Flow cytometry-based analysis of artemisinin-resistant Plasmodium falciparum in the ring-stage survival assay.
The ring-stage survival assay (RSA) is a powerful tool for phenotyping artemisinin-resistant Plasmodium falciparum but requires experienced microscopists to count viable parasites among 10,000 erythrocytes in Giemsa-stained thin blood smears. Here we describe a rapid flow cytometric assay that accurately counts viable parasites among 250,000 erythrocytes in suspension. This method performs as well as light microscopy and can be used to standardize the collection of RSA data between research groups in laboratory and field settings.


Detection and characterisation of papillomavirus in skin lesions of giraffe and sable antelope in South Africa.
Papillomavirus was detected electron microscopically in cutaneous fibropapillomas of a giraffe (Giraffa camelopardalis) and a sable antelope (Hippotragus niger). The virus particles measured 45 nm in diameter. Histopathologically, the lesions showed histopathological features similar to those of equine sarcoid as well as positive immunoperoxidase-staining of tissue sections for papillomavirus antigen. Polymerase chain reaction (PCR) detected bovine papillomavirus (BPV) DNA. Bovine papillomavirus-1 was characterised by real-time PCR in the sable and giraffe, and cloning and sequencing of the PCR product revealed a similarity to BPV-1. As in the 1st giraffe, the lesions from a 2nd giraffe revealed locally malignant pleomorphism, possibly indicating the lesional end-point of papilloma infection. Neither virus particles nor positively staining papillomavirus antigen could be demonstrated in the 2nd giraffe but papillomavirus DNA was detected by real-time PCR which corresponded with BPV-1 and BPV-2.


The effects of a lifestyle-focused text-messaging intervention on adherence to dietary guideline recommendations in patients with coronary heart disease: an analysis of the TEXT ME study.
A healthy diet is an important component of secondary prevention of coronary heart disease (CHD). The TEXT ME study was a randomised clinical trial of people with CHD that were randomised into standard care or a text-message programme in addition to standard care. This analysis aimed to: 1) assess the effects of the intervention onadherence to the dietary guideline recommendations; 2) assess the consistency of effect across sub-groups; and 3) assess whether adherence to the dietary guideline recommendations mediated the improvements in objective clinical outcomes. Dietary data were collected using a self-report questionnaire to evaluate adherence to eight dietary guideline recommendations in Australia, including consumption of vegetables, fruits, fish, type of fat used for cooking and in spreads, takeaway food, salt and standard alcohol drinks. The primary outcome of this analysis was the proportion of patients adhering to ≥ 4 dietary guideline recommendations concomitantly and each recommendation was assessed individually as secondary outcomes. Data were analysed using log-binomial regression for categorical variables and analysis of covariance for continuous variables. Among 710 patients, 54% were adhering to ≥ 4 dietary guideline recommendations (intervention 53% vs control 56%, p = 0.376) at baseline. At six months, the intervention group had a significantly higher proportion of patients adhering to ≥ 4 recommendations (314, 93%) compared to the control group (264, 75%, RR 1.23, 95% CI 1.15-1.31, p < 0.001). In addition, the intervention patients reported consuming higher amounts of vegetables, fruits, and fish per week; less takeaway foods per week; and greater salt intake control. The intervention had a similar effect in all sub-groups tested. There were significant mediational effects of the increase in adherence to the recommendations for the association between the intervention and LDL-cholesterol (p < 0.001) and body mass index (BMI) at six months follow-up (p = 0.005). A lifestyle-focused text-message programme improved adherence to the dietary guideline recommendations, and specifically improved self-reported consumption of vegetables, fruits, fish, takeaway foods and salt intake. Importantly, these improvements partially mediated improvements in LDL-cholesterol and BMI. This simple and scalable text-messaging intervention could be used as a strategy to improve diet in people with CHD. Australia and New Zealand Clinical Trials Registry ACTRN12611000161921 . Registered on 10 February 2011.


Luteinizing hormone, follicle-stimulating hormone, testosterone and dihydrotestosterone during testicular descent in the pig fetus.
To investigate the relationship between gonadotrophins, androgens and testicular descent in the pig fetus, serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and serum concentrations and testicular content of testosterone (T) and 5 alpha-dihydrotestosterone (DHT) were determined by radioimmunoassay in 95 fetuses (48 males, 47 females) between Day 60 and Day 90 post coitum (p.c.). The testes were descended in 0% of fetuses at Day 60, 8% of fetuses at Day 70, 40% of fetuses at Day 80 and 87% of fetuses at Day 90 p.c. There was a significant increase in mean serum concentrations of LH in both male and female fetuses from Day 60 to Day 90, with a significant difference in mean serum concentrations of LH between male fetuses with a body mass < 350 g (4% of testes descended) and those with a body mass > 450 g (87% of testes descended), but not between male and female fetuses < 350 g or > 450 g in body mass. There was no significant difference in mean serum concentrations of FSH between male and female fetuses. Mean serum concentrations of T were significantly higher in male fetuses at Day 60 than in those at Days 70-90, with no significant difference in serum concentrations of DHT from Day 60 to Day 90 p.c. Testicular content of T and DHT showed a non-linear increase from Day 60 to Day 90 p.c. Although the serum concentration of T is elevated before, and decreased during, the period of descent, the testicular content of T and DHT increases during the period of descent, indicating that serum concentrations of LH and FSH may have an indirect effect on descent by stimulating testicular androgen synthesis.


Clinical efficacy of lentinan on patients with stomach cancer: end point results of a four-year follow-up survey.
End-point results of a 4-yr followup survey and a randomized control trial of lentinan (LNT) on patients with advanced or recurrent stomach cancer have been investigated in order to evaluate the clinical efficacy of LNT in combination with chemotherapeutic agent tegafur (FT). Eligible (68) patients in control groups were administered with FT consecutively at doses of 600 mg/day, and eligible (96) patients in the treated group were administered LNT in combination with FT. LNT was injected intravenously 2 mg weekly. Remarkable lifespan prolongation effects of LNT have been observed both at the end of the control trial and at the end of the followup survey (p less than 0.01) using Kaplan-Meier's method and the generalized Wilcoxian test. Remarkable survival at 1, 2 and 3 years has been observed in the treated group using lifetable analysis. Side effects of LNT have been transitional and not serious. Thus, LNT should be effective in combination with FT for patients with stomach cancer.


Pretreatment with curcumin attenuates anxiety while strengthens memory performance after one short stress experience in male rats.
It is observed that memories are more strengthened in a stressful condition. Studies have also demonstrated an association between stressful events and the onset of depression and anxiety. Considering the nootropic, anxiolytic and antidepressant-like properties of curcumin in various experimental approaches, we appraised the beneficial effects of this herb on acute immobilization stress-induced behavioral and neurochemical alterations. Rats in test group were administrated with curcumin (200mg/kg/day), dissolved in neutral oil, for 1 week. Both control and curcumin-treated rats were divided into unstressed and stressed groups. Rats in the stressed group were subjected to immobilization stress for 2h. After stress, the animals were subjected to behavioral tests. Immobilization stress induced an anxiogenic behavior in rats subjected to elevated plus maze test (EPM). Locomotor activity was also significantly increased following the acute immobilization stress. Pre-administration of curcumin prevented the stress-induced behavioral deficits. Highest memory performance was observed in stressed rats that were pre-treated with curcumin in Morris water maze (MWM). Brain malondialdehyde (MDA) levels, catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and acetylcholinesterase (AChE) activities were also estimated. Present study suggests a role of antioxidant enzymes in the attenuation of acute stress induced anxiety by curcumin. The findings therefore suggest that supplementation of curcumin may be beneficial in the treatment of acute stress induced anxiety and enhancement of memory function.


Enhancing Nonfouling and Sensitivity of Surface-Enhanced Raman Scattering Substrates for Potent Drug Analysis in Blood Plasma via Fabrication of a Flexible Plasmonic Patch.
Surface-enhanced Raman scattering (SERS) is an ultrasensitive analytical technique, which is capable of providing high specificity; thus, it can be used for toxicological drug assay (detection and quantification). However, SERS-based drug analysis directly in human biofluids requires mitigation of fouling and nonspecificity effects that commonly appeared from unwanted adsorption of endogenous biomolecules present in biofluids (e.g., blood plasma and serum) onto the SERS substrate. Here, we report a bottom-up fabrication strategy to prepare ultrasensitive SERS substrates, first, by functionalizing chemically synthesized gold triangular nanoprisms (Au TNPs) with poly(ethylene glycol)-thiolate in the solid state to avoid protein fouling and second, by generating flexible plasmonic patches to enhance SERS sensitivity via the formation of high-intensity electromagnetic hot spots. Poly(ethylene glycol)-thiolate-functionalized Au TNPs in the form of flexible plasmonic patches show a twofold-improved signal-to-noise ratio in comparison to triethylamine (TEA)-passivated Au TNPs. Furthermore, the plasmonic patch displays a SERS enhancement factor of 4.5 ×107. Utilizing the Langmuir adsorption model, we determine the adsorption constant of drugs for two different surface ligands and observe that the drug molecules display stronger affinity for poly(ethylene glycol) ligands than TEA. Our density functional theory calculations unequivocally support the interaction between drug molecules and poly(ethylene glycol) moieties. Furthermore, the universality of the plasmonic patch for SERS-based drug detection is demonstrated for cocaine, JWH-018, and opioids (fentanyl, despropionyl fentanyl, and heroin) and binary mixture (trace amount of fentanyl in heroin) analyses. We demonstrate the applicability of flexible plasmonic patches for the selective assay of fentanyl at picogram/milliliter concentration levels from drug-of-abuse patients' blood plasma. The fentanyl concentration calculated in the patients' blood plasma from SERS analysis is in excellent agreement with the values determined using the paper spray ionization mass spectrometry technique. We believe that the flexible plasmonic patch fabrication strategy would be widely applicable to any plasmonic nanostructure for SERS-based chemical sensing for clinical toxicology and therapeutic drug monitoring.


Denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing: results from the FREEDOM trial.
Fracture is the major complication of osteoporosis, and it allows the identification of individuals needing medical intervention for osteoporosis. After nonvertebral fracture, patients often do not receive osteoporosis medical treatment despite evidence that this treatment reduces the risk of subsequent fracture. In this pre planned analysis of the results of the three-year, placebo-controlled FREEDOM trial, we evaluated the effect of denosumab administration on fracture-healing to address theoretical concerns related to initiating or continuing denosumab therapy in patients presenting with a nonvertebral fracture. Postmenopausal women aged sixty to ninety years with osteoporosis were randomized to receive 60 mg of denosumab (n = 3902) or a placebo (n = 3906) subcutaneously every six months for three years. Investigators reported complications associated with a fracture or its management and with fracture-healing for all nonvertebral fractures that occurred during the study. Delayed healing was defined as incomplete fracture-healing six months after the fracture. Six hundred and sixty-seven subjects (303 treated with denosumab and 364 who received a placebo) had a total of 851 nonvertebral fractures (386 in the denosumab group and 465 in the placebo group), including 199 fractures (seventy-nine in the denosumab group and 120 in the placebo group) that were treated surgically. Delayed healing was reported in seven subjects (two in the denosumab group and five in the placebo group), including one with subsequent nonunion (in the placebo group). Neither delayed healing nor nonunion was observed in any subject who had received denosumab within six weeks preceding or following the fracture. A complication associated with the fracture or intervention occurred in five subjects (2%) and twenty subjects (5%) in the denosumab and placebo groups,respectively (p = 0.009). Denosumab in a dose of 60 mg every six months does not seem to delay fracture-healing or contribute to other complications, even when it is administered at or near the time of the fracture.


Multiplexed silicon photonic sensor arrays enable facile characterization of coagulation protein binding to nanodiscs with variable lipid content.
Interactions of soluble proteins with the cell membrane are critical within the blood coagulation cascade. Of particular interest are the interactions of γ-carboxyglutamic acid-rich domain-containing clotting proteins with lipids. Variability among conventional analytical methods presents challenges for comparing clotting protein-lipid interactions. Most previous studies have investigated only a single clotting protein and lipid composition and have yielded widely different binding constants. Herein, we demonstrate that a combination of lipid bilayer nanodiscs and a multiplexed silicon photonic analysis technology enables high-throughput probing of many protein-lipid interactions among blood-clotting proteins. This approach allowed direct comparison of the binding constants of prothrombin, factor X, activated factor VII, and activated protein C to seven different binary lipid compositions. In a single experiment, the binding constants of one protein interacting with all lipid compositions were simultaneously determined. A simple surface regeneration then facilitated similar binding measurements for three other coagulation proteins. As expected, our results indicated that all proteins exhibit tighter binding (lower Kd ) as the proportion of anionic lipid increases. Interestingly, at high proportions of phosphatidylserine, the Kd values of all four proteins began to converge. We also found that although koff values for all four proteins followed trends similar to those observed for the Kd values, the variation among the proteins was much lower, indicating that much of the variation came from the kinetic binding (kon) of the proteins. These findings indicate that the combination of silicon photonic microring resonator arrays and nanodiscs enables rapid interrogation of biomolecular binding interactions at model cell membrane interfaces.


Branding the rodeo: a case study of tobacco sports sponsorship.
Rodeo is one of the few sports still sponsored by the tobacco industry, particularly the US Smokeless Tobacco Company. Rodeo is popular in rural communities, where smokeless tobacco use is more prevalent. We used previously secret tobacco industry documents to examine the history and internal motivations for tobacco company rodeo sponsorship. Rodeos allow tobacco companies to reach rural audiences and young people, enhance brand image, conduct market research, and generate positive press. Relationships with athletes and fans were used to fight proposed restrictions on tobacco sports sponsorship. Rodeo sponsorship was intended to enhance tobacco sales, not the sport. Rural communities should question the tradition of tobacco sponsorship of rodeo sports and reject these predatory marketing practices.


Novel micro-optical waveguide on micro-actuating platform for reconfigurable wavelength selective optical switch.
We propose a novel technique to add new degrees of freedom in fiber optic coupler devices. Micro-optical waveguide (MOW) on a microactuating platform (MAP) structure has been proposed and experimentally implemented using fiber waveguides, where the coupling characteristics of MOW are mechanically varied by precise axial stress control by MAP. As an application of the proposed structure, we mounted the coupling zone of fused taper coupler array on a MAP to demonstrate a novel reconfigurable 1x4 wavelength selective optical switching function. Robust mechanical tuning among output ports of a four-channel demultiplexer was realized by precise elongation control of the taper region in serially cascaded fused fiber couplers. Simultaneous reconfigurable wavelength routing and switching functions were demonstrated among four channels in 1.5-microm coarse WDM transmission window. We report the principle, design concept, and the performances of the proposed device structure along with its potential in reconfigurable fiber optics.


Coupling strength can control the polarization twist of a plasmonic antenna.
The far-field polarization of the optical response of a plasmonic antenna can be tuned by subtly engineering of its geometry. In this paper, we develop design rules for nano antennas which enable the generation of circular polarized light via the excitation of circular plasmonic modes in the structure. Two initially orthogonal plasmonic modes are coupled in such a way that a rotational current is excited in the structure. Modifying this coupling strength from a weak to a strong regime controls the helicity of the scattered field. Finally, we introduce an original sensing approach that relies on the rotation of the incident polarization and demonstrates a sensitivity of 0.23 deg·nm(-1) or 33 deg·RIU(-1), related to changes of mechanical dimensions and the refractive index, respectively.


A Systematic Review and Meta-Analysis of Inpatient Mortality Associated With Nosocomial and Community COVID-19 Exposes the Vulnerability of Immunosuppressed Adults.
Little is known about the mortality of hospital-acquired (nosocomial) COVID-19 infection globally. We investigated the risk of mortality and critical care admission in hospitalised adults with nosocomial COVID-19, relative to adults requiring hospitalisation due to community-acquired infection. We systematically reviewed the peer-reviewed and pre-print literature from 1/1/2020 to 9/2/2021 without language restriction for studies reporting outcomes of nosocomial and community-acquired COVID-19. We performed a random effects meta-analysis (MA) to estimate the 1) relative risk of death and 2) critical care admission, stratifying studies by patient cohort characteristics and nosocomial case definition. 21 studies were included in the primary MA, describing 8,251 admissions across 8 countries during the first wave, comprising 1513 probable or definite nosocomial COVID-19, and 6738 community-acquired cases. Across all studies, the risk of mortality was 1.3 times greater in patients with nosocomial infection, compared to community-acquired (95% CI: 1.005 to 1.683). Rates of critical care admission were similar between groups (Relative Risk, RR=0.74, 95% CI: 0.50 to 1.08). Immunosuppressed patients diagnosed with nosocomial COVID-19 were twice as likely to die in hospital as those admitted with community-acquired infection (RR=2.14, 95% CI: 1.76 to 2.61). Adults who acquire SARS-CoV-2 whilst already hospitalised are at greater risk of mortality compared to patients admitted following community-acquired infection; this finding is largely driven by a substantially increased risk of death in individuals with malignancy or who had undergone transplantation. These findings inform public health and infection control policy and argue for individualised clinical interventions to combat the threat of nosocomial COVID-19, particularly for immunosuppressed groups. PROSPERO CRD42021249023.


Directed evolution of the peroxidase activity of a de novo-designed protein.
Collections of de novo-designed proteins provide a unique opportunity to probe the functional potential of sequences that are stably folded, but were neither explicitly designed nor evolutionarily selected to perform any particular type of activity. A combinatorial library of folded proteins was designed previously using a strategy that exploits the binary patterning of polar and non-polar amino acids to drive sequences to fold into four-helix bundles. Although these novel four-helix bundles were not explicitly designed for function, previous characterization of several hundred arbitrarily chosen sequences showed that many of them bound the heme cofactor, and several of these novel heme proteins catalyzed peroxidase activity at levels substantially above background. Here, we show that these moderately active de novo heme proteins can serve as non-natural starting points for laboratory-based evolution: Random mutagenesis followed by color-based screening of a relatively small number (hundreds or thousands) of variants yielded novel sequences with improved peroxidase activity. Biochemical characterization of the purified proteins showed that the evolved variants were nearly 3-fold more active than the parental sequence. These results demonstrate that de novo-designed proteins can be utilized as a novel feedstock for the evolution of enzyme activity.


Retrospective study of the clinical performance of fiber posts.
To evaluate the clinical performance of C-Posts, AEstheti Posts and AEstheti Plus Posts after a period of clinical service ranging from 1-6 yrs. 1,304 posts were included in the study: 840 Composiposts, 215 AEstheti posts and 249 AEstheti Plus posts were placed into endodontically treated teeth. Four combinations of bonding/luting materials were used. The patients were recalled every 6 months and clinical and radiographic examinations were completed. Endodontic and prosthodontic results were recorded. Actuarial Life Table statistical analysis and Mantel-Haenszel comparison of survival curve have been performed at 95% level of confidence. The 3.2% failure rate was due to two reasons: 25 posts debonded during removal of temporary restorations, and 16 teeth showed periapical lesions at the radiographic examination. No statistical significant differences were found among the four groups. The results of this retrospective study indicate that fiber posts in combination with bonding/luting materials can be routinely used.


Sharpening the surface of magnetic paranematic droplets.
In a non-uniform magnetic field, the droplets of colloids of nickel nanorods and nanobeads aggregate to form a cusp at the droplet surface not deforming the entire droplet shape. When the field is removed, nanorods diffuse away and the cusp disappears. Spherical particles can form cusps in a similar way, but they stay aggregated after the release of the field; finally, the aggregates settle down to the bottom of the drop. The X-ray phase contrast imaging reveals that nanorods in the cusps stay parallel to each other without visible spatial order of their centers of mass. The formation of cusps can be explained with a model that includes magnetostatic and surface tension forces. The discovered possibility of controlled assembly and quenching of nanorod orientation under the cusped liquid surface offers vast opportunities for alignment of carbon nanotubes, nanowires and nanoscrolls, prior to spinning them into superstrong and multifunctional fibers. Magnetostatic and electrostatic analogies suggest that a similar ideal alignment can be achieved with the rod-like dipoles subject to a strong electric field.


