Short sleep duration and obesity among Australian children.
There is limited information on sleep duration and obesity among Australian children. The objective of the study is to cross-sectionally examine the relationship between sleep duration and obesity in Australian children aged 5 to 15 years. Data were collected using the South Australian Monitoring and Surveillance System between January 2004 and December 2008. Each month a representative random sample of South Australians are selected from the Electronic White Pages with interviews conducted using Computer Assisted Telephone Interviewing (CATI). Within each household, the person who was last to have a birthday was selected for interview. Parents reported the number of hours their children slept each day. Obesity was defined according to the International Obesity Task Force (IOTF) definition based on BMI calculated from reported body weight and height. Overall, parents of 3495 children aged 5-15 years (mean 10.7 years, 50.3% boys) were interviewed. The prevalence of obesity was 7.7% (8.9% in boys, 6.6% in girls). In multivariate analysis after adjusting for sociodemographic variables, intake of fruit and vegetables, physical activity and inactivity, the odds ratio (OR) for obesity comparing sleeping <9 hours with ≥10 hours was 2.23 (95% CI 1.04-4.76) among boys, 1.70(0.78-3.73) among girls, and 1.97(1.15-3.38) in both genders. The association between short sleep (<9 hours) and obesity was stronger in the younger age group. No significant association between short sleep and obesity was found among children aged 13-15. There was also an additive interaction between short sleep and low level of physical activity. Short sleep duration is associated with increased obesity in children especially among younger age groups and boys.


Bioassay of 3-chloro-p-toluidine for possible carcinogenicity.
A bioassay for the possible carcinogenicity of 3-chloro-p-toluidine was conducted using Fischer 344 rats and B6C3F1 mice. 3-Chloro-p-toluidine was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Twenty animals of each sex and species were placed on test as controls. The time-weighted average dietary concentrations of 3-chloro-p-toluidine administered to rats of both sexes were 3,269 and 1,635 ppm for the high and low dose groups, respectively. The high and low dietary concentrations of 3-chloro-p-toluidine administered to mice were, respectively, 1,200 and 600 ppm for males and 600 and 300 ppm for females. The compound was administered in the diet for 78 weeks, followed by an observation period of 24 weeks for high dose male rats, 25 weeks for all other dosed rats, and 12 weeks for mice. There were no significant positive associations between the concentrations of 3-chloro-p-toluidine administered and mortality in either species. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Mean body weight depression, relative to controls, was observed in high dose rats and mice of both sexes, indicating that the concentrations administered to these animals may have approximated the maximum tolerated dosages. The unusual incidences of nonneoplastic spleen and liver lesions in high dose rats supports this assumption. Under the conditions of this bioassay there was no convincing evidence for the carcinogenicity of 3-chloro-p-toluidine in Fischer 344 rats or B6C3F1 mice.


Dead space estimates may not be independently associated with 28-day mortality in COVID-19 ARDS.
Estimates for dead space ventilation have been shown to be independently associated with an increased risk of mortality in the acute respiratory distress syndrome and small case series of COVID-19-related ARDS. Secondary analysis from the PRoVENT-COVID study. The PRoVENT-COVID is a national, multicenter, retrospective observational study done at 22 intensive care units in the Netherlands. Consecutive patients aged at least 18 years were eligible for participation if they had received invasive ventilation for COVID-19 at a participating ICU during the first month of the national outbreak in the Netherlands. The aim was to quantify the dynamics and determine the prognostic value of surrogate markers of wasted ventilation in patients with COVID-19-related ARDS. A total of 927 consecutive patients admitted with COVID-19-related ARDS were included in this study. Estimations of wasted ventilation such as the estimated dead space fraction (by Harris-Benedict and direct method) and ventilatory ratio were significantly higher in non-survivors than survivors at baseline and during the following days of mechanical ventilation (p < 0.001). The end-tidal-to-arterial PCO2 ratio was lower in non-survivors than in survivors (p < 0.001). As ARDS severity increased, mortality increased with successive tertiles of dead space fraction by Harris-Benedict and by direct estimation, and with an increase in the VR. The same trend was observed with decreased levels in the tertiles for the end-tidal-to-arterial PCO2 ratio. After adjustment for a base risk model that included chronic comorbidities and ventilation- and oxygenation-parameters, none of the dead space estimates measured at the start of ventilation or the following days were significantly associated with 28-day mortality. There is significant impairment of ventilation in the early course of COVID-19-related ARDS but quantification of this impairment does not add prognostic information when added to a baseline risk model. ISRCTN04346342. Registered 15 April 2020. Retrospectively registered.


Two- and three-year-olds infer and reason about design intentions in order to categorize broken objects.
In naming artifacts, do young children infer and reason about the intended functions of the objects? Participants between the ages of 2 and 4 years were shown two kinds of objects derived from familiar categories. One kind was damaged so as to undermine its usual function. The other kind was also dysfunctional, but made so by adding features that appeared to be intentional. Evidence that 2-, 3- and 4-year-olds were more likely to apprehend the broken objects than the intentionally dysfunctional objects as members of the familiar lexical categories favors the conclusion that, in naming, children may spontaneously infer and reason about design intentions from an early age. This is the first evidence that 2- and 3-year-olds not only take design intentions into account in object categorization, but that they do so even without explicit mention of the objects' accidental or intentional histories. The results cast doubt on a proposal that young children's lexical categorization is based on automatic, non-deliberative processes.


Separation of AG function in floral meristem determinacy from that in reproductive organ identity by expressing antisense AG RNA.
The Arabidopsis floral homeotic gene AGAMOUS (AG) is a regulator of early flower development. The ag mutant phenotypes suggest that AG has two functions in flower development: (1) specifying the identity of stamens and carpels, and (2) controlling floral meristem determinacy. To dissect these two AG functions, we have generated transgenic Arabidopsis plants carrying an antisense AG construct. We found that all of the transgenic plants produced abnormal flowers, which can be classified into three types. Type I transgenic flowers are phenocopies of the ag-1 mutant flowers, with both floral meristem indeterminacy and floral organ conversion; type II flowers are indeterminate and have partial conversion of the reproductive organs; and type III flowers have normal stamens and carpels, but still have an indeterminate floral meristem inside the fourth whorl of fused carpels. The existence of type III flowers indicates that AG function can be perturbed to affect only floral meristem determinacy, but not floral organ identity. Furthermore, the fact that floral meristem determinacy is affected in all transformants, but floral organ identity only in a subset of them, suggests that the former may required a higher level of AG activity than the latter. This hypothesis is supported by the levels of AG mRNA detected in different transformants with different frequencies of distinct types of abnormal antisense AG transgenic flowers. Finally, since AG inhibits the expression of another floral regulatory gene AP1, we examined AP1 expression in antisense AG flowers, and found that AP1 is expressed at a relatively high level in the center of type II flowers, but very little or below detectable levels in the inner whorls of type III flowers. These results provide further insights into the interaction of AG and AP1 and how such an interaction may control both organ identity and floral meristem determinacy.


Non-heart-beating versus cadaveric and living-donor livers: differences in inflammatory markers before transplantation.
Liver transplantation from non-heart-beating donors (NHBD) has been reintroduced into clinical practice to increase the donor pool; however, little is known about the immune status of NHBD livers. The aim of this study was to assess intragraft cell populations and inflammatory markers in NHBD and to compare the findings with cadaveric and living-related donor (LRD) livers. Biopsy specimens were obtained from controlled NHBD (n=9), conventional cadaveric (n=22), and living-donor (n=10) livers at the end of cold storage. Cryostat sections were stained for monocytes-macrophages, T lymphocytes, and intercellular adhesion molecule (ICAM)-1. The levels of leukocyte infiltration in NHBD reflected those found in conventional cadaver donors and were significantly higher than in LRD livers. Similar levels of CD68+ monocytes-macrophages were detected in cadaver (4.0+/-1.2%) and NHBD livers (4.6+/-1.2%) and were significantly greater than in the LRD livers (2.6+/-0.5%, P<0.01). Furthermore, the levels of T lymphocytes in NHBD (1.1+/-0.6%) and cadaver donors (1.5+/-0.8%) were similar, and were higher than in LRD (vs. 0.47+/-0.3%, P<0.05). Twelve of 22 (60%) cadaver livers had high levels of ICAM-1 expression (grade 3), compared with only 1 of 10 (10%) LRD livers (P=0.02). Four of nine (44%) controlled NHBD livers expressed high levels of ICAM-1. The results demonstrate that livers obtained from controlled NHBD before transplantation are similar to conventional cadaver donors regarding the level of leukocyte infiltration. Nevertheless, lower levels of ICAM-1 were detected in NHBD, suggesting less exposure to inflammatory mediators than conventional cadaver donor livers.


Advocating a Paradigm Shift in Health-State Valuations: The Estimation of Time-Preference Corrected QALY Tariffs.
Despite evidence of nonproportional trade-offs in time trade-off exercises and the explicit incorporation of exponential discounting in health technology assessment calculations, quality-adjusted life-year (QALY) tariffs are currently still established under the assumption of linear time preferences. The aim of this study was to introduce a general method of accommodating for nonlinear time preferences in discrete choice experiment (DCE) duration studies and to evaluate its impact on estimated QALY tariffs. A parsimonious utility function is proposed that accommodates any discounting function and preserves linear time preferences as a special case. Based on an efficient DCE design and 1775 respondents from a nationally representative scientific household panel, preferences and QALY tariffs for the Dutch SF-6D were estimated while accommodating for nonlinear time preferences via exponential and hyperbolic discounting functions. When the discount rate was estimated directly, we found strong evidence of nonlinear time preferences (with an exponential and hyperbolic discount rate of 5.7% and 16.5%, respectively). When the discount rate was estimated as a function of health state severity, we found that years lived in better health states are discounted minus years lived in impaired health states. Finally, the best statistical fit was obtained when using a hyperbolic discount function, which resulted in smaller QALY decrements and fewer health states classified as worse than immediate death. Our results highlight the relevance and even necessity of a paradigm shift in health valuation studies in favor of time-preference corrected QALY tariffs, with potentially important implications for health technology assessment calculations and regulatory decisions.


