard, discrete, palpable nodules in a taut band of skeletal muscle that may be spontaneously painful (i.e., active) or painful only on compression (i.e., latent). MPS is a term used to describe a pain condition that can be acute or, more commonly, chronic and involves the muscle and its surrounding connective tissue (e.g. fascia). According to Travell and Simons, MTrPs are central to the syndrome-but are they necessary? Although the clinical study of muscle pain and MTrPs has proliferated over the past two centuries, the scientific literature often seems disjointed and confusing. Unfortunately, much of the terminology, theories, concepts, and diagnostic criteria are inconsistent, incomplete, or controversial. To address these deficiencies, investigators have recently applied clinical, imaging (of skeletal muscle and brain), and biochemical analyses to systematically and objectively study the MTrP and its role in MPS. Data suggest that the soft tissue milieu around the MTrP, neurogenic inflammation, sensitization, and limbic system dysfunction may all play a role in the initiation, amplification, and perpetuation of MPS. The authors chronicle the advances that have led to the current understanding of MTrP pathophysiology and its relationship to MPS, and review the contributions of clinicians and researchers who have influenced and expanded our contemporary level of clinical knowledge and practice.


Cyclosporine-loaded microspheres for treatment of uveitis: in vitro characterization and in vivo pharmacokinetic study.
A sustained intraocular level of immunosuppressive drug is desirable for the treatment of uveitis and other intraocular immune disorders. The objective of the present investigation was to assess the suitability of cyclosporine-loaded poly(lactic-co-glycolic acid) microspheres (CyS-PLGA-MS) to achieve this goal. A solvent-evaporation method was used in the preparation of CyS-PLGA-MS. These microspheres were characterized for drug loading, entrapment efficiency, and in vitro release by high-performance liquid chromatography, particle size by phase-contrast light microscopy and surface morphology by scanning electron microscopy. The 3H-CyS-PLGA-MS suspension was injected into the vitreous body of healthy rabbits, and the concentration of cyclosporine in various ocular tissues and blood at predetermined intervals was measured by a scintillation counting technique and the pharmacokinetic parameters were calculated. Intravitreous administration of 3H-CyS solution was conducted as the control. The CyS-PLGA-MS was produced, with drug-loading ranging from 11% to 16% and a high entrapment efficiency from 86% to 98%. Microspheres were discrete, spherical particles with a diameter of approximately 50 microm. The CyS was constantly and slowly released from microspheres in the in vitro release experiment. Compared with CyS solution, microspheres prolonged the release of CyS and maintained therapeutic CyS concentrations for at least 65 days in disease-related tissues such as the choroid-retina and iris-ciliary body. The percentage of CyS released in vitro correlated well with the CyS distribution rate in vivo. CyS-PLGA-MS, displaying sustained intraocular release of CyS and showing advantages over CyS solution, may meet clinical needs more efficiently.


Quasi-two-dimensional dynamics of plasmas and fluids.
In the lowest order of approximation quasi-two-dimensional dynamics of planetary atmospheres and of plasmas in a magnetic field can be described by a common convective vortex equation, the Charney and Hasegawa-Mima (CHM) equation. In contrast to the two-dimensional Navier-Stokes equation, the CHM equation admits "shielded vortex solutions" in a homogeneous limit and linear waves ("Rossby waves" in the planetary atmosphere and "drift waves" in plasmas) in the presence of inhomogeneity. Because of these properties, the nonlinear dynamics described by the CHM equation provide rich solutions which involve turbulent, coherent and wave behaviors. Bringing in nonideal effects such as resistivity makes the plasma equation significantly different from the atmospheric equation with such new effects as instability of the drift wave driven by the resistivity and density gradient. The model equation deviates from the CHM equation and becomes coupled with Maxwell equations. This article reviews the linear and nonlinear dynamics of the quasi-two-dimensional aspect of plasmas and planetary atmosphere starting from the introduction of the ideal model equation (CHM equation) and extending into the most recent progress in plasma turbulence.


A review of the predictive ability of Glasgow Coma Scale scores in head-injured patients.
According to 1999 data from the Centers for Disease Control and Prevention, traumatic brain injuries (TBI) caused by motor vehicle accidents, firearms, and falls are recorded as a leading cause of death and lifelong disability for young adults in the United States. Researchers have investigated if correlations exist between variables in the acute stage of injury and outcome measures in TBI patients. The Glasgow Coma Scale (GCS) score is one variable that was extensively studied for its ability to predict outcome in TBI patients. However, the use of different designs and methodologies in these studies makes the interpretation of the cumulative findings difficult. Therefore the purpose of this review was to provide a summary of the research findings on the ability of the GCS scores to predict outcome in TBI patients. A search was done on MEDLINE and CINAHL to identify studies that investigated the predictive ability of the GCS score. Studies that used the GCS as a variable in predicting outcome with adult patients who had sustained some type of head injury were included. GCS scores are most accurate at predicting outcome in head-injured patients when they are combined with patient age and pupillary response and when broad outcome categories are used. The motor component of the GCS yields similar prediction rates as the summed GCS score, and better prediction occurs with very high or very low GCS scores. Information about the cumulative research findings on the predictive ability of GCS scores aids nurses in providing support and education to family members during the acute stage of injury, and in coordinating the services of members of the healthcare team, which could result in improved outcomes for both patient and family.


Comparative effectiveness of malaria prevention measures: a systematic review and network meta-analysis.
Malaria causes significant morbidity and mortality worldwide. There are several preventive measures that are currently employed, including insecticide-treated nets (ITNs, including long-lasting insecticidal nets and insecticidal-treated bed nets), indoor residual spraying (IRS), prophylactic drugs (PD), and untreated nets (UN). However, it is unclear which measure is the most effective for malaria prevention. We therefore undertook a network meta-analysis to compare the efficacy of different preventive measures on incidence of malaria infection. A systematic literature review was undertaken across four medical and life sciences databases (PubMed, Cochrane Central, Embase, and Web of Science) from their inception to July 2016 to compare the effectiveness of different preventive measures on malaria incidence. Data from the included studies were analysed for the effectiveness of several measures against no intervention (NI). This was carried out using an automated generalized pairwise modeling (GPM) framework for network meta-analysis to generate mixed treatment effects against a common comparator of no intervention (NI). There were 30 studies that met the inclusion criteria from 1998-2016. The GPM framework led to a final ranking of effectiveness of measures in the following order from best to worst: PD, ITN, IRS and UN, in comparison with NI. However, only ITN (RR: 0.49, 95% CI: 0.32-0.74) showed precision while other methods [PD (RR: 0.24, 95% CI: 0.004-15.43), IRS (RR: 0.55, 95% CI: 0.20-1.56) and UN (RR: 0.73, 95% CI: 0.28-1.90)] demonstrating considerable uncertainty associated with their point estimates. Current evidence is strong for the protective effect of ITN interventions in malaria prevention. Even though ITNs were found to be the only preventive measure with statistical support for their effectiveness, the role of other malaria control measures may be important adjuncts in the global drive to eliminate malaria.


The influence of the DNA polymerase gamma accessory subunit on base excision repair by the catalytic subunit.
Mammalian DNA polymerase gamma, the sole polymerase responsible for replication and repair of mitochondrial DNA, contains a large catalytic subunit and a smaller accessory subunit, pol gammaB. In addition to the polymerase domain, the large subunit contains a 3'-5' editing exonuclease domain as well as a dRP lyase activity that can remove a 5'-deoxyribosephosphate (dRP) group during base excision repair. We show that the accessory subunit enhances the ability of the catalytic subunit to function in base excision repair mainly by stimulating two subreactions in the repair process. Pol gammaB appeared to specifically enhance the rate at which pol gamma was able to locate damage in high molecular weight DNA. One pol gammaB point mutant known to have impaired ability to bind duplex DNA stimulated repair poorly, suggesting that duplex DNA binding through pol gammaB may help the catalytic subunit locate sites of DNA damage. In addition, the small subunit significantly stimulated the dRP lyase activity of pol gammaA, although it did not increase the rate at which the dRP group dissociated from the enzyme. The ability of DNA pol gamma to process a high load of damaged DNA may be compromised by the slow release of the dRP group.


