Symptoms predicting health-related quality of life in prostate cancer patients treated with localized radiation therapy.
Patient-reported health-related quality-of-life (HRQOL) measures can provide guidance for treatment decision making, symptom management, and discharge planning. HRQOL is often influenced by the distress experienced by patients from disease or treatment-related symptoms. This study aimed to identify symptoms that can predict changes in HRQOL in men undergoing external beam radiation therapy (EBRT) for nonmetastatic prostate cancer (NMPC). Fifty-one men with NMPC scheduled for EBRT were assessed at the baseline, at the midpoint of EBRT, and at the end of EBRT. All participants received 38-42 daily doses of EBRT (five times a week), depending on the stage of their disease. Validated questionnaires were administered to evaluate depressive symptoms, urinary and sexual functions, bowel issues, symptom-related distress, fatigue, and HRQOL. Pearson correlations, repeated-measures ANOVA, and multiple regressions examined the relationships among variables. Intensification of symptoms and increased symptom-related distress, with a corresponding decline in HRQOL, were observed during EBRT in men with NMPC. Changes in symptoms and symptom distress were associated with changes in HRQOL at the midpoint of EBRT (r=-0.37 to -0.6, P=0.05) and at the end of EBRT (r=-0.3 to -0.47, P=0.01) compared with the baseline. The regression model comprising age, body mass index, Gleason score, T category, androgen-deprivation therapy use, radiation dose received, symptoms (urinary/sexual/bowel problems, fatigue), and overall symptom distress explained 70% of the variance in predicting HRQOL. Urinary problems and fatigue significantly predicted the decline in HRQOL during EBRT. Identifying specific symptoms that can influence HRQOL during EBRT for NMPC can provide feasible interventional targets to improve treatment outcomes.


The Role of Alpha-2 Adrenergic Receptors in Anti-ulcer Activity.
Although peptic ulcer disease has long been recognized, the proposed mechanisms of its etiopathogenesis change every year. This review shows that gastric ulcers have a significant relationship with alpha-2 adrenergic receptors. The aggravating factors of gastric ulcer formation have been reported to act by blocking alpha-2 adrenergic receptors, whereas drugs possessing anti-ulcer activity have been shown to ensure gastric protection by stimulating the alpha-2 adrenergic receptors. The data derived from the literature indicate the likelihood that any drug or substance selectively stimulating the alpha-2 adrenergic receptors may possess anti-ulcer activity.


Surgical overtreatment of pancreatic intraductal papillary mucinous neoplasms: Do the 2017 International Consensus Guidelines improve clinical decision making?
Significant overtreatment of intraductal papillary mucinous neoplasms can be attributed to low specificity of the current International Consensus Guidelines as well as nonconformity with the guidelines. We compare the ability of the 2012 and revised 2017 intraductal papillary mucinous neoplasms International Consensus Guidelines to predict high-grade dysplasia/invasive cancer and to determine the preoperative variables that predict resection of benign or low-grade dysplasia in tertiary care centers. Clinical, radiographic, and pathologic data for resected intraductal papillary mucinous neoplasms at 3 high-volume National Cancer Institute Cancer Centers were reviewed and the 2012 and 2017 consensus criteria were retrospectively applied. When International Consensus Guidelines were not met, clinical decision analysis was used to determine the primary indication for resection. Logistic regression identified variables associated with pathologic grade. Records for a total of 251 patients were reviewed, 129 of whom (52%) had low-grade dysplasia. The revised 2017 International Consensus Guidelines had high sensitivity (98.4%) and negative predicted value (96.1%), and all high-risk stigmata predicted high-grade dysplasia/invasive cancer; however, specificity remained low (14.8%). Nonconformity with International Consensus Guidelines was the most powerful predictor of low-grade dysplasia on final pathologic examination (9.5; 2.12-40.78). Independent predictors of low-grade dysplasia included age younger than 50 (2.46; 1.08-5.62), fine-needle aspiration without epithelial cells (2.6; 1.43-4.72), and normal duct diameter (3.07; 1.99-4.75). Diabetes developed in 30% of patients after resection. Management of intraductal papillary mucinous neoplasms remains clinically challenging. Low specificity of the International Consensus Guidelines and nonconformity with the guidelines continue to contribute to unnecessary pancreatic resections. Improved tools for disease classification as well as a better understanding of the natural history, biology, and rates of progression of intraductal papillary mucinous neoplasms are needed to avoid surgical overtreatment of low-grade intraductal papillary mucinous neoplasms.


Robust adaptive filtering algorithms based on (inverse)hyperbolic sine function.
Recently, adaptive filtering algorithms were designed using hyperbolic functions, such as hyperbolic cosine and tangent function. However, most of those algorithms have few parameters that need to be set, and the adaptive estimation accuracy and convergence performance can be improved further. More importantly, the hyperbolic sine function has not been discussed. In this paper, a family of adaptive filtering algorithms is proposed using hyperbolic sine function (HSF) and inverse hyperbolic sine function (IHSF) function. Specifically, development of a robust adaptive filtering algorithm based on HSF, and extend the HSF algorithm to another novel adaptive filtering algorithm based on IHSF; then continue to analyze the computational complexity for HSF and IHSF; finally, validation of the analyses and superiority of the proposed algorithm via simulations. The HSF and IHSF algorithms can attain superior steady-state performance and stronger robustness in impulsive interference than several existing algorithms for different system identification scenarios, under Gaussian noise and impulsive interference, demonstrate the superior performance achieved by HSF and IHSF over existing adaptive filtering algorithms with different hyperbolic functions.


Selective plane illumination microscopy techniques in developmental biology.
Selective plane illumination microscopy (SPIM) and other fluorescence microscopy techniques in which a focused sheet of light serves to illuminate the sample have become increasingly popular in developmental studies. Fluorescence light-sheet microscopy bridges the gap in image quality between fluorescence stereomicroscopy and high-resolution imaging of fixed tissue sections. In addition, high depth penetration, low bleaching and high acquisition speeds make light-sheet microscopy ideally suited for extended time-lapse experiments in live embryos. This review compares the benefits and challenges of light-sheet microscopy with established fluorescence microscopy techniques such as confocal microscopy and discusses the different implementations and applications of this easily adaptable technology.


Fructose and hepatic insulin resistance.
Excessive caloric intake in a form of high-fat diet (HFD) was long thought to be the major risk factor for development of obesity and its complications, such as fatty liver disease and insulin resistance. Recently, there has been a paradigm shift and more attention is attributed to the effects of sugar-sweetened beverages (SSBs) as one of the culprits of the obesity epidemic. In this review, we present the data invoking fructose intake with development of hepatic insulin resistance in human studies and discuss the pathways by which fructose impairs hepatic insulin action in experimental animal models. First, we described well-characterized pathways by which fructose metabolism indirectly leads to hepatic insulin resistance. These include unequivocal effects of fructose to promote de novo lipogenesis (DNL), impair fatty acid oxidation (FAO), induce endoplasmic reticulum (ER) stress and trigger hepatic inflammation. Additionally, we entertained the hypothesis that fructose can directly impede insulin signaling in the liver. This appears to be mediated by reduced insulin receptor and insulin receptor substrate 2 (IRS2) expression, increased protein-tyrosine phosphatase 1B (PTP1b) activity, whereas knockdown of ketohexokinase (KHK), the rate-limiting enzyme of fructose metabolism, increased insulin sensitivity. In summary, dietary fructose intake strongly promotes hepatic insulin resistance via complex interplay of several metabolic pathways, at least some of which are independent of increased weight gain and caloric intake. The current evidence shows that the fructose, but not glucose, component of dietary sugar drives metabolic complications and contradicts the notion that fructose is merely a source of palatable calories that leads to increased weight gain and insulin resistance.


Overexpression of BetS, a Sinorhizobium meliloti high-affinity betaine transporter, in bacteroids from Medicago sativa nodules sustains nitrogen fixation during early salt stress adaptation.
Sinorhizobium meliloti possesses several betaine transporters to cope with salt stress, and BetS represents a crucial high-affinity glycine and proline betaine uptake system involved in the rapid acquisition of betaines by cells subjected to osmotic upshock. Using a transcriptional lacZ (beta-galactosidase) fusion, we showed that betS is expressed during the establishment of the symbiosis and in mature nitrogen-fixing nodules. However, neither Nod nor Fix phenotypes were impaired in a betS mutant. BetS is functional in isolated bacteroids, and its activity is strongly activated by high osmolarity. In bacteroids from a betS mutant, glycine betaine and proline betaine uptake was reduced by 85 to 65%, indicating that BetS is a major component of the overall betaine uptake activity in bacteroids in response to osmotic stress. Upon betS overexpression (strain UNA349) in free-living cells, glycine betaine transport was 2.3-fold higher than in the wild-type strain. Interestingly, the accumulation of proline betaine, the endogenous betaine synthesized by alfalfa plants, was 41% higher in UNA349 bacteroids from alfalfa plants subjected to 1 week of salinization (0.3 M NaCl) than in wild-type bacteroids. In parallel, a much better maintenance of nitrogen fixation activity was observed in 7-day-salinized plants nodulated with the overexpressing strain than in wild-type nodulated plants. Taken altogether, these results are consistent with the major role of BetS as an emergency system involved in the rapid uptake of betaines in isolated and in planta osmotically stressed bacteroids of S. meliloti.


Insulin inhibition of the proteasome is dependent on degradation of insulin by insulin-degrading enzyme.
A consequence of insulin-dependent diabetes mellitus is the loss of lean muscle mass as a result of accelerated proteolysis by the proteasome. Insulin inhibition of proteasomal activity requires interaction with insulin-degrading enzyme (IDE), but it is unclear if proteasome inhibition is dependent merely on insulin-NIDE binding or if degradation of insulin by IDE is required. To test the hypothesis that degradation by IDE is required for proteasome inhibition, a panel of insulin analogues with variable susceptibility to degradation by IDE binding was used to assess effects on the proteasome. The analogues used were [Lys(B28), Pro(B29)]-insulin (lispro), [Asp(B10)]-insulin (Asp(B10)) and [Glu(B4), Gln(B16), Phe(B17)]-insulin (EQF). Lispro was as effective as insulin at inhibition of degradation of iodine-125 ((125)I)-labeled insulin, but Asp(B10) and EQF were somewhat more effective. All agents inhibited cross-linking of (125)I-insulin to IDE, suggesting that all were capable of IDE binding. In contrast, although insulin and lispro were readily degraded by IDE, Asp(B10) was degraded more slowly, and EQF degradation was undetectable. Both insulin and lispro inhibited the proteasome, but Asp(B10) was less effective, and EQF had little effect. In summary, despite effective IDE binding, EQF was poorly degraded by IDE, and was ineffective at proteasome inhibition. These data suggest that insulin inhibition of proteasome activity is dependent on degradation by IDE. The mechanism of proteasome inhibition may be the generation of inhibitory fragments of insulin, or by displacement of IDE from the proteasome.


Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation.
Nupr1 is a chromatin protein, which cooperates with Kras(G12D) to induce PanIN formation and pancreatic cancer development in mice, though the molecular mechanisms underlying this effect remain to be fully characterized. In the current study, we report that Nupr1 acts as a gene modifier of the effect of Kras(G12D)-induced senescence by regulating Dnmt1 expression and consequently genome-wide levels of DNA methylation. Congruently, 5-aza-2'-deoxycytydine, a general inhibitor of DNA methylation, reverses the Kras(G12D)-induced PanIN development by promoting senescence. This requirement of Nupr1 expression, however, is not restricted to the pancreas since in lung of Nupr1(-/-) mice the expression of Kras(G12D) induces senescence instead of transformation. Therefore, mechanistically this data reveals that epigenetic events, at least at the level of DNA methylation, modulate the functional outcome of common genetic mutations, such as Kras(G12D), during carcinogenesis. The biomedical relevance of these findings lies in that they support the rational for developing similar therapeutic interventions in human aimed at controlling either the initiation or progression of cancer.


Mitochondrial respiration and Ca2+ waves are linked during fertilization and meiosis completion.
Fertilization increases both cytosolic Ca(2+) concentration and oxygen consumption in the egg but the relationship between these two phenomena remains largely obscure. We have measured mitochondrial oxygen consumption and the mitochondrial NADH concentration on single ascidian eggs and found that they increase in phase with each series of meiotic Ca(2+) waves emitted by two pacemakers (PM1 and PM2). Oxygen consumption also increases in response to Ins(1,4,5)P(3)-induced Ca(2+) transients. Using mitochondrial inhibitors we show that active mitochondria sequester cytosolic Ca(2+) during sperm-triggered Ca(2+) waves and that they are strictly necessary for triggering and sustaining the activity of the meiotic Ca(2+) wave pacemaker PM2. Strikingly, the activity of the Ca(2+) wave pacemaker PM2 can be restored or stimulated by flash photolysis of caged ATP. Taken together our observations provide the first evidence that, in addition to buffering cytosolic Ca(2+), the egg's mitochondria are stimulated by Ins(1,4,5)P(3)-mediated Ca(2+) signals. In turn, mitochondrial ATP production is required to sustain the activity of the meiotic Ca(2+) wave pacemaker PM2.


Rattleback dynamics and its reversal time of rotation.
A rattleback is a rigid, semielliptic toy which exhibits unintuitive behavior; when it is spun in one direction, it soon begins pitching and stops spinning, then it starts to spin in the opposite direction, but in the other direction, it seems to spin just steadily. This puzzling behavior results from the slight misalignment between the principal axes for the inertia and those for the curvature; the misalignment couples the spinning with the pitching and the rolling oscillations. It has been shown that under the no-slip condition and without dissipation the spin can reverse in both directions, and Garcia and Hubbard obtained the formula for the time required for the spin reversal t_{r} [Proc. R. Soc. Lond. A 418, 165 (1988)1364-502110.1098/rspa.1988.0078]. In this work, we reformulate the rattleback dynamics in a physically transparent way and reduce it to a three-variable dynamics for spinning, pitching, and rolling. We obtain an expression of the Garcia-Hubbard formula for t_{r} by a simple product of four factors: (1) the misalignment angle, (2) the difference in the inverses of inertia moment for the two oscillations, (3) that in the radii for the two principal curvatures, and (4) the squared frequency of the oscillation. We perform extensive numerical simulations to examine validity and limitation of the formula, and find that (1) the Garcia-Hubbard formula is good for both spinning directions in the small spin and small oscillation regime, but (2) in the fast spin regime especially for the steady direction, the rattleback may not reverse and shows a rich variety of dynamics including steady spinning, spin wobbling, and chaotic behavior reminiscent of chaos in a dissipative system.


3D Printed Deformable Surfaces for Shape-Changing Displays.
We use interlinked 3D printed panels to fabricate deformable surfaces that are specifically designed for shape-changing displays. Our exploration of 3D printed deformable surfaces, as a fabrication technique for shape-changing displays, shows new and diverse forms of shape output, visualizations, and interaction capabilities. This article describes our general design and fabrication approach, the impact of varying surface design parameters, and a demonstration of possible application examples. We conclude by discussing current limitations and future directions for this work.


3D Organotypic Spinal Cultures: Exploring Neuron and Neuroglia Responses Upon Prolonged Exposure to Graphene Oxide.
Graphene-based nanomaterials are increasingly engineered as components of biosensors, interfaces or drug delivery platforms in neuro-repair strategies. In these developments, the mostly used derivative of graphene is graphene oxide (GO). To tailor the safe development of GO nanosheets, we need to model in vitro tissue responses, and in particular the reactivity of microglia, a sub-population of neuroglia that acts as the first active immune response, when challenged by GO. Here, we investigated central nervous system (CNS) tissue reactivity upon long-term exposure to GO nanosheets in 3D culture models. We used the mouse organotypic spinal cord cultures, ideally suited for studying long-term interference with cues delivered at controlled times and concentrations. In cultured spinal segments, the normal presence, distribution and maturation of anatomically distinct classes of neurons and resident neuroglial cells are preserved. Organotypic explants were developed for 2 weeks embedded in fibrin glue alone or presenting GO nanosheets at 10, 25 and 50 μg/mL. We addressed the impact of such treatments on premotor synaptic activity monitored by patch clamp recordings of ventral interneurons. We investigated by immunofluorescence and confocal microscopy the accompanying glial responses to GO exposure, focusing on resident microglia, tested in organotypic spinal slices and in isolated neuroglia cultures. Our results suggest that microglia reactivity to accumulation of GO flakes, maybe due to active phagocytosis, may trim down synaptic activity, although in the absence of an effective activation of inflammatory response and in the absence of neuronal cell death.


Allosteric modulation of retinal GABA receptors by ascorbic acid.
Ionotropic GABA receptors (GABA(A) and GABA(C)) belong to the Cys-loop receptor family of ligand-gated ion channels. GABA(C) receptors are highly expressed in the retina, mainly localized at the axon terminals of bipolar cells. Ascorbic acid, an endogenous redox agent, modulates the function of diverse proteins, and basal levels of ascorbic acid in the retina are very high. However, the effect of ascorbic acid on retinal GABA receptors has not been studied. Here we show that the function of GABA(C) and GABA(A) receptors is regulated by ascorbic acid. Patch-clamp recordings from bipolar cell terminals in goldfish retinal slices revealed that GABA(C) receptor-mediated currents activated by tonic background levels of extracellular GABA, and GABA(C) currents elicited by local GABA puffs, are both significantly enhanced by ascorbic acid. In addition, a significant rundown of GABA puff-evoked currents was observed in the absence of ascorbic acid. GABA-evoked Cl(-) currents mediated by homomeric ρ(1) GABA(C) receptors expressed in Xenopus laevis oocytes were also potentiated by ascorbic acid in a concentration-dependent, stereo-specific, reversible, and voltage-independent manner. Studies involving the chemical modification of sulfhydryl groups showed that the two Cys-loop cysteines and histidine 141, all located in the ρ(1) subunit extracellular domain, each play a key role in the modulation of GABA(C) receptors by ascorbic acid. Additionally, we show that retinal GABA(A) IPSCs and heterologously expressed GABA(A) receptor currents are similarly augmented by ascorbic acid. Our results suggest that ascorbic acid may act as an endogenous agent capable of potentiating GABAergic neurotransmission in the CNS.


Catechol-Functionalized Hyaluronic Acid Hydrogels Enhance Angiogenesis and Osteogenesis of Human Adipose-Derived Stem Cells in Critical Tissue Defects.
Over the last few decades, stem cell therapies have been highlighted for their potential to heal damaged tissue and aid in tissue reconstruction. However, materials used to deliver and support implanted cells often display limited efficacy, which has resulted in delaying translation of stem cell therapies into the clinic. In our previous work, we developed a mussel-inspired, catechol-functionalized hyaluronic acid (HA-CA) hydrogel that enabled effective cell transplantation due to its improved biocompatibility and strong tissue adhesiveness. The present study was performed to further expand the utility of HA-CA hydrogels for use in stem cell therapies to treat more clinically relevant tissue defect models. Specifically, we utilized HA-CA hydrogels to potentiate stem cell-mediated angiogenesis and osteogenesis in two tissue defect models: critical limb ischemia and critical-sized calvarial bone defect. HA-CA hydrogels were found to be less cytotoxic to human adipose-derived stem cells (hADSCs) in vitro compared to conventional photopolymerized HA hydrogels. HA-CA hydrogels also retained the angiogenic functionality of hADSCs and supported osteogenic differentiation of hADSCs. Because of their superior tissue adhesiveness, HA-CA hydrogels were able to mediate efficient engraftment of hADSCs into the defect regions. When compared to photopolymerized HA hydrogels, HA-CA hydrogels significantly enhanced hADSC-mediated therapeutic angiogenesis (promoted capillary/arteriole formation, improved vascular perfusion, attenuated ischemic muscle degeneration/fibrosis, and reduced limb amputation) and bone reconstruction (mineralized bone formation, enhanced osteogenic marker expression, and collagen deposition). This study proves the feasibility of using bioinspired HA-CA hydrogels as functional biomaterials for improved tissue regeneration in critical tissue defects.


