Sodium-glucose Cotransporter 2 Inhibitors: Impact on Body Weight and Blood Pressure Compared with other Antidiabetic Drugs.
Sodium-glucose co-transporters 2 inhibitors have emerged as a novel antidiabetic class of drugs offering significant ameliorating effects on a variety of cardiovascular risk factors, secondary to their mechanism of action, including blood pressure and body weight. The purpose of this article is to discuss available data on the impact of SGLT-2 inhibitors on blood pressure and body weight compared with other available anti-diabetic drugs and to present potential mechanisms mediating these effects. A comprehensive review of the literature was performed to identify studies examining the effects of SGLT-2 inhibitors on blood pressure and body weight. SGLT-2 inhibition has been related with a mild decrease in blood pressure of approximately 3-5mmHg in systolic and 1-2mmHg in diastolic blood pressure. These data have been confirmed with 24h ambulatory measurements, as well. Furthermore, given the loss of calories in the urine, a mild decrease in body weight is anticipated, as well. Studies with this class of drugs noted a reduction in body weight of 2 to 3 kg, similar to the loss noted with the use of glucagon-like peptide 1 analogues, the only class of drugs that has offered significant reductions in body weight so far. Consclusion: The beneficial effects of the SGLT-2 inhibition on an abundance of cardiovascular risk factors, including blood pressure and body weight, have created great expectations for potential benefits from the cardiovascular events standpoint, a theory that was confirmed in the two available cardiovascular studies of this promising class of drugs.


Effects of Stem Cell Treatment in Human Patients With Peyronie Disease.
Peyronie disease (PD) is a connective tissue disorder involving the formation of fibrous plaques in the tunica albuginea. Abnormal plaques and scar tissue create a chronic state of inflammation, causing increased curvature of the penis as well as erectile dysfunction. To determine the feasibility and effects of using placental matrix-derived mesenchymal stem cells (PM-MSCs) in the management of PD. In a prospective study, patients with PD were injected with PM-MSCs, and followed up at 6-week, 3-month, and 6-month intervals to assess changes in plaque volume, penile curvature, and erectile function status (measured using peak systolic velocity, end-diastolic velocity, and the International Index of Erectile Function questionnaire). In the 5 patients enrolled in the study, statistically significant increases in peak systolic velocity occurred after PM-MSC injection (P<.01). Of a total of 10 plaques managed, 7 had disappeared completely at 3-month follow-up. Changes in end-diastolic velocity, stretched penile length, and penile girth were not statistically significant. To our knowledge, this study is the first on the use of stem cells to manage PD in humans. The results suggest that PM-MSCs may be beneficial and effective as a nonsurgical treatment in patients with PD. Future studies with long-term follow-up in a larger sample of patients are warranted. (ClinicalTrials.gov number NCT02395029).


Detection and screening of chromosomal rearrangements in uterine leiomyomas by long-distance inverse PCR.
Genome instability is a hallmark of many tumors and recently, next-generation sequencing methods have enabled analyses of tumor genomes at an unprecedented level. Studying rearrangement-prone chromosomal regions (putative "breakpoint hotspots") in detail, however, necessitates molecular assays that can detect de novo DNA fusions arising from these hotspots. Here we demonstrate the utility of a long-distance inverse PCR-based method for the detection and screening of de novo DNA rearrangements in uterine leiomyomas, one of the most common types of human neoplasm. This assay allows in principle any genomic region suspected of instability to be queried for DNA rearrangements originating there. No prior knowledge of the identity of the fusion partner chromosome is needed. We used this method to screen uterine leiomyomas for rearrangements at genomic locations known to be rearrangement-prone in this tumor type: upstream HMGA2 and within RAD51B. We identified a novel DNA rearrangement upstream of HMGA2 that had gone undetected in an earlier whole-genome sequencing study. In more than 30 additional uterine leiomyoma samples, not analyzed by whole-genome sequencing previously, no rearrangements were observed within the 1,107 bp and 1,996 bp assayed in the RAD51B and HMGA2 rearrangement hotspots. Our findings show that long-distance inverse PCR is a robust, sensitive, and cost-effective method for the detection and screening of DNA rearrangements from solid tumors that should be useful for many diagnostic applications.


Neural basis of embodiment: distinct contributions of temporoparietal junction and extrastriate body area.
Embodiment, the sense of being localized within one's physical body, is a fundamental aspect of the self. Recently, researchers have started to show that self and body processing require distinct brain mechanisms, suggesting two posterior brain regions as key loci: the temporoparietal junction (TPJ), which is involved in self processing and multisensory integration of body-related information; and the extrastriate body area (EBA), which responds selectively to human bodies and body parts. Here we used evoked potential mapping and a distributed linear inverse solution to show that activations in EBA and TPJ code differentially for embodiment and self location, because the location and timing of brain activation depended on whether mental imagery is performed with mentally embodied (EBA) or disembodied (TPJ) self location. In a second experiment, we showed that only EBA activation, related to embodied self location, but not TPJ activation, related to disembodied self location, was modified by the subjects' body position during task performance (supine or sitting). This suggests that embodied self location and actual body location share neural mechanisms. Collectively, these data show that distributed brain activity at the EBA and TPJ as well as their timing are crucial for the coding of the self as embodied and as spatially situated within the human body.


Light trapping in thin film silicon solar cells via phase separated disordered nanopillars.
In this work, we have improved the absorption properties of thin film solar cells by introducing light trapping reflectors deposited onto self-assembled nanostructures. The latter consist of a disordered array of nanopillars and are fabricated by polymer blend lithography. Their broadband light scattering properties are exploited to enhance the photocurrent density of thin film devices, here based on hydrogenated amorphous silicon active layers. We demonstrate that these light scattering nanopillars yield a short-circuit current density increase of +33%rel with respect to equivalent solar cells processed on a planar reflector. Moreover, we experimentally show that they outperform randomly textured substrates that are commonly used for achieving efficient light trapping. Complementary optical simulations are conducted on an accurate 3D model to analyze the superior light harvesting properties of the nanopillar array and to derive general design rules. Our approach allows one to easily tune the morphology of the self-assembled nanostructures, is up-scalable and operated at room temperature, and is applicable to other photovoltaic technologies.


Double-barrel STA-MCA bypass for cerebral revascularization: lessons learned from a 10-year experience.
In select patients, extracranial-intracranial (EC-IC) bypass remains an important tool for cerebral revascularization. Traditionally, superficial temporal artery-middle cerebral artery (STA-MCA) bypass was performed using one limb of the STA only. In an attempt to augment flow and to direct flow to different ischemic areas of the brain, the authors adopted a "double-barrel" technique in which both branches of the STA are used to revascularize distinct MCA territories. A series of consecutive double-barrel STA-MCA bypasses performed between 2010 and 2020 were reviewed. Each anastomosis was directed to augment flow to a territory most at risk based on preoperative perfusion studies, cerebral angiography, and intraoperative indocyanine green data. CT perfusion and CTA were routinely used to evaluate postoperative augmentation and graft patency. Patient perioperative outcomes, surgical complications, and modified Rankin Scale (mRS) scores at the last follow-up were reported. Forty-four patients (16 males, 28 females) successfully underwent double-barrel STA-MCA bypass on 54 cerebral hemispheres: 28 operations were for moyamoya disease, 23 for atherosclerotic disease refractory to medical therapy, 2 for complex cerebral aneurysms, and 1 for carotid occlusion as a sequela of cavernous meningioma growth. Ten patients underwent multiple operations, 9 of whom had moyamoya disease/syndrome, with the subsequent operation on the contralateral hemisphere. The average patient age at surgery was 45.1 years (range 14-73 years), with a mean follow-up time of 22.1 months. Intraoperative graft patency was confirmed in 100% of cases, and 101 (98.1%) of the 103 anastomoses with imaging follow-up were patent. Perfusion to the revascularized hemisphere was improved in 88.2% of cases. Perioperative ischemic and hemorrhagic complications occurred in 8 procedures (2 were asymptomatic), whereas remote ischemic and hemorrhagic events occurred in 7 cases. There was no mortality in the series, and the mean patient mRS scores were 1.72 at presentation and 1.15 at the last follow-up. The high rates of intraoperative and postoperative patency support the feasibility of dual-anastomosis STA-MCA bypass for revascularization. The perioperative complication rate is not significantly different from that of single-anastomosis bypass. The functional outcomes at follow-up and perfusion improvement postoperatively support the efficacy and safety of this method as a treatment strategy.


Selection of patients with idiopathic normal-pressure hydrocephalus for shunt placement: a single-institution experience.
The ability to predict outcome after shunt placement in patients with idiopathic normal-pressure hydrocephalus (NPH) represents a challenge. To date, no single diagnostic tool or combination of tools has proved capable of reliably predicting whether the condition of a patient with suspected NPH will improve after a shunting procedure. In this paper, the authors report their experience with 120 patients with the goal of identifying CSF hydrodynamics criteria capable of selecting patients with idiopathic NPH. Specifically, they focused on the comparison between CSF-outflow resistance (R-out) and intracranial elastance (IE). Between January 1977 and December 2005, 120 patients in whom idiopathic NPH had been diagnosed (on the basis of clinical findings and imaging) underwent CSF hydrodynamics evaluation based on an intraventricular infusion test. Ninety-six patients underwent CSF shunt placement: 32 between 1977 and 1989 (Group I) on the basis of purely clinical and radiological criteria; 44 between 1990 and 2002 (Group II) on the basis of the same criteria as Group I and because they had an IE slope > 0.25; and 20 between 2003 and 2005 (Group III) on the basis of the same criteria as Group II but with an IE slope > or = 0.30. Outcomes were evaluated by means of both Stein-Langfitt and Larsson scores. Patients' conditions were considered improved when there was a stable decrease (at 6- and 12-month follow-up) of at least 1 point in the Stein-Langfitt score and 2 points in the Larsson score. Group I: while no statistically significant difference in mean R-out value between improved and unimproved cases was observed, a clear-cut IE slope value of 0.25 differentiated very sharply between unimproved and improved cases. Group II: R-out values in the 2 unimproved cases were 20 and 47 mm Hg/ml/min, respectively. The mean IE slope in the improved cases was 0.56 (range 0.30-1.4), while the IE slopes in the 2 unimproved cases were 0.26 and 0.27. Group III: the mean IE slope was 0.51 (range 0.31-0.7). The conditions of all patients improved after shunting. A significant reduction of the Evans ratio was observed in 34 (40.5%) of the 84 improved cases and in none of the unimproved cases. Our strategy based on the analysis of CSF pulse pressure parameters seems to have a great accuracy in predicting surgical outcome in clinical practice.


