Every surgical resident should know how to perform a cricothyrotomy: an inexpensive cricothyrotomy task trainer for teaching and assessing surgical trainees.
Emergency cricothyrotomy is a rare but potentially lifesaving procedure. Training opportunities for surgical residents to learn this skill are limited, and many graduating residents have never performed one during their training. We aimed to develop and validate a novel and inexpensive cricothyrotomy task trainer that can be constructed from household items. A model was constructed using a toilet paper roll (trachea and larynx), Styrofoam (soft tissue), cardboard (thyroid cartilage), zip tie (cricoid), and fabric (skin). Participants were asked to complete a simulated cricothyrotomy procedure using the model. They were then evaluated using a 10-point checklist (5 points total) devised by 6 general surgeons. Participants were also asked to complete an anonymous survey rating the educational value and the degree of enjoyment regarding the model. A tertiary care teaching hospital. A total of 54 students and general surgery residents (11 medical students, 32 interns, and 11 postgraduate year 3 residents). All 54 participants completed the training and assessment. The scores ranged from 0 to 5. The mean (range) scores were 1.8 (1-4) for medical students, 3.5 (1-5) for junior residents, and 4.9 (4-5) for senior-level residents. Medical students were significantly outperformed by junior- and senior-level residents (p < 0.001). Trainees felt that the model was educational (4.5) and enjoyable (4.0). A low-fidelity, low-cost cricothyrotomy simulator distinguished the performance of emergency cricothyrotomy between medical students and junior- and senior-level general surgery residents. This task trainer may be ideally suited to providing basic skills to all physicians in training, especially in settings with limited resources and clinical opportunities.


Regulation of HIF by the von Hippel-Lindau tumour suppressor: implications for cellular oxygen sensing.
Hypoxia-inducible factor (HIF) is central in coordinating many of the transcriptional adaptations to hypoxia. Composed of a heterodimer of alpha and beta subunits, the alpha subunit is rapidly degraded in normoxia, leading to inactivation of the hypoxic response. Many models for a molecular oxygen sensor regulating this system have been proposed, but an important finding has been the ability to mimic hypoxia by chelation or substitution of iron. A key insight has been the recognition that HIF-alpha is targeted for degradation by the ubiquitin-proteasome pathway through binding to the von Hippel-Lindau tumour suppressor protein (pVHL), which forms the recognition component of an E3 ubiquitin ligase complex leading to ubiquitylation of HIF-alpha. Importantly, the classical features of regulation by iron and oxygen availability are reflected in regulation of the HIF-alpha/pVHL interaction. It has recently been shown that HIF-alpha undergoes an iron- and oxygen-dependent modification before it can interact with pVHL, and that this results in hydroxylation of at least one prolyl residue (HIF-1alpha, Pro 564). This modification is catalysed by an enzyme termed HIF-prolyl hydroxylase (HIF-PH), and compatible with all previously described prolyl-4-hydroxylases HIF-PH also requires 2-oxoglutarate as a cosubstrate. The key position of this hydroxylation in the degradation pathway of HIF-alpha, together with its requirement for molecular dioxygen as a co-substrate, provides the potential for HIF-PH to function directly as a cellular oxygen sensor. However, the ability of these enzyme(s) to account for the full range of physiological regulation displayed by the HIF system remains to be defined.


Strong claims and weak evidence: reassessing the predictive validity of the IAT.
The authors reanalyzed data from 2 influential studies-A. R. McConnell and J. M. Leibold and J. C. Ziegert and P. J. Hanges-that explore links between implicit bias and discriminatory behavior and that have been invoked to support strong claims about the predictive validity of the Implicit Association Test. In both of these studies, the inclusion of race Implicit Association Test scores in regression models reduced prediction errors by only tiny amounts, and Implicit Association Test scores did not permit prediction of individual-level behaviors. Furthermore, the results were not robust when the impact of rater reliability, statistical specifications, and/or outliers were taken into account, and reanalysis of A. R. McConnell & J. M. Leibold (2001) revealed a pattern of behavior consistent with a pro-Black behavioral bias, rather than the anti-Black bias suggested in the original study.


Preparation of Acute Brain Slices Using an Optimized N-Methyl-D-glucamine Protective Recovery Method.
This protocol is a practical guide to the N-methyl-D-glucamine (NMDG) protective recovery method of brain slice preparation. Numerous recent studies have validated the utility of this method for enhancing neuronal preservation and overall brain slice viability. The implementation of this technique by early adopters has facilitated detailed investigations into brain function using diverse experimental applications and spanning a wide range of animal ages, brain regions, and cell types. Steps are outlined for carrying out the protective recovery brain slice technique using an optimized NMDG artificial cerebrospinal fluid (aCSF) media formulation and enhanced procedure to reliably obtain healthy brain slices for patch clamp electrophysiology. With this updated approach, a substantial improvement is observed in the speed and reliability of gigaohm seal formation during targeted patch clamp recording experiments while maintaining excellent neuronal preservation, thereby facilitating challenging experimental applications. Representative results are provided from multi-neuron patch clamp recording experiments to assay synaptic connectivity in neocortical brain slices prepared from young adult transgenic mice and mature adult human neurosurgical specimens. Furthermore, the optimized NMDG protective recovery method of brain slicing is compatible with both juvenile and adult animals, thus resolving a limitation of the original methodology. In summary, a single media formulation and brain slicing procedure can be implemented across various species and ages to achieve excellent viability and tissue preservation.


The efficacy of ginger in prevention of post-operative nausea and vomiting after outpatient gynecological laparoscopy.
To study the efficacy of ginger in prevention of nausea and vomiting after outpatient gynecological laparoscopy. Double blind randomized controlled trial. Department of Obstetrics and Gynecology, Thammasat Hospital, Faculty of Medicine, Thammasat University. From January, 2001-December, 2001, 80 patients who underwent outpatient gynecological laparoscopy were randomly allocated into group A (n = 40) and group B (n = 40). The patients in group A received 2 capsules of ginger (1 capsule contain 0.5 g of ginger powder) 1 h before the procedure while the patients in group B received the placebo. The visual analogue nausea scores (VANS) and vomiting times were evaluated at 2, 4 and 24 hours after operation. There was a significant difference in the incidence of the nausea between group A [12 (30%)] and group B [23 (57.50%)]. The VANS was lower in group A than in group B at 2 and 4 hours (p < 0.05). No difference of VANS at 24 hours was found in both groups. Incidence and frequency of vomiting in group A were lower than group B but there were not statistically different. From our data, ginger is effective in prevention of nausea after outpatient gynecological laparoscopy.


The essential role of AMPA receptor GluR2 subunit RNA editing in the normal and diseased brain.
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are comprised of different combinations of GluA1-GluA4 (also known asGluR1-GluR4 and GluR-A to GluR-D) subunits. The GluA2 subunit is subject to RNA editing by the ADAR2 enzyme, which converts a codon for glutamine (Gln; Q), present in the GluA2 gene, to a codon for arginine (Arg; R) found in the mRNA. AMPA receptors are calcium (Ca(2+))-permeable if they contain the unedited GluA2(Q) subunit or if they lack the GluA2 subunit. While most AMPA receptors in the brain contain the edited GluA2(R) subunit and are therefore Ca(2+)-impermeable, recent evidence suggests that Ca(2+)-permeable AMPA receptors are important in synaptic plasticity, learning, and disease. Strong evidence supports the notion that Ca(2+)-permeable AMPA receptors are usually GluA2-lacking AMPA receptors, with little evidence to date for a significant role of unedited GluA2 in normal brain function. However, recent detailed studies suggest that Ca(2+)-permeable AMPA receptors containing unedited GluA2 do in fact occur in neurons and can contribute to excitotoxic cell loss, even where it was previously thought that there was no unedited GluA2.This review provides an update on the role of GluA2 RNA editing in the healthy and diseased brain and summarizes recent insights into the mechanisms that control this process. We suggest that further studies of the role of unedited GluA2 in normal brain function and disease are warranted, and that GluA2 editing should be considered as a possible contributing factor when Ca(2+)-permeable AMPA receptors are observed.


Sex differences in the effects of PARP inhibition on microglial phenotypes following neonatal stroke.
Neonatal acute ischemic stroke is a cause of neonatal brain injury that occurs more frequently in males, resulting in associated neurobehavioral disorders. The bases for these sex differences are poorly understood but might include the number, morphology and activation of microglia in the developing brain when subjected to stroke. Interestingly, poly (ADP-ribose) polymerase (PARP) inhibition preferentially protects males against neonatal ischemia. This study aims to examine the effects of PJ34, a PARP inhibitor, on microglial phenotypes at 3 and 8 days and on neurobehavioral disorders in adulthood for both male and female P9 mice subjected to permanent middle cerebral artery occlusion (pMCAo). PJ34 significantly reduced the lesion size by 78% and reduced the density of CX3CR1gfp-labeled microglial cells by 46% when examined 3 days after pMCAo in male but not in female mice. Eight days after pMCAo, the number of Iba1+/Cox-2+ cells did not differ between male and female mice in the cortical peri-infarct region. In the amygdala, Iba1+/Cox-2+ (M1-like) cell numbers were significantly decreased in PJ34-treated males but not in females. Conversely, Iba1+/Arg-1+ (M2-like) and Arg-1+/Cox-2+ (Mtransitional) cell numbers were significantly increased in PJ34-treated females. Regarding neurobehavioral disorders during adulthood, pMCAo induced a motor coordination deficit and a spatial learning deficit in female mice only. PJ34 prevented MBP fibers, motor coordination and learning disorders during adulthood in female mice. Our data show significant sex differences in the effects of PARP inhibition on microglia phenotypes following neonatal ischemia, associated with improved behavior and myelination during adulthood in females only. Our findings suggest that modulating microglial phenotypes may play key roles in behavior disorders and white matter injury following neonatal stroke.


