Proper regulation of cyclic AMP-dependent protein kinase is required for growth, conidiation, and appressorium function in the anthracnose fungus Colletotrichum lagenarium.
Colletotrichum lagenarium, the casual agent of anthracnose of cucumber, forms specialized infection structures, called appressoria, during infection. To evaluate the role of cAMP signaling in C. lagenarium, we isolated and functionally characterized the regulatory subunit gene of the cAMP-dependent protein kinase (PKA). The RPK1 gene encoding the PKA regulatory subunit was isolated from C. lagenarium by polymerase chain reaction-based screening. rpk1 mutants, generated by gene replacement, exhibited high PKA activity during vegetative growth, whereas the wild-type strain had basal level activity. The rpk1 mutants showed significant reduction in vegetative growth and conidiation. Furthermore, the rpk1 mutants were nonpathogenic on cucumber plants, whereas they formed lesions when inoculated through wounds. A suppressor mutant showing restored growth and conidiation was isolated from a rpk1 mutant culture. The rpkl-suppressor mutant did not show high PKA activity, unlike the parental rpk1 mutant, suggesting that high PKA activity inhibits normal growth and conidiation. The suppressor mutant, however, was nonpathogenic on cucumber and failed to form lesions, even when inoculated through wounds. The rpk1 and suppressor mutants formed melanized appressoria on the host leaf surface but were unable to generate penetration hyphae. These results suggest that proper regulation of the PKA activity by the RPK1-encoded regulatory subunit is required for growth, conidiation, and appressorium function in C. lagenarium.


Ovarian response to controlled ovarian hyperstimulation in cancer patients is diminished even before oncological treatment.
To evaluate the results of controlled ovarian stimulation before chemotherapy for oocyte vitrification to preserve fertility in women diagnosed with cancer and compare them with a historical control group. A retrospective, multicenter, observational study performed between March 2007 and January 2011. University-affiliated infertility clinics. Of 272 patients affected by cancer in our Fertility Preservation Program, 223 women underwent a stimulated cycle for oocyte vitrification according to our protocols before cancer treatment. Their results were compared with a historical control group of 98 patients diagnosed with male factor infertility who were stimulated for a conventional IVF cycle. Controlled ovarian stimulation and oocyte retrieval. Days of stimulation, total dose of gonadotropins, estrogen levels, and number of oocytes retrieved and vitrified. No differences were found in days of stimulation, but significant differences in E(2) levels and the number of retrieved oocytes were measured, especially in the hormone-dependent cancer group. Patients with hormone-dependent cancer had a weaker response to controlled ovarian stimulation compared with patients with non-hormone-dependent cancer. Whether the oncological disease already affects the ovaries before chemo-/radiotherapy remains to be elucidated.


The contribution of color information to rapid face categorization in natural scenes.
Color's contribution to rapid categorization of natural images is debated. We examine its effect on high-level face categorization responses using fast periodic visual stimulation (Rossion et al., 2015). A high-density electroencephalogram (EEG) was recorded during presentation of sequences of natural object images every 83 ms (i.e., at F = 12.0 Hz). Natural face images were embedded in the sequence at a fixed interval of F/9 (1.33 Hz). There were four conditions: (a) full-color images; (b) grayscale images; and (c) and (d) phase-scrambled images from Conditions 1 and 2, respectively, making faces and objects unrecognizable. Observers' task was to respond to color changes of the fixation cross (Experiment 1). We found face-categorization responses at 1.33 Hz and its harmonics (2.67 Hz, etc.) over occipitotemporal areas, with right-hemisphere dominance; responses to color images were not significantly different from those to grayscale images. Behavioral analysis revealed longer response times when images contained color, despite nearly-all-correct performance in all conditions, suggesting that color change in the task might detract from color's contribution to face categorization. We subsequently changed the task to responding to fixation shape changes so that such response-time differences were eliminated (Experiment 2). The aggregate face-categorization response became 21.6% stronger to color than to grayscale images. This color advantage occurred late, at 290-415 ms after stimulus onset. Our results suggest that the color advantage for face categorization interacts with behavior, and that color only has a moderate and relatively late contribution to rapid face categorization in natural images.


Route selection in non-Euclidean virtual environments.
The way people choose routes through unfamiliar environments provides clues about the underlying representation they use. One way to test the nature of observers' representation is to manipulate the structure of the scene as they move through it and measure which aspects of performance are significantly affected and which are not. We recorded the routes that participants took in virtual mazes to reach previously-viewed targets. The mazes were either physically realizable or impossible (the latter contained 'wormholes' that altered the layout of the scene without any visible change at that moment). We found that participants could usually find the shortest route between remembered objects even in physically impossible environments, despite the gross failures in pointing that an earlier study showed are evident in the physically impossible environment. In the physically impossible conditions, the choice made at a junction was influenced to a greater extent by whether that choice had, in the past, led to the discovery of a target (compared to a shortest-distance prediction). In the physically realizable mazes, on the other hand, junction choices were determined more by the shortest distance to the target. This pattern of results is compatible with the idea of a graph-like representation of space that can include information about previous success or failure for traversing each edge and also information about the distance between nodes. Our results suggest that complexity of the maze may dictate which of these is more important in influencing navigational choices.


Pulse oximetry: fundamentals and technology update.
Oxygen saturation in the arterial blood (SaO2) provides information on the adequacy of respiratory function. SaO2 can be assessed noninvasively by pulse oximetry, which is based on photoplethysmographic pulses in two wavelengths, generally in the red and infrared regions. The calibration of the measured photoplethysmographic signals is performed empirically for each type of commercial pulse-oximeter sensor, utilizing in vitro measurement of SaO2 in extracted arterial blood by means of co-oximetry. Due to the discrepancy between the measurement of SaO2 by pulse oximetry and the invasive technique, the former is denoted as SpO2. Manufacturers of pulse oximeters generally claim an accuracy of 2%, evaluated by the standard deviation (SD) of the differences between SpO2 and SaO2, measured simultaneously in healthy subjects. However, an SD of 2% reflects an expected error of 4% (two SDs) or more in 5% of the examinations, which is in accordance with an error of 3%-4%, reported in clinical studies. This level of accuracy is sufficient for the detection of a significant decline in respiratory function in patients, and pulse oximetry has been accepted as a reliable technique for that purpose. The accuracy of SpO2 measurement is insufficient in several situations, such as critically ill patients receiving supplemental oxygen, and can be hazardous if it leads to elevated values of oxygen partial pressure in blood. In particular, preterm newborns are vulnerable to retinopathy of prematurity induced by high oxygen concentration in the blood. The low accuracy of SpO2 measurement in critically ill patients and newborns can be attributed to the empirical calibration process, which is performed on healthy volunteers. Other limitations of pulse oximetry include the presence of dyshemoglobins, which has been addressed by multiwavelength pulse oximetry, as well as low perfusion and motion artifacts that are partially rectified by sophisticated algorithms and also by reflection pulse oximetry.


U.S. Mexican-origin adolescents' bicultural competence and mental health in context.
We examined the prospective association (from Mage = 15.84 to 17.38 years) between bicultural competence and mental health among U.S. Mexican-origin adolescents relative to multiple (a) developmental niches, (b) components of bicultural competence, and (c) indicators of mental health. Participants included 749 adolescents (49% female, 29.7% Mexico-born) recruited during late childhood and followed through late adolescence. We used latent profile analyses to identify adolescents' developmental niches based on sociocultural characteristics of the family, school, and neighborhood contexts and multiple-group structural equation modeling to examine whether these niches moderated the association between bicultural competence and mental health. We identified 5 distinct adolescents' developmental niches. We found no association between bicultural competence and internalizing symptoms across niches; bicultural facility predicted lower externalizing symptoms among adolescents developing in niches characterized by immigrant families and predominantly Latino schools and neighborhoods. The diversity found among U.S. Mexican-origin adolescents' niches underscores the need to assess context broadly by including a range of settings. Studying multiple components of bicultural competence across numerous cultural domains may provide a better understanding of any mental health benefits of biculturalism. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Anti-Alzheimer's Molecules Derived from Marine Life: Understanding Molecular Mechanisms and Therapeutic Potential.
Alzheimer's disease (AD) is a devastating neurodegenerative disease and the most common cause of dementia. It has been confirmed that the pathological processes that intervene in AD development are linked with oxidative damage to neurons, neuroinflammation, tau phosphorylation, amyloid beta (Aβ) aggregation, glutamate excitotoxicity, and cholinergic deficit. Still, there is no available therapy that can cure AD. Available therapies only manage some of the AD symptoms at the early stages of AD. Various studies have revealed that bioactive compounds derived from marine organisms and plants can exert neuroprotective activities with fewer adverse events, as compared with synthetic drugs. Furthermore, marine organisms have been identified as a source of novel compounds with therapeutic potential. Thus, there is a growing interest regarding bioactive compounds derived from marine sources that have anti-AD potentials. Various marine drugs including bryostatin-1, homotaurine, anabaseine and its derivative, rifampicins, anhydroexfoliamycin, undecylprodigioisin, gracilins, 13-desmethyl spirolide-C, and dictyostatin displayed excellent bioavailability and efficacy against AD. Most of these marine drugs were found to be well-tolerated in AD patients, along with no significant drug-associated adverse events. In this review, we focus on the drugs derived from marine life that can be useful in AD treatment and also summarize the therapeutic agents that are currently used to treat AD.


The difficulties of 'living while girl'.
In this Viewpoint, Judith Bruce answers questions from Journal of Virus Eradication Editor, Sabine Kinloch-de Loës, on the importance of fulfilling the basic human rights of adolescent girls and their relationship with viral epidemics such as HIV. Judith Bruce is a graduate of Harvard University and a Senior Associate and Policy Analyst at the Population Council, New York, USA, whose work is aimed at building the health, social and cognitive assets of girls in the poorest communities in the developing world.