Do genetic recombination and gene density shape the pattern of DNA elimination in rice long terminal repeat retrotransposons?
In flowering plants, the accumulation of small deletions through unequal homologous recombination (UR) and illegitimate recombination (IR) is proposed to be the major process counteracting genome expansion, which is caused primarily by the periodic amplification of long terminal repeat retrotransposons (LTR-RTs). However, the full suite of evolutionary forces that govern the gain or loss of transposable elements (TEs) and their distribution within a genome remains unclear. Here, we investigated the distribution and structural variation of LTR-RTs in relation to the rates of local genetic recombination (GR) and gene densities in the rice (Oryza sativa) genome. Our data revealed a positive correlation between GR rates and gene densities and negative correlations between LTR-RT densities and both GR and gene densities. The data also indicate a tendency for LTR-RT elements and fragments to be shorter in regions with higher GR rates; the size reduction of LTR-RTs appears to be achieved primarily through solo LTR formation by UR. Comparison of indica and japonica rice revealed patterns and frequencies of LTR-RT gain and loss within different evolutionary timeframes. Different LTR-RT families exhibited variable distribution patterns and structural changes, but overall LTR-RT compositions and genes were organized according to the GR gradients of the genome. Further investigation of non-LTR-RTs and DNA transposons revealed a negative correlation between gene densities and the abundance of DNA transposons and a weak correlation between GR rates and the abundance of long interspersed nuclear elements (LINEs)/short interspersed nuclear elements (SINEs). Together, these observations suggest that GR and gene density play important roles in shaping the dynamic structure of the rice genome.


Histochemical profile of mouse hepatocellular adenomas and carcinomas induced by a single dose of diethylnitrosamine.
In continuation of earlier studies on murine neoplastic liver lesions, we characterized by histochemical methods the phenotype of hepatocellular adenomas and carcinomas induced by single injections of diethylnitrosamine (1.25, 2.5, or 5.0 micrograms/g of body weight) in 15-day-old C57BL/6 x male C3H F1 mice. The hepatocellular adenomas were composed predominantly of basophilic cells but stored excessive amounts of fat and glycogen in large portions of the tumors. Irrespective of the carcinogenic dose, the adenomas showed a consistent histochemical pattern. Glycogen synthase and phosphorylase were highly active in the hepatocytes that stored glycogen. In cells poor in, or free of, this polysaccharide, these enzymes were only moderately active or even inactive. In glycogen-storing parts of the adenomas, the activity of adenylate cyclase was reduced compared with normal liver parenchyma, but in fat-storing portions it was elevated. In a few adenomas, uniform increase in adenylate cyclase activity could be encountered. The levels of ATPase, acid phosphatase, and glucose-6-phosphatase were either increased or decreased. Glucose-6-phosphate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase showed an increased activity in all adenomas compared with preneoplastic foci, which in turn exhibited a higher glucose-6-phosphate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase activity than the surrounding parenchyma or the liver of untreated controls. The hepatocellular carcinomas showed remarkable histochemical changes compared with adenomas. The levels of fat and glycogen and the activities of glycogen synthase, phosphorylase, and in most cases also that of glucose-6-phosphate dehydrogenase, were reduced significantly. In contrast, adenylate cyclase, glucose-6-phosphatase, glyceraldehyde-3-phosphate dehydrogenase, and also alkaline phosphatase showed a striking elevation in developing carcinomas. Similar, although more pronounced, histochemical changes were seen in the advanced hepatocellular carcinomas. These observations indicated that progression from adenomas to hepatocellular carcinomas was associated with a change in the activity of several enzymes involved in cell membrane function, glycogen metabolism, the oxidative pentose phosphate pathway, and glycolysis.


Durability of left ventricular assist devices: Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) 2006 to 2011.
The present study compared the interval until device exchange or death from pump-related failure in patients with pulsatile versus continuous flow left ventricular assist devices. Data from Interagency Registry for Mechanically Assisted Circulatory Support (June 23, 2006, to March 31, 2011) compared the durability of implanted pulsatile and continuous flow left ventricular assist devices. The durability issues included pump replacement for infection, thrombosis-hemolysis, driveline failure, or pump drive unit failure, and death from driveline or pump drive unit failure. A total of 3302 left ventricular assist devices were implanted (486 pulsatile, 2816 continuous flow) and 98 pump exchanges or deaths from durability issues (46 pulsatile, 52 continuous flow; 3% of implants). The interval to device issue was greater for the continuous flow than for the pulsatile devices (P < .001). A comparisons of the causes for pump exchange or pump-related death showed (1) greater freedom from pump failure in the continuous flow compared with the pulsatile left ventricular assist devices (10 events/2816 continuous flow implants vs 39 events/486 pulsatile implants; P < .0001); (2) similar exchange or pump-related death for driveline failure (1/486 pulsatile vs 7/2816 continuous flow; P = .82); (3) similar exchange or pump-related death for thrombosis-hemolysis (2/486 pulsatile vs 28/2816 continuous flow; P = .25); and (4) fewer exchanges or pump-related deaths from infection in continuous flow left ventricular assist devices (4/486 pulsatile vs 7/2816 continuous flow; P = .034). Competing outcomes analysis corroborated this finding, with 54% of continuous flow versus 23% of pulsatile patients alive and receiving support at 12 months after implantation. The Analysis of Interagency Registry for Mechanically Assisted Circulatory Support data showed greater durability for continuous flow than for pulsatile left ventricular assist devices. Even longer durations of support can be expected if pump durability continues to improve.


Primary Care SHOPping intervention for cardiovascular disease prevention (PC-SHOP): protocol for a randomised controlled trial to reduce saturated fat intake.
A diet high in saturated fat (SFA) increases the risk of cardiovascular disease (CVD) and intakes in the UK exceed dietary recommendations. The Primary Care Shopping Intervention for Cardiovascular Disease Prevention (PC-SHOP) study aims to test the effect of an intervention for people with raised low-density lipoprotein (LDL) cholesterol involving health professional (HP) advice alone, or in combination with personalised feedback based on nutritional analysis of grocery store loyalty card data, on SFA intake and blood lipids in comparison with no intervention. PC-SHOP is a three-arm parallel randomised controlled trial with an allocation ratio of 1:3:3 ('no intervention': n=16, 'brief support': n=48, 'brief support plus shopping feedback': n=48, respectively). Participants with raised LDL will be recruited from general practitioner (GP) practices for a 3-month intervention period. In brief support, an HP will deliver a behaviourally informed 10 min consultation and provide a written self-help guide to inform and motivate people to reduce their SFA intake. In brief support plus shopping feedback, the participants will receive the same HP-led behavioural support and, based on data from their grocery store loyalty card, personalised feedback on the SFA content of their grocery shopping, identifying high SFA purchases and suggesting swaps to similar but lower SFA items.Measurements for the primary and secondary outcomes will be collected at baseline and at follow-up (3 months). The primary outcome measure will be the between-group difference in the reduction of SFA intake between baseline and follow-up. Secondary outcomes include changes in blood lipids and SFA content of food purchases, with process measures to consider the feasibility and acceptability of the intervention. This study has been reviewed and approved by the National Health Service Health Research Authority Research Ethics Committee (Ref: 17/SC/0168). The trial findings will be disseminated to academic and HPs through presentations at meetings and peer-reviewed journals and to the public through the media. If the intervention is effective, the results will be communicated to relevant stakeholders, including policymakers and retailers. ISRCTN14279335; Pre-results.


QD-antibody conjugates via carbodiimide-mediated coupling: a detailed study of the variables involved and a possible new mechanism for the coupling reaction under basic aqueous conditions.
A detailed study into the optimization of carbodiimide-mediated coupling of antibodies (Ab) and quantum dots (QD) for use in cellular imaging has been undertaken. This involved the grafting of commercially available carboxyl-modified QDs (Evident Technologies "Lake Placid Blue" Evitag and eBioscience's eflour nanocrystals) with anti-Cdc8 Abs to produce conjugates with specific affinity for fission yeast tropomyosin Cdc8 protein. The water-soluble carbodiimide 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) was used to activate the QDs prior to their incubation with antibody, and a range of QD-carboxyl/EDC/Ab mole ratios were used in the experiments in attempts to optimize fluorescence and bioaffinity of the conjugate products (EDC to QD-carboxyl-600 nmol/15 pmol to 0.12 nmol/15 pmol and QD to Ab 120 pmol/24 pmol to 120 pmol/1.2 pmol). It was observed that a specific "optimum" ratio of the three reactants was required to produce the most fluorescent and biologically active product and that it was generated at alkaline pH 10.8. Increasing the ratio of Ab to QD produced conjugate which was less fluorescent while reducing the ratio of EDC to QD in the activation step led to increased fluorescence of product. Conjugates were tested for their possession of antibody by measurement of their absorption at OD(280 nm) and for their fluorescence by assay λ(max(em)) at 495 nm. A quantitative assay of the bioactivity of the conjugates was developed whereby a standardized amount of Cdc8 antigen was spotted onto nylon membranes and reacted with products from conjugation reactions in a sandwich-type colormetric assay The "best" conjugate was used in intracellular imaging of yeast Cdc8 protein and produced brighter, higher definition images of fixed yeast cell actin structure than a fluorescein-Ab conjugate routinely produced in our laboratory. The QD-Ab conjugate was also significantly more resistant to photobleaching than the fluorescein-Ab conjugate. Results from other experiments involving EDC, the water-soluble carbodiimide 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulphonate (CMC), and EDC.HCl have suggested a new reaction mechanism for EDC coupling under basic aqueous conditions. In summary, a robust understanding of commercial QD-COOH surface chemistry and the variables involved in the materials' efficient conjugation with a bioligand using carbidiimide has been obtained along with an optimized approach for Ab-QD conjugate production. A novel assay has been developed for bioassay of QD-Ab conjugates and a new mechanism for EDC coupling under basic aqueous conditions is proposed.