Structural dynamics and topology of phospholamban in oriented lipid bilayers using multidimensional solid-state NMR.
Phospholamban (PLN), a single-pass membrane protein, regulates heart muscle contraction and relaxation by reversible inhibition of the sarco(endo)plasmic reticulum Ca-ATPase (SERCA). Studies in detergent micelles and oriented lipid bilayers have shown that in its monomeric form PLN adopts a dynamic L shape (bent or T state) that is in conformational equilibrium with a more dynamic R state. In this paper, we use solid-state NMR on both uniformly and selectively labeled PLN to refine our initial studies, describing the topology and dynamics of PLN in oriented lipid bilayers. Two-dimensional PISEMA (polarization inversion spin exchange at the magic angle) experiments carried out in DOPC/DOPE mixed lipid bilayers reveal a tilt angle of the transmembrane domain with respect to the static magnetic field, of 21 +/- 2 degrees and, at the same time, map the rotation angle of the transmembrane domain with respect to the bilayer. PISEMA spectra obtained with selectively labeled samples show that the cytoplasmic domain of PLN is helical and makes an angle of 93 +/- 6 degrees with respect to the bilayer normal. In addition, using samples tilted by 90 degrees , we find that the transmembrane domain of PLN undergoes fast long-axial rotational diffusion about the bilayer normal with the cytoplasmic domain undergoing this motion and other complex dynamics, scaling the values of chemical shift anisotropy. While this dynamic was anticipated by previous solution NMR relaxation studies in micelles, these measurements in the anisotropic lipid environment reveal new dynamic and conformational features encoded in the free protein that might be crucial for SERCA recognition and subsequent inhibition.


LIM Protein Ajuba Participates in the Repression of the ATR-Mediated DNA Damage Response.
LIM proteins constitute a superfamily characterized by the presence of a LIM domain, known to be involved in protein-protein interactions. Our previous work has implicated members of the Zyxin family of LIM proteins, namely TRIP6 and LPP, in the repression of the DNA damage response (DDR) at telomeres. Here, we describe a role for Ajuba, a closely related LIM molecule, in repressing the ATR-mediated DDR. We found that depletion of Ajuba led to apparent delays in the cell cycle, accompanied with increased Rb phosphorylation, Chk1 phosphorylation, induction of p53, and cell death. Ajuba could be found in a complex with replication protein A (RPA), and its depletion led to RPA phosphorylation, known to be an early event in ATR activation. We propose that Ajuba protects against unscheduled ATR signaling by preventing inappropriate RPA phosphorylation.


Laboratory procedures for human in vitro fertilization.
Successful and consistent outcomes in human in vitro fertilization (IVF) can be readily achieved by all IVF clinics through consideration and optimization of each procedure associated with the collection and processing of gametes, culminating in the resultant culture and transfer of healthy embryos. Furthermore, understanding the interactions between the individual components of the IVF cycle will assist when trouble-shooting possible problems in a laboratory which could have an adverse effect on cycle outcome. This article will review handling of oocytes and embryo culture, preparation of gametes for insemination and microinjection, selection of the most viable gametes and embryos, cryopreservation, and successful embryo transfer from the laboratory perspective.


The Influence of Role Models on the Sedentary Behaviour Patterns of Primary School-Aged Children and Associations with Psychosocial Aspects of Health.
High levels of sedentary behaviour (SB) are associated with poor health outcomes in children, but the effects on mental health are less clear. This study explored the relationship between SB and psychosocial aspects of health in children, and what influence key role models, including parents and schoolteachers, have on the SB levels of children. Physical activity (PA) and SB were measured using accelerometery in 101 children, 113 parents and 9 teachers. Children were aged 9 or 10 years old and in fourth grade. Child psychosocial outcomes were assessed using the Rosenberg Self-Esteem Scale and the Strengths and Difficulties Questionnaire. Children engaged in a high volume of SB (9.6 h/day) but interrupted SB often. They accumulated less than 11,000 steps per day, and thus, many may not meet the recommended daily levels of PA. No associations were found between child SB and teacher SB during the school day or child SB and parent SB during the after-school period. No association was found between SB and self-esteem, although children with a higher body mass index had a higher number of emotional and behavioural difficulties. Although there was no indication that children's SB was linked to that of parents and teachers, or that SB was associated with self-esteem or behavioural problems, school children were highly sedentary and insufficiently physically active. Therefore, there is a need to explore school practices and curriculum delivery methods, as well as school and home environments, to reduce the volume of SB children engage in.


Unifying Theories of Psychedelic Drug Effects.
How do psychedelic drugs produce their characteristic range of acute effects in perception, emotion, cognition, and sense of self? How do these effects relate to the clinical efficacy of psychedelic-assisted therapies? Efforts to understand psychedelic phenomena date back more than a century in Western science. In this article I review theories of psychedelic drug effects and highlight key concepts which have endured over the last 125 years of psychedelic science. First, I describe the subjective phenomenology of acute psychedelic effects using the best available data. Next, I review late 19th-century and early 20th-century theories-model psychoses theory, filtration theory, and psychoanalytic theory-and highlight their shared features. I then briefly review recent findings on the neuropharmacology and neurophysiology of psychedelic drugs in humans. Finally, I describe recent theories of psychedelic drug effects which leverage 21st-century cognitive neuroscience frameworks-entropic brain theory, integrated information theory, and predictive processing-and point out key shared features that link back to earlier theories. I identify an abstract principle which cuts across many theories past and present: psychedelic drugs perturb universal brain processes that normally serve to constrain neural systems central to perception, emotion, cognition, and sense of self. I conclude that making an explicit effort to investigate the principles and mechanisms of psychedelic drug effects is a uniquely powerful way to iteratively develop and test unifying theories of brain function.


Detection of immunoglobulin G (IgG) and IgM antibodies to Toxoplasma gondii: evaluation of four commercial immunoassay systems.
A comparative evaluation of the following commercial immunoassays for the determination of antibodies to Toxoplasma gondii was performed: Behring Diagnostics OPUS Toxo G and Toxo M, Abbott Diagnostics IMX Toxo-IgG 2.0 and Toxo-IgM, Sanofi Diagnostics Pasteur Platelia Toxo IgG and Toxo IgM, and bioMérieux Vitek VIDAS Toxo IgG and IgM. Of 676 specimens that were tested for Toxoplasma-specific immunoglobulin G (IgG) antibodies, 26% were reactive by all methods while 8% displayed some discrepancy. Of 718 specimens that were tested for Toxoplasma-specific IgM antibodies, 3% were reactive by all methods while 10% displayed some discrepancy. Analysis of discrepant specimens revealed performance shortcomings with all IgM-specific assays. The impact of such shortcomings is magnified in a population with a low prevalence of toxoplasmosis.


Serotonin transporter genotype (5-HTTLPR) and electrocortical responses indicating the sensitivity to negative emotional cues.
Growing literature indicates that emotional reactivity and regulation are strongly linked to genetic modulation of serotonergic neurotransmission. However, until now, most studies have focused on the relationship between genotypic markers, in particular the serotonin transporter-linked polymorphic region (5-HTTLPR), and neural structures using MRI. The current study aimed to bridge the gap between the relevant MRI literature on the effects of the 5-HTTLPR genotype and the research tradition focusing on transient lateralized changes of electrocortical activity in the prefrontal cortex using electroencephalography (EEG). Lateral shifts of EEG alpha asymmetry in response to an aversive film consisting of scenes of real injury and death were assessed in healthy participants (n = 165). To evaluate the specificity of the 5-HTTLPR effect, participants were also tested for the COMT Val158Met polymorphism which is linked to dopamine inactivation. While viewing the film, individuals homozygous for the 5-HTTLPR short allele displayed a clear lateral shift of dorsolateral frontal activity to the right, which was virtually absent in participants carrying the long allele. The heightened electrocortical response to the aversive stimulation and its direction indicates a greater propensity of s/s homozygotes to experience withdrawal oriented affect in response to negative emotion cues in the environment. Moreover, together with previous research the findings support the notion of a link between the serotonergic system and self-regulation related to avoidance motivation, and a link between the dopaminergic system and self-regulation related to approach motivation.


Structural basis for Streptococcus pneumoniae NanA inhibition by influenza antivirals zanamivir and oseltamivir carboxylate.
The human pathogen Streptococcus pneumoniae is the major cause of bacterial meningitis, respiratory tract infection, septicemia, and otitis media. The bacterium expresses neuraminidase (NA) proteins that contribute to pathogenesis by cleaving sialic acids from host glycoconjugates, thereby enhancing biofilm formation and colonization. Recent in vivo experiments have shown that antiviral compounds, widely used in clinics and designed to inhibit influenza NA, significantly reduce biofilm formation and nasopharyngeal colonization of S. pneumoniae in mice. Here, we present the structural basis for the beneficial effect of these compounds against pneumococcal infection. Crystal structures of pneumococcal NanA in complex with zanamivir and oseltamivir carboxylate are discussed, correlated with measured inhibitory constants K(i), and compared with the binding modes of the inhibitors in the viral enzyme. Inhibitor structures show for the first time how clinically approved anti-influenza compounds interact with an NA of the human pathogen S. pneumoniae and give a rational explanation for their antibacterial effects.


Huichol Migrant Laborers and Pesticides: Structural Violence and Cultural Confounders.
Every year, around two thousand Huichol families migrate from their homelands in the highlands of northwestern Mexico to the coastal region of Nayarit State, where they are employed on small plantations to pick and thread tobacco leaves. During their four-month stay, they live, work, eat, and sleep in the open air next to the tobacco fields, exposing themselves to an unknown cocktail of pesticides all day, every day. In this article, I describe how these indigenous migrants are more at risk to pesticides because historical and contemporary structural factors ensure that they live and work in the way of harm. I discuss the economic, social, political, and racial inequalities that exist in their every-day environment and how these forms of structural violence are mitigated by their intersection with local cultural contexts and their specific indigenous lifeworld.