Megacity pumping and preferential flow threaten groundwater quality.
Many of the world's megacities depend on groundwater from geologically complex aquifers that are over-exploited and threatened by contamination. Here, using the example of Dhaka, Bangladesh, we illustrate how interactions between aquifer heterogeneity and groundwater exploitation jeopardize groundwater resources regionally. Groundwater pumping in Dhaka has caused large-scale drawdown that extends into outlying areas where arsenic-contaminated shallow groundwater is pervasive and has potential to migrate downward. We evaluate the vulnerability of deep, low-arsenic groundwater with groundwater models that incorporate geostatistical simulations of aquifer heterogeneity. Simulations show that preferential flow through stratigraphy typical of fluvio-deltaic aquifers could contaminate deep (>150 m) groundwater within a decade, nearly a century faster than predicted through homogeneous models calibrated to the same data. The most critical fast flowpaths cannot be predicted by simplified models or identified by standard measurements. Such complex vulnerability beyond city limits could become a limiting factor for megacity groundwater supplies in aquifers worldwide.


Evidence-based identification of the most important livestock related zoonotic diseases in Kampala, Uganda.
Urban and peri-urban livestock farming in developing countries plays an important role in food security in cities; however it brings with it zoonotic risks. The present study was conducted to identify the most important livestock farming-related zoonotic diseases among the human population in urban and peri-urban areas of Kampala, Uganda and to assess the risks from such farming. A framework for identifying livestock farming-related significant zoonoses was developed. The process consisted of screening of medical record summaries for zoonotic diagnoses, selection of the zoonoses which are related to livestock farming, case estimation of the identified zoonoses and evidence-based reassurance of the importance of diseases. Medical records in the Mulago National Referral Hospital were used for the analysis. Leaders and residents of 75 Local Councils (LC1s: villages; 48 urban, 11 peri-urban and 16 rural) randomly selected in Kampala were interviewed for information regarding livestock farming systems, value chains and use of medical service units. Twelve zoonoses were identified in the screening and four out of them were related to livestock farming: animal sourced food-borne gastroenteritis, brucellosis, Taenia solium neuro-cysticercosis and Mycobacterium bovis tuberculosis. Livestock farming, value chain and severity of the diseases confirmed that all four diseases were important. Poor geographical correlation between animals in peri-urban and rural areas and patients in urban areas suggested that the majority of these zoonoses were caused by informally-marketed foods.


Technical pitfalls of collateral ligament surgery.
The technical pitfalls of collateral ligament surgery include: Failure to properly diagnose and appropriately recommend surgery; posterolateral instability is the most commonly missed acute associated instability pattern Failure to correct all components of the injury (see Table 1): lateral meniscus, arcuate ligament, and popliteus, lateral gastrocnemius, and biceps muscles Failure to properly reattach and repair the damaged structures Peroneal nerve damage during the surgical approach and repair Wound problems: breakdown, hematoma Loss of motion This article presented a concise introduction to the anatomy of the collateral and capsular ligaments of the knee. This information should prove valuable in avoiding pitfalls in the diagnostic and surgical approach to the knee. To fully appreciate the anatomy, one must study it in the anatomy laboratory by performing repeated dissections. Only then can one appreciate how beautifully all of the structures function in unison. Application of this knowledge will help surgeons continue to improve and refine their approach to knee injuries.


Acupuncture and herbal medicine in in vitro fertilisation: a review of the evidence for clinical practice.
The objectives of this systematic review were to determine the effectiveness of (a) acupuncture and (b) Chinese herbal medicine on the treatment of male and female subfertility by assisted reproductive technologies (ART). All reports from RCTs of acupuncture and/or Chinese herbal medicine in ART were obtained via searches through The Cochrane Menstrual Disorders and Sub-fertility Group's Specialised Register of controlled trials, and other major databases. The outcome measures were determined prior to starting the search, and comprised: live birth rate, ongoing pregnancy rate, clinical pregnancy rate, the incidence of ovarian hyperstimulation syndrome and multiple pregnancy, miscarriage rate and adverse effects arising from treatment. Overall, 14 trials (a total of 2670 subjects) were included in the meta-analysis. The results provided no evidence of benefit in the use of acupuncture during assisted conception. Further studies should attempt to explore the potential placebo, as well as treatment, effects of this complimentary therapy. Essential elements for a quality RCT will be the size of the trial, the use of a standardised acupuncture method and of placebo needles.


Flow synthesis of ethyl isocyanoacetate enabling the telescoped synthesis of 1,2,4-triazoles and pyrrolo-[1,2-c]pyrimidines.
The efficient flow synthesis of important heterocyclic building blocks based on the 1,2,4-triazole and pyrrolo[1,2-c]pyrimidine scaffold has been achieved. Crucially, a telescoped continuous flow process was developed based on the reaction of N-formylglycine with triphosgene to deliver a stream of ethyl isocyanoacetate in situ, which subsequently yielded the desired heterocyclic entities in a telescoped reaction. Additionally, the functionalisation of the pyrrolo[1,2-c]pyrimidine core via subsequent SEAr reactions was studied revealing insight into a 'halogen dance' phenomenon associated with these medicinally relevant architectures.


Human cortical activity correlates with stereoscopic depth perception.
Stereoscopic depth perception is based on binocular disparities. Although neurons in primary visual cortex (V1) are selective for binocular disparity, their responses do not explicitly code perceived depth. The stereoscopic pathway must therefore include additional processing beyond V1. We used functional magnetic resonance imaging (fMRI) to examine stereo processing in V1 and other areas of visual cortex. We created stereoscopic stimuli that portrayed two planes of dots in depth, placed symmetrically about the plane of fixation, or else asymmetrically with both planes either nearer or farther than fixation. The interplane disparity was varied parametrically to determine the stereoacuity threshold (the smallest detectable disparity) and the upper depth limit (largest detectable disparity). fMRI was then used to quantify cortical activity across the entire range of detectable interplane disparities. Measured cortical activity covaried with psychophysical measures of stereoscopic depth perception. Activity increased as the interplane disparity increased above the stereoacuity threshold and dropped as interplane disparity approached the upper depth limit. From the fMRI data and an assumption that V1 encodes absolute retinal disparity, we predicted that the mean response of V1 neurons should be a bimodal function of disparity. A post hoc analysis of electrophysiological recordings of single neurons in macaques revealed that, although the average firing rate was a bimodal function of disparity (as predicted), the precise shape of the function cannot fully explain the fMRI data. Although there was widespread activity within the extrastriate cortex (consistent with electrophysiological recordings of single neurons), area V3A showed remarkable sensitivity to stereoscopic stimuli, suggesting that neurons in V3A may play a special role in the stereo pathway.


Regulatory focus, coping strategies and symptoms of anxiety and depression: A comparison between Syrian refugees in Turkey and Germany.
Civil war, flight, escape and expulsion are extremely stressful and assert a negative impact on refugees' mental health. However scientific research about resilience and coping of refugees is scarce. Especially in the recent refugee crisis, calls have been made to consider factors contributing to coping and resilience in this vulnerable population. Therefore, the current research sought to investigate individual differences that could serve as antecedents of coping and contextual factors that might moderate these effects. Specifically, it took into account individual's self-regulatory differences in terms of regulatory focus (i.e., a promotion focus on nurturance needs, ideals and gains vs. a prevention focus on security needs, oughts and losses). It furthermore explored contextual influences by considering Syrian refugees in Turkey (Sample 1, N = 273) and Germany (Sample 2, N = 169). Compared to Syrian refugees in Turkey, those in Germany had a stronger promotion focus. They also reported more problem-focused and less maladaptive coping, as well as less symptoms. Both promotion and prevention focus were positively related to problem-focused coping. Problem-focused coping, in turn, predicted more symptoms in Turkey but not in Germany. Furthermore, a stronger promotion focus was associated with less symptoms and maladaptive coping was associated with more symptoms in both samples. These results contribute to the coping literature in demonstrating that under certain conditions problem-focused coping can be maladaptive and extend the scarce previous work on self-regulation and coping. Most importantly, they highlight a promotion focus as a clear resilience factor and the role of maladaptive coping in increasing vulnerability. As such, they might inform the design of effective interventions among Syrian refugees and beyond.


G-quadruplex (G4) motifs in the maize (Zea mays L.) genome are enriched at specific locations in thousands of genes coupled to energy status, hypoxia, low sugar, and nutrient deprivation.
The G-quadruplex (G4) elements comprise a class of nucleic acid structures formed by stacking of guanine base quartets in a quadruple helix. This G4 DNA can form within or across single-stranded DNA molecules and is mutually exclusive with duplex B-form DNA. The reversibility and structural diversity of G4s make them highly versatile genetic structures, as demonstrated by their roles in various functions including telomere metabolism, genome maintenance, immunoglobulin gene diversification, transcription, and translation. Sequence motifs capable of forming G4 DNA are typically located in telomere repeat DNA and other non-telomeric genomic loci. To investigate their potential roles in a large-genome model plant species, we computationally identified 149,988 non-telomeric G4 motifs in maize (Zea mays L., B73 AGPv2), 29% of which were in non-repetitive genomic regions. G4 motif hotspots exhibited non-random enrichment in genes at two locations on the antisense strand, one in the 5' UTR and the other at the 5' end of the first intron. Several genic G4 motifs were shown to adopt sequence-specific and potassium-dependent G4 DNA structures in vitro. The G4 motifs were prevalent in key regulatory genes associated with hypoxia (group VII ERFs), oxidative stress (DJ-1/GATase1), and energy status (AMPK/SnRK) pathways. They also showed statistical enrichment for genes in metabolic pathways that function in glycolysis, sugar degradation, inositol metabolism, and base excision repair. Collectively, the maize G4 motifs may represent conditional regulatory elements that can aid in energy status gene responses. Such a network of elements could provide a mechanistic basis for linking energy status signals to gene regulation in maize, a model genetic system and major world crop species for feed, food, and fuel.


Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug.
As human life expectancy has improved rapidly in industrialized societies, age-related cognitive impairment presents an increasing challenge. Targeting histopathological processes that correlate with age-related cognitive declines, such as neuroinflammation, low levels of neurogenesis, disrupted blood-brain barrier and altered neuronal activity, might lead to structural and functional rejuvenation of the aged brain. Here we show that a 6-week treatment of young (4 months) and old (20 months) rats with montelukast, a marketed anti-asthmatic drug antagonizing leukotriene receptors, reduces neuroinflammation, elevates hippocampal neurogenesis and improves learning and memory in old animals. By using gene knockdown and knockout approaches, we demonstrate that the effect is mediated through inhibition of the GPR17 receptor. This work illustrates that inhibition of leukotriene receptor signalling might represent a safe and druggable target to restore cognitive functions in old individuals and paves the way for future clinical translation of leukotriene receptor inhibition for the treatment of dementias.


Redefining accountability in health care: managing the plurality of medical interests.
Conflict in health service delivery is common. It is often attributed to disputes between clinicians and patients or their families about treatment decisions and is particularly common in intensive care units (ICUs), in the form of ;futility disputes' between families and medical clinicians about decisions to terminate the active treatment of a dying family member. More common, but less prominent in the literature, is conflict within the medical profession about patient care goals and treatment. We contend that managing the plurality of medical interests is essential in achieving a more managed and positive experience for patients and families of the care they receive, and for achieving standards of quality and resource use. From an ethnographic study undertaken in a large ICU in Sydney, Australia, we found that the knowledge and practice differences of multiple medical decision-makers generated conflict, inconsistency of practice and subjectivity of decision-making that impeded coherent clinical decision-making and integrated patient care planning, coordination and care review. Improving patients' and families' experience of care requires medical clinicians and medical managers to accept responsibility for institutionalizing effective communication and decision-making processes within clinical networks and between clinical and managerial domains. Thus, strategies to improve patient care will need to extend beyond the medical profession to incorporate administrative management. We conclude that restructuring communication and decision-making processes is imperative to achieve clinical accountability in the workplace and systems accountability in the organization.


Visceral fat accumulation is an independent risk factor for hepatocellular carcinoma recurrence after curative treatment in patients with suspected NASH.
Visceral fat accumulation reportedly increases the risk of hepatocellular carcinoma (HCC) development in patients with chronic liver disease. However, it has not been fully elucidated whether visceral fat accumulation increases the risk of HCC recurrence after curative treatment in patients with suspected non-alcoholic steatohepatitis (NASH). Therefore this was investigated in the current study. 62 patients with naive HCC with suspected NASH were enrolled. All were curatively treated with percutaneous radiofrequency ablation between 1999 and 2006. The visceral fat area (VFA) was determined in each patient from CT images, taken at the time of HCC diagnosis. Patients were divided into two groups based on VFA: the high VFA group (>130 cm(2) in males, >90 cm(2) in females, n = 27) and the others (n = 35). The effects of VFA on HCC recurrence were analysed together with other factors including patients' background, tumour-related factors and liver function-related factors. The cumulative recurrence rates differed significantly between the two groups; 15.9, 56.5 and 75.1% at 1, 2 and 3 years, respectively, in the high VFA group, and 9.7, 31.1 and 43.1%, respectively, in the controls (p = 0.018). Multivariate analysis indicated visceral fat accumulation (risk ratio 1.08, per 10 cm(2), p = 0.046) and older age (risk ratio 1.06 per 1 year, p = 0.04) as independent risk factors of HCC recurrence. Visceral fat accumulation is an independent risk factor of HCC recurrence after curative treatment in patients with suspected NASH.


The configuration of bi-level ventilator circuits may affect compensation for non-intentional leaks during volume-targeted ventilation.
To assess the behaviour of a pressure-preset volume-guaranteed (V(TG)) mode of ventilation in the presence of non-intentional leaks in single-limb circuit (SLC) home ventilators. All SLC home ventilators commercially available in Italy can be used in a V(TG) mode with an intentional leak ("vented") or a true expiratory valve ("non-vented") configuration were selected. Using an experimental model consisting of a mannequin connected to an active lung simulator, for each level of leak (15, 25 and 37 l/min) three different conditions of respiratory mechanics (normal, restrictive and obstructive) were simulated using the ventilators in either a "vented" or "non-vented" configuration. Three home ventilators were tested: Vivo50 (Breas), PB560 (Covidien) and Ventilogic LS (Weimann). In a "vented" circuit configuration all three ventilators kept constant or increased inspiratory pressure in all leak conditions to guarantee the V(TG). Conversely, in a "non-vented" circuit configuration, all tested ventilators showed a drop in inspiratory pressure in all leak conditions, resulting in a concomitant reduction in delivered tidal volume. The same behaviour was found in all conditions of respiratory mechanics. In the absence of leaks, all the ventilators, independently of circuit configuration, were able to maintain the set V(TG) in the presence of modifications of the respiratory mechanics. The ability of the V(TG) mode to compensate for non-intentional leaks depends strictly on whether a "vented" or "non-vented" circuit configuration is used. This difference must be taken into account as a possible risk when a V(TG) mode is used in the presence of non-intentional leaks.


The efficacy of adjuvant radiotherapy in dermatofibrosarcoma protuberans: a systemic review and meta-analysis.
Dermatofibrosarcoma protuberans (DFSP) is a rare and locally aggressive tumour, with a high recurrence rate, even after complete surgical excision. Adjuvant radiotherapy (RT) has been suggested to reduce the risk of local recurrence after inadequate surgical resection in patients with narrow or positive surgical margins. However, the overall efficacy of adjuvant RT has not been well studied because of the rarity of DFSP and lack of an appropriate comparison group. We sought to evaluate the efficacy of adjuvant RT for DFSP by conducting a systemic review and meta-analysis to provide a more evidence-based measure of its effectiveness. We conducted a systemic review of articles published before 31 June 2015. Due to the rarity of the disease, we included all studies that reported DFSP patients who received adjuvant RT (postoperatively). The pooled recurrence rates were analysed from these extracted data. Twelve studies met the inclusion criteria. The pooled estimate of the recurrence rate for all adjuvant radiotherapy was 11.74% (95% CI 7.4-17.38; n = 167). Patients with positive/close had a pooled recurrence rate of 14.23% (95% CI 8.13-22.49; n = 92), whereas there was no recurrence in patients with negative margins. The pooled estimate of the recurrence rate between surgery alone and surgery combined with adjuvant radiotherapy showed no significant difference (odds ratio 0.31, P = 0.07), although there was a trend that adjuvant RT had a lower recurrence rate than surgery alone. Adjuvant RT might be considered for all patients undergoing surgical excision, even if a negative surgical margin has been achieved. Furthermore, for patients with large or recurrent tumours, especially when wide excision with negative margin would result in a significant functional or cosmetic deficit, postoperative radiotherapy is highly recommended in order to achieve a lower recurrence rate.


Joint effects between five identified risk variants, allergy, and autoimmune conditions on glioma risk.
Common variants in two of the five genetic regions recently identified from genome-wide association studies (GWAS) of risk of glioma were reported to interact with a history of allergic symptoms. In a pooled analysis of five epidemiologic studies, we evaluated the association between the five GWAS implicated gene variants and allergies and autoimmune conditions (AIC) on glioma risk (851 adult glioma cases and 3,977 controls). We further evaluated the joint effects between allergies and AIC and these gene variants on glioma risk. Risk estimates were calculated as odds ratios (OR) and 95 % confidence intervals (95 % CI), adjusted for age, gender, and study. Joint effects were evaluated by conducting stratified analyses whereby the risk associations (OR and 95 % CI) with the allergy or autoimmune conditions for glioma were evaluated by the presence or absence of the 'at-risk' variant, and estimated p interaction by fitting models with the main effects of allergy or autoimmune conditions and genotype and an interaction (product) term between them. Four of the five SNPs previously reported by others were statistically significantly associated with increased risk of glioma in our study (rs2736100, rs4295627, rs4977756, and rs6010620); rs498872 was not associated with glioma in our study. Reporting any allergies or AIC was associated with reduced risks of glioma (allergy: adjusted OR = 0.71, 95 % CI 0.55-0.91; AIC: adjusted OR = 0.65, 95 % CI 0.47-0.90). We did not observe differential association between allergic or autoimmune conditions and glioma by genotype, and there were no statistically significant p interactions. Stratified analysis by glioma grade (low and high grade) did not suggest risk differences by disease grade. Our results do not provide evidence that allergies or AIC modulate the association between the four GWAS-identified SNPs examined and risk of glioma.


Anthrax vaccine antigen-adjuvant formulations completely protect New Zealand white rabbits against challenge with Bacillus anthracis Ames strain spores.
In an effort to develop an improved anthrax vaccine that shows high potency, five different anthrax protective antigen (PA)-adjuvant vaccine formulations that were previously found to be efficacious in a nonhuman primate model were evaluated for their efficacy in a rabbit pulmonary challenge model using Bacillus anthracis Ames strain spores. The vaccine formulations include PA adsorbed to Alhydrogel, PA encapsulated in liposomes containing monophosphoryl lipid A, stable liposomal PA oil-in-water emulsion, PA displayed on bacteriophage T4 by the intramuscular route, and PA mixed with Escherichia coli heat-labile enterotoxin administered by the needle-free transcutaneous route. Three of the vaccine formulations administered by the intramuscular or the transcutaneous route as a three-dose regimen induced 100% protection in the rabbit model. One of the formulations, liposomal PA, also induced significantly higher lethal toxin neutralizing antibodies than PA-Alhydrogel. Even 5 months after the second immunization of a two-dose regimen, rabbits vaccinated with liposomal PA were 100% protected from lethal challenge with Ames strain spores. In summary, the needle-free skin delivery and liposomal formulation that were found to be effective in two different animal model systems appear to be promising candidates for next-generation anthrax vaccine development.