Oxidative Stress and Dementia in Alzheimer's Patients: Effects of Synbiotic Supplementation.
Alzheimer's disease (AD) is the most common cause of dementia in elderly patients. Recently, several studies have shown that inflammation and oxidative stress precede the cardinal neuropathological manifestations of AD. In view of the proven antioxidant effects of probiotics, we proposed that continuous dietary supplementation with milk fermented with kefir grains might improve cognitive and metabolic and/or cellular disorders in the AD patients. This study was designed as an uncontrolled clinical investigation to test the effects of probiotic-fermented milk supplementation (2 mL/kg/daily) for 90 days in AD patients exhibiting cognitive deficit. Cognitive assessment, cytokine expression, systemic oxidative stress levels, and blood cell damage biomarkers were evaluated before (T0) and after (T90) kefir synbiotic supplementation. When the patients were challenged to solve 8 classical tests, the majority exhibit a marked improvement in memory, visual-spatial/abstraction abilities, and executive/language functions. At the end of the treatment, the cytometric analysis showed an absolute/relative decrease in several cytokine markers of inflammation and oxidative stress markers (·O2 -, H2O2, and ONOO-, ~30%) accompanied by an increase in NO bioavailability (100%). In agreement with the above findings by using the same technique, we observed in a similar magnitude an improvement of serum protein oxidation, mitochondrial dysfunction, DNA damage/repair, and apoptosis. In conclusion, we demonstrated that kefir improves cognitive deficits, which seems to be linked with three important factors of the AD-systemic inflammation, oxidative stress, and blood cell damage-and may be a promising adjuvant therapy against the AD progression.


DNA binding properties of a chemically synthesized DNA binding domain of hRFX1.
The RFX DNA binding domain (DBD) is a novel highly conserved motif belonging to a large number of dimeric DNA binding proteins which have diverse regulatory functions in eukaryotic organisms, ranging from yeasts to human. To characterize this novel motif, solid phase synthesis of a 76mer polypeptide corresponding to the DBD of human hRFX1 (hRFX1/DBD), a prototypical member of the RFX family, has been optimized to yield large quantities (approximately 90 mg) of pure compound. Preliminary two-dimensional1H NMR experiments suggested the presence of helical regions in this sequence in agreement with previously reported secondary structure predictions. In gel mobility shift assays, this synthetic peptide was shown to bind in a cooperative manner the 23mer duplex oligodeoxynucleotide corresponding to the binding site of hRFX1, with a 2:1 stoichoimetry due to an inverse repeat present in the 23mer. The stoichiometry of this complex was reduced to 1:1 by decreasing the length of the DNA sequence to a 13mer oligonucleotide containing a single half-site. Surface plasmon resonance measurements were achieved using this 5'-biotylinated 13mer oligonucleotide immobilized on an avidin-coated sensor chip. Using this method an association constant (K a = 4 x 10(5)/M/s), a dissociation constant (K d = 6 x 10(-2)/s) and an equilibrium dissociation constant (K D = 153 nM) were determined for binding of hRFX1/DBD to the double-stranded 13mer oligonucleotide. In the presence of hRFX1/DBD the melting temperature of the 13mer DNA was increased by 16 degreesC, illustrating stabilization of the double-stranded conformation induced by the peptide.


The roles and interactions of symbiont, host and environment in defining coral fitness.
Reef-building corals live in symbiosis with a diverse range of dinoflagellate algae (genus Symbiodinium) that differentially influence the fitness of the coral holobiont. The comparative role of symbiont type in holobiont fitness in relation to host genotype or the environment, however, is largely unknown. We addressed this knowledge gap by manipulating host-symbiont combinations and comparing growth, survival and thermal tolerance among the resultant holobionts in different environments. Offspring of the coral, Acropora millepora, from two thermally contrasting locations, were experimentally infected with one of six Symbiodinium types, which spanned three phylogenetic clades (A, C and D), and then outplanted to the two parental field locations (central and southern inshore Great Barrier Reef, Australia). Growth and survival of juvenile corals were monitored for 31-35 weeks, after which their thermo-tolerance was experimentally assessed. Our results showed that: (1) Symbiodinium type was the most important predictor of holobiont fitness, as measured by growth, survival, and thermo-tolerance; (2) growth and survival, but not heat-tolerance, were also affected by local environmental conditions; and (3) host population had little to no effect on holobiont fitness. Furthermore, coral-algal associations were established with symbiont types belonging to clades A, C and D, but three out of four symbiont types belonging to clade C failed to establish a symbiosis. Associations with clade A had the lowest fitness and were unstable in the field. Lastly, Symbiodinium types C1 and D were found to be relatively thermo-tolerant, with type D conferring the highest tolerance in A. millepora. These results highlight the complex interactions that occur between the coral host, the algal symbiont, and the environment to shape the fitness of the coral holobiont. An improved understanding of the factors affecting coral holobiont fitness will assist in predicting the responses of corals to global climate change.


Associations between Specialist Tactical Response Police Unit Selection Success and Urban Rush, along with 2.4 km and 10 km Loaded Carriage Events.
Officers serving in specialist tactical response police teams are highly trained personnel who are required to carry heavy loads and perform explosive tasks. The aim of this study was to determine whether performance on a loaded explosive occupational task (urban rush) or distance-based load carriage tasks (2.4 km or 10 km) were indicative of officer success on a specialist selection course (SSC). Eighteen male police officers (mean age = 32.11 ± 5.04 years) participated in the SSC over five consecutive days. Data were categorized into Group 1 (successful applicants, n = 11) and Group 2 (unsuccessful applicants, n = 7). Independent sample t-tests were performed to determine differences between groups, along with point-biserial correlations to investigate associations between anthropometric and event performance data and course completion success. Alpha levels were set at p = 0.05 a priori. Height (p = 0.025), body weight (p = 0.007), and 2.4 km loaded performance (p = 0.013) were significantly different between groups, where being shorter (rpb(16) = -0.526, p < 0.05), lighter (rpb(16) = -0.615, p < 0.01), and faster (rpb(16) = -0.572, p < 0.05) were associated with course success. While a loaded 2.4 km event is associated with success, a ceiling effect for an explosive anaerobic task and a longer 10 km task may exist, whereby increases in performance are not associated with selection success.


The effect of bilateral globus pallidus internus deep brain stimulation plus ventralis oralis thalamotomy on patients with cerebral palsy.
We compared bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) with bilateral GPi DBS plus ventralis oralis (Vo) thalamotomy to analyze the effect of the combined Vo thalamotomy. Between March 2003 and December 2008, 10 patients underwent DBS and/or Vo thalamotomy for treatment of cerebral palsy in our institute of neurosurgery and rehabilitation medicine. Four patients received bilateral posteroventral GPi DBS as group I and 6 patients received GPi DBS plus unilateral thalamotomy as group II. The movement and disability scores of group I improved by 32 and 14.3%, respectively, at the last follow-up compared with baseline. The movement and disability scores of group II improved by 31.5 and 0.18%. The BFMDRS-movement subscores of group II demonstrated statistically significant improvement in the contralateral arm compared to group I (p = 0.042). Body pain, vitality and mental health seemed to improve in group II, in terms of health-related quality of life. Contrary to our expectations, we were unable to demonstrate clear improvements in overall BFMDRS scores between group I and group II. However, movements of the contralateral upper extremities improved and health-related quality of life in group II showed satisfactory results.


Methods for calculating dose conversion coefficients for terrestrial and aquatic biota.
Plants and animals may be exposed to ionizing radiation from radionuclides in the environment. This paper describes the underlying data and assumptions to assess doses to biota due to internal and external exposure for a wide range of masses and shapes living in various habitats. A dosimetric module is implemented which is a user-friendly and flexible possibility to assess dose conversion coefficients for aquatic and terrestrial biota. The dose conversion coefficients have been derived for internal and various external exposure scenarios. The dosimetric model is linked to radionuclide decay and emission database, compatible with the ICRP Publication 38, thus providing a capability to compute dose conversion coefficients for any nuclide from the database and its daughter nuclides. The dosimetric module has been integrated into the ERICA Tool, but it can also be used as a stand-alone version.


Functional properties and effect on growth suppression of human neuroblastoma tumors by isotype switch variants of monoclonal antiganglioside GD2 antibody 14.18.
A complete family of IgG isotype switch variant hybridomas was generated from the anti-GD2 monoclonal IgG3-producing hybridoma, 14.18, with the aid of the fluorescence-activated cell sorter. The IgG1, IgG2b, and IgG2a monoclonal antibodies (Mabs) produced by respective isotype switch variant hybridomas 14G1, 14G2b, or 14G2a, have binding activities for the biochemically defined GD2 antigen and GD2-expressing neuroblastoma target cell lines identical to that of IgG3 Mabs produced by the 14.18 parent cell line. This permitted us to examine the relative in vitro and in vivo cytotoxic capacities of each of the anti-GD2 antibodies for GD2-expressing neuroblastoma cells independent of antibody binding affinity or specificity. Mabs produced by 14.18, 14G2a, or 14G2b, but not 14G1, can direct efficient complement-dependent cytotoxicity against neuroblastoma tumor cells in the presence of human complement. Mabs produced by the parent 14.18 or by 14G2a are more efficient in directing antibody-dependent cell-mediated cytotoxicity than Mabs produced by 14G2b, and Mabs of 14G1 are inactive. However, despite these noted in vitro differences, antibodies produced by each member of this switch variant family suppress the growth of human neuroblastoma tumor cells in BALB/c athymic nu/nu mice. These studies suggest that a mechanism(s) other than Fc-directed complement-dependent cytotoxicity or antibody-dependent cell-mediated cytotoxicity may account for the in vivo antitumor effects of these particular antibodies.


Diagnostic and prognostic value of soluble syndecan-1 in pleural malignancies.
The distinction between malignant and benign pleural effusions is a diagnostic challenge today and measuring soluble biomarkers could add to the diagnostic accuracy. Syndecan-1 is a proteoglycan involved in various cellular functions and is cleaved from the cell surface in a regulated manner. The shed fragment, which can be recovered in effusion supernatant and in serum, retains its binding capacities, but often with different functions and signalling properties than the cell-bound form. This study aimed to investigate the diagnostic and prognostic value of soluble syndecan-1 in pleural effusions and sera from patients with pleural malignancies. Using two cohorts of patients, we assessed the diagnostic and prognostic value of soluble syndecan-1 in pleural effusions and sera, using enzyme-linked immunosorbent assays. In pleural effusions, syndecan-1 distinguished malignant and benign diseases, with an odds ratio of 8.59 (95% CI 3.67 to 20.09). Furthermore, syndecan-1 in pleural effusions predicted a survival difference for patients with pleural metastatic disease and malignant mesothelioma of 11.2 and 9.2 months, respectively. However, no such effects were seen when syndecan-1 was measured in serum. Soluble syndecan-1 is a promising candidate biomarker for the cytopathological diagnosis and prognostication of malignant pleural effusions.