Socio-demographic predictors of dimensions of the AUDIT score in a population sample of working-age men in Izhevsk, Russia.
To investigate the relationship between socio-demographic factors and alcohol drinking patterns identified through a formal analysis of the factor structure of the Alcohol Use Disorders Identification Test (AUDIT) score in a population sample of working-age men in Russia. In 2008-2009, a sample of 1005 men aged 25-59 years living in Izhevsk, Russia were interviewed and information collected about socio-demographic circumstances. Responses to the AUDIT questions were obtained through a self-completed questionnaire. Latent dimensions of the AUDIT score were determined using confirmatory factor analysis and expressed as standard deviation (SD) units. Structural equation modelling was used to estimate the strength of association of these dimensions with socio-demographic variables. The AUDIT was found to have a two-factor structure: alcohol consumption and alcohol-related problems. Both dimensions were higher in men who were unemployed seeking work compared with those in regular paid employment. For consumption, there was a difference of 0.59 SDs, (95% confidence interval (CI): 0.23, 0.88) and for alcohol-related problems one of 0.66 SD (95% CI: 0.31, 1.00). Alcohol-related problems were greater among less educated compared with more educated men (P-value for trend = 0.05), while consumption was not related to education. Similar results were found for associations with an amenity index based on car ownership and central heating. Neither dimension was associated with marital status. While we found evidence that the consumption component of AUDIT was underestimated, this did not appear to explain the associations of this dimension with socio-demographic factors. Education and amenity index, both measures of socio-economic position, were inversely associated with alcohol-related problems but not with consumption. This discordance suggests that self-reported questions on frequency and volume may be less sensitive markers of socio-economic variation in drinking than are questions about dependence and harm. Further investigation of the validity of the consumption component of AUDIT in Russia is warranted as it appears that the concept of a standard 'drink' as used in the instrument is not understood.


The carboxyl-terminal end of Cox1 is required for feedback assembly regulation of Cox1 synthesis in Saccharomyces cerevisiae mitochondria.
Synthesis of the largest cytochrome c oxidase (CcO) subunit, Cox1, on yeast mitochondrial ribosomes is coupled to assembly of CcO. The translational activator Mss51 is sequestered in early assembly intermediate complexes by an interaction with Cox14 that depends on the presence of newly synthesized Cox1. If CcO assembly is prevented, the level of Mss51 available for translational activation is reduced. We deleted the C-terminal 11 or 15 residues of Cox1 by site-directed mutagenesis of mtDNA. Although these deletions did not prevent respiratory growth of yeast, they eliminated the assembly-feedback control of Cox1 synthesis. Furthermore, these deletions reduced the strength of the Mss51-Cox14 interaction as detected by co-immunoprecipitation, confirming the importance of the Cox1 C-terminal residues for Mss51 sequestration. We surveyed a panel of mutations that block CcO assembly for the strength of their effect on Cox1 synthesis, both by pulse labeling and expression of the ARG8(m) reporter fused to COX1. Deletion of the nuclear gene encoding Cox6, one of the first subunits to be added to assembling CcO, caused the most severe reduction in Cox1 synthesis. Deletion of the C-terminal 15 amino acids of Cox1 increased Cox1 synthesis in the presence of each of these mutations, except pet54. Our data suggest a novel activity of Pet54 required for normal synthesis of Cox1 that is independent of the Cox1 C-terminal end.


The bacterial signal molecule, ppGpp, regulates Salmonella virulence gene expression.
Numerous, overlapping global regulatory systems mediate the environmental signalling controlling the virulence of Salmonella typhimurium. With both extra- and intracellular lifestyles, unravelling the mechanisms involved in regulating Salmonella pathogenesis has been complex. Here, we report a factor co-ordinating environmental signals with global regulators involved in pathogenesis. An S. typhimuriumDeltarelADeltaspoT strain deficient in guanosine tetraphosphate (ppGpp) synthesis was found to be highly attenuated in vivo and non-invasive in vitro. The DeltarelADeltaspoT strain exhibited severely reduced expression of hilA and invF, encoding major transcriptional activators required for Salmonella pathogenicity island 1 (SPI-1) gene expression and at least two other pathogenicity islands. None of the growth conditions intended to mimic the intestinal milieu was capable of inducing hilA expression in the absence of ppGpp. However, the expression of global regulators of Salmonella virulence, RpoS and PhoP/Q, and RpoS- and PhoP/Q-dependent, non-virulence-related genes was not significantly different from the wild-type strain. The results indicate that ppGpp plays a central role as a regulator of virulence gene expression in S. typhimurium and implicates ppGpp as a major factor in the environmental and host-dependent regulation of Salmonella pathogenesis.


Bandwidth-efficient phase modulation techniques for stimulated Brillouin scattering suppression in fiber optic parametric amplifiers.
Two novel bandwidth efficient pump-dithering Stimulated Brillouin Scattering (SBS) suppression techniques are introduced. The techniques employ a frequency-hopped chirp and an RF noise source to impart phase modulation on the pumps of a two pump Fiber Optical Parametric Amplifier (FOPA). The effectiveness of the introduced techniques is confirmed by measurements of the SBS threshold increase and the associated improvements relative to the current state of the art. Additionally, the effect on the idler signal integrity is presented as measured following amplification from a two pump FOPA employing both techniques. The measured 0.8 dB penalty with pumps dithered by an RF noise source, after accruing 160 ps/nm of dispersion with 38 dB conversion gain in a two-pump FOPA is the lowest reported to date.


DNA-Nanostructure-Gold-Nanorod Hybrids for Enhanced In Vivo Optoacoustic Imaging and Photothermal Therapy.
A functional cancer theranostic nanoplatform is developed, specifically tailored toward the optoacoustic modality by combining gold nanorods with DNA nanostructures (D-AuNR). DNA origami is used as an efficient delivery vehicle owing to its prominent tumor-targeting property. The D-AuNR hybrids display an enhanced tumor diagnostic sensitivity by improved optoacoustic imaging and excellent photothermal therapeutic properties in vivo.


Evaluation of two community-controlled peer support services for assessment and treatment of hepatitis C virus infection in opioid substitution treatment clinics: The ETHOS study, Australia.
Peer support services have been shown to be beneficial in increasing uptake and adherence to treatment in other areas but few examples of these services exist in hepatitis C (HCV) care. This study examined the performance of two community-controlled peer support services operating within a larger study aimed at increasing access to HCV care and treatment for opiate substitution treatment (OST) clients, ETHOS. Semi-structured interviews were conducted in two clinics with three groups of participants: clients (n=31), staff (n=8) and peer workers (n=3) and examined the operation of the service in relation to process, outputs and impacts. There was a very strong positive response to the peer worker services reported by staff and clients who had and had not interacted with a peer worker. A number of changes were reported that were not explicit goals of the service including providing access to additional services for clients and staff, peer workers acting as mediators between clients and staff and a less tangible notion of a changing "feel" of the clinic to a more positive and client-friendly social and physical space. Explicit goals of the service were also reported in peer workers supporting clients to consider and prepare for treatment (via blood tests and other assessments) as well as provide information and support about treatment. The peer support service was acceptable to clients and clinic staff. All groups of participants noted that the service met its goals of engaging clients, building trusting relationships and providing instrumental support for clients to access HCV treatment. Peer workers may also contribute to more effective deployment of health resources by preparing clients for clinical engagement with HCV health workers.


The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management.
Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by unexplained, persistent hypereosinophilia. These disorders have eluded a unique molecular explanation, and therapy has primarily been oriented toward palliation of symptoms related to organ involvement. Recent reports indicate that HES and CEL are imatinib-responsive malignancies, with rapid and complete hematologic remissions observed at lower doses than used in chronic myelogenous leukemia (CML). These BCR-ABL-negative cases lack activating mutations or abnormal fusions involving other known target genes of imatinib, implicating a novel tyrosine kinase in their pathogenesis. A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-alpha gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1). However, not all HES and CEL patients respond to imatinib, suggesting disease heterogeneity. Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity. This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management.


