A genetic dissection of antipsychotic induced movement disorders.
Antipsychotic medications (APM) are the first line pharmacological treatment for psychotic disorders and other behavioral disorders. Nevertheless, their use causes a number of side effects, including extrapyramidal symptoms (EPS). EPS decrease the efficacy of the antipsychotic treatments by causing poorer compliance to the treatment, stigma and a poorer quality of life for patients. Genetic studies hold the potential to unravel the molecular underpinnings of the EPS induced by APM but results are not conclusive and are far to be used in clinical practice despite decades of research. A more sophisticated selection of the list of genetic mutations explaining the genetic variance of EPS induced by APM could help in the definition of a personalized treatments for patients. Moreover, it would increase the quality of the current treatments with APM. We reviewed the literature searching for the genetic association studies focused on dystonia, parkinsonism, akathisia and tardive dyskinesia. Moreover, we reviewed the current biological knowledge of the APM induced side effects. Finally, we provide a reasoned list of candidate genes and their genetic variations, with the aim of identifying a list of candidates for APM induced EPS genetic investigations. Variations located within PIK3CA (phosphoinositide-3- kinase, catalytic, alpha polypeptide), PLA2G4A (phospholipase A2, group IVA, cytosolic, calcium-dependent), PRKCA (protein kinase C, alpha), PRKACG (Phosphatidylinositol-4,5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma), ERK-1 (extracellular signalregulated kinase 1 (MAPK3)), ERK-2 (extracellular signal-regulated kinase 2 (MAPK1)), GNAS (guanine nucleotide binding protein (G protein), alpha stimulating activity polypeptide 1), PLCB1 (phospholipase C, beta 1 (phosphoinositide-specific)) and ITPR1 (inositol 1,4,5-triphosphate receptor type 1) were found to be relevant for APM induced EPS. Some of the genes are classical candidates for this kind of research, others were never investigated. For each of these genes we provide a list of variations that balances the limitations of multitesting with the advantages of the tagging approach. We undertook a review of the literature about the APM induced EPM to provide some rational genetic candidates to be tested in further genetic investigations.


Analysis of repolarization of presynaptic motor terminals in Drosophila larvae using potassium-channel-blocking drugs and mutations.
In Drosophila melanogaster muscles and neuronal cell bodies at least four different potassium currents have been identified whose activity shapes the electrical properties of these cells. Potassium currents also control repolarization of presynaptic terminals and, therefore, exert a major effect on transmitter release and synaptic plasticity. However, because of the small size of presynaptic terminals in Drosophila, it has not been possible to analyze the potassium currents they express. As a first approach to characterizing the ionic currents present at presynaptic motor terminals of Drosophila larvae, we recorded synaptic currents at the neuromuscular junction. From the alterations in evoked synaptic currents caused by various drugs and by mutations known to affect potassium currents in other tissues, we suggest that the repolarizing mechanism in presynaptic terminals consists of at least four distinct currents. One is affected by aminopyridines or Sh mutations, a second component is affected by the slo mutation, a third is sensitive to quinidine and one or more additional components are blocked by tetraethylammonium. Depolarization depends on a presynaptic calcium current, which displays only slight voltage-dependent inactivation. Because the mechanism of repolarization exerts a major effect on synaptic activity, this analysis provides a framework for further genetic and molecular dissection of the basic processes involved in the regulation of transmitter release.


Clinical prediction rules for pulmonary embolism: a systematic review and meta-analysis.
Pretest probability assessment is necessary to identify patients in whom pulmonary embolism (PE) can be safely ruled out by a negative D-dimer without further investigations. Review and compare the performance of available clinical prediction rules (CPRs) for PE probability assessment. We identified studies that evaluated a CPR in patients with suspected PE from Embase, Medline and the Cochrane database. We determined the 95% confidence intervals (CIs) of prevalence of PE in the various clinical probability categories of each CPR. Statistical heterogeneity was tested. We identified 9 CPR and included 29 studies representing 31215 patients. Pooled prevalence of PE for three-level scores (low, intermediate or high clinical probability) was: low, 6% (95% CI, 4-8), intermediate, 23% (95% CI, 18-28) and high, 49% (95% CI, 43-56) for the Wells score; low, 13% (95% CI, 8-19), intermediate, 35% (95% CI, 31-38) and high, 71% (95% CI, 50-89) for the Geneva score; low, 9% (95% CI, 8-11), intermediate, 26% (95% CI, 24-28) and high, 76% (95% CI, 69-82) for the revised Geneva score. Pooled prevalence for two-level scores (PE likely or PE unlikely) was 8% (95% CI,6-11) and 34% (95% CI,29-40) for the Wells score, and 6% (95% CI, 3-9) and 23% (95% CI, 11-36) for the Charlotte rule. Available CPR for assessing clinical probability of PE show similar accuracy. Existing scores are, however, not equivalent and the choice among various prediction rules and classification schemes (three- versus two-level) must be guided by local prevalence of PE, type of patients considered (outpatients or inpatients) and type of D-dimer assay applied.


Structural basis of integrin regulation and signaling.
Integrins are cell adhesion molecules that mediate cell-cell, cell-extracellular matrix, and cell-pathogen interactions. They play critical roles for the immune system in leukocyte trafficking and migration, immunological synapse formation, costimulation, and phagocytosis. Integrin adhesiveness can be dynamically regulated through a process termed inside-out signaling. In addition, ligand binding transduces signals from the extracellular domain to the cytoplasm in the classical outside-in direction. Recent structural, biochemical, and biophysical studies have greatly advanced our understanding of the mechanisms of integrin bidirectional signaling across the plasma membrane. Large-scale reorientations of the ectodomain of up to 200 A couple to conformational change in ligand-binding sites and are linked to changes in alpha and beta subunit transmembrane domain association. In this review, we focus on integrin structure as it relates to affinity modulation, ligand binding, outside-in signaling, and cell surface distribution dynamics.


Single Nucleotide Polymorphism Analysis Indicates Genetic Distinction and Reduced Diversity of Swine-Associated Methicillin Resistant Staphylococcus aureus (MRSA) ST5 Isolates Compared to Clinical MRSA ST5 Isolates.
Livestock associated methicillin resistant S. aureus (LA-MRSA) are lineages adapted to livestock species. LA-MRSA can be transmitted to humans and public health concerns exist because livestock may be the largest MRSA reservoir outside of hospital settings. Although the predominant European (ST398) and Asian (ST9) lineages of LA-MRSA are considered livestock adapted, North American swine also harbor ST5, a globally disseminated and highly pathogenic lineage. This study applied whole genome sequencing and single nucleotide polymorphism (SNP) typing to compare the population structure and genetic relatedness between swine associated and human clinical MRSA ST5 isolates. The established high-resolution phylogenomic framework revealed that LA-MRSA and human clinical MRSA ST5 are genetically distinct. LA-MRSA isolates were found to be clonal within farms, while greater genome diversity was observed among sampled clinical MRSA ST5. Analysis of the accessory genome demonstrated that LA-MRSA ST5 isolates and clinical MRSA ST5 isolates harbor different AMR genes and virulence factors, consistent with the SNP analysis. Collectively, our data indicate LA-MRSA and clinical MRSA ST5 isolates are distinct and the swine reservoir is likely of minimal significance as a source of clinical MRSA ST5 infections.


An online programme to reduce depression in patients with multiple sclerosis: a randomised controlled trial.
With a lifetime risk for major depressive disorder of up to 50%, depression is a common comorbidity in multiple sclerosis but remains widely underdiagnosed and untreated. We investigated the potential of a fully automated, internet-based, cognitive behavioural therapy programme, Deprexis, to reduce depressive symptoms in patients with multiple sclerosis. For this randomised controlled trial, we recruited patients from an outpatient clinic in Hamburg, Germany. Patients aged 18-65 years were eligible for inclusion if they had multiple sclerosis and self-reported depressive symptoms. By use of a computer-generated randomisation sequence, we allocated 90 patients (1:1; no blocking or stratification) to either the intervention group or a waitlist control group for 9 weeks. The primary endpoint was the Beck Depression Inventory (BDI), as assessed by an intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01663649. 71 patients completed the trial: 35 patients in the intervention group and 36 patients in the control group. During the intervention, BDI scores decreased in the Deprexis group and increased in the control group, yielding a positive effect of Deprexis relative to the waitlist group (mean group difference -4·02 points [95% CI -7·26 to -0·79], p=0·015, effect size d=0·53). Worsening of depressive symptoms from below to above the clinical cutoff (BDI >13) occurred in three (7%) of 45 patients in the control group and no patients in the Deprexis group. We noted no adverse events with respect to new occurrence of suicidal ideation during the trial. Psychological online-intervention programmes could be suitable for patients with multiple sclerosis who are unable to regularly attend therapeutic sessions because of mobility impairments. European Union and the Deutsche Forschungsgemeinschaft.


Predicting transmission of pulmonary tuberculosis in Daerah Istimewa Yogyakarta Province, Indonesia.
This study aims to explain the current dispersion of tuberculosis (TB) and provide evidence that could help predicting its future transmission in Daerah Istimewa Yogyakarta (DIY) Province, Java Island, Indonesia. One hundred thirty-two adult (>14 years old) individuals, with TB diagnosed by health professionals using the Directly Observed Treatment, Short Course strategy, were identified Their residential addresses and geographical patterns of movement were investigated by global positioning systems and descriptive spatial analysis using standard deviation ellipse analysis and kernel estimation. The dispersion of TB cases was studied by ellipse regression, which showed a pattern extending in a direction oriented from north-west to south-east centred on Kasihan District, Bantul Regency, DIY Province, located near Yogyakarta City. Levels of TB risk in the study area varied from non-existent to high as calculated by kernel estimation. We conclude that suburban communities, followed by densely populated residential areas, enabled by socio-economic factors, are more likely to see increased TB transmission in the future.