CCL19 and CCR7 Expression, Signaling Pathways, and Adjuvant Functions in Viral Infection and Prevention.
Chemokine (C-C motif) ligand 19 (CCL19) is a critical regulator of the induction of T cell activation, immune tolerance, and inflammatory responses during continuous immune surveillance, homeostasis, and development. Migration of CC-chemokine receptor 7 (CCR7)-expressing cells to secondary lymphoid organs is a crucial step in the onset of adaptive immunity, which is initiated by a complex interaction between CCR7 and its cognate ligands. Recent advances in knowledge regarding the response of the CCL19-CCR7 axis to viral infections have elucidated the complex network of interplay among the invading virus, target cells and host immune responses. Viruses use various strategies to evade or delay the cytokine response, gaining additional time to replicate in the host. In this review, we summarize the impacts of CCL19 and CCR7 expression on the regulation of viral pathogenesis with an emphasis on the corresponding signaling pathways and adjuvant mechanisms. We present and discuss the expression, signaling adaptor proteins and effects of CCL19 and CCR7 as these molecules differentially impact different viral infections and viral life cycles in host homeostatic strategies. The underlying mechanisms discussed in this review may assist in the design of novel agents to modulate chemokine activity for viral prevention.


Measurement of Thermal Effects of Doppler Ultrasound: An In Vitro Study.
Ultrasound is considered a safe imaging modality and is routinely applied during early pregnancy. However, reservations are expressed concerning the application of Doppler ultrasound in early pregnancy due to energy emission of the ultrasound probe and its conversion to heat. The objective of this study was to evaluate the thermal effects of emitted Doppler ultrasound of different ultrasound machines and probes by means of temperature increase of in-vitro test-media. We investigated the energy-output of 5 vaginal and abdominal probes of 3 ultrasound machines (GE Healthcare, Siemens, Aloka). Two in-vitro test objects were developed at the Center for Medical Physics and Biomedical Engineering, Medical University Vienna (water bath and hydrogel bath). Temperature increase during Doppler ultrasound emission was measured via thermal sensors, which were placed inside the test objects or on the probes' surface. Each probe was emitting for 5 minutes into the absorbing test object with 3 different TI/MI settings in Spectral Doppler mode. During water bath test, temperature increase varied between 0.1 and 1.0°C, depending on probe, setting and focus, and was found highest for spectral Doppler mode alone. Maximum temperature increase was found during the surface heating test, where values up to 2.4°C could be measured within 5 minutes of emission. Activation of Doppler ultrasound in the waterbath model causes a significant increase of temperature within one minute. Thermally induced effects on the embryo cannot be excluded when using Doppler ultrasound in early pregnancy.


When they believe in miracles.
Brierley et al argue that in cases where it is medically futile to continue providing life-sustaining therapies to children in intensive care, medical professionals should be allowed to withdraw such therapies, even when the parents of these children believe that there is a chance of a miracle cure taking place. In reasoning this way, Brierley et al appear to implicitly assume that miracle cures will never take place, but they do not justify this assumption and it would be very difficult for them to do so. Instead of seeking to override the wishes of parents, who are waiting for a miracle, it is suggested that a better response may be to seek to engage devout parents on their own terms, and encourage them to think about whether or not continuing life-sustaining therapies will make it more likely that a miracle cure will occur.


Randomized controlled trial of ultrasound-guided peripheral intravenous catheter placement versus traditional techniques in difficult-access pediatric patients.
We hypothesized that the use of ultrasound guidance would improve the success rate of peripheral intravenous catheter placement in pediatric patients with difficult access in a pediatric emergency department (ED). Our secondary hypotheses were that ultrasound guidance would reduce the number of attempts, the number of needle redirections, and the overall time to catheter placement. This was a prospective randomized study of pediatric ED patients younger than 10 years old requiring intravenous access, presenting between August 2006 and May 2007. Inclusion criteria were 2 unsuccessful traditional attempts at peripheral intravenous access or history of difficult access. Exclusion was critical illness or instability. Patients were randomized to undergo peripheral intravenous catheter placement using continued traditional approaches or real-time, dual-operator ultrasound-guided technique. Measured outcomes were success of cannulation, number of attempts, number of needle redirections, and overall time to catheter placement. Fifty patients were enrolled, with 25 patients randomized to each group. The overall success rates for the ultrasound-guided group were 80% and for the traditional-attempts group, 64%, with a difference in proportions of 16% (95% confidence interval, -9% to 38%, P = 0.208). The ultrasound-guided group required less overall time (6.3 vs 14.4 minutes, difference of -8.1 minutes [95% confidence interval, -12.5 to -3.6], P = 0.001), fewer attempts (median, 1 vs 3; P = 0.004), and fewer needle redirections (median, 2 vs 10; P G 0.0001) than traditional approaches. In a sample of pediatric ED patients with difficult access, ultrasound-guided intravenous cannulation required less overall time, fewer attempts, and fewer needle redirections than traditional approaches.


Macroeconomic evidence suggests that asylum seekers are not a "burden" for Western European countries.
This paper aims to evaluate the economic and fiscal effects of inflows of asylum seekers into Western Europe from 1985 to 2015. It relies on an empirical methodology that is widely used to estimate the macroeconomic effects of structural shocks and policies. It shows that inflows of asylum seekers do not deteriorate host countries' economic performance or fiscal balance because the increase in public spending induced by asylum seekers is more than compensated for by an increase in tax revenues net of transfers. As asylum seekers become permanent residents, their macroeconomic impacts become positive.


Prognostic role of a comprehensive geriatric assessment on the management of elderly patients with advanced non-small cell lung cancer (NSCLC): a pooled analysis of two prospective phase II trials by the GFPC Group.
The prognostic role of a comprehensive geriatric assessment (CGA) on the management of elderly patients with advanced-stage non-small cell lung cancer (NSCLC) remains to be established. The objective of this analysis was to determine the prognostic role of each CGA domain on overall survival (OS) among elderly patients with advanced-stage NSCLC. We pooled individual data from two prospective, randomized phases II trials in patients over 65 years old with advanced-stage NSCLC, who were considered fit (0405 trial) or no-fit (0505 trial) based on a CGA. Both trials compared first-line chemotherapy followed by second-line erlotinib with the reverse strategy in terms of progression-free survival (PFS) and OS. Factors prognostic of OS were sought by using the Kaplan-Meier method and the log rank test for univariate analysis, and a Cox model for multivariate analysis. Analysis performed on 194 patients (mean age: 77 years, male gender: 70%, never- or ex-smokers: 56%) showed, in univariate analysis that performance status (PS), smoking status, Charlson, simplified Charlson, nutritional scores, and a mobility score were prognostics of OS. In multivariate analysis, PS [HR: 1.4 (1.02-1.9), P=0.04] and the Charlson score [HR: 1.46 (1.07-1.99), P=0.02] were independently prognostic of OS, while the nutritional score [HR: 0.69 (0.46-1.04), P=0.07] and the mobility score [HR: 0.25 (0.06-1.01), P=0.06] were close to significance. PS and comorbidities appear to be the main predictors of OS in elderly advanced NSCLC patients selected on the basis of CGA.


The role of the health physicist in nuclear security.
Health physics is a recognized safety function in the holistic context of the protection of workers, members of the public, and the environment against the hazardous effects of ionizing radiation, often generically designated as radiation protection. The role of the health physicist as protector dates back to the Manhattan Project. Nuclear security is the prevention and detection of, and response to, criminal or intentional unauthorized acts involving or directed at nuclear material, other radioactive material, associated facilities, or associated activities. Its importance has become more visible and pronounced in the post 9/11 environment, and it has a shared purpose with health physics in the context of protection of workers, members of the public, and the environment. However, the duties and responsibilities of the health physicist in the nuclear security domain are neither clearly defined nor recognized, while a fundamental understanding of nuclear phenomena in general, nuclear or other radioactive material specifically, and the potential hazards related to them is required for threat assessment, protection, and risk management. Furthermore, given the unique skills and attributes of professional health physicists, it is argued that the role of the health physicist should encompass all aspects of nuclear security, ranging from input in the development to implementation and execution of an efficient and effective nuclear security regime. As such, health physicists should transcend their current typical role as consultants in nuclear security issues and become fully integrated and recognized experts in the nuclear security domain and decision making process. Issues regarding the security clearances of health physics personnel and the possibility of insider threats must be addressed in the same manner as for other trusted individuals; however, the net gain from recognizing and integrating health physics expertise in all levels of a nuclear security regime far outweighs any negative aspects. In fact, it can be argued that health physics is essential in achieving an integrated approach toward nuclear safety, security, and safeguards.