Use of robotic colonoscopy in patients with previous incomplete colonoscopy.
Conventional colonoscopy (CC) is the gold standard to diagnostic and therapeutic approach to colon. However, in few cases, cecal intubation could fail due to colon anatomy, patient compliance and physician expertise. Endotics robotic colonoscopy is a novel, safe, mini-invasive modality to explore the entire colon. Our aim was to assess, in a retrospective study, Endotics ability of cecal intubation in all cases in which CC failed. Between January 2008 and December 2012, 276 Endotics robotic colonscopy examinations were performed at the Gastroenterology and Metabolic Diseases Unit of Pisa University Hospital, Pisa, Italy, in a series of consecutive patients who had undergone CC and failed cecal intubation. We assessed the cecal intubation rate in 102 patients addressed to Endotics after previous incomplete CC. Overall, endotics system was successful in 93.1% of the incomplete conventional colonoscopy cases (95% performance). Whenever the intended exploration of the entire colon with CC failed, the endotics robotic endoscopy represented a useful tool as it helped examine the entire colon in almost all cases.


On the diverse roles of fluid dynamic drag in animal swimming and flying.
Questions of energy dissipation or friction appear immediately when addressing the problem of a body moving in a fluid. For the most simple problems, involving a constant steady propulsive force on the body, a straightforward relation can be established balancing this driving force with a skin friction or form drag, depending on the Reynolds number and body geometry. This elementary relation closes the full dynamical problem and sets, for instance, average cruising velocity or energy cost. In the case of finite-sized and time-deformable bodies though, such as flapping flyers or undulatory swimmers, the comprehension of driving/dissipation interactions is not straightforward. The intrinsic unsteadiness of the flapping and deforming animal bodies complicates the usual application of classical fluid dynamic forces balance. One of the complications is because the shape of the body is indeed changing in time, accelerating and decelerating perpetually, but also because the role of drag (more specifically the role of the local drag) has two different facets, contributing at the same time to global dissipation and to driving forces. This causes situations where a strong drag is not necessarily equivalent to inefficient systems. A lot of living systems are precisely using strong sources of drag to optimize their performance. In addition to revisiting classical results under the light of recent research on these questions, we discuss in this review the crucial role of drag from another point of view that concerns the fluid-structure interaction problem of animal locomotion. We consider, in particular, the dynamic subtleties brought by the quadratic drag that resists transverse motions of a flexible body or appendage performing complex kinematics, such as the phase dynamics of a flexible flapping wing, the propagative nature of the bending wave in undulatory swimmers, or the surprising relevance of drag-based resistive thrust in inertial swimmers.


Modeling autism: a systems biology approach.
Autism is the fastest growing developmental disorder in the world today. The prevalence of autism in the US has risen from 1 in 2500 in 1970 to 1 in 88 children today. People with autism present with repetitive movements and with social and communication impairments. These impairments can range from mild to profound. The estimated total lifetime societal cost of caring for one individual with autism is $3.2 million US dollars. With the rapid growth in this disorder and the great expense of caring for those with autism, it is imperative for both individuals and society that techniques be developed to model and understand autism. There is increasing evidence that those individuals diagnosed with autism present with highly diverse set of abnormalities affecting multiple systems of the body. To this date, little to no work has been done using a whole body systems biology approach to model the characteristics of this disorder. Identification and modelling of these systems might lead to new and improved treatment protocols, better diagnosis and treatment of the affected systems, which might lead to improved quality of life by themselves, and, in addition, might also help the core symptoms of autism due to the potential interconnections between the brain and nervous system with all these other systems being modeled. This paper first reviews research which shows that autism impacts many systems in the body, including the metabolic, mitochondrial, immunological, gastrointestinal and the neurological. These systems interact in complex and highly interdependent ways. Many of these disturbances have effects in most of the systems of the body. In particular, clinical evidence exists for increased oxidative stress, inflammation, and immune and mitochondrial dysfunction which can affect almost every cell in the body. Three promising research areas are discussed, hierarchical, subgroup analysis and modeling over time. This paper reviews some of the systems disturbed in autism and suggests several systems biology research areas. Autism poses a rich test bed for systems biology modeling techniques.


Effect of the H1N1 influenza pandemic on the incidence of epidemic keratoconjunctivitis and on hygiene behavior: a cross-sectional study.
EKC is transmitted chiefly by direct hand contact. It is suspected that the 2009/2010 influenza pandemic influenced hand washing. This study aims to examine the relationship between the 2009/2010 H1N1 influenza pandemic and hygiene behavior. We compared the EKC prevalence trends before, during and after the 2009/2010 influenza pandemic by using a t-test comparison of EKC sentinel surveillance. During the pre-pandemic period, the incidence of EKC increased from the 21st to the 44th week each year. However, during the pandemic period in 2009, there was no epidemic peak. In the post-pandemic period, the epidemic curve was similar to that in the pre-pandemic period. Compared to the pre-pandemic period, the total number of EKC patients during the pandemic period showed a decrease of 44.9% (t value = -7.23, p = 0.002). Comparing the pre-pandemic and pandemic periods by age group, we found there to be a significant decrease in the number of EKC patients for all age groups (-4.12≤t value≤-7.23, all P<0.05). This finding was most evident in the teenage group (62%) compared to the other age groups (decreases of 29 to 44%). A continuing effort should be made to educate the public on basic infection prevention behaviors in the aftermath of the pandemic, particularly to teenagers.


Central nervous system cancers.
Primary and metastatic tumors of the central nervous system are a heterogeneous group of neoplasms with varied outcomes and management strategies. Recently, improved survival observed in 2 randomized clinical trials established combined chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion. For metastatic disease, increasing evidence supports the efficacy of stereotactic radiosurgery in treating patients with multiple metastatic lesions but low overall tumor volume. These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus. This version includes expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, and brain metastases. The full online version, available at NCCN. org, contains recommendations on additional subtypes.


Breastfeeding, HIV status and weights in South African children: a comparison of HIV-exposed and unexposed children.
To examine growth of children by maternal and infant HIV status allowing for infant feeding mode. Women enrolled into a nonrandomized intervention cohort. Children of HIV-infected and uninfected women weighed and assessed for HIV status, monthly: from birth to 9 months; quarterly: 10-24 months. Daily infant feeding practices recorded at weekly intervals. Weight-for-age z-scores of children born to HIV-infected mothers compared with the reference population of children of HIV-uninfected mothers. Changes in z-scores over age were examined by HIV infection status and infant feeding practice using linear mixed effects models. The 1261 children of HIV-infected mothers grew as well as the reference group of 1061 children of HIV-uninfected mothers, irrespective of feeding mode. z-scores for HIV-infected children were consistently lower than those of HIV-exposed but uninfected children: a difference of 420 g for male children and 405 g for female children at 52 weeks of age. Breastfed HIV-infected infants had consistently higher z-scores for weight, especially during first 6 weeks (difference of 130 g for male children; 110 g for female children). In an adjusted regression analysis, maternal mid-upper arm circumference, CD4 cell count, infant birth weight and HIV status had the biggest impact on infant growth (z-score coefficient: 0.38 for mid-upper arm circumference > or =28.35 vs. <25.7 cm; P < 0.001; -0.32 for CD4 cell count <200 vs. > or =500; P = 0.001; -2.01 for birth weight <2500 vs. > or =2500 g; P < 0.001; -0.20 for infected vs. uninfected children; P < 0.001). Optimal early feeding practices ameliorate the effect of being born to an HIV-infected mother and strengthen the recommendation of exclusive breastfeeding for HIV-infected women in terms of long-term child health.


SETDB2 Links Glucocorticoid to Lipid Metabolism through Insig2a Regulation.
Transcriptional and chromatin regulations mediate the liver response to nutrient availability. The role of chromatin factors involved in hormonal regulation in response to fasting is not fully understood. We have identified SETDB2, a glucocorticoid-induced putative epigenetic modifier, as a positive regulator of GR-mediated gene activation in liver. Insig2a increases during fasting to limit lipid synthesis, but the mechanism of induction is unknown. We show Insig2a induction is GR-SETDB2 dependent. SETDB2 facilitates GR chromatin enrichment and is key to glucocorticoid-dependent enhancer-promoter interactions. INSIG2 is a negative regulator of SREBP, and acute glucocorticoid treatment decreased active SREBP during refeeding or in livers of Ob/Ob mice, both systems of elevated SREBP-1c-driven lipogenesis. Knockdown of SETDB2 or INSIG2 reversed the inhibition of SREBP processing. Overall, these studies identify a GR-SETDB2 regulatory axis of hepatic transcriptional reprogramming and identify SETDB2 as a potential target for metabolic disorders with aberrant glucocorticoid actions.


Thrombogenicity and intimal hyperplasia after conventional and thermal balloon dilation in normal rabbit iliac arteries.
Acute occlusion and restenosis are the major complications of percutaneous transluminal coronary balloon angioplasty. Application of heat during balloon dilation was postulated to reduce these complications. We evaluated thrombogenicity and intimal hyperplasia of normal rabbit iliac arteries after conventional (37 degrees C) and thermal balloon dilation. Thermal dilation was performed with a radio-frequency-heated balloon, provided with three thermocouples attached to the inside of the balloon skin. In a previous in vitro study, thrombogenicity of human subendothelium was increased at 55 degrees C and greatly decreased at temperatures over 70 degrees C. Thermal balloon dilation was therefore performed at 55 and 90 degrees C in vivo. Rabbits survived 2 h for evaluation of platelet adhesion or either 3 or 8 weeks for intimal hyperplasia. Angiograms revealed no occlusions or thrombi after any procedure. Platelet adhesion was quantified on 20 scanning electron microscopic pictures per balloon dilation site and was expressed as the percentage of the luminal surface covered by platelets. Platelet adhesion was similar in all groups, although large thrombi were present in the 90 degrees C group. Intimal hyperplasia was measured morphometrically at regular intervals over the balloon site. After 3 weeks, the average intimal hyperplasia was significantly reduced in the 90 degrees C balloon dilation group, which was mainly due to the absence of intimal hyperplasia in the midpart of these segments. After 8 weeks, intimal hyperplasia was equal in all groups. Thus, in the applied model, platelet coverage was equal after conventional balloon angioplasty and after 55 and 90 degrees C balloon angioplasty.(ABSTRACT TRUNCATED AT 250 WORDS)