Nutritional rickets in Turkey.
Nutritional rickets (NR) remains the most common form of developmental bone disease, in spite of the efforts of clinicians and health care providers to reduce the incidence of the disease in Turkey. Today, it is well known that the etiology of NR exists along a spectrum ranging from isolated vitamin D deficiency to isolated calcium deficiency. In Turkey, almost all NR results from vita-min D deficiency that may have temporary but profound effects on short- and long-term skeletal development. Recent evidence suggests that vitamin D deficiency during infancy may predispose a patient to diseases such as diabetes mellitus, cancer, multiple sclerosis, etc. The factors responsible for the high prevalence of vitamin D deficiency in developing countries and its resurgence in developed countries include the following: limited sunshine exposure as individuals spend more time indoors watching television and working on computers or intentional sunshine avoidance for skin cancer prevention. Traditional clothing (covered dress) further limits the exposure to sunshine and thus decreases the endogenous synthesis of vitamin D. In Turkey, maternal vitamin D deficiency and breast feeding without supplementation are the most prominent reasons. The diagnosis of NR is established with a thorough history and physical examination and confirmed by laboratory evaluation. In conclusion, recent literature has drawn attention to the supplemental doses of vitamin D required to achieve a serum 25-hydroxyvitamin D level of at least 20 ng/ml (50 nmol/l), the serum concentration that is needed to optimize absorption of dietary calcium, suppress excess secretion of parathyroid hormone, and reduce fracture risk as well as prevent long-term negative effects.


The α1-adrenoceptor inhibitor ρ-TIA facilitates net hunting in piscivorous Conus tulipa.
Cone snails use separately evolved venoms for prey capture and defence. While most use a harpoon for prey capture, the Gastridium clade that includes the well-studied Conus geographus and Conus tulipa, have developed a net hunting strategy to catch fish. This unique feeding behaviour requires secretion of "nirvana cabal" peptides to dampen the escape response of targeted fish allowing for their capture directly by mouth. However, the active components of the nirvana cabal remain poorly defined. In this study, we evaluated the behavioural effects of likely nirvana cabal peptides on the teleost model, Danio rerio (zebrafish). Surprisingly, the conantokins (NMDA receptor antagonists) and/or conopressins (vasopressin receptor agonists and antagonists) found in C. geographus and C. tulipa venom failed to produce a nirvana cabal-like effect in zebrafish. In contrast, low concentrations of the non-competitive adrenoceptor antagonist ρ-TIA found in C. tulipa venom (EC50 = 190 nM) dramatically reduced the escape response of zebrafish larvae when added directly to aquarium water. ρ-TIA inhibited the zebrafish α1-adrenoceptor, confirming ρ-TIA has the potential to reverse the known stimulating effects of norepinephrine on fish behaviour. ρ-TIA may act alone and not as part of a cabal, since it did not synergise with conopressins and/or conantokins. This study highlights the importance of using ecologically relevant animal behaviour models to decipher the complex neurobiology underlying the prey capture and defensive strategies of cone snails.


Care and competence in medical practice: Francis Peabody confronts Jason Posner.
In this paper, I discuss the role of care and competence, as well as their relationship to one another, in contemporary medical practice. I distinguish between two types of care. The first type, care(1), represents a natural concern that motivates physicians to help or to act on the behalf of patients, i.e. to care about them. However, this care cannot guarantee the correct technical or right ethical action of physicians to meet the bodily and existential needs of patients, i.e. to take care of them-care(2). To that end, physicians must be competent in the practice of medicine both as evidence-based science (technical competence) and as patient-centered art (ethical competence). Only then, I argue, can physicians take care of (care(2)) patients' bodily and existential needs in a compassionate and comprehensive manner. Importantly, although care(1) precedes competence, competence--both technical and ethical--is required for genuine care(2), which in turn reinforces an authentic care(1). I utilize the play Wit, especially the character Jason Posner, and Francis Peabody's exposition on caring for patients, to illustrate the role of care and competence in contemporary medical practice.


Combined DFT and experimental studies of C-C and C-X elimination reactions promoted by a chelating phosphine-alkene ligand: the key role of penta-coordinate Pd(II.).
A combined computational and experimental study of the coordination chemistry of phosphine-alkene ligand L1 (N-diphenylphosphino-7-aza-benzobicyclo[2.2.1]hept-2-ene) with Pd(0) and Pd(II) is presented. Experimentally it is established that ligand L1 promotes direct alkyl-alkyl and indirect alkyl-halide reductive elimination from Pd(II) species, affording the palladium(0) complex [Pd(κ(2)-P,C-L1)2] (2) in each case. The effectiveness of L1 in promoting these reactions is attributed to the initial formation of a penta-coordinate intermediate [PdMe(X)(κ(1)-P-L1)(κ(2)-P,C-L1)] (X = Me, Cl) coupled with the ease with which it transforms to 2. From computation, a lower activation barrier for C(sp(3))-C(sp(3)) coupling and subsequent elimination has been computed for a stepwise associative pathway involving the initial formation of [PdMe2(κ(1)-P-L1)(κ(2)-P,C-L1)], compared to that computed for direct elimination from its parent, cis-[PdMe2(κ(2)-P,C-L1)]. Moreover, the C(sp(3))-C(sp(3)) coupling reaction has been found to be primarily under thermodynamic control. It has also been demonstrated computationally that the methyl group of penta-coordinate [PdCl(Me)(κ(1)-P-L1)(κ(2)-P,C-L1)] is susceptible to nucleophilic attack by the phosphorus lone pair of a further equivalent of ligand L1, which proceeds through an SN2-like transition state. This initiates an unusual, indirect intermolecular reductive elimination process, resulting in the formation of equimolar quantities of the methyl phosphonium chloride salt of L1 and complex 2, in agreement with experimental observations. In contrast to the C(sp(3))-C(sp(3)) coupling, computation shows that this indirect C(sp(3))-Cl reductive elimination process is essentially under kinetic control.


The safety attitudes questionnaire - ambulatory version: psychometric properties of the Norwegian translated version for the primary care setting.
Patient safety culture is how leader and staff interaction, attitudes, routines and practices protect patients from adverse events in healthcare. The Safety Attitudes Questionnaire is the most widely used instrument to measure safety attitudes among health care providers. The instrument may identify possible weaknesses in clinical settings, and motivate and guide quality improvement interventions and reductions in medical errors. The Safety Attitudes Questionnaire - Ambulatory Version was developed for measuring safety culture in the primary care setting. The original version includes six major patient safety factors: Teamwork climate, Safety climate, Job satisfaction, Perceptions of management, Working conditions and Stress recognition. We describe the results of a validation study using the Norwegian translation of the questionnaire in the primary care setting, and present the psychometric properties of this version. The study was done in seven Out-of-hours casualty clinics and 17 regular GP practices employing a total of 510 primary health care providers (194 nurses and 316 medical doctors). In October and November 2012, the translated Safety Attitudes Questionnaire - Ambulatory Version was distributed by e-mail. Data were collected electronically using the program QuestBack, whereby the participants responded anonymously. SPSS was used to estimate the Cronbach's alphas, item-to-own-factor correlations, intercorrelations of factors and item-descriptive statistics. The confirmatory factor analysis was done by AMOS. Of the 510 invited health care providers, 266 (52%) answered the questionnaire - 72% of the registered nurses (n = 139) and 39% of the medical doctors (n = 124). In the confirmatory factor analysis, the following five factor model was shown to have acceptable goodness-of-fit values in the Norwegian primary care setting: Teamwork climate, Safety climate, Job satisfaction, Working conditions and Perceptions of management. The results of our study indicate that the Norwegian translated version of the Safety Attitudes Questionnaire - Ambulatory Version, with the five confirmed factors, might be a useful tool for measuring several aspects of patient safety culture in the primary care setting. Further research should investigate whether there is an association between patient safety culture in primary care, as measured by the Safety Attitudes Questionnaire - Ambulatory Version, and occurrence of medical errors and negative patient outcome.


Single cell transcriptomics of mouse kidney transplants reveals a myeloid cell pathway for transplant rejection.
Myeloid cells are increasingly recognized as major players in transplant rejection. Here, we used a murine kidney transplantation model and single cell transcriptomics to dissect the contribution of myeloid cell subsets and their potential signaling pathways to kidney transplant rejection. Using a variety of bioinformatic techniques, including machine learning, we demonstrate that kidney allograft-infiltrating myeloid cells followed a trajectory of differentiation from monocytes to proinflammatory macrophages, and they exhibited distinct interactions with kidney allograft parenchymal cells. While this process correlated with a unique pattern of myeloid cell transcripts, a top gene identified was Axl, a member of the receptor tyrosine kinase family Tyro3/Axl/Mertk (TAM). Using kidney transplant recipients with Axl gene deficiency, we further demonstrate that Axl augmented intragraft differentiation of proinflammatory macrophages, likely via its effect on the transcription factor Cebpb. This, in turn, promoted intragraft recruitment, differentiation, and proliferation of donor-specific T cells, and it enhanced early allograft inflammation evidenced by histology. We conclude that myeloid cell Axl expression identified by single cell transcriptomics of kidney allografts in our study plays a major role in promoting intragraft myeloid cell and T cell differentiation, and it presents a potentially novel therapeutic target for controlling kidney allograft rejection and improving kidney allograft survival.


Multifunctional role of dysprosium in HfO2: stabilization of the high temperature cubic phase, and magnetic and photoluminescence properties.
Hafnium oxide (HfO2) can exist in different crystalline structures such as monoclinic at room temperature, tetragonal at 1700 °C and cubic at 2600 °C. In the present study, nanocrystalline powders of HfO2 synthesized by a Pechini type sol-gel technique show a monoclinic phase, P21/c, at room temperature. By incorporating Dy into the HfO2 lattice, the intensity of all diffraction peaks corresponding to P21/c decreases and at a concentration of 11 at% of Dy, the monoclinic phase transforms completely to the cubic phase, Fm3[combining macron]m, showing a mixed phase of monoclinic and cubic at intermediate concentrations (5-9 at%) of Dy. For the first time, we have stabilized the high temperature cubic phase of HfO2 at room temperature by incorporating Dy. Selected area electron diffraction patterns confirm the monoclinic and the cubic phase as observed from the X-ray diffraction patterns. A mechanism for stabilization of the high temperature cubic phase in Hf1-xDyxO2 has been analyzed based on the substitution of dysprosium for hafnium ions and the formation of oxygen vacancies. While ferromagnetic ordering at room temperature observed in HfO2 nanoparticles is quenched after incorporating 1 at% of Dy, photoluminescence (PL) studies demonstrate excellent emissions in the blue and yellow region after exciting with UV light of wavelength 352 nm. Combining excitation and emission profiles, we have proposed a tentative energy band diagram illustrating the energetic processes taking place in Hf1-xDyxO2.