Extensive apoptosis in lymphoid organs during primary SIV infection predicts rapid progression towards AIDS.
The acute phase of HIV and SIV infections leads to a host/virus equilibrium, and accumulating evidence suggests that this early phase dictates further progression towards AIDS. To gain insight into the early events that determine rapid disease progression, we performed a longitudinal study in the SIV rhesus macaque model, allowing an in-depth analysis of the primary stage of infection. We assessed viral replication (quantification of replicating and infected cells in lymph nodes, plasma viral load), immune response (cytotoxic T lymphocyte, antibody, proliferative responses), apoptosis and cycling cells (Ki-67 labelling) on lymph nodes and blood in nine rhesus macaques infected with the pathogenic SIVmac251 isolate. Six primates remained asymptomatic during the one year follow-up period of the study, whereas three developed AIDS within 5-6 months. During the first 2 weeks of infection, peak numbers of apoptotic cells in the lymph node T-cell areas were significantly higher in the three future rapid progressors than in the six future slow progressors, and were correlated with subsequent viraemia levels measured 6 months after infection. The numbers of infected or cycling cells in the same lymph node T-cell areas, however, only became significantly different in future rapid and slow progressors 8 weeks after infection, at the end of the primary phase. Our findings identified extensive apoptosis induction in peripheral lymphoid organs as an early and predictive event that may play a crucial role in impairing the capacity of the immune system to control viral replication and progression towards disease.


A Qualitative Evaluation of the Acceptability of a Tailored Smartphone Alcohol Intervention for a Military Population: Information About Drinking for Ex-Serving Personnel (InDEx) App.
Alcohol consumption in the UK Armed Forces is higher than in the general population, and this pattern continues after leaving the service. Smartphone apps may be useful to increase ex-serving personnel's awareness of their alcohol consumption, support self-monitoring, and prompt a change in behavior. The study aimed to explore the acceptability of Information about Drinking in Ex-serving personnel (InDEx), a tailored smartphone app, combined with personalized short message service (SMS) text messaging designed to target ex-serving personnel who meet the criteria for hazardous alcohol use. The InDEx intervention included 4 key modules: (1) assessment and normative feedback, (2) self-monitoring and feedback, (3) goal setting and review, and (4) personalized SMS text messaging. A semistructured telephone interview study was conducted with ex-serving personnel after using the app for a 28-day period. Interviews were used to explore the acceptability of app modules and its functionality and the perceived changes in participant's drinking. Interview transcripts were analyzed using inductive thematic analysis. Overall, 94% (29/31) participants who used InDEx agreed to take part in a telephone interview. Overall, 4 themes were identified: Credibility, Meeting their needs, Simplicity, and Helpful for ex-serving personnel. The importance of credibility, functionality, and meeting the individual needs of ex-serving personnel was emphasized. Acceptability and engagement with specific modules of the app and text messages were influenced by the following: (1) if they felt it provided credible information, (2) whether the content was appropriately personalized to them, (3) the ease of use, and (4) beliefs about their own drinking behaviors. Participants recommended that the app would be most suitable for personnel about to leave the Armed Forces. InDEx was an acceptable smartphone app for ex-serving personnel for monitoring alcohol consumption and in providing meaningful feedback to the individual. Pages that met the participant's interests and provided real time personalized, credible feedback on their drinking and text messages tailored to participant's interactions with the app were particularly favored.


OAS1 polymorphisms are associated with susceptibility to West Nile encephalitis in horses.
West Nile virus, first identified within the United States in 1999, has since spread across the continental states and infected birds, humans and domestic animals, resulting in numerous deaths. Previous studies in mice identified the Oas1b gene, a member of the OAS/RNASEL innate immune system, as a determining factor for resistance to West Nile virus (WNV) infection. A recent case-control association study described mutations of human OAS1 associated with clinical susceptibility to WNV infection. Similar studies in horses, a particularly susceptible species, have been lacking, in part, because of the difficulty in collecting populations sufficiently homogenous in their infection and disease states. The equine OAS gene cluster most closely resembles the human cluster, with single copies of OAS1, OAS3 and OAS2 in the same orientation. With naturally occurring susceptible and resistant sub-populations to lethal West Nile encephalitis, we undertook a case-control association study to investigate whether, similar to humans (OAS1) and mice (Oas1b), equine OAS1 plays a role in resistance to severe WNV infection. We identified naturally occurring single nucleotide mutations in equine (Equus caballus) OAS1 and RNASEL genes and, using Fisher's Exact test, we provide evidence that mutations in equine OAS1 contribute to host susceptibility. Virtually all of the associated OAS1 polymorphisms were located within the interferon-inducible promoter, suggesting that differences in OAS1 gene expression may determine the host's ability to resist clinical manifestations associated with WNV infection.


Misreporting of Physical Activity and Sedentary Behavior in Parents-to-Be: A Validation Study across Sex.
This study validated the International Physical Activity Questionnaire (IPAQ) and the Context-specific Sedentary Behavior Questionnaire (CSBQ) against accelerometry among parents-to-be. Sex-differences in potential misreporting of physical activity (PA) and sedentary behavior (SB) were also investigated. Self-reported total PA (TPA), light-intensity PA (LPA), moderate-intensity PA (MPA), vigorous-intensity PA (VPA), moderate-to-vigorous-intensity PA (MVPA), and SB of 91 parents-to-be (41 men and 50 women) were compared with Actigraph data according to sex. Furthermore, the extent of misreporting was compared between sexes. Strong correlations for TPA and weak-to-moderate correlations for LPA, MPA, VPA, MVPA, and SB were observed. Participants underestimated TPA by 1068 min/week (=17.8 h/week; -50%), LPA by 1593 min/week (=26.6 h/week; -83%), and SB by 428 min/week (=7.1 h/week; -11%) and overestimated MPA by 384 min/week (=6.4 h/week; +176%) and MVPA by 525 min/week (=8.8 h/week; +224%). Males overreported VPA more than females in absolute minutes per week (238 min/week, i.e., 4.0 h/week vs. 62 min/week, i.e., 1.0 h/week), whereas, in relative terms, the opposite (+850% vs. +1033%) was true. The IPAQ and CSBQ can be used with caution to estimate TPA and SB among parents-to-be considering a strong correlation but low agreement for TPA and a weak-to-moderate correlation but acceptable agreement for SB. We disadvise using these self-reports to estimate PA on the distinct intensity levels.


Effects of Patients' Expectation in Dermatology: Evidence from Experimental and Clinical Placebo Studies and Implications for Dermatologic Practice and Research.
Patients' expectations towards the benefit of a treatment are key determinants of placebo responses and can affect the development and course of medical conditions and the efficacy and tolerability of active medical treatment. The mechanisms mediating these placebo and nocebo effects have been best described in the field of experimental pain and placebo analgesia. However, also in dermatology experimental and clinical studies demonstrate that various skin diseases such as inflammatory dermatoses and allergic reactions can be modulated by patients' expectations. Dermatologists should consider the important modulatory role of patients' expectations on the efficacy and tolerability of specific treatments and the key role of verbal information, patients' prior treatment experiences (associative learning), and the quality and quantity of doctor-patient communication in shaping treatment expectation. As a consequence, techniques aiming at maximizing patients' expectation effects should be implemented into daily clinical routine. By contrast, in clinical studies expectation effects should be maximally controlled and harmonized to improve the "assay sensitivity" to detect new compounds. Further translational studies, also in dermatoses that have not been investigated yet, are needed to better characterize the mechanisms underlying patients' expectation and to gain further insights into potential clinical implications of these effects in dermatologic conditions. Therefore, in this review, we provide a brief overview on the concept of expectation effects on treatment outcome in general, summarize what is already known about this topic for dermatologic diseases, and finally present the relevance of this topic in clinical dermatology.