Evidence that replication-associated mutation alone does not explain between-chromosome differences in substitution rates.
Since Haldane first noticed an excess of paternally derived mutations, it has been considered that most mutations derive from errors during germ line replication. Miyata et al. (1987) proposed that differences in the rate of neutral evolution on X, Y, and autosome can be employed to measure the extent of this male bias. This commonly applied method assumes replication to be the sole source of between-chromosome variation in substitution rates. We propose a simple test of this assumption: If true, estimates of the male bias should be independent of which two chromosomal classes are compared. Prior evidence from rodents suggested that this might not be true, but conclusions were limited by a lack of rat Y-linked sequence. We therefore sequenced two rat Y-linked bacterial artificial chromosomes and determined evolutionary rate by comparison with mouse. For estimation of rates we consider both introns and synonymous rates. Surprisingly, for both data sets the prediction of congruent estimates of alpha is strongly rejected. Indeed, some comparisons suggest a female bias with autosomes evolving faster than Y-linked sequence. We conclude that the method of Miyata et al. (1987) has the potential to provide incorrect estimates. Correcting the method requires understanding of the other causes of substitution that might differ between chromosomal classes. One possible cause is recombination-associated substitution bias for which we find some evidence. We note that if, as some suggest, this association is dominantly owing to male recombination, the high estimates of alpha seen in birds is to be expected as Z chromosomes recombine in males.


Biomonitoring of fast-elimination endocrine disruptors - Results from a 6-month follow up on human volunteers with repeated urine and hair collection.
The assessment of human exposure to fast-elimination endocrine disruptors (ED) such as phthalates, bisphenols or pesticides is usually based on urinary biomarkers. The variability of biomarkers concentration, due to rapid elimination from the body combined with frequent exposure is however pointed out as a major limitation to exposure assessment. Other matrices such as hair, less sensitive to short-term variations in the exposure, have been proposed as possible alternatives. Nevertheless, no study compared the information obtained from hair and urine respectively in a follow-up allowing to assess biomarkers variability over time in these two matrices, and to compare the correlation between them. In the present study, hair and urine samples were collected from 16 volunteers over a 6 months follow-up. All in all, 92 hair samples and 805 urines samples were collected and analyzed for the presence of 16 phthalate metabolites, 4 bisphenols and 8 pesticides/metabolites. All the biomarkers analyzed were detected in at least one of the two matrices. 21 biomarkers were more frequently detected in hair, 6 in urine, and 1 was equivalent. Biomarkers intraclass correlation coefficients (ICC) ranged from 0.1 to 0.8 (ten above 0.4) in hair, and from 0.09 to 0.51 in urine (two above 0.4). The concentrations of biomarkers in hair and urine were significantly correlated for only one compound. This study highlights the complexity of assessing exposure to fast-elimination ED and suggests considering with caution the specificity of the matrix in data interpretation. The results document the respective advantages and limitations of urine and hair, and provide new insight in the understanding of the information provided by these biological matrices and their relevance for the assessment of human exposure to fast elimination contaminants. 92 hair and 805 urine samples collected from 16 volunteers over 6 months, tested for phthalate metabolites, bisphenols and pesticides. 19 biomarkers (in hair) and 24 (in urine) were detected in >50% of the samples.


The reflective zombie: Problematizing the conceptual framework of reflection in medical education.
Reflection is an ambiguous and profoundly complex human activity. We celebrate the developments in teaching and researching reflection in education, yet have identified flaws in the way reflection has been operationalized: medical education has translated the age-old concept into a teachable and measureable construct. We fear that in this process of operationalization, the philosophical underpinnings of reflection have been discarded. We illustrate this with a thought experiment about a 'reflective zombie': students who have been conditioned to follow prescribed thought steps rather than engaging in truly reflective behaviour. In research and assessment of reflection, measuring tools might be unable to distinguish reflective zombies from students who authentically reflect. We argue that the instrumental approach lies at the root of this problem as it limits the rich concept of reflection and illustrate our point by describing problems related to paradigm (we are looking at reflection in the wrong way), methods (we are using the wrong tools), and epistemics (can we even know what we want to know?). We offer three suggestions for implementing reflection into the curriculum and for research into reflection. First, acknowledge the diversity of reflection and let go of the 'checklist approach'. Second, embrace the personal nature of reflection by stimulating awareness of one's personal reflection styles as part of the reflective process. Third, shift the focus of research to the practice of reflection. We believe that a strong vision on reflection can lead to a balanced curriculum, setting students up for a lifelong learning as a reflective practitioner.


Screening for Asymptomatic Bacteriuria in Adults: US Preventive Services Task Force Recommendation Statement.
Among the general adult population, women (across all ages) have the highest prevalence of asymptomatic bacteriuria, although rates increase with age among both men and women. Asymptomatic bacteriuria is present in an estimated 1% to 6% of premenopausal women and an estimated 2% to 10% of pregnant women and is associated with pyelonephritis, one of the most common nonobstetric reasons for hospitalization in pregnant women. Among pregnant persons, pyelonephritis is associated with perinatal complications including septicemia, respiratory distress, low birth weight, and spontaneous preterm birth. To update its 2008 recommendation, the USPSTF commissioned a review of the evidence on potential benefits and harms of screening for and treatment of asymptomatic bacteriuria in adults, including pregnant persons. This recommendation applies to community-dwelling adults 18 years and older and pregnant persons of any age without signs and symptoms of a urinary tract infection. Based on a review of the evidence, the USPSTF concludes with moderate certainty that screening for and treatment of asymptomatic bacteriuria in pregnant persons has moderate net benefit in reducing perinatal complications. There is adequate evidence that pyelonephritis in pregnancy is associated with negative maternal outcomes and that treatment of screen-detected asymptomatic bacteriuria can reduce the incidence of pyelonephritis in pregnant persons. The USPSTF found adequate evidence of harms associated with treatment of asymptomatic bacteriuria (including adverse effects of antibiotic treatment and changes in the microbiome) to be at least small in magnitude. The USPSTF concludes with moderate certainty that screening for and treatment of asymptomatic bacteriuria in nonpregnant adults has no net benefit. The known harms associated with treatment include adverse effects of antibiotic use and changes to the microbiome. Based on these known harms, the USPSTF determined the overall harms to be at least small in this group. The USPSTF recommends screening pregnant persons for asymptomatic bacteriuria using urine culture. (B recommendation) The USPSTF recommends against screening for asymptomatic bacteriuria in nonpregnant adults. (D recommendation).


Regional cerebral blood flow in the anesthetized mouse as measured by local hydrogen clearance.
Platinum microelectrodes were used to measure H2 clearance in mouse brain, and the clearance curves were used to calculate regional cerebral blood flow (rCBF). The curves were usually biexponential, whether or not electrode placement was confined to the cortex. When calculated by the height over area method, rCBF in anesthetized mice averaged 37+/-14 and 49+/-15 ml/100 gm per minute in two successive groups where cortical placement had been made. After CO2 breathing, which raised PaCO2 to 77+/-18 torr, the mean rCBF of the latter group was elevated to 70+/-36 ml/100 gm per minute. Our basal rCBF values are lower than literature values for rats or mice, when compared with data obtained by other techniques. However, our data are comparable to rat rCBF data obtainted by others using H2 electrodes and are comparable also to data for whole brain CBF obtained by a variety of methods in larger anesthetized mammals. It is possible that H2 electrodes provide low values for supposedly "cortical" rCBF in the very small mouse brain, because is such brains the electrode is usually close enough to a slow clearing compartment for the electrode reading to be influenced by that compartment. At the same time one cannot rule out the possibility that other techniques when applied to small rodents may, on occasion, produce spuriously high values for CBF. Indeed, while some studies using the latter techniques do show unusually high values for cortical flow in these animals, other studies using similar methods do not.


Erythropoietin's inhibiting impact on hepcidin expression occurs indirectly.
Under conditions of accelerated erythropoiesis, elevated erythropoietin (Epo) levels are associated with inhibition of hepcidin synthesis, a response that ultimately increases iron availability to meet the enhanced iron needs of erythropoietic cells. In the search for erythroid regulators of hepcidin, many candidates have been proposed, including Epo itself. We aimed to test whether direct interaction between Epo and the liver is required to regulate hepcidin. We found that prolonged administration of high doses of Epo in mice leads to great inhibition of liver hepcidin mRNA levels, and concomitant induction of the hepcidin inhibitor erythroferrone (ERFE). Epo treatment also resulted in liver iron mobilization, mediated by increased ferroportin activity and accompanied by reduced ferritin levels and increased TfR1 expression. The same inhibitory effect was observed in mice that do not express the homodimeric Epo receptor (EpoR) in liver cells because EpoR expression is restricted to erythroid cells. Similarly, liver signaling pathways involved in hepcidin regulation were not influenced by the presence or absence of hepatic EpoR. Moreover, Epo analogs, possibly interacting with the postulated heterodimeric β common EpoR, did not affect hepcidin expression. These findings were supported by the lack of inhibition on hepcidin found in hepatoma cells exposed to various concentrations of Epo for different periods of times. Our results demonstrate that hepcidin suppression does not require the direct binding of Epo to its liver receptors and rather suggest that the role of Epo is to stimulate the synthesis of the erythroid regulator ERFE in erythroblasts, which ultimately downregulates hepcidin.


The lakes of Titan.
The surface of Saturn's haze-shrouded moon Titan has long been proposed to have oceans or lakes, on the basis of the stability of liquid methane at the surface. Initial visible and radar imaging failed to find any evidence of an ocean, although abundant evidence was found that flowing liquids have existed on the surface. Here we provide definitive evidence for the presence of lakes on the surface of Titan, obtained during the Cassini Radar flyby of Titan on 22 July 2006 (T16). The radar imaging polewards of 70 degrees north shows more than 75 circular to irregular radar-dark patches, in a region where liquid methane and ethane are expected to be abundant and stable on the surface. The radar-dark patches are interpreted as lakes on the basis of their very low radar reflectivity and morphological similarities to lakes, including associated channels and location in topographic depressions. Some of the lakes do not completely fill the depressions in which they lie, and apparently dry depressions are present. We interpret this to indicate that lakes are present in a number of states, including partly dry and liquid-filled. These northern-hemisphere lakes constitute the strongest evidence yet that a condensable-liquid hydrological cycle is active in Titan's surface and atmosphere, in which the lakes are filled through rainfall and/or intersection with the subsurface 'liquid methane' table.