Validation of the inhalable dust algorithm of the Advanced REACH Tool using a dataset from the pharmaceutical industry.
As it is often difficult to obtain sufficient numbers of measurements to adequately characterise exposure levels, occupational exposure models may be useful tools in the exposure assessment process. This study aims to refine and validate the inhalable dust algorithm of the Advanced REACH Tool (ART) to predict airborne exposure of workers in the pharmaceutical industry. The ART was refined to reflect pharmaceutical situations. Largely task based workplace exposure data (n = 192) were collated from a multinational pharmaceutical company with exposure levels ranging from 5 × 10(-5) to 12 mg m(-3). Bias, relative bias and uncertainty around geometric mean exposure estimates were calculated for 16 exposure scenarios. For 12 of the 16 scenarios the ART geometric mean exposure estimates were lower than measured exposure levels with on average, a one-third underestimation of exposure (relative bias -32%). For 75% of the scenarios the exposure estimates were, within the 90% uncertainty factor of 4.4, as reported for the original calibration study, which may indicate more uncertainty in the ART estimates in this industry. While the uncertainty was higher than expected this is likely due to the limited number of measurements per scenario, which were largely derived from single premises.


Clinical features and evolution of bacterial infection-related acute-on-chronic liver failure.
Bacterial infections can trigger the development of organ failure(s) and acute-on-chronic liver failure (ACLF). Geographic variations in bacteriology and clinical practice could lead to worldwide differences in ACLF epidemiology, phenotypes and associated outcomes. Herein, we aimed to evaluate regional differences in bacterial infection-related ACLF in patients with cirrhosis admitted to hospital. This post hoc analysis included 1,175 patients with decompensated cirrhosis (with bacterial infection on admission or nosocomial infection) from 6 geographic regions worldwide. Clinical, laboratory and microbiological data were collected from the diagnosis of infection. Patients were followed-up for organ failure(s) and ACLF development according to the EASL-CLIF criteria from enrolment to discharge/death. A total of 333 patients (28%) had ACLF at diagnosis of infection, while 230 patients developed ACLF after diagnosis of infection, resulting in an overall rate of bacterial infection related-ACLF of 48%, with rates differing amongst different geographic regions (38% in Southern Europe vs. 75% in the Indian subcontinent). Bacterial infection related-ACLF more frequently developed in younger patients (55 ± 13 vs. 58 ± 14 years), males (73% vs. 62%), patients with alcohol-related cirrhosis (59% vs. 45%) and those with a higher baseline MELD score (25 ± 11 vs. 16 ± 5) (all p <0.001). Spontaneous bacterial peritonitis, pneumonia or infections caused by extensively drug resistant (XDR) bacteria were more frequently associated with ACLF development. More patients with ACLF had a positive quick sequential organ failure assessment score and septic shock, resulting in a lower infection resolution rate (all p <0.001). Bacterial infections, especially with XDR organisms, are associated with the highest risk of ACLF development, accounting for almost half of cases globally. Geographic differences result in variable epidemiology and clinical outcomes. Bacterial infections can trigger a sudden deterioration in an otherwise stable cirrhotic patient, a condition known as acute-on-chronic liver failure or ACLF. This study has found that the development of ACLF following bacterial infection occurs most commonly in the Indian subcontinent and less so in Southern Europe. The common infections that can trigger ACLF include infection of the abdominal fluid, known as spontaneous bacterial peritonitis, pneumonia and by bacteria that are resistant to multiple antibiotics. Patients who develop ACLF following a bacterial infection have high death rates and are frequently unable to clear the infection.


T-helper 2 cytokines, transforming growth factor β1, and eosinophil products induce fibrogenesis and alter muscle motility in patients with eosinophilic esophagitis.
Patients with eosinophilic esophagitis (EoE) often become dysphagic from the combination of organ fibrosis and motor abnormalities. We investigated mechanisms of dysphagia, assessing the response of human esophageal fibroblasts (HEFs), human esophageal muscle cells (HEMCs), and esophageal muscle strips to eosinophil-derived products. Biopsy specimens were collected via endoscopy from the upper, middle, and lower thirds of the esophagus of 18 patients with EoE and 21 individuals undergoing endoscopy for other reasons (controls). Primary cultures of esophageal fibroblasts and muscle cells were derived from 12 freshly resected human esophagectomy specimens. Eosinophil distribution was investigated by histologic analyses of full-thickness esophageal tissue. Active secretion of EoE-related mediators was assessed from medium underlying mucosal biopsy cultures. We quantified production of fibronectin and collagen I by HEF and HEMC in response to eosinophil products. We also measured the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 by, and adhesion of human eosinophils to, HEFs and HEMCs. Eosinophil products were tested in an esophageal muscle contraction assay. Activated eosinophils were present in all esophageal layers. Significantly higher concentrations of eosinophil-related mediators were secreted spontaneously in mucosal biopsy specimens from patients with EoE than controls. Exposure of HEFs and HEMCs to increasing concentrations of eosinophil products or co-culture with eosinophils caused HEFs and HEMCs to increase secretion of fibronectin and collagen I; this was inhibited by blocking transforming growth factor β1 and p38 mitogen-activated protein kinase signaling. Eosinophil binding to HEFs and HEMCs increased after incubation of mesenchymal cells with eosinophil-derived products, and decreased after blockade of transforming growth factor β1 and p38 mitogen-activated protein kinase blockade. Eosinophil products reduced electrical field-induced contraction of esophageal muscle strips, but not acetylcholine-induced contraction. In an analysis of tissues samples from patients with EoE, we linked the presence and activation state of eosinophils in EoE with altered fibrogenesis and motility of esophageal fibroblasts and muscle cells. This process might contribute to the development of dysphagia.


Quantitative chemoproteomic profiling reveals multiple target interactions of spongiolactone derivatives in leukemia cells.
The spongiolactones are marine natural products with an unusual rearranged spongiane skeleton and a fused β-lactone ring. These compounds have potential anticancer properties but their mode of action has yet to be explored. Here we employ activity-based protein profiling to identify the targets of a more potent spongiolactone derivative in live cancer cells, and compare these to the targets of a simpler β-lactone. These hits provide the first insights into the covalent mechanism of action of this natural product class.


The impact of 2D cine MR imaging parameters on automated tumor and organ localization for MR-guided real-time adaptive radiotherapy.
2D cine MR imaging may be utilized to monitor rapidly moving tumors and organs-at-risk for real-time adaptive radiotherapy. This study systematically investigates the impact of geometric imaging parameters on the ability of 2D cine MR imaging to guide template-matching-driven autocontouring of lung tumors and abdominal organs. Abdominal 4D MR images were acquired of six healthy volunteers and thoracic 4D MR images were obtained of eight lung cancer patients. At each breathing phase of the images, the left kidney and gallbladder or lung tumor, respectively, were outlined as volumes of interest. These images and contours were used to create artificial 2D cine MR images, while simultaneously serving as 3D ground truth. We explored the impact of five different imaging parameters (pixel size, slice thickness, imaging plane orientation, number and relative alignment of images as well as strategies to create training images). For each possible combination of imaging parameters, we generated artificial 2D cine MR images as training and test images. A template-matching algorithm used the training images to determine the tumor or organ position in the test images. Subsequently, a 3D base contour was shifted to the determined position and compared to the ground truth via centroid distance and Dice similarity coefficient. The median centroid distance between adapted and ground truth contours was 1.56 mm for the kidney, 3.81 mm for the gallbladder and 1.03 mm for the lung tumor (median Dice similarity coefficient: 0.95, 0.72 and 0.93). We observed that a decrease in image resolution led to a modest decrease in localization accuracy, especially for the small gallbladder. However, for all volumes of interest localization accuracy varied substantially more between subjects than due to the different imaging parameters. Automated tumor and organ localization using 2D cine MR imaging and template-matching-based autocontouring is robust against variation of geometric imaging parameters. Future work and optimization efforts of 2D cine MR imaging for real-time adaptive radiotherapy is needed to characterize the influence of sequence- and anatomical site-specific imaging contrast.


Combining knowledge- and data-driven methods for de-identification of clinical narratives.
A recent promise to access unstructured clinical data from electronic health records on large-scale has revitalized the interest in automated de-identification of clinical notes, which includes the identification of mentions of Protected Health Information (PHI). We describe the methods developed and evaluated as part of the i2b2/UTHealth 2014 challenge to identify PHI defined by 25 entity types in longitudinal clinical narratives. Our approach combines knowledge-driven (dictionaries and rules) and data-driven (machine learning) methods with a large range of features to address de-identification of specific named entities. In addition, we have devised a two-pass recognition approach that creates a patient-specific run-time dictionary from the PHI entities identified in the first step with high confidence, which is then used in the second pass to identify mentions that lack specific clues. The proposed method achieved the overall micro F1-measures of 91% on strict and 95% on token-level evaluation on the test dataset (514 narratives). Whilst most PHI entities can be reliably identified, particularly challenging were mentions of Organizations and Professions. Still, the overall results suggest that automated text mining methods can be used to reliably process clinical notes to identify personal information and thus providing a crucial step in large-scale de-identification of unstructured data for further clinical and epidemiological studies.


Electrophoresis for genotyping: temporal thermal gradient gel electrophoresis for profiling of oligonucleotide dissociation.
Traditional use of an oligonucleotide probe to determine genotype depends on perfect base pairing to a single-stranded target which is stable to a higher temperature than when imperfect binding occurs due to a mismatch in the target sequence. Bound oligonucleotide is detected at a predetermined single temperature 'snapshot' of the melting profile, allowing the distinction of perfect from imperfect base pairing. In heterozygotes, the presence of the alternative sequence must be verified with a second oligonucleotide complementary to the variant. Here we describe a system of real-time variable temperature electrophoresis during which the oligonucleotide dissociates from its target. In 20% polyacrylamide the target strand has minimal mobility and released oligonucleotide migrates extremely quickly so that the 'freed' rather than the 'bound' is displayed. The full profile of oligonucleotide dissociation during gel electrophoresis is represented along the gel track, and a single oligonucleotide is sufficient to confirm heterozygosity, since the profile displays two separate peaks. Resolution is great, with use of short track lengths enabling analysis of dense arrays of samples. Each gel track can contain a different target or oligonucleotide and the temperature gradient can accommodate oligonucleotides of different melting temperatures. This provides a convenient system to examine the interaction of many different oligonucleotides and target sequences simultaneously and requires no prior knowledge of the mutant sequence(s) nor of oligonucleotide melting temperatures. The application of the technique is described for screening of a hotspot for mutations in the LDL receptor gene in patients with familial hypercholesterolaemia.