First Report of Leaf Spot on Tibouchina semidecandra Caused by Beltrania rhombica in China.
Tibouchina semidecandra Cogn. is a popular ornamental plant in tropical and subtropical areas (1). In August 2011, a leaf spot was observed on approximately 70% of 5,000 potted plants of T. semidecandra in a nursery in Zhongshan, Guangdong Province, China. Each leaf spot was round with a brown center surrounded by a reddish brown border, and ranged from 8 to 10 mm in diameter. A fungus was isolated consistently from the lesions by surface-sterilizing symptomatic leaf sections (each 3 cm2) with 75% alcohol for 8 s, washing the sections with sterile water, soaking the sections in 3% NaOCl for 15 s, rinsing the sections with sterile water three times, and then placing the sections on potato dextrose agar (PDA) at 28°C. Each of three single-spore isolates on PDA produced gray, floccose colonies that reached 70 mm in diameter after 5 days at 28°C. Setae were dark brown, straight, erect, distantly and inconspicuously septate, and 125 to 193 × 3.0 to 4.5 μm. Conidiophores were light brown, cylindrical, simple or sometimes branched at the base, and 105 to 202 × 3 to 5 μm. Separating cells were hyaline, oval, and 12 to 13 × 4 to 5 μm. Conidia were unequally biconic, unicellular, dark brown with a pale brown or subhyaline band just above the widest part, and 26 to 31 × 8.5 to 12 μm (mean 27.3 × 10.6 μm) with a conspicuous appendage at the apex that was 6 to 14 × 1 to 1.8 μm. These characteristics were consistent with the description of Beltrania rhombica Penz. (3). The internal transcribed spacer (ITS) region of the ribosomal DNA (rDNA) of one isolate (GenBank Accession No. JN853777) was amplified using primers ITS4 and ITS5 (4) and sequenced. A BLAST search in GenBank revealed 97% similarity to the ITS sequence of an isolate of B. rhombica (GU797390.1). To confirm pathogenicity of the isolate, ten detached leaves from 3-month-old plants of T. semidecandra 'Purple Glorybush' were inoculated in vitro with 5-mm diameter, colonized mycelial plugs from the periphery of 5-day-old cultures of the isolated fungus. The agar plugs were put on the leaf surface and secured with sterile, moist cotton. Sterile PDA plugs were similarly used as the control treatment on ten detached leaves. Leaves were placed in petri dishes and incubated in a growth chamber with 12 h of light/day at 28°C. Necrotic lesions appeared on leaves after 2 to 3 days of incubation, whereas control leaves inoculated with sterile PDA plugs remained asymptomatic. B. rhombica was consistently reisolated from the lesions using the same method described above, but was not reisolated from the control leaves. Although there are approximately 77 reported hosts of B. rhombica (2), to our knowledge, this is the first report of B. rhombica causing a leaf spot on T. semidecandra. Because the disease caused foliar damage and reduced the ornamental value of the nursery plants, control measures may need to be implemented for this species in nurseries. References: (1) M. Faravani and B. H. Bakar. J. Food Agric. Env. Pap. 5:234, 2007. (4) D. F. Farr and A. Y. Rossman. Fungal Databases. Systematic Microbiology Laboratory, ARS, USDA. Retrieved from http://nt.ars-grin.gov/fungaldatabases/ , 30 Mar. 2012. (2) K. A. Pirozyski and S. D. Patil. Can. J. Bot. Pap. 48:567, 1970. (3) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. M. A. Innis et al., eds. Academic Press, San Diego, CA, 1990.


Presence of unfavorable cytogenetic abnormalities is the strongest predictor of poor survival in secondary myelofibrosis.
Postpolycythemic (PV) and postthrombocythemic (ET) myeloid metaplasia are consensually referred to as secondary myelofibrosis (sMF). Prognostic variables in sMF are not as well defined as they are for de novo myelofibrosis with myeloid metaplasia (MMM), which is also known as agnogenic myeloid metaplasia (AMM). Such information is particularly crucial for management decisions in transplant-eligible patients. Diagnoses of PV and ET required fulfillment of the World Health Organization criteria for the diagnosis of MMM as well as an antecedent history of either polycythemia vera or essential thrombocythemia that was supported by bone marrow examination. Cytogenetic findings were classified as being either favorable (normal or isolated 13q- or 20q- clones) or unfavorable (presence of abnormalities other than 13q- and 20q-). The study population was comprised of 66 young patients (age <60 yrs) with sMF, including 37 patients with PV and 29 patients with ET. Multivariate analysis of parameters other than cytogenetics identified older age (P = .02), anemia (hemoglobin level <10 g/dL [P = .007]), and PV (P = .009) to be independent risk factors for shortened survival. However, when such analysis was restricted to patients in whom cytogenetic studies were performed (n = 31 patients), the presence of unfavorable cytogenetic abnormalities (i.e., clones other than 20q- and 13q-) became the only adverse prognostic factor for survival (P = .001). A similar analysis in a temporal cohort of 50 age-matched patients with AMM also identified unfavorable cytogenetics as an independent predictor of poor survival, along with thrombocytopenia and anemia. The results of the current study suggest that cytogenetic findings might supersede AMM-derived prognostic scoring systems for predicting survival in patients with sMF.


Efficacy of integrated treatment of UV light and low-dose gamma irradiation on inactivation of Escherichia coli O157:H7 and Salmonella enterica on grape tomatoes.
The study evaluated the efficacy of integrated ultraviolet-C light (UVC) and low-dose gamma irradiation treatments to inactivate mixed strains of Escherichia coli O157:H7 and Salmonella enterica on inoculated whole grape tomatoes. A mixed bacterial cocktail composed of a 3 strain mixture of E. coli O157:H7 (C9490, E02128, and F00475) and a 3 serotype mixture of S. enterica (S. Montevideo G4639, S. Newport H1275, and S. Stanley H0558) was used based on their association with produce-related outbreaks. Spot inoculation (50 to 100 μmL) on tomato surfaces was performed to achieve a population of appropriately 10(7-8) CFU/tomato. Inoculated tomatoes were subjected to UVC (253.7 nm) dose of 0.6 kJ/m(2) followed by 4 different low doses of gamma irradiations (0.1 kGy, 0.25 kGy, 0.5 kGy, 0.75 kGy). The fate of background microflora (mesophilic aerobic) including mold and yeast counts were also determined during storage at 5 °C over 21 d. Integrated treatment significantly (P < 0.05) reduced the population of target pathogens. Results indicate about 3.4 ± 0.3 and 3.0 ± 0.1 log CFU reduction of E. coli O157:H7 and S. enterica, respectively, per tomato with UVC (0.6 kJ/m(2) ) and 0.25 kGy irradiation. More than a 4 log and higher reduction (>5 log) per fruit was accomplished by combined UVC treatment with 0.5 kGy and 0.75 kGy irradiation, respectively, for all tested pathogens. Furthermore, the combined treatment significantly (P < 0.05) reduced the native microflora compared to the control during storage. The data suggest efficacious treatment strategy for produce indicating 5 or higher log reduction which is consistent with the recommendations of the Natl. Advisory Committee on Microbiological Criteria for Foods.


Association between U.S. state AIDS Drug Assistance Program (ADAP) features and HIV antiretroviral therapy initiation, 2001-2009.
U.S. state AIDS Drug Assistance Programs (ADAPs) are federally funded to provide antiretroviral therapy (ART) as the payer of last resort to eligible persons with HIV infection. States differ regarding their financial contributions to and ways of implementing these programs, and it remains unclear how this interstate variability affects HIV treatment outcomes. We analyzed data from HIV-infected individuals who were clinically-eligible for ART between 2001 and 2009 (i.e., a first reported CD4+ <350 cells/uL or AIDS-defining illness) from 14 U.S. cohorts of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Using propensity score matching and Cox regression, we assessed ART initiation (within 6 months following eligibility) and virologic suppression (within 1 year) based on differences in two state ADAP features: the amount of state funding in annual ADAP budgets and the implementation of waiting lists. We performed an a priori subgroup analysis in persons with a history of injection drug use (IDU). Among 8,874 persons, 56% initiated ART within six months following eligibility. Persons living in states with no additional state contribution to the ADAP budget initiated ART on a less timely basis (hazard ratio [HR] 0.73, 95% CI 0.60-0.88). Living in a state with an ADAP waiting list was not associated with less timely initiation (HR 1.12, 95% CI 0.87-1.45). Neither additional state contributions nor waiting lists were significantly associated with virologic suppression. Persons with an IDU history initiated ART on a less timely basis (HR 0.67, 95% CI 0.47-0.95). We found that living in states that did not contribute additionally to the ADAP budget was associated with delayed ART initiation when treatment was clinically indicated. Given the changing healthcare environment, continued assessment of the role of ADAPs and their features that facilitate prompt treatment is needed.


Cytochrome P450 gene polymorphism and cancer.
Human cytochrome P450 (CYP) enzymes play a key role in the metabolism of drugs and environmental chemicals. Several CYP enzymes metabolically activate procarcinogens to genotoxic intermediates. Phenotyping analyses revealed an association between CYP enzyme activity and the risk to develop several forms of cancer. Research carried out in the last decade demonstrated that several CYP enzymes are polymorphic due to single nucleotide polymorphisms, gene duplications and deletions. As genotyping procedures became available for most human CYP, an impressive number of association studies on CYP polymorphisms and cancer risk were conducted. Here we review the findings obtained in these studies regarding CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP8A1 and CYP21 gene polymorphisms. Consistent evidences for association between CYP polymorphisms and lung, head and neck, and liver cancer were reported. Controversial findings suggest that colorectal and prostate cancers may be associated to CYP polymorphisms, whereas no evidences for a relevant association with breast or bladder cancers were reported. We summarize the available information related to the association of CYP polymorphisms with leukaemia, lymphomas and diverse types of cancer that were investigated only for some CYP genes, including brain, esophagus, stomach, pancreas, pituitary, cervical epithelium, melanoma, ovarian, kidney, anal and vulvar cancers. This review discusses on causes of heterogeneity in the proposed associations, controversial findings on cancer risk, and identifies topics that require further investigation. In addition, some recommendations on study design, in order to obtain more conclusive findings in further studies, are provided.


