Automated electronic reminders to facilitate primary cardiovascular disease prevention: randomised controlled trial.
Primary care databases contain cardiovascular disease risk factor data, but practical tools are required to improve identification of at-risk patients. To test the effects of a system of electronic reminders (the 'e-Nudge') on cardiovascular events and the adequacy of data for cardiovascular risk estimation. Randomised controlled trial. Nineteen general practices in the West Midlands, UK. The e-Nudge identifies four groups of patients aged over 50 years on the basis of estimated cardiovascular risk and adequacy of risk factor data in general practice computers. Screen messages highlight individuals at raised risk and prompt users to complete risk profiles where necessary. The proportion of the study population in the four groups was measured, as well as the rate of cardiovascular events in each arm after 2 years. Over 38 000 patients' electronic records were randomised. The intervention led to an increase in the proportion of patients with sufficient data who were identifiably at risk, with a difference of 1.94% compared to the control group (95% confidence interval [CI] = 1.38 to 2.50, P<0.001). A corresponding reduction occurred in the proportion potentially at risk but requiring further data for a risk estimation (difference = -3.68%, 95% CI = -4.53 to -2.84, P<0.001). No significant difference was observed in the incidence of cardiovascular events (rate ratio = 0.96, 95% CI = 0.85 to 1.10, P = 0.59). Automated electronic reminders using routinely collected primary care data can improve the adequacy of cardiovascular risk factor information during everyday practice and increase the visibility of the at-risk population.


Fast noncontact measurements of tablet dye concentration.
A non-contact, non-destructive technique for estimating the dye concentration of a tablet is presented. These measurements are performed by an optoelectronic system capable for fast acquisition of two-dimensional distribution of reflection spectra with high spatial resolution by using a subspace vector model of surface reflection. Vector components representing compressed spectral data are used directly (without reconstruction of the reflection spectra) for discrimination of tablets with small dye-concentration difference. Analysis of the data obtained after tablet illumination by 7 mutually orthogonal spectral functions allows us to find a single optimal spectral function which is enough for estimating the dye concentration. Using the optimal spectral function, either the mean concentration of riboflavin or distribution of the concentration over the tablet surface can be evaluated with high rate which ensures application of the technique for online quality control of each tablet.


Induction of vitellogenin and gonadal impairment in chub (Leuciscus cephalus L.) after exposure to 17beta-estradiol and testosterone.
A controlled laboratory study was carried out to quantify vitellogenin (VTG) concentrations in a common cyprinid freshwater fish, the chub (Leuciscus cephalus L.), exposed to steroid hormones. The effect of 17betaestradiol, testosterone and testosterone-estradiol mixture was investigated on vitellogenin induction. Gonad status was also determined. Oral exposure to estradiol and a testosterone-estradiol mixture increased (p < 0.01) blood plasma concentrations of VTG in blood plasma of both sexes. The testosterone-estradiol mixture had a negative effect on the investigated chub gonads. The effects were signified by histological changes when compared to control fish. Our results showed a significant VTG increase in blood plasma of both sexes, indicating that vitellogenic response in the chub is sensitive to steroid hormones.


The contribution of lumbar sympathetic neurones activity to rat's skin blood flow oscillations.
Skin blood flow on the rat's paws using laser Doppler flowmeter, electrical activity of the heart (ECG) and respiration were measured simultaneously. The signals were recorded for 20 minutes, both before and after denervation, at core temperature 37 degrees C and 38.5 degrees C, that was maintained constant during the recordings. Spinal nerve fibres, at the level L3-L4, were transected. Experiments were performed on 15 adult Wistar rats under general anaesthesia. The oscillations in the measured signals were analysed in the time-frequency domain using wavelet transform. On the frequency region from 0.7 Hz to 5 Hz two characteristic peaks were observed in the skin blood flow spectrum. They correspond to the main peaks in the spectra of the ECG (around 3.3 Hz) and respiration (around 1.3 Hz). Several additional peaks were observed in the low frequency region, from 0.01 to 0.7 Hz, in all measured signals. In this frequency region the relative energy contribution of the blood flow oscillations decreased after denervation only in the denervated left hind paw. This difference was not statistically significant at 37 degrees C (p=0.098, Kruskal-Wallis test) but became statistically significant at 38.5 degrees C (p=0.017). Relative energy contribution of the low frequency region, from 0.01 to 0.7 Hz, decreased 2.5-fold in the blood flow of the denervated paw. Within this region the relative energy contribution decreased significantly in two intervals, from 0.01 to 0.08 Hz and from 0.08 to 0.2 Hz (p=0.023). In the higher frequency region, from 0.7 to 5 Hz, o statistically significant differences were obtained in any paws when compared before and after denervation at the same core temperature. We conclude that the activity of lumbar sympathetic neurones contributes to low frequency skin blood flow oscillations.


The Stillbirth Collaborative Research Network (SCRN) placental and umbilical cord examination protocol.
The Stillbirth Collaborative Research Network (SCRN) was organized to study the scope and causes of stillbirth (SB) in the United States. The objective of this report is to describe the approach used for the placental examination performed as part of the study. The SCRN consists of a multidisciplinary team of investigators from five clinical sites, the National Institute of Child Health and Human Development, and the Data Coordination and Analysis Center. The study is a population-based cohort and nested case-control study, with prospective enrollment of women with SB and live births (LB) at the time of delivery. Detailed and standardized postmortem examination was performed on SB and placental examination in both groups. A total of 663 women with SB and 1932 women with LB were enrolled into the case-control study. In the SB group, there were 707 fetuses. Of these cases, 654 (98.6%) had placental examination. Of these LB controls, 1804 (93.4%) had placental examination. This is the largest prospective study to include population-based SB and LB, using standardized postmortem and placental examination, medical record review, maternal interview, collection of samples, and a multidisciplinary team of investigators collaborating in the analyses. Thus it has the potential to provide high-level evidence regarding the contribution of placental abnormalities to stillbirth.


Strain patterns during tensile, compressive, and shear fatigue of human cortical bone and implications for bone biomechanics.
It is a common theme in basic bone biomechanics and in biomechanical applications that much of the behavior can be determined and is dictated by the level of strain, whether this pertains to bone physiology, bone remodeling, osseoinduction, osseointegration, or the development of damage. The development of damage, demonstrated by stiffness loss measurements, has already been reported in detail in the literature. However, the systematic study of the development of "plastic" (residual) strains, which are associated with the inelastic mechanical behavior of bone tissue, has generally been overlooked. The present study compares the rates at which the elastic (e(a)) and plastic components (e(p)) of strain developed during tensile, compressive, and shear fatigue in human cortical bone of six individuals aged between 53 and 79 years. The overall hypothesis of this investigation is that there is a common underlying factor in the damage-related behavior of bone, which may allow us to link together the various aspects of the damage related behavior of bone. The rate of development of plastic strain (Deltae(p)/DeltaN) and the rate of growth in elastic strain amplitude (Deltae(a)/DeltaN) are described as a function of the stress (sigma), and/or stress normalized by the modulus of elasticity (sigma/E). The implications of our findings are discussed with respect to simple models/mechanisms, which may underlie the observed behavior.


Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS.
Amyotrophic Lateral Sclerosis (ALS), is a fatal neurodegenerative disorder, with TDP-43 inclusions as a major pathological hallmark. Using a Drosophila model of TDP-43 proteinopathy we found significant alterations in glucose metabolism including increased pyruvate, suggesting that modulating glycolysis may be neuroprotective. Indeed, a high sugar diet improves locomotor and lifespan defects caused by TDP-43 proteinopathy in motor neurons or glia, but not muscle, suggesting that metabolic dysregulation occurs in the nervous system. Overexpressing human glucose transporter GLUT-3 in motor neurons mitigates TDP-43 dependent defects in synaptic vesicle recycling and improves locomotion. Furthermore, PFK mRNA, a key indicator of glycolysis, is upregulated in flies and patient derived iPSC motor neurons with TDP-43 pathology. Surprisingly, PFK overexpression rescues TDP-43 induced locomotor deficits. These findings from multiple ALS models show that mechanistically, glycolysis is upregulated in degenerating motor neurons as a compensatory mechanism and suggest that increased glucose availability is protective.


Eating well: ageing gracefully!
The potential impact of dietary manipulation on the maintenance of physical and cognitive function between middle and old age has profound consequences for optimization of health, independence and well-being for the latter years. This review article considers four key areas: the role of diet and longevity; potential dietary measures to prevent sarcopenia; diet and cognitive function; and dietary interventions with regard to primary or secondary prevention of age-related chronic disorders. Caloric restriction has been shown to slow ageing and maintain health status in both primates and rats. The evidence has limited applicability to humans, since it is unlikely that 30% reduced diets could be maintained long-term. The causes of sarcopenia, which manifests as loss of strength, disability and reduced quality of life, are multifactorial. However, resistance with ageing to regulatory amino acids known to modulate translation and initiation, particularly leucine, raise possibilities with regard to dietary intervention. The pattern of protein intake appears to be important in whole-body protein retention in older adults. A body of evidence is emerging that associates various dietary factors with a reduction in cognitive decline with age, or a delay in the progression of Alzheimer's disease, particularly with regard to intake of vitamin E and C-containing foods, as well as fish intake. Epidemiological evidence demonstrates a role for dietary intervention in the primary prevention of chronic diseases, even in old age. However, the potentially harmful effects of micronutrient supplementation in the secondary prevention of coronary heart disease raise concern regarding appropriate dietary messages for the elderly. The role of the antioxidants, lycopene, lutein and zeaxanthin, in the prevention of cataracts and age-related macular degeneration support the almost universal dietary guideline 'eat more fruit and vegetables'. In future dietary guidelines for the elderly need to be evidence-based and take into account protective food patterns, rather than target specific foods.