Synthetic cannabimimetic agents metabolized by carboxylesterases.
Synthetic cannabimimetic agents are a large group of diverse compounds which act as agonists at cannabinoid receptors. Since 2004, synthetic cannabinoids have been used recreationally, although several of the compounds have been shown to cause severe toxicity in humans. In this study, the metabolism of two indazole carboxamide derivatives, AB-PINACA and AB-FUBINACA, was investigated by using human liver microsomes (HLM). For both compounds, a major metabolic pathway was the enzymatic hydrolysis of the primary amide, resulting in the major metabolites AB-PINACA-COOH and AB-FUBINACA-COOH. Other major metabolic pathways were mono-hydroxylation of the N-pentyl chain in AB-PINACA and mono-hydroxylation of the 1-amino-3-methyl-1-oxobutane moiety in AB-FUBINACA. To identify the enzyme(s) responsible for the amide hydrolysis, incubations with recombinant carboxylesterases and human serum, as well as inhibition studies in HLM and human pulmonary microsomes (HPM) were performed. Carboxylesterase 1 (CES1) was identified as the major human hepatic and pulmonary enzyme responsible for the amide hydrolysis.We employed similar studies to identify the esterase(s) involved in the previously described hydrolytic metabolism of two quinolineindole synthetic cannabinoids, PB-22 and 5F-PB-22, as well as the closely related compound, BB-22. Our investigations again revealed CES1 to be the key enzyme catalyzing these reactions. The identified major metabolites of AB-PINACA and AB-FUBINACA are likely to be useful in documenting drug usage in forensic and clinical screening. Additionally, the identification of CES1 as the main enzyme hydrolyzing these compounds improves our knowledge in the emerging field of xenobiotic metabolism by esterases.


SU-E-T-141: Dosimetry and Error Analysis of HDR Brachytherapy Tandem Applicator Using A16 Microchamber and Monte Carlo Simulation.
Absolute dosimetry with the associated uncertainties for 192Ir High Dose Rate (HDR) Brachytherapy Tandem applicator are presented using A16 microchamber and Monte Carlo simulation. The results are compared to the TG-43 protocol. An A16 Exradin MicroChamber, MCNPX 2.6 Monte Carlo simulation code and PTW farmer chamber with an ADCL calibration coefficient were used in this work. The A16 microchamber was calibrated using MCNPX simulation and PTW farmer chamber. Statistical and systematic uncertainty analyses associated with each experimental technique were analyzed quantitatively using MCNPX 2.6 to evaluate source positional error, Tandem positional error, phantom size effect, volume averaging, stem and wall effects, and Tandem effect. A16 microchamber was calibrated according to the AAPM TG-21 protocol and resulted in a value of 3.21E+09 Gy/C for Ngas in 60CO. To use the A16 with 192Ir spectrum, a correction factor of 1.13 was generated along the source transverse axis using MCNPX to account for energy difference. Absolute dose and uncertainty analyses along the transverse axis of a Tandem applicator were calculated using MCNPX and A16 microchamber and compared to the TG-43 protocol. The generated overall uncertainties associated with the A16 microchamber are 22%, 17%, 15%, 15%, 16%, 17%, and 19% at 1cm, 2cm, 3cm, 4cm, and 5cm, respectively. In this work, the author investigated the absolute dosimetry for 192Ir HDR brachytherapy for a Tandem applicator using A16 microchamber and compared the results to the TG-43 protocol. A16 microchamber has an effective volume of 0.007cc which makes it suitable to measure extremely small field sizes and enables high spatial resolution while minimizing volume averaging near the source. Furthermore, the author also investigated and analyzed the systematic and statistical uncertainties associated with A16 experimental dosimetry as recommended by AAPM TG-138 and GEC-ESTRO. Based on this work, dosimetry of HDR brachytherapy using A16 microchamber can be used, within uncertainties, as an alternative or redundant for the LiF TLDs.


Malaria abrogates O'nyong-nyong virus pathologies by restricting virus infection in nonimmune cells.
O'nyongnyong virus (ONNV) is a re-emerging alphavirus previously known to be transmitted by main malaria vectors, thus suggesting the possibility of coinfections with arboviruses in co-endemic areas. However, the pathological outcomes of such infections remain unknown. Using murine coinfection models, we demonstrated that a preexisting blood-stage Plasmodium infection suppresses ONNV-induced pathologies. We further showed that suppression of viremia and virus dissemination are dependent on Plasmodium-induced IFNγ and are associated with reduced infection of CD45- cells at the site of virus inoculation. We further proved that treatment with IFNγ or plasma samples from Plasmodium vivax-infected patients containing IFNγ are able to restrict ONNV infection in human fibroblast, synoviocyte, skeletal muscle, and endothelial cell lines. Mechanistically, the role of IFNγ in restricting ONNV infection was confirmed in in vitro infection assays through the generation of an IFNγ receptor 1 α chain (IFNγR1)-deficient cell line.


Statements of Agreement From the Targeted Evaluation and Active Management (TEAM) Approaches to Treating Concussion Meeting Held in Pittsburgh, October 15-16, 2015.
Conventional management for concussion involves prescribed rest and progressive return to activity. Recent evidence challenges this notion and suggests that active approaches may be effective for some patients. Previous concussion consensus statements provide limited guidance regarding active treatment. To describe the current landscape of treatment for concussion and to provide summary agreements related to treatment to assist clinicians in the treatment of concussion. On October 14 to 16, 2015, the Targeted Evaluation and Active Management (TEAM) Approaches to Treating Concussion meeting was convened in Pittsburgh, Pennsylvania. Thirty-seven concussion experts from neuropsychology, neurology, neurosurgery, sports medicine, physical medicine and rehabilitation, physical therapy, athletic training, and research and 12 individuals representing sport, military, and public health organizations attended the meeting. The 37 experts indicated their agreement on a series of statements using an audience response system clicker device. A total of 16 statements of agreement were supported covering (1) Summary of the Current Approach to Treating Concussion, (2) Heterogeneity and Evolving Clinical Profiles of Concussion, (3) TEAM Approach to Concussion Treatment: Specific Strategies, and (4) Future Directions: A Call to Research. Support (ie, response of agree or somewhat agree) for the statements ranged from to 97% to 100%. Concussions are characterized by diverse symptoms and impairments and evolving clinical profiles; recovery varies on the basis of modifying factors, injury severity, and treatments. Active and targeted treatments may enhance recovery after concussion. Research is needed on concussion clinical profiles, biomarkers, and the effectiveness and timing of treatments. ARS, audience response systemCDC, Centers for Disease Control and PreventionDoD, Department of DefensemTBI, mild traumatic brain injuryNCAA, National Collegiate Athletic AssociationNFL, National Football LeagueNIH, National Institutes of HealthRCT, randomized controlled trialRTP, return to playSRC, sport- and recreation-related concussionTBI, traumatic brain injuryTEAM, Targeted Evaluation and Active Management.


An in silico model to demonstrate the effects of Maspin on cancer cell dynamics.
Most cancer treatments efficacy depends on tumor metastasis suppression, where tumor suppressor genes play an important role. Maspin (Mammary Serine Protease Inhibitor), an non-inhibitory serpin has been reported as a potential tumor suppressor to influence cell migration, adhesion, proliferation and apoptosis in in vitro and in vivo experiments in last two decades. Lack of computational investigations hinders its ability to go through clinical trials. Previously, we reported first computational model for maspin effects on tumor growth using artificial neural network and cellular automata paradigm with in vitro data support. This paper extends the previous in silico model by encompassing how maspin influences cell migration and the cell-extracellular matrix interaction in subcellular level. A feedforward neural network was used to define each cell behavior (proliferation, quiescence, apoptosis) which followed a cell-cycle algorithm to show the microenvironment impacts over tumor growth. Furthermore, the model concentrates how the in silico experiments results can further confirm the fact that maspin reduces cell migration using specific in vitro data verification method. The data collected from in vitro and in silico experiments formulates an unsupervised learning problem which can be solved by using different clustering algorithms. A density based clustering technique was developed to measure the similarity between two datasets based on the number of links between instances. Our proposed clustering algorithm first finds the nearest neighbors of each instance, and then redefines the similarity between pairs of instances in terms of how many nearest neighbors share the two instances. The number of links between two instances is defined as the number of common neighbors they have. The results showed significant resemblances with in vitro experimental data. The results also offer a new insight into the dynamics of maspin and establish as a metastasis suppressor gene for further molecular research.


Relative kinematics of the rib cage and abdomen during speech and nonspeech behaviors of 15-month-old children.
Speech motor control emerges in the neurophysiologic context of widely distributed, powerful coordinative mechanisms, including those mediating respiratory function. It is unknown, however, whether developing children are able to exploit the capabilities of neural circuits controlling homeostasis for the production of speech and voice. Speech and rest breathing were investigated in eleven 15-month-old children using inductance plethysmography (Respitrace). Rib cage and abdominal kinematics were studied using a time-varying correlational index of thoracoabdominal coupling (i.e., reflecting the synchrony of movement of the rib cage and abdomen) as well as simple classification of the moment-to-moment kinematic relationship of these two functional components (i.e., concurrent expansion or compression, or oppositional movement). Results revealed markedly different patterns of movement for rest breathing and speech breathing, although within types of vocalization (nonspeech vocalization, babbling, true word production) no differences were apparent. Whereas rest breathing was characterized by tight coupling of rib cage and abdominal movement (average correlation coefficients usually exceeded .90), speech breathing exhibited weak coupling (the correlation coefficient ranged widely, but averaged about .60). Furthermore, speech production by these toddlers included the occurrence of both rib cage and abdominal paradoxing, which are observed infrequently in adult speakers. These results fail to support the suggestion that speech emerges from the extant coordinative organization of rest breathing. Rather, even in its earliest stages breathing for speech and voice exhibits kinematic properties distinct from those of other observed behaviors.