Nephropathy in model combining genetic hypertension with experimental diabetes. Enalapril versus hydralazine and metoprolol therapy.
We compared the effects of the angiotensin-converting enzyme inhibitor enalapril and a conventional antihypertensive regimen (hydralazine and metoprolol) on kidney function, albuminuria, and glomerular ultrastructure in hypertensive diabetic and nondiabetic rats. Diabetes was induced with streptozocin at 8 wk of age in spontaneously hypertensive (SHR) rats. Antihypertensive drugs were administered in drinking water from the time of induction of diabetes in all groups. Blood pressure reduction was equal in the diabetic and nondiabetic SHR rats receiving either enalapril or hydralazine plus metoprolol. In diabetic SHR rats, there was a rise in serum creatinine after 32 wk, which did not occur in diabetic rats treated with either antihypertensive regimen or in nondiabetic rats. Both drug regimens reduced albuminuria in diabetic and nondiabetic SHR rats to a similar degree. Enalapril and the combination of hydralazine and metoprolol were associated with decreased glomerular basement membrane thickness and glomerular volume in diabetic and nondiabetic SHR rats without significant effect on fractional mesangial volume. Thus, antihypertensive therapy retards the development of albuminuria, glomerular basement membrane thickening, and glomerular hypertrophy in the rat in the presence or absence of diabetes. No specific benefit of angiotensin-converting enzyme inhibition was observed in these hypertensive models of nephropathy. Human studies comparing the effects of different classes of antihypertensive drugs on kidney function, proteinuria, and glomerular morphology are warranted.


Allelopathy of Bracken Fern (Pteridium arachnoideum): New Evidence from Green Fronds, Litter, and Soil.
The neotropical bracken fern Pteridium arachnoideum (Kaulf.) Maxon. (Dennstaedtiaceae) is described as an aggressive pioneer plant species. It invades abandoned or newly burned areas and represents a management challenge at these invaded sites. Native to the Atlantic Forest and Cerrado (Tropical Savanna) Brazilian biomes, P. arachnoideum has nevertheless become very problematic in these conservation hotspots. Despite some reports suggesting a possible role of allelopathy in this plant's dominance, until now there has been little evidence of isolated and individually identified compounds with phytotoxic activities present in its tissues or in the surrounding environment. Thus, the aim of this study was to investigate the allelopathic potential of P. arachnoideum by isolating and identifying any secondary metabolites with phytotoxic activity in its tissues, litter, and soil. Bioguided phytochemical investigation led to the isolation and identification of the proanthocyanidin selligueain A as the major secondary compound in the green fronds and litter of this fern. It is produced by P. arachnoideum in its green fronds, remains unaltered during the senescence process, and is the major secondary compound present in litter. Selligueain A showed phytotoxic activity against the selected target species sesame (Sesamum indicum) early development. In particular, the compound inhibited root and stem growth, and root metaxylem cell size but did not affect chlorophyll content. This compound can be considered as an allelochemical because it is present in the soil under P. arachnoideum patches as one of the major compounds in the soil solution. This is the first report of the presence of selligueain A in any member of the Dennstaedtiaceae family and the first time an isolated and identified allelochemical produced by members of the Pteridium species complex has been described. This evidence of selligueain A as a putative allelochemical of P. arachnoideum reinforces the role of allelopathy in the dominance processes of this plant in the areas where it occurs.


Tobamoviral movement protein transiently expressed in a single epidermal cell functions beyond multiple plasmodesmata and spreads multicellularly in an infection-coupled manner.
Cell-to-cell movement of a plant virus requires expression of the movement protein (MP). It has not been fully elucidated, however, how the MP functions in primary infected cells. With the use of a microprojectile bombardment-mediated DNA infection system for Tomato mosaic virus (ToMV), we found that the cotransfected ToMV MP gene exerts its effects in the initially infected cells and in their surrounding cells to achieve multicellular spread of movement-defective ToMV. Five other tobamoviral MPs examined also transcomplemented the movement-defective phenotype of ToMV, but the Cucumber mosaic virus 3a MP did not. Together with the cell-to-cell movement of the mutant virus, a fusion between the MP and an enhanced green fluorescent protein variant (EGFP) expressed in trans was distributed multicellularly and localized primarily in plasmodesmata between infected cells. In contrast, in noninfected sites the MP-EGFP fusion accumulated predominantly inside the bombarded cells as irregularly shaped aggregates, and only a minute amount of the fusion was found in plasmodesmata. Thus, the behavior of ToMV MP is greatly modulated in the presence of a replicating virus and it is highly likely that the MP spreads in the infection sites, coordinating with the cell-to-cell movement of the viral genome.


Conductive nanogel-interfaced neural microelectrode arrays with electrically controlled in-situ delivery of manganese ions enabling high-resolution MEMRI for synchronous neural tracing with deep brain stimulation.
Chronic brain stimulation has become a promising physical therapy with increased efficacy and efficiency in the treatment of neurodegenerative diseases. The application of deep brain electrical stimulation (DBS) combined with manganese-enhanced magnetic resonance imaging (MEMRI) provides an unbiased representation of the functional anatomy, which shows the communication between areas of the brain responding to the therapy. However, it is challenging for the current system to provide a real-time high-resolution image because the incorporated MnCl2 solution through microinjection usually results in image blurring or toxicity due to the uncontrollable diffusion of Mn2+. In this study, we developed a new type of conductive nanogel-based neural interface composed of amphiphilic chitosan-modified poly(3,4 -ethylenedioxythiophene) (PMSDT) that can exhibit biomimic structural/mechanical properties and ionic/electrical conductivity comparable to that of Au. More importantly, the PMSDT enables metal-ligand bonding with Mn2+ ions, so that the system can release Mn2+ ions rather than MnCl2 solution directly and precisely controlled by electrical stimulation (ES) to achieve real-time high-resolution MEMRI. With the integration of PMSDT nanogel-based coating in polyimide-based microelectrode arrays, the post-implantation DBS enables frequency-dependent MR imaging in vivo, as well as small focal imaging in response to channel site-specific stimulation on the implant. The MR imaging of the implanted brain treated with 5-min electrical stimulation showed a thalamocortical neuronal pathway after 36 h, confirming the effective activation of a downstream neuronal circuit following DBS. By eliminating the susceptibility to artifact and toxicity, this system, in combination with a MR-compatible implant and a bio-compliant neural interface, provides a harmless and synchronic functional anatomy for DBS. The study demonstrates a model of MEMRI-functionalized DBS based on functional neural interface engineering and controllable delivery technology, which can be utilized in more detailed exploration of the functional anatomy in the treatment of neurodegenerative diseases.


Adherence to tamoxifen over the five-year course.
To estimate the proportion of older women who fail to complete 5 years of tamoxifen therapy and to identify predictors of non-adherence. We followed 462 women 65-years-old or older with stage I-IIIA breast cancer diagnosed in four US regions between 1996 and 1999 and who initiated tamoxifen therapy. We interviewed patients annually to assess tamoxifen adherence and collected information about predictors of adherence by medical record review, patient interview, and physician questionnaire. Thirty-one percent of patients who started tamoxifen failed to complete the recommended 5-year course. Patients who had initial severe side effects [hazard ratio (HR) per side effect=1.2, 95% confidence interval (CI) 0.97, 1.5] or developed them (HR per new side effect=1.3, 95% CI 1.0, 1.6) were more likely to discontinue. Patients with more prescription medications at baseline were less likely to discontinue (HR per baseline prescription equaled 0.90, 95% CI 0.81, 0.99), whereas patients who added a prescription were more likely to discontinue (HR per new prescription equaled 1.2, 95% CI 1.0, 1.4). Patients with positive views of tamoxifen at baseline (HR for a 10-point higher score=0.93, 95% CI 0.83, 1.0) and an improving view over follow-up (HR for a 10-point positive change=0.93, 95% CI 0.87, 1.0) were less likely to discontinue. Five years of tamoxifen confers a significant benefit beyond 1-2 years of tamoxifen, so physicians should ask patients about side effects, other prescriptions, and beliefs about tamoxifen and should educate them about the benefits of completing adjuvant therapy.


Engineering analysis of the effects of bulging sinuses in a newly designed pediatric pulmonary heart valve on hemodynamic function.
The purpose of this study was to examine the hemodynamic characteristics of expanded polytetrafluoroethylene (ePTFE) pulmonary valves with bulging sinuses quantitatively in a pediatric pulmonary mechanical circulatory system designed by us, in order to propose the optimal design for clinical applications. In this study, we developed a pediatric pulmonary mock circulation system, which consisted of a pneumatic right ventricular model, a pulmonary heart valve chamber, and a pulmonary elastic compliance tubing with resistive units. The hemodynamic characteristics of four different types of ePTFE valves and a monoleaflet mechanical heart valve were examined. Relationships between the leaflet movements and fluid characteristics were evaluated based on engineering analyses using echocardiography and a high-speed video camera under the pediatric circulatory conditions of the mock system. We successfully performed hemodynamic simulations in our pediatric pulmonary circulatory system that could be useful for quantitatively evaluating the pediatric heart valves. In the simulation study, the ePTFE valve with bulging sinuses exhibited a large eddy in the vicinity of the leaflets, whereas the straight tubing exhibited turbulent flow. The Reynolds number obtained in the valve with bulging sinuses was calculated to be 1667, which was smaller than that in the straight tubing (R (e) = 2454).The hemodynamic characteristics of ePTFE pediatric pulmonary heart valves were examined in our mock circulatory system. The presence of the bulging sinuses in the pulmonary heart valve decreased the hydrodynamic energy loss and increased the systolic opening area. Based on an in vitro experiment, we were able to propose an optimal selection of pulmonary valve design parameters that could yield a more sophisticated pediatric ePTFE valve shape.