Treatment of neurodevelopmental disorders in adulthood.
Brain development in neurodevelopmental disorders has been considered to comprise a sequence of critical periods, and abnormalities occurring during early development have been considered irreversible in adulthood. However, findings in mouse models of neurodevelopmental disorders, including fragile X, Rett syndrome, Down syndrome, and neurofibromatosis type I suggest that it is possible to reverse certain molecular, electrophysiological, and behavioral deficits associated with these disorders in adults by genetic or pharmacological manipulations. Furthermore, recent studies have suggested that critical period-like plasticity can be reactivated in the adult brain by environmental manipulations or by pharmacotherapy. These studies open up a tantalizing possibility that targeted pharmacological treatments in combination with regimes of training or rehabilitation might alleviate or reverse the symptoms of neurodevelopmental disorders even after the end of critical developmental periods. Even though translation from animal experimentation to clinical practice is challenging, these results suggest a rational basis for treatment of neurodevelopmental disorders in adulthood.


Chitosan-stabilized silver nanoclusters with luminescent, photothermal and antibacterial properties.
The aim of this paper is to achieve in situ photochemical synthesis of silver nanoclusters (AgNCs) stabilized by the multiple-amine groups of chitosan (Ch@AgNCs) with luminescent and photothermal properties. Ch@AgNCs were obtained by applying a fast and simple methodology previously described by our group. Direct functionalization of AgNCs with chitosan template provided new nanohybrids directly in water solution, both in the presence or absence of oxygen. The formation of hybrid AgNCs could be monitored by the rapid increase of the absorption and emission maximum band with light irradiation time. New Ch@AgNCs not only present photoluminescent properties but also photothermal properties when irradiated with near infrared light (NIR), transducing efficiently NIR into heat and increasing the temperature of the medium up to 23 °C. The chitosan polymeric shell associated to AgNCs works as a protective support stabilizing the metal cores, facilitating the storage of nanohybrids and preserving luminescent, photothermal and bactericide properties.


Early indices of deviance detection in humans and animal models.
Detecting unexpected stimuli in the environment is a critical function of the auditory system. Responses to unexpected "deviant" sounds are enhanced compared to responses to expected stimuli. At the human scalp, deviance detection is reflected in the mismatch negativity (MMN) and in an enhancement of the middle-latency response (MLR). Single neurons often respond more strongly to a stimulus when rare than when common, a phenomenon termed stimulus-specific adaptation (SSA). Here we compare stimulus-specific adaptation with scalp-recorded deviance-related responses. We conclude that early markers of deviance detection in the time range of the MLR could be a direct correlate of cortical SSA. Both occur at an early level of cortical activation, both are robust findings with low-probability stimuli, and both show properties of genuine deviance detection. Their causal relation with the later scalp-recorded MMN is a key question in this field.


Steatosis in the liver.
Accumulation of triacylglycerols within the cytoplasm of hepatocytes to the degree that lipid droplets are visible microscopically is called liver steatosis. Most commonly, it occurs when there is an imbalance between the delivery or synthesis of fatty acids in the liver and their disposal through oxidative pathways or secretion into the blood as a component of triacylglycerols in very low density lipoprotein. This disorder is called nonalcoholic fatty liver disease (NAFLD) in the absence of alcoholic abuse and viral hepatitis, and it is often associated with insulin resistance, obesity and type 2 diabetes. Also, liver steatosis can be induced by many other causes including excessive alcohol consumption, infection with genotype 3 hepatitis C virus and certain medications. Whereas hepatic triacylglycerol accumulation was once considered the ultimate effector of hepatic lipotoxicity, triacylglycerols per se are quite inert and do not induce insulin resistance or cellular injury. Rather, lipotoxic injury in the liver appears to be mediated by the global ongoing fatty acid enrichment in the liver, paralleling the development of insulin resistance. A considerable number of fatty acid metabolites may be responsible for hepatic lipotoxicity and liver injury. Additional key contributors include hepatic cytosolic lipases and the "lipophagy" of lipid droplets, as sources of hepatic fatty acids. The specific origin of the lipids, mainly triacylglycerols, accumulating in liver has been unraveled by recent kinetic studies, and identifying the origin of the accumulated triacylglycerols in the liver of patients with NAFLD may direct the prevention and treatment of this condition.


VirSim - a model to support pandemic policy making.
A simulation model called VirSim was developed to aid policy making in Sweden. The model simulates the spread of pandemic influenza, using real population data on a national and regional level. Swedish authorities wanted a model that was both quick to run and to implement as a complement to the existing model MicroSim. The possibility to interactively investigate the effect of varying different assumptions was an important aspect. The VirSim model proved useful for comparing different interventions strategies, and for forecasting the societal burden in terms of hospitalization and workplace absenteeism. This paper points out the usefulness of System Dynamics models in public policy making, as a complement to more detailed and time-consuming models.


Red wine consumption, coronary calcification, and long-term clinical evolution.
Coronary artery calcification (CAC) is associated with atherosclerotic complications. However, elevated CAC may not always imply a worse prognosis. Herein, we report the clinical evolution of long-term red wine (RW) drinkers in relation to CAC. We followed 200 healthy male habitual RW drinkers and compared them to 154 abstainers for a period of 5.5 years. The initial evaluation included coronary computed tomography angiography (CTA), clinical, demographics, and laboratory data. CAC was quantified by the Agatston score. The follow-up process was conducted by telephone calls and/or hospital record review. The composite end-point of total death, acute myocardial infarction (AMI), or coronary revascularization (or major adverse cardiac event - MACE) was assessed. The RW drinkers ingested 28.9±15 g of alcohol/day for 23.4±12.3 years. They had higher high-density lipoprotein and low-density lipoprotein, but lower C-reactive protein than abstainers. Age, total cholesterol, triglycerides, glucose, and liver enzymes were similar. History of diabetes was lower among drinkers, but other risk factors were similar. However, drinkers had higher CAC than abstainers; the mean value was 131.5±362 in drinkers vs 40.5±320 in abstainers (P<0.001). The median and interquartile range were 15 (0.0-131.5) in RW drinkers and 1 (0.0-40.5) in abstainers (P=0.003). During the follow-up, MACE was significantly lower in drinkers than in abstainers, despite their higher CAC. The difference was driven mainly by AMI (0 vs 6; P<0.03). Greater CAC values in this setting did not predict worse prognosis. A possible underlying mechanism is lesion calcification, which leads to plaque stabilization and less clinical events.


Can pancreatic neuroendocrine tumour biopsy accurately determine pathological characteristics?
Assessment of the pathological characteristics of pancreatic neuroendocrine tumours is crucial for appropriate management. We compared preoperative pathological data with surgical specimens for accuracy. Surgical patients with pancreatic neuroendocrine tumours who underwent preoperative endoscopic ultrasound-guided fine needle aspiration of the primary tumour or biopsy of liver metastasis were retrospectively included. Tumour differentiation and the Ki67 proliferation index on biopsies were compared with pancreatic specimens. Fifty-seven patients were included. A preoperative biopsy of the primary tumour or of a liver metastasis was obtained in 48 and 9 patients respectively. Tumour differentiation was high in 98%, and poor in 2% on biopsy and high in 100% of surgical specimens. Ki67 index values were 0 (0-19) and 2 (0-15) on biopsy and surgical specimens (p=0.01). Correlation between preoperative and surgical findings was stronger for liver (r=0.62, p=0.001) than for pancreas (r=0.23, p=0.11). Correlation for pancreas varied according to the tumour pattern: solid (r=0.24, p=0.16), mixed (r=0.91, p=0.0036) or cystic (r=0.04, p=0.89). Tumour grade was different between pancreatic biopsies and surgical specimens, for grade 1 (63% vs 37%) and grade 2 (28% vs 72%), p=0.0007. Tumour grade assessment is accurate in biopsies of liver metastases of pancreatic neuroendocrine tumours, while pancreatic fine-needle aspiration biopsies are less accurate.


Visible-light-induced multicomponent cascade cycloaddition involving N-propargyl aromatic amines, diaryliodonium salts and sulfur dioxide: rapid access to 3-arylsulfonylquinolines.
A visible-light-induced, Eosin Y catalyzed three-component synthesis of 3-arylsulfonylquinoline derivatives through N-propargyl aromatic amines, diaryliodonium salts and sulfur dioxide has been discovered. This transformation represents an efficient and attractive method for the straightforward synthesis of 3-arylsulfonylquinoline derivatives via the formation of C-S bonds and quinolines in one step. In addition, it exhibits good substrate scope and functional group tolerance. The use of easy-to-handle diaryliodonium salts, sulfur dioxide sources and the cheap photocatalyst Eosin Y together with facile operation at room temperature makes this protocol very practical.


Postinfectious encephalopathy in a child following Campylobacter jejuni enteritis.
We report a case of acute postinfectious encephalopathy in a child following Campylobacter jejuni enteritis. Serial MR scans showed lesions involving predominantly gray matter and the adjacent subcortical white matter--findings different from those in other immune-mediated disorders, such as systemic lupus erythematosus, in which either white or gray matter may be involved, and acute disseminated encephalomyelitis, in which white matter abnormalities predominate with involvement of the subcortical white matter.


A 26-week analysis of a double-blind, placebo-controlled trial of the ginkgo biloba extract EGb 761 in dementia.
This intent-to-treat (ITT) analysis was performed to provide a realistic image of the efficacy that could be expected after 26 weeks treatment with a 120-mg dose (40 mg t.i.d.) of EGb 761 (EGb). The data were collected during a 52-week, double-blind, placebo-controlled, fixed dose, parallel-group, multicenter study. Patients were mildly to severely impaired and diagnosed with uncomplicated Alzheimer's disease or multi-infarct dementia according to ICD-10 and DSM-III-R criteria. The primary outcome measures included the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Geriatric Evaluation by Relative's Rating Instrument (GERRI) and Clinical Global Impression of Change. From 309 patients included in the ITT analysis, 244 patients (76% for placebo and 73% for EGb) actually reached the 26th week visit. In comparison to the baseline values, the placebo group showed a statistically significant worsening in all domains of assessment, while the group receiving EGb was considered slightly improved on the cognitive assessment and the daily living and social behavior. Mean treatment differences favored EGb with 1.3 and 0.12 points, respectively, on the ADAS-Cog (p = 0.04) and the GERRI (p = 0.007). In the group receiving EGb, 26% of the patients achieved at least a 4-point improvement on the ADAS-Cog, compared to 17% with placebo (p = 0.04). On the GERRI, 30% of the EGb group improved and 17% worsened, while the placebo group showed an opposite trend with 37% of patients worsening for 25% improved (p = 0.006). Regarding safety, no differences between EGb and placebo were observed.