Whole genome sequencing of the fish pathogen Francisella noatunensis subsp. orientalis Toba04 gives novel insights into Francisella evolution and pathogenecity.
Francisella is a genus of gram-negative bacterium highly virulent in fishes and human where F. tularensis is causing the serious disease tularaemia in human. Recently Francisella species have been reported to cause mortality in aquaculture species like Atlantic cod and tilapia. We have completed the sequencing and draft assembly of the Francisella noatunensis subsp. orientalisToba04 strain isolated from farmed Tilapia. Compared to other available Francisella genomes, it is most similar to the genome of Francisella philomiragia subsp. philomiragia, a free-living bacterium not virulent to human. The genome is rearranged compared to the available Francisella genomes even though we found no IS-elements in the genome. Nearly 16% percent of the predicted ORFs are pseudogenes. Computational pathway analysis indicates that a number of the metabolic pathways are disrupted due to pseudogenes. Comparing the novel genome with other available Francisella genomes, we found around 2.5% of unique genes present in Francisella noatunensis subsp. orientalis Toba04 and a list of genes uniquely present in the human-pathogenic Francisella subspecies. Most of these genes might have transferred from bacterial species through horizontal gene transfer. Comparative analysis between human and fish pathogen also provide insights into genes responsible for pathogenecity. Our analysis of pseudogenes indicates that the evolution of Francisella subspecies's pseudogenes from Tilapia is old with large number of pseudogenes having more than one inactivating mutation. The fish pathogen has lost non-essential genes some time ago. Evolutionary analysis of the Francisella genomes, strongly suggests that human and fish pathogenic Francisella species have evolved independently from free-living metabolically competent Francisella species. These findings will contribute to understanding the evolution of Francisella species and pathogenesis.


Domain motions of the Mip protein from Legionella pneumophila.
The homodimeric 45.6 kDa (total mass) Mip protein, a virulence factor from Legionella pneumophila, was investigated with solution NMR spectroscopy and molecular dynamics (MD) simulations. Two Mip monomers are dimerized via an N-terminal helix bundle that is connected via a long alpha-helix to a C-terminal FKBP domain in each subunit. More than 85% of the amino acids were identified in triple-resonance NMR spectra. (15)N relaxation analysis showed a bimodal distribution of R(1)/R(2) values, with the lower ratio in the N-terminal domain. Relaxation dispersion measurements confirmed that these reduced ratios did not originate from conformational exchange. Thus, two different correlation times (tau(c)) can be deduced, reflecting partly uncoupled motions of both domains. Relaxation data of a Mip(77)(-)(213) monomer mutant were similar to those observed in the dimer, corroborating that the FKBP domain, including part of the connecting helix, behaves as one dynamic entity. MD simulations (18 ns) of the Mip dimer also yielded two different correlation times for the two domains and thus confirm the independence of the domain motions. Principal component analysis of the dihedral space covariance matrix calculated from the MD trajectory suggests a flexible region in the long connecting helix that acts as a hinge between the two domains. Such motion provides a possible explanation of how Mip can bind to complex molecular components of the extracellular matrix and mediate alveolar damage and bacterial spread in the lung.


The pattern of breathing in patients with chronic airflow obstruction.
1. The pattern of breathing in 12 patients with severe irreversible airflow obstruction has been studied during ventilatory stimulation by rebreathing CO2. Mean maximum tidal volume response was only 1.23 +/- 0.30 litres (mean +/- SD); this represented 65% of mean measured vital capacity and 82% of mean measured inspiratory capacity. During the course of rebreathing mean total breath duration was reduced from 3.48 +/- 0.93 to 2.44 +/- 0.48 s. 2. End-expiratory thoracic gas volume (FRC) was elevated at rest in all subjects and increased significantly by a further 0.50 +/- 1.90 litres during ventilatory stimulation in 10 of the 12 subjects. The maximum increase in FRC was proportional to the degree of airflow obstruction afforded by the airways in each subject. 3. It is suggested that the increase in FRC during ventilatory stimulation is responsible for the diminished tidal volume response and is an important determinant of breathing pattern and symptomatology in patients with airflow obstruction.


UV oxidation of cyclic AMP receptor protein, a global bacterial gene regulator, decreases DNA binding and cleaves DNA at specific sites.
UV light is a widely-employed, and environmentally-sensitive bactericide but its mechanism of action is not fully defined. Proteins are major chromophores and targets for damage due to their abundance, but the role of proteins in inducing damage to bound DNA, and the effects on DNA-protein interactions is less well characterized. In E. coli (and other Gram-negative bacteria) the cyclic AMP receptor protein (CRP/CAP) regulates more than 500 genes. In this study we show that exposure of isolated dimeric CRP-cAMP to UV modifies specific Met, Trp, Tyr, and Pro side-chains, induces inter-protein Tyr63-Tyr41 cross-links, and decreases DNA binding via oxidation of Met114/Pro110 residues in close proximity at the CRP dimer interface. UV exposure also modifies DNA-bound cAMP-CRP, with this resulting in DNA cleavage at specific G/C residues within the sequence bound to CRP, but not at other G/C sites. Oxidation also increases CRP dissociation from DNA. The modifications at the CRP dimer interface, and the site-specific DNA strand cleavage are proposed to occur via oxidation of two species Met residues (Met114 and Met189, respectively) to reactive persulfoxides that damage neighbouring amino acids and DNA bases. These data suggest that modification to CRP, and bound DNA, contributes to UV sensitivity.


Epidemiology of Andean cutaneous leishmaniasis: incrimination of Lutzomyia ayacuchensis (Diptera: psychodidae) as a vector of Leishmania in geographically isolated, upland valleys of Peru.
The southernmost limit of the distribution of endemic Andean cutaneous leishmaniasis (CL), commonly known as Uta, is localized in the western Andean valleys of Ayacucho, Peru. This area is completely isolated from other regions endemic for this disease. Identification of the insect vector for Andean CL was carried out by combining entomologic and parasitologic approaches. Two Lutzomyia species were captured: Lutzomyia ayacuchensis and Lu. noguchii. The former species was considered responsible for transmission of Leishmania because 1) there was a coincidence in space and time between the presence of this insect and the distribution of Andean CL, 2) it was shown to be highly anthropophilic, 3) Leishmania parasites of the subgenus Viannia were detected by a specific polymerase chain reaction assay, 4) promastigotes isolated from this insect were shown by multilocus enzyme electrophoresis and molecular karyotyping to belong to the same deme of Leishmania (Viannia) peruviana as the one circulating in humans living in the study area, and 5) the complete cycle of L. (V.) peruviana was observed in experimental infections of Lu. ayacuchensis. Parasite and vector homogeneity found in Ayacucho contrasted with the heterogeneity reported for other areas endemic for Andean CL. The potential influence of ecologic determinants on this geographically isolated area is discussed.


The temperature dependence of cell mechanics measured by atomic force microscopy.
The cytoskeleton is a complex polymer network that regulates the structural stability of living cells. Although the cytoskeleton plays a key role in many important cell functions, the mechanisms that regulate its mechanical behaviour are poorly understood. Potential mechanisms include the entropic elasticity of cytoskeletal filaments, glassy-like inelastic rearrangements of cross-linking proteins and the activity of contractile molecular motors that sets the tensional stress (prestress) borne by the cytoskeleton filaments. The contribution of these mechanisms can be assessed by studying how cell mechanics depends on temperature. The aim of this work was to elucidate the effect of temperature on cell mechanics using atomic force microscopy. We measured the complex shear modulus (G*) of human alveolar epithelial cells over a wide frequency range (0.1-25.6 Hz) at different temperatures (13-37 degrees C). In addition, we probed cell prestress by mapping the contractile forces that cells exert on the substrate by means of traction microscopy. To assess the role of actomyosin contraction in the temperature-induced changes in G* and cell prestress, we inhibited the Rho kinase pathway of the myosin light chain phosphorylation with Y-27632. Our results show that with increasing temperature, cells become stiffer and more solid-like. Cell prestress also increases with temperature. Inhibiting actomyosin contraction attenuated the temperature dependence of G* and prestress. We conclude that the dependence of cell mechanics with temperature is dominated by the contractile activity of molecular motors.


Parasite invasion following host reintroduction: a case study of Yellowstone's wolves.
Wildlife reintroductions select or treat individuals for good health with the expectation that these individuals will fare better than infected animals. However, these individuals, new to their environment, may also be particularly susceptible to circulating infections and this may result in high morbidity and mortality, potentially jeopardizing the goals of recovery. Here, using the reintroduction of the grey wolf (Canis lupus) into Yellowstone National Park as a case study, we address the question of how parasites invade a reintroduced population and consider the impact of these invasions on population performance. We find that several viral parasites rapidly invaded the population inside the park, likely via spillover from resident canid species, and we contrast these with the slower invasion of sarcoptic mange, caused by the mite Sarcoptes scabiei. The spatio-temporal patterns of mange invasion were largely consistent with patterns of host connectivity and density, and we demonstrate that the area of highest resource quality, supporting the greatest density of wolves, is also the region that appears most susceptible to repeated disease invasion and parasite-induced declines. The success of wolf reintroduction appears not to have been jeopardized by infectious disease, but now shows signs of regulation or limitation modulated by parasites.