Transfrontal and Transsphenoidal Approaches to Pediatric Craniopharyngioma: A National Perspective.
This study compared transsphenoidal (TS) and transfrontal (TF) approaches to craniopharyngioma utilizing a national database. The Kids' Inpatient Database (2003, 2006, and 2009) was surveyed for patients with a diagnosis of craniopharyngioma who underwent a subset of surgical interventions to compare TS and TF surgery. Demographics, hospital variables, and complications/comorbidities were analyzed with multivariate regression. 314 admissions (TS = 104, TF = 210) were identified. The mean age was 14.8 (TS) versus 9.8 (TF) years (p < 0.001). The mean number of diagnoses was 4.6 (TS) versus 6.2 (TF) (p < 0.001). Diabetes insipidus was associated with 38% (TS) and 69% (TF). Cerebrospinal fluid (CSF) leak affected 19% TS and 4% TF resections. Other complications and comorbidities included postoperative stroke (2% TS vs. 5% TF), panhypopituitarism (5 vs. 8%), death (0 vs. 1%), cranial nerve deficits (1 vs. 6%), thrombotic events (7 vs. 17%), and seizures (0 vs. 12%). 98% of patients were discharged home after a mean 6-day length of stay (LOS) after TS, whereas 90% of TF patients had a LOS of 12 days. TS cases were more likely to be privately insured (68%) and from higher income brackets (61%) than TF ones (56 and 2%, respectively) (p < 0.05). In multivariate regression models adjusting for age, sex, race, number of diagnoses, surgical approach, hospital volume, and insurance type, the TS approach was associated with an increased incidence of CSF leak (OR 10, p < 0.001). More documented diagnoses (OR 16-60, p < 0.01) and TF approach (OR 2.6, p < 0.01) were associated with an increased incidence of other complications and comorbidities. Age younger than 10 (β-coefficient 2.3, p = 0.01), more diagnoses (β-coefficient 1.2, p < 0.001), and TF approach (β- coefficient 3.0, p < 0.01) were associated with increased LOS. A higher number of diagnoses were associated with nonhome discharge destinations (β-coefficient 1.29, p < 0.001). TS surgery was associated with an increased incidence of CSF leak but shorter LOS; TF surgery was associated with an increased incidence of other complications. Patients undergoing TS surgery were more likely to have private insurance and a higher family income bracket.


Prion protein and Abeta-related synaptic toxicity impairment.
Alzheimer's disease (AD), the most common neurodegenerative disorder, goes along with extracellular amyloid-beta (Abeta) deposits. The cognitive decline observed during AD progression correlates with damaged spines, dendrites and synapses in hippocampus and cortex. Numerous studies have shown that Abeta oligomers, both synthetic and derived from cultures and AD brains, potently impair synaptic structure and functions. The cellular prion protein (PrP(C)) was proposed to mediate this effect. We report that ablation or overexpression of PrP(C) had no effect on the impairment of hippocampal synaptic plasticity in a transgenic model of AD. These findings challenge the role of PrP(C) as a mediator of Abeta toxicity.


Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit.
The mitochondrial inner membrane possesses distinct subdomains including cristae, which are lamellar structures invaginated into the mitochondrial matrix and contain the respiratory complexes. Generation of inner membrane domains requires the complex interplay between the respiratory complexes, mitochondrial lipids and the recently identified mitochondrial contact site and cristae organizing system (MICOS) complex. Proper organization of the mitochondrial inner membrane has recently been shown to be important for respiratory function in yeast. Here we aimed at a molecular diagnosis in a brother and sister from a consanguineous family who presented with a neurodegenerative disorder accompanied by hyperlactatemia, 3-methylglutaconic aciduria, disturbed hepatocellular function with abnormal cristae morphology in liver and cerebellar and vermis atrophy, which suggest mitochondrial dysfunction. Using homozygosity mapping and exome sequencing the patients were found to be homozygous for the p.(Gly15Glufs*75) variant in the QIL1/MIC13 (C19orf70) gene. QIL1/MIC13 is a constituent of MICOS, a six subunit complex that helps to form and/or stabilize cristae junctions and determine the placement, distribution and number of cristae within mitochondria. In patient fibroblasts both MICOS subunits QIL1/MIC13 and MIC10 were absent whereas MIC60 was present in a comparable abundance to that of the control. We conclude that QIL1/MIC13 deficiency in human, is associated with disassembly of the MICOS complex, with the associated aberration of cristae morphology and mitochondrial respiratory dysfunction. 3-Methylglutaconic aciduria is associated with variants in genes encoding mitochondrial inner membrane organizing determinants, including TAZ, DNAJC19, SERAC1 and QIL1/MIC13.


Cytoplasmic recruitment of INI1 and PML on incoming HIV preintegration complexes: interference with early steps of viral replication.
During the early phase of the retroviral life cycle, only a fraction of internalized virions end up integrating their genome into the chromosome, even though the resulting proviruses are almost systematically expressed. Here, we reveal that incoming retroviral preintegration complexes trigger the exportin-mediated cytoplasmic export of the SWI/SNF component INI1 and of the nuclear body constituent PML. We further show that the HIV genome associates with these proteins before nuclear migration. In the presence of arsenic, PML is sequestered in the nucleus, and the efficiency of HIV-mediated transduction is markedly increased. These results unveil a so far unsuspected cellular response that interferes with the early steps of HIV replication.


Disordered binding regions and linear motifs--bridging the gap between two models of molecular recognition.
Intrinsically disordered proteins (IDPs) exist without the presence of a stable tertiary structure in isolation. These proteins are often involved in molecular recognition processes via their disordered binding regions that can recognize partner molecules by undergoing a coupled folding and binding process. The specific properties of disordered binding regions give way to specific, yet transient interactions that enable IDPs to play central roles in signaling pathways and act as hubs of protein interaction networks. An alternative model of protein-protein interactions with largely overlapping functional properties is offered by the concept of linear interaction motifs. This approach focuses on distilling a short consensus sequence pattern from proteins with a common interaction partner. These motifs often reside in disordered regions and are considered to mediate the interaction roughly independent from the rest of the protein. Although a connection between linear motifs and disordered binding regions has been established through common examples, the complementary nature of the two concepts has yet to be fully explored. In many cases the sequence based definition of linear motifs and the structural context based definition of disordered binding regions describe two aspects of the same phenomenon. To gain insight into the connection between the two models, prediction methods were utilized. We combined the regular expression based prediction of linear motifs with the disordered binding region prediction method ANCHOR, each specialized for either model to get the best of both worlds. The thorough analysis of the overlap of the two methods offers a bioinformatics tool for more efficient binding site prediction that can serve a wide range of practical implications. At the same time it can also shed light on the theoretical connection between the two co-existing interaction models.


Interpretation of automated perimetry for glaucoma by neural network.
Neural networks were trained to interpret the visual fields from an automated perimeter. The authors evaluated the reliability of the trained neural networks to discriminate between normal eyes and eyes with glaucoma. Inclusion criteria for glaucomatous and normal eyes were the intraocular pressure and the appearance of the optic nerve; previous visual fields were not used. The authors compared the backpropagation learning method used by automated neural networks to those used by two specialists in glaucoma to classify the central 24 degrees automated perimetric visual fields from 60 normal and 60 glaucomatous eyes. The glaucoma experts and a trained two-layered network were each correct at approximately 67%. The average sensitivity of this test was 59% for the two glaucoma specialists and 65% for the two-layered network. The corresponding specificities were 74% and 71% for the specialists and the two-layered network, respectively. The experts and the network were in agreement about 74% of the time, which indicated no significant disagreement between the methods of testing. Feature analysis with a one-layered network determined the most important visual field positions. The authors conclude that a neural network can be taught to be as proficient as a trained reader in interpreting visual fields for glaucoma.


Investigation of the chemical stability of the laser-induced fluorescence tracers acetone, diethylketone, and toluene under IC engine conditions using Raman spectroscopy.
This paper reports on an investigation of the chemical stability of the common laser-induced fluorescence (LIF) tracers acetone, diethylketone, and toluene. Stability is analyzed using linear Raman spectroscopy inside a heated pressure cell with optical access, which is used for the LIF calibration of these tracers. The measurements examine the influence of temperature, pressure, and residence time on tracer oxidation, which occurs without a rise in temperature or pressure inside the cell, highlighting the need for optical detection. A comparison between the three different tracers shows large differences, with diethylketone having the lowest and toluene by far the highest stability. An analysis of the sensitivity of the measurement shows that the detection limit of the oxidized tracer is well below 3% molar fraction, which is typical for LIF applications in combustion devices such as internal combustion (IC) engines. Furthermore, the effect on the LIF signal intensity is examined in an isothermal turbulent mixing study.


Comparison of plasminogen activator inhibitor-1 concentration in insulin-resistant versus insulin-sensitive healthy women.
The primary goal of this investigation was to see whether plasminogen activator inhibitor-1 (PAI-1) concentrations varied as a function of differences in insulin-mediated glucose disposal in 2 groups of healthy women matched for every other variable that might play a role in regulation of PAI-1. For this purpose, we recruited 32 healthy women, divided on the basis of their steady-state plasma glucose (SSPG) concentrations during the insulin suppression test into an insulin-resistant (SSPG=216+/-12 mg/dL, n=16) and an insulin-sensitive (94+/-6 mg/dL, n=16) group. PAI-1 antigen concentrations were significantly higher (26+/-4 versus 14+/-3 ng/mL, P<0.02) in the insulin-resistant group. In addition, fasting plasma insulin (18+/-3 versus 11+/-2 microU/mL, P<0.02) and triglyceride (160+/-19 versus 93+/-10 mg/dL, P<0.001) concentrations were higher in the insulin-resistant individuals, whereas HDL concentrations were lower (44+/-3 versus 58+/-3 mg/dL, P<0.005). However, the 2 groups were essentially identical in terms of age, menopausal status, hormone replacement therapy, body mass index (BMI), ratio of waist-to-hip girth, and blood pressure. When the experimental population was considered as 1 group, there were statistically significant correlations between PAI-1 antigen and the following variables: adjusting for differences in age and BMI, SSPG (r=0.56, P<0.001); triglyceride (r=0.39, P<0.05); and HDL cholesterol (r=-0. 65, P<0.001) concentrations. Finally, multiple regression analysis revealed the major determinants of PAI-1 to be insulin resistance, or insulin concentration, and HDL cholesterol. These results: 1) demonstrate that PAI-1 concentrations are higher in healthy, insulin-resistant women as compared with insulin-sensitive individuals, independent of differences in BMI or ratio of waist-to-hip girth; and 2) provide another mechanism by which insulin-resistant individuals are at increased thrombotic cardiovascular risk.