Attitudes towards deprescribing and the influence of health literacy among older Australians.
This study aimed to explore attitudes, beliefs and experiences regarding polypharmacy and discontinuing medications, or deprescribing, among community living older adults aged ≥65 years, using ≥5 medications. It also aimed to investigate if health literacy capabilities influenced attitudes and beliefs towards deprescribing. Polypharmacy use is common among Australian older adults. However, little is known about their attitudes towards polypharmacy use or towards stopping medications. Previous studies indicate that health literacy levels tend to be lower in older adults, resulting in poor knowledge about medications. A self-administered survey was conducted using two previously validated tools; the Patients' Attitude Towards Deprescribing (PATD) tool to measure attitudes towards polypharmacy use and deprescribing and the All Aspects of Health Literacy Scale (AAHLS) to measure functional, communicative and critical health literacy. Descriptive statistical analysis was conducted. The 137 responses showed that 80% thought all their medications were necessary and were comfortable with the number taken. Wanting to reduce the number of medications taken was associated with concerns about the amount taken (P<0.001), experiencing side effects (P<0.001), or believing that one or more medications were no longer needed (P<0.000). Those who were using ten or more medications were more likely to want to reduce the number taken (P=0.019). Most (88%) respondents would be willing to stop medication/s in the context of receiving this advice from their doctor. Willingness to consider stopping correlated with higher scores on the critical health literacy subscale (P<0.021) and overall AAHLS score (P<0.009). Those with higher scores on the overall AAHLS measure were more likely to report that they understood why their medications were prescribed (P<0.000) and were more likely to participate in decision-making (P=0.027). Opportunities to proactively consider deprescribing may be missed, as one third of the respondents could not recall a recent review of their medications.


HIV/STI Prevention Interventions: A Systematic Review and Meta-analysis.
Behavioral interventions can prevent the transmission of HIV and sexually transmitted infections. This systematic review and meta-analysis assesses the effectiveness and quality of available evidence of HIV prevention interventions for people living with HIV in high-income settings. Searches were conducted in MEDLINE, EMBASE, PsycINFO, and CDC Compendium of Effective Interventions. Interventions published between January, 1998 and September, 2015 were included. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Forty-six articles and 63 datasets involving 14,096 individuals met inclusion criteria. Included articles were grouped by intervention type, comparison group and outcome. Few of these had high or moderate quality of evidence and statistically significant effects. One intervention type, group-level health education interventions, were effective in reducing HIV/STI incidence when compared to attention controls. A second intervention type, comprehensive risk counseling and services, was effective in reducing sexual risk behaviors when compared to both active and attention controls. All other intervention types showed no statistically significant effect or had low or very low quality of evidence. Given that the majority of interventions produced low or very low quality of evidence, researchers should commit to rigorous evaluation and high quality reporting of HIV intervention studies.


Correlation between 18F-FDG Positron-Emission Tomography 18F-FDG Uptake Levels at Diagnosis and Histopathologic and Immunohistochemical Factors in Patients with Breast Cancer.
In this study, we aimed to determine the correlation between pretreatment-staging 18F-FDG total body positron-emission tomography/computed tomography (PET/CT) maximum standardized uptake value (SUVmax) levels and histopathologic and immunohistochemical predictive and prognostic factors in patients with breast cancer. One hundred thirty-nine women with breast cancer who were treated between 2009 and 2015 at our hospital and who had pretreatment-staging PET/CT were included in the study. SUVmax levels and histopathologic and immunohistochemical results were compared. The median age was 48 years (range, 29-79 years). The mean tumor diameter was 33.4 mm (range, 7-120 mm). The histology was invasive ductal carcinoma in 80.6% of the patients. In the univariate analysis, SUVmax levels were significantly higher in patients with invasive ductal carcinoma; in patients with a maximum tumor diameter more than 2 cm; patients who were estrogen, progesterone, and combined hormone receptor-negative, triple-negative patients, and in tumors with higher grades (p<0.05). In HER2-positive patients, SUVmax levels were higher even if it was not statistically significant. There was no correlation between lymph node metastases and pathologic stage. In multivariate analysis, tumor diameter was an independent factor. SUVmax levels are correlated with known histopathologic and immunohistochemical prognostic factors. PET/CT could be useful in preoperative evaluation of patients with breast cancer to predict biologic characteristics of tumors and prognosis.


A subset of Ly-1 inducer T cell clones activates B cell proliferation but directly inhibits subsequent IgG secretion.
We find that a fraction of Ly-1+2- inducer T cell clones inhibits differentiation of memory B cells into IgG-secreting plaque-forming cells. Inhibition of secondary antibody responses was not the result of induction of Ly-2+ T suppressors. Instead, inducer cells directly inactivated B cells, requiring an antigen bridge as well as identity at the major histocompatibility complex (I-A) locus. The interaction between the inducer T cell clone and hapten-specific B memory cells results in an early proliferative response and subsequent failure of B cells to secrete antibody in response to T helper cell signals. Possible mechanisms for this novel type of B cell inactivation are explored.


3D-Printed Ophthalmic-Retrobulbar-Anesthesia Simulator: Mimicking Anatomical Structures and Providing Tactile Sensations.
Objective: A simulator for retrobulbar anesthesia administration mimicking the orbital anatomy and providing tactile sensation is proposed. Methods: The production process involves 3D modeling of anatomical structures on the basis of computerized tomography (CT) images, printing the models using a 3D printer, and casting the silicone. Twenty ophthalmologists administered retrobulbar anesthesia using the simulator with four different ocular axial lengths (including extreme myopes); the position of the needle tip was evaluated. The effectiveness of this simulator for training was also surveyed. Results: The proportions of the final location of the needle tip were 59.25%, 36.25%, and 4.5% for the retrobulbar space, peribulbar space, and intraocular space, respectively. Experienced ophthalmologists showed lower complication rates than residents (0.5% vs 8.5%, [Formula: see text]) and agreed that this simulator will help young ophthalmologists advance their anesthesia-administering skills. Discussion/Conclusion: The 3D-printered simulator for retrobulbar anesthesia was produced and performance was verified. The technology could be used to simulate critical orbital anatomic features and could be used as a training tool for resident ophthalmologists.


What is the optimal duration for vigabatrin monotherapy in patients with infantile spasms: 6 months or longer?
Vigabatrin (VGB) is approved as monotherapy for pediatric patients with Infantile Spasms (IS). Duration of VGB use should be limited because of the risk of retinal and neurotoxicity, but the optimal length of treatment is unknown. Our study aimed to determine the risk of spasms relapse after 6 months of VGB as first-line therapy in IS patients deemed VGB good responders. The participants were 44 infants with IS who demonstrated both absence of clinical spasms and hypsarrhythmia four weeks after starting VGB, obtained from two cohorts: 29 patients from a multicenter prospective cohort and 15 patients from a retrospective single-center cohort. We divided them post hoc into two groups according to the duration of VGB treatment: 6-month group (n=34) and >6-month group (n=10) and compared outcome between the two groups. No patient in either group had a relapse of spasms. For patients with non-identified etiology (NIE) in the 6 months treatment group, no other seizure types were observed. Late epilepsy, in the form of focal seizures, emerged in only 5/37 patients (3/30 in the 6-month treatment group; 2/7 in the extended treatment group); all within the first 6-9 months after VGB initiation. Our study provides substantial evidence that a shortened VGB course of 6 months could be sufficient to treat and prevent relapse of spasms in children with IS, particularly those with NIE.


The effects of pH and intraliposomal buffer strength on the rate of liposome content release and intracellular drug delivery.
Targeted liposomal drug formulations may enter cells by receptor-mediated endocytosis and then traffick by membrane flow into acidic intracellular compartments. In order to understand the impact of these intracellular pH changes on liposomal drug unloading, the effect of pH on the release from folate-targeted liposomes of three model compounds with distinct pH dependencies was examined. 5(6)-carboxyfluorescein, which titrates from its anionic to uncharged form following internalization by KB cells, displays strong endocytosis-dependent release, since only its uncharged (endosomal) form is membrane permeable. Endocytosis-triggered unloading of drugs of this sort is enhanced by encapsulating the drug in a weak buffer at neutral pH, so that acidification of the intraliposomal compartment following cellular uptake can occur rapidly. Sulforhodamine B, in contrast, retains both anionic and cationic charges at endosomal pH (approximately pH 5), and consequently, escapes the endosomes only very slowly. Doxorubicin, which is commonly loaded into liposomes in its membrane-impermeable (cationic) form using an acidic buffer, still displays endocytosis-triggered unloading, since sufficient uncharged doxorubicin remains at endosomal pHs to allow rapid re-equilibration of the drug according to the new proton gradient across the membrane. In this case, when the extraliposomal [H+] increases 250-fold from 4 x 10(-8) M (pH 7.4, outside the cell) to 10(-5) M (pH 5, inside the endosome), the ratio of doxorubicin inside to outside the liposome must decrease by a factor of 250. Therefore, the collapse of the transliposomal pH gradient indirectly drives an efflux of the drug molecule from the liposome. Since a change in intraliposomal pH is not required to unload drugs of this type, the intraliposomal compartment can be buffered strongly at acidic pH to prevent premature release of the drug outside the cell. In summary, pH triggered release of liposome-encapsulated drugs can be achieved both with drugs that increase as well as decrease their membrane permeabilities upon acidification, as long as the intraliposomal buffer strength and pH is rationally selected.


Spleen-preserving surgery in treatment of large mesothelial splenic cyst in children--a case report and review of the literature.
The nonparasitic primary splenic cysts are very rare clinical entity. In the past, splenectomy was the treatment of choice but with the recognition of the spleen's important immunological function, spleen-preserving surgery is the preferred treatment modality. We hereby present a case of a large splenic mesothelial cyst and its treatment with preservation of the remaining splenic parenchyma. Our case shows that spleen-preserving surgery in treatment of the large splenic cysts is possible and safe procedure with maintenance of the splenic function.