Bacterial production and solution NMR studies of a viral membrane ion channel.
Advances in solution nuclear magnetic resonance (NMR) methodology that enable studies of very large proteins have also paved the way for studies of membrane proteins that behave like large proteins due to the added weight of surfactants. Solution NMR has been used to determine the high-resolution structures of several small, membrane proteins dissolved in detergent micelles and small bicelles. However, the usual difficulties with membrane proteins in producing, purifying, and stabilizing the proteins away from native membranes remain, requiring intensive screening efforts. Low levels of heterologous expression can be the most detrimental aspect to studying membrane proteins. This is exacerbated for NMR studies because of the costs of isotopically enriched media. Thus, solution NMR studies have tended to focus on relatively small, membrane proteins that can be expressed into inclusion bodies and refolded. Here, we describe the methods used to produce, purify, and refold the proton channel M2 into detergent micelles, and the procedures used to determine chemical shift assignments and the atomic level structure of the closed form of the homotetrameric channel.


A therapist's guide to children's self-esteem.
The term self-esteem is frequently used by occupational therapists and other health care professionals who work with children. There are differing interpretations as to what this term actually means. In this article, we use Susan Harter's model of self-esteem to define the nature of self-esteem and apply it to clinical practice. We outline the developmental characteristics important to consider when addressing the self-esteem of young children, such as the findings that young children's self-esteem is often more related to their perceptions of parental acceptance than perceptions of competence and that children are generally unable to accurately verbalize their level of self-esteem until 8 years of age. Specific implications for occupational therapy evaluation include whether the use of self-report or observer-report measures is preferable and whether self-esteem or self-concept should be measured. We discuss when to address self-esteem and which dimensions of self-esteem should be treated. The dimensions of self-esteem that are identified as low during the evaluation and that the child perceives to be important are addressed. The reevaluation issue of what specifically should be measured after intervention is also discussed. For example, it is recommended that the reevaluation instrument be sensitive to the domains of self-concept targeted for intervention.


A sensitivity analysis of the New Zealand standard model of foot and mouth disease.
Disease simulation models can be a valuable tool for planning a response to exotic disease incursions, as they provide a fast, low-cost mechanism for identifying the likely outcomes of a range of outbreak scenarios and disease control strategies. To use these tools effectively and with confidence, decision-makers must understand the simplifications and framing assumptions that underlie a model's structure. Sensitivity analysis, the analytical process of identifying which input variables are the key drivers of the model's output, is a crucial process in developing this understanding. This paper describes the application of a sampling-based sensitivity analysis to the New Zealand standard model (NZSM). This model is a parameter set developed for the InterSpread Plus model platform to allow the exploration of different outbreak scenarios for an epidemic of foot and mouth disease in New Zealand. Based on 200 iterations of the NZSM, run for a simulation period of 60 days, settings related to farm-to-saleyard movements and the detection of disease during the active surveillance phase of the epidemic had the greatest influence on the predicted number of infected premises. A small number of counter-intuitive findings indicated areas of model design, implementation and/or parameterisation that should be investigated further. A potentially useful result from this work would be information to aid the grouping or elimination of non-influential model settings. This would go some way towards reducing the overall complexity of the NZSM, while still allowing it to remain fit for purpose.


Ultrasound-assisted liquid-liquid spray extraction for the determination of multi-class trace organic compounds in high-volume water samples.
In order to extract trace organic compounds (TrOCs) from large volumes of water (over 10 L), an ultrasound-assisted liquid-liquid spray extraction (UA-LLSE) technique is proposed. The UA-LLSE integrates liquid-liquid extraction, spray atomisation and ultrasonication in a single step. Under an acoustic field, a water sample is continuously spray injected into an extracting organic solvent to generate numerous water microdroplets in the organic phase. As a result, the extraction time and efficiency are significantly improved through increasing the interactive surface area, collision probability and mass transfer between two liquid phases. Other major parameters affecting the extraction efficiency such as nozzle type, spray angle, flow rate, nozzle position, ultrasonication energy, and extraction cycle were optimised. This newly developed technique has been applied to determine the trace organic compounds in real-world environmental matrices, and the results were compared with the results of the conventional liquid-liquid extraction method. For the analysis of high-volume water samples, UA-LLSE is a simple, inexpensive, time-saving (20 min for 10 L of water sample) and environmentally friendly method (reduction in solvent usage), with high extraction efficiency (over 90% average recoveries) and excellent precision (lower than 7% relative standard deviation, RSD). Most importantly, it is an ideal on-site pre-treatment technique for the in situ extraction of trace organic compounds in high-volume water matrices.


Psychological aspects in patients with advanced cancer receiving lifelong systemic treatment: protocol for a scoping review.
A better understanding of the molecular, genetic and immunological characteristics of cancer and the introduction of new systemic treatment regimens in the last decades, has led to better treatment outcomes and increased survival rates for patients with previously short lived cancers. However, there is no uniform description to refer to this growing group of patients with advanced cancer who now respond to new systemic treatments for longer periods. Furthermore, little is known about the unique psychological challenges these patients face, living with ongoing uncertainty about the course of their disease and life expectancy. The objective of this scoping review is to identify the psychological aspects experienced by, and the definitions used to refer to patients with advanced cancer receiving lifelong systemic treatment. This review will be among the first to summarise literature on the psychological issues in the growing group of advanced cancer patients undergoing long-term systemic treatment. Articles will be retrieved from six databases (MEDLINE, Embase, Web of Science, PsycINFO, CINAHL and the Cochrane Database of Systematic Reviews) and reviewed for eligibility by two investigators independently. Definitions and psychological challenges will be extracted and narratively summarised following a descriptive approach. Furthermore, results will contribute in providing a uniform definition for this patient group, and help to identify knowledge gaps to give direction to further research in this field. No ethical approval is required. The results of the scoping review will be submitted for publication to a scientific journal and presented at relevant conferences.


Do all inter-patch movements represent dispersal? A mixed kernel study of butterfly mobility in fragmented landscapes.
1. In times of ongoing habitat fragmentation, the persistence of many species is determined by their dispersal abilities. Consequently, understanding the rules underlying movement between habitat patches is a key issue in conservation ecology. 2. We have analysed mark-release-recapture (MRR) data on inter-patches movements of the Dusky Large Blue butterfly Maculinea nausithous in a fragmented landscape in northern Bavaria, Germany. The aim of the analysis was to quantify distance dependence of dispersal as well as to evaluate the effect of target patch area on immigration probability. For statistical evaluation, we apply a 'reduced version' of the virtual migration model (VM), only fitting parameters for dispersal distance and immigration. In contrast to other analyses, we fit a mixed dispersal kernel to the MRR data. 3. A large fraction of recaptures happened in other habitat patches than those where individuals were initially caught. Further, we found significant evidence for the presence of a mixed dispersal kernel. The results indicate that individuals follow different strategies in their movements. Most movements are performed over small distances, nonetheless involving travelling between nearby habitat patches (median distance c. 480 m). A small fraction (c. 0·025) of the population has a tendency to move over larger distances (median distance c. 3800 m). Further, immigration was positively affected by patch area (I∼A(ζ) ), with the scaling parameter ζ = 0·5. 4. Our findings should help to resolve the long-lasting dispute over the suitability of the negative exponential function vs. inverse-power one for modelling dispersal. Previous studies on various organisms found that the former typically gives better overall fit to empirical distance distributions, but that the latter better represents long-distance movement probabilities. As long-distance movements are more important for landscape-level effects and thus, e.g. for conservation-oriented analyses like PVAs, fitting inverse-power kernels has often been preferred. 5. We conclude that the above discrepancy may simply stem from the fact that recorded inter-patch movements are an outcome of two different processes: daily routine movements and genuine dispersal. Consequently, applying mixed dispersal kernels to disentangle the two processes is recommended.