Localization of Drosophila retinal degeneration B, a membrane-associated phosphatidylinositol transfer protein.
The Drosophila retinal degeneration B (rdgB) mutation causes abnormal photoreceptor response and light-enhanced retinal degeneration. Immunoblots using polyclonal anti-rdgB serum showed that rdgB is a 160-kD membrane protein. The antiserum localized the rdgB protein in photoreceptors, antennae, and regions of the Drosophila brain, indicating that the rdgB protein functions in many sensory and neuronal cells. In photoreceptors, the protein localized adjacent to the rhabdomeres, in the vicinity of the subrhabdomeric cisternae. The rdgB protein's amino-terminal 281 residues are > 40% identical to the rat brain phosphatidylinositol transfer protein (PI-TP). A truncated rdgB protein, which contains only this amino-terminal domain, possesses a phosphatidylinositol transfer activity in vitro. The remaining 773 carboxyl terminal amino acids have additional functional domains. Nitrocellulose overlay experiments reveal that an acidic amino acid domain, adjacent to the PI transfer domain, binds 45Ca+2. Six hydrophobic segments are found in the middle of the putative translation product and likely function as membrane spanning domains. These results suggest that the rdgB protein, unlike the small soluble PI-TPs, is a membrane-associated PI-TP, which may be directly regulated by light-induced changes in intracellular calcium.


Smart investments in sustainable food production: revisiting mixed crop-livestock systems.
Farmers in mixed crop-livestock systems produce about half of the world's food. In small holdings around the world, livestock are reared mostly on grass, browse, and nonfood biomass from maize, millet, rice, and sorghum crops and in their turn supply manure and traction for future crops. Animals act as insurance against hard times and supply farmers with a source of regular income from sales of milk, eggs, and other products. Thus, faced with population growth and climate change, small-holder farmers should be the first target for policies to intensify production by carefully managed inputs of fertilizer, water, and feed to minimize waste and environmental impact, supported by improved access to markets, new varieties, and technologies.


Pharmacologically active microcarriers delivering BDNF within a hydrogel: Novel strategy for human bone marrow-derived stem cells neural/neuronal differentiation guidance and therapeutic secretome enhancement.
Stem cells combined with biodegradable injectable scaffolds releasing growth factors hold great promises in regenerative medicine, particularly in the treatment of neurological disorders. We here integrated human marrow-isolated adult multilineage-inducible (MIAMI) stem cells and pharmacologically active microcarriers (PAMs) into an injectable non-toxic silanized-hydroxypropyl methylcellulose (Si-HPMC) hydrogel. The goal is to obtain an injectable non-toxic cell and growth factor delivery device. It should direct the survival and/or neuronal differentiation of the grafted cells, to safely transplant them in the central nervous system, and enhance their tissue repair properties. A model protein was used to optimize the nanoprecipitation conditions of the neuroprotective brain-derived neurotrophic factor (BDNF). BDNF nanoprecipitate was encapsulated in fibronectin-coated (FN) PAMs and the in vitro release profile evaluated. It showed a prolonged, bi-phasic, release of bioactive BDNF, without burst effect. We demonstrated that PAMs and the Si-HPMC hydrogel increased the expression of neural/neuronal differentiation markers of MIAMI cells after 1week. Moreover, the 3D environment (PAMs or hydrogel) increased MIAMI cells secretion of growth factors (b-NGF, SCF, HGF, LIF, PlGF-1, SDF-1α, VEGF-A & D) and chemokines (MIP-1α & β, RANTES, IL-8). These results show that PAMs delivering BDNF combined with Si-HPMC hydrogel represent a useful novel local delivery tool in the context of neurological disorders. It not only provides neuroprotective BDNF but also bone marrow-derived stem cells that benefit from that environment by displaying neural commitment and an improved neuroprotective/reparative secretome. It provides preliminary evidence of a promising pro-angiogenic, neuroprotective and axonal growth-promoting device for the nervous system. Combinatorial tissue engineering strategies for the central nervous system are scarce. We developed and characterized a novel injectable non-toxic stem cell and protein delivery system providing regenerative cues for central nervous system disorders. BDNF, a neurotrophic factor with a wide-range effect, was nanoprecipitated to maintain its structure and released in a sustained manner from novel polymeric microcarriers. The combinatorial 3D support, provided by fibronectin-microcarriers and the hydrogel, to the mesenchymal stem cells guided the cells towards a neuronal differentiation and enhanced their tissue repair properties by promoting growth factors and cytokine secretion. The long-term release of physiological doses of bioactive BDNF, combined to the enhanced secretion of tissue repair factors from the stem cells, constitute a promising therapeutic approach.


The Role of Affect in Attitude Formation toward New Technologies: The Case of Stratospheric Aerosol Injection.
This article analyzes determinants of technology acceptance and their interdependence. It highlights the role of affect in attitude formation toward new technologies and examines how it mediates the influence of stable psychological variables on the technology's acceptability. Based on theory and previous empirical evidence, we develop an analytical framework of attitude formation. We test this framework using survey data on attitudes toward stratospheric aerosol injection (SAI), a technology that could be used to counteract global warming. We show that affect is more important than risk and benefit perception in forming judgment about SAI. Negative and positive affect directly alter the perception of risks and benefits of SAI and its acceptability. Furthermore, affect is an important mediator between stable psychological variables-such as trust in governmental institutions, values, and attitudes-and acceptability. A person's affective response is thus guided by her general attitudes and values.


Intracellular effectors regulating the activity of the Lactococcus lactis CodY pleiotropic transcription regulator.
CodY is a pleiotropic transcriptional regulator conserved in low-G+C Gram-positive bacteria. Two distinct signals have been shown independently to influence the activity of this regulator: the level of intracellular GTP in Bacillus subtilis and the level of intracellular branched-chain amino acids (BCAA) isoleucine, leucine and valine in Lactococcus lactis. Measurement of BCAA and GTP levels in several environmental conditions showed that L. lactis CodY responded to the intracellular BCAA concentrations but not to physiological fluctuations in intracellular GTP. In addition, we demonstrated that CodY from L. lactis did not respond to intracellular GTP even when complementing CodY activity in B. subtilis. However, L. lactis CodY activity could still be modulated in B. subtilis by adding a rich nitrogen source to the growth media. This finding suggests that only BCAA are sensed by L. lactis CodY, whereas both GTP and BCAA signals may be integrated by B. subtilis CodY. The difference in the function of CodY from B. subtilis and L. lactis seems to reflect the difference in the physiology of these two bacteria.


Viscoelastic characteristics of muscle: passive stretching versus muscular contractions.
This study compared the effects of repeated contractions and repeated passive stretches on the viscoelastic properties of muscle. The tibialis anterior (TA) muscles of eight anesthetized male New Zealand white rabbits were studied. In each rabbit, one hindlimb was randomly assigned to the repeated muscular contraction group (CON) and the contralateral hindlimb to the repeated passive stretch group (STRETCH). The passive tension at neutral length was measured in all muscles before and after both repeated muscular contractions or repeated passive stretches. In the CON hindlimb, the peroneal nerve was stimulated with a nerve stimulator for 1 s, and the resulting contractile force was measured. Stimulations were repeated every 10 s for a total of 10 contractions. In the STRETCH hindlimb, the TA was stretched from its shortest in vivo length to its maximum in vivo length 10 times at 20 cm x min-1. The maximum force generated during the first contraction in the CON group averaged 21.74 +/- 1.41 N, with a subsequent reduction with each muscle contraction to 13.66 +/- 0.81 N by the tenth contraction. The average peak tensile force in the STRETCH group was 17.39 +/- 2.61 N for the first passive stretch, decreasing to 13.57 +/- 1.84 by the tenth stretch. After repeated muscular contractions in the CON hindlimbs, the passive tension at neutral length decreased from 0.88 +/- 0.22 N to 0.42 +/- 0.08 N. After repeated passive stretches in the STRETCH hindlimbs, the passive tension at neutral length decreased from 1.16 +/- 0.17 N to 0.67 +/- 0.09 N. The percentage decreases in passive tension between the CON and STRETCH groups were not statistically significant (P = 0.24). The results show that stretching and contracting both result in tissue relaxation of the muscle-tendon unit. This finding may be a result of changes in the viscous elements of the connective tissue secondary to the forces generated by either stretches or contractions. This study suggests that well controlled isometric muscular contractions may result in decreased passive tension in a muscle at neutral length, a finding that one normally associates with passive stretching.


Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study.
Atrial fibrillation contributes to substantial increases in morbidity and mortality. We aimed to develop a risk score to predict individuals' absolute risk of developing the condition, and to provide a framework for researchers to assess new risk markers. We assessed 4764 participants in the Framingham Heart Study from 8044 examinations (55% women, 45-95 years of age) undertaken between June, 1968, and September, 1987. Thereafter, participants were monitored for the first event of atrial fibrillation for a maximum of 10 years. Multivariable Cox regression identified clinical risk factors associated with development of atrial fibrillation in 10 years. Secondary analyses incorporated routine echocardiographic measurements (5152 participants, 7156 examinations) to reclassify the risk of atrial fibrillation and to assess whether these measurements improved risk prediction. 457 (10%) of the 4764 participants developed atrial fibrillation. Age, sex, body-mass index, systolic blood pressure, treatment for hypertension, PR interval, clinically significant cardiac murmur, and heart failure were associated with atrial fibrillation and incorporated in a risk score (p<0.05, except body-mass index p=0.08), clinical model C statistic 0.78 (95% CI 0.76-0.80). Risk of atrial fibrillation in 10 years varied with age: more than 15% risk was recorded in 53 (1%) participants younger than 65 years, compared with 783 (27%) older than 65 years. Additional incorporation of echocardiographic measurements to enhance the risk prediction model only slightly improved the C statistic from 0.78 (95% CI 0.75-0.80) to 0.79 (0.77-0.82), p=0.005. Echocardiographic measurements did not improve risk reclassification (p=0.18). From clinical factors readily accessible in primary care, our risk score could help to identify risk of atrial fibrillation for individuals in the community, assess technologies or markers for improvement of risk prediction, and target high-risk individuals for preventive measures.