Biodistribution, tumor detection, and radiation dosimetry of 18F-DCFBC, a low-molecular-weight inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer.
Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein expressed on the surface of prostate cancer (PCa) cells, particularly in androgen-independent, advanced, and metastatic disease. Previously, we demonstrated that N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-(18)F-fluorobenzyl-L-cysteine ((18)F-DCFBC) could image an experimental model of PSMA-positive PCa using PET. Here, we describe the initial clinical experience and radiation dosimetry of (18)F-DCFBC in men with metastatic PCa. Five patients with radiologic evidence of metastatic PCa were studied after the intravenous administration of 370 MBq (10 mCi) of (18)F-DCFBC. Serial PET was performed until 2 h after administration. Time-activity curves were generated for selected normal tissues and metastatic foci. Radiation dose estimates were calculated using OLINDA/EXM 1.1. Most vascular organs demonstrated a slow decrease in radioactivity concentration over time consistent with clearance from the blood pool, with primarily urinary radiotracer excretion. Thirty-two PET-positive suspected metastatic sites were identified, with 21 concordant on both PET and conventional imaging for abnormal findings compatible with metastatic disease. Of the 11 PET-positive sites not identified on conventional imaging, most were within the bone and could be considered suggestive for the detection of early bone metastases, although further validation is needed. The highest mean absorbed dose per unit administered radioactivity (μGy/MBq) was in the bladder wall (32.4), and the resultant effective dose was 19.9 ± 1.34 μSv/MBq (mean ± SD). Although further studies are needed for validation, our findings demonstrate the potential of (18)F-DCFBC as a new positron-emitting imaging agent for the detection of metastatic PCa. This study also provides dose estimates for (18)F-DCFBC that are comparable to those of other PET radiopharmaceuticals such as (18)F-FDG.


Parapedobacter pyrenivorans sp. nov., isolated from a pyrene-degrading microbial enrichment, and emended description of the genus Parapedobacter.
A novel pyrene-degrading, Gram-negative bacterium, designated strain P-4(T), was isolated from a polycyclic aromatic hydrocarbon-degrading enrichment of polluted soils from a coking chemical plant. Cells of strain P-4(T) were non-motile rods. Strain P-4(T) grew at 15-45 °C (optimum, 37 °C), pH 6.0-10.0 (optimum, pH 8.5) and 0-4 % (w/v) NaCl. Analysis of the 16S rRNA gene sequence showed that strain P-4(T) was related phylogenetically to members of the genus Parapedobacter, with sequence similarity of 93.7-95.1 %. The cellular fatty acids of strain P-4(T) were iso-C15 : 0, summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c), iso-C17 : 0 3-OH, summed feature 9 (iso-C17 : 1ω9c and/or 10-methyl C16 : 0), anteiso-C15 : 0, iso-C15 : 0 3-OH, C16 : 0, iso-C15 : 1 G, C16 : 0 3-OH and C17 : 0 2-OH. Cells contained menaquinone 7 as the major quinone. The polyamine of strain P-4(T) was homospermidine, and the main polar lipids were phosphatidylethanolamine and a sphingolipid. The G+C content of the DNA was 45.4 mol%. Strain P-4(T) showed a range of phenotypic characteristics that differentiated it from previously recognized Parapedobacter species, particularly its ability to use pyrene as a sole carbon source for growth and its alkaline optimal pH for growth (pH 8.5). On the basis of these results, it is concluded that strain P-4(T) represents a novel species of the genus Parapedobacter, for which the name Parapedobacter pyrenivorans (type strain P-4(T) = NBRC 109113(T) = CGMCC 1.12195(T)) is proposed. An emended description of the genus Parapedobacter is also provided.


Rhinoplasty Education Using a Standardized Patient Encounter.
Comprehensive aesthetic surgery training continues to be a challenge for residency programs. Our residency program developed a rhinoplasty-based objective structured clinical examination (OSCE) based upon validated methods as part of the residency education curriculum. We report our experience with the rhinoplasty-based OSCE and offer guidance to its incorporation within residency programs. The encounter involved resident evaluation and operative planning for a standardized patient desiring a rhinoplasty procedure. Validated OSCE methods currently used at our medical school were implemented. Residents were evaluated on appropriate history taking, physical examination, and explanation to the patient of treatment options. Examination results were evaluated using analysis of variance (statistical significance P<0.05). Twelve residents completed the rhinoplasty OSCE. Medical knowledge assessment showed increasing performance with clinical year, 50% versus 84% for postgraduate year 3 and 6, respectively (P<0.005). Systems-based practice scores showed that all residents incorrectly submitted forms for billing and operative scheduling. All residents confirmed that the OSCE realistically represents an actual patient encounter. All faculty confirmed the utility of evaluating resident performance during the OSCE as a useful assessment tool for determining the Next Accreditation System Milestone level. Aesthetic surgery training for residents will require innovative methods for education. Our examination showed a program-educational weakness in billing/coding, an area that will be improved upon by topic-specific lectures. A thoroughly developed OSCE can provide a realistic educational opportunity to improve residents' performance on the nonoperative aspects of rhinoplasty and should be considered as an adjunct to resident education.


A qualitative study of professional caregivers' perceptions of processes contributing to mealtime agitation in persons with dementia in nursing home wards and strategies to attain calmness.
Describe professional caregivers' perceptions of factors and processes contributing to mealtime agitation and strategies for attaining and maintaining calm mealtimes. Qualitative and descriptive. A convenience sample of professional caregivers working in two wards for residents with dementia was used. Data were collected during two focus-group interviews and supplemented with field notes from six reflection groups. Thematic content analysis was conducted. Data collection occurred from 2010-2011. Professional caregivers perceived agitation during mealtime as resulting from negative feelings in residents triggered by a lack of or negative social interaction, too much or ambiguous stimuli or demands exceeding residents' capacity. Strategies for attaining calm mealtimes involved thorough planning beforehand. During mealtime, professional caregivers focused on establishing a positive community around the table, helping residents focus on eating and continuously observing residents for subtle signals indicating that agitation was about to develop. The prerequisites to succeed with the strategies were knowledge of the residents' preferences and abilities, knowledge sharing within the team and awareness of one's own communication style. Thus, the professional caregivers operationalized person-centred care in a mealtime context.


Impact of dietary and exercise interventions on weight change and metabolic outcomes in obese children and adolescents: a systematic review and meta-analysis of randomized trials.
Diet and exercise represent the mainstays of obesity treatment. No systematic review has been conducted comparing the effect of dietary and exercise intervention in reducing metabolic risks in overweight children. To compare the effects of diet-only intervention with those of diet plus exercise or exercise only on weight loss and metabolic risk reduction in overweight children. English-language articles from 1975 to 2010 available from 7 databases were reviewed. One person searched the databases. Two independent reviewers assessed abstracts and articles against the following eligibility criteria: randomized controlled trials conducted in overweight and obese children aged 18 years or younger, comparing dietary intervention with a diet plus exercise program or an exercise-only program. Study quality was critically appraised by 2 reviewers using established criteria. The main outcome measures were body mass index, body fat percentage, lean body mass, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, fasting glucose, and fasting insulin. Fifteen studies were identified and included. Based on the small number of short-term trials currently available, both diet-only and diet plus exercise interventions resulted in weight loss and metabolic profile improvement. However, the addition of exercise to dietary intervention led to greater improvements in levels of high-density lipoprotein cholesterol (3.86 mg/dL [to convert to millimoles per liter, multiply by 0.0259]; 95% CI, 2.70 to 4.63), fasting glucose (-2.16 mg/dL [to convert to millimoles per liter, multiply by 0.0555]; 95% CI, -3.78 to -0.72), and fasting insulin (-2.75 μIU/mL [to convert to picomoles per liter, multiply by 6.945]; 95% CI, -4.50 to -1.00) over 6 months. The diet-only intervention caused greater reductions in levels of triglycerides (at the end of active intervention) and low-density lipoprotein cholesterol (at subsequent follow-up). This review provides insights into the impact of dietary and exercise interventions on metabolic risk reduction in the pediatric population. However, further studies are required to confirm the evidence with rigorous design, appropriate sample size, longer duration of follow-up, and better strategies to improve compliance and achieve long-term sustainability.


Correlations induced by depressing synapses in critically self-organized networks with quenched dynamics.
In a recent work, mean-field analysis and computer simulations were employed to analyze critical self-organization in networks of excitable cellular automata where randomly chosen synapses in the network were depressed after each spike (the so-called annealed dynamics). Calculations agree with simulations of the annealed version, showing that the nominal branching ratio σ converges to unity in the thermodynamic limit, as expected of a self-organized critical system. However, the question remains whether the same results apply to the biological case where only the synapses of firing neurons are depressed (the so-called quenched dynamics). We show that simulations of the quenched model yield significant deviations from σ=1 due to spatial correlations. However, the model is shown to be critical, as the largest eigenvalue of the synaptic matrix approaches unity in the thermodynamic limit, that is, λ_{c}=1. We also study the finite size effects near the critical state as a function of the parameters of the synaptic dynamics.


Rivers and flooded areas identified by medium-resolution remote sensing improve risk prediction of the highly pathogenic avian influenza H5N1 in Thailand.
Thailand experienced several epidemic waves of the highly pathogenic avian influenza (HPAI) H5N1 between 2004 and 2005. This study investigated the role of water in the landscape, which has not been previously assessed because of a lack of high-resolution information on the distribution of flooded land at the time of the epidemic. Nine Landsat 7 - Enhanced Thematic Mapper Plus scenes covering 174,610 km(2) were processed using k-means unsupervised classification to map the distribution of flooded areas as well as permanent lakes and reservoirs at the time of the main epidemic HPAI H5N1 wave of October 2004. These variables, together with other factors previously identified as significantly associated with risk, were entered into an autologistic regression model in order to quantify the gain in risk explanation over previously published models. We found that, in addition to other factors previously identified as associated with risk, the proportion of land covered by flooding along with expansion of rivers and streams, derived from an existing, sub-district level (administrative level no. 3) geographical information system database, was a highly significant risk factor in this 2004 HPAI epidemic. These results suggest that water-borne transmission could have partly contributed to the spread of HPAI H5N1 during the epidemic. Future work stemming from these results should involve studies where the actual distribution of small canals, rivers, ponds, rice paddy fields and farms are mapped and tested against farm-level data with respect to HPAI H5N1.