Orientation dependence of trinucleotide CAG repeat instability in Saccharomyces cerevisiae.
To examine the chromosomal stability of repetitions of the trinucleotide CAG, we have cloned CAG repeat tracts onto the 3' end of the Saccharomyces cerevisiae ADE2 gene and placed the appended gene into the ARO2 locus of chromosome VII. Examination of chromosomal DNA from sibling colonies arising from clonal expansion of strains harboring repeat tracts showed that repeat tracts often change in length. Most changes in tract length are decreases, but rare increases also occur. Longer tracts are more unstable than smaller tracts. The most unstable tracts, of 80 to 90 repeats, undergo changes at rates as high as 3 x 10(-2) changes per cell per generation. To examine whether repeat orientation or adjacent sequences alter repeat stability, we constructed strains with repeat tracts in both orientations, either with or without sequences 5' to ADE2 harboring an autonomously replicating sequence (ARS; replication origin). When CAG is in the ADE2 coding strand of strains harboring the ARS, the repeat tract is relatively stable regardless of the orientation of ADE2. When CTG is in the ADE2 coding strand of strains harboring the ARS, the repeat tract is relatively unstable regardless of the orientation of ADE2. Removal of the ARS as well as other sequences adjacent to the 5' end of ADE2 alters the orientation dependence such that stability now depends on the orientation of ADE2 in the chromosome. These results suggest that the proximity of an ARS or another sequence has a profound effect on repeat stability.


For a structured response to the psychosocial consequences of the restrictive measures imposed by the global COVID-19 health pandemic: the MAVIPAN longitudinal prospective cohort study protocol.
The COVID-19 pandemic and associated restrictive measures have caused important disruptions in economies and labour markets, changed the way we work and socialise, forced schools to close and healthcare and social services to reorganise. This unprecedented crisis forces individuals to make considerable efforts to adapt and will have psychological and social consequences, mainly on vulnerable individuals, that will remain once the pandemic is contained and will most likely exacerbate existing social and gender health inequalities. This crisis also puts a toll on the capacity of our healthcare and social services structures to provide timely and adequate care. The MAVIPAN (Ma vie et la pandémie/ My Life and the Pandemic) study aims to document how individuals, families, healthcare workers and health organisations are affected by the pandemic and how they adapt. MAVIPAN is a 5-year longitudinal prospective cohort study launched in April 2020 across the province of Quebec (Canada). Quantitative data will be collected through online questionnaires (4-6 times/year) according to the evolution of the pandemic. Qualitative data will be collected with individual and group interviews and will seek to deepen our understanding of coping strategies. Analysis will be conducted under a mixed-method umbrella, with both sequential and simultaneous analyses of quantitative and qualitative data. MAVIPAN aims to support the healthcare and social services system response by providing high-quality, real-time information needed to identify those who are most affected by the pandemic and by guiding public health authorities' decision making regarding intervention and resource allocation to mitigate these impacts. MAVIPAN was approved by the Ethics Committees of the Primary Care and Population Health Research Sector of CIUSSS de la Capitale-Nationale (Committee of record) and of the additional participating institutions. NCT04575571.


The role of exosomes and miRNAs in drug-resistance of cancer cells.
Chemotherapy, one of the principal approaches for cancer patients, plays a crucial role in controlling tumor progression. Clinically, tumors reveal a satisfactory response following the first exposure to the chemotherapeutic drugs in treatment. However, most tumors sooner or later become resistant to even chemically unrelated anticancer agents after repeated treatment. The reduced drug accumulation in tumor cells is considered one of the significant mechanisms by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell membrane. The mechanisms of treatment failure of chemotherapeutic drugs have been investigated, including drug efflux, which is mediated by extracellular vesicles (EVs). Exosomes, a subset of EVs with a size range of 40-150 nm and a lipid bilayer membrane, can be released by all cell types. They mediate specific cell-to-cell interactions and activate signaling pathways in cells they either fuse with or interact with, including cancer cells. Exosomal RNAs are heterogeneous in size but enriched in small RNAs, such as miRNAs. In the primary tumor microenvironment, cancer-secreted exosomes and miRNAs can be internalized by other cell types. MiRNAs loaded in these exosomes might be transferred to recipient niche cells to exert genome-wide regulation of gene expression. How exosomal miRNAs contribute to the development of drug resistance in the context of the tumor microenvironment has not been fully described. In this review, we will highlight recent studies regarding EV-mediated microRNA delivery in formatting drug resistance. We also suggest the use of EVs as an advancing method in antiresistance treatment.


Haplotype trees and modern human origins.
A haplotype is a multisite haploid genotype at two or more polymorphic sites on the same chromosome in a defined DNA region. An evolutionary tree of the haplotypes can be estimated if the DNA region had little to no recombination. Haplotype trees can be used to reconstruct past human gene-flow patterns and historical events, but any single tree captures only a small portion of evolutionary history, and is subject to error. A fuller view of human evolution requires multiple DNA regions, and errors can be minimized by cross-validating inferences across loci. An analysis of 25 DNA regions reveals an out-of-Africa expansion event at 1.9 million years ago. Gene flow with isolation by distance was established between African and Eurasian populations by about 1.5 million years ago, with no detectable interruptions since. A second out-of-Africa expansion occurred about 700,000 years ago, and involved interbreeding with at least some Eurasian populations. A third out-of-Africa event occurred around 100,000 years ago, and was also characterized by interbreeding, with the hypothesis of a total Eurasian replacement strongly rejected (P < 10(-17)). This does not preclude the possibility that some Eurasian populations could have been replaced, and the status of Neanderthals is indecisive. Demographic inferences from haplotype trees have been inconsistent, so few definitive conclusions can be made at this time. Haplotype trees from human parasites offer additional insights into human evolution and raise the possibility of an Asian isolate of humanity, but once again not in a definitive fashion. Haplotype trees can also indicate which genes were subject to positive selection in the lineage leading to modern humans. Genetics provides many insights into human evolution, but those insights need to be integrated with fossil and archaeological data to yield a fuller picture of the origin of modern humans.


Hospitalization of hospice patients with cancer.
To identify factors associated with hospitalization of elderly hospice patients with cancer and to describe their hospital experiences. Retrospective analysis of the last year of life. Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Medicare beneficiaries dying of lung or colorectal cancer between 1988 and 1998 who enrolled in hospice. Hospitalization after hospice entry. For hospitalized patients, we describe admission diagnoses, aggressiveness of care, and in-hospital death. Of the 23608 patients, 1423 (6.0%) were hospitalized after hospice enrollment. Hospitalization declined over time by 7.0% per year of hospice enrollment. Factors associated with higher hospitalization rates were younger age, male gender, black race/ethnicity, local cancer stage at diagnosis, and hospice enrollment within 4 months of cancer diagnosis. The most common reasons for hospital admission were lung cancer, metastatic disease, bone fracture, pneumonia, and volume depletion. Of the 1423 patients hospitalized, 34.6% received aggressive care and 35.8% died in the hospital. The rates of hospitalization for elderly hospice patients with lung or colorectal cancer appear to be declining. However, patients who are hospitalized undergo aggressive care and often die in the hospital rather than at home. This aggressive care may be consistent with changes in patients' care preferences, but could also reflect the current culture of acute care hospitals, which focuses on curative treatment and is ill-equipped to provide palliative care.


Reversible phenotype in a mouse model of Hutchinson-Gilford progeria syndrome.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare progeroid syndrome caused by mutations in the LMNA gene. Currently there is no treatment available for HGPS, but promising results from several studies using farnesyl transferase inhibitors (FTIs) on cells and animal models of HGPS have been published and a clinical trial using FTIs has been started in patients with HGPS. However, the published data from animal models treated with FTIs come from studies where the treatment was started before pronounced disease development. This study used an inducible transgenic animal model of HGPS with abnormalities of the skin and teeth. After phenotype development, the transgenic expression was turned off and a rapid improvement of the phenotype was noted, within 4 weeks of transgenic suppression. After 13 weeks, the skin was almost indistinguishable from wild-type skin. This study shows that in these tissues, expression of the progeria mutation does not cause irreversible damage and that reversal of disease phenotype is possible, which gives promise for a treatment for this disease.


Change in Fluid and Crystallized Intelligence and Student Achievement: The Role of Intellectual Engagement.
Intellectual engagement (IE) refers to enjoyment of intellectual activities and is proposed as causal for knowledge acquisition. The role of IE for cognitive development was examined utilizing 2-year longitudinal data from 112 ninth graders (average baseline age: 14.7 years). Higher baseline IE predicted higher baseline crystallized ability but not changes therein, and was not associated with fluid ability. Furthermore, IE predicted change in school grades in language but not in mathematics grades or in standardized tests. These findings suggest that IE is not a major predictor of knowledge acquisition in adolescence, where degree of self-determination in intellectual behaviors may be relatively limited. Open questions for future research are addressed, including reciprocal longitudinal associations between IE and academic and cognitive development.


Low thermodynamic but high kinetic stability of an antifreeze protein from Rhagium mordax.
The equilibrium heat stability and the kinetic heat tolerance of a recombinant antifreeze protein (AFP) from the beetle Rhagium mordax (RmAFP1) are studied through differential scanning calorimetry and circular dichroism spectroscopy. In contrast to other insect AFPs studied with this respect, the RmAFP1 has only one disulfide bridge. The melting temperature, Tm , of the protein is determined to be 28.5°C (pH 7.4), which is much lower than most of those reported for AFPs or globular proteins in general. Despite its low melting temperature, both biophysical and activity measurements show that the protein almost completely refolds into the native state after repeated exposure of 70°C. RmAFP1 thus appears to be kinetically stable even far above its melting temperature. Thermodynamically, the insect AFPs seem to be dividable in three groups, relating to their content of disulfide bridges and widths of the ice binding motifs; high melting temperature AFPs (high disulfide content, TxT motifs), low melting temperature but high refolding capability AFPs (one disulfide bridge, TxTxTxT motifs) and irreversibly unfolded AFPs at low temperatures (no disulfide bridges, TxTxTxTxT motifs). The property of being able to cope with high temperature exposures may appear peculiar for proteins which strictly have their effect at subzero temperatures. Different aspects of this are discussed.