A myocardial lineage derives from Tbx18 epicardial cells.
Understanding the origins and roles of cardiac progenitor cells is important for elucidating the pathogenesis of congenital and acquired heart diseases. Moreover, manipulation of cardiac myocyte progenitors has potential for cell-based repair strategies for various myocardial disorders. Here we report the identification in mouse of a previously unknown cardiac myocyte lineage that derives from the proepicardial organ. These progenitor cells, which express the T-box transcription factor Tbx18, migrate onto the outer cardiac surface to form the epicardium, and then make a substantial contribution to myocytes in the ventricular septum and the atrial and ventricular walls. Tbx18-expressing cardiac progenitors also give rise to cardiac fibroblasts and coronary smooth muscle cells. The pluripotency of Tbx18 proepicardial cells provides a theoretical framework for applying these progenitors to effect cardiac repair and regeneration.


Human papillomavirus and cancer prevention: gaps in knowledge and prospects for research, policy, and advocacy.
The recognition that human papillomavirus (HPV) infection is the central, necessary cause of cervical cancer paved the way to new fronts of prevention via improved screening methods and HPV vaccination. Much has been learned in all fronts, from the molecular basis of our understanding of how HPV causes disease to the health economics of preventive strategies at the individual and population levels. Progress in other areas of cancer control has yet to show the same multi- and trans-disciplinary gains seen in research on HPV-associated malignancies, which is one of the unequivocal success stories in disease prevention. Yet, as an embarrassment of riches, much more research is needed to fill the gaps in knowledge that remain before we are able to reap the benefits from the knowledge translation from all fronts. Public health research on setting-specific implementation of HPV-based preventive strategies and more concerted advocacy to counter barriers facing the adoption of these strategies are likely to yield major dividends in reducing the burden of HPV-associated diseases. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.


Gold nanoparticles decorated with oligo(ethylene glycol) thiols: protein resistance and colloidal stability.
The interactions between proteins and gold colloids functionalized with protein-resistant oligo(ethylene glycol) (OEG) thiol, HS(CH2)11(OCH2CH2)6OMe (EG6OMe), in aqueous solution have been studied by small-angle X-ray scattering (SAXS) and UV-vis spectroscopy. The mean size, 2R, and the size distribution of the decorated gold colloids have been characterized by SAXS. The monolayer-protected gold colloids have no correlations due to the low volume fraction in solution and are stable in a wide range of temperatures (5-70 degrees C), pH (1.3-12.4), and ionic strength (0-1.0 M). In contrast, protein (bovine serum albumin) solutions with concentrations in the range of 60-200 mg/mL (4.6-14.5 vol %) show a pronounced correlation peak in SAXS, which results from the repulsive electrostatic interaction between charged proteins. These protein interactions show significant dependence on ionic strength, as would be expected for an electrostatic interaction (Zhang et al. J. Phys. Chem. B 2007, 111, 251). For a mixture of proteins and gold colloids, the protein-protein interaction changes little upon mixing with OEG-decorated gold colloids. In contrast, the colloid-colloid interaction is found to be strongly dependent on the protein concentration and the size of the colloid itself. Adding protein to a colloidal solution results in an attractive depletion interaction between functionalized gold colloids, and above a critical protein concentration, c*, the colloids form aggregates and flocculate. Adding salt to such mixtures enhances the depletion effect and decreases the critical protein concentration. The aggregation is a reversible process (i.e., diluting the solution leads to dissolution of aggregates). The results also indicate that the charge of the OEG self-assembled monolayer at a curved interface has a rather limited effect on the colloidal stabilization and the repulsive interaction with proteins.


Adult zebrafish as a model organism for behavioural genetics.
Recent research has demonstrated the suitability of adult zebrafish to model some aspects of complex behaviour. Studies of reward behaviour, learning and memory, aggression, anxiety and sleep strongly suggest that conserved regulatory processes underlie behaviour in zebrafish and mammals. The isolation and molecular analysis of zebrafish behavioural mutants is now starting, allowing the identification of novel behavioural control genes. As a result of this, studies of adult zebrafish are now helping to uncover the genetic pathways and neural circuits that control vertebrate behaviour.


Panic and epilepsy in adults: A systematic review.
The purpose of the current paper was to review the empirical literature on the cooccurrence of panic and epilepsy, in order to determine whether there is an increased risk of panic attacks and panic disorder among adults with epilepsy and an increased risk of epilepsy among adults with panic disorder. Given the overlap between panic and ictal fear, a preliminary aim of the current review was to critically evaluate the methodology used to differentiate between diagnoses of panic disorder and epilepsy in existing research. A literature search was conducted in relevant electronic databases, and articles that directly focused on panic and epilepsy among adults were selected for the current review (n = 17). Overall, results suggest that rates of epilepsy are elevated among individuals with panic disorder and that panic attacks are elevated among individuals with epilepsy, but rates of panic disorder among people with epilepsy are inconsistent. However, most studies did not use sufficiently rigorous methods to differentiate between panic disorder and epilepsy. Therefore, a critical next step in this area of research is to develop a standard procedure for differentiating ictal fear from panic attacks and panic disorder.


MicroRNA Profile in CD8+ T-Lymphocytes from HIV-Infected Individuals: Relationship with Antiviral Immune Response and Disease Progression.
The relationship between host microRNAs (miRNA), viral control and immune response has not yet been elucidated in the field of HIV. The aim of this study was to assess the differential miRNA profile in CD8+ T-cells between HIV-infected individuals who differ in terms of viral replication control and immune response. miRNA profile from resting and CD3/CD28-stimulated CD8+ T-cells from uninfected individuals (HIV-, n = 11), Elite Controllers (EC, n = 15), Viremic Controllers (VC, n = 15), Viremic Progressors (VP, n = 13) and HIV-infected patients on therapy (ART, n = 14) was assessed using Affymetrix miRNA 3.1 arrays. After background correction, quantile normalization and median polish summarization, normalized data were fit to a linear model. The analysis comprised: resting samples between groups; stimulated samples between groups; and stimulated versus resting samples within each group. Enrichment analyses of the putative target genes were perfomed using bioinformatic algorithms. A downregulated miRNA pattern was observed when resting samples from all infected groups were compared to HIV-. A miRNA downregulation was also observed when stimulated samples from EC, ART and HIV- groups were compared to VP, being hsa-miR-4492 the most downregulated. Although a preferential miRNA downregulation was observed when stimulated samples were compared to the respective resting samples, VP presented a differential miRNA expression pattern. In fact, hsa-miR-155 and hsa-miR-181a were downregulated in VP whereas in the other groups, either an upregulation or no differences were observed after stimulation, respectively. Overall, functional enrichment analysis revealed that the predicted target genes were involved in signal transduction pathways, metabolic regulation, apoptosis, and immune response. Resting CD8+ T-cells do not exhibit a differential miRNA expression between HIV-infected individuals but they do differ from non-infected individuals. Moreover, a specific miRNA pattern is present in stimulated CD8+ T-cells from VP which could reflect a detrimental pattern in terms of CD8+ T-cell immune response.


Dopamine auto- and postsynaptic receptors: electrophysiological evidence for differential sensitivity to dopamine agonists.
The responses of dopamine cells in the substantia nigra to iontophoretically administered dopamine and intravenous apomorphine were compared to the responses of spontaneously active neurons in the caudate nucleus. Dopaminergic cells were six to ten times more sensitive to dopamine and intravenous apomorphine than 86 percent of the caudate cells tested. This differential sensitivity of dopamine auto- and postsynaptic receptors may explain the apparently paradoxical behavioral effects induced by small compared to large doses of some dopamine agonists and may provide a means of developing new types of drugs to antagonize dopaminergic influence in the central nervous system.


First Report of Spencermartinsia viticola, Neofusicoccum australe, and N. parvum Causing Branch Canker of Citrus in California.
Dothiorella gummosis and canker on citrus is generally viewed as a minor disease but can result in serious decline of trees. Symptoms, mostly found on branches, include grayish-to-brown cast on cankered bark, which can extend into the xylem. Dothiorella gummosis was earlier believed to be caused by Dothiorella gregaria (2). In a continuing survey on citrus in six California counties (Fresno, Riverside, San Diego, San Luis Obispo, Tulare, and Ventura) in 2010, branch cankers were collected. Small pieces of symptomatic tissues were plated onto potato dextrose agar amended with 0.01% tetracycline (PDA-tet) and incubated at 25°C for 4 days. Fungi most frequently isolated were initially identified as Botryosphaeriaceae based on morphological characters (1,3). Total genomic DNA was PCR amplified with primers Bt2a/2b for the β-tubulin (BT); EF1-728F/986R for the elongation factor α-1 (EF); and ITS4/5 for the internal transcribed spacer ITS1-5.8S-ITS2 regions (3). Sequences were compared in a BLAST search. Spencermartinsia viticola UCP105 was isolated from cv. Parent Washington on Sour Orange rootstock in Tulare County, Neofusicoccum australe UCR1110 from cv. Satsuma in Riverside County, and N. parvum UCR1166 from cv. Meyer Lemon on Volkameriana rootstock in Ventura County. Sequences of UCP105, UCR1110, and UCR1166 have been deposited in GenBank under Accession Nos. JF271766, JF271776, and JF271780 for BT; JF271784, JF271793, and JF271796 for EF; and JF271748, JF271758, and JF271762 for the ITS regions. The sequences matched with isolates in GenBank as follows: ITS region of strain UCP105-98% match with Accession Nos. AY905556-8; BT of strain UCR1110-99% with GU251879-80; and EF of strain UCR1166-98% with GU251238. Pathogenicity tests were conducted by inoculating green shoots of healthy citrus trees similar to cultivar/rootstock from which each isolate was obtained. Fresh wounds were made on 1-year-old citrus shoots with a 3-mm cork borer, and the freshly wounded surfaces were inoculated with 3-mm mycelial plugs from 5-day-old cultures on PDA-tet. Control shoots were inoculated with sterile agar plugs and each treatment had 10 replicates. Inoculated wounds and shoot ends were covered with petroleum jelly and wrapped with Parafilm to prevent desiccation. Shoots were incubated at 25°C in moist chambers for 4 weeks. Lesions were observed on all inoculated shoots except for the control. Mean lesion lengths were 6.4, 7.0, and 6.9 cm for UCP105, UCR1110, and UCR1166, respectively, which were significantly (P = 0.05) different from the control (0.8 cm). The three isolates were reisolated from symptomatic tissues of inoculated shoots to confirm their pathogenicity. This test was repeated and similar results were obtained. Results indicate that there are multiple species in the Botryosphaeriaceae family causing symptoms on citrus that were previously believed to be caused by D. gregaria. To our knowledge, this is the first report of S. viticola, N. australe, and N. parvum on citrus in California. References: (1) P. W. Crous et al. Stud. Mycol. 55:235, 2006. (2) V. McDonald et al. Plant Dis. 93:967, 2009. (3) B. Slippers et al. Mycologia 96:83, 2004.