Protective effects of aqueous and ethanolic extracts of Nigella sativa L. and Portulaca oleracea L. on free radical induced hemolysis of RBCs.
It has been shown that Nigella sativa L. and Portulaca oleracea L. have many antioxidant components. In the present study, the cytoprotective effect of ethanolic and aqueous extracts of N.sativa and P.oleracea against hemolytic damages induced by free radical initiator, AAPH [2, 2' azobis (2- amidinopropane) hydrochloride] was evaluated. Hemolysis was induced by addition of AAPH. To study the cytoprotective effect, aqueous (50, 200, 300, 400, 800 µg/ml) and ethanolic (25, 100, 150, 200 and 400 µg/ml) extracts of N. sativa and aqueous (25, 50, 100, 150, 200 and 400 µg/ml) and ethanolic (300, 600, 900, 1200 and 1800 µg/ml) extracts of P. oleracea were employed. RBCs were incubated with both extracts and AAPH at 37 °C for 6 hrs. In order to evaluate the impact of the time of addition, extracts were added one and 2 hrs after AAPH. Samples of suspensions were removed at different times and the degree of hemolysis was assessed spectrophotometrically by reading the absorption of supernatants at 540 nm. Aqueous (300, 400 and 800 µg/ml) and ethanolic (150, 200 and 400 µg/ml) extracts of N.sativa and also, aqueous (100, 150, 200 and 400 µg/ml) and ethanolic (1200, 1800 µg/ml) extracts of P.oleracea showed concentration-dependent cytoprotective effects. Addition of extracts one hour after AAPH reduced but did not eliminate protective activities of extracts. Cytorotective effect of aqueous and ethanolic extracts of N. sativa and P. oleracea against AAPH- induced hemolysis may be related to antioxidant properties of these plants.


Acid phosphatase.
Acid phosphatase is a ubiquitous lysosomal enzyme that hydrolyses organic phosphates at an acid pH. Although the postpuberteral prostatic epithelial cell contains a uniquely high concentration of acid phosphatase, cellular components of bone, spleen, kidney, liver, intestine, and blood also contain this enzyme. The discovery that prostatic carcinoma cells often retain a high concentration of acid phosphatase characteristic of the normal postpubertal gland led to the recognition of the first clinically useful tumor marker. Recognition that the serum of patients with prostatic malignancy frequently contains an increased concentration of this enzyme has resulted in persistent efforts to identify the source, to accurately quantitate the level of serum acid phosphatase, and to determine the clinical significance of those levels. A variety of enzymatic and immunologic techniques have been employed to measure acid phosphatase. In the past, various substrates and inhibitors were utilized to increase specificity and sensitivity. Emphasis has now shifted to the development of radioimmunoassay and counterimmunoelectrophoresis in an attempt to enhance those parameters. Judgment of their efficacy awaits further testing and evaluation. The clinical significance of normal and abnormal serum acid phosphatase is constantly being reevaluated. In order to maximize the value of laboratory measurements, the clinical and pathologic status of the patient, the techniques employed in obtaining and storing the blood sample and the procedures used in analysis must be known and considered. Traditionally, the serum prostatic acid phosphatase has been thought to originate in the prostatic cancer cell and has been used to stage the disease. Until recently, elevated serum values have been accepted as an indication of extraprostatic disease, and were thought to rule out lesions confined to the prostate. The elevation of acid phosphatase levels in patients with disseminated disease or the failure of elevated levels to return to normal with treatment have been assumed to indicate a poor prognosis. However, unequivocal documentation of the validity of these statements is not available. Newer immunologic techniques for measuring acid phosphatase may significantly alter our current concept of its role as a tumor marker.


Shared and unique features of morphological differentiation between predator regimes in Gambusia caymanensis.
When multiple groups of organisms experience similar environmental gradients, their patterns of differentiation might exhibit both shared and unique features. Here, we investigated the relative importance of three factors in generating body shape variation in a livebearing fish, Gambusia caymanensis, inhabiting the Cayman Islands: (i) shared patterns of divergent selection between predator regimes (presence/absence of piscivorous fish) driving replicated morphological differentiation, (ii) historical island effects yielding different morphologies across the three islands and (iii) unique effects of predation on morphological differentiation within each island. Shared effects of predation proved much more important than historical or unique effects. Populations coexisting with piscivorous fish exhibited larger caudal regions and smaller heads than conspecifics found in the absence of predatory fish. These results match a priori predictions, and mirror recent findings in a number of fish species, suggesting predation might often drive predictable morphological trends in disparate fishes. However, interestingly, the sexes achieved this morphological pattern through different means: head depth, caudal peduncle length and depth in males; head length, caudal peduncle depth in females. In G. caymanensis, we quantitatively confirmed that predation intensity represents a primary driver of body shape differentiation.


Disentangling Chromophore States in a Reversibly Switchable Green Fluorescent Protein: Mechanistic Insights from NMR Spectroscopy.
The photophysical properties of fluorescent proteins, including phototransformable variants used in advanced microscopy applications, are influenced by the environmental conditions in which they are expressed and used. Rational design of improved fluorescent protein markers requires a better understanding of these environmental effects. We demonstrate here that solution NMR spectroscopy can detect subtle changes in the chemical structure, conformation, and dynamics of the photoactive chromophore moiety with atomic resolution, providing such mechanistic information. Studying rsFolder, a reversibly switchable green fluorescent protein, we have identified four distinct configurations of its p-HBI chromophore, corresponding to the cis and trans isomers, with each one either protonated (neutral) or deprotonated (anionic) at the benzylidene ring. The relative populations and interconversion kinetics of these chromophore species depend on sample pH and buffer composition that alter in a complex way the strength of H-bonds that contribute in stabilizing the chromophore within the protein scaffold. We show in particular the important role of histidine-149 in stabilizing the neutral trans chromophore at intermediate pH values, leading to ground-state cis-trans isomerization with a peculiar pH dependence. We discuss the potential implications of our findings on the pH dependence of the photoswitching contrast, a critical parameter in nanoscopy applications.


Nanoparticulate titanium dioxide-inhibited dendritic development is involved in apoptosis and autophagy of hippocampal neurons in offspring mice.
Background: Numerous studies have demonstrated that, upon maternal exposure, nano-TiO2 can cross the placental barrier, accumulate in offspring animals, and cause neurotoxicity. However, the neurotoxic mechanisms are not fully understood. The aim of this study is to determine the effects of nano-TiO2 on the dendritic outgrowth of hippocampal neurons and confirm the role of apoptosis and excessive autophagy in the neurotoxicity of offspring mice caused by nano-TiO2, as well as its molecular mechanisms. Methods: Pregnant mice were intragastrically administered 1, 2, or 3 mg per kg body weight nano-TiO2 consecutively from prenatal day 7 to postpartum day 21. The ultrastructure, mitochondrial membrane potential (MMP), levels of reactive oxygen species (ROS) and peroxides, and ATP contents, along with the expression of apoptosis- and autophagy-related factors, were investigated. Results: The dendritic length of hippocampal neurons was lower in the group treated with nano-TiO2 than in the control group. Apoptosis, excessive autophagy, and nano-TiO2 aggregation in hippocampal neurons resulted from maternal exposure to nano-TiO2. Maternal exposure to nano-TiO2 also resulted in the over-production of ROS, increases in malondialdehyde and protein carbonylation, reductions in MMP and ATP contents, up-regulation of apoptosis- or autophagy-related factors including histone H2AX at serine 139 (γH2AX), cytochrome C (Cyt C), caspase 3, phosphoinositide 3-kinase (PI3K3C), Beclin 1, c-Jun, LC3I, LC3II, JNK and p-JNK expression, and an increase of LC3II/LC3I, as well as down-regulation of Bcl-2 expression in hippocampal neurons of offspring mice. Conclusions: Maternal exposure to nano-TiO2 inhibited the dendritic outgrowth of hippocampal neurons. This effect is closely associated with excessive autophagy, which is related to severe oxidative stress and alterations in the expressions of apoptosis- and autophagy-related factors in the hippocampal neurons of offspring mice, due to maternal exposure to nano-TiO2.


Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis.
Gradients of signalling and transcription factors govern many aspects of embryogenesis, highlighting the need for spatiotemporal control of regulatory protein levels. MicroRNAs are phylogenetically conserved small RNAs that regulate the translation of target messenger RNAs, providing a mechanism for protein dose regulation. Here we show that microRNA-1-1 (miR-1-1) and miR-1-2 are specifically expressed in cardiac and skeletal muscle precursor cells. We found that the miR-1 genes are direct transcriptional targets of muscle differentiation regulators including serum response factor, MyoD and Mef2. Correspondingly, excess miR-1 in the developing heart leads to a decreased pool of proliferating ventricular cardiomyocytes. Using a new algorithm for microRNA target identification that incorporates features of RNA structure and target accessibility, we show that Hand2, a transcription factor that promotes ventricular cardiomyocyte expansion, is a target of miR-1. This work suggests that miR-1 genes titrate the effects of critical cardiac regulatory proteins to control the balance between differentiation and proliferation during cardiogenesis.


Gastrocnemius and soleus spasticity and muscle length in Friedreich's ataxia.
Lower limb spasticity compromises the independence of people with Friedreich's ataxia (FRDA). This study sought to examine lower limb spasticity in FRDA in order to offer new insight as to the best approach and timing of spasticity management. Gastrocnemius and soleus spasticity and muscle length were measured by the Modified Tardieu Scale (MTS) in 31 participants with typical and late-onset FRDA. Relationships between the MTS and the Friedreich Ataxia Rating Scale (FARS), Functional Independence Measure (FIM), and disease duration were analysed. Differences between ambulant (n=18) and non-ambulant (n=13) participants were also examined. All participants had spasticity in at least one muscle, and 38.9% of ambulant and 69.2% of non-ambulant participants had contracture in one or both of their gastrocnemius muscles. Significant negative correlations were found between both gastrocnemius and soleus angle of catch and the FARS score. The FIM score also demonstrated significant correlations with gastrocnemius muscle length and angle of catch. Gastrocnemius and soleus spasticity and contracture is apparent in people with FRDA. Spasticity is evident early in the disease and in ambulant participants. Management of spasticity and reduced muscle length should be considered in people with FRDA at disease onset to optimise function.