Modifying the catalytic preference of tributyrin in Bacillus thermocatenulatus lipase through in-silico modeling of enzyme-substrate complex.
In this study, rational design for Bacillus thermocatenulatus lipase (BTL2) was carried out to lower the activation barrier for hydrolysis of short-chain substrates. In this design, we used computational models for the enzyme-substrate (ES) complexes of tributyrin (C4) and tricaprylin (C8), which were generated through docking and molecular dynamics (MD) simulations. These ES complexes were employed in steered MD (SMD) simulations with Jarzynski's equality to estimate their relative binding free energies. Potential mutation sites for modifying the chain-length selectivity of BTL2 were found by inspecting the SMD trajectories and fine-tuning the volume and hydrophobicity of the cleft. Seven mutations (F17A, L57F, V175A, V175F, I320A, I320F and L360F) were performed to cover three binding pockets for sn-1, sn-2 and sn-3 acyl chains. The relative binding free energies of the mutant ES complexes formed by C4 and C8 ligands were calculated similarly. The experimental routines of protein engineering including site-directed mutagenesis, heterologous protein expression and purification were performed for all lipases. Steady-state specific activities towards C4 and C8 were determined for wild-type and mutant lipases, which gave an estimate of the relative change in the binding free energy of transition state complex (ES(‡)). The chain-length selectivity of mutants was determined from the relative changes in the activation barrier of hydrolysis of C4 and C8 triacylglycerol with respect to wild-type using computational and experimental findings. The most promising mutant for C4 over C8 preference was found to be L360F. We suggest that L360F may be at a critical position to lower the activation barrier for C4 and elevate it for C8 hydrolysis.


Initiation of bladder voiding with epidural stimulation in paralyzed, step trained rats.
The inability to control timely bladder emptying is one of the most serious challenges among the several functional deficits that occur after a complete spinal cord injury. Having demonstrated that electrodes placed epidurally on the dorsum of the spinal cord can be used in animals and humans to recover postural and locomotor function after complete paralysis, we hypothesized that a similar approach could be used to recover bladder function after paralysis. Also knowing that posture and locomotion can be initiated immediately with a specific frequency-dependent stimulation pattern and that with repeated stimulation-training sessions these functions can improve even further, we reasoned that the same two strategies could be used to regain bladder function. Recent evidence suggests that rats with severe paralysis can be rehabilitated with a multisystem neuroprosthetic training regime that counteracts the development of neurogenic bladder dysfunction. No data regarding the acute effects of locomotion on bladder function, however, were reported. In this study we show that enabling of locomotor-related spinal neuronal circuits by epidural stimulation also influences neural networks controlling bladder function and can play a vital role in recovering bladder function after complete paralysis. We have identified specific spinal cord stimulation parameters that initiate bladder emptying within seconds of the initiation of epidural stimulation. The clinical implications of these results are substantial in that this strategy could have a major impact in improving the quality of life and longevity of patients while simultaneously dramatically reducing ongoing health maintenance after a spinal cord injury.


Iron biology in immune function, muscle metabolism and neuronal functioning.
The estimated prevalence of iron deficiency in the world suggests that there should be widespread negative consequences of this nutrient deficiency in both developed and developing countries. In considering the reality of these estimates, the Belmont Conference seeks to reconsider the accepted relationships of iron status to physiological, biochemical and neurological outcomes. This review focuses on the biological processes that we believe are the basis for alterations in the immune system, neural systems, and energy metabolism and exercise. The strength of evidence is considered in each of the domains and the large gaps in knowledge of basic biology or iron-dependent processes are identified. Iron is both an essential nutrient and a potential toxicant to cells; it requires a highly sophisticated and complex set of regulatory approaches to meet the demands of cells as well as prevent excess accumulation. It is hoped that this review of the more basic aspects of the biology of iron will set the stage for subsequent in-depth reviews of the relationship of iron to morbidity, mortality and functioning of iron-deficient individuals and populations.


Minds on the move: Crossing disciplines to shed new light on human cognition.
Mobility is integral to mankind, but current cognitive research on migrants is almost nonexistent. Most of the existing knowledge on human cognition is based on data collected from (and by) the wealthiest and least mobile citizens of the world. In turn, most of the migration literature relies on superficial, and at times erroneous, assumptions regarding the cognitive processes underlying migratory phenomenon. However, research conducted to date in reveals striking convergences between core issues relevant to scholars in cognitive science on the one hand, and in migration studies on the other. This current lack on cross-disciplinary dialog has no scientific grounds for two fields, which are inherently interdisciplinary, and yet it has concerning sociopolitical implications. Mapping out a novel research agenda at the crossroads of the cognitive and social sciences, this article stands as an invitation for researchers to engage in further collaborative work involving joint data collections and joint data analyses. This paper argues that researching migrant cognition would give more breadth to cognitive science and more depth to migration studies, which has the potential to better inform the design of public policies. Though the examples of (a) visual perception, (b) future-oriented cognition, and (c) language acquisition, this article shows that pairing the discoveries of migration scholars and cognitive scientists can move forward our understanding on the human mind, in an ever-moving world. This article is categorized under: Economics > Individual Decision-Making Psychology > Theory and Methods Psychology > Comparative Psychology Psychology > Language.


Parallel Inhibitory and Excitatory Trigemino-Facial Feedback Circuitry for Reflexive Vibrissa Movement.
Animals employ active touch to optimize the acuity of their tactile sensors. Prior experimental results and models lead to the hypothesis that sensory inputs are used in a recurrent manner to tune the position of the sensors. A combination of electrophysiology, intersectional genetic viral labeling and manipulation, and classical tracing allowed us to identify second-order sensorimotor loops that control vibrissa movements by rodents. Facial motoneurons that drive intrinsic muscles to protract the vibrissae receive a short latency inhibitory input, followed by synaptic excitation, from neurons located in the oralis division of the trigeminal sensory complex. In contrast, motoneurons that retract the mystacial pad and indirectly retract the vibrissae receive only excitatory input from interpolaris cells that further project to the thalamus. Silencing this feedback alters retraction. The observed pull-push circuit at the lowest-level sensorimotor loop provides a mechanism for the rapid modulation of vibrissa touch during exploration of peri-personal space.


Pandemic influenza A (H1N1) 2009 vaccine: an update.
The world witnessed a the first influenza pandemic in this century and fourth overall since first flu pandemic was reported during the World War I. The past experiences with influenza viruses and this pandemic of H1N1 place a consider-able strain on health services and resulted in serious illnesses and a large number of deaths. Develop-ing countries were declared more likely to be at risk from the pandemic effects, as they faced the dual problem of highly vulnerable populations and limited resources to respond H1N1. The public health experts agreed that vaccination is the most effective ways to mitigate the negative effects of the pandemic. The vaccines for H1N1 virus have been used in over 40 countries and administered to over 200 million people helped in a great way and on August 10, 2010, World Health Organization (WHO) announced H1N1 to be in postpandemic period. But based on knowledge about past pandemics, the H1N1 (2009) virus is expected to continue to circulate as a seasonal virus and may undergo some agenic-variation. As WHO strongly recommends vaccination, vigilance for regular updating of the composition of influenza vaccines, based on an assessment of the future impact of circulating viruses along with safety surveillance of the vaccines is necessary. This review has been done to take a stock of the currently available H1N1 vaccines and their possible use as public health intervention in the postpandemic period.


The effect of rectal administration of insulin on the short-term treatment of alloxan-diabetic dogs.
Six alloxan-diabetic dogs with fasting plasma glucose levels above 200 mg/100 mL were treated with rectal administration of insulin suppositories twice a day for 6--9 days. The effectiveness was compared with that of subcutaneous insulin injections. In three diabetic dogs with fasting plasma glucose levels below 300 mg/100 mL, both insulin suppository at a dose of 20 U (2.3 U/kg) and subcutaneous insulin at a dose of 0.2 U/kg showed a similar effect in reducing fasting glucose levels and daily urinary glucose amounts. In dogs with higher fasting glucose levels, 0.5 U of subcutaneous insulin/kg is less effective in reducing fasting glucose than 50 U (5.2 U/kg) suppositories, in spite of the same effects on daily urinary glucose output. Postprandial glucose responses were significantly lessened with rectal administration of insulin suppositories. The integrated area of increase in peripheral insulin concentration after subcutaneous infection of 0.2 or 0.5 U insulin/kg was significantly greater than that after rectal administration of an insulin suppository (2.3 or 5.2 U/kg, respectively). These results indicate that diabetes could be controlled by the daily rectal administration of an insulin suppository instead of the conventional subcutaneous injection.


Predictors of surgical site infections among patients undergoing major surgery at Bugando Medical Centre in Northwestern Tanzania.
Surgical site infection (SSI) continues to be a major source of morbidity and mortality in developing countries despite recent advances in aseptic techniques. There is no baseline information regarding SSI in our setting therefore it was necessary to conduct this study to establish the prevalence, pattern and predictors of surgical site infection at Bugando Medical Centre Mwanza (BMC), Tanzania. This was a cross-sectional prospective study involving all patients who underwent major surgery in surgical wards between July 2009 and March 2010. After informed written consent for the study and HIV testing, all patients who met inclusion criteria were consecutively enrolled into the study. Pre-operative, intra-operative and post operative data were collected using standardized data collection form. Wound specimens were collected and processed as per standard operative procedures; and susceptibility testing was done using disc diffusion technique. Data were analyzed using SPSS software version 15 and STATA. Surgical site infection (SSI) was detected in 65 (26.0%) patients, of whom 56 (86.2%) and 9 (13.8%) had superficial and deep SSI respectively. Among 65 patients with clinical SSI, 56(86.2%) had positive aerobic culture. Staphylococcus aureus was the predominant organism 16/56 (28.6%); of which 3/16 (18.8%) were MRSA. This was followed by Escherichia coli 14/56 (25%) and Klebsiella pneumoniae 10/56 (17.9%). Among the Escherichia coli and Klebsiella pneumoniae isolates 9(64.3%) and 8(80%) were ESBL producers respectively. A total of 37/250 (14.8%) patients were HIV positive with a mean CD4 count of 296 cells/ml. Using multivariate logistic regression analysis, presence of pre-morbid illness (OR = 6.1), use of drain (OR = 15.3), use of iodine alone in skin preparation (OR = 17.6), duration of operation ≥ 3 hours (OR = 3.2) and cigarette smoking (OR = 9.6) significantly predicted surgical site infection (SSI) CONCLUSION: SSI is common among patients admitted in surgical wards at BMC and pre-morbid illness, use of drain, iodine alone in skin preparation, prolonged duration of the operation and cigarette smoking were found to predict SSI. Prevention strategies focusing on factors associated with SSI is necessary in order to reduce the rate of SSI in our setting.