Early expression of grain hardness in the developing wheat endosperm.
Seeds from near-isogenic hard and soft wheat lines were harvested at regular intervals from 5 days post-anthesis to maturity and examined for hardness using the single kernel characterisation system (SKCS). SKCS analysis revealed that hard and soft lines could be distinguished from 15 days post-anthesis (dpa). This trend continued until maturity where the difference between the hard and soft lines was most marked. SKCS could not be applied to the small 5- and 10-dpa wheat kernels. Fresh developing endosperm material was examined using light microscopy and no visible differences between the cultivars were detected. When air-dried material was examined using scanning electron microscopy (SEM) differences between soft and hard lines were visible from as early as 5 dpa. Accumulation of puroindoline a and puroindoline b was investigated in developing seeds using both Western blotting and ELISA. Low levels of puroindoline a could be detected in the soft cultivar from 10 dpa, reaching a maximum at 32 dpa. In the hard cultivar, puroindoline a levels were negligible throughout grain development. Puroindoline b accumulates in both the soft and hard cultivars from 15 dpa, but overall contents were higher in the soft cultivar. These findings indicate that endosperm hardness is expressed very early in developing grain when few starch granules and storage proteins were deposited in the endosperm cells. Further, the near-isogenic soft and hard Heron lines could be differentiated by SEM at a stage in development when the accumulation of puroindolines could not be detected by the methods used in this study.


Sex-specific effects of prenatal testosterone on nestling plasma antioxidant capacity in the zebra finch.
Trans-generational transfer of non-genetic, maternal resources such as hormones can have a substantial influence on offspring phenotype in many vertebrate species. In birds, maternal androgens enhance both growth and competitive behaviour, but also suppress the immune system. It has been hypothesised that high levels of egg androgens could also influence the prooxidant-antioxidant balance through their positive effect on growth and metabolism. We tested this hypothesis in the zebra finch (Taeniopygia guttata). Eggs were injected with testosterone dissolved in sesame oil or sesame oil only (control). We subsequently assessed the effect of the egg hormone manipulation on nestling growth and nestling plasma total antioxidant capacity (TAC). Growth rates of zebra finch nestlings were not significantly affected by egg hormone treatment. However, male offspring hatched from eggs with experimentally elevated testosterone had reduced plasma TAC at 10 days of age compared with male offspring hatching from control eggs. At the age of 34 days, males had similar plasma TAC irrespective of egg treatment. No effects of egg testosterone manipulation on nestling plasma TAC were found in females. Our results demonstrate that embryonic exposure to elevated levels of testosterone modulates chick antioxidant status, but this seems to be independent of chick growth. Sex-specific effects of prenatal testosterone on plasma TAC of zebra finch nestlings may have important consequences for sex allocation.


Growth hormone (GH) treatment acts on the endocrine and autocrine/paracrine GH/IGF-axis and on TNF-α expression in bony fish pituitary and immune organs.
There exist indications that the growth hormone (GH)/insulin-like growth factor (IGF) axis may play a role in fish immune regulation, and that interactions occur via tumour necrosis factor (TNF)-α at least in mammals, but no systematic data exist on potential changes in GH, IGF-I, IGF-II, GH receptor (GHR) and TNF-α expression after GH treatment. Thus, we investigated in the Nile tilapia the influence of GH injections by real-time qPCR at different levels of the GH/IGF-axis (brain, pituitary, peripheral organs) with special emphasis on the immune organs head kidney and spleen. Endocrine IGF-I served as positive control for GH treatment efficiency. Basal TNF-α gene expression was detected in all organs investigated with the expression being most pronounced in brain. Two consecutive intraperitoneal injections of bream GH elevated liver IGF-I mRNA and plasma IGF-I concentration. Also liver IGF-II mRNA and TNF-α were increased while the GHR was downregulated. In brain, no change occurred in the expression levels of all genes investigated. GH gene expression was exclusively detected in the pituitary where the GH injections elevated both GH and IGF-I gene expression. In the head kidney, GH upregulated IGF-I mRNA to an even higher extent than liver IGF-I while IGF-II and GHR gene expressions were not affected. Also in the spleen, no change occurred in GHR mRNA, however, IGF-I and IGF-II mRNAs were increased. In correlation, in situ hybridisation showed a markedly higher amount of IGF-I mRNA in head kidney and spleen after GH injection. In both immune tissues, TNF-α gene expression showed a trend to decrease after GH treatment. The stimulation of IGF-I and also partially of IGF-II expression in the fish immune organs by GH indicates a local role of the IGFs in immune organ regulation while the differential changes in TNF-α support the in mammals postulated interactions with the GH/IGF-axis which demand for further investigations.


Characterization of an Escherichia coli plasmid encoding for synthesis of heat-labile toxin: molecular cloning of the toxin determinant.
P307 is a plasmid isolated from a strain of Escherichia coli that was responsible for an outbreak of diarrheal disease in piglets. This 60 X 10(6)-dalton plasmid was subsequently shown to encode for the synthesis of a heat-labile toxin (LT). Using recombinant DNA technology, we isolated a 7.8 X 10(6)-dalton DNA fragment that contains the LT gene(s). This fragment was generated using an EcoRI partial digestion of P307 DNA, and the fragment was joined to a small multicopy plasmid, RSF2124. E. coli strains harboring the chimeric plasmid produced greater amounts of LT than did the same strains containing P307. The LT genes were also isolated on a 5.8 X 10(6)-dalton DNA fragment made by BamHI digestion, and we identified an EcoRI recognition sequence that is located in a position essential for LT synthesis.


What are the clinical questions of practicing veterinarians?
Clinical questions are central to learning among veterinarians and drive informal learning during clinical practice. We set out to classify the clinical questions of practicing veterinarians using a taxonomy previously validated in human medicine. This prospective observational study used a convenience sample of 12 veterinarians in private, small-animal practices. We used three methods to gather clinical questions from the veterinarians: direct observation (asking veterinarians after each encounter), self-report via e-mail, and self-report via data-collection pocket cards. We then classified these questions using a validated taxonomy of question types, as well as by clinical category. A total of 157 clinical questions were collected; 99 were about dogs, 33 were about cats, and 25 were about multiple species or did not specify a species. Nearly half of the questions were rated as high priority, and only 11.5% as low priority. Over half of the questions (53%) were about treatment and 20% were about diagnosis. The two most common question types were "Is drug X indicated in situation Y or for condition Y?" and "How should I treat finding/condition Y (given situation Z)?" Overall, 5 of 57 question-type categories accounted for over half of the questions. The most common clinical categories were pharmacology, endocrine, musculoskeletal, and general surgery. This is the first study to systematically identify and classify the clinical questions of veterinarians. A better understanding of these questions can be used to inform the development of continuing-education (CE) activities that are directly responsive to the information needs of participants.


Mesenchymal stem cells and neural crest stem cells from adult bone marrow: characterization of their surprising similarities and differences.
The generation of neuronal cells from stem cells obtained from adult bone marrow is of significant clinical interest in order to design new cell therapy protocols for several neurological disorders. The recent identification in adult bone marrow of stem cells derived from the neural crest stem cells (NCSC) might explain the neuronal phenotypic plasticity shown by bone marrow cells. However, little information is available about the nature of these cells compared to mesenchymal stem cells (MSC), including their similarities and differences. In this paper, using transcriptomic as well as proteomic technologies, we compared NCSC to MSC and stromal nestin-positive cells, all of them isolated from adult bone marrow. We demonstrated that the nestin-positive cell population, which was the first to be described as able to differentiate into functional neurons, was a mixed population of NCSC and MSC. More interestingly, we demonstrated that MSC shared with NCSC the same ability to truly differentiate into Tuj1-positive cells when co-cultivated with paraformaldehyde-fixed cerebellar granule neurons. Altogether, those results suggest that both NCSC and MSC can be considered as important tools for cellular therapies in order to replace neurons in various neurological diseases.


Local intraarterial fibrinolysis in the carotid territory.
A series comprising 12 patients who had intraarterial local fibrinolysis in the carotid territory is reported. A classification is proposed that divides the different types of occlusions into three groups on the basis of angiographic location. Group 1 (two cases) comprises occlusion of the extra- and/or intracranial carotid artery with patency of the circle of Willis and the lenticulostriate arteries. In this group, there is no brain infarction, the CT findings are normal, and the clinical signs are mainly hemodynamic and intermittent. Fibrinolysis may be performed late and rather safely and completed by surgery or angioplasty of the neck vessel stenosis responsible for the occlusion. Group 2 (five cases) comprises occlusions of the cortical arteries without involvement of the lenticulostriate arteries. The mechanism of the occlusion can be hemodynamic or embolic. Group 3 (five cases) comprises occlusions of intracerebral arteries involving the lenticulostriate arteries. In groups 2 and 3 with brain infarction, fibrinolysis will only be able to restore viability of the area of cerebral tissue surrounding the infarction (penumbra). The time factor is particularly critical in group 3 because lenticulostriate arteries are terminal vessels whose revascularization may induce hemorrhages with increasing frequency as the occlusion time is prolonged. The time factor is less critical in group 2 because collaterals make the ischemia less severe in the infarcted area and the vital and functional consequences of hemorrhage are not as serious as in group 3 because of the location. In this series, all the symptomatic complications of hemorrhage (two cases) occurred in group 3, in patients treated later than 6 hr after clinical onset. Given the time delay inherent in performing CT and angiography and in making the medical decision, it is considered dangerous to undertake fibrinolytic therapy in group 3, unless it can be started before 4 or 5 hr after clinical onset.


Variations in erythropoiesis-stimulating agent administration in transfusion-dependent myelodysplastic syndromes impact response.
Erythropoiesis-stimulating agents (ESAs) reduce red blood cell (RBC) transfusions in approximately 40% of patients with myelodysplastic syndrome (MDS) in clinical trials. We studied the association of timing of ESA initiation, agent (epoetin alfa, darbepoetin) and number of weeks of ESA use with response in MDS patients in routine practice. Patients diagnosed with MDS from 2001 to 2005 were identified in the Surveillance Epidemiology and End Results-Medicare linked database. The study cohort consisted of patients with new-onset transfusion dependence (TD). All patients received an ESA at least once during the study period, which began the week that criteria for TD were met and continued until transfusion independence (TI). Kaplan-Meier statistics and Cox Proportional Hazard models were used to assess relationships between time to ESA initiation, agent and number of weeks of ESA use and TI attainment. Of 610 TD patients treated with ESAs, 210 (34.4%) achieved TI. Median time from ESA initiation to TI was 13 weeks. Shorter time from TD to ESA initiation and use of darbepoetin were associated with higher probability of achieving TI. The probability of achieving TI decreased beyond 8 weeks of treatment, and was very low beyond 16 weeks (8-15 weeks: HR=0.64, 16-31 weeks: HR=0.25, 32+ weeks HR=0.10). In this observational, population-based study, variations in ESA administration impacted response in transfusion-dependent MDS patients, with higher response rates with early administration and use of darbepoetin, and low response likelihood in non-responders beyond 16 weeks of therapy.