Sleep and circadian rhythm in response to the COVID-19 pandemic.
This commentary highlights the critical role of sleep as a public health issue, particularly during a stressful life period such as the COVID-19 pandemic, and provides evidence-based practical guidelines to manage sleep disturbances during this crisis. The COVID-19 pandemic and the imposed social confinement have produced significant stress, anxiety, and worries about health and the fear of being infected, jobs and financial problems, and uncertainty about the future. The incidence of sleep disturbances has also increased dramatically during this period. Aside from stress and anxiety, two other factors are likely to contribute to increased sleep disturbances during this crisis. First, alterations of our daily routines such as arising at a specific time, showing up at work, eating, exercising, and engaging in social and leisure activities at relatively fixed times are all important timekeepers for our sleep-wake cycles to remain synchronized with the day (light) and night (dark) cycles. Alterations of these timekeepers, combined with reduced daylight exposure, also essential to keep our biological clock synchronized, are likely to disrupt sleep and circadian rhythms. Sleep plays a fundamental role for mental and physical health, and adequate sleep duration and quality are essential for coping with major life events such as the COVID-19 pandemic. Public health education is warranted to keep the population well informed about the importance of sleep and healthy sleep practices in order to cope with the pandemic and prevent or minimize long-term adverse outcomes.


Effect of Contralateral Medial Olivocochlear Feedback on Perceptual Estimates of Cochlear Gain and Compression.
The active cochlear mechanism amplifies responses to low-intensity sounds, compresses the range of input sound intensities to a smaller output range, and increases cochlear frequency selectivity. The gain of the active mechanism can be modulated by the medial olivocochlear (MOC) efferent system, creating the possibility of top-down control at the earliest level of auditory processing. In humans, MOC function has mostly been measured by the suppression of otoacoustic emissions (OAEs), typically as a result of MOC activation by a contralateral elicitor sound. The exact relationship between OAE suppression and cochlear gain reduction, however, remains unclear. Here, we measured the effect of a contralateral MOC elicitor on perceptual estimates of cochlear gain and compression, obtained using the established temporal masking curve (TMC) method. The measurements were taken at a signal frequency of 2 kHz and compared with measurements of click-evoked OAE suppression. The elicitor was a broadband noise, set to a sound pressure level of 54 dB to avoid triggering the middle ear muscle reflex. Despite its low level, the elicitor had a significant effect on the TMCs, consistent with a reduction in cochlear gain. The amount of gain reduction was estimated as 4.4 dB on average, corresponding to around 18 % of the without-elicitor gain. As a result, the compression exponent increased from 0.18 to 0.27.


Fast and robust learning by reinforcement signals: explorations in the insect brain.
We propose a model for pattern recognition in the insect brain. Departing from a well-known body of knowledge about the insect brain, we investigate which of the potentially present features may be useful to learn input patterns rapidly and in a stable manner. The plasticity underlying pattern recognition is situated in the insect mushroom bodies and requires an error signal to associate the stimulus with a proper response. As a proof of concept, we used our model insect brain to classify the well-known MNIST database of handwritten digits, a popular benchmark for classifiers. We show that the structural organization of the insect brain appears to be suitable for both fast learning of new stimuli and reasonable performance in stationary conditions. Furthermore, it is extremely robust to damage to the brain structures involved in sensory processing. Finally, we suggest that spatiotemporal dynamics can improve the level of confidence in a classification decision. The proposed approach allows testing the effect of hypothesized mechanisms rather than speculating on their benefit for system performance or confidence in its responses.


Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 Macrodomain of SARS-CoV-2.
The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 152 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated protein dynamics within the active site, and key inhibitor motifs that will template future drug development against Mac1.


First Report of the Cyst Nematode (Heterodera elachista) on Rice in Hunan Province, China.
During a survey for the cyst nematodes (Heterodera elachista) from May to June of 2011, cyst nematodes were detected in hilly rice fields in five counties (Changsha, Pingjiang, Hengdong, Shaoyang, and Xiangxiang) of Hunan Province, China. Cyst nematodes obtained from soil samples and harvested rice root samples at these five locations had uniform morphological and molecular characteristics. Cysts (n = 20) had the following characteristics: spherical to lemon shaped, vulval cone ambifenestrate, vulval bridge narrow, medium sized underbridge, with a few dark brown bullae, body length (not including the neck) ranging from 354 to 586 μm (mean = 438.9 μm, st. dev. = 63.7); body width ranged from 283 to 495 μm (354.5, 60.1); fenestrate length of 30 to 50 μm (37.4, 5.0) and width of 25 to 47.5 μm (35.1, 7.1); underbridge length from 70 to 95 μm (83.4, 8.2); and vulval slit length from 30.3 to 55.5 μm (40.3, 9.1). J2 (n = 20) had the following characteristics: body length ranging from 404 to 525 μm (mean of 461.6 μm, st. dev. = 34.5); stylet length from 20 to 25 μm (22.5, 1.1) with rounded knob; tail length of 60 to 87.5 μm (67.3, 6.9); and hyaline terminal tail ranged from 30 to 50 μm (37.5, 6.4); lateral field with three lines. The mean and range of J2 were longer than those reported for H. elachista by Nobbs et al. (1) and Tanha et al. (4), but other morphological character values were within the range of those reported (4). DNA from a single cyst was extracted, the rDNA-internal transcribed spacer (ITS) and D2/D3 fragments of the 28S RNA were amplified with universal primers TW81 and AB28, D2A and D3B, respectively. Five ITS sequences (JN202913, JN202914, JN202915, JN202916, and JN202917) and five D2/D3 sequences (JN202918, JN202919, JN202920, JN202921, and JN202922) from nematode samples collected in Changsha, Hengdong, Shaoyang, Pingjiang, and Xiangxiang, respectively, were submitted to GenBank. These ITS sequences were remarkably similar to each other and exhibited 98.6 to 99.3% similarity with that of H. elachista isolate from Iran (AF498391), and 98.8 to 99.4% similarity with that of H. elachista isolates from Ningxia Province, China (HM560778 and HM560779). The D2/D3 sequences exhibited 99.7 to 100% similarity with that of H. elachista isolates from Ningxia Province, China (HM560842 and HM560843). These characteristics indicated that the five populations were H. elachista belonging to the 'cyperi' group (1,2). In glasshouse evaluations of the pathogenicity of these isolates, 500 second-stage juveniles were inoculated onto five 20-day-old seedlings of rice (Weiyou No.227) in 4.5-cm diameter 30-cm high tubes with six replicates. After 8 weeks, stunting and reduction of leaf length were observed and cysts were extracted from dried soil of each tube using sieves. Brown cysts (92 to 204) and white females (14 to 40) were obtained from inoculated rice from each tube. H. elachista can decrease yield by 7 to 19% and has the most severe impact during the later stages of plant growth (3). H. elachista has been previously identified from rice fields in Japan and Iran (3). To our knowledge, this is the first report of H. elachista on rice in Hunan Province, China. References: (1) J. M. Nobbs et al. Fundam. Appl. Nematol. 15:551, 1992. (2) S. A. Subbotin et al. Mol. Phylogenet. Evol. 21:1, 2001. (3) S. A. Subbotin et al. Systematics of Cyst Nematodes (Nematoda: Heteroderinae). Volume 8 Part B. Brill, Leiden, the Netherlands, 2010. (4) M. Z. Tanha et al. Nematology 5:99, 2003.


The interactive effects of stratospheric ozone depletion, UV radiation, and climate change on aquatic ecosystems.
This assessment summarises the current state of knowledge on the interactive effects of ozone depletion and climate change on aquatic ecosystems, focusing on how these affect exposures to UV radiation in both inland and oceanic waters. The ways in which stratospheric ozone depletion is directly altering climate in the southern hemisphere and the consequent extensive effects on aquatic ecosystems are also addressed. The primary objective is to synthesise novel findings over the past four years in the context of the existing understanding of ecosystem response to UV radiation and the interactive effects of climate change. If it were not for the Montreal Protocol, stratospheric ozone depletion would have led to high levels of exposure to solar UV radiation with much stronger negative effects on all trophic levels in aquatic ecosystems than currently experienced in both inland and oceanic waters. This "world avoided" scenario that has curtailed ozone depletion, means that climate change and other environmental variables will play the primary role in regulating the exposure of aquatic organisms to solar UV radiation. Reductions in the thickness and duration of snow and ice cover are increasing the levels of exposure of aquatic organisms to UV radiation. Climate change was also expected to increase exposure by causing shallow mixed layers, but new data show deepening in some regions and shoaling in others. In contrast, climate-change related increases in heavy precipitation and melting of glaciers and permafrost are increasing the concentration and colour of UV-absorbing dissolved organic matter (DOM) and particulates. This is leading to the "browning" of many inland and coastal waters, with consequent loss of the valuable ecosystem service in which solar UV radiation disinfects surface waters of parasites and pathogens. Many organisms can reduce damage due to exposure to UV radiation through behavioural avoidance, photoprotection, and photoenzymatic repair, but meta-analyses continue to confirm negative effects of UV radiation across all trophic levels. Modeling studies estimating photoinhibition of primary production in parts of the Pacific Ocean have demonstrated that the UV radiation component of sunlight leads to a 20% decrease in estimates of primary productivity. Exposure to UV radiation can also lead to positive effects on some organisms by damaging less UV-tolerant predators, competitors, and pathogens. UV radiation also contributes to the formation of microplastic pollutants and interacts with artificial sunscreens and other pollutants with adverse effects on aquatic ecosystems. Exposure to UV-B radiation can decrease the toxicity of some pollutants such as methyl mercury (due to its role in demethylation) but increase the toxicity of other pollutants such as some pesticides and polycyclic aromatic hydrocarbons. Feeding on microplastics by zooplankton can lead to bioaccumulation in fish. Microplastics are found in up to 20% of fish marketed for human consumption, potentially threatening food security. Depletion of stratospheric ozone has altered climate in the southern hemisphere in ways that have increased oceanic productivity and consequently the growth, survival and reproduction of many sea birds and mammals. In contrast, warmer sea surface temperatures related to these climate shifts are also correlated with declines in both kelp beds in Tasmania and corals in Brazil. This assessment demonstrates that knowledge of the interactive effects of ozone depletion, UV radiation, and climate change factors on aquatic ecosystems has advanced considerably over the past four years and confirms the importance of considering synergies between environmental factors.