Bats eavesdrop on the sound of copulating flies.
The idea that copulation might increase predation risk is a classic suggestion, but empirical evidence to support it is surprisingly scarce. While some early work found decreased vulnerability to predation during mating, two lab and one very recent field study documented increased predation during mating in freshwater amphipods, water striders and locusts. Decreased vigilance, less efficient escape responses, and increased conspicuousness of mating pairs have been suggested as mechanisms that might underpin elevated predation risk during copulation. However, these putative mechanisms have never been investigated empirically. Here we describe a bat-insect system within which copulation greatly increases predation risk. We experimentally demonstrate that wild Natterer's bats (Myotis nattereri) 'eavesdrop' on acoustic cues emanating from copulating flies (Musca domestica) in a cowshed (). With this evidence, we pinpoint increased conspicuousness as a relevant mechanism for elevated predation risk during mating.


Gd(III)-labeled peptide nanofibers for reporting on biomaterial localization in vivo.
Bioactive supramolecular nanostructures are of great importance in regenerative medicine and the development of novel targeted therapies. In order to use supramolecular chemistry to design such nanostructures, it is extremely important to track their fate in vivo through the use of molecular imaging strategies. Peptide amphiphiles (PAs) are known to generate a wide array of supramolecular nanostructures, and there is extensive literature on their use in areas such as tissue regeneration and therapies for disease. We report here on a series of PA molecules based on the well-established β-sheet amino acid sequence V3A3 conjugated to macrocyclic Gd(III) labels for magnetic resonance imaging (MRI). These conjugates were shown to form cylindrical supramolecular assemblies using cryogenic transmission electron microscopy and small-angle X-ray scattering. Using nuclear magnetic relaxation dispersion analysis, we observed that thermal annealing of the nanostructures led to a decrease in water exchange lifetime (τm) of hundreds of nanoseconds only for molecules that self-assemble into nanofibers of high aspect ratio. We interpret this decrease to indicate more solvent exposure to the paramagnetic moiety on annealing, resulting in faster water exchange within angstroms of the macrocycle. We hypothesize that faster water exchange in the nanofiber-forming PAs arises from the dehydration and increase in packing density on annealing. Two of the self-assembling conjugates were selected for imaging PAs after intramuscular injections of the PA C16V3A3E3-NH2 in the tibialis anterior muscle of a murine model. Needle tracts were clearly discernible with MRI at 4 days postinjection. This work establishes Gd(III) macrocycle-conjugated peptide amphiphiles as effective tracking agents for peptide amphiphile materials in vivo over the timescale of days.


Longitudinal evaluation of periodontitis and development of cognitive decline among older adults.
To determine whether having periodontitis is associated with cognitive decline among older adults. A prospective population study of older adults, Swedish National Study on Ageing and Care, (SNAC) provided repeated registrations of cognitive functions. Cognitive decline was defined as ≥3-points deterioration from a predetermined level at baseline, using the Mini-Mental State Examination (MMSE). Between 2001 and 2003, 715 individuals had a medical as well as a clinical and radiographic dental examination. The individuals were re-examined after 6 years. Periodontitis was defined as ≥4 mm bone loss at ≥30% of tooth sites. Social variables were captured from questionnaires. The multivariate logistic regression analysis demonstrated a statistically significant association between prevalence of periodontitis and cognitive decline after adjustments of confounding factors of importance. A history of periodontitis may be of importance for cognitive functions among older adults.


Injury pattern in correlation with the height of fatal falls.
Death due to blunt trauma as a sequel of falls, as a cause of an increased life span is expected. The aim of this retrospective study was to examine the correlation between the height of fall and the frequency, the extensiveness, and the type of injuries of certain body regions and organs. The study included 201 cases of fatal falls, which consisted 118 male and 83 female cases. All subjects were assessed in a standard autopsy for height of fall, cause of death, and injury pattern. Concerning the height of fall, 111 (55.2 %) cases involved falls on a plane level, 72 (35.8 %) from one level to another lower level, less than 5 meters, and 18 (9 %) cases from one level to another lower level, more than 5 meters. Mean age at the time of death was 66.7-years-old (range 22-98). The immediate cause of death was in 94 cases blunt head trauma, in 40 cases cardiovascular diseases, in 56 cases bronchopulmonal diseases, in 3 patients Polytrauma, in 5 patients multi organ failure, and in 3 patients other causes were identified. At the autopsy, 66 patients showed fractures of the skeletal system. The most common cause of death independent from the height of fall was head trauma with 46.7 %. Both post-mortem findings and medical and psychiatric history, in conjunction with the findings at the death scene and toxicology results have to be considered to obtain the clearest possible picture of the circumstance of death.


Pathways through services for offenders with intellectual disability: a one- and two-year follow-up study.
The pathways through services for offenders with intellectual disability were reviewed. Participants were 197 offenders with intellectual disability accepted into three types of community and three types of secure forensic intellectual disability services. They were first compared with 280 participants referred but not accepted into services and were then followed-up for 2 years to review pathways through services. Those accepted into services had a higher charge rate than did those who were referred (46% and 25%, respectively). The greatest diversity in pathway was seen in participants in community forensic intellectual disability and inpatient services. Individuals in secure settings showed the least diversity over time, and, similarly, a relatively high percentage of those accepted into generic community services remained in these services.


Angiopoietin-2 interferes with anti-VEGFR2-induced vessel normalization and survival benefit in mice bearing gliomas.
In brain tumors, cerebral edema is a significant source of morbidity and mortality. Recent studies have shown that inhibition of vascular endothelial growth factor (VEGF) signaling induces transient vascular normalization and reduces cerebral edema, resulting in a modest survival benefit in glioblastoma patients. During anti-VEGF treatment, circulating levels of angiopoietin (Ang)-2 remained high after an initial minor reduction. It is not known, however, whether Ang-2 can modulate anti-VEGF treatment of glioblastoma. Here, we used an orthotopic glioma model to test the hypothesis that Ang-2 is an additional target for improving the efficacy of current anti-VEGF therapies in glioma patients. To recapitulate high levels of Ang-2 in glioblastoma patients during anti-VEGF treatment, Ang-2 was ectopically expressed in U87 glioma cells. Animal survival and tumor growth were assessed to determine the effects of Ang-2 and anti-VEGF receptor 2 (VEGFR2) treatment. We also monitored morphologic and functional vascular changes using multiphoton laser scanning microscopy and immunohistochemistry. Ectopic expression of Ang-2 had no effect on vascular permeability, tumor growth, or survival, although it resulted in higher vascular density, with dilated vessels and reduced mural cell coverage. On the other hand, when combined with anti-VEGFR2 treatment, Ang-2 destabilized vessels without affecting vessel regression and compromised the survival benefit of VEGFR2 inhibition by increasing vascular permeability. VEGFR2 inhibition normalized tumor vasculature whereas ectopic expression of Ang-2 diminished the beneficial effects of VEGFR2 blockade by inhibiting vessel normalization. Cancer treatment regimens combining anti-VEGF and anti-Ang-2 agents may be an effective strategy to improve the efficacy of current anti-VEGF therapies.


Prenatal risk factors for depression: a critical review of the evidence and potential mechanisms.
Exposure to adverse experiences in early life increases the risk of depression during adulthood. Recent findings have highlighted that exposure of a fetus to an adverse intrauterine environment may also have implications for later offspring depression. This review considers the status of the evidence for these associations and the potential mechanisms underlying prenatal developmental risks for later depression, addressing the challenging possibility that environmental predisposition to depression may begin before birth.


Estimation of carbon storage based on individual tree detection in Pinus densiflora stands using a fusion of aerial photography and LiDAR data.
The objective of this study was to estimate the carbon storage capacity of Pinus densiflora stands using remotely sensed data by combining digital aerial photography with light detection and ranging (LiDAR) data. A digital canopy model (DCM), generated from the LiDAR data, was combined with aerial photography for segmenting crowns of individual trees. To eliminate errors in over and under-segmentation, the combined image was smoothed using a Gaussian filtering method. The processed image was then segmented into individual trees using a marker-controlled watershed segmentation method. After measuring the crown area from the segmented individual trees, the individual tree diameter at breast height (DBH) was estimated using a regression function developed from the relationship observed between the field-measured DBH and crown area. The above ground biomass of individual trees could be calculated by an image-derived DBH using a regression function developed by the Korea Forest Research Institute. The carbon storage, based on individual trees, was estimated by simple multiplication using the carbon conversion index (0.5), as suggested in guidelines from the Intergovernmental Panel on Climate Change. The mean carbon storage per individual tree was estimated and then compared with the field-measured value. This study suggested that the biomass and carbon storage in a large forest area can be effectively estimated using aerial photographs and LiDAR data.


One-component thioxanthone acetic acid derivative photoinitiator for free radical polymerization.
Acetic acid-based thioxanthone (TXCH2 COOH) was synthesized and characterized and used as a photoinitiator for free radical photopolymerization of methyl methacrylate (MMA) in the absence and presence of a tertiary amine (MDEA) in different solvents. Different absorption properties were observed depending on the solvent. Fluorescence and phosphorescence experiments were also carried out successfully. The fluorescence quantum yield was found to be 0.09 and the phosphorescence lifetime was calculated as 138 ms at 77 K. The photoinitiator undergoes efficient intersystem crossing into the triplet state and the lowest triplet state possesses π-π* configuration. Laser flash photolysis experiments show that transient absorption of TXCH2 COOH is similar to the parent thioxanthone and the triplet lifetime was calculated as 2.3 μs at 630 nm.


Moral perspectives on stimulant use by healthy students.
The quest for enhancement has been part of human culture for thousands of years. Progress in scientific developments and especially in medical science has enabled previously unimaginable advances to be employed in endeavours to improve human functioning in its various forms. Previously enhancement focused on aspects such as prolonging life, improving the immune system or cosmetic enhancements. Cognitive enhancement is currently receiving substantial attention. The use of stimulants such as methylphenidate, especially among students at tertiary institutions aiming to enhance their cognitive abilities, has raised concerns, ranging from safety issues and the risk of drug abuse to moral issues relating to the broader context of enhancement. We consider arguments used to debate both the promotion of enhancement therapies and the restriction and possibly even prevention of their use.