A database and API for variation, dense genotyping and resequencing data.
Advances in sequencing and genotyping technologies are leading to the widespread availability of multi-species variation data, dense genotype data and large-scale resequencing projects. The 1000 Genomes Project and similar efforts in other species are challenging the methods previously used for storage and manipulation of such data necessitating the redesign of existing genome-wide bioinformatics resources. Ensembl has created a database and software library to support data storage, analysis and access to the existing and emerging variation data from large mammalian and vertebrate genomes. These tools scale to thousands of individual genome sequences and are integrated into the Ensembl infrastructure for genome annotation and visualisation. The database and software system is easily expanded to integrate both public and non-public data sources in the context of an Ensembl software installation and is already being used outside of the Ensembl project in a number of database and application environments. Ensembl's powerful, flexible and open source infrastructure for the management of variation, genotyping and resequencing data is freely available at http://www.ensembl.org.


Common TDP1 Polymorphisms in Relation to Survival among Small Cell Lung Cancer Patients: A Multicenter Study from the International Lung Cancer Consortium.
Purpose: DNA topoisomerase inhibitors are commonly used for treating small-cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common TDP1 single-nucleotide polymorphisms (SNP) are associated with overall survival among SCLC patients.Experimental Design: Two TDP1 SNPs (rs942190 and rs2401863) were analyzed in 890 patients from 10 studies in the International Lung Cancer Consortium (ILCCO). The Kaplan-Meier method and Cox regression analyses were used to evaluate genotype associations with overall mortality at 36 months postdiagnosis, adjusting for age, sex, race, and tumor stage.Results: Patients homozygous for the minor allele (GG) of rs942190 had poorer survival compared with those carrying AA alleles, with a HR of 1.36 [95% confidence interval (CI): 1.08-1.72, P = 0.01), but no association with survival was observed for patients carrying the AG genotype (HR = 1.04, 95% CI, 0.84-1.29, P = 0.72). For rs2401863, patients homozygous for the minor allele (CC) tended to have better survival than patients carrying AA alleles (HR = 0.79; 95% CI, 0.61-1.02, P = 0.07). Results from the Genotype Tissue Expression (GTEx) Project, the Encyclopedia of DNA Elements (ENCODE), and the ePOSSUM web application support the potential function of rs942190.Conclusions: We found the rs942190 GG genotype to be associated with relatively poor survival among SCLC patients. Further investigation is needed to confirm the result and to determine whether this genotype may be a predictive marker for treatment efficacy of DNA topoisomerase inhibitors. Clin Cancer Res; 23(24); 7550-7. ©2017 AACR.


A panel of lung injury biomarkers enhances the definition of primary graft dysfunction (PGD) after lung transplantation.
We aimed to identify combinations of biomarkers to enhance the definition of primary graft dysfunction (PGD) for translational research. Biomarkers reflecting lung epithelial injury (soluble receptor for advance glycation end products [sRAGE] and surfactant protein-D [SP-D]), coagulation cascade (plasminogen activator inhibitor-1 [PAI-1] and protein C), and cell adhesion (intracellular adhesion molecule-1 [ICAM-1]) were measured in the plasma of 315 individuals derived from the Lung Transplant Outcomes Group cohort at 6 and 24 hours after transplantation. We assessed biomarker utility in 2 ways: first, we tested the discrimination of grade 3 PGD within 72 hours; second, we tested the predictive utility of plasma biomarkers for 90-day mortality. PGD developed in 86 of 315 individuals (27%). Twenty-patients (8%) died within 90 days of transplantation, of which 16 (70%) had PGD. Biomarkers measured at 24 hours had greater discrimination than at 6 hours. Individually, sRAGE (area under the curve [AUC], 0.71) and PAI-1 (AUC, 0.73) had the best discrimination of PGD. The combinations of sRAGE with PAI-1 (AUC, 0.75), PAI-1 with ICAM-1 (AUC, 0.75), and PAI-1 with SP-D (AUC, 0.76) had the best discrimination. Combinations of greater than 2 biomarkers did not significantly enhance discrimination of PGD. ICAM-1 with PAI-1 (AUC, 0.72) and ICAM-1 with sRAGE (AUC, 0.72) had the best prediction for 90-day mortality. The addition of ICAM-1, PAI-1, or sRAGE to the concurrent clinical PGD grade significantly improved the prediction of 90-day mortality (p < 0.001 each). Measurement of the combination of a marker of impaired fibrinolysis with an epithelial injury or cell adhesion marker had the best discrimination for PGD and prediction for early death and may provide an alternative outcome useful in future research.


Barriers and drivers of health information technology use for the elderly, chronically ill, and underserved.
We reviewed the evidence on the barriers and drivers to the use of interactive consumer health information technology (health IT) by specific populations, namely the elderly, those with chronic conditions or disabilities, and the underserved. We searched MEDLINE, CINHAHL, PsycINFO the Cochrane Controlled Trials Register and Database of Systematic Reviews, ERIC, and the American Association of Retired Persons (AARP) AgeLine databases. We focused on literature 1990 to present. We included studies of all designs that described the direct use of interactive consumer health IT by at least one of the populations of interest. We then assessed the quality and abstracted and summarized data from these studies with regard to the level of use, the usefulness and usability, the barriers and drivers of use, and the effectiveness of the interactive consumer health IT applications. We identified and reviewed 563 full-text articles and included 129 articles for abstraction. Few of the studies were specifically designed to compare the elderly, chronically ill, or underserved with the general population. We did find that several types of interactive consumer health IT were usable and effective in multiple settings and with all of our populations of interest. Of the studies that reported the impact of interactive consumer health IT on health outcomes, a consistent finding of our review was that these systems tended to have a positive effect when they provided a complete feedback loop that included: Monitoring of current patient status. Interpretation of this data in light of established, often individualized, treatment goals. Adjustment of the management plan as needed. Communication back to the patient with tailored recommendations or advice. Repetition of this cycle at appropriate intervals. Systems that provided only one or a subset of these functions were less consistently effective. The barriers and drivers to use were most often reported as secondary outcomes. Many studies were hampered by usability problems and unreliable technology, primarily due to the research being performed on early stage system prototypes. However, the most common factor influencing the successful use of the interactive technology by these specific populations was that the consumers' perceived a benefit from using the system. Convenience was an important factor. It was critical that data entry not be cumbersome and that the intervention fit into the user's daily routine. Usage was more successful if the intervention could be delivered on technology consumers used every day for other purposes. Finally, rapid and frequent interactions from a clinician improved use and user satisfaction. The systems described in the studies we examined depended on the active engagement of consumers and patients and the involvement of health professionals, supported by the specific technology interventions. Questions remain as to: The optimal frequency of use of the system by the patient, which is likely to be condition-specific. The optimal frequency of use or degree of involvement by health professionals. Whether the success depends on repeated modification of the patient's treatment regimen or simply ongoing assistance with applying a static treatment plan. However, it is clear that the consumer's perception of benefit, convenience, and integration into daily activities will serve to facilitate the successful use of the interactive technologies for the elderly, chronically ill, and underserved.


Dual-Task Cost and Related Clinical Features in Patients With Multiple Sclerosis.
This study aimed to investigate the dual-task cost of both motor and cognitive performances in patients with multiple sclerosis (PwMS) and in healthy controls and to determine their relationships with clinical features in PwMS. The participants performed motor tasks (postural stability, walking, and manual dexterity) and cognitive tasks (mental tracking and verbal fluency) under single- and dual-task conditions. The results showed that postural stability under dual-task conditions did not change, whereas walking and manual dexterity deteriorated, regardless of the concurrent cognitive task, in PwMS (median Expanded Disability Status Scale score: 1) and the healthy controls. Verbal fluency decreased during postural stability, whereas it increased during walking, and it was maintained during manual dexterity in both groups. Mental tracking did not change during walking; it declined during manual dexterity in both groups. Mental tracking during postural stability deteriorated in PwMS, while it did not change in the healthy controls. In general, dual-task costs were associated with baseline performances of tasks rather than clinical features. Therefore, baseline performances of both tasks should be increased for improving dual-task performance in PwMS.


Impact of incident vertebral fractures on health related quality of life (HRQOL) in postmenopausal women with prevalent vertebral fractures.
Vertebral fractures are a common complication of osteoporosis and may cause a decrease of health-related quality of life (HRQOL). This study was designed to determine the impact of incident vertebral fractures on HRQOL. The Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter, randomized, double blind trial, in which women were taking raloxifene or placebo. This study was done in European centers only in a subset of 361 women from seven European countries, all with prevalent vertebral fractures. A specific questionnaire for osteoporosis developed by the International Osteoporosis Foundation was used for assessment at baseline, 1, 2 and 3 years. This questionnaire, Qualeffo, contains 41 questions in the domains pain, physical function, social function, general health perception and mental function. Domain and total scores are expressed on a 100-point scale with 0 corresponding to the best HRQOL. Standardized lateral spinal radiographs were made at baseline, 2 and 3 years and evaluated in a central facility. Sixty-seven patients sustained a fracture in a vertebra that was not fractured at baseline (incident vertebral fractures). Twenty of these were accompanied by signs and symptoms necessitating immediate doctor's attention (clinical vertebral fractures) and 47 vertebral fractures were only diagnosed on radiographs (subclinical vertebral fractures). Incident vertebral fractures (clinical and subclinical) were associated with an increase of back pain (mean score change 6.4; 95% CI 2.1-10.7), deterioration of physical function (mean score change 2.4; 95% CI 0.1-4.8), and worse general health perception (mean score change 3.8; 95% CI 0.1-7.5). Score changes for patients with subclinical vertebral fractures were intermediate between those for patients with clinical vertebral fractures and patients without incident vertebral fracture. Clinical and subclinical incident vertebral fractures both have an adverse impact on HRQOL.