Bronchiolitis obliterans after lung transplantation: detection using expiratory HRCT.
The objective of this study was to determine if air trapping, as detected on expiratory high-resolution CT (HRCT), is useful as an indicator of bronchiolitis obliterans (BO) in lung transplant recipients. Corresponding inspiratory and expiratory HRCT images at five different levels and spirometry were obtained in 21 lung transplant recipients. Eleven patients had BO proved by transbronchial biopsy specimens; the remaining 10 patients had no pathologic or functional evidence of airways disease. Two "blinded" observers assessed the inspiratory images for the presence of bronchiectasis and mosaic pattern of lung attenuation, and the expiratory images for presence and extent of air trapping. Statistical comparison of the frequency of HRCT findings between patients with and without BO was performed using Fisher's Exact Test. On inspiratory images, bronchiectasis and mosaic pattern of lung attenuation were present in 4 (36%) and 7 (64%) of 11 patients with BO, and 2 (20%) and 1 (10%) of 10 patients without BO (p>0.05 and p<0.05), respectively. The sensitivity, specificity, and accuracy of bronchiectasis and mosaic pattern for BO were 36%, 80%, and 57%, and 64%, 90%, and 70%, respectively. On expiratory images, air trapping was found in 10 of 11 (91%) patients with BO compared to 2 of 10 (20%) patients without BO (p<0.002). Air trapping was found to have a sensitivity of 91%, specificity of 80%, and accuracy of 86% for BO. Air trapping was identified in one patient with BO who had normal results of baseline spirometric function tests. Air trapping, as detected on expiratory HRCT, was the most sensitive and accurate radiologic indicator of BO in the lung transplant population.


Retinal hemorrhage in Plasmodium vivax malaria.
Retinal hemorrhage is a frequently observed sign in Plasmodium falciparum infection. In Plasmodium vivax infection, however, retinal hemorrhage is very rare; only five cases have been reported in the literature. In this case report, we review the literature and the case of 52-year-old man who had retinal hemorrhages in P. vivax infection. We analyzed the structural characteristics of the lesions using fluorescein angiography and spectral-domain optical coherence tomography. Physicians should be aware of the possibility of retinal hemorrhage in malaria patients, even those with P. vivax infection, and should consider a diagnosis of malaria in a patient with unexplained retinal hemorrhage and fever.


Hyaluronatelyase production by Streptococcus pneumoniae isolated from patients and carriers.
Hyaluronatelyase produced by various microorganisms are capable of degrading hyaluronic acid in connective tissues and initiating the spread of infection by opening an access for the pathogen into host tissues. The present study attempts to determine the distribution of hyaluronatelyase-producing Streptococcus pneumoniae among invasive, non invasive and carriage isolates, and correlate it with the clinical sources, year of isolation, colonial morphology and their serotypes. A total of 100 isolates from various clinical samples were selected and screened for hyaluronatelyase production and presence of the encoding SpnHyl gene. All isolates possessed SpnHyl gene. Ninety-six isolates including 34 carriage isolates were positive for production of hyaluronatelyase. Four hyaluronatelyase-negative isolates were from blood (2 isolates) and sputum (2 isolates). No significant association was detected among hyaluronatelyase production and bacterial characteristics except for colonial morphology (p = 0.040). High percentages of hyaluronatelyase production in these isolates suggest their possible role as human pathogens.


Evaluation of Rhodiola rosea supplementation on skeletal muscle damage and inflammation in runners following a competitive marathon.
Adaptogens modulate intracellular signaling and increase expression of heat shock protein 72 (HSP72). Rhodiola rosea (RR) is a medicinal plant with demonstrated adaptogenic properties. The purpose of this study was to measure the influence of RR supplementation on exercise-induced muscle damage, delayed onset of muscle soreness (DOMS), plasma cytokines, and extracellular HSP72 (eHSP72) in experienced runners completing a marathon. Experienced marathon runners were randomized to RR (n=24, 6 female, 18 male) or placebo (n=24, 7 female, 17 male) groups and under double-blinded conditions ingested 600mg/day RR extract or placebo for 30days prior to, the day of, and seven days post-marathon. Blood samples were collected, and vertical jump and DOMS assessed the day before, 15min post- and 1.5h post-marathon. DOMS was also assessed for seven days post-marathon. Marathon race performance did not differ between RR and placebo groups (3.87±0.12h and 3.93±0.12h, respectively, p=0.722). Vertical jump decreased post-marathon (time effect, p<0.001) with no difference between groups (interaction effect, p=0.673). Post-marathon DOMS increased significantly (p<0.001) but the pattern of change did not differ between groups (p=0.700). Myoglobin (Mb), creatine phosphokinase (CPK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin (IL)-6, IL-8, IL-10, monocyte chemotactic protein-1 (MCP-1), granulocyte-colony-stimulating factor (G-CSF), C-reactive protein (CRP), and eHSP72 all increased post-marathon (all p<0.001), with no group differences over time (all p>0.300). In conclusion, RR supplementation (600mg/day) for 30days before running a marathon did not attenuate the post-marathon decrease in muscle function, or increases in muscle damage, DOMS, eHSP72, or plasma cytokines in experienced runners.


Regulation of liver metabolism by the endosomal GTPase Rab5.
The liver maintains glucose and lipid homeostasis by adapting its metabolic activity to the energy needs of the organism. Communication between hepatocytes and extracellular environment via endocytosis is key to such homeostasis. Here, we addressed the question of whether endosomes are required for gluconeogenic gene expression. We took advantage of the loss of endosomes in the mouse liver upon Rab5 silencing. Strikingly, we found hepatomegaly and severe metabolic defects such as hypoglycemia, hypercholesterolemia, hyperlipidemia, and glycogen accumulation that phenocopied those found in von Gierke's disease, a glucose-6-phosphatase (G6Pase) deficiency. G6Pase deficiency alone can account for the reduction in hepatic glucose output and glycogen accumulation as determined by mathematical modeling. Interestingly, we uncovered functional alterations in the transcription factors, which regulate G6Pase expression. Our data highlight a requirement of Rab5 and the endosomal system for the regulation of gluconeogenic gene expression that has important implications for metabolic diseases.


Factors that determine the magnitude and time course of human H-reflexes in locomotion.
The soleus H-reflex amplitude is deeply modulated during locomotion in humans (Capaday and Stein, 1986). Moreover, at a constant stimulus intensity, the slope of the relationship between the amplitude of the soleus H-reflex and the background electromyogram (EMG) changes with different locomotor tasks (Capaday and Stein, 1987a). Two further aspects are studied here. First, we recorded the reflex during overlapping speeds of walking (2.0-7.5 km/hr) and running (5-9 km/hr) to determine whether the speed, the motor output, or the form of locomotion was most important in setting the slope of this relationship between H-reflex and background EMG. Second, we determined the time course of change in the H-reflex amplitude and the possible site of action for the reflex depression during the transition from standing to walking. The primary determinant of the slope was found to be the form of locomotion. The differences between running and walking could not be explained entirely by either movement speed or motor output. For walking, the slope varied inversely with the speed and the motor output of locomotion. This compensation in slope as a function of motor output may prevent saturation of the motoneuron pool. The appropriate reflex amplitudes for a particular locomotor pattern are activated rapidly and completely within a reaction time, and simultaneously with the activation of muscle activity for the initiation of walking. Mechanisms for the rapid change seen during the initiation of locomotion most likely act presynaptically on the muscle spindle afferents. The time course and magnitude of this change are correlated with the activity of the tibialis anterior muscle.


Molecular structure upon compression and stability toward oxidation of Langmuir films of unsaturated fatty acids: a vibrational sum frequency spectroscopy study.
Vibrational sum frequency spectroscopy (VSFS) has been used to determine the stability toward oxidation in air of a series of unsaturated fatty acids, measuring as a function of time the changes in the chemical structure and conformational order of films spread on a Langmuir trough. The fatty acids studied consisted of a 20-carbon backbone with increasing numbers of cis double bonds in the chain: 11c-eicosenoic acid (20:1 EA, omega-9), 11c,14c-eicosadienoic acid (20:2 EA, omega-6), and 11c,14c,17c-eicosatrienoic acid (20:3 EA, omega-3). Measurements at constant surface pressure show that double bonds are lost from the surface region and that drops in intensity of the vinyl CH stretch are detectable within a few minutes of spreading the monolayer. The results are consistent with the fatty acid peroxidation free radical mechanism. The sum frequency spectra also reveal that what remains on the surface is conformationally more disordered with a larger number of gauche defects. The oxidation kinetics are found to be strongly dependent on the packing density of the monolayer, being more stable at higher pressures. Oxidation can be avoided by purging the system in an inert atmosphere. Finally, the molecular structure upon compression was tracked in unoxidized monolayers. The results suggest that the packing and orientation of the double bond sections of all three unsaturated fatty acids show remarkable similarities, with the direction of the double bonds approximately parallel to each other irrespective of the number of unsaturations in the chain, with the 20:3 EA probably forming "iron-angle" structures. The possibility of unsaturated chains in a "hairpin" configuration is discarded for area per molecules smaller than approximately 50 A(2), which corresponds to the lowest surface pressure measured with VSFS.


Structure of the RXR-RAR DNA-binding complex on the retinoic acid response element DR1.
The 9-cis retinoic acid receptor (retinoid X receptor, RXR) forms heterodimers with the all-trans retinoic acid receptor (RAR) and other nuclear receptors on DNA regulatory sites composed of tandem binding elements. We describe the 1.70 A resolution structure of the ternary complex of RXR and RAR DNA-binding regions in complex with the retinoic acid response element DR1. The receptors recognize identical half-sites through extensive base-specific contacts; however, RXR binds exclusively to the 3' site to form an asymmetric complex with the reverse polarity of other RXR heterodimers. The subunits associate in a strictly DNA-dependent manner using the T-box of RXR and the Zn-II region of RAR, both of which are reshaped in forming the complex. The protein-DNA contacts, the dimerization interface and the DNA curvature in the RXR-RAR complex are distinct from those of the RXR homodimer, which also binds DR1. Together, these structures illustrate how the nuclear receptor superfamily exploits conformational flexibility and locally induced structures to generate combinatorial transcription factors.