Clinical Pharmacokinetics and Pharmacodynamics of Biologic Therapeutics for Treatment of Systemic Lupus Erythematosus.
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with potentially severe clinical manifestation that mainly affects women of child-bearing age. Patients who do not respond to standard-of-care therapies, such as corticosteroids and immunosuppressants, require biologic therapeutics that specifically target a single or multiple SLE pathogenesis pathways. This review summarizes the clinical pharmacokinetic and pharmacodynamic characteristics of biologic agents that are approved, used off-label, or in the active pipeline of drug development for SLE patients. Depending on the type of target, the interacting biologics may exhibit linear (non-specific) or non-linear (target-mediated) disposition profiles, with terminal half-lives varying from approximately 1 week to 1 month. Biologics given by subcutaneous administration, which offers dosing flexibility over intravenous administration, demonstrated a relatively slow absorption with a time to maximum concentration of approximately 1 day to 2 weeks and a variable bioavailability of 30-82 %. The population pharmacokinetics of monoclonal antibodies were best described by a two-compartment model with central clearance and steady-state volume of distribution ranging from 0.176 to 0.215 L/day and 3.60-5.29 L, respectively. The between-subject variability in pharmacokinetic parameters were moderate (20-79 %) and could be partially explained by body size. The development of linked pharmacokinetic-pharmacodynamic models incorporating SLE disease biomarkers are an attractive strategy for use in dosing regimen simulation and optimization. The relationship between efficacy/adverse events and biologic concentration should be evaluated to improve clinical trial outcomes, especially for biologics in the advanced phase of drug development. New strategies, such as model-based precision dosing dashboards, could be utilized to incorporate information collected from therapeutic drug monitoring into pharmacokinetic/pharmacodynamic models to enable individualized dosing in real time.


Linkage between increased nociception and olfaction via a SCN9A haplotype.
Mutations reducing the function of Nav1.7 sodium channels entail diminished pain perception and olfactory acuity, suggesting a link between nociception and olfaction at ion channel level. We hypothesized that if such link exists, it should work in both directions and gain-of-function Nav1.7 mutations known to be associated with increased pain perception should also increase olfactory acuity. SCN9A variants were assessed known to enhance pain perception and found more frequently in the average population. Specifically, carriers of SCN9A variants rs41268673C>A (P610T; n = 14) or rs6746030C>T (R1150W; n = 21) were compared with non-carriers (n = 40). Olfactory function was quantified by assessing odor threshold, odor discrimination and odor identification using an established olfactory test. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (punctate and blunt mechanical pressure, heat and electrical stimuli). The number of carried alleles of the non-mutated SCN9A haplotype rs41268673C/rs6746030C was significantly associated with the comparatively highest olfactory threshold (0 alleles: threshold at phenylethylethanol dilution step 12 of 16 (n = 1), 1 allele: 10.6±2.6 (n = 34), 2 alleles: 9.5±2.1 (n = 40)). The same SCN9A haplotype determined the pain threshold to blunt pressure stimuli (0 alleles: 21.1 N/m(2), 1 allele: 29.8±10.4 N/m(2), 2 alleles: 33.5±10.2 N/m(2)). The findings established a working link between nociception and olfaction via Nav1.7 in the gain-of-function direction. Hence, together with the known reduced olfaction and pain in loss-of-function mutations, a bidirectional genetic functional association between nociception and olfaction exists at Nav1.7 level.


Recent trends in the epidemiology of inflammatory bowel diseases: up or down?
Inflammatory bowel disease (IBD) is traditionally considered to be common in the Western world, and its incidence has sharply increased since the early 1950s. In contrast, until the last decade, low prevalence and incidence rates have been reported from other parts of the world including Eastern Europe, South America, Asia and the Pacific region. Recent trends indicate a change in the epidemiology of IBD with previously low incidence areas now reporting a progressive rise in the incidence, while in West European and North American countries the figures have stabilized or slightly increased, with decreasing incidence rates for ulcerative colitis. Some of these changes may represent differences in diagnostic practices and increasing awareness of the disease. The quality of studies is also variable. Additional epidemiologic studies are needed to better define the burden of illness, explore the mechanism of association with environmental factors, and identify new risk factors.


Effects of phenobarbital in cerebral ischemia. Part I: cerebral energy metabolism during pronounced incomplete ischemia.
Changes in cerebral cortex concentrations of high-energy phosphates, glycolytic metabolites, citric acid cycle intermediates, associated amino acids, and ammonia, were studied after 5, 15 and 30 min of incomplete ischemia in rats anesthetized with 70% N2O or 150 mg.kg-1 of phenobartibal. Previous results have shown that with this type of ischemia (bilateral carotid artery occlusion combined with reduction in blood pressure to 50 mm Hg) cortical blood flow is reduced to below 10% of nitrous oxide values, whether animals are anesthetized with 70% N2O or 150 mg.kg-1 of phenobarbital. In animals under 70% N2O, changes in tissue concentrations of phosphocreatine, ATP, ADP and AMP were similar to those previously obtained in complete ischemia. However, some glucose remained in the tissue, and the lactate concentrations gradually rose to reach excessive values. Changes occuring in glycolytic and citric acid cycle intermediates were similar to those seen in complete ischemia but, after 30 min, there was some reduction in the pool size of amino acids. In those animals given phenobarbital and which lost all EEG activity during ischemia, changes in cerebral metabolites were virtually identical to those observed in nitrous oxide-anesthetized animals. However, some animals exposed to 5 or 15 min of ischemia had some remaining EEG activity. In these, cerebral energy state was significantly less deranged, and levels of glycogen, glucose and pyruvate were higher.


Incidence, Spatial Pattern and Temporal Progress of Fusarium Wilt of Bananas.
The effective management of Fusarium wilt of bananas (FWB) depends on the knowledge of the disease dynamics in time and space. The objectives of this work were: to estimate disease intensity and impact, and to investigate the spatial and temporal dynamics of FWB. Fields planted with Silk (n = 10), Pome (n = 17), or Cavendish (n = 3) banana subgroups were surveyed in Brazil, totaling 95 ha. In each field, all plants were visually assessed, and diseased plants were georeferenced. The incidence of FWB and the impact of the disease on the yield on a regional scale were estimated. Spatial patterns were analyzed using quadrat- and distance-based methods. FWB incidence ranged from 0.09% to 41.42%, being higher in Silk fields (median = 14.26%). Impacts of epidemics on yield ranged from 18.4 to 8192.5 kg ha-1 year-1, with an average of 1856.7 kg ha-1 year-1. The higher economic impact of the disease was observed on Silk cultivar with an average loss of USD 1974.2 ha-1 year-1. Overall, estimated losses increased on average by USD 109.8 ha-1 year-1 at each 1% of incidence. Aggregation of FWB was detected by all analytical methods in 13 fields (1 of Cavendish, 11 of Pome, and 1 of Silk). In the other 17 fields, at least one analytical method did not reject the null hypothesis of randomness. One field (5 ha), composed of six plots, was selected for spatial and temporal studies during two years with bi-monthly assessments. A sigmoidal curve represented the FWB progress and the Gompertz model best-fitted disease progress. The level of aggregation varied over time, and evidence of secondary infection to neighboring and distant plants was detected. FWB is a widespread problem in Brazil and yield losses can be of high magnitude. Epidemiology-based management strategies can now be better established.


A snapshot of current Objective Structured Clinical Examination (OSCE) practice at Australian medical schools.
Objective: The objective of this collaborative study was to compare current practices of conducting high-stake, exit-level Objective Structured Clinical Examinations (OSCEs) at all Australian medical schools. We aimed to document similarities and differences between schools, and compare existing practice against available gold standard, evidence-based practice. We also aimed to identify areas where gold standards do not currently exist, and could be developed in the future. Methods: A 72-item semi-structured questionnaire was sent to all 19 Australian medical schools with graduating students. Results: A total of 18/19 schools responded. Of these, 16/18 schools had summative exit-level OSCEs representing content from multiple medical specialties. The total number of OSCE stations varied from 8 to 16, with total OSCE testing time ranging from 70 to 160 min. All schools blueprinted their OSCE to their curriculum, and trained simulated patients and examiners. There was variation in the format of marking rubric used. Conclusions: This study has provided insight into the current OSCE practices of the majority of medical schools in Australia. Whilst the comparative data reveal a wide variation in OSCE practices between schools, many recommended "gold standard" OSCE practices are implemented. The collective awareness of our similarities and differences provides us with a baseline platform, as well as an impetus for iterative quality improvement. Such discourse also serves to develop new gold standards in practice where none have previously existed.


Investigating the genetic structure of Phytophthora capsici populations.
Phytophthora capsici Leonian is a destructive soilborne pathogen that infects economically important solanaceous, cucurbitaceous, fabaceous, and other crops in the United States and worldwide. The objective of this study was to investigate the genetic structure of 255 P. capsici isolates assigned to predefined host, geographical, mefenoxam-sensitivity, and mating-type categories. Isolates from six continents, 21 countries, 19 U.S. states, and 26 host species were genotyped for four mitochondrial and six nuclear loci. Bayesian clustering revealed some population structure by host, geographic origin, and mefenoxam sensitivity, with some clusters occurring more or less frequently in particular categories. Bayesian clustering, split networks, and statistical parsimony genealogies also detected the presence of non-P. capsici individuals in our sample corresponding to P. tropicalis (n = 9) and isolates of a distinct cluster closely related to P. capsici and P. tropicalis (n = 10). Our findings of genetic structuring in P. capsici populations highlight the importance of including isolates from all detected clusters that represent the genetic variation in P. capsici for development of diagnostic tools, fungicides, and host resistance. The population structure detected will also impact the design and interpretation of association studies in P. capsici. This study provides an initial map of global population structure of P. capsici but continued genotyping of isolates will be necessary to expand our knowledge of genetic variation in this important plant pathogen.


Identification of novel spartin-interactors shows spartin is a multifunctional protein.
Hereditary spastic paraplegia describes a group of neurodegenerative diseases characterized by lower limb progressive weakness and spasticity. Troyer syndrome is an autosomal recessive form of hereditary spastic paraplegia caused by a frameshift mutation (1110delA) in the SPG20 gene encoding spartin protein, the cellular function of which remains unknown. Knowledge about spartin-interactors is also very limited. In this study, we apply a broad spectrum of proteomics techniques to identify novel spartin-binding proteins. We used a Tandem Affinity Purification technique followed by HPLC-mass spectrometry to characterize potential spartin-binding partners. Selected putative interactions were confirmed by co-immunoprecipitation experiments. We identified 94 potential spartin-binding proteins which were grouped into functional categories. We performed co-immunoprecipitation experiments to confirm that spartin interacts with GRP78, GRP75 and nucleolin proteins. Additionally, our mass spectrometry results confirmed previously published information about spartin interaction with ubiquitin and the E3 ubiquitin-protein ligases, AIP4/Itch and AIP5/WWP1. Our studies suggest that spartin is a multifunctional protein and for the first time we suggest a role for spartin in protein folding and turnover both in mitochondria and endoplasmic reticulum. We also show for the first time interaction between spartin and a nucleolar protein, nucleolin.