Outcomes of Split-thickness Skin Grafting for Foot and Ankle Wounds in Patients With Peripheral Arterial Disease.
Tissue ischemia resulting from arterial insufficiency is a major factor affecting lower extremity wound healing in patients with peripheral arterial disease (PAD). Accelerated wound closure with split-thickness skin grafting (STSG) provides a durable barrier to infection and can prevent limb loss. Published STSG outcomes data are minimal in the post endovascular intervention population. In this study, the authors examine factors predictive of STSG healing in patients with PAD following vascular intervention, including the effect of non-inline flow via arterial-arterial and non-arterial collateralization. Patients with PAD and wounds of the foot and ankle who underwent STSG between January 2014 and December 2016 were retrospectively reviewed. All patients received angiographic evaluation and endovascular or open revascularization where necessary. Effects of extremity revascularizations, STSG percent take, and amputation rate were evaluated. Thirty-five patients with 47 wounds underwent STSG. There were 21 men and 14 women with a mean age of 64 ± 13 years. Revascularization was required in 23 patients (25 extremities) before STSG, with balloon angioplasty for tibial artery lesions as the most common revascularization. Patent pedal arch was present in 8 patients; 35 patients had an absent or incomplete pedal arch. Patients with a fully patent pedal arch healed at a significantly higher rate than those with an absent or incomplete pedal arch at 1 month (62.5% vs. 17.1%, P ⟨ .05). At 90-day follow-up, 9 of 35 (25.7%) patients with 9 of 47 (19.1%) wounds were lost to follow-up, leaving 18 of 38 (47.37%) wounds healed and 20 (52.63%) still open. Ultimately, 36 of 47 (76.60%) wounds healed and 6 major amputations in 6 patients were required at a mean 502 ± 342 days follow-up. These results suggest the importance of arterial-arterial connections such as the pedal arch to the healing potential of foot and ankle wounds after STSG in this high-risk patient population.


Modeling the Comorbidity of Cannabis Abuse and Conduct Disorder/Conduct Problems from a Cognitive Neuroscience Perspective.
Objective: A cognitive neuroscience perspective seeks to understand behavior, in this case the comorbidity of cannabis abuse and conduct disorder/conduct problems, in terms of dysfunction in cognitive processes underpinned by neural processes. The goal of this review is to articulate a cognitive neuroscience account of this comorbidity. Methods: Literature on the following issues will be reviewed: (i) the longitudinal relationship between cannabis abuse and conduct disorder/conduct problems (CD/CP); (ii) the extent to which there are genetic and environmental (specifically maltreatment) factors that underpin this relationship; (iii) forms of neurocognitive function that are reported dysfunctional in CD/CP and also, when dysfunctional, appear to be risk factors for future cannabis abuse; and (iv) the extent to which cannabis abuse may further compromise these systems leading to increased future abuse and greater conduct problems. Results: CD/CP typically predate cannabis abuse. There appear to be shared genetic factors that contribute to the relationship between CD/CP and cannabis abuse. Moreover, trauma exposure increases risk for both cannabis abuse and CP/CD. One form of neurocognitive dysfunction, response disinhibition, that likely exacerbates the symptomatology of many individuals with CD also appears to increase the risk for cannabis abuse. The literature with respect to other forms of neurocognitive dysfunction remains inconclusive. Conclusions: Based on the literature, a causal model of the comorbidity of cannabis abuse and CD/CP is developed.


pHEMA-nHA encapsulation and delivery of vancomycin and rhBMP-2 enhances its role as a bone graft substitute.
Bone grafts are widely used in orthopaedic procedures. Autografts are limited by donor site morbidity while allografts are known for considerable infection and failure rates. A synthetic composite bone graft substitute poly(2-hydroxyethyl methacrylate)-nanocrystalline hydroxyapatite (pHEMA-nHA) was previously developed to stably press-fit in and functionally repair critical-sized rat femoral segmental defects when it was preabsorbed with a single low dose of 300 ng recombinant human bone morphogenetic protein-2/7 (rhBMP-2/7). To facilitate clinical translation of pHEMA-nHA as a synthetic structural bone graft substitute, we examined its ability to encapsulate and release rhBMP-2 and the antibiotic vancomycin. We analyzed the compressive behavior and microstructure of pHEMA-nHA as a function of vancomycin incorporation doses using a dynamic mechanical analyzer and a scanning electron microscope. In vitro release of vancomycin was monitored by ultraviolet-visible spectroscopy. Release of rhBMP-2 from pHEMA-nHA-vancomycin was determined by ELISA. Bioactivity of the released vancomycin and rhBMP-2 was examined by bacterial inhibition and osteogenic transdifferentiation capabilities in cell culture, respectively. Up to 4.8 wt% of vancomycin was incorporated into pHEMA-nHA without compromising its structural integrity and compressive modulus. Encapsulated vancomycin was released in a dose-dependent and sustained manner in phosphate-buffered saline over 2 weeks, and the released vancomycin inhibited Escherichia coli culture. The pHEMA-nHA-vancomycin composite released preabsorbed rhBMP-2 in a sustained manner over 8 days and locally induced osteogenic transdifferentiation of C2C12 cells in culture. pHEMA-nHA can encapsulate and deliver vancomycin and rhBMP-2 in a sustained and localized manner with reduced loading doses. The elasticity, osteoconductivity, and rhBMP-2/vancomycin delivery characteristics of pHEMA-nHA may benefit orthopaedic reconstructions or fusions with enhanced safety and efficiency and reduced infection risk.


Two ways to the top: evidence that dominance and prestige are distinct yet viable avenues to social rank and influence.
The pursuit of social rank is a recurrent and pervasive challenge faced by individuals in all human societies. Yet, the precise means through which individuals compete for social standing remains unclear. In 2 studies, we investigated the impact of 2 fundamental strategies-Dominance (the use of force and intimidation to induce fear) and Prestige (the sharing of expertise or know-how to gain respect)-on the attainment of social rank, which we conceptualized as the acquisition of (a) perceived influence over others (Study 1), (b) actual influence over others' behaviors (Study 1), and (c) others' visual attention (Study 2). Study 1 examined the process of hierarchy formation among a group of previously unacquainted individuals, who provided round-robin judgments of each other after completing a group task. Results indicated that the adoption of either a Dominance or Prestige strategy promoted perceptions of greater influence, by both group members and outside observers, and higher levels of actual influence, based on a behavioral measure. These effects were not driven by popularity; in fact, those who adopted a Prestige strategy were viewed as likable, whereas those who adopted a Dominance strategy were not well liked. In Study 2, participants viewed brief video clips of group interactions from Study 1 while their gaze was monitored with an eye tracker. Dominant and Prestigious targets each received greater visual attention than targets low on either dimension. Together, these findings demonstrate that Dominance and Prestige are distinct yet viable strategies for ascending the social hierarchy, consistent with evolutionary theory.


Microvascular Networks From Endothelial Cells and Mesenchymal Stromal Cells From Adipose Tissue and Bone Marrow: A Comparison.
A promising approach to overcome hypoxic conditions in tissue engineered constructs is to use the potential of endothelial cells (EC) to form networks in vitro when co-cultured with a supporting cell type in a 3D environment. Adipose tissue-derived stromal cells (ASC) as well as bone marrow-derived stromal cells (BMSC) have been shown to support vessel formation of EC in vitro, but only very few studies compared the angiogenic potential of both cell types using the same model. Here, we aimed at investigating the ability of ASC and BMSC to induce network formation of EC in a co-culture model in fibrin. While vascular structures of BMSC and EC remained stable over the course of 3 weeks, ASC-EC co-cultures developed more junctions and higher network density within the same time frame. Both co-cultures showed positive staining for neural glial antigen 2 (NG2) and basal lamina proteins. This indicates that vessels matured and were surrounded by perivascular cells as well as matrix molecules involved in stabilization. Gene expression analysis revealed a significant increase of vascular endothelial growth factor (VEGF) expression in ASC-EC co-culture compared to BMSC-EC co-culture. These observations were donor-independent and highlight the importance of organotypic cell sources for vascular tissue engineering.


Heavy metal and arsenic content in seabirds affected by the Prestige oil spill on the Galician coast (NW Spain).
Seabirds are top consumers in marine foodchains which offer opportunities to detect and assess the toxicological effects of different inorganic elements on the marine ecosystem. In order to provide baseline data concerning trace element levels in seabird species from NW Spain, zinc, copper, arsenic, chromium, lead, cadmium and mercury concentrations were analyzed in liver of three different seabird species (common guillemot, Atlantic puffin and razorbill) affected by the Prestige oil spill in September 2002 on the Galician coast. In general, with the exception of mercury, levels of all the analyzed elements were similar or lower in comparison with those reported for the same species in other Atlantic areas, and did not exceed levels indicative of increased environmental exposure.


Non-traumatic paralysis of the posterior interosseous nerve.
We treated 31 patients with non-traumatic paralysis of the posterior interosseous nerve over 15 years. There were 10 men and 21 women of mean age 40.3 years (17 to 71). Six were managed conservatively, and 25 by operation. In 14 patients entrapment occurred at the supinator, including three who had double compression at both the entrance and exit from the muscle. In four it was caused by a ganglion, in one by a lipoma, in one by a dislocated radial head and in two by a marked constriction in the nerve of unknown cause. The remaining three patients were retrospectively diagnosed as having neuralgic amyotrophy, the only observable change at operation being slight oedema of the nerve. Paralysis recovered in 24 out of the 25 patients at between 2 to 18 months (mean 5.6) after operation, and the one failure was treated later by tendon transfer.