Decision-support models for empiric antibiotic selection in Gram-negative bloodstream infections.
Early empiric antibiotic therapy in patients can improve clinical outcomes in Gram-negative bacteraemia. However, the widespread prevalence of antibiotic-resistant pathogens compromises our ability to provide adequate therapy while minimizing use of broad antibiotics. We sought to determine whether readily available electronic medical record data could be used to develop predictive models for decision support in Gram-negative bacteraemia. We performed a multi-centre cohort study, in Canada and the USA, of hospitalized patients with Gram-negative bloodstream infection from April 2010 to March 2015. We analysed multivariable models for prediction of antibiotic susceptibility at two empiric windows: Gram-stain-guided and pathogen-guided treatment. Decision-support models for empiric antibiotic selection were developed based on three clinical decision thresholds of acceptable adequate coverage (80%, 90% and 95%). A total of 1832 patients with Gram-negative bacteraemia were evaluated. Multivariable models showed good discrimination across countries and at both Gram-stain-guided (12 models, areas under the curve (AUCs) 0.68-0.89, optimism-corrected AUCs 0.63-0.85) and pathogen-guided (12 models, AUCs 0.75-0.98, optimism-corrected AUCs 0.64-0.95) windows. Compared to antibiogram-guided therapy, decision-support models of antibiotic selection incorporating individual patient characteristics and prior culture results have the potential to increase use of narrower-spectrum antibiotics (in up to 78% of patients) while reducing inadequate therapy. Multivariable models using readily available epidemiologic factors can be used to predict antimicrobial susceptibility in infecting pathogens with reasonable discriminatory ability. Implementation of sequential predictive models for real-time individualized empiric antibiotic decision-making has the potential to both optimize adequate coverage for patients while minimizing overuse of broad-spectrum antibiotics, and therefore requires further prospective evaluation. Readily available epidemiologic risk factors can be used to predict susceptibility of Gram-negative organisms among patients with bacteraemia, using automated decision-making models.


Bacteriophages of Bacteroides.
Sixty-eight bacteriophages specific for nine species (DNA homology groups) of Bacteroides were isolated from sewage. Four distinct morphological types were isolated, three of which had not previously been described. Attempts to use these phages to transduce Bacteroides fragilis were unsuccessful. A total of 91 phage-susceptible strains of Bacteroides were used with these phages in a study of the feasibility of developing a scheme for identification of Bacteroides species. Blind trials were performed with 10 B. fragilis-specific phages and a collection of over 200 bacterial strains, including 144 strains of B. fragilis. Of the strains of B. fragilis, 78% were identified correctly within 24 hr. A phage-carrier state, or pseudolysogeny, was observed with most of the phage-host systems, and this state was studied in detail with B. fragilis phage Bf-1. The presence of a thick capsule around some cells in a pure culture of a host strain appears to render these cells resistant to phage infection, thus perpetuating the carrier state. It is suggested that such capsules may play a role in the virulence of strains of Bacteroides.


"Slow" Voltage-Dependent Inactivation of CaV2.2 Calcium Channels Is Modulated by the PKC Activator Phorbol 12-Myristate 13-Acetate (PMA).
CaV2.2 (N-type) voltage-gated calcium channels (Ca2+ channels) play key roles in neurons and neuroendocrine cells including the control of cellular excitability, neurotransmitter / hormone secretion, and gene expression. Calcium entry is precisely controlled by channel gating properties including multiple forms of inactivation. "Fast" voltage-dependent inactivation is relatively well-characterized and occurs over the tens-to- hundreds of milliseconds timeframe. Superimposed on this is the molecularly distinct, but poorly understood process of "slow" voltage-dependent inactivation, which develops / recovers over seconds-to-minutes. Protein kinases can modulate "slow" inactivation of sodium channels, but little is known about if/how second messengers control "slow" inactivation of Ca2+ channels. We investigated this using recombinant CaV2.2 channels expressed in HEK293 cells and native CaV2 channels endogenously expressed in adrenal chromaffin cells. The PKC activator phorbol 12-myristate 13-acetate (PMA) dramatically prolonged recovery from "slow" inactivation, but an inactive control (4α-PMA) had no effect. This effect of PMA was prevented by calphostin C, which targets the C1-domain on PKC, but only partially reduced by inhibitors that target the catalytic domain of PKC. The subtype of the channel β-subunit altered the kinetics of inactivation but not the magnitude of slowing produced by PMA. Intracellular GDP-β-S reduced the effect of PMA suggesting a role for G proteins in modulating "slow" inactivation. We postulate that the kinetics of recovery from "slow" inactivation could provide a molecular memory of recent cellular activity and help control CaV2 channel availability, electrical excitability, and neurotransmission in the seconds-to-minutes timeframe.


Identification and characterization of genes required for compensatory growth in Drosophila.
To maintain tissue homeostasis, some organs are able to replace dying cells with additional proliferation of surviving cells. Such proliferation can be localized (e.g., a regeneration blastema) or diffuse (compensatory growth). The relationship between such growth and the growth that occurs during development has not been characterized in detail. Drosophila melanogaster larval imaginal discs can recover from extensive damage, producing normally sized adult organs. Here we describe a system using genetic mosaics to screen for recessive mutations that impair compensatory growth. By generating clones of cells that carry a temperature-sensitive cell-lethal mutation, we conditionally ablate patches of tissue in the imaginal disc and assess the ability of the surviving sister clones to replace the lost tissue. We have used this system together with a modified whole-genome resequencing (WGS) strategy to identify several mutations that selectively compromise compensatory growth. We find specific alleles of bunched (bun) and Ribonucleoside diphosphate reductase large subunit (RnrL) reduce compensatory growth in the imaginal disc. Other genes identified in the screen, including two alleles of Topoisomerase 3-alpha (Top3α), while also required for developmental growth, appear to have an enhanced requirement during compensatory growth. Compensatory growth occurs at a higher rate than normal growth and may therefore have features in common with some types of overgrowth. Indeed, the RnrL allele identified compromises both these types of altered growth and mammalian ribonucleotide reductase and topoisomerases are targets of anticancer drugs. Finally, the approach we describe is applicable to the study of compensatory growth in diverse tissues in Drosophila.


Technetium complexes with arylselenolato and aryltellurolato ligands.
Reactions of (NBu4)[TcOCl4] or [TcCl3(PPh3)2(CH3CN)] with in situ-prepared lithium arylselenolates and -tellurolates give (NBu4)[TcVO(ArE)4] (E = Se, Te; Ar = phenyl) and [TcIII(ArE)3(PPh3)(CH3CN)] (E = Se, Te; Ar = phenyl, 2,6-Me2phenyl, mesityl) complexes, respectively. The products contain square-pyramidal (TcV compounds) and trigonal bipyramidal (TcIII complexes) coordinated technetium atoms. Density functional theory calculations indicate that the Tc-chalcogen bonds in the TcIII compounds have a greater bond order than those in the TcV compounds.


Assessing patient characteristics and radiation-induced non-targeted effects in vivo for high dose-rate (HDR) brachytherapy.
To test whether blood, urine, and tissue based colony-forming assays are a useful clinical detection tool for assessing fractionated treatment responses and non-targeted radiation effects in bystander cells. To assess patients' responses to radiation treatments, blood serum, urine, and an esophagus explant-based in vivo colony-forming assay were used from oesophageal carcinoma patients. These patients underwent three fractions of high dose rate (HDR) intraluminal brachytherapy (ILBT). Human keratinocyte reporters exposed to blood sera taken after the third fraction of brachytherapy had a significant increase in cloning efficiency compared to baseline samples (p < 0.001). Such results may suggest an induced radioresistance response in bystander cells. The data also revealed a clear inverse dose-rate effect during late treatment fractions for the blood sera data only. Patient characteristics such as gender had no statistically significant effect (p > 0.05). Large variability was observed among the patients' tissue samples, these colony-forming assays showed no significant changes throughout fractionated brachytherapy (p > 0.05). Large inter-patient variability was found in the urine and tissue based assays, so these techniques were discontinued. However, the simple blood-based assay had much less variability. This technique may have future applications as a biological dosimeter to predict treatment outcome and assess non-targeted radiation effects.


Pooled analysis of case-control studies on acoustic neuroma diagnosed 1997-2003 and 2007-2009 and use of mobile and cordless phones.
We previously conducted a case-control study of acoustic neuroma. Subjects of both genders aged 20-80 years, diagnosed during 1997-2003 in parts of Sweden, were included, and the results were published. We have since made a further study for the time period 2007-2009 including both men and women aged 18-75 years selected from throughout the country. These new results for acoustic neuroma have not been published to date. Similar methods were used for both study periods. In each, one population-based control, matched on gender and age (within five years), was identified from the Swedish Population Registry. Exposures were assessed by a self-administered questionnaire supplemented by a phone interview. Since the number of acoustic neuroma cases in the new study was low we now present pooled results from both study periods based on 316 participating cases and 3,530 controls. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index (SEI). Use of mobile phones of the analogue type gave odds ratio (OR) = 2.9, 95% confidence interval (CI) = 2.0-4.3, increasing with >20 years latency (time since first exposure) to OR = 7.7, 95% CI = 2.8-21. Digital 2G mobile phone use gave OR = 1.5, 95% CI = 1.1-2.1, increasing with latency >15 years to an OR = 1.8, 95% CI = 0.8-4.2. The results for cordless phone use were OR = 1.5, 95% CI = 1.1-2.1, and, for latency of >20 years, OR = 6.5, 95% CI = 1.7-26. Digital type wireless phones (2G and 3G mobile phones and cordless phones) gave OR = 1.5, 95% CI = 1.1-2.0 increasing to OR = 8.1, 95% CI = 2.0-32 with latency >20 years. For total wireless phone use, the highest risk was calculated for the longest latency time >20 years: OR = 4.4, 95% CI = 2.2-9.0. Several of the calculations in the long latency category were based on low numbers of exposed cases. Ipsilateral use resulted in a higher risk than contralateral for both mobile and cordless phones. OR increased per 100 h cumulative use and per year of latency for mobile phones and cordless phones, though the increase was not statistically significant for cordless phones. The percentage tumour volume increased per year of latency and per 100 h of cumulative use, statistically significant for analogue phones. This study confirmed previous results demonstrating an association between mobile and cordless phone use and acoustic neuroma.