New pyrrole-based histone deacetylase inhibitors: binding mode, enzyme- and cell-based investigations.
Aroyl-pyrrolyl-hydroxy-amides (APHAs) are a class of synthetic HDAC inhibitors described by us since 2001. Through structure-based drug design, two isomers of the APHA lead compound 1, the 3-(2-benzoyl-1-methyl-1H-pyrrol-4-yl)-N-hydroxy-2-propenamide 2 and the 3-(2-benzoyl-1-methyl-1H-pyrrol-5-yl)-N-hydroxy-2-propenamide 3 (iso-APHAs) were designed, synthesized and tested in murine leukemia cells as antiproliferative and cytodifferentiating agents. To improve their HDAC activity and selectivity, chemical modifications at the benzoyl moieties were investigated and evaluated using three maize histone deacetylases: HD2, HD1-B (class I human HDAC homologue), and HD1-A (class II human HDAC homologue). Docking experiments on HD1-A and HD1-B homology models revealed that the different compounds selectivity profiles could be addressed to different binding modes as observed for the reference compound SAHA. Smaller hydrophobic cap groups improved class II HDAC selectivity through the interaction with HD1-A Asn89-Ser90-Ile91, while bulkier aromatic substituents increased class I HDAC selectivity. Taking into account the whole enzyme data and the functional test results, the described iso-APHAs showed a behaviour of class I/IIb HDACi, with 4b and 4i preferentially inhibiting class IIb and class I HDACs, respectively. When tested in the human leukaemia U937 cell line, 4i showed altered cell cycle (S phase arrest), joined to high (51%) apoptosis induction and significant (21%) differentiation activity.


Of Huge Mice and Tiny Elephants: Exploring the Relationship Between Inhibitory Processes and Preschool Math Skills.
The cognitive mechanisms underpinning the well-established relationship between inhibitory control and early maths skills remain unclear. We hypothesized that a specific aspect of inhibitory control drives its association with distinct math skills in very young children: the ability to ignore stimulus dimensions that are in conflict with task-relevant representations. We used an Animal Size Stroop task in which 3- to 6-year-olds were required to ignore the physical size of animal pictures to compare their real-life dimensions. In Experiment 1 (N = 58), performance on this task correlated with standardized early mathematics achievement. In Experiment 2 (N = 48), performance on the Animal Size Stroop task related to the accuracy of magnitude comparison, specifically for trials on which the physical size of dot arrays was incongruent with their numerosity. This highlights a process-oriented relationship between interference control and resolving conflict between discrete and continuous quantity, and in turn calls for further detailed empirical investigations of whether, how and why inhibitory processes matter to emerging numerical cognition.


Lotus japonicus karrikin receptors display divergent ligand-binding specificities and organ-dependent redundancy.
Karrikins (KARs), smoke-derived butenolides, are perceived by the α/β-fold hydrolase KARRIKIN INSENSITIVE2 (KAI2) and thought to mimic endogenous, yet elusive plant hormones tentatively called KAI2-ligands (KLs). The sensitivity to different karrikin types as well as the number of KAI2 paralogs varies among plant species, suggesting diversification and co-evolution of ligand-receptor relationships. We found that the genomes of legumes, comprising a number of important crops with protein-rich, nutritious seed, contain two or more KAI2 copies. We uncover sub-functionalization of the two KAI2 versions in the model legume Lotus japonicus and demonstrate differences in their ability to bind the synthetic ligand GR24ent-5DS in vitro and in genetic assays with Lotus japonicus and the heterologous Arabidopsis thaliana background. These differences can be explained by the exchange of a widely conserved phenylalanine in the binding pocket of KAI2a with a tryptophan in KAI2b, which arose independently in KAI2 proteins of several unrelated angiosperms. Furthermore, two polymorphic residues in the binding pocket are conserved across a number of legumes and may contribute to ligand binding preferences. The diversification of KAI2 binding pockets suggests the occurrence of several different KLs acting in non-fire following plants, or an escape from possible antagonistic exogenous molecules. Unexpectedly, L. japonicus responds to diverse synthetic KAI2-ligands in an organ-specific manner. Hypocotyl growth responds to KAR1, KAR2 and rac-GR24, while root system development responds only to KAR1. This differential responsiveness cannot be explained by receptor-ligand preferences alone, because LjKAI2a is sufficient for karrikin responses in the hypocotyl, while LjKAI2a and LjKAI2b operate redundantly in roots. Instead, it likely reflects differences between plant organs in their ability to transport or metabolise the synthetic KLs. Our findings provide new insights into the evolution and diversity of butenolide ligand-receptor relationships, and open novel research avenues into their ecological significance and the mechanisms controlling developmental responses to divergent KLs.


Human Plasmodium vivax diversity, population structure and evolutionary origin.
More than 200 million malaria clinical cases are reported each year due to Plasmodium vivax, the most widespread Plasmodium species in the world. This species has been neglected and understudied for a long time, due to its lower mortality in comparison with Plasmodium falciparum. A renewed interest has emerged in the past decade with the discovery of antimalarial drug resistance and of severe and even fatal human cases. Nonetheless, today there are still significant gaps in our understanding of the population genetics and evolutionary history of P. vivax, particularly because of a lack of genetic data from Africa. To address these gaps, we genotyped 14 microsatellite loci in 834 samples obtained from 28 locations in 20 countries from around the world. We discuss the worldwide population genetic structure and diversity and the evolutionary origin of P. vivax in the world and its introduction into the Americas. This study demonstrates the importance of conducting genome-wide analyses of P. vivax in order to unravel its complex evolutionary history.


Endoscopic ultrasound-guided fine-needle aspiration in the diagnosis of adrenal lesions.
The use of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) appears to be a safe and feasible means of confirming or excluding malignancy in the adrenal glands. EUS-FNA with biopsy of suspicious masses in either adrenal gland allows for assessment of these lesions while keeping complications relatively rare. The main advantages of EUS-FNA are that it can be done as an outpatient procedure, with good results, minimal morbidity, and a short hospital stay. Nevertheless, EUS-FNA of adrenal masses should be indicated only in selected cases, in which there is potential to either decrease unnecessary treatment or guide therapy in cancer patients by aiding in either staging of malignancy or treatment of recurrence.v.


Hyperchloremic acidosis in the critically ill: one of the strong-ion acidoses?
Decreases in plasma bicarbonate are associated with hyperchloremic acidosis and lactic acidosis. According to the Stewart approach to acid-base physiology, the strong-ion difference regulates plasma bicarbonate, with chloride and lactate being the only strong anions routinely measured in clinical chemistry. We hypothesized that the plasma strong-ion difference, both with and without lactate, would have a stronger association with plasma bicarbonate than plasma chloride alone would have with bicarbonate. We used plasma acid-base data from 300 critically ill patients. The correlation with bicarbonate became progressively weaker (P < 0.001): all measured strong ions, r = 0.60; measured strong ions without lactate, r = 0.42; chloride alone, r = -0.27. In a subgroup of 26 patients with traditional hyperchloremic acidosis (base excess < -2 mmol/L and anion gap <17 mmol/L), the measured strong-ion difference (without lactate) had a stronger correlation (P < 0.001) with bicarbonate than chloride had: r = 0.85 versus r = -0.60. We conclude that hyperchloremic acidosis and lactic acidosis are strong-ion acidoses. Hyperchloremia should be viewed relative to the plasma strong cations. A practical conclusion is that both managing and preventing acid-base disorders with IV fluid therapy involves manipulating each of the plasma strong ions, particularly sodium and chloride.


Dependence of dispersive and birefringence properties of silicon nanowires on waveguide dimensions.
We study numerically the dependence of dispersive and birefringence properties of silicon nanowires on waveguide dimensions and show that they have a strong geometrical dependence when nanowire dimensions become comparable to the wavelength of light inside the device. We develop a graphical method for engineering two or more dispersion parameters simultaneously and use it to demonstrate the possibility of fabricating silicon nanowires with flattened dispersion curves over a wide spectral range with normal or anomalous nominal values. We quantify polarization-mode dispersion through the differential group delay and show that it can acquire large values for properly designed nanowires. Our analysis should help in designing silicon-based photonic integrated circuits.


Cloning and phenotypic characterization of fleS and fleR, new response regulators of Pseudomonas aeruginosa which regulate motility and adhesion to mucin.
This work has identified two genes (designated fleS and fleR) in Pseudomonas aeruginosa which are highly homologous to members of the subclass of two-component systems involved in transcriptional regulation of a diverse array of genes from sigma 54 promoters. The genes are located upstream from fliE, a flagellar gene of P. aeruginosa, and they are arranged in a putative fleSR operon. FleS has a predicted molecular mass of 43.87 kDa and shows strong homology to histidine kinases which in other two-component systems have been shown to be sensor proteins. FleR has a predicted molecular mass of 51.26 kDa and is homologous to other regulatory proteins that bind to specific upstream activating elements to enhance transcription of genes with sigma 54 promoters. The fleSR system is believed to control both flagellar synthesis and adhesion to mucin. Several lines of evidence are presented. (i) A nonpiliated mutant of P. aeruginosa PAK containing a gentamicin cassette in fleR is nonmotile and nonadhesive. (ii) The fleR mutant regained motility and adhesion when complemented with a wild-type copy of fleR. (iii) A Western blot (immunoblot) of the fleR mutant showed no synthesis of flagellin, and electron microscopy of the fleR mutant confirmed the lack of flagella. Previous work has shown that flagellar mutants with mutations in fliA (sigma 28) or fliC (the structural gene for flagellin) retain adhesion; therefore, these new observations suggest that FleSR regulates both the expression of flagella and the nonpilus adhesin(s) for mucin or that one of the flagellar proteins (other than flagellin) may be responsible for adhesion to mucins.