Eating lizards: a millenary habit evidenced by Paleoparasitology.
Analyses of coprolites have contributed to the knowledge of diet as well as infectious diseases in ancient populations. Results of paleoparasitological studies showed that prehistoric groups were exposed to spurious and zoonotic parasites, especially food-related. Here we report the findings of a paleoparasitological study carried out in remote regions of Brazil's Northeast. Eggs of Pharyngodonidae (Nematoda, Oxyuroidea), a family of parasites of lizards and amphibians, were found in four human coprolites collected from three archaeological sites. In one of these, lizard scales were also found. Through the finding of eggs of Pharyngodonidae in human coprolites and reptilescales in one of these, we have provided evidence that humans have consumed reptiles at least 10,000 years ago. This food habit persists to modern times in remote regions of Brazil's Northeast. Although Pharyngodonidae species are not known to infect humans, the consumption of raw or undercooked meat from lizards and other reptiles may have led to transmission of a wide range of zoonotic agents to humans in the past.


Evaluation of performance characteristics in a diallel among Simmental, Limousin, Polled Hereford and Brahman beef cattle. I. Growth, hip height and pelvic size.
Progeny of a diallel among Simmental, Limousin, Polled Hereford and Brahman breeds of cattle were evaluated over 5 yr for preweaning and postweaning growth, hip height and pelvic size. Calves from Brahman and Simmental dams had the highest preweaning gains and weaning weights, and those from Polled Hereford dams had the lowest (P less than .05). Differences in the availability of milk and postpartum compensatory gains in progeny of Brahman dams could have contributed to these results. However, calves from Simmental, Limousin and Polled Hereford dams had significantly greater feedlot daily gains than those from Brahman dams. Yearling hip height and pelvic area were lower for progeny of Polled Hereford dams, whereas calves from Simmental, Limousin and Brahman dams were not different for these traits. A series of linear comparisons among these four breeds using least-squares means to estimate general and specific combining ability and maternal effects found significant, negative maternal effects for Polled Hereford for preweaning gain and weaning weight. A positive maternal effect (P less than .05) for Limousin was found for feedlot gain. General combining ability and maternal estimates were significant and variable in most comparisons for yearling hip height and pelvic area. Heterosis estimates were positive and significant in all crosses with Brahman for preweaning gain, weaning weight, yearling weight, hip height and pelvic area. Significant, positive heterosis was also found in Polled Hereford crosses with Limousin and Simmental for preweaning gain, weaning weight and yearling weight.


Clustervision: Visual Supervision of Unsupervised Clustering.
Clustering, the process of grouping together similar items into distinct partitions, is a common type of unsupervised machine learning that can be useful for summarizing and aggregating complex multi-dimensional data. However, data can be clustered in many ways, and there exist a large body of algorithms designed to reveal different patterns. While having access to a wide variety of algorithms is helpful, in practice, it is quite difficult for data scientists to choose and parameterize algorithms to get the clustering results relevant for their dataset and analytical tasks. To alleviate this problem, we built Clustervision, a visual analytics tool that helps ensure data scientists find the right clustering among the large amount of techniques and parameters available. Our system clusters data using a variety of clustering techniques and parameters and then ranks clustering results utilizing five quality metrics. In addition, users can guide the system to produce more relevant results by providing task-relevant constraints on the data. Our visual user interface allows users to find high quality clustering results, explore the clusters using several coordinated visualization techniques, and select the cluster result that best suits their task. We demonstrate this novel approach using a case study with a team of researchers in the medical domain and showcase that our system empowers users to choose an effective representation of their complex data.


Tracer uptake in mediastinal and paraaortal thoracic lymph nodes as a potential pitfall in image interpretation of PSMA ligand PET/CT.
Since the introduction of 68Ga-PSMA-11 PET/CT for imaging prostate cancer (PC) we have frequently observed mediastinal lymph nodes (LN) showing tracer uptake despite being classified as benign. The aim of this evaluation was to further analyze such LN. Two patient groups with biphasic 68Ga-PSMA-11 PET/CT at 1 h and 3 h p.i. were included in this retrospective evaluation. Group A (n = 38) included patients without LN metastases, and group B (n = 43) patients with LN metastases of PC. SUV of mediastinal/paraaortal LN of group A (n = 100) were compared to SUV of LN metastases of group B (n = 91). Additionally, 22 randomly selected mediastinal and paraaortal LN of patients without PC were immunohistochemically (IHC) analyzed for PSMA expression. In group A, 7/38 patients (18.4%) presented with at least one PSMA-positive mediastinal LN at 1 h p.i. and 3/38 (7.9%) positive LN at 3 h p.i. with a SUVmax of 2.3 ± 0.7 at 1 h p.i. (2.0 ± 0.7 at 3 h p.i.). A total of 11 PSMA-positive mediastinal/paraaortal LN were detected in nine patients considering both imaging timing points. SUVmax of LN-metastases was 12.5 ± 13.2 at 1 h p.i. (15.8 ± 17.0 at 3 h p.i.). SUVmax increased clearly (> 10%) between 1 h and 3 h p.i. in 76.9% of the LN metastases, and decreased significantly in 72.7% of the mediastinal/paraaortal LN. By IHC, PSMA-expression was observed in intranodal vascular endothelia of all investigated LN groups and to differing degrees within germinal centers of 15/22 of them (68.1%). Expression was stronger in mediastinal nodes (p = 0.038) and when follicular hyperplasia was present (p = 0.050). PSMA-positive mediastinal/paraaortal benign LN were visible in a notable proportion of patients. PSMA-positivity on the histopathological level was associated with the activation state of the LN. However, in contrast to LN metastases of PC, they presented with significantly lower uptake, which, in addition, usually decreased over time.


Talking about the 'r' word: a right to a health system that is free of racism.
Australia's local, state, territory and federal governments have agreed that the 10-year life expectancy gap between Indigenous and non-Indigenous Australians will be closed by 2031. However, annual Closing the Gap reports tabled by the various prime ministers in the Australian Parliament (for the past 12 years) have consistently indicated that the life expectancy gap continues to widen. Australia has seen more than three decades of government policies since the landmark 1989 National Aboriginal health strategy. What has been missing from these policy commitments is the genuine enactment of the knowledges that are held by Indigenous Australians relating to their cultural ways of being, knowing and doing. Privileging Indigenous knowledges, cultures and voices must be front and centre in developing, designing and implementing policies and programs. The sharing of power, provision of resources, culturally informed reflective policy making, and program design are critical elements. In this paper, we provide a conceptual model of practice, working at the cultural interface where knowledges are valued and innovations can occur. This model of practice is where knowledges and cultures can co-exist, and it could be the answer to Closing the Gap in life expectancy by 2031. Despite a growing willingness and need to consider these models, there remains a deep-seated resistance to identifying and addressing institutional and systemic racism and racist attitudes, including unconscious biases held by individuals. Further, western non-Indigenous worldviews of ways of being, knowing and doing continue to dominate the decisions and actions of governments - and consequentially dominate public health policies and practices. There is an unacceptable standard approach, for and about Indigenous health instead of with Indigenous peoples, resulting in the neglectful dismissal of Indigenous knowledges and Indigenous cultures of ways of being, knowing and doing.


Towards a multiscale crop modelling framework for climate change adaptation assessment.
Predicting the consequences of manipulating genotype (G) and agronomic management (M) on agricultural ecosystem performances under future environmental (E) conditions remains a challenge. Crop modelling has the potential to enable society to assess the efficacy of G × M technologies to mitigate and adapt crop production systems to climate change. Despite recent achievements, dedicated research to develop and improve modelling capabilities from gene to global scales is needed to provide guidance on designing G × M adaptation strategies with full consideration of their impacts on both crop productivity and ecosystem sustainability under varying climatic conditions. Opportunities to advance the multiscale crop modelling framework include representing crop genetic traits, interfacing crop models with large-scale models, improving the representation of physiological responses to climate change and management practices, closing data gaps and harnessing multisource data to improve model predictability and enable identification of emergent relationships. A fundamental challenge in multiscale prediction is the balance between process details required to assess the intervention and predictability of the system at the scales feasible to measure the impact. An advanced multiscale crop modelling framework will enable a gene-to-farm design of resilient and sustainable crop production systems under a changing climate at regional-to-global scales.


Contributions of woody and herbaceous vegetation to tropical savanna ecosystem productivity: a quasi-global estimate.
To estimate the relative contributions of woody and herbaceous vegetation to savanna productivity, we measured the 13C/12C isotopic ratios of leaves from trees, shrubs, grasses and the surface soil carbon pool for 22 savannas in Australia, Brazil and Ghana covering the full savanna spectrum ranging from almost pure grassland to closed woodlands on all three continents. All trees and shrubs sampled were of the C3 pathway and all grasses of the C4 pathway with the exception of Echinolaena inflexa (Poir.) Chase, a common C3 grass of the Brazilian cerrado. By comparing the carbon isotopic compositions of the plant and carbon pools, a simple model relating soil delta 13C to the relative abundances of trees + shrubs (woody plants) and grasses was developed. The model suggests that the relative proportions of a savanna ecosystem's total foliar projected cover attributable to grasses versus woody plants is a simple and reliable index of the relative contributions of grasses and woody plants to savanna net productivity. Model calibrations against woody tree canopy cover made it possible to estimate the proportion of savanna productivity in the major regions of the world attributable to trees + shrubs and grasses from ground-based observational maps of savanna woodiness. Overall, it was estimated that 59% of the net primary productivity (Np) of tropical savannas is attributable to C4 grasses, but that this proportion varies significantly within and between regions. The C4 grasses make their greatest relative contribution to savanna Np in the Neotropics, whereas in African regions, a greater proportion of savanna Np is attributable to woody plants. The relative contribution of C4 grasses in Australian savannas is intermediate between those in the Neotropics and Africa. These differences can be broadly ascribed to large scale differences in soil fertility and rainfall.


Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Adults in an Open-Label Phase 1 Multiple Ascending Dose and Food Effect Study.
Neurocysticercosis and trichuriasis are difficult-to-treat parasitic infections that affect more than 1.5 billion people worldwide. Oxfendazole, a potent broad-spectrum benzimidazole anthelmintic approved for use in veterinary medicine, has shown substantial antiparasitic activity against neurocysticercosis and intestinal helminths in preclinical studies. As part of a program to transition oxfendazole from veterinary medicine to human use, phase I multiple ascending dose and food effect studies were conducted. Thirty-six healthy adults were enrolled in an open-label study which evaluated (i) the pharmacokinetics and safety of oxfendazole following multiple ascending doses of oxfendazole oral suspension at 3, 7.5, and 15 mg/kg once daily for 5 days and (ii) the effect of food on oxfendazole pharmacokinetics and safety after a single 3-mg/kg dose administered following an overnight fast or the consumption of a fatty breakfast. Following multiple oral dose administration, the intestinal absorption of oxfendazole was rapid, with the time to maximum concentration of drug in serum (Tmax) ranging from 1.92 to 2.56 h. A similar half-life of oxfendazole (9.21 to 11.8 h) was observed across all dose groups evaluated, and oxfendazole exhibited significantly less than a dose-proportional increase in exposure. Oxfendazole plasma exposures were higher in female subjects than in male subjects. Following daily administration, oxfendazole reached a steady state in plasma on study day 3, with minimal accumulation. Food delayed the oxfendazole Tmax by a median of 6.88 h and resulted in a 49.2% increase in the maximum observed drug concentration in plasma (Cmax) and an 86.4% increase in the area under the concentration-time curve (AUC). Oxfendazole was well tolerated in all study groups, and there were no major safety signals identified in this study. (This study has been registered at ClinicalTrials.gov under identifier NCT03035760.).


Herpes simplex virus type 1 DNA polymerase requires the mammalian chaperone hsp90 for proper localization to the nucleus.
Many viruses and bacteriophage utilize chaperone systems for DNA replication and viral morphogenesis. We have previously shown that in the herpes simplex virus type 1 (HSV-1)-infected cell nucleus, foci enriched in the Hsp70/Hsp40 chaperone machinery are formed adjacent to viral replication compartments (A. D. Burch and S. K. Weller, J. Virol. 78:7175-7185, 2004). These foci have now been named virus-induced chaperone-enriched (VICE) foci. Since the Hsp90 chaperone machinery is known to engage the Hsp70/Hsp40 system in eukaryotes, the subcellular localization of Hsp90 in HSV-1-infected cells was analyzed. Hsp90 is found within viral replication compartments as well as in the Hsp70/Hsp40-enriched foci. Geldanamycin, an inhibitor of Hsp90, results in decreased HSV-1 yields and blocks viral DNA synthesis. Furthermore, we have found that the viral DNA polymerase is mislocalized to the cytoplasm in both infected and transfected cells in the presence of geldanamycin. Additionally, in the presence of an Hsp90 inhibitor, proteasome-dependent degradation of the viral polymerase was detected by Western blot analysis. These data identify the HSV-1 polymerase as a putative client protein of the Hsp90 chaperone system. Perturbations in this association appear to result in degradation, aberrant folding, and/or intracellular localization of the viral polymerase.


Changing patterns of psychiatric inpatient care in the United States, 1988-1994.
Using data from the National Hospital Discharge Survey and the Inventory of Mental Health Organizations, this article examines national trends in psychiatric inpatient care from 1988 to 1994 in general hospitals and mental hospitals. We find that discharges with a primary diagnosis of mental illness in general hospitals increased from 1.4 to 1.9 million during this period. The total increase of 1.2 million days of care in general hospitals was small relative to the reduction of 12.5 million inpatient days in mental hospitals. General hospital discharges increased most in private nonprofit hospitals and declined substantially in public hospitals. Length of stay has fallen most substantially in private nonprofit hospitals. Public programs have increasingly replaced private insurance as the major source of payment. These observations suggest that psychiatric inpatient care in general hospitals can be characterized as a process in which patients who would have been clients of public mental hospitals in a prior period replace privately insured patients who, under managed care, are largely treated in community settings. Private nonprofit general hospitals increasingly treat publicly financed patients with more severe illnesses.


Changes in Na-K ATPase and protein kinase C activities in peripheral nerve of acrylamide-treated rats.
In previous studies on rat peripheral nerve, we showed that acrylamide (ACR) exposure was associated with alterations in axonal and Schwann cell elemental composition that were consistent with decreased Na-K ATPase activity. In the present corollary study, the effects of ACR exposure on Na-K ATPase activity were determined in sciatic and tibial nerves. Subacute ACR treatment (50 mg/kg/d x 10 d, ip) significantly (p < .05) decreased Na-K ATPase activity by 45% in sciatic nerve but did not affect this activity in tibial nerve. Subchronic ACR treatment (2.8 mM in drinking water for 30 d) significantly decreased (p < .05) Na-K ATPase activities by 19% and 35% in sciatic and tibial nerves, respectively. Na-K ATPase activity was not altered in sciatic nerve homogenates exposed to 1.0 mM ACR in vitro. Since protein kinase C (PKC) has been proposed to play a role in the modulation of membrane Na-K ATPase function, PKC activity was also measured in sciatic nerve homogenates and subcellular fractions prepared from control and ACR-treated rats. Regardless of the ACR treatment protocol, PKC activity was elevated in nerve cytosol, but not in a particulate fraction. The results of this study suggest that decreased Na-K ATPase activity is involved in ACR-induced perturbation of axoplasmic and Schwann cell elemental composition in rat peripheral nerves and that loss of activity is not due to direct chemical inhibition of the enzyme. The role of PKC in ACR neurotoxicity requires further elucidation.


Additional metabolic effects of adding GH receptor antagonist to long-acting somatostatin analog in patients with active acromegaly.
Somatostatin analogs, dopamine agonists and GH-receptor antagonist--pegvisomant are used in medical therapy of acromegaly. Since pegvisomant has not antitumor effect, the combination of pegvisomant and somatostatin analog could be an attractive option. Aim of study was to assess the effects of pegvisomant and octreotide LAR treatment on GH and IGF-1 levels, and glucose tolerance in acromegaly, and to assess efficacy and tolerability of rapid (after 7 days) pegvisomant dose titration. Six patients (4 men, 2 women) aged 47.5 years (median) with active acromegaly, after neurosurgery failed, resistant to maximal doses of octreotide, received daily 10-20 mg pegvisomant throughout 2 weeks. They were given octreotide LAR 30 mg monthly for at least 6 months before pegvisomant therapy. Clinical symptoms, GH, IGF-1, fasting glucose and insulin levels were measured on the 0, 8th and 15th day of pegvisomant therapy. On the 8th day pegvisomant dose was titrated based on serum IGF-1 level. IGF-1 levels reduced from 739 at the beginning to 418 ng/ml (medians) on the 15th day of treatment and normalized in one patient. These changes were associated with improvement of glucose metabolism. One diabetic patient could even stop insulin therapy. Pegvisomant is an attractive adjuvant therapy for controlling acromegaly. Pegvisomant improves insulin sensitivity as well as glucose tolerance. The GH receptor antagonist is good option for patients with active acromegaly coexistent with disturbances of glucose metabolism, especially with diabetes mellitus. Rapid pegvisomant dose increasing to efficient or maximal is well tolerated and effective.


Disentangling the contribution of multiple land covers to fire-mediated carbon emissions in Amazonia during the 2010 drought.
In less than 15 years, the Amazon region experienced three major droughts. Links between droughts and fires have been demonstrated for the 1997/1998, 2005, and 2010 droughts. In 2010, emissions of 510 ± 120 Tg C were associated to fire alone in Amazonia. Existing approaches have, however, not yet disentangled the proportional contribution of multiple land cover sources to this total. We develop a novel integration of multisensor and multitemporal satellite-derived data on land cover, active fires, and burned area and an empirical model of fire-induced biomass loss to quantify the extent of burned areas and resulting biomass loss for multiple land covers in Mato Grosso (MT) state, southern Amazonia-the 2010 drought most impacted region. We show that 10.77% (96,855 km2) of MT burned. We estimated a gross carbon emission of 56.21 ± 22.5 Tg C from direct combustion of biomass, with an additional 29.4 ± 10 Tg C committed to be emitted in the following years due to dead wood decay. It is estimated that old-growth forest fires in the whole Brazilian Legal Amazon (BLA) have contributed to 14.81 Tg of C (11.75 Tg C to 17.87 Tg C) emissions to the atmosphere during the 2010 fire season, with an affected area of 27,555 km2. Total C loss from the 2010 fires in MT state and old-growth forest fires in the BLA represent, respectively, 77% (47% to 107%) and 86% (68.2% to 103%) of Brazil's National Plan on Climate Change annual target for Amazonia C emission reductions from deforestation.


Quantifying and comparing the predictive accuracy of continuous prognostic factors for binary outcomes.
The positive and negative predictive values are standard ways of quantifying predictive accuracy when both the outcome and the prognostic factor are binary. Methods for comparing the predictive values of two or more binary factors have been discussed previously (Leisenring et al., 2000, Biometrics 56, 345-351). We propose extending the standard definitions of the predictive values to accommodate prognostic factors that are measured on a continuous scale and suggest a corresponding graphical method to summarize predictive accuracy. Drawing on the work of Leisenring et al. we make use of a marginal regression framework and discuss methods for estimating these predictive value functions and their differences within this framework. The methods presented in this paper have the potential to be useful in a number of areas including the design of clinical trials and health policy analysis.


DYRK1A in Down syndrome: an oncogene or tumor suppressor?
Children with Down syndrome (DS) have a markedly increased risk of developing acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia compared with that of children without DS. Despite recent breakthroughs, it is not clear which genes on chromosome 21, the chromosome that is trisomic in individuals with DS, cause this predisposition. In this issue of the JCI, Malinge et al. report their loss- and gain-of-function experiments in mouse and human cells that show that increased expression of the kinase encoded by the chromosome 21 gene DYRK1A suppresses the nuclear factor of activated T cells pathway and promotes AMKL. Interestingly, the same protein has been suggested to contribute to the reduced risk of epithelial cancers in adults with DS, leading to the possibility that it could be proleukemic in children and antitumorigenic in adults.