Cannabinoids as Anticancer Drugs.
The endocannabinoid system encompassing cannabinoid receptors, endogenous receptor ligands (endocannabinoids), as well as enzymes conferring the synthesis and degradation of endocannabinoids has emerged as a considerable target for pharmacotherapeutical approaches of numerous diseases. Besides palliative effects of cannabinoids used in cancer treatment, phytocannabinoids, synthetic agonists, as well as substances that increase endogenous endocannabinoid levels have gained interest as potential agents for systemic cancer treatment. Accordingly, cannabinoid compounds have been reported to inhibit tumor growth and spreading in numerous rodent models. The underlying mechanisms include induction of apoptosis, autophagy, and cell cycle arrest in tumor cells as well as inhibition of tumor cell invasion and angiogenic features of endothelial cells. In addition, cannabinoids have been shown to suppress epithelial-to-mesenchymal transition, to enhance tumor immune surveillance, and to support chemotherapeutics' effects on drug-resistant cancer cells. However, unwanted side effects include psychoactivity and possibly pathogenic effects on liver health. Other cannabinoids such as the nonpsychoactive cannabidiol exert a comparatively good safety profile while exhibiting considerable anticancer properties. So far experience with anticarcinogenic effects of cannabinoids is confined to in vitro studies and animal models. Although a bench-to-bedside conversion remains to be established, the current knowledge suggests cannabinoid compounds to serve as a group of drugs that may offer significant advantages for patients suffering from cancer diseases. The present review summarizes the role of the endocannabinoid system and cannabinoid compounds in tumor progression.


Exploiting rhodium-catalysed ynamide hydroacylation as a platform for divergent heterocycle synthesis.
The first examples of ynamide hydroacylation are described. Using rhodium catalysis, linear β-enaminone products are generated in high yield and excellent regioselectivity from the combination of aldehydes and ynamides. The enaminone products are subsequently used as a platform to construct a diverse array of substituted pyrazoles, pyrimidines, and isoxazoles in a two-step, one-pot sequence. It was found that with judicious choice of catalyst system it was possible to overturn the regioselectivity of the hydroacylation reaction to generate α-enaminone products.


Country-specific correlations across Europe between modelled atmospheric cadmium and lead deposition and concentrations in mosses.
Previous analyses at the European scale have shown that cadmium and lead concentrations in mosses are primarily determined by the total deposition of these metals. Further analyses in the current study show that Spearman rank correlations between the concentration in mosses and the deposition modelled by the European Monitoring and Evaluation Programme (EMEP) are country and metal-specific. Significant positive correlations were found for about two thirds or more of the participating countries in 1990, 1995, 2000 and 2005 (except for Cd in 1990). Correlations were often not significant and sometimes negative in countries where mosses were only sampled in a relatively small number of EMEP grids. Correlations frequently improved when only data for EMEP grids with at least three moss sampling sites per grid were included. It was concluded that spatial patterns and temporal trends agree reasonably well between lead and cadmium concentrations in mosses and modelled atmospheric deposition.


A new saccadic indicator of peripheral vestibular function based on the video head impulse test.
While compensatory saccades indicate vestibular loss in the conventional head impulse test paradigm (HIMP), in which the participant fixates an earth-fixed target, we investigated a complementary suppression head impulse paradigm (SHIMP), in which the participant is fixating a head-fixed target to elicit anticompensatory saccades as a sign of vestibular function. HIMP and SHIMP eye movement responses were measured with the horizontal video head impulse test in patients with unilateral vestibular loss, patients with bilateral vestibular loss, and in healthy controls. Vestibulo-ocular reflex gains showed close correlation (R(2) = 0.97) with slightly lower SHIMP than HIMP gains (mean gain difference 0.06 ± 0.05 SD, p < 0.001). However, the 2 paradigms produced complementary catch-up saccade patterns: HIMP elicited compensatory saccades in patients but rarely in controls, whereas SHIMP elicited large anticompensatory saccades in controls, but smaller or no saccades in bilateral vestibular loss. Unilateral vestibular loss produced covert saccades in HIMP, but later and smaller saccades in SHIMP toward the affected side. Cumulative HIMP and SHIMP saccade amplitude differentiated patients from controls with high sensitivity and specificity. While compensatory saccades indicate vestibular loss in conventional HIMP, anticompensatory saccades in SHIMP using a head-fixed target indicate vestibular function. SHIMP saccades usually appear later than HIMP saccades, therefore being more salient to the naked eye and facilitating vestibulo-ocular reflex gain measurements. The new paradigm is intuitive and easy to explain to patients, and the SHIMP results complement those from the standard video head impulse test. This case-control study provides Class III evidence that SHIMP accurately identifies patients with unilateral or bilateral vestibulopathies.


Determining the Presence of Thin-Walled Regions at High-Pressure Areas in Unruptured Cerebral Aneurysms by Using Computational Fluid Dynamics.
Thin-walled regions (TWRs) of cerebral aneurysms are at high risk of rupture, and careful attention should be paid during surgical procedures. Despite this, an optimal imaging technique to estimate TWRs has not been established. Previously, pressure elevation at TWRs was reported with computational fluid dynamics (CFD) but not fully evaluated. To investigate the possibility of predicting aneurysmal TWRs at high-pressure areas with CFD. Fifty unruptured middle cerebral artery aneurysms were analyzed. Spatial and temporal maximum pressure (Pmax) areas were determined with a fluid-flow formula under pulsatile blood flow conditions. Intraoperatively, TWRs of aneurysm domes were identified as reddish areas relative to the healthy normal middle cerebral arteries; 5 neurosurgeons evaluated and divided these regions according to Pmax area and TWR correspondence. Pressure difference (PD) was defined as the degree of pressure elevation on the aneurysmal wall at Pmax and was calculated by subtracting the average pressure from the Pmax and dividing by the dynamic pressure at the aneurysm inlet side for normalization. In 41 of the 50 cases (82.0%), the Pmax areas and TWRs corresponded. PD values were significantly higher in the correspondence group than in the noncorrespondence group (P = .008). A receiver-operating characteristic curve demonstrated that PD accurately predicted TWRs at Pmax areas (area under the curve, 0.764; 95% confidence interval, 0.574-0.955; cutoff value, 0.607; sensitivity, 66.7%; specificity, 82.9%). A high PD may be a key parameter for predicting TWRs in unruptured cerebral aneurysms. CFD, computational fluid dynamicsMCA, middle cerebral arteryPave, average pressurePD, pressure differencePmax, maximum pressureTWR, thin-walled regionWSS, wall shear stress.


The Applicability of the Patient-Specific Functional Scale (PSFS) in Rehabilitation for Patients with Acquired Brain Injury (ABI) - A Cohort Study.
The primary aim of this study was to investigate the applicability of the Patient-Specific Functional Scale (PSFS) in patients with acquired brain injury (ABI) admitted to a specialized rehabilitation unit in a regional hospital. A secondary aim was to identify patient characteristics and functioning that predicted changes in the PSFS. In a cohort study, 59 patients with ABI were assessed for the ability to complete the PSFS. A trained multidisciplinary team applied the PSFS as part of a collaborative development of rehabilitation goals. The modified Rankin Scale (mRS), the Functional Ambulation Categories (FAC), the Rivermead Behavioural Memory Test (RBMT), the Norwegian Basic Aphasia Assessment (NBAA) and the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) were used to identify characteristics of the sample. Multivariate regression analyses were performed to investigate associations between changes in the PSFS score from admission to discharge and a selected set of participant baseline characteristics and functioning. Fifty-four patients (92%) of the patients with ABI were able to complete the PSFS. The five (8%) who were unable to complete the PSFS had severe cognitive or language impairment. The PSFS score improved by a mean of 2.6 (SD 2.0) points from admission to discharge. The LOTCA score made the strongest unique contribution to explain the change in the PSFS score (beta = 0.477, p= 0.020). In the present study, most patients with ABI (92%) were able to complete the PSFS. Cognitive function on admission was a predictor of improved functioning on the PSFS.


Infants' learning of novel words in a stochastic environment.
In everyday word learning words are only sometimes heard in the presence of their referent, making the acquisition of novel words a particularly challenging task. The current study investigated whether children (18-month-olds who are novice word learners) can track the statistics of co-occurrence between words and objects to learn novel mappings in a stochastic environment. Infants were briefly trained on novel word-novel object pairs with variable degrees of co-occurrence: Words were either paired reliably with 1 referent or stochastically paired with 2 different referents with varying probabilities. Infants were sensitive to the co-occurrence statistics between words and referents, tracking not just the strongest available contingency but also low-frequency information. The statistical strength of the word-referent mapping may also modulate real-time online lexical processing in infants. Infants are thus able to track stochastic relationships between words and referents in the process of learning novel words.


Distinct cytoplasmic regions of the human granulocyte colony-stimulating factor receptor involved in induction of proliferation and maturation.
The granulocyte colony-stimulating factor receptor (G-CSF-R) transduces signals important for the proliferation and maturation of myeloid progenitor cells. To identify functionally important regions in the cytoplasmic domain of the G-CSF-R, we compared the actions of the wild-type receptor, two mutants, and a natural splice variant in transfectants of the mouse pro-B cell line BAF3 and two myeloid cell lines, 32D and L-GM. A region of 55 amino acids adjacent to the transmembrane domain was found to be sufficient for generating a growth signal. The immediate downstream sequence of 30 amino acids substantially enhanced the growth signaling in the three cell lines. In contrast, the carboxy-terminal part of 98 amino acids strongly inhibited growth signaling in the two myeloid cell lines but not in BAF3 cells. Truncation of this region lead to an inability of the G-CSF-R to transduce maturation signals in L-GM cells. An alternative carboxy tail present in a splice variant of the G-CSF-R also inhibited growth signaling, notably in both the myeloid cells and BAF3 cells, but appeared not to be involved in maturation.