Effectiveness of assistive technology in improving the safety of people with dementia: a systematic review and meta-analysis.
Objectives: Assistive technology (AT) may enable people with dementia to live safely at home for longer, preventing care home admission. This systematic review assesses the effectiveness of AT in improving the safety of people with dementia living in the domestic setting, by searching for randomised controlled trials, non-randomised controlled trials and controlled before-after studies which compared safety AT with treatment as usual. Measures of safety include care home admission; risky behaviours, accidents and falls at home; and numbers of deaths. The review updates the safety aspect of Fleming and Sum's 2014 systematic review. Method: Seven bibliographic databases, the Social Care Institute for Excellence website and the Alzheimer's Society website were searched for published and unpublished literature between 2011-2016. Search terms related to AT, dementia and older people. Common outcomes were meta-analysed. Results: Three randomised controlled trials were identified, including 245 people with dementia. No significant differences were found between intervention and control groups in care home admission (risk ratio 0.85 95% CI [0.37, 1.97]; Z = 0.37; p = 0.71). The probability of a fall occurring was 50% lower in the intervention group (risk ratio 0.50 95% CI [0.32, 0.78]; Z = 3.03; p = 0.002). One included study found that a home safety package containing AT significantly reduced risky behaviour and accidents (F(45) = 4.504, p < 0.001). Limitations include the few studies found and the inclusion of studies in English only. Conclusion: AT's effectiveness in decreasing care home admission is inconclusive. However, the AT items and packages tested improved safety through reducing falls risk, accidents and other risky behaviour.


Focal osteolysis at the junctions of a modular stainless-steel femoral intramedullary nail.
During routine follow-up of patients treated with a three-piece stainless-steel modular femoral nail, osteolysis and periosteal reaction around the modular junctions of some of the nails were noted on radiographs. The purpose of this study was to evaluate the prevalence, etiology, and clinical relevance of these radiographic findings. Forty-four femoral fractures or nonunions in forty-two patients were treated with a modular stainless-steel femoral intramedullary nail. Seventeen nails were excluded, leaving twenty-seven intramedullary nails in twenty-seven patients for this study. All patients had had a femoral diaphyseal fracture; nineteen had had an acute fracture and eight, a nonunion. These twenty-seven patients returned for radiographs, a physical examination, assessment of functional outcomes, assessment of thigh pain with a visual analog scale, determination of serum chromium levels, and nail removal if desired. A control group of sixteen patients treated with a one-piece stainless-steel femoral intramedullary nail was evaluated with use of the same outcome measures and was compared with the group treated with the modular femoral nail with regard to prevalence of thigh pain and serum chromium levels. Twelve modular femoral nails were removed according to the study protocol. The modular nail junctions were analyzed for corrosion products, and histopathologic analysis of tissue specimens from the femoral canal was performed. The twenty-seven patients were seen at a mean of twenty-one months after fracture fixation; twenty-six of the twenty-seven fractures healed. Twenty-three femora had at least one of three types of abnormalities-osteolysis, periosteal reaction, or cortical thickening--localized to one or both modular junctions. Eighteen patients had severe reactions, defined as osteolysis of > or =2 mm, cortical thickening of > or =5 mm, and/or a periosteal reaction (group 1). Nine patients had mild or no reactions (group 2). Serum chromium levels in group 1 (mean, 1.27 ng/ mL; range, 0.34 to 3.12 ng/mL) were twice as high as those in group 2 (mean, 0.53 ng/mL; range, 0.12 to 1.26 ng/mL). However, this difference did not reach significance with the numbers available. The differences in serum chromium levels between group 1 and the control group with a one-piece nail (mean, 0.26 ng/mL; range, 0.015 to 1.25 ng/mL) (p<0.01) and a control group without an implant (mean, 0.05 ng/mL; range, 0.015 to 0.25 ng/ mL) (p<0.01) were significant. The level of thigh pain recorded on the visual analog scale was also significantly different between group 1 and the control group with a one-piece implant (p = 0.03). Retrieved modular nails had signs of fretting corrosion as well as stainless-steel corrosion products adherent to the junction where the osteolysis occurred. Histologic and spectrographic analysis revealed two types of corrosion products that were consistent with stainless-steel within the peri-implant tissue and were associated with a foreign-body granulomatous response. The presence of corrosion products at the taper junctions suggests that particulate debris was a major factor in the etiology of the radiographic findings of osteolysis, periosteal reaction, and cortical thickening. Serum chromium levels were substantially elevated in the patients with a modular femoral nail, and such levels may serve as a marker of fretting corrosion of these devices.


Subxiphoid uniportal video-assisted thoracoscopic surgery for synchronous bilateral lung resection.
With advancements in medical imaging and current emphasis on regular physical examinations, multiple pulmonary lesions increasingly are being detected, including bilateral pulmonary lesions. Video-assisted thoracic surgery is an important method for treating such lesions. Most of video-assisted thoracic surgeries for bilateral pulmonary lesions were two separate operations. Herein, we report a novel technique of synchronous subxiphoid uniportal video-assisted thoracic surgery for bilateral pulmonary lesions. Synchronous bilateral lung resection procedures were performed through a single incision (~4 cm, subxiphoid). This technique was used successfully in 11 patients with bilateral pulmonary lesions. There were no intraoperative deaths or mortality recorded at 30 days. Our results show that the subxiphoid uniportal thoracoscopic procedure is a safe and feasible surgical procedure for synchronous bilateral lung resection with less surgical trauma, postoperative pain and better cosmetic results in qualifying patients. Further analysis is ongoing, involving a larger number of subjects.


Mechanisms of quantum dot energy engineering by metalorganic vapor phase epitaxy on patterned nonplanar substrates.
A novel technique for tuning the strength of quantum confinement in site-controlled semiconductor quantum dots (QDs) is introduced and investigated theoretically and experimentally. The method makes use of controlled local growth rates during metalorganic vapor phase epitaxy on patterned arrays of inverted pyramids. A model accounting for precursor migration and adatom incorporation predicts the tuning in QD thickness as a function of the pattern parameters. The results are in good agreement with experimental findings. This technique offers means for designing QD photonic structures with potential applications in QD-based cavity quantum electrodynamics and quantum information processing.


Prolonged Exposure for Treating PTSD Among Female Methadone Patients Who Were Survivors of Sexual Abuse in Israel.
The aims of this pilot study were: (a) to test the feasibility of prolonged exposure (PE) therapy conducted by a social worker staff on female patients in methadone program clinics who were survivors of child sexual abuse or rape and (b) to examine preliminary outcomes of PE on posttraumatic stress disorder (PTSD), depression, and illicit drug use at pre- and posttreatment, and up to 12-month follow-ups. Twelve female methadone patients who were survivors of child sexual abuse or rape diagnosed with PTSD were enrolled in 13-19 weekly individual PE sessions. Assessments were conducted at pre-, mid-, and posttreatment, as well as at 3, 6, and 12-month follow-ups. The treatment outcomes measures included PTSD symptoms, depressive symptoms, and illicit drug use. Ten of the 12 study patients completed treatment. PTSD and depressive symptoms showed significant reduction. No relapse to illicit drug use was detected. These preliminary results suggest that PE may be delivered by methadone social workers with successful outcomes. Further research should test the efficacy of PE among methadone patients in a randomized control trial with standard care as the control condition.


Phosphate transporters in marine phytoplankton and their viruses: cross-domain commonalities in viral-host gene exchanges.
Phosphate (PO(4)) is an important limiting nutrient in marine environments. Marine cyanobacteria scavenge PO(4) using the high-affinity periplasmic phosphate binding protein PstS. The pstS gene has recently been identified in genomes of cyanobacterial viruses as well. Here, we analyse genes encoding transporters in genomes from viruses that infect eukaryotic phytoplankton. We identified inorganic PO(4) transporter-encoding genes from the PHO4 superfamily in several virus genomes, along with other transporter-encoding genes. Homologues of the viral pho4 genes were also identified in genome sequences from the genera that these viruses infect. Genome sequences were available from host genera of all the phytoplankton viruses analysed except the host genus Bathycoccus. Pho4 was recovered from Bathycoccus by sequencing a targeted metagenome from an uncultured Atlantic Ocean population. Phylogenetic reconstruction showed that pho4 genes from pelagophytes, haptophytes and infecting viruses were more closely related to homologues in prasinophytes than to those in what, at the species level, are considered to be closer relatives (e.g. diatoms). We also identified PHO4 superfamily members in ocean metagenomes, including new metagenomes from the Pacific Ocean. The environmental sequences grouped with pelagophytes, haptophytes, prasinophytes and viruses as well as bacteria. The analyses suggest that multiple independent pho4 gene transfer events have occurred between marine viruses and both eukaryotic and bacterial hosts. Additionally, pho4 genes were identified in available genomes from viruses that infect marine eukaryotes but not those that infect terrestrial hosts. Commonalities in marine host-virus gene exchanges indicate that manipulation of host-PO(4) uptake is an important adaptation for viral proliferation in marine systems. Our findings suggest that PO(4) -availability may not serve as a simple bottom-up control of marine phytoplankton.


Evaluating Cognitive Relationships with Resting-State and Task-driven Blood Oxygen Level-Dependent Variability.
Recent functional magnetic resonance imaging studies have reported that moment-to-moment variability in the blood oxygen level-dependent (BOLD) signal is positively associated with task performance and, thus, may reflect a behaviorally sensitive signal. However, it is not clear whether estimates of resting-state and task-driven BOLD variability are differentially related to cognition, as they may be driven by distinct sources of variance in the BOLD signal. Moreover, other studies have suggested that age differences in resting-state BOLD variability may be particularly sensitive to individual differences in cardiovascular, rather than neural, factors. In this study, we tested relationships between measures of behavioral task performance and BOLD variability during both resting-state and task-driven runs of a Stroop and an animacy judgment task in a large, well-characterized sample of cognitively normal middle-aged to older adults. Resting-state BOLD variability was related to composite measures of global cognition and attentional control, but these relationships were eliminated after correction for age or cardiovascular estimates. In contrast, task-driven BOLD variability was related to attentional control measured both inside and outside the scanner, and importantly, these relationships persisted after correction for age and cardiovascular measures. Overall, these results suggest that BOLD variability is a behaviorally sensitive signal. However, resting-state and task-driven estimates of BOLD variability may differ in the degree to which they are sensitive to age-related, cardiovascular, and neural mechanisms.


Shape based assignment tests suggest transgressive phenotypes in natural sculpin hybrids (Teleostei, Scorpaeniformes, Cottidae).
Hybridization receives attention because of the potential role that it may play in generating evolutionary novelty. An explanation for the emergence of novel phenotypes is given by transgressive segregation, which, if frequent, would imply an important evolutionary role for hybridization. This process is still rarely studied in natural populations as samples of recent hybrids and their parental populations are needed. Further, the detection of transgressive segregation requires phenotypes that can be easily quantified and analysed. We analyse variability in body shape of divergent populations of European sculpins (Cottus gobio complex) as well as natural hybrids among them. A distance-based method is developed to assign unknown specimens to known groups based on morphometric data. Apparently, body shape represents a highly informative set of characters that parallels the discriminatory power of microsatellite markers in our study system. Populations of sculpins are distinct and "unknown" specimens can be correctly assigned to their source population based on body shape. Recent hybrids are intermediate along the axes separating their parental groups but display additional differentiation that is unique and coupled with the hybrid genetic background. There is a specific hybrid shape component in natural sculpin hybrids that can be best explained by transgressive segregation. This inference of how hybrids differ from their ancestors provides basic information for future evolutionary studies. Furthermore, our approach may serve to assign candidate specimens to their source populations based on morphometric data and help in the interpretation of population differentiation.