How the host fights against Candida infections.
Candida albicans is the predominant cause of both superficial and invasive forms of candidosis, although the proportion of serious infections attributed to other members of the genus is rising.. The spectrum of host defences include cell mediated immunity which is comprised of cytokine release by lymphocytes and activation of natural killer cells and lymphocytes by interleukins.. An increasing body of evidence supports a role for specific antibody in protection against invasive Candida infection. Clinical observations indicate that mucocutaneous Candida infections are commonly associated with defective cell-mediated immune responses. Innate immunity is the dominant protective mechanism against disseminated candidosis. Quantitative and qualitative abnormalities of neutrophils and monocytes are associated with systemic candidosis. In the present review virulence factors and the spectrum of immune responses are discussed in relation to the perspective for the development of appropriate vaccines against Candida. Here we present an overview of toll-like receptor signalling, cellular-dependent responses, the role of specific antibodies in protection against Candida, and the array of immune mechanisms that operate in gastrointestinal, vaginal and oral candidosis.


Metabolic syndrome and prediabetes in ndokwa community of Nigeria: preliminary study.
Global prevalence of metabolic syndrome (MS) and diabetes is increasing, but the reference ranges for MS indices have yet to be established for sub-Saharan African countries. As part of the international research collaboration agenda for Prediabetes and Cardiovascular Complications Study (PACCS), a pilot study was conducted in one of the Ndokwa communities of Nigeria in 2013. The study was to obtain preliminary indication of prevalence and reference values of MS in the rural communities of a low-mid income country. Seventy-four volunteer participants were recruited, after public lectures in high schools and churches in the community. Body mass index (BMI), blood pressure and waist circumference (WC), blood glucoselevel, and lipid profile were measured. Percentage prevalence MS was determined using commonest three criteria (Third Adult Treatment Panel (ATP III) 2001, International Diabetes Federation (IDF) 2005, and World Health Organization (WHO) 1999). When individual indices of MS are considered separately; the males seem healthier than females. However, the prevalence of high-density lipoprotein (HDL) cholesterol was higher in males than in females. Equal 3% prevalence of MS was seen in both genders using the WHO standard. Other criteria show prevalence of 8% females and 11% males (ATP III), 5% females and 8% males (IDF 2005 European), and 14% females and 17% males (IDF 2005 Ethnic). The prevalence of MS is higher in males than females; and relative to ATP III 2001 criteria, either the IDF 2005 European may underestimate MS, or the ethnic specific could overestimate the prevalence. Hence, it is important to define the criteria to be used.


Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway.
Multiciliated cells lining the surface of some vertebrate epithelia are essential for various physiological processes, such as airway cleansing. However, the mechanisms governing motile cilia biosynthesis remain poorly elucidated. We identify miR-449 microRNAs as evolutionarily conserved key regulators of vertebrate multiciliogenesis. In human airway epithelium and Xenopus laevis embryonic epidermis, miR-449 microRNAs strongly accumulated in multiciliated cells. In both models, we show that miR-449 microRNAs promote centriole multiplication and multiciliogenesis by directly repressing the Delta/Notch pathway. We established Notch1 and its ligand Delta-like 1(DLL1) as miR-449 bona fide targets. Human DLL1 and NOTCH1 protein levels were lower in multiciliated cells than in surrounding cells, decreased after miR-449 overexpression and increased after miR-449 inhibition. In frog, miR-449 silencing led to increased Dll1 expression. Consistently, overexpression of Dll1 mRNA lacking miR-449 target sites repressed multiciliogenesis, whereas both Dll1 and Notch1 knockdown rescued multiciliogenesis in miR-449-deficient cells. Antisense-mediated protection of miR-449-binding sites of endogenous human Notch1 or frog Dll1 strongly repressed multiciliogenesis. Our results unravel a conserved mechanism whereby Notch signalling must undergo miR-449-mediated inhibition to permit differentiation of ciliated cell progenitors.


Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoN.
Smad proteins mediate transforming growth factor-beta (TGF-beta) signaling to regulate cell growth and differentiation. SnoN is an important negative regulator of TGF-beta signaling that functions to maintain the repressed state of TGF-beta target genes in the absence of ligand. On TGF-beta stimulation, Smad3 and Smad2 translocate into the nucleus and induce a rapid degradation of SnoN, allowing activation of TGF-beta target genes. We show that Smad2- or Smad3-induced degradation of SnoN requires the ubiquitin-dependent proteasome and can be mediated by the anaphase-promoting complex (APC) and the UbcH5 family of ubiquitin-conjugating enzymes. Smad3 and to a lesser extent, Smad2, interact with both the APC and SnoN, resulting in the recruitment of the APC to SnoN and subsequent ubiquitination of SnoN in a destruction box (D box)-dependent manner. In addition to the D box, efficient ubiquitination and degradation of SnoN also requires the Smad3 binding site in SnoN as well as key lysine residues necessary for ubiquitin attachment. Mutation of either the Smad3 binding site or lysine residues results in stabilization of SnoN and in enhanced antagonism of TGF-beta signaling. Our studies elucidate an important mechanism and pathway for the degradation of SnoN and more importantly, reveal a novel role of the APC in the regulation of TGF-beta signaling.


Mechanisms of 4-hydroxy-2-nonenal induced pro- and anti-apoptotic signaling.
In recent years, 4-hydroxy-2-nonenal (4-HNE) has emerged as an important second messenger in cell cycle signaling. Here, we demonstrate that 4-HNE induces signaling for apoptosis via both the Fas-mediated extrinsic and the p53-mediated intrinsic pathways in HepG2 cells. 4-HNE induces a Fas-mediated DISC independent apoptosis pathway by activating ASK1, JNK, and caspase-3. Parallel treatment of 4-HNE to HepG2 cells also induces apoptosis by the p53 pathway through activation of Bax, p21, JNK, and caspase-3. Exposure of HepG2 cells to 4-HNE leads to the activation of both Fas and Daxx, promotes the export of Daxx from the nucleus to cytoplasm, and facilitates Fas-Daxx binding. Depletion of Daxx by siRNA results in the potentiation of apoptosis, indicating that Fas-Daxx binding in fact is inhibitory to Fas-mediated apoptosis in cells. 4-HNE-induced translocation of Daxx is also accompanied by the activation and nuclear accumulation of HSF1 and up-regulation of heat shock protein Hsp70. All these effects of 4-HNE in cells can be attenuated by ectopic expression of hGSTA4-4, the isozyme of glutathione S-transferase with high activity for 4-HNE. Through immunoprecipitation and liquid chromatography-tandem mass spectrometry, we have demonstrated the covalent binding of 4-HNE to Daxx. We also demonstrate that 4-HNE modification induces phosphorylation of Daxx at Ser668 and Ser671 to facilitate its cytoplasmic export. These results indicate that while 4-HNE exhibits toxicity through several mechanisms, in parallel it evokes signaling for defense mechanisms to self-regulate its toxicity and can simultaneously affect multiple signaling pathways through its interactions with membrane receptors and transcription factors/repressors.


Oxidation of low-density lipoprotein by hypochlorite causes aggregation that is mediated by modification of lysine residues rather than lipid oxidation.
Peroxidation of low-density lipoprotein (LDL) lipid is generally thought to represent the initial step in a series of modification reactions that ultimately transform the protein moiety of the lipoprotein into a form recognized by receptors different from those that bind native LDL. Uptake of LDL via these alternative receptors can lead to the formation of lipid-laden cells, which are typical for the early stages of atherogenesis. We have studied the oxidative modification of LDL by hypochlorite (-OCl), a powerful oxidant produced from H2O2 and chloride via the action of myeloperoxidase which is released from activated neutrophils and monocytes. Exposure of LDL to reagent or enzymically generated -OCl at 4 or 37 degrees C resulted in immediate and preferential oxidation of amino acid residues of apolipoprotein B-100, the single protein associated with LDL. Lysine residues quantitatively represented the major target and, like tryptophan, were oxidized to approximately the same extent with reagent or enzymically generated -OCl. In contrast, LDL lipid oxidation was less favoured than protein oxidation, as judged by the amounts of lipid hydroperoxides, chlorohydrins, cholesterol or fatty acid oxidation products formed. Treatment with -OCl caused aggregation of LDL, as shown by an increased turbidity of the oxidized LDL solution and elution from a size-exclusion h.p.l.c. column of high-molecular-mass LDL complexes. Chemical modification of lysine residues before oxidation with -OCl prevented aggregation, while it enhanced the extent of lipid peroxidation. Treatment of LDL with -OCl also caused the formation of carbonyl groups and release of ammonia; both these modifications were inhibited by lysine-residue modification before oxidation. These results demonstrate that aggregation reactions are dependent on initial lysine oxidation by -OCl, followed by deamination and carbonyl formation, but do not involve lipid (per)oxidation. We propose that the observed -OCl-mediated aggregation of LDL is caused, at least in part, by cross-linking of apoproteins by Schiff-base formation independently of lipid peroxidation.


Tensions of difference: reconciling organisational imperatives for risk management with consumer-focused care from the perspectives of clinicians and managers.
To understand the impact of risk management and assessment on the delivery of mental health care from the perspectives of managers and clinicians. The concept of risk is now embedded in contemporary mental health services. A focus on risk has been identified as a barrier to the provision of consumer-focused care; however, there is a paucity of research in this area, particularly being drawn from key stakeholders in the field. Qualitative exploratory methods. In-depth interviews were conducted with managers and clinicians from a large metropolitan aged-care mental health service in Australia. The participants represented a range of disciplines and expertise across practice settings (community, inpatient and residential). The theme tensions of difference emerged from this research. This theme referred to the tensions between accountability and attending to risk issues and consumer-centred care, with concerns being raised that procedural and bureaucratic accountability influence (often negatively) the provision of care. Differences in the perspectives of clinicians and managers were also evident in the perceived contribution of evidence-based practice in relation to risk. Prioritising risk management may be interfering with the capacity of clinicians and managers to provide quality and consumer-focused mental health care. A deeper examination and reconceptualisation of the role and importance of risk in mental health care are needed to ensure the focus of service delivery remains consumer-focused.