Combined therapy for selected chronic uremic patients: infrequent hemodialysis and nutritional management.
The results are described of a combined nutritional (supplemented diet) and dialytic (once a week hemodialysis) therapy, employed in 17 selected chronic uremics for a mean period of 18.2 months/patient. The clinical findings, blood chemical abnormalities and changes of renal function were examined and compared with those of patients on the standard thrice-a-week dialysis schedule and free diet. The clinical findings were not significantly different in the two groups. The residual renal function of patients on combined therapy declined faster than in patients on conservative treatment, but at a slower rate than in those on thrice-a-week dialysis. The time averages of serum urea, methylguanidine and phosphate concentrations and their postdialytic rebounds were lower in the patients on combined therapy than in those on thrice-a-week dialysis, whereas the time averages of the serum creatinine concentration were higher, and those of serum bicarbonate and serum oxalate were not significantly different in the two groups. It is concluded that this combined therapy is a valid alternative to the conventional thrice-a-week hemodialysis and free diet for selected patients and for periods of time whose duration is conditioned by the rate of decline of the residual renal function.


Intracellular sodium and the response to nitrendipine or atenolol in African blacks.
The relationship between the hypotensive effect of nitrendipine (N), 20 mg/day (n = 17), or atenolol (A), 100 mg/day (n = 17), and the erythrocyte sodium [( Na]i) and potassium [( K]i) concentrations was investigated in hypertensive African blacks during a randomized double-blind study. After 6 weeks, both treatments significantly reduced supine and standing blood pressures; however, the magnitude of the decrease in supine systolic (-22.0 +/- 2.0 vs -12.1 +/- 3.4 mm Hg) and diastolic (-14.1 +/- 1.3 vs -7.6 +/- 2.1 mm Hg) pressures and in standing diastolic pressure (-16.0 +/- 1.7 vs -9.2 +/- 2.0 mm Hg) was more pronounced (p less than 0.05) in the N-treated than in the A-treated group. Pulse rate, plasma aldosterone, and plasma renin activity were lower (p less than 0.05) in the A-treated patients. Neither treatment had significant influence on [Na]i, [K]i, or ouabain-sensitive sodium efflux. The N-induced changes in supine systolic and diastolic pressure correlated (p less than 0.05) with age (r = -0.65 and r = -0.58, respectively) and pretreatment plasma renin activity (r = 0.71). Multiple regression analysis demonstrated a negative association between pretrial [Na]i and the change in systolic pressure during N treatment that was independent of age, pretreatment blood pressure, and change in pulse rate. Age and the change in supine pulse rate were also independently correlated with the change in diastolic pressure during N treatment. The results show a greater antihypertensive efficacy of N than A in the patients entered in this study and suggest that a higher intracellular sodium concentration could predict a better hypotensive response to N.


Short-Term and Long-Term Educational Outcomes of Infants Born Moderately and Late Preterm.
To assess the relationship of moderate and late preterm birth (320/7-366/7 weeks) to long-term educational outcomes. We hypothesized that moderate and late preterm birth would be associated with adverse outcomes in elementary school. To test this, we linked vital statistics patient discharge data from the Office of Statewide Health Planning and Development including birth outcomes, to the 2015-2016 school year administrative data of a large, urban school district (n = 72 316). We compared the relative risk of moderate and late preterm and term infants for later adverse neurocognitive and behavioral outcomes in kindergarten through the 12th grade. After adjusting for socioeconomic status, compared with term birth, moderate and late preterm birth was associated with an increased risk of low performance in mathematics and English language arts, chronic absenteeism, and suspension. These risks emerged in kindergarten through grade 2 and remained in grades 3-5, but seemed to wash out in later grades, with the exception of suspension, which remained through grades 9-12. Confirming our hypothesis, moderate and late preterm birth was associated with adverse educational outcomes in late elementary school, indicating that it is a significant risk factor that school districts could leverage when targeting early intervention. Future studies will need to test these relations in geographically and socioeconomically diverse school districts, include a wider variety of outcomes, and consider how early interventions moderate associations between birth outcomes and educational outcomes.


Requirement of cyclin E-Cdk2 inhibition in p16(INK4a)-mediated growth suppression.
Loss-of-function mutations of p16(INK4a) have been identified in a large number of human tumors. An established biochemical function of p16 is its ability to specifically inhibit cyclin D-dependent kinases in vitro, and this inhibition is believed to be the cause of the p16-mediated G1 cell cycle arrest after reintroduction of p16 into p16-deficient tumor cells. However, a mutant of Cdk4, Cdk4(N158), designed to specifically inhibit cyclin D-dependent kinases through dominant negative interference, was unable to arrest the cell cycle of the same cells (S. van den Heuvel and E. Harlow, Science 262:2050-2054, 1993). In this study, we determined functional differences between p16 and Cdk4(N158). We show that p16 and Cdk4(N158) inhibit the kinase activity of cellular cyclin D1 complexes through different mechanisms. p16 dissociated cyclin D1-Cdk4 complexes with the release of bound p27(KIP1), while Cdk4(N158) formed complexes with cyclin D1 and p27. In cells induced to overexpress p16, a higher portion of cellular p27 formed complexes with cyclin E-Cdk2, and Cdk2-associated kinase activities were correspondingly inhibited. Cells engineered to express moderately elevated levels of cyclin E became resistant to p16-mediated growth suppression. These results demonstrate that inhibition of cyclin D-dependent kinase activity may not be sufficient to cause G1 arrest in actively proliferating tumor cells. Inhibition of cyclin E-dependent kinases is required in p16-mediated growth suppression.


Kimura's disease - An unusual presentation involving subcutaneous tissue, parotid gland and lymph node.
Kimura's disease is a rare chronic inflammatory condition of uncertain etiology which has an affinity for the Asian population. It primarily involves the head and neck region, presenting as deep subcutaneous masses and is often accompanied by regional lymphadenopathy and salivary gland involvement. Peripheral blood eosinophilia and elevated serum immunoglobulin E (IgE) levels are characteristic features and the microscopic picture reveals lymphoid proliferation with eosinophilic infiltration. For years, Kimura's disease was believed to be identical to or part of the same disease spectrum as angiolymphoid hyperplasia with eosinophilia (ALHE). Recent reports, however, have confirmed that the two are, in fact, separate entities. We report a case of Kimura's disease in a 22-year-old Indian male who presented with a subcutaneous mass, parotid enlargement and lymphadenopathy. The clinical presentation was suggestive of Kimura's disease and microscopic examination following biopsy of the lesion allowed us to make a definitive diagnosis.


Mammary collective cell migration involves transient loss of epithelial features and individual cell migration within the epithelium.
Normal mammary morphogenesis involves transitions between simple and multilayered epithelial organizations. We used electron microscopy and molecular markers to determine whether intercellular junctions and apico-basal polarity were maintained in the multilayered epithelium. We found that multilayered elongating ducts had polarized apical and basal tissue surfaces both in three-dimensional culture and in vivo. However, individual cells were only polarized on surfaces in contact with the lumen or extracellular matrix. The basolateral marker scribble and the apical marker atypical protein kinase C zeta localized to all interior cell membranes, whereas PAR3 displayed a cytoplasmic localization, suggesting that the apico-basal polarity was incomplete. Despite membrane localization of E-cadherin and β-catenin, we did not observe a defined zonula adherens connecting interior cells. Instead, interior cells were connected through desmosomes and exhibited complex interdigitating membrane protrusions. Single-cell labeling revealed that individual cells were both protrusive and migratory within the epithelial multilayer. Inhibition of Rho kinase (ROCK) further reduced intercellular adhesion on apical and lateral surfaces but did not disrupt basal tissue organization. Following morphogenesis, segregated membrane domains were re-established and junctional complexes re-formed. We observed similar epithelial organization during mammary morphogenesis in organotypic culture and in vivo. We conclude that mammary epithelial morphogenesis involves a reversible, spatially limited, reduction in polarity and intercellular junctions and active individualistic cell migration. Our data suggest that reductions in polarity and adhesion during breast cancer progression might reflect partial recapitulation of a normal developmental program.


Third-party reproduction in the Internet Age: the new, patient-centered landscape.
The rise of the Internet Age has brought a host of sweeping changes to the landscape of third-party reproduction. What began as a dyadic relationship between doctor and patient has evolved into a more complex system in which patients are able to access information online from a variety of external sources. Patients often seek to play a more active role in their third-party reproductive care, and the Internet allows them to do so. Further, demand for both medical and psychosocial information about donors and donor-conceived siblings, available online through patient forums and genetic registries, has altered the perception of gamete donation from a one-time event to an ongoing relationship. The advantages and disadvantages for patients and providers of this freer flow of information between third-party participants are examined. Search motivations of recipients and offspring, as well as types of information sought, are detailed. Recommendations are made regarding strategies fertility programs can use to optimally support their patients and navigate this new landscape.


Can malaria be eliminated?
Since the perceived failure of the Global Programme for Malaria Eradication in 1969, the eradication of malaria has not been considered a feasible goal. However, in October 2007 the goal of malaria eradication was resurrected by Melinda and Bill Gates, and this aspiration has subsequently been endorsed by the WHO and by the Roll Back Malaria Partnership. This change in direction of malaria control has provoked a vigorous debate within the malaria research and control communities as to whether resurrection of the goal of eradication at this point in time is helpful or likely to be counterproductive. The consensus that has emerged is that eradication of malaria, although theoretically possible, is not likely to be feasible within the medium term using existing control tools. However, malaria elimination (cessation of local transmission) is a realistic short- to medium-term goal for an increasing number of countries that are already bringing malaria under control.