Distribution of phenylethanolamine N-methyltransferase cell bodies, axons, and terminals in monkey brainstem: an immunohistochemical mapping study.
Adrenaline (epinephrine) is an important candidate transmitter in descending spinal control systems. To date intrinsic spinal adrenergic neurons have not been reported; thus adrenergic input is presumably derived from brainstem sites. In this regard, the localization of adrenergic neurons in the brainstem is an important consideration. Maps of adrenergic cell bodies and to a lesser extent axons and terminal fields have been made in various species, but not in monkeys. Thus, the present study concerns the organization of adrenergic systems in the brainstem of a monkey (Macaca fascicularis) immunohistochemically mapped by means of an antibody to the enzyme phenylethanolamine N-methyltransferase (PNMT). PNMT-immunostained cell bodies are distributed throughout the medulla in two principal locations. One concentration of labeled cells is in the dorsomedial medulla and includes the nucleus of the solitary tract (NTS), the dorsal motor nucleus of the vagus (X), and an area ventral to X in a region of the reticular formation (RF) known as the central nucleus dorsalis (CnD) of the medulla. A few scattered cells are observed in the periventricular gray just ventral to the IVth ventricle and on midline in the raphe. The second major concentration of PNMT-immunostained cells is located in the ventrolateral RF, lateral and dorsolateral to the inferior olive (IO), including some cells in the rostral part of the lateral reticular nucleus (LRN). Terminal fields are located in the NTS, X, area postrema (AP), and the floor of the IVth ventricle in the medulla and pons. A light terminal field is also observed in the raphe, particularly raphe pallidus (RP). A heavy terminal field is present in locus coeruleus (LC). Fibers labeled for PNMT form two major fiber tracts. One is in the dorsomedial RF extending as a well-organized bundle through the medulla, pons, and midbrain. A second tract is located on the ventrolateral edge of the medulla and caudal pons. Fibers in this tract appear to descend to the spinal cord. A comparison with maps of other catecholamine neurons in primates is discussed, confirming that the distribution of the adrenergic system in monkeys is similar to that described in the human.


Cellular senescence mediated by p16INK4A-coupled miRNA pathways.
p16 is a key regulator of cellular senescence, yet the drivers of this stable state of proliferative arrest are not well understood. Here, we identify 22 senescence-associated microRNAs (SA-miRNAs) in normal human mammary epithelial cells. We show that SA-miRNAs-26b, 181a, 210 and 424 function in concert to directly repress expression of Polycomb group (PcG) proteins CBX7, embryonic ectoderm development (EED), enhancer of zeste homologue 2 (EZH2) and suppressor of zeste 12 homologue (Suz12), thereby activating p16. We demonstrate the existence of a tight positive feedback loop in which SA-miRNAs activate and re-enforce the expression of other SA-miRNA members. In contrast, PcG members restrain senescence by epigenetically repressing the expression of these SA-miRNAs. Importantly, loss of p16 leads to repression of SA-miRNA expression, intimately coupling this effector of senescence to the SA-miRNA/PcG self-regulatory loop. Taken together, our findings illuminate an important regulatory axis that underpins the transition from proliferation to cellular senescence.


Phonon lateral confinement enables thermal rectification in asymmetric single-material nanostructures.
We show that thermal rectification (TR) in asymmetric graphene nanoribbons (GNRs) is originated from phonon confinement in the lateral dimension, which is a fundamentally new mechanism different from that in macroscopic heterojunctions. Our molecular dynamics simulations reveal that, though TR is significant in nanosized asymmetric GNRs, it diminishes at larger width. By solving the heat diffusion equation, we prove that TR is indeed absent in both the total heat transfer rate and local heat flux for bulk-size asymmetric single materials, regardless of the device geometry or the anisotropy of the thermal conductivity. For a deeper understanding of why lateral confinement is needed, we have performed phonon spectra analysis and shown that phonon lateral confinement can enable three possible mechanisms for TR: phonon spectra overlap, inseparable dependence of thermal conductivity on temperature and space, and phonon edge localization, which are essentially related to each other in a complicated manner. Under such guidance, we demonstrate that other asymmetric nanostructures, such as asymmetric nanowires, thin films, and quantum dots, of a single material are potentially high-performance thermal rectifiers.


Magnetic resonance imaging of presumptive lumbosacral discospondylitis in a dog.
A three-year-old male Boxer dog had hyperesthesia, symmetrical epaxial, gluteal and hind limb muscular atrophy and rear limb ataxia. Neurological deficits included decreased conscious proprioception of the left hind limb, decreased withdrawal and increased patellar reflexes of both hind limbs. The dog had a urinary tract infection with positive culture for Staphylococcus intermedius. On survey radiography of the lumbosacral spine there was active bone proliferation spanning the L7 S1 intervertebral disc space with an epidural filling defect at the ventral aspect of the vertebral canal on epidurography. On magnetic resonance imaging (MRI), findings were similar to those described for human diskospondylitis including altered signal intensity and nonuniform contrast enhancement of the L7-S1 intervertebral disc, adjacent vertebral end plates and epidural and sublumbar soft tissues. Although skeletal radiography is usually sufficient to reach a diagnosis of discospondylitis, MRI of this patient made it possible to reach a presumptive diagnosis of discospondylitis prior to development of definitive radiographic abnormalities.


Monoclonal antibodies for the S2 subunit of spike of SARS-CoV-1 cross-react with the newly-emerged SARS-CoV-2.
BackgroundA novel coronavirus, SARS-CoV-2, which emerged at the end of 2019 and causes COVID-19, has resulted in worldwide human infections. While genetically distinct, SARS-CoV-1, the aetiological agent responsible for an outbreak of severe acute respiratory syndrome (SARS) in 2002-2003, utilises the same host cell receptor as SARS-CoV-2 for entry: angiotensin-converting enzyme 2 (ACE2). Parts of the SARS-CoV-1 spike glycoprotein (S protein), which interacts with ACE2, appear conserved in SARS-CoV-2.AimThe cross-reactivity with SARS-CoV-2 of monoclonal antibodies (mAbs) previously generated against the S protein of SARS-CoV-1 was assessed.MethodsThe SARS-CoV-2 S protein sequence was aligned to those of SARS-CoV-1, Middle East respiratory syndrome (MERS) and common-cold coronaviruses. Abilities of mAbs generated against SARS-CoV-1 S protein to bind SARS-CoV-2 or its S protein were tested with SARS-CoV-2 infected cells as well as cells expressing either the full length protein or a fragment of its S2 subunit. Quantitative ELISA was also performed to compare binding of mAbs to recombinant S protein.ResultsAn immunogenic domain in the S2 subunit of SARS-CoV-1 S protein is highly conserved in SARS-CoV-2 but not in MERS and human common-cold coronaviruses. Four murine mAbs raised against this immunogenic fragment could recognise SARS-CoV-2 S protein expressed in mammalian cell lines. In particular, mAb 1A9 was demonstrated to detect S protein in SARS-CoV-2-infected cells and is suitable for use in a sandwich ELISA format.ConclusionThe cross-reactive mAbs may serve as useful tools for SARS-CoV-2 research and for the development of diagnostic assays for COVID-19.


"I'm still here": Exploring what matters to people with intellectual disability during advance care planning.
This study sought to identify, from the perspective of people with intellectual disabilities and life limiting conditions, the factors that strengthened and inhibited their Advance Care Planning. This in depth qualitative study explored the experiences of four people with intellectual disability and life limiting conditions, through interviews and documentation reviews. There was strong agreement across all participants about what positively influenced Advance Care Planning, namely; going at my pace; supporting me to make my own choices; adapting the process to suit me, and, most importantly; continuing to support and plan the life I'm still living. With the exception of being comfortable/skilled in end-of-life support, the skills required of facilitators were similar to those required for all forms of person-centred planning. The findings are encouraging and demonstrate that Advance Care Planning is a useful tool in ensuring that people with intellectual disability have control and choice over their lives, right to the end.


Targeted mRNA degradation by deadenylation-independent decapping.
Modulating the rate of mRNA degradation is a fast and efficient way to control gene expression. In a yeast strain deleted of EDC3, a component of the decapping machinery conserved in eukaryotes, the transcript coding the ribosomal protein Rps28b is specifically stabilized, as demonstrated by microarray and time course experiments. This stabilization results from the loss of RPS28B autoregulation, which occurs at the level of mRNA decay. Using mutants of the major deadenylase, we show that this regulation occurs at the level of decapping and bypasses deadenylation. Rps28b interacts with a conserved hairpin structure within the 3'UTR of its own mRNA and with components of the decapping machinery, including Edc3. We conclude that Rps28b, in the presence of Edc3, directly recruits the decapping machinery on its own mRNA. These findings show that specific modulation of the decapping efficiency on natural transcripts can control mRNA turnover.


Spatiotemporal Changes Posttreatment in Peripheral Arterial Disease.
Accumulating evidence suggests revascularization of peripheral arterial disease (PAD) limbs results in limited improvement in functional gait parameters, suggesting underlying locomotor system pathology. Spatial and temporal (ST) gait parameters are well studied in patients with PAD at baseline and are abnormal when compared to controls. The purpose of this study was to systematically review and critically analyze the available data on ST gait parameters before and after interventions. A full review of literature was conducted and articles were included which examined ST gait parameters before and after intervention (revascularization and exercise). Thirty-three intervention articles were identified based on 154 articles that evaluated ST gait parameters in PAD. Four articles fully assessed ST gait parameters before and after intervention and were included in our analysis. The systematic review of the literature revealed a limited number of studies assessing ST gait parameters. Of those found, results demonstrated the absence of improvement in gait parameters due to either exercise or surgical intervention. Our study demonstrates significant lack of research examining the effectiveness of treatments on ST gait parameters in patients with PAD. Based on the four published articles, ST gait parameters failed to significantly improve in patients with PAD following intervention.