Tetrapolar fungal mating types: sexes by the thousands.
In order to achieve genetic rearrangement in a sexual cycle, eukaryotes go through the processes of meiosis and mating. Different mating types assure that mating is only possible between two genetically diverse individuals. Basidiomycetous fungi display thousands of different mating types that are determined by two genetically unlinked loci. One locus is multiallelic and contains genes for homeodomain transcription factors which are able to form heterodimers. The activation of target genes is dependent on heterodimers formed from the monomeric transcription factor proteins originating from different alleles of this genetic locus. The interactions between the two monomeric transcription factors and the activation of target genes by the heterodimeric proteins make this regulatory system both complex and interesting. The second locus contains a pheromone receptor system: the pheromone receptor is similar to the G protein-linked serpentine receptors in Saccharomyces cerevisiae that activate the pheromone response via a phosphorylation signal transduction cascade in S. cerevisiae. This pheromone perception is a trigger of sexual development and not, as with yeast, itself under control of mating type genes. Rather it directly senses diversity at the mating type loci. Whereas heterobasidiomycetes display a bi-allelic structure for this locus with recognition between one receptor and the opposite pheromone, homobasidiomycetes contain multiple specificities for pheromone receptors and pheromones.


Development of a liposome formulation for D-cycloserine local delivery.
Multilamellar liposomes loaded with D-cycloserine (D-CS) were prepared by a thin layer evaporation technique, followed by freezing and thawing cycles. Charged components and bioadhesive material, such as distearolylphosphatitylethanolamine covalently coupled with methoxypolyethyleneglycol, were used to prepare liposomes with different physico-chemical and technological properties. Negatively charged liposomes showed higher D-CS encapsulation efficiency (about 37%, w/w) than neutral and positively charged liposomes (about 5 and 17%, w/w, respectively). All formulations showed in vitro, after a burst effect, a prolonged release of the encapsulated drug. Lipid vesicles made of dipalmitoylphosphatidylcholine (DPPC) were used as a biomembrane model to evaluate in vitro the interaction of D-CS with biological membranes. Differential scanning calorimetry was used as a simple and noninvasive technique of analysis. D-CS was distributed in the aqueous compartments of liposomes for interaction with the phospholipid polar head-groups (enhancement of Delta H value). However, due to its high diffusibility the drug was also able to freely permeate through DPPC liposomes, altering during this passage the hydrophobic domains of the bilayers. Stability studies were performed at different temperatures and pH values to assay the integrity of the drug during the liposome production steps. D-CS was rapidly degraded at acidic pH, but no significant hydrolysis was observed at pH 7.4 after 7 days.


Impact of Ocean Acidification on the Intestinal Microbiota of the Marine Sea Bream (Sparus aurata L.).
Within a scenario of increasing atmospheric CO2 and ocean acidification (OA), it is highly relevant to investigate its impacts not only on fish performance but also on fish intestinal microbiome and how that reflects on host performance and health. The main objective of this study was to establish if the intestinal microbiota of the sea bream (Sparus aurata) was affected by high level of CO2 in line with the predictions for this century. The bacterial communities of the intestinal fluid were characterized in animals kept at the present-day level of CO2 (400 μatm) and in animals switched to high CO2 (1200 μatm) for 1 month. Bacterial taxa identification was based on molecular methods, using the DNA coding for the 16S ribosomal RNA and primers targeting the regions V1-V3. Amplicons obtained from DNA samples of animals in the same tank were combined, cloned to obtain a bacterial DNA library, and the clones were sequenced. No significant differences were found between the two treatments for alpha diversity. However, beta diversity analysis revealed distinct dysbiosis in response to hypercapnia, with phylum Firmicutes absent from the bacterial communities of fish exposed to 1200 μatm CO2, whereas Proteobacteria relative abundance was increased at elevated CO2, due to the presence of Gammaproteobacteria (Vibrionaceae and Alteromonadaceae), a class not present in the control samples. This study provides a first glimpse at the impact of OA in fish intestinal microbiota and highlights potential downstream effects to the general condition of fishes under hypercapnia.


DNA sequence analysis of the genetic environment of various blaCTX-M genes.
Over a 3 year period (2000-2003) 21 Escherichia coli, 5 Klebsiella pneumoniae, 1 Serratia marcescens and 1 Proteus mirabilis producing CTX-M-type beta-lactamase were collected from five different hospitals in Paris, France. This study was conducted to analyse the genetic environment of these 28 bla(CTX-M) genes. Antimicrobial susceptibility testing was performed by the disc diffusion method and MICs of various beta-lactams were determined by an agar dilution method. PCR was used to detect and sequence alleles encoding CTX-M, TEM, SHV and CMY enzymes. The genetic environment was analysed by amplification and direct sequencing using various set of PCR primers or cloning in pBK-CMV. Sequence analysis revealed that these isolates contained seven different bla(CTX-M) genes: bla(CTX-M-1) (4 strains), bla(CTX-M-2) (2 strains), bla(CTX-M-3) (4 strains), bla(CTX-M-9) (1 strain), bla(CTX-M-14) (5 strains), bla(CTX-M-15) (11 strains), bla(CTX-M-24) (1 strain). TEM-1 was associated with CTX-M-type enzymes in 15 isolates. Two strains produced both CTX-M-15 and SHV-2 or CTX-M-14 and CMY-2. In 25 strains the insertion sequence ISEcp1 was located upstream of the 5' end of the bla(CTX-M) gene. Among these strains, in five isolates, ISEcp1 was disrupted by insertion sequences such as IS26 (in three of them) or IS1 or IS10. Insertion sequence IS903 was found downstream of bla(CTX-M-14) or bla(CTX-M-24). Examination of the other three bla(CTX-M) genes (two bla(CTX-M-2) and one bla(CTX-M-9)) by cloning, sequencing and PCR analysis revealed the presence of complex Class 1 integrons, In35, an integron similar to In60 and a novel integron. This work further confirmed the predominant role of ISEcp1 in the mobilization of bla(CTX-M) genes of the CTX-M-1 cluster and the presence of In35, of an integron similar to In60 and a novel complex Class 1 integron.


Severe pseudomonal infections.
To review the most recent data on severe Pseudomonas aeruginosa infections. The focus will be on clinical studies with an emphasis on the critically ill. The frequency of P. aeruginosa as the etiologic agent of infections associated with high morbidity and mortality in hospitalized patients continues to increase. Unfortunately, pan-resistant isolates are now emerging as a significant clinical problem. Highly or pan-resistant isolates are associated with more frequent inappropriate initial therapy and increased mortality. Prevention relies on limitation of antibiotic pressure. Unfortunately, antibiotic class rotation has not resulted in persistent decreases in resistant isolates and the increased use of treatment protocols may actually increase selection. Because of the frequency of antibiotic resistance in clinical isolates of P. aeruginosa and the high associated mortality, combination, broad-spectrum antibiotic therapy should be used for empiric coverage of suspected P. aeruginosa infections. Accurate diagnostic testing can help to discontinue unnecessary antibiotics and decrease the overall selective pressure. Increasing resistance without new antibiotic classes on the horizon suggests the need for better use of available antibiotics and an emphasis on innovative treatment strategies in the future.


TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation.
Innate lymphoid cells (ILCs) are a recently identified family of heterogeneous immune cells that can be divided into three groups based on their differential developmental requirements and expression of effector cytokines. Among these, group 2 ILCs produce the type 2 cytokines interleukin-5 (IL-5) and IL-13 and promote type 2 inflammation in the lung and intestine. However, whether group 2 ILCs reside in the skin and contribute to skin inflammation has not been characterized. We identify a population of skin-resident group 2 ILCs present in healthy human skin that are enriched in lesional human skin from atopic dermatitis (AD) patients. Group 2 ILCs were also found in normal murine skin and were critical for the development of inflammation in a murine model of AD-like disease. Remarkably, in contrast to group 2 ILC responses in the intestine and lung, which are critically regulated by IL-33 and IL-25, group 2 ILC responses in the skin and skin-draining lymph nodes were independent of these canonical cytokines but were critically dependent on thymic stromal lymphopoietin (TSLP). Collectively, these results demonstrate an essential role for IL-33- and IL-25-independent group 2 ILCs in promoting skin inflammation.


Causal Agent of Red Stripe Disease of Rice.
A variety of methods that included natural and synthetic media for isolating bacteria and fungi were used to isolate the causal agent of the red stripe disease of rice. A fungus was isolated consistently from leaves with red stripe symptoms using the blotter method. In this method, surface-sterilized leaves were placed on sterile petri plates, lined with moistened filter paper, and the plates were incubated for 14 days at 28 to 30°C. The fungal isolate was reisolated from the lesions of inoculated plants and reinoculated on test plants that became symptomatic, thus fulfilling Koch's postulates. Based on the morphological characteristics of the fungus, the causal agent of red stripe was identified as a species of Gonatophragmium. Colonies of the latter are slow-growing, reaching an average of 29.0 ± 0.9 mm in diameter after incubation on potato dextrose agar (PDA) for 18 days at 28 to 30°C in the dark. It can be overgrown easily by saprophytes when infected leaves are incubated using the blotter method without sterilization. Yellow-orange pigmentation was observed on PDA with mycelial growth and on filter paper with infected leaves, a unique characteristic which facilitates the isolation of the fungus. Studies are in progress using traditional and molecular techniques to identify the pathogen to the species level.


Ethynylene-linked Figure-Eight Octaphyrin(220.127.116.11.220.127.116.11): Synthesis and Characterization of Its Two Oxidation States.
An octaphyrin(188.8.131.52.184.108.40.206) containing two conjugated ethynylene bridges has been synthesized and characterized. The macrocycle reveals complex conformational dynamics dependent on its protonation and oxidation state. The [40]annulenoid macrocycle and its [38]annulenoid oxidized form display residual macrocyclic ring currents. In spite of its low apparent aromaticity the new octaphyrin is a potent chromophore with a vis-NIR absorption profile strongly influenced by the redox and acid-base chemistry.