Joint position sense is not altered during shoulder medial and lateral rotations in female assembly line workers with shoulder impingement syndrome.
This study evaluated joint position sense (JPS) during medial and lateral rotations of the shoulder in female workers with and without shoulder impingement syndrome (SIS). Three groups were assessed. The case group consisted of 15 female assembly line workers (35.5, SD 5.8 years) with unilateral SIS. Control group 1 consisted of 15 female assembly line workers asymptomatic for SIS (34.4, SD 5.5 years) and control group 2 consisted of 15 female subjects (33.1, SD 6.2 years) asymptomatic for SIS and with no exposure to activities with the upper limbs. The JPS was evaluated bilaterally during passive (2°/sec) and active (5°/sec) repositioning tests using an isokinetic dynamometer. The target angles were 45° of lateral rotation (achieved by medially rotating the shoulder from 90° of lateral rotation) and 75° of lateral rotation (achieved by laterally rotating the shoulder from neutral rotation). There were no differences between sides for all groups (p > 0.05). There were no differences in any of the variables between the case group and the control groups (p > 0.05). The results of this study suggest that JPS during medial and lateral rotations of the shoulder is not altered in female assembly line workers with SIS.


Treatment strategies for genu recurvatum in adult patients with hemiparesis: a case series.
To report our clinical experience and propose a biomechanical factor-based treatment strategy for improvement of genu recurvatum (GR) to reduce the need for knee-ankle-foot orthosis (KAFO) or surgical treatment. Case series. Outpatient clinic of a Department of Physical Medicine and Rehabilitation in an academic medical center. Adult subjects (n = 22) with hemiparesis and GR who received botulinum injections alone or in combination with multiple types of orthotic interventions that included solid ankle-foot orthosis (AFO) ± heel lift, hinged AFO with an adjustable posterior stop ± heel lift, AFO with dual-channel ankle joint ± heel lift, or KAFO with offset knee joint. Biomechanical factors reviewed included muscle strength, modified Ashworth score for spasticity, presence of clonus, posterior capsule laxity, sensory deficits, and proprioception. Outcome factors were improvement or elimination of GR based on subjective assessment before and after the interventions by the same experienced clinician. More than one biomechanical factor contributed to GR in all patients. Botulinum toxin A injection was used in patients who had significant plantar flexor spasticity and/or clonus. Four types of orthotic interventions were used based on the biomechanical factor: solid AFO in patients with severe ankle dorsiflexion and plantar flexion weakness or clonus; hinged ankle joint with adjustable posterior stop in patients with less severe ankle dorsiflexion weakness in the absence of clonus; AFO with a dual-channel ankle joint for quadriceps weakness or severe proprioceptive deficits; and KAFO with offset knee joints in patients with Achilles tendon contracture or severe proprioceptive deficits. Adjunctive options included the addition of heel lifts and toeplate modifications. Combinatorial interventions of botulinum injection, modified AFOs, and heel lifts improved or eliminated GR and avoided the need for cumbersome orthotics or surgical interventions. GR in hemiparesis is multifactorial and can be successfully controlled by using a conservative biomechanical factor-based approach and combined medical and orthotic interventions. An algorithmic approach and a prospective study design is proposed to determine a combination of effective interventions to correct GR.


Variation in the apparent importance of health-related problems with the instrument used to measure patient welfare.
This paper investigates the distributional implications for eight population groups of using six different instruments to measure wellbeing and to prioritise access to health services. Specifically, it examines the importance of different physical and psycho-social problems for the scores obtained using each instrument and whether scores differ because of differences in the concept measured by the instrument or because of the instrument's construction. Patients with seven chronic conditions and a sample of the 'healthy' public were administered six instruments: two utility instruments; two self-rating scales; a subjective wellbeing instrument and the ICECAP measure of capability. Scores were regressed upon the subscales of the SF-36 and the AQoL-8D. Each instrument's 'problem mix' was measured by the numerical importance of the subscales for the instrument's score and compared with the problem mix of patients constructed from all of the instruments. The apparent importance of different problems varied significantly with the instrument used to assess welfare but not with the chronic conditions. The correspondence between an instrument's problem mix and the patients' problem mix was highly variable. Different instruments give prominence to different physical and psycho-social problems and consequently favour different groups of patients. Budgetary decisions which appear to be based on efficiency criteria such as the cost per quality-adjusted life year (QALY) conceal distributive effects attributable to the instrument used in the analysis. The effects are additional to the ethical questions considered in making an equity-efficiency trade-off as they arise from the measurement of efficiency.


Can Siberian alder N-fixation offset N-loss after severe fire? Quantifying post-fire Siberian alder distribution, growth, and N-fixation in boreal Alaska.
Fire severity affects both ecosystem N-loss and post-fire N-balance. Climate change is altering the fire regime of interior Alaska, although the effects on Siberian alder (Alnus viridis ssp. fruticosa) annual N-fixation input (kg N ha-1 yr-1) and ecosystem N-balance are largely unknown. We established 263 study plots across two burn scars within the Yukon-Tanana Uplands ecoregion of interior Alaska. Siberian alder N-input was quantified by post-fire age, fire severity, and stand type. We modeled the components of Siberian alder N-input using environmental variables and fire severity within and across burn scars and estimated post-fire N-balance using N-loss (volatilized N) and N-gain [biological N-fixation and atmospheric deposition]. Mean nodule-level N-fixation rate was 70% higher 11-years post-fire (12.88 ± 1.18 μmol N g-1 hr-1) than 40-years post-fire (7.58 ± 0.59 μmol N g-1 hr-1). Structural equation modeling indicated that fire severity had a negative effect on Siberian alder density, but a positive effect on live nodule biomass (g nodule m-2 plant-1). Post-fire Siberian alder N-input was highest in 11-year old moderately burned deciduous stands (11.53 ± 0.22 kg N ha-1 yr-1), and lowest in 11-year old stands that converted from black spruce to deciduous dominance after severe fire (0.06 ± 0.003 kg N ha-1 yr-1). Over a 138-year fire return interval, N-gains in converted black spruce stands are estimated to offset 15% of volatilized N, whereas N-gains in burned deciduous stands likely exceed volatilized N by an order of magnitude. High Siberian alder density and nodule biomass drives N-input in burned deciduous stands, while low N-fixer density (including Siberian alder) limits N-input in high severity black spruce stands not underlain by permafrost. A severe fire regime that converts black spruce stands to deciduous dominance without alder recruitment may induce progressive N-losses which alter boreal forest ecosystem patterns and processes.


First Report of Canker on Pecan (Carya cathayensis) Caused by Botryosphaeria dothidea in China.
In the late 1990s, sporadic occurrence of Botryosphaeria canker on Carya cathayensis was recorded in Zhejiang Province, China. From 2005 to 2009, nearly 90% of orchards in Zhejiang and Anhui provinces were seriously affected by this disease. Symptoms were similar to those of canker of C. illinoinensis (2); small, elliptical lesions that developed on the bark at points of infection and then enlarged to form large, sunken, elongated cankers. The cankers coalesced, forming large diffuse areas of blighted tissue, which turned black. Tissue samples from the margin of trunk lesions from 35 different diseased trees from five counties were surface sterilized with 1.5% sodium hypochlorite for 3 min, plated on 2% potato dextrose agar (PDA), and incubated at 25°C in the dark for 1 week. Gray-black mycelia and colorless, aseptate, thin-walled conidia, 17.3 ± 0.8 long and 4.5 ± 0.5 μm wide, were produced. On the basis of these morphological characteristics, the fungus was identified as Botryosphaeria dothidea (Moug. ex Fr.) Ces. & De Not (1). The internal transcribed spacer (ITS) region was amplified with primers ITS1/ITS4 from DNA extracted from mycelium produced on PDA and was recorded as GenBank Accession Nos. HQ731442 and HQ731443. The results of BLAST showed that it had more than 98% similarity to records for B. dothidea. Uninfected twigs and stems of C. cathayensis were wounded with a scalpel and then sprayed with a conidia suspension of 106 conidia per ml in distilled water as inoculum or distilled water only to provide an noninoculated control, wrapped in plastic bags to retain moisture, and incubated for 48 h. For each isolate, five twigs and stems per tree and a total of 10 trees were inoculated. After 2 weeks, 14 of 15 isolates caused lesions on inoculated stems and twigs, whereas no symptoms developed on the noninoculated controls. Cultures isolated from lesions and cultured on PDA exhibited morphological characteristics identical to those of B. dothidea, confirming completion of Koch's postulates. Currently, the distribution of Botryosphaeria canker of C. cathayensis is confined to Zhejiang and Anhui provinces. The identification of the pathogen now allows for appropriate forest management measures. To our knowledge, this is the first report of Botryosphaeria canker of pecan (C. cathayensis) in China. References: (1) S. Denman et al. Stud. Mycol. 45:129, 2000. (2) W. A. Sinclair and H. H. Lyon. Diseases of Trees and Shrubs. 2nd ed. Cornell University Press, Ithaca, NY, 2005.


Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism.
The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology.


Simultaneous separation of hydrophobic and hydrophilic peptides with a silica hydride stationary phase using aqueous normal phase conditions.
The application of a silica hydride modified stationary phase with low organic loading has been investigated as a new type of chromatographic material suitable for the separation and analysis of peptides with electrospray ionization mass spectrometric detection. Retention maps were established to delineate the chromatographic characteristics of a series of peptides with physical properties ranging from strongly hydrophobic to very hydrophilic and encompassing a broad range of pI values (pI 5.5-9.4). The effects of low concentrations of two additives (formic acid and acetic acid) in the mobile phase were also investigated with respect to their contribution to separation selectivity and retention under comparable conditions. Significantly, strong retention of both the hydrophobic and the hydrophilic peptides was observed when high-organic low-aqueous mobile phases were employed, thus providing a new avenue to achieve high resolution peptide separations. For example, simultaneous separation of hydrophobic and hydrophilic peptides was achieved under aqueous normal phase (ANP) chromatographic conditions with linear gradient elution procedures in a single run, whilst further gradient optimization enabled improved peak efficiencies of the more strongly retained hydrophobic and hydrophilic peptides.


Contextual influences of dimension, speed, and direction of motion on subjective time perception.
Research has indicated that the direction of motion and the speed of motion can influence the subjective estimates of temporal duration of two-dimensional (2-D) stimuli expanding and contracting within the picture plane. In this study, we investigated whether the contextual cues of stimulus/movement-plane dimensionality (2-D stimuli with implied movement in the picture plane or depth-rendered "3-D" stimuli with implied movement in the depth plane) influence and interact with speed and implied movement direction during interval estimation. Participants viewed a series of standard stimulus durations followed by a test stimulus duration and determined whether the test and standard durations differed. The results indicated that moving stimuli were overestimated relative to stationary stimuli, regardless of the direction of motion or dimensionality. Also, faster-moving stimuli were overestimated relative to slower-moving stimuli. Importantly, an interaction between movement direction and dimensional cues indicated that the loom/recede distinction occurs for 2-D but not for 3-D stimuli. It is possible that the loom/recede distinction for the 2-D condition may be an artifact arising from reduced or from a lack of perceived motion in 2-D "recede" conditions, rather than a specific overestimation for looming stimuli.


The impact of bilingual environments on language development in children with autism spectrum disorders.
The impact of bilingual exposure on language learning has not been systematically studied in children with Autism Spectrum Disorders. This study compared the social abilities and language levels of children (mean age = 56 months) with ASDs from bilingual (n = 45) and monolingual (n = 30) environments. Bilingually-exposed children were subgrouped based on simultaneous bilingual exposure from infancy (SIM, n = 24) versus sequential post-infancy bilingual exposure (SEQ, n = 21). Despite significantly different amounts of bilingual exposure across all groups (p = <0.001) and significantly stronger social interaction scores in the SIM group compared to the SEQ group on the Vineland Adaptive Behavior Scales-II Interpersonal subdomain (p = 0.025), there were no significant group differences in language level. Bilingually-exposed children with ASDs did not experience additional delays in language development.


Transgenic interleukin 10 prevents induction of experimental autoimmune encephalomyelitis.
The effectiveness of interleukin 10 (IL-10) in the treatment of autoimmune-mediated central nervous system inflammation is controversial. Studies of the model system, experimental autoimmune encephalomyelitis (EAE), using various routes, regimens, and delivery methods of IL-10 suggest that these variables may affect its immunoregulatory function. To study the influence of these factors on IL-10 regulation of EAE pathogenesis, we have analyzed transgenic mice expressing human IL-10 (hIL-10) transgene under the control of a class II major histocompatibility complex (MHC) promoter. The hIL-10 transgenic mice are highly resistant to EAE induced by active immunization, and this resistance appears to be mediated by suppression of autoreactive T cell function. Myelin-reactive T helper 1 cells are induced but nonpathogenic in the IL-10 transgenic mice. Antibody depletion confirmed that EAE resistance is dependent on the presence of the transgenic IL-10. Mice expressing the hIL-10 transgene but not the endogenous murine IL-10 gene demonstrated that transgenic IL-10 from MHC class II-expressing cells is sufficient to block induction of EAE. This study demonstrates that IL-10 can prevent EAE completely if present at appropriate levels and times during disease induction.


Development of Quality Assurance and Quality Control Guidelines for Respiratory Oscillometry in Clinic Studies.
The guidelines to conduct and interpret conventional pulmonary function (PFT) tests are frequently reviewed and updated. However, the quality assurance and quality control (QA/QC) guidelines for respiratory oscillometry testing remain limited. QA/QC guidelines are essential for oscillometry to be used as a diagnostic pulmonary function test (PFT) in a clinical setting. We developed a QA/QC protocol shortly after oscillometry was introduced in our laboratory as part of a clinical study. The first clinical study began after the research personnel completed 3 h of combined didactic and hands-on training and establishment of a standard operating protocol (SOP) for oscillometry testing. All oscillometry tests were conducted using the initial SOP protocol from October 17, 2017, to April 6, 2018. At this time, the first QA/QC audit took place, followed by revisions to the SOP, the addition of a QA/QC checklist, and the development of a 12-h training program. A second audit of oscillometry tests was conducted from April 9, 2018, to June 30, 2019. Both audits were completed by a registered cardiopulmonary technologist from the Toronto General Pulmonary Function Lab. The first audit evaluated 197 paired oscillometry-PFT tests and found 10 tests (5.08%) to be invalid, with a coefficient of variation > 15%. The second audit examined 1,930 paired oscillometry-PFT tests; only 3 tests (0.16%) were unacceptable, with a coefficient of variation > 15%. Improvement in QA/QC was significantly better compared to the first audit (P < .001). Although oscillometry requires minimal subject cooperation, application of the principles that govern the conduct and application of a PFT are important for ensuring that oscillometry testing is performed according to acceptability and reproducibility. Specifically, the inclusion of a SOP, a proper training program, a QA/QC checklist, and regular audits with feedback are vital to ensure that oscillometry is conducted accurately and precisely.


Loss of Angiotensin-converting enzyme-related (ACER) peptidase disrupts night-time sleep in adult Drosophila melanogaster.
Drosophila Acer (Angiotensin-converting enzyme-related) encodes a member of the angiotensin-converting enzyme family of metallopeptidases that have important roles in the endocrine regulation of blood homeostasis in mammals. Acer is expressed in the embryonic heart of Drosophila and expression in the adult head appears to be regulated by two clock genes. To study the role of Acer in development and in circadian activity, we have generated Acer null mutants by imprecise excision of a P-element and have compared their development and circadian behaviour with that of wild-type flies with the same genetic background. We show that Acer is not required for normal development, but that night sleep, which is clock regulated, is disrupted in adult flies lacking ACER. Acer null adults have reduced night-time sleep and greater sleep fragmentation, but normal levels of daytime sleep. The quality of night sleep in flies fed inhibitors of ACER is affected in a very similar manner. We have shown, using specific antibodies, that ACER is present in the adult fat body of the head and abdomen, and is secreted into the haemolymph. ACER might therefore have a role in cleaving regulatory peptides involved in metabolism and activity behaviour. There are similarities with mammals, where ACE peptidases are also expressed in adipose tissue and are thought to be part of a signalling system linking metabolism with sleep.


Sputum Testing as the New Mass Screening Method for COVID-19 Patients in India - A Public Health Perspective.
In December 2019, an unusual form of pneumonia of unknown origin was identified in Wuhan and soon expanded into an intercontinental pandemic that affected nations all over the world. The unusual pneumonia was subsequently named COVID-19. The management of COVID-19 disease has been highly dependent on the early identification of patients who are positive for SARS-CoV-2 infection. For detecting the SARS-CoV-2 virus in upper or lower respiratory tracts, the Centers for Disease Control and Prevention (CDC) recommend strategic sampling approaches. Most countries collect nasopharyngeal swabs and oropharyngeal swabs for rapid viral testing by experienced healthcare workers. Due to the increase in single-day cases, the high cost of RT-PCR, and the requirement for greater coverage in order to detect COVID-19 infections, the screening method has been changed to the Rapid Antigen Test during this phase of the pandemic in India. Considering the limited sensitivity of the fast antigen test compared to the sputum test, and the benefit of having additional resources available from an already established TB network, policymakers should consider implementing COVID-19 with sputum testing. For India, which has 1.3 billion people and limited resources, contemplating a community level sample collection of COVID-19 samples will be an effective decision if scientific data is used for this purpose will be an effective choice for the country with more than 1.3 billion population and limited resources.


Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.
With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.


Multicenter case-control study of risk factors associated with development of vaccine-associated sarcomas in cats.
To determine whether particular vaccine brands, other injectable medications, customary vaccination practices, or various host factors were associated with the formation of vaccine-associated sarcomas in cats. Prospective multicenter case-control study. Cats in the United States and Canada with soft tissue sarcomas or basal cell tumors. Veterinarians submitting biopsy specimens from cats with a confirmed diagnosis of soft tissue sarcoma or basal cell tumor were contacted for patient medical history. Time window statistical analyses were used in conjunction with various assumptions about case definitions. No single vaccine brand or manufacturer within antigen class was found to be associated with sarcoma formation. Factors related to vaccine administration were also not associated with sarcoma development, with the possible exception of vaccine temperature prior to injection. Two injectable medications (long-acting penicillin and methyl prednisolone acetate) were administered to case cats more frequently than to control cats. Findings do not support the hypotheses that specific brands or types of vaccine within antigen class, vaccine practices such as reuse of syringes, concomitant viral infection, history of trauma, or residence either increase or decrease the risk of vaccine-associated sarcoma formation in cats. There was evidence to suggest that certain long-acting injectable medications may also be associated with sarcoma formation.