Hepatitis B vaccination practices in hospital newborn nurseries before and after changes in vaccination recommendations.
Routine use of hepatitis B vaccine for low-risk newborns was suspended on July 7, 1999, because of concern about the potential risk of thimerosal, a mercury-containing vaccine preservative. Reinstatement of the birth dose was recommended when a thimerosal-free vaccine became available. To explore changes in hepatitis B vaccination practices for newborns related to the revised recommendations for low-risk infants (in this study, the terms newborn and infant are used interchangeably). A telephone survey of a random sample of 1000 US hospitals. Nurse managers, nursery directors, and staff nurses of the newborn nurseries. Nursery vaccination practices before and after July 7, 1999, and the availability and use of thimerosal-free vaccine. Interviews were conducted with 773 (87%) of 886 eligible hospitals. Before July 7, 1999, 78% of the hospitals reported vaccination practices that were consistent with recommendations at that time, although only 47% vaccinated all low-risk infants at birth. After July 7, 1999, almost all hospitals discontinued vaccination of low-risk infants, in accordance with the recommendation change; however, there was a 6-fold increase in the number of hospitals that were not vaccinating all high-risk infants. After the introduction of thimerosal-free vaccine, only 39% of the hospitals reported vaccinating all low-risk infants. Most hospital nurseries altered their newborn hepatitis B vaccination practices consistent with changes in national recommendations. However, unintended consequences included the failure of some hospitals to continue vaccinating all high-risk infants and the delay in reintroducing vaccination for low-risk newborns after the introduction of a thimerosal-free vaccine. Assessments of the appropriateness of this country's response to the threat of thimerosal in vaccines should consider these findings.


Influence of the 5A's Counseling Strategy on Weight Gain During Pregnancy: An Observational Study.
Healthy weight gain during pregnancy may improve health outcomes for women and infants. The objective of this study was to examine providers' use of the 5A's (Assess, Advise, Agree, Assist, and Arrange) in discussions of weight, nutrition, and physical activity during prenatal visits and evaluate the effect of this approach on gestational weight gain. We studied audio recordings of prenatal visits between 22 obstetrics providers and 120 of their patients, coding visits for providers' use of the 5A's. The relationship between the 5A's and gestational weight gain (total weight gain and excess gestational weight gain) was evaluated using multilevel models to account for patient clustering within provider, and adjusted for prepregnancy body mass index, parent study intervention assignment, gestational age at the study visit, and study visit length. Overall, 55% of prenatal visits included any weight-related behavioral counseling. Of these, 59.1% included one of the 5A's and 40.9% included two or more of the 5A's. Counseling conversations most commonly included Assess or Advise (49% and 85% of counseling conversations, respectively). No recorded visits used all 5A's. In adjusted analyses, patients who received counseling with two or more of the 5A's gained an average of 11.8 fewer pounds than patients who received no counseling (p = 0.001). The odds of excess gestational weight gain were lower among women receiving counseling with at least one of the 5A's (p < 0.05). The 5A's were associated with lower gestational weight gain and may be a promising counseling strategy to promote healthy weight gain during pregnancy.


Association Between Maternal Prepregnancy Body Mass Index and Plasma Folate Concentrations With Child Metabolic Health.
Previous reports have linked maternal prepregnancy obesity with low folate concentrations and child overweight or obesity (OWO) in separate studies. To our knowledge, the role of maternal folate concentrations, alone or in combination with maternal OWO, in child metabolic health has not been examined in a prospective birth cohort. To test the hypotheses that maternal folate concentrations can significantly affect child metabolic health and that sufficient maternal folate concentrations can mitigate prepregnancy obesity-induced child metabolic risk. This prospective birth cohort study was conducted at the Boston Medical Center, Boston, Massachusetts. It included 1517 mother-child dyads recruited at birth from 1998 to 2012 and followed up prospectively up to 9 years from 2003 to 2014. Child body mass index z score calculated according to US reference data, OWO defined as a body mass index in the 85th percentile or greater for age and sex, and metabolic biomarkers (leptin, insulin, and adiponectin). The mean (SD) age was 28.6 (6.5) years for mothers and 6.2 (2.4) years for the children. An L-shaped association between maternal folate concentrations and child OWO was observed: the risk for OWO was higher among those in the lowest quartile (Q1) as compared with those in Q2 through Q4, with an odds ratio of 1.45 (95% CI, 1.13-1.87). The highest risk for child OWO was found among children of obese mothers with low folate concentrations (odds ratio, 3.05; 95% CI, 1.91-4.86) compared with children of normal-weight mothers with folate concentrations in Q2 through Q4 after accounting for multiple covariables. Among children of obese mothers, their risk for OWO was associated with a 43% reduction (odds ratio, 0.57; 95% CI, 0.34-0.95) if their mothers had folate concentrations in Q2 through Q4 compared with Q1. Similar patterns were observed for child metabolic biomarkers. In this urban low-income prospective birth cohort, we demonstrated an L-shaped association between maternal plasma folate concentrations and child OWO and the benefit of sufficient folate concentrations, especially among obese mothers. The threshold concentration identified in this study exceeded the clinical definition of folate deficiency, which was primarily based on the hematological effect of folate. Our findings underscore the need to establish optimal rather than minimal folate concentrations for preventing adverse metabolic outcomes in the offspring.


Reteplase: a review of its use in the management of thrombotic occlusive disorders.
Reteplase (Retavase) is a plasminogen activator, mimicking endogenous tissue plasminogen activator (t-PA), a serine protease, converting plasminogen to plasmin and thereby precipitating thrombolysis. It is a third-generation recombinant form of t-PA that operates in the presence of fibrin (i.e. it is fibrin specific). Reteplase can be administered as a bolus dose (nonweight-based) rather than an infusion, which promotes rapid and safe administration. The ease of administration of this reteplase dosage regimen (two 10U bolus doses, each over 2 minutes, 30 minutes apart) is conducive to prehospital initiation of thrombolytic treatment in patients with ST-segment elevation myocardial infarction (STEMI), which reduces the time to treatment, a critical factor in improving long-term survival. In large randomized clinical trials of patients with STEMI, reteplase was superior to alteplase for coronary artery patency (according to TIMI [thrombolysis in myocardial infarction] flow) at 60 and 90 minutes, but there was no significant difference between agents for mortality rate and incidence of intracranial bleeding. The 35-day mortality rates were equivalent for reteplase and streptokinase recipients; there was reduced incidence of some cardiac events with reteplase versus streptokinase, but a greater incidence of hemorrhagic stroke. Reteplase has also shown thrombolytic efficacy (in nonapproved indications) as a catheter-directed intra-arterial or intravenous infusion for peripheral vessel occlusions, as 5-minute bolus doses (in 1U increments) for acute ischemic stroke, as a low-dose solution for occluded catheters or grafts, and as an intravenous double bolus for massive pulmonary embolism. Across studies in these indications, the incidence of bleeding complications associated with reteplase treatment appeared to be similar to that associated with other thrombolytic agents. With its efficacy, and the ease of administration of the bolus doses potentially minimizing dosage errors when treatment is administered under time pressure, reteplase is a valuable option for pre- or in-hospital thrombolytic treatment in patients with STEMI, and is a useful thrombolytic for the treatment of the other thrombotic occlusive disorders described.


Comparison of physical therapy with energy healing for improving range of motion in subjects with restricted shoulder mobility.
Two forms of energy healing, Reconnective Healing (RH) and Reiki, which involve light or no touch, were tested for efficacy against physical therapy (PT) for increasing limited range of motion (ROM) of arm elevation in the scapular plane. Participants were assigned to one of 5 groups: PT, Reiki, RH, Sham Healing, or no treatment. Except for no treatment, participants were blinded as to grouping. Range of Motion, self-reported pain, and heart rate variability (HRV) were assessed before and after a 10-minute session. On average, for PT, Reiki, RH, Sham Healing, and no treatment, respectively, ROM increased by 12°, 20°, 26°, 0.6°, and 3° and pain score decreased by 11.5%, 10.1%, 23.9%, 15.4%, and 0%. Physical therapy, Reiki, and RH were more effective than Sham Healing for increasing ROM (PT: F = 8.05, P = 0.008; Reiki: F = 10.48, P = 0.003; RH: F = 30.19, P < 0.001). It is possible that this improvement was not mediated by myofascial release because the subjects' HRV did not change, suggesting no significant increase in vagal activity. Sham treatment significantly reduced pain compared to no treatment (F = 8.4, P = 0.007) and was just as effective as PT, Reiki, and RH. It is the authors' opinion that the accompanying pain relief is a placebo effect.


Influence of Sociodemographic Factors and Provider Specialty on Anticoagulation Prescription Fill Patterns and Outcomes in Atrial Fibrillation.
Early cardiology involvement after atrial fibrillation (AF) diagnosis is associated with increased oral anticoagulant prescription fills and reduced stroke risk. It is unknown if this association varies by race, sex, or education. We examined anticoagulant fills in 223,891 patients with incident nonvalvular AF (mean age = 71 years; 44% women; 84% white; 9% black; 5% Hispanic; 2% Asian) from the Optum Clinformatics database (2009 to 2014). Provider specialty and filled anticoagulant prescriptions 3 months before and 6 months after AF diagnosis were obtained. Poisson regression was used to compute the probability of oral anticoagulant prescription fill and Cox regression was used to estimate the risk of stroke and major bleeding. Cardiology involvement was less likely among nonwhites (white = Referent; black = relative risk = 0.96, 95% confidence interval (0.95 to 0.97); Hispanic = 0.99 (0.98 to 1.00); Asian = 0.95 (0.93 to 0.97)) and women (0.92 (0.91 to 0.93)), but more likely with higher education level (high school or less = Referent; some college = 1.03 (1.02 to 1.04); college or more = 1.08 (1.07 to 1.09)). Patients seen by cardiology providers were more likely to fill anticoagulant prescriptions (Any = 1.67 (1.64 to 1.69); direct oral anticoagulants = 2.59 (2.49 to 2.68); warfarin = 1.38 (1.35 to 1.41)) compared with patients not seen by a cardiology provider. Patients seen by a cardiologist had a reduced stroke risk (hazard ratio = 0.84 (0.79 to 0.88)) and similar bleeding risk (1.01 (0.96 to 1.06)). Outcomes did not vary by race, sex, or education level. In conclusion, although race, sex, and education differences exist in early cardiology involvement after AF diagnosis, the influence of cardiology involvement on anticoagulant prescription fills and AF-related outcomes does not vary by these factors. Initiatives to improve early cardiology referral in nonwhites, women, and those with lower educational attainment may improve AF outcomes.