Low level or absent in vivo replication of hepatitis C virus and hepatitis G virus/GB virus C in peripheral blood mononuclear cells.
To investigate which subsets of peripheral blood mononuclear cells (PBMCs) are susceptible to infection with hepatitis C virus (HCV) and hepatitis G virus (HGV) or GB virus C (GBV-C), a PCR-based assay using tagged primers in the core region (HCV) and NS3 region (HGV/GBV-C) for the specific detection of negative strand (replicating) viral RNA sequences was developed. In liver biopsy samples both positive and negative strands of HCV RNA were detected, at levels ranging from 3 to 11 x 10(6) RNA copies per 10(6) cells and 3.7-4.2 x 10(3) copies per 10(6) cells respectively, while lower frequencies of positive strands of GBV-C/HGV RNA were detected (from 13 biopsies, the highest frequency was 7.3 x 10(3) per 10(6) cells). In no samples were negative RNA strands detected. To investigate extra-hepatic replication of HCV and GBV-C/HGV, CD4+, CD8+ and B lymphocytes, monocytes and putative dendritic cell populations were separated from PBMCs from ten study subjects. Detection of positive strand HCV RNA was largely confined to B lymphocytes (at levels of up to 5 x 10(3) copies per 10(6) cells), while detection of negative strands was confined to a single subset (dendritic cells) of one of the study individuals. Similarly, GBV-C/HGV was detected at low levels in only twelve of twenty PBMC samples, while negative strands were uniformly absent. The low levels of HCV and GBV-C/HGV RNA in PBMCs suggest that these cells are at most a minor reservoir for virus replication. The absence of detectable replication of GBV-C/HGV suggests that the actual site of GBV-C/HGV replication remains to be discovered.


DSM-III disorders in preadolescent children. Prevalence in a large sample from the general population.
We investigated the prevalence of DSM-III disorders in 792 children aged 11 years from the general population and found an overall prevalence of disorder of 17.6% with a sex ratio (boys-girls) of 1.7:1. The most prevalent disorders were attention deficit, oppositional, and separation anxiety disorders, and the least prevalent were depression and social phobia. Conduct disorder, overanxious disorder, and simple phobia had intermediate prevalences. Pervasive disorders, reported by more than one source, had an overall prevalence of 7.3%. Examination of background behavioral data disclosed that children identified at 11 years as having multiple disorders had a history of behavior problems since 5 years of age on parent and teacher reports. Fifty-five percent of the disorders occurred in combination with one or more other disorders, and 45% as a single disorder.


Catholic identity and charity care in the era of health reform.
Catholic healthcare institutions live amidst tension between three intersecting primary values, namely, a commitment of service to the poor and vulnerable, promoting the common good for all, and financially sustainability. Within this tension, the question sometimes arises as to whether it is ever justifiable, i.e., consistent with Catholic identity, to place limits on charity care. In this article we will argue that the health reform measures of the Affordable Care Act do not eliminate this tension but actually increase the urgency of addressing it. Moreover, we will conclude that the question of limiting charity care in a manner that is consistent with the obligations of Catholic identity around serving the poor and vulnerable, promoting the common good, and remaining financially sustainable is not a question of if, but of how such limits are established. Such limits, however, cannot be established in light of one overriding moral consideration or principle, but must be established in light of a multitude of principles guiding us to a holistic understanding of the interrelatedness of the moral dimensions of Catholic identity.


The psychological and social characteristics of patients referred for NHS cosmetic surgery: quantifying clinical need.
Elective cosmetic surgery is expanding in the UK in both the public and private sectors. Because resources are constrained, many cosmetic procedures are being excluded within the National Health Service. If guidelines on who can receive such surgery are to be evidence-based, information is needed about the level of dysfunction in patients referred for elective surgery and whether this is related to their degree of physical abnormality. Consecutive patients referred to a regional plastic surgery and burns unit for assessment for elective cosmetic surgery completed standardised measures of physical and psychosocial dysfunction, and indicated their perception of the degree of their abnormality and their preoccupation with it. We distinguished between patients referred for physical reasons or appearance reasons only, and compared levels of physical and psychosocial dysfunction in each with published values for community and clinical samples. Surgeons indicated patients' degree of objective abnormality, and we identified the relationship of dysfunction with perceived and objective abnormality and preoccupation. Whether patients sought surgery for physical or appearance reasons, physical function was normal. Those seeking surgery for appearance reasons only had moderate psychosocial dysfunction, but were not as impaired as clinical groups with psychological problems. Patients seeking the correction of minor skin lesions for purely appearance reasons reported excellent physical and psychosocial function. Level of function was related (negatively) to patients' preoccupation with abnormality rather than to their perceived or objective abnormality. In general, patients referred for elective cosmetic surgery did not present with significant levels of dysfunction. Moreover, levels of functioning were related to preoccupation rather than to objective abnormality. Therefore, for most patients, whether surgical treatment is generally appropriate is questionable. Future guidelines must seek to identify the small minority who do have a clinical need for surgery.


Naloxone for severe traumatic brain injury: a meta-analysis.
The efficiency of naloxone for the management of secondary brain injury after severe traumatic brain injury (sTBI) remains undefined. The aim of this study is to evaluate the current evidence regarding the clinical efficiency and safety of naloxone as a treatment for sTBI in mainland China. A systematic search of the China Biology Medicine disc (CBM), China Science and Technology Journal Database (VIP), China National Knowledge Internet (CNKI), and Wan Fang Database was performed to identify randomized controlled trials (RCTs) of naloxone treatment for patients with sTBI in mainland China. The quality of the included trials was assessed, and the RevMan 5.1 software was employed to conduct this meta-analysis. Nineteen RCTs including 2332 patients were included in this study. The odds ratio (OR) showed statistically significant differences between the naloxone group and the control group (placebo) in terms of mortality at 18 months after treatment (OR, 0.51, 95%CI: 0.38-0.67; p<0.00001), prevalence of abnormal heart rates (OR, 0.30, 95%CI: 0.21-0.43; p<0.00001), abnormal breathing rate (OR, 0.25, 95%CI: 0.17-0.36; p<0.00001) at discharge, the level of intracranial pressure at discharge (OR, 2.00, 95%CI: 1.41-2.83; p = 0.0001), verbal or physical dysfunction rate (OR, 0.65, 95%CI: 0.43-0.98; p = 0.04), and severe disability rate (OR, 0.47, 95%CI: 0.30-0.73; p = 0.0001) at 18 months after the treatment. The mean difference (MD) showed statistically significant differences in awakening time at discharge (MD, -4.81, 95%CI: -5.49 to -4.12; p<0.00001), and GCS at 3 days (MD, 1.00, 95%CI: 0.70-1.30; p<0.00001) and 10 days (MD, 1.76, 95%CI: 1.55-1.97; p<0.00001) after treatment comparing naloxone with placebo group. This study indicated that applying naloxone in the early stage for sTBI patients might effectively reduce mortality, control intracranial pressure (ICP), and significantly improve the prognosis.


Surgical trial in lobar intracerebral haemorrhage (STICH II) protocol.
Within the spectrum of spontaneous intracerebral haemorrhage there are some patients with large or space occupying haemorrhage who require surgery for neurological deterioration and others with small haematomas who should be managed conservatively. There is equipoise about the management of patients between these two extremes. In particular there is some evidence that patients with lobar haematomas and no intraventricular haemorrhage might benefit from haematoma evacuation. The STICH II study will establish whether a policy of earlier surgical evacuation of the haematoma in selected patients will improve outcome compared to a policy of initial conservative treatment. An international multicentre randomised parallel group trial. Only patients for whom the treating neurosurgeon is in equipoise about the benefits of early craniotomy compared to initial conservative treatment are eligible. All patients must have a CT scan confirming spontaneous lobar intracerebral haemorrhage (≤1 cm from the cortex surface of the brain and 10-100 ml in volume). Any clotting or coagulation problems must be corrected and randomisation must take place within 48 hours of ictus. With 600 patients, the study will be able to demonstrate a 12% benefit from surgery (2p < 0.05) with 80% power.Stratified randomisation is undertaken using a central 24 hour randomisation service accessed by telephone or web. Patients randomised to early surgery should have the operation within 12 hours. Information about the status (Glasgow Coma Score and focal signs) of all patients through the first five days of their trial progress is also collected in addition to another CT scan at about five days (+/- 2 days). Outcome is measured at six months via a postal questionnaire to the patient. Primary outcome is death or severe disability defined using a prognosis based 8 point Glasgow Outcome Scale. Secondary outcomes include: Mortality, Rankin, Barthel, EuroQol, and Survival. ISRCTN: ISRCTN22153967.


Predicting the rate of cognitive decline in aging and early Alzheimer disease.
To determine prognostic factors affecting the course of Alzheimer disease (AD) and to determine the role of region-specific brain volumes as predictors of cognitive decline. Longitudinal data from 166 normal elderly individuals and 59 early AD patients were analyzed. Brain volumes were extracted from MRI scans using semiautomated recursive segmentation methods. Prognostic factors were considered significant if they had a significant effect on the rate of cognitive decline. In multivariate analysis, higher Clinical Dementia Rating Scale (CDR) score at entry was a significant prognostic factor for an increased rate of cognitive decline. Significant prognostic factors within the baseline CDR = 0 group were base rate of progression and percent total high signal intensity (HSI), percent ventricular, and percent CSF volumes. Base rate of progression, family history, and percent ventricular volume were significant prognostic factors within the CDR = 0.5 group and APOE had a marginally significant effect on the rate of cognitive decline in the CDR = 1 group. Percent total HSI, ventricular, and total CSF volume measures can independently predict the rate of cognitive decline and improve the predictive power of statistical models that use only clinical data. Brain volumetric measures from MRI can be used to estimate the rate of cognitive decline even among normal elderly individuals and thus may aid in the prediction of time of onset of disease.