Functional partnership between mGlu3 and mGlu5 metabotropic glutamate receptors in the central nervous system.
mGlu5 receptors are involved in mechanisms of activity-dependent synaptic plasticity, and are targeted by drugs developed for the treatment of CNS disorders. We report that mGlu3 receptors, which are traditionally linked to the control of neurotransmitter release, support mGlu5 receptor signaling in neurons and largely contribute to the robust mGlu5 receptor-mediated polyphosphoinositide hydrolysis in the early postnatal life. In cortical pyramidal neurons, mGlu3 receptor activation potentiated mGlu5 receptor-mediated somatic Ca2+ mobilization, and mGlu3 receptor-mediated long-term depression in the prefrontal cortex required the endogenous activation of mGlu5 receptors. The interaction between mGlu3 and mGlu5 receptors was also relevant to mechanisms of neuronal toxicity, with mGlu3 receptors shaping the influence of mGlu5 receptors on excitotoxic neuronal death. These findings shed new light into the complex role played by mGlu receptors in physiology and pathology, and suggest reconsideration of some of the current dogmas in the mGlu receptor field.


FMRP-dependent Mdm2 dephosphorylation is required for MEF2-induced synapse elimination.
The Myocyte Enhancer Factor 2 (MEF2) transcription factors suppress an excitatory synapse number by promoting degradation of the synaptic scaffold protein, postsynaptic density protein 95 (PSD-95), a process that is deficient in the mouse model of Fragile X Syndrome, Fmr1 KO. How MEF2 activation results in PSD-95 degradation and why this is defective in Fmr1 KO neurons is unknown. Here we report that MEF2 induces a Protein phosphatase 2A (PP2A)-mediated dephosphorylation of murine double minute-2 (Mdm2), the ubiquitin E3 ligase for PSD-95, which results in nuclear export and synaptic accumulation of Mdm2 as well as PSD-95 degradation and synapse elimination. In Fmr1 KO neurons, Mdm2 is hyperphosphorylated, nuclear localized basally, and unaffected by MEF2 activation, which our data suggest due to an enhanced interaction with Eukaryotic Elongation Factor 1α (EF1α), whose protein levels are elevated in Fmr1 KO. Expression of a dephosphomimetic of Mdm2 rescues PSD-95 ubiquitination, degradation and synapse elimination in Fmr1 KO neurons. This work reveals detailed mechanisms of synapse elimination in health and a developmental brain disorder.


Financial and psychological risk attitudes associated with two single nucleotide polymorphisms in the nicotine receptor (CHRNA4) gene.
With recent advances in understanding of the neuroscience of risk taking, attention is now turning to genetic factors that may contribute to individual heterogeneity in risk attitudes. In this paper we test for genetic associations with risk attitude measures derived from both the psychology and economics literature. To develop a long-term prospective study, we first evaluate both types of risk attitudes and find that the economic and psychological measures are poorly correlated, suggesting that different genetic factors may underlie human response to risk faced in different behavioral domains. We then examine polymorphisms in a spectrum of candidate genes that affect neurotransmitter systems influencing dopamine regulation or are thought to be associated with risk attitudes or impulsive disorders. Analysis of the genotyping data identified two single nucleotide polymorphisms (SNPs) in the gene encoding the alpha 4 nicotine receptor (CHRNA4, rs4603829 and rs4522666) that are significantly associated with harm avoidance, a risk attitude measurement drawn from the psychology literature. Novelty seeking, another risk attitude measure from the psychology literature, is associated with several COMT (catechol-O-methyl transferase) SNPs while economic risk attitude measures are associated with several VMAT2 (vesicular monoamine transporter) SNPs, but the significance of these associations did not withstand statistical adjustment for multiple testing and requires larger cohorts. These exploratory results provide a starting point for understanding the genetic basis of risk attitudes by considering the range of methods available for measuring risk attitudes and by searching beyond the traditional direct focus on dopamine and serotonin receptor and transporter genes.


Is supramolecular filament chirality the underlying cause of major morphology differences in amyloid fibrils?
The unique enhanced sensitivity of vibrational circular dichroism (VCD) to the formation and development of amyloid fibrils in solution is extended to four additional fibril-forming proteins or peptides where it is shown that the sign of the fibril VCD pattern correlates with the sense of supramolecular filament chirality and, without exception, to the dominant fibril morphology as observed in AFM or SEM images. Previously for insulin, it has been demonstrated that the sign of the VCD band pattern from filament chirality can be controlled by adjusting the pH of the incubating solution, above pH 2 for "normal" left-hand-helical filaments and below pH 2 for "reversed" right-hand-helical filaments. From AFM or SEM images, left-helical filaments form multifilament braids of left-twisted fibrils while the right-helical filaments form parallel filament rows of fibrils with a flat tape-like morphology, the two major classes of fibril morphology that from deep UV resonance Raman scattering exhibit the same cross-β-core secondary structure. Here we investigate whether fibril supramolecular chirality is the underlying cause of the major morphology differences in all amyloid fibrils by showing that the morphology (twisted versus flat) of fibrils of lysozyme, apo-α-lactalbumin, HET-s (218-289) prion, and a short polypeptide fragment of transthyretin, TTR (105-115), directly correlates to their supramolecular chirality as revealed by VCD. The result is strong evidence that the chiral supramolecular organization of filaments is the principal underlying cause of the morphological heterogeneity of amyloid fibrils. Because fibril morphology is linked to cell toxicity, the chirality of amyloid aggregates should be explored in the widely used in vitro models of amyloid-associated diseases.


An examination of suicide attempts among incarcerated sex offenders.
Little is known about suicide attempts among sex offenders. This study examines the rates of nonfatal suicide attempts among a sample (N = 3,030) of incarcerated male sex offenders. Overall, the authors found that 14% of sex offenders in the study sample had made a suicide attempt at some point in their lives. Of those, 11% had reported a suicide attempt prior to incarceration, 0.5% had made a suicide attempt while incarcerated, and 2.5% made suicide attempts both prior to and during incarceration. Sex offenders who made suicide attempts were significantly more likely than those who did not make suicide attempts to have had an abusive childhood, a history of psychiatric problems, intellectual impairment, male victims, and related victims. Suicide attempters also scored higher on actuarial risk measures than nonattempters. No differences were found in attempter status between sex offenders who committed sex offenses against children and those who committed sex offenses against adults. A history of psychiatric problems and treatment as well as childhood abuse/neglect and perpetration against male victims predicted suicide attempter status. These findings are discussed as they pertain to suicide prevention, risk assessment, and the collateral consequences of sex offender legislation.


Identification of bacteria in total mixed ration silage produced with and without crop silage as an ingredient.
As a forage source for total mixed ration (TMR) silage production, locally produced crop silage is now used in addition to imported hay. This type of TMR ensiling is regarded as a two-step fermentation process; hence, a survey was carried out to determine whether the bacteria in crop silage affect the subsequent TMR ensiling. Fermentation product contents and bacterial community were determined for TMR silage and its ingredient silages collected in August, October and November. August product contained corn, sorghum and Italian ryegrass silages, October product had wheat silage exclusively and November product did not include any crop silages. Acetic acid, lactic acid, 2,3-butanediol and ethanol were predominant fermentation products in corn, sorghum, Italian ryegrass and wheat silages, respectively. Robust lactic acid fermentation was seen in TMR silage, even if acetate-type and alcohol-type silages were mixed as ingredients. The finding that bacterial community of the TMR silage appeared unrelated to those of ingredient silage supported this. Silages of various fermentation types can therefore be formulated without interfering with lactate-type fermentation in TMR silage.


Comparisons of trabecular and cortical bone in late adolescent black and white females.
Few childhood studies have investigated racial differences in volumetric bone mineral density (vBMD), bone geometry, and bone strength indices measured by three-dimensional bone imaging. The purpose of this study was to compare trabecular and cortical bone parameters at the radius and tibia between late adolescent white and black females using peripheral quantitative computed tomography (QCT). White (n = 25) and black females (n = 25), 18-19 years of age, were pair-matched for age, height, and fat-free soft tissue mass. Peripheral QCT scans were obtained at the 4% (trabecular bone), 20% (cortical bone), and 66% [muscle cross-sectional area (CSA)] sites from the distal metaphyses. Bone strength was determined from vBMD and bone geometry to calculate bone strength index (BSI; trabecular site) and polar strength-strain index (SSI; cortical site). Radial SSI was not different between groups; however, blacks had greater radial BSI (P = 0.02) than whites. After adjustment for the longer forearm in blacks, the greater radial BSI in blacks no longer remained. At the tibia, blacks versus whites had greater bone strength at the trabecular and cortical bone sites (BSI, P = 0.03; SSI, P = 0.04, respectively). When controlling for differences in tibial length and muscle CSA, the higher estimates of bone strength persisted in blacks versus whites (BSI, P = 0.01; SSI, P = 0.02). Our data suggest that when differences in body size are considered, late adolescent black versus white females have a stronger bone profile, due to greater bone geometry and vBMD, at the trabecular and cortical regions of the tibia but not at the radius.


Reproducibility and variability of the rectal mucosal proliferation index using proliferating cell nuclear antigen immunohistochemistry.
Rectal mucosal proliferation has been shown to be increased in patients with neoplastic lesions of the large bowel and may serve as a marker of risk for colorectal malignancy. We conducted analyses to determine reliability and components of variability that might suggest optimal analysis strategies for studies of proliferation. Endoscopic pinch biopsies were obtained from 17 adult patients, labeled using proliferating cell nuclear antigen, scored using strict rules, and then rescored. Labeling index, defined as the proportion of labeled cells in a crypt, was calculated for each crypt, biopsy, subject, and group. There was excellent reproducibility. The technician was able to select previously scored crypts 95% of the time. The overall labeling index was identical on repeat. There was considerable variability in labeling index among crypts from a single biopsy and between biopsies of a single subject. Variance component estimates suggested that 20% of the variability of labeling index was due to subject, 30% due to the biopsy within a subject, and 50% due to crypts within a biopsy. There were substantial gains in statistical power by scoring two biopsies rather than one. There was less gain from further increases in biopsy number. There was little statistical advantage for counting more than 8 crypts/biopsy. Demonstrating a decrease of 25% in the mean labeling index with 90% power could require more than 100 subjects/group. We conclude that proliferating cell nuclear antigen is an extremely reproducible method to determine proliferation index. There is considerable variability among subjects, biopsies, and crypts.(ABSTRACT TRUNCATED AT 250 WORDS)