SU-E-T-407: Freedom from Conventional: Application of RapidArc for SBRT Lung Treatments.
Stereotactic body radiotherapy (SBRT) has been applied in treating early stage small lung lesions, delivering hypofractionated doses in a conformai manner. Studies have shown that SBRT has similar outcomes compared with surgery. Conventionally, SBRT lung treatments rely on utilization of multiple small, conformai, static fields in coplanar and non- coplanar arrangements. With the advent of RapidArc, it is important to evaluate the differences in dosimetry and delivery of conformai SBRT lung treatments for both conventional static field and VMAT techniques. A retrospective study of 12 patients at our institution who have received SBRT for primary lung lesions was used to evaluate the application of RapidArc for such cases. Originally treated plans utilized eight to ten conformai static coplanar and non-coplanar fields. RapidArc plans were generated in Eclipse using single and multiple arc setups. As an ntensity-modulated modality, RapidArc provides greater freedom as compared to conventional static field delivery, as one can achieve dose uniformity throughout the PTV or replicate the dosimetry synonymous with conventional SBRT. RapidArc is capable of reproducing the high conformality achieved by conventional SBRT; dual arc plans, delivering uniform dose distributions, yielded an average CI100% of 1.11 and D2cm maximum of 63% of the prescribed dose, compared to 1.33 and 77% (p- values of .002 and .005, respectively) for conventional SBRT. Application of a short, non-coplanar arc, in conjunction with dual coplanar arcs, improved sparing of OARs in direct proximity of the PTV at the expense of treatment time. RapidArc allows for faster treatment delivery; conventional SBRT delivery averages 13.7 minutes at our institution, whereas coplanar dual arcs are estimated to average treatment durations of 4.2 minutes. RapidArc is capable of generating conformai dose distributions and sparing of OARs, allows greater freedom in plan optimization, and reduces treatment time significantly.


The effects of teaching methods of palliative care on life pattern of old women with chronic pain.
Chronic pain is among problems of old people and causes changes in their life pattern and processes. Teaching palliative care can help old people suffering from chronic pain to live an active life. The aim of this research was to determine effects of educating of palliative care on life pattern of elderly women with chronic pain. The present study was a Quasi-experimental design with pre-test and post test was conducted on 30 elderly women suffering from chronic pain in 2018 in Iran. The Questionnaire for evaluating the Pattern of Life with Pain in the elderly was filled before the intervention, group educating of palliative care was carried out using an educational package, and the questionnaire was completed again immediately and one and three months after. The data was analyzed using mean, standard deviations, Fisher's F test, and Greenhouse-Geisser and Bonferroni post-hoc test by employing SPSS- 16. Mean changes before teaching palliative care significantly differed from those of immediately and one and three months after the educational program (p = 0.0), (p = 0.004). There were significant differences between the stages of immediately and one month after the educational program and that of three months after it (p = 0.001), (p = 0.002). Concerning the personal life patterns, there were statistically significant differences between the stage immediately after the educational program and those before the intervention and three months after it (p = 0.005), (p = 0.000). Regarding the social life pattern, only the stage of one month after the educational program significantly differed from that of three months (p = 0.005). Mean growth in life pattern of the old women suffering from chronic pain in the stages after the intervention indicated the importance of and the necessity for palliative care during old age. Moreover, the success of this education three months after the educational program as compared to immediately and one month after it indicates that allocation of sufficient time plays a very important role in transferring information and in teaching methods of palliative care to old people.


Frequency-specific amplification of heart rate rhythms using oscillatory tilt.
Heart rate rhythms have been demonstrated to parallel specific psychological processes. Efficient experimental control of the amplitude of these rhythms would allow evaluation of bidirectional psychophysiological hypotheses. This experiment was performed to examine the specificity of the heart rate rhythm response to oscillatory head-up tilt. Seventy-one adults (36 male, 35 female) aged 18-30 were positioned on a tilt-table and oscillated at 0.08 Hz with a maximum tilt angle of +21 degrees for a 10-min period. Heart period, heart period variability at 0.08 Hz (i.e., Traube-Hering-Mayer (THM) variance), and respiratory sinus arrhythmia (quantified using vagal tone, V) were measured. For a subset of 21 subjects, continuous measures were derived to examine the response to onset of oscillatory tilt. Respiratory activity was also measured in these subjects. There was a significant increase in the amplitude of the THM variance during tilt stimulation. Tilt did not significantly change heart period, V, or respiration frequency. Following cessation of tilt, THM variance returned to baseline levels, heart period lengthened for males, and V increased for both sexes. Subjects with higher amplitude baseline V were characterized by more rapid THM variance response to tilt. Results suggest that parasympathetic tone moderates the THM variance increase elicited by low-frequency oscillatory tilt.


ADAM15 deficiency attenuates pulmonary hyperpermeability and acute lung injury in lipopolysaccharide-treated mice.
ADAM15 is a disintegrin and metalloprotease recently implicated in cancer and chronic immune disorders. We have recently characterized ADAM15 as a mediator of endothelial barrier dysfunction. Whether this molecule contributes to acute inflammation has not been evaluated. The purpose of this study was to investigate the role of ADAM15 in mediating pulmonary microvascular leakage during acute inflammatory injury. Immunofluorescent staining and Western blotting revealed that the endothelium was the main source of ADAM15 in lung tissue. In a mouse model of acute lung injury induced by lipopolysaccharide (LPS), upregulation of ADAM15 was observed in association with pulmonary edema and neutrophil infiltration. The LPS-induced inflammatory injury, as demonstrated by bronchoalveolar lavage neutrophil count, lung wet-to-dry weight ratio, and myeloperoxidase activity, was significantly attenuated in Adam15(-/-) mice. Studies with primary cell culture demonstrated abundant ADAM15 expression in endothelial cells (ECs) of mouse lung but not in neutrophils. Deficiency of ADAM15 in ECs had no obvious effect on basal permeability but significantly attenuated hyperpermeability response to LPS as evidenced by albumin flux assay and measurements of transendothelial electrical resistance, respectively. ADAM15 deficiency also reduced neutrophil chemotactic transmigration across endothelial barriers in the presence or absence of formyl-methionyl-leucyl-phenylalanine (fMLP). Rescue expression of ADAM15 in Adam15(-/-) ECs restored neutrophil transendothelial migration. These data indicate that ADAM15 upregulation contributes to inflammatory lung injury by promoting endothelial hyperpermeability and neutrophil transmigration.


Charge state of the globular histone core controls stability of the nucleosome.
Presented here is a quantitative model of the wrapping and unwrapping of the DNA around the histone core of the nucleosome that suggests a mechanism by which this transition can be controlled: alteration of the charge state of the globular histone core. The mechanism is relevant to several classes of posttranslational modifications such as histone acetylation and phosphorylation; several specific scenarios consistent with recent in vivo experiments are considered. The model integrates a description based on an idealized geometry with one based on the atomistic structure of the nucleosome, and the model consistently accounts for both the electrostatic and nonelectrostatic contributions to the nucleosome free energy. Under physiological conditions, isolated nucleosomes are predicted to be very stable (38 +/- 7 kcal/mol). However, a decrease in the charge of the globular histone core by one unit charge, for example due to acetylation of a single lysine residue, can lead to a significant decrease in the strength of association with its DNA. In contrast to the globular histone core, comparable changes in the charge state of the histone tail regions have relatively little effect on the nucleosome's stability. The combination of high stability and sensitivity explains how the nucleosome is able to satisfy the seemingly contradictory requirements for thermodynamic stability while allowing quick access to its DNA informational content when needed by specific cellular processes such as transcription.


Early Results of the A.L.P.S. Proximal Humerus Locking Plate.
Open reduction internal fixation of displaced 3 and 4-part proximal humerus fractures is an effective treatment modality particularly for the younger age group, but it is not without complications. Fixed angled locking screw plates are the mainstay of fixation. The A.L.P.S. Proximal Humerus Plating System is a new implant that has smooth locking pegs in the place of humeral head screws to help reduce glenoid damage in the event of cut-out and is designed to sit low on the humerus in order to reduce the risk of subacromial impingement. Retrospective analysis of 15 consecutive patients who sustained closed displaced 3-part or 4-part fractures and had fixation surgery using the A.L.P.S. plate. Outcome measures were the time to radiographic and clinical union, Oxford Shoulder Score, quick DASH score and complications. Average follow-up was 31.9 weeks. Union was achieved in 100% of patients with a mean time to union of 15.1 weeks. In terms of function, mean OSS was 33.6 and mean quick DASH was 32.5. There were no instances of AVN. Our preliminary results of 15 patients followed up for a mean of 31.9 weeks show equitable union rates and time to union as well as functional scores compared to other available plating systems. This is the first study to report on this implant to date.


Effect of diagnosis with a chronic disease on physical activity behavior in middle-aged women.
Although regular physical activity is an effective secondary prevention strategy for patients with a chronic disease, it is unclear whether patients change their daily physical activity after being diagnosed. Therefore, the aims of this study were to (1) describe changes in levels of physical activity in middle-aged women before and after diagnosis with a chronic disease (heart disease, diabetes, asthma, breast cancer, arthritis, depression); and to (2) examine whether diagnosis with a chronic disease affects levels of physical activity in these women. Data from 5 surveys (1998-2010) of the Australian Longitudinal Study on Women's Health (ALSWH) were used. Participants (N=4840, born 1946-1951) completed surveys every three years, with questions about diseases and leisure time physical activity. The main outcome measure was physical activity, categorized as: nil/sedentary, low active, moderately active, highly active. At each survey approximately half the middle-aged women did not meet the recommended level of physical activity. Between consecutive surveys, 41%-46% of the women did not change, 24%-30% decreased, and 24%-31% increased their physical activity level. These proportions of change were similar directly after diagnosis with a chronic disease, and in the years before or after diagnosis. Generalized estimating equations showed that there was no statistically significant effect of diagnosis with a chronic disease on levels of physical activity in women. Despite the importance of physical activity for the management of chronic diseases, most women did not increase their physical activity after diagnosis. This illustrates a need for tailored interventions to enhance physical activity in newly diagnosed patients.


