Digging deeper: fine-root responses to rising atmospheric CO concentration in forested ecosystems.
Experimental evidence from a diverse set of forested ecosystems indicates that CO2 enrichment may lead to deeper rooting distributions. While the causes of greater root production at deeper soil depths under elevated CO2 concentration ([CO2]) require further investigation, altered rooting distributions are expected to affect important ecosystem processes. The depth at which fine roots are produced may influence root chemistry, physiological function, and mycorrhizal infection, leading to altered nitrogen (N) uptake rates and slower turnover. Also, soil processes such as microbial decomposition are slowed at depth in the soil, potentially affecting the rate at which root detritus becomes incorporated into soil organic matter. Deeper rooting distributions under elevated [CO2] provide exciting opportunities to use novel sensors and chemical analyses throughout the soil profile to track the effects of root proliferation on carbon (C) and N cycling. Models do not currently incorporate information on root turnover and C and N cycling at depth in the soil, and modification is necessary to accurately represent processes associated with altered rooting depth distributions. Progress in understanding and modeling the interface between deeper rooting distributions under elevated [CO2] and soil C and N cycling will be critical in projecting the sustainability of forest responses to rising atmospheric [CO2].


Histamine H(3) receptor-mediated modulation of perivascular nerve transmission in rat mesenteric arteries.
The rat mesenteric artery has been shown to be innervated by adrenergic vasoconstrictor nerves and calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves. The present study was designed to investigate the involvement of histamine H(3) receptors in the neurotransmission of perivascular adrenergic and CGRPergic nerves. The mesenteric vascular beds without an endothelium isolated from male Wistar rats were perfused with Krebs solution and perfusion pressure was measured. In preparations with resting tension, the selective H(3) receptor agonist (R)-α-methylhistamine (α-methylhistamine; 10-100nM) significantly reduced periarterial nerve stimulation (2-8Hz)-induced vasoconstriction and noradrenaline release in the perfusate without an effect on the vasoconstriction induced by exogenously injected noradrenaline (0.5, 1.0nmol). In preparations with active tone produced by methoxamine (2μM) and in the presence of guanethidine (5μM), the periarterial nerve stimulation (1, 2Hz)-induced vasodilator response was inhibited by α-methylhistamine (0.1-1μM) perfusion without affecting vasodilation induced by exogenously injected CGRP (5pmol). Clobenpropit (histamine H(3) receptor antagonist, 1μM) canceled the α-methylhistamine-induced decrease in the periarterial nerve stimulation-induced vasoconstriction and noradrenaline release and periarterial nerve stimulation-induced vasodilation. These results suggest that the stimulation of H(3) receptors located in rat perivascular nerves inhibits presynaptically the neurotransmission of not only adrenergic nerves, but also CGRP nerves, by decreasing neurotransmitters.


A randomized trial of intraarterial treatment for acute ischemic stroke.
In patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion, intraarterial treatment is highly effective for emergency revascularization. However, proof of a beneficial effect on functional outcome is lacking. We randomly assigned eligible patients to either intraarterial treatment plus usual care or usual care alone. Eligible patients had a proximal arterial occlusion in the anterior cerebral circulation that was confirmed on vessel imaging and that could be treated intraarterially within 6 hours after symptom onset. The primary outcome was the modified Rankin scale score at 90 days; this categorical scale measures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). The treatment effect was estimated with ordinal logistic regression as a common odds ratio, adjusted for prespecified prognostic factors. The adjusted common odds ratio measured the likelihood that intraarterial treatment would lead to lower modified Rankin scores, as compared with usual care alone (shift analysis). We enrolled 500 patients at 16 medical centers in The Netherlands (233 assigned to intraarterial treatment and 267 to usual care alone). The mean age was 65 years (range, 23 to 96), and 445 patients (89.0%) were treated with intravenous alteplase before randomization. Retrievable stents were used in 190 of the 233 patients (81.5%) assigned to intraarterial treatment. The adjusted common odds ratio was 1.67 (95% confidence interval [CI], 1.21 to 2.30). There was an absolute difference of 13.5 percentage points (95% CI, 5.9 to 21.2) in the rate of functional independence (modified Rankin score, 0 to 2) in favor of the intervention (32.6% vs. 19.1%). There were no significant differences in mortality or the occurrence of symptomatic intracerebral hemorrhage. In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe. (Funded by the Dutch Heart Foundation and others; MR CLEAN Netherlands Trial Registry number, NTR1804, and Current Controlled Trials number, ISRCTN10888758.).


Information-rate analysis of a fiber-optic transmission system including 2R signal regenerators.
Performance of a single-channel fiber-optic transmission system in which signal regenerators are periodically inserted is analyzed in terms of information rate (IR) considering channel memory. Limitations in using regenerators in a system having non-zero residual dispersion between the regenerators are discussed. It is shown that a type of signal impairment caused by the interaction between the transmission-fiber dispersion and the regenerator nonlinearity is pattern-dependent and will be mitigated by the use of sequence estimation after detection at the receiver.