R-citalopram functionally antagonises escitalopram in vivo and in vitro: evidence for kinetic interaction at the serotonin transporter.
1. Clinical observations with the selective serotonin reuptake inhibitor (SSRI), S-citalopram, indicate that S-citalopram is more efficacious and produces earlier symptom relief than RS-citalopram. Since R-citalopram is at least 20-fold weaker than S-citalopram as inhibitor of the 5-HT transporter (SERT) in preclinical studies, the clinical data suggest an unexpected antagonistic interaction between the two enantiomers. We therefore characterised the interaction of R- and S-citalopram with the SERT in in vivo and in vitro assays. 2. In both behavioural (potentiation of 5-hydroxytryptophan (5-HTP)-induced behaviour) and electrophysiological studies (inhibition of 5-HT-elicited ion currents in Xenopus oocytes expressing the human SERT (hSERT) R-citalopram inhibited the effects of S-citalopram in a dose-dependent manner. With S-citalopram : R-citalopram ratios of 1 : 2 and 1 : 4, 5-HTP potentiation was significantly smaller than with S-citalopram alone. 3. R-citalopram did not antagonise the effects of another SSRI (fluoxetine) in either behavioural or electrophysiological studies. 4. In oocytes, inhibition of hSERT-mediated currents by R-citalopram was almost completely reversible and characterised by fast on- and off-sets of action. In contrast, the off-set for S-citalopram was 35-fold slower than for R-citalopram. 5. Kinetic analysis of the oocyte experiments suggests that S-citalopram binding to SERT induces a long-lasting, inhibited state of the transporter and that coapplication of R-citalopram partially relieves SERT of this persistent inhibition. 6. We propose that the kinetic interaction of R- and S-citalopram with SERT is a critical factor contributing to the antagonistic effects of R-citalopram on S-citalopram in vitro and in vivo.


Demographics and perioperative outcome in patients with depression and anxiety undergoing total joint arthroplasty: a population-based study.
Depression and anxiety are highly prevalent psychiatric disorders. However, little is known about their impact on outcomes in the perioperative setting. This study is intended to gain insight into epidemiology and effects on perioperative morbidity, mortality, length of hospital stay, discharge and cost. We obtained the National Inpatient Sample from the Hospital Cost and Utilization Project for each year between 2000 and 2008. Entries indicating the performance of primary total hip and knee arthroplasty were identified and separated into four groups: (1) those with concomitant diagnosis of depression or (2) anxiety, (3) both, and (4) none of these diagnoses. The incidence of major complications, non-routine discharge, length, and cost of hospitalization were assessed. Regression analysis was performed to identify if psychiatric comorbidity was an independent risk factor for each outcome. We identified 1,212,493 patients undergoing arthroplasty between 2000 and 2008. The prevalence of depression and anxiety significantly increased over time. Patients with either condition had higher hospital charges, rates of non-routine discharges and comorbidity index. Depression or anxiety were associated with significantly decreased adjusted odds for in-hospital mortality (OR = 0.53, p = 0.0147; OR = 0.58, p = 0.0064). The risk of developing a major complication was slightly lower in patients with depression, anxiety or both (OR=0.95, p = 0.0738; OR = 0.95, p = 0.0259; OR = 0.94, p = 0.7349). Patients suffering from depression, anxiety, or both require more healthcare resources in a perioperative setting. However, lower short-term mortality in spite of higher comorbidity burden and without extensive changes in perioperative complication profile indicates better outcome for this group of patients.


Object Detection Applied to Indoor Environments for Mobile Robot Navigation.
To move around the environment, human beings depend on sight more than their other senses, because it provides information about the size, shape, color and position of an object. The increasing interest in building autonomous mobile systems makes the detection and recognition of objects in indoor environments a very important and challenging task. In this work, a vision system to detect objects considering usual human environments, able to work on a real mobile robot, is developed. In the proposed system, the classification method used is Support Vector Machine (SVM) and as input to this system, RGB and depth images are used. Different segmentation techniques have been applied to each kind of object. Similarly, two alternatives to extract features of the objects are explored, based on geometric shape descriptors and bag of words. The experimental results have demonstrated the usefulness of the system for the detection and location of the objects in indoor environments. Furthermore, through the comparison of two proposed methods for extracting features, it has been determined which alternative offers better performance. The final results have been obtained taking into account the proposed problem and that the environment has not been changed, that is to say, the environment has not been altered to perform the tests.


Epidemiology of complementary alternative medicine for asthma and allergy in Europe and Germany.
To describe and discuss the epidemiologic characteristics and determinants of the use of complementary alternative medicine (CAM) from a European, particularly German, perspective. An unrestricted literature search using the keywords alternative, allergy, complementary, epidemiology, and medicine was performed in PubMed (National Library of Medicine). In addition, background literature and the opinion of the author contributed to the article. European studies that provided data on the epidemiology of the use of CAM were selected and discussed in more detail. Approximately 30% of patients with allergies report experiences with CAM in Europe. In selected in-patient populations, the prevalence reaches 50%. Users of CAM tend to be younger women with a higher educational background. Furthermore, users and nonusers differ in terms of psychomedical characteristics, such as health locus of control or health-related quality of life. Although a larger number of different CAM modalities are provided, only a few techniques account for the majority of use (eg, acupuncture, homeopathy, herbalism, bioresonance, autologous blood injection). The use of CAM is associated with considerable costs, reaching an estimated amount of 0.9 billion Euro (approximately 1 billion US dollars) in Germany. CAM is widely used by the public to treat allergies. National peculiarities concerning the individual methods, providers, or reimbursement must be considered. The economic and public health implications should be discussed in context with the limited evidence of efficacy.


Contracting for health services: effects of utilization and quality on the costs of the Basic Package of Health Services in Afghanistan.
To research the effects of changes in health service utilization and quality on the costs of the Basic Package of Health Services (BPHS) in 13 provinces of Afghanistan. The study grouped data from 355 health facilities and more than 4000 health posts into 21 data points that represented 21 different nongovernmental organization contracts for service delivery between April 2006 and March 2007. Data were pooled from five data sets on expenditure, service utilization, quality (i.e. client satisfaction and the availability of essential medicines and female health-care providers), pharmaceuticals, and security and remoteness scores. Pearson's partial correlation and multiple linear regression models were used to examine correlations between expenditure and other study variables. Fixed costs were found to comprise most of the cost of BPHS contracts. There was no correlation between cost and utilization rate or security. The distance to the health facility was negatively correlated with costs (R(2) = 0.855, F-significance < 0.001). The presence of female health workers, indicative of good quality in this cultural context, was negatively correlated with security (r = -0.70; P < 0.001). There was a significant correlation between the use of curative services and client satisfaction but not between the use of preventive services and client satisfaction (R(2) = 0.389 and 0.272 for two types of health facilities studied). Access to health services can be extended through contracting mechanisms in a post-conflict state even in the presence of security problems. Service characteristics, geographical distance and the security situation failed to consistently explain, alone or in combination, the observed variations in per capita costs or visits. Therefore, using these parameters as the basis for planning does not necessarily lead to better resource allocation.


Impairment of Gag-specific CD8(+) T-cell function in mucosal and systemic compartments of simian immunodeficiency virus mac251- and simian-human immunodeficiency virus KU2-infected macaques.
The identification of several simian immunodeficiency virus mac251 (SIV(mac251)) cytotoxic T-lymphocyte epitopes recognized by CD8(+) T cells of infected rhesus macaques carrying the Mamu-A*01 molecule and the use of peptide-major histocompatibility complex tetrameric complexes enable the study of the frequency, breadth, functionality, and distribution of virus-specific CD8(+) T cells in the body. To begin to address these issues, we have performed a pilot study to measure the virus-specific CD8(+) and CD4(+) T-cell response in the blood, lymph nodes, spleen, and gastrointestinal lymphoid tissues of eight Mamu-A*01-positive macaques, six of those infected with SIV(mac251) and two infected with the pathogenic simian-human immunodeficiency virus KU2. We focused on the analysis of the response to peptide p11C, C-M (Gag 181), since it was predominant in most tissues of all macaques. Five macaques restricted viral replication effectively, whereas the remaining three failed to control viremia and experienced a progressive loss of CD4(+) T cells. The frequency of the Gag 181 (p11C, C-->M) immunodominant response varied among different tissues of the same animal and in the same tissues from different animals. We found that the functionality of this virus-specific CD8(+) T-cell population could not be assumed based on the ability to specifically bind to the Gag 181 tetramer, particularly in the mucosal tissues of some of the macaques infected by SIV(mac251) that were progressing to disease. Overall, the functionality of CD8(+) tetramer-binding T cells in tissues assessed by either measurement of cytolytic activity or the ability of these cells to produce gamma interferon or tumor necrosis factor alpha was low and was even lower in the mucosal tissue than in blood or spleen of some SIV(mac251)-infected animals that failed to control viremia. The data obtained in this pilot study lead to the hypothesis that disease progression may be associated with loss of virus-specific CD8(+) T-cell function.


Adapting Poisson-Boltzmann to the self-consistent mean field theory: application to protein side-chain modeling.
We present an extension of the self-consistent mean field theory for protein side-chain modeling in which solvation effects are included based on the Poisson-Boltzmann (PB) theory. In this approach, the protein is represented with multiple copies of its side chains. Each copy is assigned a weight that is refined iteratively based on the mean field energy generated by the rest of the protein, until self-consistency is reached. At each cycle, the variational free energy of the multi-copy system is computed; this free energy includes the internal energy of the protein that accounts for vdW and electrostatics interactions and a solvation free energy term that is computed using the PB equation. The method converges in only a few cycles and takes only minutes of central processing unit time on a commodity personal computer. The predicted conformation of each residue is then set to be its copy with the highest weight after convergence. We have tested this method on a database of hundred highly refined NMR structures to circumvent the problems of crystal packing inherent to x-ray structures. The use of the PB-derived solvation free energy significantly improves prediction accuracy for surface side chains. For example, the prediction accuracies for χ(1) for surface cysteine, serine, and threonine residues improve from 68%, 35%, and 43% to 80%, 53%, and 57%, respectively. A comparison with other side-chain prediction algorithms demonstrates that our approach is consistently better in predicting the conformations of exposed side chains.