Severe pediculosis capitis in a nursery school girl
Pediculosis capitis is the most frequent ectoparasitosis around the world. The infestation is caused by Pediculus humanus capitis (head louse), which affects hair, scalp, and skin. It rarely presents with more symptoms and in the majority of the cases, it shows a benign course if treated properly. We present the case of a nursery school girl with head lice infestation for 18 months. She did not improve after the shampoo treatment. This case was associated with furunculosis, skin lesions, multiple adenopathies, and anemia. Initially, the presence of boils, alopecia, and lymphadenopathy was evident. The persistence of pediculosis capitis and intense scratching induced changes on skin integrity, facilitating opportunistic bacterial superinfection that led to impetiginization, furunculosis, excoriations, hematic scabs, anemia, alopecia, and lymphadenopathies. Pediculosis capitis affected the patient triggering psychological, economic, social, and other health problems. The patient presented uncommon symptoms (furunculosis, anemia, fever, alopecia, and adenopathies) resulting from the persistence of risk factors and the absence of head inspection and mechanical removal of insects. The education about the risk factors, as well as sanitary controls, are essential to contain the infestation.


A comparative evaluation of ProSeal laryngeal mask airway, I-gel and Supreme laryngeal mask airway in adult patients undergoing elective surgery: A randomised trial.
Second-generation supraglottic airway devices are widely used in current anaesthesia practice. This randomised study was undertaken to evaluate and compare laryngeal mask airway: ProSeal laryngeal mask airway (PLMA), Supreme laryngeal mask airway (SLMA) and I-gel. Eighty-four adult patients undergoing elective surgery were randomly allocated to three groups: group P (PLMA), group I (I-gel) and group S (SLMA) of 28 patients each. Insertion times, number of insertion attempts, haemodynamic response to insertion, ease of insertion of airway device and gastric tube, oropharyngeal leak pressure (OLP) and pharyngolaryngeal morbidity were assessed. The primary outcome measure was the OLP after successful device insertion. Statistical analysis was performed using Statistical Package for the Social Sciences version 18.0 software using Chi-squared/Fisher's exact test (categorical data) and analysis of variance (continuous data) tests. P < 0.05 was considered statistically significant. The demographic profile of patients was comparable. OLP measured after insertion, 30 minutes later and at the end of surgery differed significantly between the three groups (P < 0.001). The mean OLP was 32.64 ± 4.14 cm·H2O in group P and 29.79 ± 3.70 cm·H2O in group S. In group I, the mean OLP after insertion was 26.71 ± 3.45 cm H2O, which increased to 27.36 ± 3.22 cm H2O at 30 minutes and to 27.50 ± 3.24 cm H2O towards the end of surgery. However, these increases were not statistically significant (P = 0.641). Device insertion time was longest for group P (P = 0.001) and gastric tube insertion time was longest for group I (P = 0.001). Haemodynamic response to insertion and pharyngolaryngeal morbidity were similar with all three devices. PLMA provides better sealing pressure but takes longer to insert. I-gel and SLMA have similar sealing pressures. I-gel insertion time is quicker.


Genetic association studies and the effect of misclassification and selection bias in putative confounders.
Genetic epidemiology studies often adjust for numerous potential confounders, yet the influences of confounder misclassification and selection bias are rarely considered. We used simulated data to evaluate the effect of confounder misclassification and selection bias in a case-control study of incident myocardial infarction. We show that putative confounders traditionally included in genetic association studies do not alter effect estimates, even when excessive levels of misclassification are incorporated. Conversely, selection bias resulting from covariates affected by the single-nucleotide polymorphism of interest can bias effect estimates upward or downward. These results support careful consideration of how well a study population represents the target population because selection bias may result even when associations are modest.


A revised role for P-glycoprotein in the brain distribution of dexamethasone, cortisol, and corticosterone in wild-type and ABCB1A/B-deficient mice.
The ABCB1-type multidrug resistance efflux transporter P-glycoprotein (P-gp) has been hypothesized to regulate hypothalamic-pituitary-adrenal axis activity by limiting the access of glucocorticoids to the brain. In vivo systemic administration studies using P-gp-deficient mice have shown increased glucocorticoid entry to the brain compared with wild-type controls. However, these studies did not control for the presence of radiolabeled drug in the capillaries, verify an intact blood-brain barrier, or confirm stability of the glucocorticoids used. In the present study, an in situ brain perfusion method, coupled with capillary depletion and HPLC analyses, was used to quantify brain uptake of [3H]dexa-methasone, [3H]cortisol, and [3H]corticosterone in P-gp-deficient and control mice. A vascular marker was included in these experiments. The results show that brain uptake of [3H]dexamethasone was increased in the frontal cortex, hippocampus, hypothalamus, and cerebellum of P-gp-deficient mice compared with wild-type controls. Brain uptake of [3H]cortisol was increased in the hypothalamus of P-gp-deficient mice compared with wild-type controls, but no differences were detected in other regions. Brain uptake of [3H]corticosterone was not increased in P-gp-deficient mice compared with wild-type controls in any brain areas. After our systemic administration of the same radiolabeled glucocorticoids, HPLC analysis of plasma samples identified additional radiolabeled components, likely to be metabolites. This could explain previous findings from systemic administration studies, showing an effect of P-gp not only for dexamethasone and cortisol, but also for corticosterone. This in situ study highlights the different affinities of dexamethasone, cortisol, and corticosterone for P-gp, and suggests that the entry of the endogenous glucocorticoids into the mouse brain is not tightly regulated by P-gp. Therefore, our current understanding of the role of P-gp in hypothalamic-pituitary-adrenal regulation in mice requires revision.


Optical imaging of progenitor cell homing to patient-derived tumors.
Capitalizing on cellular homing to cancer is a promising strategy for targeting malignant cells for diagnostic, monitoring and therapeutic purposes. Murine C17.2 neural progenitor cells (NPC) demonstrate a tropism for cell line-derived tumors, but their affinity for patient-derived tumors is unknown. We tested the hypothesis that NPC accumulate in patient-derived tumors at levels detectable by optical imaging. Mice bearing solid tumors after transplantation with patient-derived leukemia cells and untransplanted controls received 10(6) fluorescent DiR-labeled NPC daily for 1-4 days, were imaged, then sacrificed. Tissues were analyzed by immunofluorescence and flow cytometry to detect tumor cell engraftment (CD45) and NPC (FITC-β galactosidase or DiR). Tumors consisted primarily of CD45-positive cells and demonstrated mild fluorescence, corresponding to frequent clusters of FITC-β gal-positive cells. Both transplanted and control mice demonstrated the highest fluorescent signal in the spleens and other tissues of the reticuloendothelial activating system. However, only rare FITC-β gal-positive cells were detected in the mildly engrafted transplanted spleens and none in the control spleens, suggesting that their high DiR signal reflects the sequestration of DiR-positive debris. The mildly engrafted transplanted kidneys demonstrated low fluorescent signal and rare FITC-β gal-positive cells whereas control kidneys were negative. Results indicate that NPC accumulate in tissues containing patient-derived tumor cells in a manner that is detectable by ex vivo optical imaging and proportional to the level of tumor engraftment, suggesting a capacity to home to micrometastatic disease. As such, NPC could have significant clinical applications for the targeted diagnosis and treatment of cancer.


Effect of high-dose vs standard-dose multivitamin supplementation at the initiation of HAART on HIV disease progression and mortality in Tanzania: a randomized controlled trial.
Large randomized trials have previously shown that high-dose micronutrient supplementation can increase CD4 counts and reduce human immunodeficiency virus (HIV) disease progression and mortality among individuals not receiving highly active antiretroviral therapy (HAART); however, the safety and efficacy of such supplementation has not been established in the context of HAART. To test the hypothesis that high-dose multivitamin supplementation vs standard-dose multivitamin supplementation decreases the risk of HIV disease progression or death and improves immunological, virological, and nutritional parameters in patients with HIV initiating HAART. A randomized, double-blind, controlled trial of high-dose vs standard-dose multivitamin supplementation for 24 months in 3418 patients with HIV initiating HAART between November 2006 and November 2008 in 7 clinics in Dar es Salaam, Tanzania. INTERVENTION The provision of daily oral supplements of vitamin B complex, vitamin C, and vitamin E at high levels or standard levels of the recommended dietary allowance. The composite of HIV disease progression or death from any cause. The study was stopped early in March 2009 because of evidence of increased levels of alanine transaminase (ALT) in patients receiving the high-dose multivitamin supplement. At the time of stopping, 3418 patients were enrolled (median follow-up, 15 months), and there were 2374 HIV disease progression events and 453 observed deaths (2460 total combined events). Compared with standard-dose multivitamin supplementation, high-dose supplementation did not reduce the risk of HIV disease progression or death. The absolute risk of HIV progression or death was 72% in the high-dose group vs 72% in the standard-dose group (risk ratio [RR], 1.00; 95% CI, 0.96-1.04). High-dose supplementation had no effect on CD4 count, plasma viral load, body mass index, or hemoglobin level concentration, but increased the risk of ALT elevations (1239 events per 1215 person-years vs 879 events per 1236 person-years; RR, 1.44; 95% CI, 1.11-1.87) vs standard-dose supplementation. CONCLUSION In adults receiving HAART, use of high-dose multivitamin supplements compared with standard-dose multivitamin supplements did not result in a decrease in HIV disease progression or death but may have resulted in an increase in ALT levels. Clinicaltrials.gov Identifier: NCT00383669.


TA-2, a thrombin-like enzyme from the Chinese white-lipped green pitviper (Trimeresurus albolabris): isolation, biochemical and biological characterization.
Through three chromatographic steps, a new thrombin-like enzyme (TLE), named TA-2, from the venom of the Chinese white-lipped green pitviper (Trimeresurus albolabris) has been isolated and purified to homogeneity. TA-2 was a single-chain glycoprotein with about 6% sugar, pI 3.9 and a molecular weight of 38.8 kD. Its N-terminal sequence (VVGGDECNIN) showed high sequence conformity with many other TLEs. In vitro, it coagulated bovine fibrinogen (108.6 NIH units/mg) and cleaved the Aα and Bβ chains of bovine fibrinogen-releasing fibrinopeptide A and B, but did not degrade bovine fibrin; displayed high stability at different temperature, pH, and presence of several divalent cations and inhibitors; also exhibited strong activity towards casein (192.3 units/mg) and high esterase activity upon Nα-p-tosyl-L-arginine methyl ester (11 units/mg); and behaved as a promoter to platelet aggregation induced by ADP or collagen. In vivo, TA-2 caused dose-dependent prolongation of bleeding time in mice, but had no hemorrhagic and edema-inducing activities even at high concentrations.