Development of a variable number of tandem repeats typing scheme for the bacterial rice pathogen Xanthomonas oryzae pv. oryzicola.
Xanthomonas oryzae pv. oryzicola is an important bacterial pathogen responsible for outbreaks of bacterial leaf streak (BLS) on rice, mostly occurring in Asia and parts of Africa. To better monitor epidemics and assess population structures, efficient tools that allow the precise identification and diagnosis of pathogenic populations are needed. In this study, we explored variable numbers of tandem repeats (VNTR) as a fast, reliable, and cost-effective molecular typing tool. Screening of three X. oryzae pv. oryzicola genome sequences (Philippine strain BLS256, Chinese strain GX01, and Malian strain MAI10) predicted 28 candidate VNTR loci. Primer pairs for polymerase chain reaction (PCR) amplification of all 28 loci were designed and applied to a panel of 20 X. oryzae pv. oryzicola strains originating from Asia and Africa. Sequencing of PCR amplicons revealed 25 robust and polymorphic VNTR loci that are shared among Asian and African X. oryzae pv. oryzicola strains. A dendrogram constructed from 25 VNTR loci indicated that most Asian strains are clearly discriminated from African strains. However, in agreement with previous reports, one strain from Mali is related to Asian strains, pointing to a possible introduction of Asian strains to the African continent. The new VNTR-based tool described here is useful for studies of population structures and epidemiological monitoring of X. oryzae pv. oryzicola.


Echolocation and pursuit of prey by bats.
Echolocating bats use different information-gathering strategies for hunting prey in open, uncluttered environments, in relatively open environments with some obstacles, and in densely cluttered environments. These situations differ in the extent to which individual targets such as flying insects can be detected as isolated objects or must be separated perceptually from backgrounds. Echolocating bats also differ in whether they use high-resolution, multidimensional images of targets or concentrate specifically on one particular target dimension, such as movement, to detect prey.


Organizational Savvy: Critical to Career Development in Academic Medicine.
Organizational savvy is critical to career development, but is rarely discussed as a learnable skill. Drawing on >45 years of working closely with Academic Health Center professionals, the author offers an introduction to navigating organizational dynamics that will be especially valuable to women, as they tend to be less effectively mentored than men; mentors may also find this guide of use in coaching these skills. Common misconceptions that interfere with acquiring organizational savvy include assuming that academic medicine is a meritocracy, that hard work will assure success, and that disagreements are personal. People who learn to navigate competitive hierarchies are continuously expanding their understanding of significant events, of how their unit fits within the larger system, and of which constraints they can influence. Strategies suggested for developing a political compass focus on building relationships, learning from surprises and disappointments, facilitating dialogue with open-ended questions, and handling sensitive topics as they arise. The author opens with a case illustrating common new faculty dilemmas and closes with examples applying the mentioned recommendations. Becoming more organizationally savvy helps professionals advance not only their own careers but also improvements in their institutions.


The relationship between yoga involvement, mindfulness and psychological well-being.
The aim of this study was to examine how different levels of yoga involvement are related to different parameters of mental health and illness. A total sample of 455 participants (410 females) were investigated by means of an internet survey. 362 yoga practitioners (327 females) rated their degree of yoga involvement on the Yoga Immersion Scale. A control group was comprised of 93 gymnastics practitioners (83 females). All participants completed the Multidimensional Inventory for Religious/Spiritual Well-Being, the Freiburger Mindfulness Inventory and the Brief Symptom Inventory for psychiatric symptoms. Highly involved yoga practitioners exhibited a significantly increased amount of mindfulness and religious/spiritual well-being (both p<0.01) and lower psychiatric symptoms such as depression (p<0.01) compared to those who were only marginally/moderately yoga-involved or who were in the gymnastics control group. In accordance with the literature, yoga practice might have its biggest impact on mental health when it is part of a practitioner's worldview. Further research focusing on the impact of yoga involvement in clinical groups is encouraged.


Does the choice of tariff matter?: A comparison of EQ-5D-5L utility scores using Chinese, UK, and Japanese tariffs on patients with psoriasis vulgaris in Central South China.
There is an increasing trend globally to develop country-specific tariffs that can theoretically better reflect population's preferences on health states for preference-based health-related quality-of-life instruments, also known as multiattribute utility instruments. This study focused on the most recently developed 5-level version of EuroQol-5 Dimension (EQ-5D) questionnaire, 1 of the world's most well-known multiattribute utility instruments, and aimed to empirically explore the agreements and known-group validities of applying the country-specific tariff versus tariffs developed from other countries using a sample of psoriasis vulgaris patients in Mainland China.A convenience sampling framework was adopted to recruit patients diagnosed with psoriasis vulgaris from Xiangya Hospital, Central South University, China, between May 2014 and February 2015. The 5-level EuroQol-5 dimensions (EQ-5D-5L) utilities were scored by using the Chinese, Japanese, and UK tariffs. Health state utilities were compared using a range of nonparametric test. The intraclass correlation coefficients and Bland-Altman plots were used to examine the agreements among the 3 EQ-5D-5L scores. Health state utility decrements between known groups were investigated using both effect size and a regression analysis.In all, 350 patients (aged 16 years or older) were recruited. There were significant differences among the 3 national tariff sets. Overall, 3 tariffs showed excellent agreements (intraclass correlation coefficient >0.90); however, the wide limits of agreement from the Bland-Altman plots suggest that these tariffs cannot be used interchangeably. The EQ-5D-5L scores using the Chinese-specific tariff showed the best known-group validity than the other 2 tariffs in this Chinese patient sample. The evidence from this study supports the choice of the country-specific tariff to be used in Mainland China.


Effects of PDH activation by dichloroacetate in human skeletal muscle during exercise in hypoxia.
During the onset of exercise in hypoxia, the increased lactate accumulation is associated with a delayed activation of pyruvate dehydrogenase (PDH; Parolin ML, Spreit LL, Hultman E, Hollidge-Horvat MG, Jones NL, and Heigenhauser GJF. Am J Physiol Endocrinol Metab 278: E522-E534, 2000). The present study investigated whether activation of PDH with dichloroacetate (DCA) before exercise would reduce lactate accumulation during exercise in acute hypoxia by increasing oxidative phosphorylation. Six subjects cycled on two occasions for 15 min at 55% of their normoxic maximal oxygen uptake after a saline (control) or DCA infusion while breathing 11% O(2). Muscle biopsies of the vastus lateralis were taken at rest and after 1 and 15 min of exercise. DCA increased PDH activity at rest and at 1 min of exercise, resulting in increased acetyl-CoA concentration and acetylcarnitine concentration at rest and at 1 min. In the first minute of exercise, there was a trend toward a lower phosphocreatine (PCr) breakdown with DCA compared with control. Glycogenolysis was lower with DCA, resulting in reduced lactate concentration ([lactate]), despite similar phosphorylase a mole fractions and posttransformational regulators. During the subsequent 14 min of exercise, PDH activity was similar, whereas PCr breakdown and muscle [lactate] were reduced with DCA. Glycogenolysis was lower with DCA, despite similar mole fractions of phosphorylase a, and was due to reduced posttransformational regulators. The results from the present study support the hypothesis that lactate production is due in part to metabolic inertia and cannot solely be explained by an oxygen limitation, even under conditions of acute hypoxia.


Breath Analysis: A Systematic Review of Volatile Organic Compounds (VOCs) in Diagnostic and Therapeutic Management of Pleural Mesothelioma.
Malignant pleural mesothelioma (MPM) is a rare neoplasm related to asbestos exposure and with high mortality rate. The management of patients with MPM is complex and controversial, particularly with regard to early diagnosis. In the last few years, breath analysis has been greatly implemented with this aim. In this review the strengths of breath analysis and preliminary results in searching breath biomarkers of MPM are highlighted and discussed, respectively. Through a systematic electronic literature search, collecting papers published from 2000 until December 2018, fifteen relevant scientific papers were selected. All papers considered were prospective, comparative, observational case-control studies although every single one pilot and based on a relatively small number of samples. The identification of diagnostic VOCs pattern, through breath sample characterization and the statistical data treatment, allows to obtain a strategic information for clinical diagnostics. To date the collected data provide just preliminary information and, despite the promising results and diagnostic accuracy, conclusions cannot be generalized due to the limited number of individuals included in each cohort study. Furthermore none of studies was externally validated, although validation process is a necessary step towards clinical implementation. Breathomics-based biomarker approach should be further explored to confirm and validate preliminary findings and to evaluate its potential role in monitoring the therapeutic response.


New Onset Diabetes and Non-Alcoholic Fatty Liver Disease after Liver Transplantation.
Non-alcoholic fatty liver disease (NAFLD) is an emerging cause of graft dysfunction after liver transplantation (LT) frequently related to the development of new onset diabetes after LT (NODAT). This study was undertaken to evaluate the frequencies of NODAT and NAFLD after LT, to investigate their major risk factors and the impact of de novo or recurrent NAFLD in graft function. 119 patients submitted to LT were prospectively evaluated. After 4 ± 1 years, NODAT, recurrent and de novo NAFLD were observed in 31%, 56% and 43% of the subjects, respectively. Only 3 patients had non-alcoholic steatohepatitis (NASH) without fibrosis. Other risk factors for NAFLD such as arterial hypertension (AHT), metabolic syndrome (MS), hypertriglyceridemia and obesity were seen in 51%, 50%, 35% and 24% of the subjects, respectively. In addition, insulin resistance (IR), assessed by HOMA-IR and β-cell dysfunction, determined by HOMA-β, were observed in 16% and 94% of the patients, respectively. Occurrence of NODAT was associated with male gender, higher waist circumference, higher HOMA-IR and lower HOMA-β values. No correlation was found between NAFLD and NODAT, MS, hypertriglyceridemia, obesity and HOMAIR and HOMA-β levels. NODAT, recurrent and de novo NAFLD are common after LT but are not associated with signs of graft dysfunction, possibly due to the low frequency of IR and NASH. No correlation is observed between NAFLD and NODAT, MS, hypertriglyceridemia, obesity and IR. β-cell dysfunction and diabetes, however, are seen in most of the patients, possibly due to calcineurin inhibitor toxicity.