Expanding the clinical spectrum of COL1A1 mutations in different forms of glaucoma.
Primary congenital glaucoma (PCG) and early onset glaucomas are one of the major causes of children and young adult blindness worldwide. Both autosomal recessive and dominant inheritance have been described with involvement of several genes including CYP1B1, FOXC1, PITX2, MYOC and PAX6. However, mutations in these genes explain only a small fraction of cases suggesting the presence of further candidate genes. To elucidate further genetic causes of these conditions whole exome sequencing (WES) was performed in an Italian patient, diagnosed with PCG and retinal detachment, and his unaffected parents. Sanger sequencing of the complete coding region of COL1A1 was performed in a total of 26 further patients diagnosed with PCG or early onset glaucoma. Exclusion of pathogenic variations in known glaucoma genes as CYP1B1, MYOC, FOXC1, PITX2 and PAX6 was additionally done per Sanger sequencing and Multiple Ligation-dependent Probe Amplification (MLPA) analysis. In the patient diagnosed with PCG and retinal detachment, analysis of WES data identified compound heterozygous variants in COL1A1 (p.Met264Leu; p.Ala1083Thr). Targeted COL1A1 screening of 26 additional patients detected three further heterozygous variants (p.Arg253*, p.Gly767Ser and p.Gly154Val) in three distinct subjects: two of them diagnosed with early onset glaucoma and mild form of osteogenesis imperfecta (OI), one patient with a diagnosis of PCG at age 4 years. All five variants affected evolutionary, highly conserved amino acids indicating important functional restrictions. Molecular modeling predicted that the heterozygous variants are dominant in effect and affect protein stability and thus the amount of available protein, while the compound heterozygous variants act as recessive alleles and impair binding affinity to two main COL1A1 binding proteins: Hsp47 and fibronectin. Dominant inherited mutations in COL1A1 are known causes of connective tissues disorders such as OI. These disorders are also associated with different ocular abnormalities, although recognition of the common pathology for both features is seldom being recognized. Our results expand the role of COL1A1 mutations in different forms of early-onset glaucoma with and without signs of OI. Thus, we suggest including COL1A1 mutation screening in the genetic work-up of glaucoma cases and detailed ophthalmic examinations with fundus analysis in patients with OI.


Patients' and carers' experiences of gaining access to acute stroke care: a qualitative study.
Rapid access to acute stroke care is essential to improve stroke patient outcomes. Policy recommendations for the emergency management of stroke have resulted in significant changes to stroke services, including the introduction of hyper-acute care. To explore patients' and carers' experiences of gaining access to acute stroke care and identify the factors that enabled or prevented stroke from being treated as a medical emergency. Qualitative semi-structured interviews were conducted with 59 stroke survivors and carers who had received care at seven UK centres. The interviews were recorded and transcribed verbatim and thematic analysis was undertaken. Themes emerging showed that participants recognised signs and symptoms, they were satisfied with access to emergency medical services (EMS), and they experienced setbacks in the emergency department and delays caused by the lack of availability of specialist services outside normal working hours. Awareness of the importance of time to treatment was generally attributed to the UK stroke awareness campaign, although some felt the message was not sufficiently comprehensive. This awareness led to increased frustration when participants perceived a lack of urgency in the provision of assessment and medical care. The stroke awareness social marketing campaign has contributed to public knowledge and was perceived to assist in reducing prehospital delay. It has also resulted in an enhanced knowledge of the significance of rapid treatment on admission to hospital and raised public expectation of EMS and stroke services to act fast. More research is required to assist organisational change to reduce in-hospital delay.


Mean-field approach to evolving spatial networks, with an application to osteocyte network formation.
We consider evolving networks in which each node can have various associated properties (a state) in addition to those that arise from network structure. For example, each node can have a spatial location and a velocity, or it can have some more abstract internal property that describes something like a social trait. Edges between nodes are created and destroyed, and new nodes enter the system. We introduce a "local state degree distribution" (LSDD) as the degree distribution at a particular point in state space. We then make a mean-field assumption and thereby derive an integro-partial differential equation that is satisfied by the LSDD. We perform numerical experiments and find good agreement between solutions of the integro-differential equation and the LSDD from stochastic simulations of the full model. To illustrate our theory, we apply it to a simple model for osteocyte network formation within bones, with a view to understanding changes that may take place during cancer. Our results suggest that increased rates of differentiation lead to higher densities of osteocytes, but with a smaller number of dendrites. To help provide biological context, we also include an introduction to osteocytes, the formation of osteocyte networks, and the role of osteocytes in bone metastasis.


Self-assembled isoporous block copolymer membranes with tuned pore sizes.
The combination of nonsolvent-induced phase separation and the self-assembly of block copolymers can lead to asymmetric membranes with a thin highly ordered isoporous skin layer. The effective pore size of such membranes is usually larger than 15 nm. We reduced the pore size of these membranes by electroless gold deposition. We demonstrate that the pore sizes can be controlled precisely between 3 and 20 nm leading to a tunable sharp size discrimination in filtration processes. Besides fractionation of nanoparticles and biomaterials, controlled drug delivery is an attractive potential application.


Cyclin D2-knock-out mice with attenuated dentate gyrus neurogenesis have robust deficits in long-term memory formation.
Neurobehavioral studies have produced contradictory findings concerning the function of neurogenesis in the adult dentate gyrus. Previous studies have proved inconsistent across several behavioral endpoints thought to be dependent on dentate neurogenesis, including memory acquisition, short-term and long-term retention of memory, pattern separation, and reversal learning. We hypothesized that the main function of dentate neurogenesis is long-term memory formation because we assumed that a newly formed and integrated neuron would have a long-term impact on the local neural network. We used a cyclin D2-knock-out (cyclin D2-/-) mouse model of endogenously deficient dentate neurogenesis to test this hypothesis. We found that cyclin D2-/- mice had robust and sustained loss of long-term memory in two separate behavioral tasks, Morris water maze (MWM) and touchscreen intermediate pattern separation. Moreover, after adjusting for differences in brain volumes determined by magnetic resonance (MR) imaging, reduced dentate neurogenesis moderately correlated with deficits in memory retention after 24 hours. Importantly, cyclin D2-/- mice did not show deficits in learning acquisition in a touchscreen paradigm of intermediate pattern separation or MWM platform location, indicating intact short-term memory. Further evaluation of cyclin D2-/- mice is necessary to confirm that deficits are specifically linked to dentate gyrus neurogenesis since cyclin D2-/- mice also have a reduced size of the olfactory bulb, hippocampus, cerebellum and cortex besides reduced dentate gyrus neurogenesis.


Korean Medication Algorithm for Bipolar Disorder 2014: comparisons with other treatment guidelines.
Our goal was to compare the recommendations of the Korean Medication Algorithm Project for Bipolar Disorder 2014 (KMAP-BP 2014) with other recently published guidelines for the treatment of bipolar disorder. We reviewed a total of four recently published global treatment guidelines and compared each treatment recommendation of the KMAP-BP 2014 with those in other guidelines. For the initial treatment of mania, there were no significant differences across treatment guidelines. All recommended mood stabilizer (MS) or atypical antipsychotic (AAP) monotherapy or the combination of an MS with an AAP as a first-line treatment strategy for mania. However, the KMAP-BP 2014 did not prefer monotherapy with MS or AAP for dysphoric/psychotic mania. Aripiprazole, olanzapine, quetiapine, and risperidone were the first-line AAPs in nearly all of the phases of bipolar disorder across the guidelines. Most guidelines advocated newer AAPs as first-line treatment options in all phases, and lamotrigine in depressive and maintenance phases. Lithium and valproic acid were commonly used as MSs in all phases of bipolar disorder. As research evidence accumulated over time, recommendations of newer AAPs - such as asenapine, paliperidone, lurasidone, and long-acting injectable risperidone - became prominent. This comparison identifies that the treatment recommendations of the KMAP-BP 2014 are similar to those of other treatment guidelines and reflect current changes in prescription patterns for bipolar disorder based on accumulated research data. Further studies are needed to address several issues identified in our review.


Beta-thalassemia.
Beta-thalassemias are a group of hereditary blood disorders characterized by anomalies in the synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. The total annual incidence of symptomatic individuals is estimated at 1 in 100,000 throughout the world and 1 in 10,000 people in the European Union. Three main forms have been described: thalassemia major, thalassemia intermedia and thalassemia minor. Individuals with thalassemia major usually present within the first two years of life with severe anemia, requiring regular red blood cell (RBC) transfusions. Findings in untreated or poorly transfused individuals with thalassemia major, as seen in some developing countries, are growth retardation, pallor, jaundice, poor musculature, hepatosplenomegaly, leg ulcers, development of masses from extramedullary hematopoiesis, and skeletal changes that result from expansion of the bone marrow. Regular transfusion therapy leads to iron overload-related complications including endocrine complication (growth retardation, failure of sexual maturation, diabetes mellitus, and insufficiency of the parathyroid, thyroid, pituitary, and less commonly, adrenal glands), dilated myocardiopathy, liver fibrosis and cirrhosis). Patients with thalassemia intermedia present later in life with moderate anemia and do not require regular transfusions. Main clinical features in these patients are hypertrophy of erythroid marrow with medullary and extramedullary hematopoiesis and its complications (osteoporosis, masses of erythropoietic tissue that primarily affect the spleen, liver, lymph nodes, chest and spine, and bone deformities and typical facial changes), gallstones, painful leg ulcers and increased predisposition to thrombosis. Thalassemia minor is clinically asymptomatic but some subjects may have moderate anemia. Beta-thalassemias are caused by point mutations or, more rarely, deletions in the beta globin gene on chromosome 11, leading to reduced (beta+) or absent (beta0) synthesis of the beta chains of hemoglobin (Hb). Transmission is autosomal recessive; however, dominant mutations have also been reported. Diagnosis of thalassemia is based on hematologic and molecular genetic testing. Differential diagnosis is usually straightforward but may include genetic sideroblastic anemias, congenital dyserythropoietic anemias, and other conditions with high levels of HbF (such as juvenile myelomonocytic leukemia and aplastic anemia). Genetic counseling is recommended and prenatal diagnosis may be offered. Treatment of thalassemia major includes regular RBC transfusions, iron chelation and management of secondary complications of iron overload. In some circumstances, spleen removal may be required. Bone marrow transplantation remains the only definitive cure currently available. Individuals with thalassemia intermedia may require splenectomy, folic acid supplementation, treatment of extramedullary erythropoietic masses and leg ulcers, prevention and therapy of thromboembolic events. Prognosis for individuals with beta-thalassemia has improved substantially in the last 20 years following recent medical advances in transfusion, iron chelation and bone marrow transplantation therapy. However, cardiac disease remains the main cause of death in patients with iron overload.