Diagnostic Performance and Interreader Agreement of a Standardized MR Imaging Approach in the Prediction of Small Renal Mass Histology.
Purpose To assess the diagnostic performance and interreader agreement of a standardized diagnostic algorithm in determining the histologic type of small (≤4 cm) renal masses (SRMs) with multiparametric magnetic resonance (MR) imaging. Materials and Methods This single-center retrospective HIPAA-compliant institutional review board-approved study included 103 patients with 109 SRMs resected between December 2011 and July 2015. The requirement for informed consent was waived. Presurgical renal MR images were reviewed by seven radiologists with diverse experience. Eleven MR imaging features were assessed, and a standardized diagnostic algorithm was used to determine the most likely histologic diagnosis, which was compared with histopathology results after surgery. Interreader variability was tested with the Cohen κ statistic. Regression models using MR imaging features were used to predict the histopathologic diagnosis with 5% significance level. Results Clear cell renal cell carcinoma (RCC) and papillary RCC were diagnosed, with sensitivities of 85% (47 of 55) and 80% (20 of 25), respectively, and specificities of 76% (41 of 54) and 94% (79 of 84), respectively. Interreader agreement was moderate to substantial (clear cell RCC, κ = 0.58; papillary RCC, κ = 0.73). Signal intensity (SI) of the lesion on T2-weighted MR images and degree of contrast enhancement (CE) during the corticomedullary phase were independent predictors of clear cell RCC (SI odds ratio [OR]: 3.19; 95% confidence interval [CI]: 1.4, 7.1; P = .003; CE OR, 4.45; 95% CI: 1.8, 10.8; P < .001) and papillary RCC (CE OR, 0.053; 95% CI: 0.02, 0.2; P < .001), and both had substantial interreader agreement (SI, κ = 0.69; CE, κ = 0.71). Poorer performance was observed for chromophobe histology, oncocytomas, and minimal fat angiomyolipomas, (sensitivity range, 14%-67%; specificity range, 97%-99%), with fair to moderate interreader agreement (κ range = 0.23-0.43). Segmental enhancement inversion was an independent predictor of oncocytomas (OR, 16.21; 95% CI: 1.0, 275.4; P = .049), with moderate interreader agreement (κ = 0.49). Conclusion The proposed standardized MR imaging-based diagnostic algorithm had diagnostic accuracy of 81% (88 of 109) and 91% (99 of 109) in the diagnosis of clear cell RCC and papillary RCC, respectively, while achieving moderate to substantial interreader agreement among seven radiologists. © RSNA, 2018 Online supplemental material is available for this article.


Prevention of mutation, cancer, and other age-associated diseases by optimizing micronutrient intake.
I review three of our research efforts which suggest that optimizing micronutrient intake will in turn optimize metabolism, resulting in decreased DNA damage and less cancer as well as other degenerative diseases of aging. (1) Research on delay of the mitochondrial decay of aging, including release of mutagenic oxidants, by supplementing rats with lipoic acid and acetyl carnitine. (2) The triage theory, which posits that modest micronutrient deficiencies (common in much of the population) accelerate molecular aging, including DNA damage, mitochondrial decay, and supportive evidence for the theory, including an in-depth analysis of vitamin K that suggests the importance of achieving optimal micronutrient intake for longevity. (3) The finding that decreased enzyme binding constants (increased Km) for coenzymes (or substrates) can result from protein deformation and loss of function due to an age-related decline in membrane fluidity, or to polymorphisms or mutation. The loss of enzyme function can be compensated by a high dietary intake of any of the B vitamins, which increases the level of the vitamin-derived coenzyme. This dietary remediation illustrates the importance of understanding the effects of age and polymorphisms on optimal micronutrient requirements. Optimizing micronutrient intake could have a major effect on the prevention of cancer and other degenerative diseases of aging.


Dietary exposure to fumonisins and evaluation of nutrient intake in a group of adult celiac patients on a gluten-free diet.
The main objectives of this study were to estimate dietary fumonisin exposure and nutrient intake in a group of patients diagnosed with celiac disease compared to non-celiac subjects. The fumonisin level in 118 frequently consumed corn-based products was determined and dietary habits were recorded using a 7-day weighed food record. Data were then compared to those obtained for a control group. The fumonisin intake in the celiac patients was significantly higher than in controls, with mean values (± SE) of 0.395 ± 0.049 and 0.029 ± 0.006 μg/kg body weight per day, respectively. With regard to nutritional habits, celiac patients showed a preference for a high fat diet, coupled with a high intake of sweets and soft drinks and a low intake of vegetables, iron, calcium and folate. These findings may have serious health implications for the celiac population due to the widespread occurrence of fumonisins in most of the widely consumed gluten-free products, leading to continuous exposure to this particular mycotoxin. Moreover, the recorded nutritional quality of the celiac patient's diet raises concerns regarding its long-term adequacy and its potential impact on chronic conditions such as type 2 diabetes and cardiovascular diseases.


Functional peptide-based nanoparticles for photodynamic therapy.
Photodynamic therapy as a non-invasive approach has obtained great research attention during the last decade. However, photodynamic therapy still suffers from low tumor selectivity and therapeutic inefficacy due to the unspecific distribution of photosensitizers in normal tissues/cells. To overcome these hurdles, functional peptides have been introduced in photodynamic therapy systems due to their advantages of functional diversity, bioactivity, high biocompatibility and biodegradability. Herein, we review various peptide-based self-assemblies or hybrid nanoparticles that have already been reported to achieve tumor tissue, cell or subcellular organelle targeted photodynamic therapy. The role of tumor microenvironments, cellular/subcellular location, and physical/chemical properties of peptide-based nanoparticles in facilitating the photodynamic therapy efficiency are discussed in-depth. The novel development of peptide-based nanoparticles described here should offer great potential to achieve better photodynamic therapy in tumors.


Relations between psychological avoidance, symptom severity and embarrassment in essential tremor.
Research with community- and clinic-based samples of essential tremor (ET) sufferers has identified embarrassment as a common consequence of the condition, leading to social anxiety and avoidance. We sought to ascertain whether psychological avoidance was related to embarrassment in ET, and whether any such relation was independent of symptom severity. Establishing whether psychological avoidance is related to embarrassment in ET would be a first indicator that mindfulness-based therapeutic approaches may be appropriate for sufferers of ET. Ninety-two participants were recruited through online support groups run by the International Tremor Foundation and the UK National Tremor Foundation, with the self-reported inclusion criteria being a clinical diagnosis of ET. Participants completed three validated questionnaires concerning ET-related embarrassment, ET symptom severity and psychological avoidance. Females had slightly higher embarrassment scores than males, and symptom severity and psychological avoidance made significant moderate (each accounting for 10-15% of variance approximately), but independent contributions to embarrassment scores. These results suggest that to address the potentially debilitating effects of embarrassment in ET, both symptom severity and psychological avoidance need to be targeted, with intervention research being required.


Obstructive sleep apnea syndrome and erectile dysfunction: does long term continuous positive airway pressure therapy improve erections?
The aim of this age-matched, controlled, prospective clinical study was to investigate frequency and degree of erectile dysfunction (ED) in patients with obstructive sleep apnea syndrome (OSAS) and to evaluate the results of only continuous positive airway pressure (CPAP) therapy on ED in patients with OSAS. A total of 90 patients were evaluated for potential OSAS. They were given an International Index of Erectile Function questionnaire (IIEF) and Beck Depression Inventory. Sixty-two patients with the diagnosis of OSAS were regarded as study group. Twenty-eight patients in whom the OSAS was excluded, were regarded as the control group. Biochemical and hormonal laboratory evaluation were performed. Then all patients underwent a full-night in laboratory polysomnography examination. The degree of OSAS were evaluated by an expert from chest diseases department. When compared to the control group, a decrease in IIEF-5 scores was found in patients with OSAS. However, this decrease was not statistically significant. After 3 months of CPAP usage in patients with mild to moderate and severe degree OSAS, improvement in IIEF-5 scores was statistically significant. Mean value of IIEF-5 score was 16.63±5.91 before CPAP and were improved up to 20.92±6.79 (P=0.001). It is not certainly possible to say that OSAS is clearly associated with ED. However, after 3 months of regular CPAP usage, ED complaints in patients with OSAS might improve positively. Trials with larger series may give more conclusive data.


Co-encapsulation of human serum albumin and superparamagnetic iron oxide in PLGA nanoparticles: part I. Effect of process variables on the mean size.
PLGA (poly d,l-lactic-co-glycolic acid) nanoparticles (NPs) encapsulating magnetite nanoparticles (MNPs) along with a model drug human serum albumin (HSA) were prepared by double emulsion solvent evaporation method. This Part I will focus on size and size distribution of prepared NPs, whereas encapsulation efficiency will be discussed in Part II. It was found that mean hydrodynamic particle size was influenced by five important process variables. To explore their effects, a five-factorial, three-level experimental design and statistical analysis were carried out using STATISTICA® software. Effect of process variables on the mean size of nanoparticles was investigated and finally conditions to minimize size of NPs were proposed. GAMS™/MINOS software was used for optimization. The mean hydrodynamic size of nanoparticles ranged from 115 to 329 nm depending on the process conditions. Smallest possible mean particle size can be achieved by using low polymer concentration and high dispersion energy (enough sonication time) along with small aqueous/organic volume ratio.


[Food intake during pregnancy and postpartum according to skin color in Rio de Janeiro, Brazil].
To assess dietary intake during pregnancy and postpartum according to skin color. A longitudinal prospective study was carried out comprising 467 postpartum women aged between 15-45 years in the city of Rio de Janeiro, Southeastern Brazil, in 1999-2001. A food frequency questionnaire was administered at two weeks postpartum (intake covering the pregnancy period) and at six months postpartum (intake covering the postpartum period). Analysis of covariance was performed to evaluate differences in food intake among skin color groups, adjusted for educational level. During pregnancy, black and mulatto women had 13.4% and 9.1% higher energy intake (p=0.009 and p=0.028) and 15.1% and 10.5% higher carbohydrate intake (p=0.005 and p=0.014) than white women, respectively. Energy intake of black and white women exceeded the nutritional recommendations by 34% and 20%, respectively (p=0.035). During the postpartum period, black women had 7.7% higher energy intake (p=0.030) and 14.8% higher lipid intake (p=0.008) than white women, as well as 23.8% and 13% higher saturated fatty acids intake than white (p = 0.003) and mulatto (p = 0.046) women, respectively. The adequacy of lipid and saturated fatty acids intake was higher in black (p=0.024) than white women (p=0.011). The study suggests the need to revise nutritional interventions strategies in the prenatal period, and to implement nutritional guidance programs during the postpartum period in order to adjust food intake to adequate levels, taking into consideration racial differences identified.