Development of a Robust Screening Method for Pathogenicity of Colletotrichum spp. on Strawberry Seedlings Enabling Forward Genetic Studies.
Generation and screening for nonpathogenic mutants is a popular tool for identifying pathogenicity-related genes. Successful application of this technique for plant fungal pathosystems requires reliable and rapid screening procedures. This study reports on the development of a rapid in vitro bioassay enabling large-scale screening and isolation of nonpathogenic mutants of Colletotrichum gloeosporioides and C. acutatum on strawberry seedlings. Inoculation was carried out on strawberry seedlings at two different developmental stages: 12-week-old (young) and 15-week-old (older) seedlings. A comparison was made between two inoculation techniques, (i) foliar dip and (ii) root soak, at two incubation temperatures (19 and 25°C). Mortality of young seedlings was observed 4 days after inoculation with both species, reaching 50% within 10 days, using both techniques at 25°C. However, mortality of older seedlings was delayed by 4 days compared with that in the young seedlings when using the root-soak method. Disease development decreased in young and older seedlings at the lower temperature. This method also was reliable in determining pathogenicity of the cucurbit-specific C. magna that did not cause disease symptoms on strawberry by either inoculation method. The proposed method enabled screening of more than 980 restriction enzyme-mediated integration mutants resulting in a selection of five reduced-virulence isolates. Initial characterization of some of these mutants revealed large differences in germination and appressorial formation compared with pathogenic isolates.


Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model.
Despite treatment with therapeutic hypothermia, almost 50% of infants with neonatal encephalopathy still have adverse outcomes. Additional treatments are required to maximize neuroprotection. Melatonin is a naturally occurring hormone involved in physiological processes that also has neuroprotective actions against hypoxic-ischaemic brain injury in animal models. The objective of this study was to assess neuroprotective effects of combining melatonin with therapeutic hypothermia after transient hypoxia-ischaemia in a piglet model of perinatal asphyxia using clinically relevant magnetic resonance spectroscopy biomarkers supported by immunohistochemistry. After a quantified global hypoxic-ischaemic insult, 17 newborn piglets were randomized to the following: (i) therapeutic hypothermia (33.5°C from 2 to 26 h after resuscitation, n = 8) and (ii) therapeutic hypothermia plus intravenous melatonin (5 mg/kg/h over 6 h started at 10 min after resuscitation and repeated at 24 h, n = 9). Cortical white matter and deep grey matter voxel proton and whole brain (31)P magnetic resonance spectroscopy were acquired before and during hypoxia-ischaemia, at 24 and 48 h after resuscitation. There was no difference in baseline variables, insult severity or any physiological or biochemical measure, including mean arterial blood pressure and inotrope use during the 48 h after hypoxia-ischaemia. Plasma levels of melatonin were 10 000 times higher in the hypothermia plus melatonin than hypothermia alone group. Melatonin-augmented hypothermia significantly reduced the hypoxic-ischaemic-induced increase in the area under the curve for proton magnetic resonance spectroscopy lactate/N-acetyl aspartate and lactate/total creatine ratios in the deep grey matter. Melatonin-augmented hypothermia increased levels of whole brain (31)P magnetic resonance spectroscopy nucleotide triphosphate/exchangeable phosphate pool. Correlating with improved cerebral energy metabolism, TUNEL-positive nuclei were reduced in the hypothermia plus melatonin group compared with hypothermia alone in the thalamus, internal capsule, putamen and caudate, and there was reduced cleaved caspase 3 in the thalamus. Although total numbers of microglia were not decreased in grey or white matter, expression of the prototypical cytotoxic microglial activation marker CD86 was decreased in the cortex at 48 h after hypoxia-ischaemia. The safety and improved neuroprotection with a combination of melatonin with cooling support phase II clinical trials in infants with moderate and severe neonatal encephalopathy.


Severe growth deficiency is associated with STAT5b mutations that disrupt protein folding and activity.
The first genetic defect in human signal transducer and activator of transcription (STAT)5b was identified in an individual with profound short stature and GH insensitivity, immune dysfunction, and severe pulmonary disease, and was caused by an alanine to proline substitution (A630P) within the Src homology-2 (SH2) domain. STAT5b(A630P) was found to be an inactive transcription factor based on its aberrant folding, diminished solubility, and propensity for aggregation triggered by its misfolded SH2 domain. Here we have characterized the second human STAT5b amino acid substitution mutation in an individual with similar pathophysiological features. This single nucleotide transition, predicted to change phenyalanine 646 to serine (F646S), also maps to the SH2 domain. Like STAT5b(A630P), STAT5b(F646S) is prone to aggregation, as evidenced by its detection in the insoluble fraction of cell extracts, the presence of dimers and higher-order oligomers in the soluble fraction, and formation of insoluble cytoplasmic inclusion bodies in cells. Unlike STAT5b(A630P), which showed minimal GH-induced tyrosine phosphorylation and no transcriptional activity, STAT5b(F646S) became tyrosine phosphorylated after GH treatment and could function as a GH-activated transcription factor, although to a substantially lesser extent than STAT5b(WT). Biochemical characterization demonstrated that the isolated SH2 domain containing the F646S substitution closely resembled the wild-type SH2 domain in secondary structure, but exhibited reduced thermodynamic stability and altered tertiary structure that were intermediate between STAT5b(A630P) and STAT5b(WT). Homology-based structural modeling suggests that the F646S mutation disrupts key hydrophobic interactions and may also distort the phosphopeptide-binding face of the SH2 domain, explaining both the reduced thermodynamic stability and impaired biological activity.


Use of shadows to retrieve water vapor in hazy atmospheres.
Techniques aimed at retrieving water vapor from satellite data of reflected near-infrared solar radiation have progressed significantly in recent years. These techniques rely on observation of water vapor attenuation of near-infrared solar radiation reflected by the Earth's surface. Ratios of measured radiances at wavelengths inside and outside water vapor absorbing channels are used for retrieval purposes. These ratios partially remove the dependence of surface reflectance on wavelength and are used to retrieve the total column water vapor amount. Hazy atmospheric conditions, however, introduce errors into this widely used technique. A new method based on radiance differences between clear and nearby shadowed surfaces, combined with ratios between water vapor absorbing and window regions, is presented that improves water vapor retrievals under hazy atmospheric conditions. Radiative transfer simulations are used to demonstrate the advantage offered by this technique.


Geometry-adapted hexahedral meshes improve accuracy of finite-element-method-based EEG source analysis.
Mesh generation in finite-element- (FE) method-based electroencephalography (EEG) source analysis generally influences greatly the accuracy of the results. It is thus important to determine a meshing strategy well adopted to achieve both acceptable accuracy for potential distributions and reasonable computation times and memory usage. In this paper, we propose to achieve this goal by smoothing regular hexahedral finite elements at material interfaces using a node-shift approach. We first present the underlying theory for two different techniques for modeling a current dipole in FE volume conductors, a subtraction and a direct potential method. We then evaluate regular and smoothed elements in a four-layer sphere model for both potential approaches and compare their accuracy. We finally compute and visualize potential distributions for a tangentially and a radially oriented source in the somatosensory cortex in regular and geometry-adapted three-compartment hexahedra FE volume conductor models of the human head using both the subtraction and the direct potential method. On the average, node-shifting reduces both topography and magnitude errors by more than a factor of 2 for tangential and 1.5 for radial sources for both potential approaches. Nevertheless, node-shifting has to be carried out with caution for sources located within or close to irregular hexahedra, because especially for the subtraction method extreme deformations might lead to larger overall errors. With regard to realistic volume conductor modeling, node-shifted hexahedra should thus be used for the skin and skull compartments while we would not recommend deforming elements at the grey and white matter surfaces.


Possible Therapeutic Effects of Adjuvant Quercetin Supplementation Against Early-Stage COVID-19 Infection: A Prospective, Randomized, Controlled, and Open-Label Study.
Quercetin, a well-known naturally occurring polyphenol, has recently been shown by molecular docking, in vitro and in vivo studies to be a possible anti-COVID-19 candidate. Quercetin has strong antioxidant, anti-inflammatory, immunomodulatory, and antiviral properties, and it is characterized by a very high safety profile, exerted in animals and in humans. Like most other polyphenols, quercetin shows a very low rate of oral absorption and its clinical use is considered by most of modest utility. Quercetin in a delivery-food grade system with sunflower phospholipids (Quercetin Phytosome®, QP) increases its oral absorption up to 20-fold. In the present prospective, randomized, controlled, and open-label study, a daily dose of 1000 mg of QP was investigated for 30 days in 152 COVID-19 outpatients to disclose its adjuvant effect in treating the early symptoms and in preventing the severe outcomes of the disease. The results revealed a reduction in frequency and length of hospitalization, in need of non-invasive oxygen therapy, in progression to intensive care units and in number of deaths. The results also confirmed the very high safety profile of quercetin and suggested possible anti-fatigue and pro-appetite properties. QP is a safe agent and in combination with standard care, when used in early stage of viral infection, could aid in improving the early symptoms and help in preventing the severity of COVID-19 disease. It is suggested that a double-blind, placebo-controlled study should be urgently carried out to confirm the results of our study.


White light differential interference contrast microscope with a Sagnac interferometer.
A new technique for producing a white light differential interference contrast (DIC) image using a lateral shearing, rotation phase shifting Sagnac interferometer (SI) is proposed. The SI, placed in the image space after the tube lens of a microscope system with spatially coherent white light Kohler illumination, splits the image forming beam into coherent components with small lateral shear. Phase shifts, between the interfering components, which can be considered as biased phase difference (BPD), are introduced by applying small angular rotation of the SI in its own plane. This variable BPD between the interfering white light components produces a uniform intensity colored background. The object related phase shift, due to the height difference between two close points on the object surface with separation on the order of least resolvable separation of the microscope objective, in addition to the BPD would produce a change in intensity/hue/color against a uniform background due to the BPD. Thus a DIC image is formed and the variable BPD provides an excellent means of improving the contrast of the image.