Accidental ingestion of a component of a fixed orthodontic appliance--a case report.
Most dental patients are treated in the supine position, enhancing the risk of accidental aspiration or swallowing of foreign objects. This article presents a case report of an orthodontic patient who accidentally ingested a section of orthodontic wire and coil spring from a fixed expansion device placed in the maxillary dental arch. Some guidelines for the prevention of such occurrences in the practice and at home, and possible courses of remedial action, are discussed.


Tie them up tight: wrapping by Philoponella vicina spiders breaks, compresses and sometimes kills their prey.
We show that uloborid spiders, which lack the poison glands typical of nearly all other spiders, employ thousands of wrapping movements with their hind legs and up to hundreds of meters of silk line to make a shroud that applies substantial compressive force to their prey. Shrouds sometimes break the prey's legs, buckle its compound eyes inward, or kill it outright. The compressive force apparently results from the summation of small tensions on sticky lines as they are applied to the prey package. Behavioral details indicate that wrapping is designed to compact prey; in turn, compaction probably functions to facilitate these spiders' unusual method of feeding. This is the first demonstration that prey wrapping by spiders compacts and physically damages their prey, rather than simply restraining them.


The use of systems biology and immunological big data to guide vaccine development.
High-throughput technologies applied to the analysis of vaccine responses are likely to reveal the mechanisms responsible for vaccine-induced protection, aid understanding of vaccine safety and help accelerate vaccine development and clinical trials.


Complex comorbidity clusters in OEF/OIF veterans: the polytrauma clinical triad and beyond.
A growing body of research on US Veterans from Afghanistan and Iraq [Operations Enduring and Iraqi Freedom, and Operation New Dawn (OEF/OIF)] has described the polytrauma clinical triad (PCT): traumatic brain injury (TBI), posttraumatic stress disorder (PTSD), and pain. Extant research has not explored comorbidity clusters in this population more broadly, particularly co-occurring chronic diseases. The aim of the study was to identify comorbidity clusters among diagnoses of deployment-specific (TBI, PTSD, pain) and chronic (eg, hypertension, diabetes) conditions, and to examine the association of these clusters with health care utilization and adverse outcomes. This was a retrospective cohort study. The cohort comprised OEF/OIF Veterans who received care in the Veterans Health Administration in fiscal years (FY) 2008-2010. We identified comorbidity using validated ICD-9-CM code-based algorithms and FY08-09 data, followed by which we applied latent class analysis to identify the most statistically distinct and clinically meaningful patterns of comorbidity. We examined the association of these clusters with process measures/outcomes using logistic regression to correlate medication use, acute health care utilization, and adverse outcomes in FY10. In this cohort (N=191,797), we found 6 comorbidity clusters. Cluster 1: PCT+Chronic Disease (5%); Cluster 2: PCT (9%); Cluster 3: Mental Health+Substance Abuse (24%); Cluster 4: Sleep, Amputation, Chronic Disease (4%); Cluster 5: Pain, Moderate PTSD (6%); and Cluster 6: Relatively Healthy (53%). Subsequent health care utilization patterns and adverse events were consistent with disease patterns. These comorbidity clusters extend beyond the PCT and may be used as a foundation to examine coordination/quality of care and outcomes for OEF/OIF Veterans with different patterns of comorbidity.


Therapeutic potential of serotonin 4 receptor for chronic depression and its associated comorbidity in the gut.
The latest estimates from world health organization suggest that more than 450 million people are suffering from depression and other psychiatric conditions. Of these, 50-60% have been reported to have progression of gut diseases. In the last two decades, researchers introduced incipient physiological roles for serotonin (5-HT) receptors (5-HTRs), suggesting their importance as a potential pharmacological target in various psychiatric and gut diseases. A growing body of evidence suggests that 5-HT systems affect the brain-gut axis in depressive patients, which leads to gut comorbidity. Recently, preclinical trials of 5-HT4R agonists and antagonists were promising as antipsychotic and prokinetic agents. In the current review, we address the possible pharmacological role and contribution of 5-HT4R in the pathophysiology of chronic depression and associated gut abnormalities. Physiologically, during depression episodes, centers of the sympathetic and parasympathetic nervous system couple together with neuroendocrine systems to alter the function of hypothalamic-pituitary-adrenal (HPA) axis and enteric nervous system (ENS), which in turn leads to onset of gastrointestinal tract (GIT) disorders. Consecutively, the ENS governs a broad spectrum of physiological activities of gut, such as visceral pain and motility. During the stages of emotional stress, hyperactivity of the HPA axis alters the ENS response to physiological and noxious stimuli. Consecutively, stress-induced flare, swelling, hyperalgesia and altered reflexes in gut eventually lead to GIT disorders. In summary, the current review provides prospective information about the role and mechanism of 5-HT4R-based therapeutics for the treatment of depressive disorder and possible consequences for the gut via brain-gut axis interactions. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.