Intravital live cell triggered imaging system reveals monocyte patrolling and macrophage migration in atherosclerotic arteries.
Intravital multiphoton imaging of arteries is technically challenging because the artery expands with every heartbeat, causing severe motion artifacts. To study leukocyte activity in atherosclerosis, we developed the intravital live cell triggered imaging system (ILTIS). This system implements cardiac triggered acquisition as well as frame selection and image registration algorithms to produce stable movies of myeloid cell movement in atherosclerotic arteries in live mice. To minimize tissue damage, no mechanical stabilization is used and the artery is allowed to expand freely. ILTIS performs multicolor high frame-rate two-dimensional imaging and full-thickness three-dimensional imaging of beating arteries in live mice. The external carotid artery and its branches (superior thyroid and ascending pharyngeal arteries) were developed as a surgically accessible and reliable model of atherosclerosis. We use ILTIS to demonstrate Cx3cr1GFP monocytes patrolling the lumen of atherosclerotic arteries. Additionally, we developed a new reporter mouse (Apoe−/−Cx3cr1GFP/+Cd11cYFP) to image GFP+ and GFP+YFP + macrophages "dancing on the spot" and YFP+ macrophages migrating within intimal plaque. ILTIS will be helpful to answer pertinent open questions in the field, including monocyte recruitment and transmigration, macrophage and dendritic cell activity, and motion of other immune cells.


Pancreatic pseudocyst.
Pseudocyst formation is a well-known complication of pancreatitis. Pseudocysts of the pancreas are localized collections of fluid occurring within the pancreatic mass or the peripancreatic spaces often following acute pancreatitis or in a patient with chronic pancreatitis without any previous history of an acute episode. The pathogenesis depends on the etiology: in acute pancreatitis, enzyme-rich fluid and products of autodegradation accumulate; in chronic pancreatitis, the cyst results from an obstructed duct. The natural history of the diseases has become clearer with the advent of ultrasound and computed tomographic scanning. The incidence of pseudocysts is noted to be higher as a result of better diagnostic techniques. Pseudocysts must be suspected in patients who have persistent abdominal pain or consistently elevated levels of pancreatic enzymes. Nearly one third of pancreatic pseudocysts resolve spontaneously. Some, however, require intervention. Surgery was the only option available for many years. Recently, newer methods, such as percutaneous drainage and endoscopic cystenterostomy, have been used. Percutaneous drainage is inexpensive, has a low complication rate, and is done under local anesthesia. The recurrence rate is high with a one-time needle aspiration; this rate can be reduced to less than 10% by using an indwelling catheter. On the basis of a review of literature and our own experience, we believe that percutaneous continuous catheter drainage should be the first choice in the management of pseudocysts that require intervention. Experience with the endoscopic technique is increasing, and it may prove to be a viable alternative in skilled hands in the future.


The auto-inhibitory role of the EPAC hinge helix as mapped by NMR.
The cyclic-AMP binding domain (CBD) is the central regulatory unit of exchange proteins activated by cAMP (EPAC). The CBD maintains EPAC in a state of auto-inhibition in the absence of the allosteric effector, cAMP. When cAMP binds to the CBD such auto-inhibition is released, leading to EPAC activation. It has been shown that a key feature of such cAMP-dependent activation process is the partial destabilization of a structurally conserved hinge helix at the C-terminus of the CBD. However, the role of this helix in auto-inhibition is currently not fully understood. Here we utilize a series of progressive deletion mutants that mimic the hinge helix destabilization caused by cAMP to show that such helix is also a pivotal auto-inhibitory element of apo-EPAC. The effect of the deletion mutations on the auto-inhibitory apo/inactive vs. apo/active equilibrium was evaluated using recently developed NMR chemical shift projection and covariance analysis methods. Our results show that, even in the absence of cAMP, the C-terminal region of the hinge helix is tightly coupled to other conserved allosteric structural elements of the CBD and perturbations that destabilize the hinge helix shift the auto-inhibitory equilibrium toward the apo/active conformations. These findings explain the apparently counterintuitive observation that cAMP binds more tightly to shorter than longer EPAC constructs. These results are relevant for CBDs in general and rationalize why substrates sensitize CBD-containing systems to cAMP. Furthermore, the NMR analyses presented here are expected to be generally useful to quantitatively evaluate how mutations affect conformational equilibria.


The lateral batting backlift technique: is it a contributing factor to success for professional cricket players at the highest level?
This study aimed primarily to investigate the lateral batting backlift technique (LBBT) among semi-professional, professional and current international cricket players. A key question was to investigate whether this technique is a factor that contributes to success for cricket players at the highest levels of the game. The participants in this study's sample (n = 130) were South African semi-professional players (SP) (n = 69), professional players (PP) (n = 49) and South African international professional players (SAI) (n = 12). Biomechanical and video analyses were performed on all the participating groups. Classifiers were utilised to identify the batting backlift technique type (BBTT) employed by all batsmen. All statistics and wagon wheels (scoring areas of the batsmen on a cricket field) were sourced online. A Pearson's Chi-squared test, Student T-test, one-way analysis of variance and T-test were performed in this study. All analyses were performed using R (R Core Team) at a significance level of α = 0.05. This study found that a LBBT is more common at the highest levels of batsmanship with batsmen at the various levels of cricket having percentages of the LBBT as follows: SP = 37%; PP = 38%; SAI = 75%; p = 0.001. There was also a noticeably higher difference in the highest scores and career averages between all groups of players, as well as batsmen who either use a straight batting backlift technique (SBBT) or a LBBT. This study also found that SAI batsmen who used the LBBT were more proficient at scoring runs in various areas around the cricket field (according to the wagon wheel analysis). This study found that a LBBT is a contributing factor for success regarding players wanting to play cricket at the highest levels. Cricket coaches should also pay attention to the direction of the backlift with players, especially when correlating it to various scoring areas on the cricket field. Further in-depth research is required to fully investigate the change in batting backlift techniques among cricket players over a long-term period.


Pathogen detection using engineered bacteriophages.
Bacteriophages, or phages, are bacterial viruses that can infect a broad or narrow range of host organisms. Knowing the host range of a phage allows it to be exploited in targeting various pathogens. Applying phages for the identification of microorganisms related to food and waterborne pathogens and pathogens of clinical significance to humans and animals has a long history, and there has to some extent been a recent revival in these applications as phages have become more extensively integrated into novel detection, identification, and monitoring technologies. Biotechnological and genetic engineering strategies applied to phages are responsible for some of these new methods, but even natural unmodified phages are widely applicable when paired with appropriate innovative detector platforms. This review highlights the use of phages as pathogen detector interfaces to provide the reader with an up-to-date inventory of phage-based biodetection strategies.


A model-based iterative reconstruction algorithm DIRA using patient-specific tissue classification via DECT for improved quantitative CT in dose planning.
To develop and evaluate-in a proof-of-concept configuration-a novel iterative reconstruction algorithm (DIRA) for quantitative determination of elemental composition of patient tissues for application to brachytherapy with low energy (< 50 keV) photons and proton therapy. DIRA was designed as a model-based iterative reconstruction algorithm, which uses filtered backprojection, automatic segmentation and multimaterial tissue decomposition. The evaluation was done for a phantom derived from the voxelized ICRP 110 male phantom. Soft tissues were decomposed to the lipid, protein and water triplet, bones were decomposed to the compact bone and bone marrow doublet. Projections were derived using the Drasim simulation code for an axial scanning configuration resembling a typical DECT (dual-energy CT) scanner with 80 kV and Sn140 kV x-ray spectra. The iterative loop produced mono-energetic images at 50 and 88 keV without beam hardening artifacts. Different noise levels were considered: no noise, a typical noise level in diagnostic imaging and reduced noise level corresponding to tenfold higher doses. An uncertainty analysis of the results was performed using type A and B evaluations. The two approaches were compared. Linear attenuation coefficients averaged over a region were obtained with relative errors less than 0.5% for all evaluated regions. Errors in average mass fractions of the three-material decomposition were less than 0.04 for no noise and reduced noise levels and less than 0.11 for the typical noise level. Mass fractions of individual pixels were strongly affected by noise, which slightly increased after the first iteration but subsequently stabilized. Estimates of uncertainties in mass fractions provided by the type B evaluation differed from the type A estimates by less than 1.5% for most cases. The algorithm was fast, the results converged after 5 iterations. The algorithmic complexity of forward polyenergetic projection calculation was much reduced by using material doublets and triplets. The simulations indicated that DIRA is capable of determining elemental composition of tissues, which are needed in brachytherapy with low energy (< 50 keV) photons and proton therapy. The algorithm provided quantitative monoenergetic images with beam hardening artifacts removed. Its convergence was fast, image sharpness expressed via the modulation transfer function was maintained, and image noise did not increase with the number of iterations.


Cardiovascular risk factors in subjects with psoriasis: a cross-sectional general population study.
Epidemiological data have established an association between cardiovascular disease and psoriasis. Only one general population study has so far compared prevalences of cardiovascular risk factors among subjects with psoriasis and control subjects. We aimed to determine the prevalence of cardiovascular risk factors in subjects with and without psoriasis in the general population. During 2006-2008, a cross-sectional study was performed in the general population in Copenhagen, Denmark. A total of 3471 subjects participated in a general health examination that included assessment of current smoking status, weight, height, waist and hip circumferences, systolic and diastolic blood pressures, resting heart rate, and plasma lipids, hemoglobin A1c, fasting glucose, and insulin levels. Physician-diagnosed psoriasis was reported by 238 (7.1%) of 3374 participants. There were no differences between subjects with and without psoriasis with regard to traditional cardiovascular risk factors. Our results contrast with the hitherto-reported increased prevalence of metabolic syndrome in subjects with psoriasis in the general U.S. population. However, our results agree with those of other previous studies in which the association between mild psoriasis and cardiovascular risk factors is often non-significant. Further controlled research is needed to describe the prevalence of cardiovascular risk factors in subjects with mainly mild to moderate psoriasis in the general population.