Prevention of mother-to-child transmission of HIV in rural Uganda: modelling effectiveness and impact of scaling-up PMTCT services.
The reported coverage of any antiretroviral (ARV) prophylaxis for prevention of mother-to-child transmission (PMTCT) has increased in sub-Saharan Africa in recent years, but was still only 60% in 2010. However, the coverage estimate is subject to overestimations since it only considers enrolment and not completion of the PMTCT programme. The PMTCT programme is complex as it builds on a cascade of sequential interventions that should take place to reduce mother-to-child transmission (MTCT) of HIV: starting with antenatal care (ANC), HIV testing, and ARVs for the woman and the baby. The objective was to estimate the number of children infected with HIV in a district population, using empirical data on uptake of PMTCT components combined with data on MTCT rates. This study is based on a population-based cohort of pregnant women recruited in the Iganga-Mayuge Health and Demographic Surveillance Site in rural Uganda 2008-2010. We later modelled different scenarios assuming increased uptake of specific PMTCT components to estimate the impact on MTCT for each scenario. In this setting, HIV infections in children could be reduced by 28% by increasing HIV testing capacity at health facilities to ensure 100% testing among women seeking ANC. Providing ART to all women who received ARV prophylaxis would give an 18% MTCT reduction. Our results highlight the urgency in scaling-up universal access to HIV testing at all ANC facilities, and the potential gains of early enrolment of all pregnant women on antiretroviral treatment for PMTCT. Further, to determine the effectiveness of PMTCT programmes in different settings, it is crucial to analyse at what stages of the PMTCT cascade that dropouts occur to target interventions accordingly.


The marine nano- and microplastics characterisation by SEM-EDX: The potential of the method in comparison with various physical and chemical approaches.
The marine microplastic (MMs) is an interdisciplinary problem. The polymer debris are ubiquitous (soil, hydrosphere, atmosphere) and the majority ends, transported by the freshwaters, in the global ocean system: from pelagial waters, surface gyres and benthos up to the animals at different trophic levels. Their quantitative, qualitative and eco-toxicological analyses, based on analytical, physical and chemical methods, are still a challenge due to the complex matrices, materials weathering, limited concentration, and size. Moreover, further fragmentation due to the waves and UV radiation leads to the constant increase of their surface. The aim of this article is to present the advantages, drawbacks and future perspectives of using SEM-EDX method in the analyses of marine polymer debris from macro to the nanoscale. Theoretical issues are presented in comparison to the commonly used approaches. The practical aspects will be discussed based on case studies. Examples of the results, high-resolution SEM pictures are included.


Acute Immune Signatures and Their Legacies in Severe Acute Respiratory Syndrome Coronavirus-2 Infected Cancer Patients.
Given the immune system's importance for cancer surveillance and treatment, we have investigated how it may be affected by SARS-CoV-2 infection of cancer patients. Across some heterogeneity in tumor type, stage, and treatment, virus-exposed solid cancer patients display a dominant impact of SARS-CoV-2, apparent from the resemblance of their immune signatures to those for COVID-19+ non-cancer patients. This is not the case for hematological malignancies, with virus-exposed patients collectively displaying heterogeneous humoral responses, an exhausted T cell phenotype and a high prevalence of prolonged virus shedding. Furthermore, while recovered solid cancer patients' immunophenotypes resemble those of non-virus-exposed cancer patients, recovered hematological cancer patients display distinct, lingering immunological legacies. Thus, while solid cancer patients, including those with advanced disease, seem no more at risk of SARS-CoV-2-associated immune dysregulation than the general population, hematological cancer patients show complex immunological consequences of SARS-CoV-2 exposure that might usefully inform their care.


Isolation of pathogenic yeasts in the air from hospital environments in the city of Fortaleza, northeast Brazil.
This paper reports the results of environmental surveillance of yeasts in specific areas of two tertiary local hospitals. From March 2007 to February 2008, samples from the air of two public hospitals were collected on a monthly basis. The samples were collected through passive sedimentation method (day and night exposure) of Petri dishes. A total of 240 air samples from 10 hospital environments were analyzed. These environments presented similar contamination levels, from which 80 fungi isolates were isolated: Candida parapsilosis (n = 34), Rhodotorula spp. (19), Trichosporon asahii (11), C. tropicalis (8), C. albicans (4), C. glabrata (1), C. guilliermondii (1), C. krusei (1) and Saccharomyces spp. (1). Regarding the presence of yeasts and climatic conditions, there were 40 strains (50%) in semi-critical areas (natural ventilation) and critical areas (air conditioned). Considering the presence of microorganisms with pathogenic potential, environmental monitoring is necessary to prevent possible hospital infections.


Parental smoking in childhood and adult obstructive lung disease: results from the European Community Respiratory Health Survey.
Early exposure to parental smoking appears to influence the development of the airways and predispose to respiratory symptoms. A study was undertaken to determine whether the consequences of parental smoking could be traced in adulthood. Information from interviewer-led questionnaires was available for 18 922 subjects aged 20-44 years from random population samples in 37 areas participating in the European Community Respiratory Health Survey. Lung function data were available for 15,901 subjects. In men, father's smoking in childhood was associated with more respiratory symptoms (ORwheeze 1.13 (95% CI 1.00 to 1.28); never smokers: ORwheeze 1.21 (95% CI 0.96 to 1.50)) and there was a dose-dependent association between number of parents smoking and wheeze (one: OR 1.08 (95% CI 0.94 to 1.24); both: OR 1.24 (95% CI 1.05 to 1.47); ptrend = 0.010). A reduced ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) was related to father's smoking (-0.3% (95% CI -0.6 to 0)) and number of parents smoking (ptrend <0.001) among men. In women, mother's smoking was associated with more respiratory symptoms and poorer lung function (ORwheeze 1.15 (95% CI 1.01 to 1.31), never smokers: ORwheeze 1.21 (95% CI 0.98-1.51); FEV1 -24 ml (95% CI -45 to -3); FEV1/FVC ratio -0.6% (95% CI -0.9 to -0.3)). These effects were possibly accounted for by maternal smoking in pregnancy (ORwheeze 1.39 (95% CI 1.17 to 1.65); FEV1 -23 ml (95% CI -52 to 7); FEV1/FVC ratio -0.9% (95% CI -1.3 to -0.4)) as there was no association with paternal smoking among women (interaction by sex, p<0.05). These results were homogeneous across centres. Both intrauterine and environmental exposure to parental tobacco smoking was related to more respiratory symptoms and poorer lung function in adulthood in this multicultural study. The age window of particular vulnerability appeared to differ by sex, postnatal exposure being important only in men and a role for prenatal exposure being more evident in women.


Noise effects on human performance: a meta-analytic synthesis.
Noise is a pervasive and influential source of stress. Whether through the acute effects of impulse noise or the chronic influence of prolonged exposure, the challenge of noise confronts many who must accomplish vital performance duties in its presence. Although noise has diffuse effects, which are shared in common with many other chronic forms of stress, it also exerts its own specific influences on various forms of cognitive and motor response. We present a quantitative evaluation of these influences so that their harmful effects can be mitigated, their beneficial effects exploited, and any residual effects incorporated and synthesized into selection, training, and design strategies to facilitate human performance capacities. Predictions of single and joint moderator effects were made on the basis of major theories of noise and performance, specifically those explanations based on arousal, masking, or cognitive-resource mechanisms. These predictions were tested through moderator analyses of effects as a function of task type, performance measure, noise type and schedule, and the intensity and duration of exposure. Observed outcome effects (797 effect sizes derived from 242 studies) varied as a function of each of these moderators. Collective findings identified continuous versus intermittent noise, noise type, and type of task as the major distinguishing characteristics that moderated response. Mixed evidence was obtained for the traditional arousal and masking explanations for noise effects. The overall pattern of findings was most consistent with the maximal adaptability theory, a mental-resource-based explanation of stress and performance variation.


Organization of circadian functions: interaction with the body.
The hypothalamus integrates information from the brain and the body; this activity is essential for survival of the individual (adaptation to the environment) and the species (reproduction). As a result, countless functions are regulated by neuroendocrine and autonomic hypothalamic processes in concert with the appropriate behaviour that is mediated by neuronal influences on other brain areas. In the current chapter attention will be focussed on fundamental hypothalamic systems that control metabolism, circulation and the immune system. Herein a system is defined as a physiological and anatomical functional unit, responsible for the organisation of one of these functions. Interestingly probably because these systems are essential for survival, their function is highly dependent on each other's performance and often shares same hypothalamic structures. The functioning of these systems is strongly influenced by (environmental) factors such as the time of the day, stress and sensory autonomic feedback and by circulating hormones. In order to get insight in the mechanisms of hypothalamic integration we have focussed on the influence of the biological clock; the suprachiasmatic nucleus (SCN) on processes that are organized by and in the hypothalamus. The SCN imposes its rhythm onto the body via three different routes of communication: 1.Via the secretion of hormones; 2. via the parasympathetic and 3.via the sympathetic autonomous nervous system. The SCN uses separate connections via either the sympathetic or via the parasympathetic system not only to prepare the body for the coming change in activity cycle but also to prepare the body and its organs for the hormones that are associated with such change. Up till now relatively little attention has been given to the question how peripheral information might be transmitted back to the SCN. Apart from light and melatonin little is known about other systems from the periphery that may provide information to the SCN. In this chapter attention will be paid to e.g. the role of the circumventricular organs in passing info to the SCN. Herein especially the role of the arcuate nucleus (ARC) will be highlighted. The ARC is crucial in the maintenance of energy homeostasis as an integrator of long- and short-term hunger and satiety signals. Receptors for metabolic hormones like insulin, leptin and ghrelin allow the ARC to sense information from the periphery and signal it to the central nervous system. Neuroanatomical tracing studies using injections of a retrograde and anterograde tracer into the ARC and SCN showed a reciprocal connection between the ARC and the SCN which is used to transmit feeding related signals to the SCN. The implications of multiple inputs and outputs of the SCN to the body will be discussed in relation with metabolic functions.