Different modes of activating phosphofructokinase, a key regulatory enzyme of glycolysis, in working vertebrate muscle.
Glycolytic flux in white muscle can be increased several-hundredfold by exercise. Phosphofructokinase (PFK; EC 184.108.40.206) is a key regulatory enzyme of glycolysis, but how its activity in muscle is controlled is not fully understood. In order not to neglect integrative aspects of metabolic regulation, we have studied in frogs (Rana temporaria) a physiological form of muscle work (swimming) that can be triggered like a reflex. We analysed swimming to fatigue in well rested frogs, recovery from exercise, and repeated exercise after 2 h of recovery. At various times, gastrocnemius muscles were tested for glycolytic intermediates and effectors of PFK. All metabolites responded similarly to the two periods of exercise, with the notable exception of fructose 2,6-bisphosphate (F2,6P(2)), which we proved to be a most potent activator of frog muscle PFK. The first bout of exercise triggered a more than 10-fold increase in F2,6P(2); PFK activity and the content of F2,6P(2) in muscle were well correlated. F2,6P(2) decreased to pre-exercise levels in fatigued frogs and it virtually disappeared during recovery. Varying by a factor of 70, F2,6P(2) was the most dynamic of all metabolites in muscle. Even more surprisingly, F2,6P(2) did not respond at all to a second bout of exercise. Other activators of PFK, such as Pi, AMP and ADP, are increased as a consequence of increased ATP turnover in contracting muscle cells. This does not apply to F2,6P(2) which is likely to respond to extracellular signals and could be involved in mechanisms by which muscle metabolism is integrated into the metabolism of the whole body. Whether this phenomenon exists in vertebrates other than the frog, and maybe even in humans, and how the content of F2,6P(2)in muscle is controlled are intriguing open questions.


Development and Validation of a Chronic Pancreatitis Prognosis Score in 2 Independent Cohorts.
The clinical course of chronic pancreatitis is unpredictable. There is no model to assess disease severity or progression or predict patient outcomes. We performed a prospective study of 91 patients with chronic pancreatitis; data were collected from patients seen at academic centers in Europe from January 2011 through April 2014. We analyzed correlations between clinical, laboratory, and imaging data with number of hospital readmissions and in-hospital days over the next 12 months; the parameters with the highest degree of correlation were used to develop a 3-stage chronic pancreatitis prognosis score (COPPS). The predictive strength was validated in 129 independent subjects identified from 2 prospective databases. The mean number of hospital admissions was 1.9 (95% confidence interval [CI], 1.39-2.44) and 15.2 for hospital days (95% CI, 10.76-19.71) for the development cohort and 10.9 for the validation cohort (95% CI, 7.54-14.30) (P = .08). Based on bivariate correlations, pain (numeric rating scale), level of glycated hemoglobin A1c, level of C-reactive protein, body mass index, and platelet count were used to develop the COPPS system. The patients' median COPPS was 8.9 points (range, 5-14). The system accurately discriminated stages of disease severity (low to high): A (5-6 points), B (7-9), and C (10-15). In Pearson correlation analysis of the development cohort, the COPPS correlated with hospital admissions (0.39; P < .01) and number of hospital days (0.33; P < .01). The correlation was validated in the validation set (Pearson correlation values of 0.36 and 0.44; P < .01). COPPS did not correlate with results from the Cambridge classification system. We developed and validated an easy to use dynamic multivariate scoring system, similar to the Child-Pugh-Score for liver cirrhosis. The COPPS allows objective monitoring of patients with chronic pancreatitis, determining risk for readmission to hospital and potential length of hospital stay.


Unexpected abundance of coenzyme F(420)-dependent enzymes in Mycobacterium tuberculosis and other actinobacteria.
Regimens targeting Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), require long courses of treatment and a combination of three or more drugs. An increase in drug-resistant strains of M. tuberculosis demonstrates the need for additional TB-specific drugs. A notable feature of M. tuberculosis is coenzyme F(420), which is distributed sporadically and sparsely among prokaryotes. This distribution allows for comparative genomics-based investigations. Phylogenetic profiling (comparison of differential gene content) based on F(420) biosynthesis nominated many actinobacterial proteins as candidate F(420)-dependent enzymes. Three such families dominated the results: the luciferase-like monooxygenase (LLM), pyridoxamine 5'-phosphate oxidase (PPOX), and deazaflavin-dependent nitroreductase (DDN) families. The DDN family was determined to be limited to F(420)-producing species. The LLM and PPOX families were observed in F(420)-producing species as well as species lacking F(420) but were particularly numerous in many actinobacterial species, including M. tuberculosis. Partitioning the LLM and PPOX families based on an organism's ability to make F(420) allowed the application of the SIMBAL (sites inferred by metabolic background assertion labeling) profiling method to identify F(420)-correlated subsequences. These regions were found to correspond to flavonoid cofactor binding sites. Significantly, these results showed that M. tuberculosis carries at least 28 separate F(420)-dependent enzymes, most of unknown function, and a paucity of flavin mononucleotide (FMN)-dependent proteins in these families. While prevalent in mycobacteria, markers of F(420) biosynthesis appeared to be absent from the normal human gut flora. These findings suggest that M. tuberculosis relies heavily on coenzyme F(420) for its redox reactions. This dependence and the cofactor's rarity may make F(420)-related proteins promising drug targets.


Incomplete uptake of EGFR mutation testing and its impact on estimation of mutation prevalence in patients with non-squamous NSCLC: A population-based study in New Zealand.
Epidermal Growth Factor Receptor (EGFR) mutation testing is recommended for patients with non-squamous non-small cell lung cancer (NSCLC) but not all eligible patients get tested, which may bias the mutation prevalence estimated. This study aims to examine trends in the uptake of EGFR mutation testing in patients with non-squamous NSCLC in New Zealand; to develop a composite metric that quantifies the influences of demographic and clinico-pathological factors on the testing uptake; and to estimate the prevalence of EGFR mutation if all patients were tested. This population-based study involved all patients who were diagnosed with non-squamous NSCLC in four health regions in New Zealand between January 2010 and December 2015. Eligible patients were identified from the New Zealand Cancer Registry and information on EGFR mutation testing was obtained through linkage to TestSafe, a clinical information sharing service, and laboratory records. Of 2701 eligible patients, 1059 (39.2%) were tested for EGFR mutation. The testing prevalence increased (3.7% in 2010 to 64.6% in 2014) and the influences of demographic and clinic-pathological factors decreased from 2010 to June 2014, and remained stable afterward. Of the tested patients, 229 (21.6%) were mutation positive with a decreasing trend observed from 2010 (43.8%) to June 2014 (16.8%). The best-fit log-linear model estimated the prevalence of EGFR mutation, if all patients were tested, as 15.5% (95% CI: 13.2%-18.0%). The methods described here allowed a more accurate estimation of the prevalence of EGFR mutation.


Alternative treatments for indoor residual spraying for malaria control in a village with pyrethroid- and DDT-resistant vectors in the Gambia.
Malaria vector control is threatened by resistance to pyrethroids, the only class of insecticides used for treating bed nets. The second major vector control method is indoor residual spraying with pyrethroids or the organochloride DDT. However, resistance to pyrethroids frequently confers resistance to DDT. Therefore, alternative insecticides are urgently needed. Insecticide resistance and the efficacy of indoor residual spraying with different insecticides was determined in a Gambian village. Resistance of local vectors to pyrethroids and DDT was high (31% and 46% mortality, respectively) while resistance to bendiocarb and pirimiphos methyl was low (88% and 100% mortality, respectively). The vectors were predominantly Anopheles gambiae s.s. with 94% of them having the putative resistant genotype kdr 1014F. Four groups of eight residential compounds were each sprayed with either (1) bendiocarb, a carbamate, (2) DDT, an organochlorine, (3) microencapsulated pirimiphos methyl, an organophosphate, or (4) left unsprayed. All insecticides tested showed high residual activity up to five months after application. Mosquito house entry, estimated by light traps, was similar in all houses with metal roofs, but was significantly less in IRS houses with thatched roofs (p=0.02). Residents participating in focus group discussions indicated that IRS was considered a necessary nuisance and also may decrease the use of long-lasting insecticidal nets. Bendiocarb and microencapsulated pirimiphos methyl are viable alternatives for indoor residual spraying where resistance to pyrethroids and DDT is high and may assist in the management of pyrethroid resistance.


Outcome of isolated congenital complete heart block diagnosed in utero.
To establish identifiable prenatal factors in fetal heart block which might predict death in utero, the need for intervention, or the probability of pacemaker requirement. Tertiary referral unit for fetal echocardiography. 36 fetuses with congenital complete heart block and structurally normal hearts identified between 1980 and 1993. Maternal anti-Ro antibody status was documented. Prenatal variables examined included absolute heart (ventricular) rate, change in rate, and development of hydrops fetalis. Postnatally, heart rate, need for pacing, and the indications for pacing were detailed. Of the total of 36 patients, there are 24 survivors; 11 are paced. Of those fetuses which died, two were electively aborted for severe hydrops, seven died in utero, two were immediate postnatal deaths, and one was an unrelated infant death. The trend was for the heart rate to decrease during fetal life and postnatally. Fetuses with deteriorating cardiac function did not always show the lowest heart rates. Bradycardia of less than 55 beats/min in early pregnancy or rapid decrease in heart rate prenatally were poor prognostic signs. Hydrops was also associated with bad outcome, 10 out of the 12 hydropic fetuses dying (83%). Of 10 fetuses presenting with a heart rate above 60/min, nine survived of whom three required pacing. Of seven presenting with heart rates of 50/min or less, only three survived and two of these required pacing. Of the two fetuses with negative maternal anti-Ro antibody status one died in utero and one required heart transplantation after pacemaker insertion. Isolated complete heart block identified in fetal life does not always have a good prognosis. An individual heart rate does not accurately predict the outcome in utero or the need for postnatal pacing. Regular, careful monitoring during pregnancy is required in order to optimise care and timing of any interventions.