Current role of multiparametric magnetic resonance imaging in the management of prostate cancer.
The purpose of this review was to evaluate the current role of multiparametric magnetic resonance imaging (mp-MRI) in the management of prostate cancer (PC). The diagnosis of PC remains controversial owing to overdetection of indolent disease, which leads to overtreatment and subsequent patient harm. mp-MRI has the potential to equilibrate the imbalance between detection and treatment. The limitation of the data for analysis with this new technology is problematic, however. This issue has been compounded by a paradigm shift in clinical practice aimed at utilizing this modality, which has been rolled out in an ad hoc fashion often with commercial motivation. Despite a growing body of literature, pertinent clinical questions remain. For example, can mp-MRI be calibrated to reliably detect biologically significant disease? As with any new technology, objective evaluation of the clinical applications of mp-MRI is essential. The focus of this review was on the evaluation of mp-MRI of the prostate with respect to clinical utility.


Cancer Survivors' Use of Fertility Preservation.
Some cancer diagnoses and treatments can place patients at risk for infertility. The American Society of Clinical Oncology recommends that health care providers address the possibility of infertility with cancer patients who are treated during their reproductive years; however, research suggests that many providers do not disclose the risk of infertility to their patients. This study examines adolescent/young adult (AYA) cancer survivors' use of and costs for fertility preservation (FP) over time. The study included 550 AYA cancer survivors diagnosed at the ages of 15 and 39 years between 2006 and 2012. Logistic regression analyses and chi-squared tests were conducted to identify factors associated with FP use, barriers, and expenses. One hundred eighty two (33%) of the AYA survivors took steps to preserve their fertility. Men, survivors who did not have children, those who received chemotherapy, and those who lived in the Northeast (vs. the South) were more likely to have FP. The majority of men using FP used sperm banking (99%), whereas women used egg preservation (40%), embryo preservation (40%), and other methods (37%). On average, women paid more for FP than men (p < 0.001); however, costs for women significantly declined over time (p = 0.021). The study points to other areas for research in women's health, including the development of educational interventions with patients and providers to reduce gender disparities in FP and ensure timely patient-provider discussions related to fertility issues.


Serial reversal learning and the evolution of behavioral flexibility in three species of North American corvids (Gymnorhinus cyanocephalus, Nucifraga columbiana, Aphelocoma californica).
In serial reversal learning, subjects learn to respond differentially to 2 stimuli. When the task is fully acquired, reward contingencies are reversed, requiring the subject to relearn the altered associations. This alternation of acquisition and reversal can be repeated many times, and the ability of a species to adapt to this regimen has been considered as an indication of behavioral flexibility. Serial reversal learning of 2-choice discriminations was contrasted in 3 related species of North American corvids: pinyon jays (Gymnorhinus cyanocephalus), which are highly social; Clark's nutcrackers (Nucifraga columbiana), which are relatively solitary but specialized for spatial memory; and western scrub jays (Aphelocoma californica), which are ecological generalists. Pinyon jays displayed significantly lower error rates than did nutcrackers or scrub jays after reversal of reward contingencies for both spatial and color stimuli. The effect was most apparent in the 1st session following each reversal and did not reflect species differences in the rate of initial discrimination learning. All 3 species improved their performance over successive reversals and showed significant transfer between color and spatial tasks, suggesting a generalized learning strategy. The results are consistent with an evolutionary association between behavioral flexibility and social complexity.


Subtype-selective expression of the five somatostatin receptors (hSSTR1-5) in human pancreatic islet cells: a quantitative double-label immunohistochemical analysis.
We have developed a panel of rabbit polyclonal antipeptide antibodies against the five human somatostatin receptor subtypes (hSSTR1-5) and used them to analyze the pattern of expression of hSSTR1-5 in normal human islet cells by quantitative double-label confocal fluorescence immunocytochemistry. All five hSSTR subtypes were variably expressed in islets. The number of SSTR immunopositive cells showed a rank order of SSTR1 > SSTR5 > SSTR2 > SSTR3 > SSTR4. SSTR1 was strongly colocalized with insulin in all beta-cells. SSTR5 was also an abundant isotype, being colocalized in 87% of beta-cells. SSTR2 was found in 46% of beta-cells, whereas SSTR3 and SSTR4 were relatively poorly expressed. SSTR2 was strongly colocalized with glucagon in 89% of alpha-cells, whereas SSTR5 and SSTR1 colocalized with glucagon in 35 and 26% of alpha-cells, respectively. SSTR3 was detected in occasional alpha-cells, and SSTR4 was absent. SSTR5 was preferentially expressed in 75% of SST-positive cells and was the principal delta-cell SSTR subtype, whereas SSTR1-3 were colocalized in only a few delta-cells, and SSTR4 was absent. These studies reveal predominant expression of SSTR1, SSTR2, and SSTR5 in human islets. Beta-cells, alpha-cells, and delta-cells each express multiple SSTR isoforms, beta-cells being rich in SSTR1 and SSTR5, alpha-cells in SSTR2, and delta-cells in SSTR5. Although there is no absolute specificity of any SSTR for an islet cell type, SSTR1 is beta-cell selective, and SSTR2 is alpha-cell selective. SSTR5 is well expressed in beta-cells and delta-cells and moderately well expressed in alpha-cells, and thereby it lacks the islet cell selectivity displayed by SSTR1 and SSTR2. Subtype-selective SSTR expression in islet cells could be the basis for preferential insulin suppression by SSTR1-specific ligands and of glucagon inhibition by SSTR2-selective compounds.


Single chip SPR and fluorescent ELISA assay of prostate specific antigen.
A multi-channel system combining fluidics and micropatterned plasmonic materials with wavelength interrogation surface plasmon resonance (SPR) and fluorescence detection was integrated from the combination of a small and motorized fluorescence microscope mounted on a portable 4-channel SPR instrument. The SPR and fluorescent measurements were performed based on the same detection area in a multi-channel fluidic, with a sensing scheme for prostate-specific antigen (PSA) consisting of a sandwich assay with a capture anti-PSA immobilized onto the SPR sensor and a detection anti-PSA modified with horseradish peroxidase (HRP). In this dual-detection instrument, fluorescence was measured from the solution side of the micropatterned gold film, while the interface between the glass prism and the gold film served to interrogate the SPR response. The SPR sensors were comprised of microhole arrays fabricated by photolithography to enhance the instrumental response for PSA detection by approximately a factor of 2 to 3 and they were coated with a self-assembled monolayer of a peptide (3-MPA-HHHDD-OH) to minimize nonspecific adsorption. PSA was successfully detected at clinical concentrations from 10 pM to 50 nM with this integrated system in a single assay lasting 12 minutes, almost centering on the desired range for PSA diagnostic tests (>4 ng mL(-1) or >150 pM). The combination of two robust techniques in a single chip and instrument has led to a simple and effective assay that can be carried out on a small and portable instrument providing rapid biodetection of an important cancer biomarker with a dynamic range of nearly 4 orders of magnitude in the clinical range.


Exploring the behaviour of the hydrated excess proton at hydrophobic interfaces.
The affinity of the excess proton for the aqueous solution-hydrophobic interface was examined for two specific examples, the air-water and hydrophobic wall-water cases, using a multiconfigurational molecular dynamics algorithm. The use of a reactive simulation method is important as it allows for a realistic description of the excess proton, namely, its propensity to hop between water molecules via the Grotthuss mechanism. The free energy profile reveals a minimum at these interfaces due to a favourable enthalpic term that outweighs the entropic penalty. The key factors that contribute to this enthalpic minimum were examined using a generalization of a scheme that decomposes the interaction energy into separate terms arising from various local environments [Otten et al., Proc. Natl. Acad. Sci. USA, 109, 701 (2012)] (coordination shell, bulk, and interface) and the delocalization energy (which allows the proton to hop). For both systems, it was observed that the energetic penalty for loss of coordinating water molecules as the excess proton moves toward the hydrophobic interface is more than compensated by the displacement of unfavourable interfacial water molecules. In addition, the ion becomes more delocalized, more Zundel-like, and therefore possesses a larger effective radius as it moves to the interface. The fluctuations of the instantaneous interface were reduced near the vicinity of the ion, thereby giving rise to an entropic penalty. This paper will discuss the application of energy decomposition schemes to multiconfigurational simulations and the resulting consequences realized for the excess proton at hydrophobic interfaces.


Patterns of care in the initial management of women with ovarian cancer in Ontario.
To facilitate the planning of future resources for cancer services in Ontario, Cancer Care Ontario commissioned an evaluation of operative services delivered for ovarian cancers. The affected population was characterized in terms of age, location of residence, and SES. Operative care delivery was described in terms of inpatient verses outpatient access, LHIN of treatment, surgical specialist providing treatment, and specific operative procedures. The investigations and consults around the time of diagnosis are described. Women with an incident diagnosis of an ovarian malignancy were identified from 1 April 2003 to 31 March 2004 using the Ontario Cancer Registry. Record linkages were created to other provincial health databases such as the Ontario Health Insurance Plan. We report on 963 women with ovarian cancer. The incidence of disease was related to increasing age. Access to surgery correlated with the highest income quintile, urban residence and LHIN. Twenty-seven percent of women did not have surgery for their ovarian cancer. Women of younger age were more like to receive surgery for ovarian cancer. Use of a laparotomy for biopsy was most common in community hospital (40%). Lymphadenectomy rates were low overall; rates for gynecologic oncologists were 13.2%. All women were assessed by CXR. CT scan of abdomen and pelvis occurred in 77% of women. MRIs were done infrequently. Medical oncology were involved in 26.6% of the patients. These pilot data would be enhanced with further information such as comorbidity, treatment intent (palliative/curative), histology, grade and stage. However, there are clear referral patterns to academic centres which means a need for manpower and hospital resources to deal with this population.