Changes in macrophage phenotype and induction of epithelial-to-mesenchymal transition genes following acute Achilles tenotomy and repair.
Tendon injuries occur frequently in physically active individuals, but the clinical outcomes for these injuries can be poor. In many injured tissues the repair process is orchestrated by two types of cells, macrophages and fibroblasts. Macrophages, which have both pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, can directly participate in tissue remodeling and direct the response of other cells through the secretion of cytokines and growth factors. In many organ systems, epithelial cells can trans-differentiate into fibroblasts, which can then regenerate damaged ECM. This process is triggered via activation of epithelial-to-mesenchymal transition (EMT) signaling programs. Most tendons are surrounded by sheets of epithelial cells, and these tissue layers could provide a source of fibroblasts to repair injured tendons. To gain greater insight into the biology of tendon repair, we performed a tenotomy and repair in Achilles tendons of adult rats and determined changes in macrophage phenotype, and ECM- and EMT-related genes over a 4-week time course. The results from this study suggest that changes in macrophage phenotype and activation of EMT-related programs likely contribute to the degradation and subsequent repair of injured tendon tissue.


Identification of thresholds for accuracy comparisons of heart rate and respiratory rate in neonates.
Background: Heart rate (HR) and respiratory rate (RR) can be challenging to measure accurately and reliably in neonates. The introduction of innovative, non-invasive measurement technologies suitable for resource-constrained settings is limited by the lack of appropriate clinical thresholds for accuracy comparison studies. Methods: We collected measurements of photoplethysmography-recorded HR and capnography-recorded exhaled carbon dioxide across multiple 60-second epochs (observations) in enrolled neonates admitted to the neonatal care unit at Aga Khan University Hospital in Nairobi, Kenya. Trained study nurses manually recorded HR, and the study team manually counted individual breaths from capnograms. For comparison, HR and RR also were measured using an automated signal detection algorithm. Clinical measurements were analyzed for repeatability. Results: A total of 297 epochs across 35 neonates were recorded. Manual HR showed a bias of -2.4 (-1.8%) and a spread between the 95% limits of agreement (LOA) of 40.3 (29.6%) compared to the algorithm-derived median HR. Manual RR showed a bias of -3.2 (-6.6%) and a spread between the 95% LOA of 17.9 (37.3%) compared to the algorithm-derived median RR, and a bias of -0.5 (1.1%) and a spread between the 95% LOA of 4.4 (9.1%) compared to the algorithm-derived RR count. Manual HR and RR showed repeatability of 0.6 (interquartile range (IQR) 0.5-0.7), and 0.7 (IQR 0.5-0.8), respectively. Conclusions: Appropriate clinical thresholds should be selected a priori when performing accuracy comparisons for HR and RR. Automated measurement technologies typically use median values rather than counts, which significantly impacts accuracy. A wider spread between the LOA, as much as 30%, should be considered to account for the observed physiological nuances and within- and between-neonate variability and different averaging methods. Wider adoption of thresholds by data standards organizations and technology developers and manufacturers will increase the robustness of clinical comparison studies.


Reduced efficacy of insecticide-treated nets and indoor residual spraying for malaria control in pyrethroid resistance area, Benin.
The pyrethroid knockdown resistance gene (kdr) has become widespread in Anopheles gambiae in West Africa. A trial to test the continuing efficacy of insecticide-treated nets (ITN) and indoor residual spraying (IRS) was undertaken in experimental huts at 2 sites in Benin, the first where kdr is present at high frequency (Ladji), the second-where An. gambiae is susceptible (Malanville). Holes were made in the nets to mimic worn nets. At Malanville, 96% of susceptible An. gambiae were inhibited from blood-feeding, whereas at Ladji feeding was uninhibited by ITNs. The mortality rate of An. gambiae in ITN huts was 98% in Malanville but only 30% at Ladji. The efficacy of IRS was equally compromised. Mosquitoes at Ladji had higher oxidase and esterase activity than in a laboratory-susceptible strain, but this fact did not seem to contribute to resistance. Pyrethroid resistance in An. gambiae appears to threaten the future of ITN and IRS in Benin.


Plasmodial Hsp40s: New Avenues for Antimalarial Drug Discovery.
Malaria, an infectious disease caused by Plasmodium spp, is one of the world's most dangerous diseases, accounting for more than half a million deaths yearly. The long years of co-habitation between the parasite and its hosts (human and mosquito), is a testimony to the parasite's ability to escape the immune system and develop drug resistance mechanisms. Currently, an important search area for improved pharmacotherapy are molecular chaperones of the heat shock protein family, abundant in Plasmodium falciparum and contributing to its continuous survival and development. Thus far, small molecule inhibitor studies on P. falciparum Hsp70s and Hsp90s have indicated that they are promising antimalarial targets. However, not much attention has been given to Hsp40s as potential antimalarial drug targets. Hsp40s are known to function as chaperones by preventing protein aggregation, and as co-chaperones, by regulating the chaperone activities of Hsp70s to ensure proper protein folding. There are only a limited number of reviews on Hsp40s as drug targets, and the few reviews on plasmodial Hsp40s tend to focus largely on the intra-erythrocytic stage of the parasite life cycle. Therefore, this review will summarize what is known about Hsp40s throughout the malaria parasite life cycle, and critically evaluate their potential to serve as new avenues for antimalarial drug discovery.


Cross-Sectional Study on MRI Restaging After Chemoradiotherapy and Interval to Surgery in Rectal Cancer: Influence on Short- and Long-Term Outcomes.
The time interval between CRT and surgery in rectal cancer patients is still the subject of debate. The aim of this study was to first evaluate the nationwide use of restaging magnetic resonance imaging (MRI) and its impact on timing of surgery, and, second, to evaluate the impact of timing of surgery after chemoradiotherapy (CRT) on short- and long-term outcomes. Patients were selected from a collaborative rectal cancer research project including 71 Dutch centres, and were subdivided into two groups according to time interval from the start of preoperative CRT to surgery (< 14 and ≥ 14 weeks). From 2095 registered patients, 475 patients received preoperative CRT. MRI restaging was performed in 79.4% of patients, with a median CRT-MRI interval of 10 weeks (interquartile range [IQR] 8-11) and a median MRI-surgery interval of 4 weeks (IQR 2-5). The CRT-surgery interval groups consisted of 224 (< 14 weeks) and 251 patients (≥ 14 weeks), and the long-interval group included a higher proportion of cT4 stage and multivisceral resection patients. Pathological complete response rate (n = 34 [15.2%] vs. n = 47 [18.7%], p = 0.305) and CRM involvement (9.7% vs. 15.9%, p = 0.145) did not significantly differ. Thirty-day surgical complications were similar (20.1% vs. 23.1%, p = 0.943), however no significant differences were found for local and distant recurrence rates, disease-free survival, and overall survival. These real-life data, reflecting routine daily practice in The Netherlands, showed substantial variability in the use and timing of restaging MRI after preoperative CRT for rectal cancer, as well as time interval to surgery. Surgery before or after 14 weeks from the start of CRT resulted in similar short- and long-term outcomes.


Lessons learnt from an atypical mycobacterium infection post-anterior cruciate ligament reconstruction.
Infections following anterior cruciate ligament reconstruction are rare, with no previous reports citing Mycobacterium abscessus as the culprit pathogen. A 22-year-old man presented twice over three years with a painful discharging sinus over his right tibia tunnel site necessitating repeated arthroscopy and washout, months of antibiotic therapy, and ultimately culminating in the removal of the implants. In both instances, M. abscessus was present in the wound cultures, along with a coinfection of Staphyloccocus aureus during the second presentation. Though rare, M. abscessus is an important pathogen to consider in postoperative wounds presenting with chronic discharging sinuses, even in healthy non-immunocompromised patients. This case illustrates how the organism can cause an indolent infection, and how the removal of implants can be necessary to prevent the persistence of infection. Coinfection with a second organism is not uncommon and necessitates a timely change in treatment regime as well.


Phase-of-firing coding of natural visual stimuli in primary visual cortex.
We investigated the hypothesis that neurons encode rich naturalistic stimuli in terms of their spike times relative to the phase of ongoing network fluctuations rather than only in terms of their spike count. We recorded local field potentials (LFPs) and multiunit spikes from the primary visual cortex of anaesthetized macaques while binocularly presenting a color movie. We found that both the spike counts and the low-frequency LFP phase were reliably modulated by the movie and thus conveyed information about it. Moreover, movie periods eliciting higher firing rates also elicited a higher reliability of LFP phase across trials. To establish whether the LFP phase at which spikes were emitted conveyed visual information that could not be extracted by spike rates alone, we compared the Shannon information about the movie carried by spike counts to that carried by the phase of firing. We found that at low LFP frequencies, the phase of firing conveyed 54% additional information beyond that conveyed by spike counts. The extra information available in the phase of firing was crucial for the disambiguation between stimuli eliciting high spike rates of similar magnitude. Thus, phase coding may allow primary cortical neurons to represent several effective stimuli in an easily decodable format.


Stroke risk factors prepare rat brainstem tissues for modified local Shwartzman reaction.
Stroke risk factors such as hypertension, diabetes, advanced age, and genetic predisposition to stroke were demonstrated to prepare rat brainstem tissues for a modified local Shwartzman reaction. A single intracisternal injection of endotoxin provoked the reaction, and affected rats manifested neurologic deficits accompanied by pathologic lesions. Brainstem infarcts developed in only a small proportion of rats without recognized risk factors after intracisternal injection of endotoxin. Thus, stroke risk factors, which are ordinarily regarded as operating through acceleration of atherosclerosis, may predispose to brain ischemia by local effects on brain microcirculation such as those thought to underlie preparation of a tissue for the local Shwartzman reaction.


Structured Development and Promotion of a Research Field: Hormesis in Biology, Toxicology, and Environmental Regulatory Science.
The ability of powerful and well-funded interest groups to steer scientific research in ways that advance their goals has become a significant social concern. This steering ability is increasingly being recognized in the peer-reviewed scientific literature and in findings of deliberative scientific bodies. This paper provides a case study that illustrates some of the major strategies that can be used to structure and advance a controversial research field. It focuses on hormesis, described as a type of dose-response relationship in toxicology and biology showing low-dose stimulation but high-dose inhibition, or the reverse. Hormesis proponents tout its significance, arguing that substances toxic at high doses and beneficial at lower doses should be regulated less stringently. We identify five strategies employed by hormesis proponents to foster its acceptance: (1) creating institutions focused on supporting hormesis; (2) developing terminology, study designs, and data interpretations that cast it in a favorable light; (3) using bibliometric techniques and surveys to attract attention; (4) aggressively advocating for the phenomenon and challenging critics; and (5) working with outside interest groups to apply the hormesis phenomenon in the economic and political spheres. We also suggest a number of oversight strategies that can be implemented to help promote credible and socially responsible research in cases like this one.