Design and statistical issues in the homocysteinemia in kidney and end stage renal disease (HOST) study.
The Homocysteine Study (HOST) Veterans Affairs Cooperative Studies Program No. 453, is a prospective, randomized, two arm, double blind study of patients with end stage renal disease (ESRD) or advanced chronic kidney disease (ACKD, defined as an estimated creatinine clearance of 30 ml/min or less). Its primary objective is to determine whether administration of high doses of three vitamins, folic acid, vitamin B6 and vitamin B12, to lower the high plasma homocysteine levels, will reduce all cause mortality. The secondary objectives are to examine whether the treatment lowers the incidence of myocardial infarction, stroke, amputation of a lower extremity, a composite of death and the foregoing three events, the plasma homocysteine level, and, in ESRD patients undergoing hemodialysis, thrombosis of the vascular access. A unique feature of this trial is that after initial evaluation at enrollment and one return visit the follow up is exclusively by phone (or, if necessary, by mail). The subject is contacted every three months throughout the duration of the study from a central location. The study drug is shipped to the patient from a central location rather supplied locally. In a two year enrollment period, 2006 patients are to be enrolled. The duration of the observation period is four to six years. Data will be stored and analyzed at a coordinating center. The study design has the power to detect a reduction in all cause mortality rate of 17%. Issues related to the unique features of the design of this study are discussed.


Two years' study of Tetanus cases in a Paediatric Intensive Care Unit.
To study the demographic and clinical features, outcome, complications and treatment cost of tetanus patients admitted in Paediatirc Intensive Care Unit (PICU) of Civil Hospital Karachi (CHK). It is a descriptive observational study conducted at Civil Hospital Karachi from July 2013 to June 2015. Patients of tetanus admitted in PICU during the study period were enrolled. Data was collected from the file records of patients and included the demographic profile, clinical presentation, grade of severity, length of stay, complications and outcome. It also included the cost of treatment. Descriptive statistics were applied to describe the results. During the study period, 23 cases of tetanus were admitted in P.I.C.U. twelve were male and 11 female. Majority of cases (13) belonged to age group 2-6 years. Seventeen cases were unvaccinated and 6 had received only BCG & OPV. None was appropriately vaccinated for age. There were 9 cases of post injury tetanus, 6 of them were males, 5 cases of otogenic tetanus and 9 cases had no clinically identifiable portal of entry. Eleven cases belonged to grade III severity of Ablett classification and 6 had grade IV severity. Mortality in our case series was 26%. Autonomic instability was seen in 17 patients and all of them needed ionotropic support. The estimated cost of per day treatment of a tetanus patient with mechanical ventilation was approximatly 31, 979/Pak Rs and without mechanical ventilation was 20,000/Pak Rs. Tetanus is an entirely preventable disease with a high mortality. Treatment is very costly as compared to vaccination which is free of cost. Complete vaccination and proper wound care is the only option to reduce the ongoing burden of tetanus.


Aquaculture genomics, genetics and breeding in the United States: current status, challenges, and priorities for future research.
Advancing the production efficiency and profitability of aquaculture is dependent upon the ability to utilize a diverse array of genetic resources. The ultimate goals of aquaculture genomics, genetics and breeding research are to enhance aquaculture production efficiency, sustainability, product quality, and profitability in support of the commercial sector and for the benefit of consumers. In order to achieve these goals, it is important to understand the genomic structure and organization of aquaculture species, and their genomic and phenomic variations, as well as the genetic basis of traits and their interrelationships. In addition, it is also important to understand the mechanisms of regulation and evolutionary conservation at the levels of genome, transcriptome, proteome, epigenome, and systems biology. With genomic information and information between the genomes and phenomes, technologies for marker/causal mutation-assisted selection, genome selection, and genome editing can be developed for applications in aquaculture. A set of genomic tools and resources must be made available including reference genome sequences and their annotations (including coding and non-coding regulatory elements), genome-wide polymorphic markers, efficient genotyping platforms, high-density and high-resolution linkage maps, and transcriptome resources including non-coding transcripts. Genomic and genetic control of important performance and production traits, such as disease resistance, feed conversion efficiency, growth rate, processing yield, behaviour, reproductive characteristics, and tolerance to environmental stressors like low dissolved oxygen, high or low water temperature and salinity, must be understood. QTL need to be identified, validated across strains, lines and populations, and their mechanisms of control understood. Causal gene(s) need to be identified. Genetic and epigenetic regulation of important aquaculture traits need to be determined, and technologies for marker-assisted selection, causal gene/mutation-assisted selection, genome selection, and genome editing using CRISPR and other technologies must be developed, demonstrated with applicability, and application to aquaculture industries.Major progress has been made in aquaculture genomics for dozens of fish and shellfish species including the development of genetic linkage maps, physical maps, microarrays, single nucleotide polymorphism (SNP) arrays, transcriptome databases and various stages of genome reference sequences. This paper provides a general review of the current status, challenges and future research needs of aquaculture genomics, genetics, and breeding, with a focus on major aquaculture species in the United States: catfish, rainbow trout, Atlantic salmon, tilapia, striped bass, oysters, and shrimp. While the overall research priorities and the practical goals are similar across various aquaculture species, the current status in each species should dictate the next priority areas within the species. This paper is an output of the USDA Workshop for Aquaculture Genomics, Genetics, and Breeding held in late March 2016 in Auburn, Alabama, with participants from all parts of the United States.


Carrier-carrier scattering and negative dynamic conductivity in pumped graphene.
We theoretically examine the effect of carrier-carrier scattering processes on the intraband radiation absorption and their contribution to the net dynamic conductivity in optically or electrically pumped graphene. We demonstrate that the radiation absorption assisted by the carrier-carrier scattering is comparable with Drude absorption due to impurity scattering and is even stronger in sufficiently clean samples. Since the intraband absorption of radiation effectively competes with its interband amplification, this can substantially affect the conditions of the negative dynamic conductivity in the pumped graphene and, hence, the interband terahertz and infrared lasing. We find the threshold values of the frequency and quasi-Fermi energy of nonequilibrium carriers corresponding to the onset of negative dynamic conductivity. The obtained results show that the effect of carrier-carrier scattering shifts the threshold frequency of the radiation amplification in pumped graphene to higher values. In particular, the negative dynamic conductivity is attainable at the frequencies above 6 THz in graphene on SiO2 substrates at room temperature. The threshold frequency can be decreased to markedly lower values in graphene structures with high-κ substrates due to screening of the carrier-carrier scattering, particularly at lower temperatures.


Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.
Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.


Factors of thoracic cage deformity that affect pulmonary function in adolescent idiopathic thoracic scoliosis.
This clinical study examined the association between pulmonary function and thoracic cage deformities in scoliosis. To determine the factors in spinal and thoracic cage deformities that affect pulmonary function in scoliosis. Pulmonary function in scoliosis has generally been evaluated in terms of lateral spinal curvature. No previous report has evaluated changes in pulmonary function taking into consideration measurements reflecting not only spinal curvature but also thoracic cage deformities, although scoliosis is a three-dimensional deformity. A total of 109 patients (mean age, 14.2 years) with adolescent idiopathic right thoracic scoliosis (mean lateral spinal curvature, 37.7 degrees) had full assessment of pulmonary function and a radiographic evaluation from radiographs of the whole spine, Moiré topography, and thoracic computed tomography. Multiple regression analysis (stepwise method) was performed at each vertebral level from T3-T12 to identify the factor that most strongly affects %VC. The correlation coefficient was highest at T9 and next highest at T8, with values of 0.641 (r2 = 0.411, P < 0.0001) and 0.625 (r2 = 0.390, P < 0.0001), respectively. At T9, multiple regression analysis showed that the sagittal diameter of the thoracic cage and the total lung area were identified as factors that most strongly affect %VC. Similarly, the sagittal diameter of the thoracic cage and the rotation angle to the sagittal plane were identified at T8. The factors that reduced %VC were the sagittal diameter of the thoracic cage, total lung area and vertebral rotation at the T8 and T9 levels.


Determination of molecular parameters by fitting sedimentation data to finite-element solutions of the Lamm equation.
A method for fitting experimental sedimentation velocity data to finite-element solutions of various models based on the Lamm equation is presented. The method provides initial parameter estimates and guides the user in choosing an appropriate model for the analysis by preprocessing the data with the G(s) method by van Holde and Weischet. For a mixture of multiple solutes in a sample, the method returns the concentrations, the sedimentation (s) and diffusion coefficients (D), and thus the molecular weights (MW) for all solutes, provided the partial specific volumes (v) are known. For nonideal samples displaying concentration-dependent solution behavior, concentration dependency parameters for s(sigma) and D(delta) can be determined. The finite-element solution of the Lamm equation used for this study provides a numerical solution to the differential equation, and does not require empirically adjusted correction terms or any assumptions such as infinitely long cells. Consequently, experimental data from samples that neither clear the meniscus nor exhibit clearly defined plateau absorbances, as well as data from approach-to-equilibrium experiments, can be analyzed with this method with enhanced accuracy when compared to other available methods. The nonlinear least-squares fitting process was accomplished by the use of an adapted version of the "Doesn't Use Derivatives" nonlinear least-squares fitting routine. The effectiveness of the approach is illustrated with experimental data obtained from protein and DNA samples. Where applicable, results are compared to methods utilizing analytical solutions of approximated Lamm equations.


Fiber-integrated concept to electrically tune pulsed fiber lasers based on step-chirped fiber Bragg grating arrays.
We present a novel method to discretely tune the emission wavelength of pulsed fiber-integrated lasers. As spectral filter, a step-chirped fiber Bragg grating (FBG) array is employed combining a monolithic structure with an unrivaled design freedom enabling large tuning bandwidths as well as tailored spectral characteristics towards fingerprint tuning features. Together with an electrical control mechanism ensuring programmable operation, this tuning method promotes fiber-integrated lasers to access new fields of applications e.g. in biophotonics and distributed sensing. The potential of this tuning concept is investigated based on an Ytterbium-doped fiber laser. The system shows superb emission properties including excellent wavelength stability, high spectral signal contrast (up to 50dB) and narrow linewidth (15GHz) as well as adjustable pulse durations in the nanosecond range with peak powers up to 100W. Additionally, the unique spectral potential of this method is demonstrated by realizing filter designs enabling e.g. a record tuning range of 74nm for fiber-integrated lasers.