Significance of routine annual esophagram for early detection of carcinoma of the esophagus.
In order to achieve increased survival rates for patients with carcinoma of the esophagus, early detection of the disease is vital. Serial esophagrams were evaluated to clarify which interval would be effective for early detection of carcinoma of the esophagus during routine examination. One hundred eighty-nine patients with carcinoma of the esophagus were grouped into three, according to the experience and the time of the previous roentgenograms before the definite diagnosis. Five patients were in Group 1, in which roentgenographic examination had been done within 12 months prior to the diagnosis. Retrospective observation revealed a slight but certain abnormal shadow at the same location as the esophageal tumor seen on the second films. In Group 2, seven had received an esophagram between 12 and 24 months before the diagnosis. In contrast to Group 1, neither abnormality nor findings indicating esophageal tumors were detected on the former x-ray films, in all seven cases. Group 2 was characterized by relatively small tumors and low stage of the disease. Mean tumor length was 4.1 +/- 2.9 cm, and three of seven were classified as Stage I and two as Stage IIA. On the other hand, most of the 177 patients in Group 3, with no previous examination of the esophagus within 24 months before the diagnosis, had far advanced disease. Mean tumor length was 6.3 +/- 2.6 cm. Only nine (5.1%) were classified as Stage I, whereas 115 (65.0%) were classified as Stage III or IV. In light of these data, for populations in which esophageal cancer frequently occurs, esophageal examination every 12 months will no doubt contribute towards the early detection of lesions.


Pharmacovigilance in Hospice/Palliative Care: De-Prescribing Combination Controlled Release Oxycodone-Naloxone.
Background: Pharmacovigilance studies in hospice/palliative care provide extra information to improve medication safety. Combination controlled release oxycodone-naloxone offers an alternative opioid with less risk of opioid-induced constipation. Objective: To examine why palliative care clinicians chose to cease oxycodone-naloxone and to explore immediate and short-term benefits and harms of this medication change. Design: A consecutive cohort study. Setting: 112 adults from 13 palliative care centers. Measurements: Reasons for ceasing medication and the harms and benefits that followed this 24 and 72 hours later. Symptom burdens were summarised by the National Cancer Institute Common Terminology Criteria for Adverse Events Toxicity Gradings. Results: Combination medication was most commonly ceased because of poor pain control or impaired hepatic function. The last median oral morphine equivalent oxycodone dose before the switch was 45 mg (range 7.5-240 mg) with 76 switched to an alternative long-acting opioid (initial median oral morphine equivalent dose being 45 mg [range 5-210 mg]). Subgroup analysis of those switched because of clinicians' concerns about hepatic dysfunction demonstrated this group were receiving significantly lower opioid doses pre-cessation compared to those switched because of other reasons( p = 0.007). Regardless of why the medication was changed, improvements in pain and constipation scores were seen, the latter associated with an attendant increase in laxatives. Conclusions: This preliminary work suggests that despite theoretical concerns regarding the effect of the naloxone on opioid doses, most people were switched safely to very similar opioid doses with attendant improvements in pain control.


In vivo evaluation of the adsorptive capacity of activated charcoal for camphor.
Camphor, a cyclic terpene, is the toxic ingredient in many over-the-counter (OTC) products. Early seizure activity due to camphor ingestion often contraindicates the use of traditional decontamination therapies in favor of oral activated charcoal use. No research data supports the affinity of activated charcoal for camphor. This study was conducted to evaluate the effectiveness of activated charcoal in preventing camphor absorption in a rat model. Camphor 40% in cottonseed oil (1 g/kg) was administered to 100 male Sprague-Dawley rats via oral gavage. Aqueous activated charcoal suspension (2 g/kg) was administered to the study group of 50 rats. Serum camphor concentrations were determined by gas chromatography at defined intervals over 10 h. No mortality occurred in either the control or activated charcoal-treated group. Area-under-the-curve bioavailability comparisons of each group revealed no significant differences (activated charcoal 421 micrograms x h/ml vs camphor 409 micrograms x h/ml). The absorption rate constants (Ka) and T 1/2 and elimination rate constants (Ke) and T 1/2 of each group were nearly identical and similar to those reported for humans. These preliminary data indicate the need for careful evaluation of the efficacy of oral activated charcoal administration as the sole means of preventing the absorption of camphor.


[Phosphate binders in renal patients: a point estimate from rationale, through evidences to the real world setting].
Phosphate binders represent a common intervention in renal patients affected by chronic kidney disease and mineral bone disorder (CKD-MBD). Although counteracting P overload through binders adoption is argued by a physiology-driven approach, the efficacy of this intervention on hard endpoints remains poorly evident. The inconsistencies between rationale and methodological weakness, concerning the clinical relevance of P binding in chronic kidney disease, will be herein discussed with special focus on the need of a multi-factorial treatment against CKD-MBD, which is currently more achievable due to the variety of P binders and the rapid evolution of nutritional therapy, dialysis techniques and nursing science.


Effect of Isothermic Dialysis on Intradialytic Hypertension.
The primary outcome was incidence of intradialytic hypertension (IDH) during standard and cooler isothermic dialysate temperatures. Two pair of haemodialysis sessions were done at 37°C (SHD) and at isothermic temperature (IHD). All the four dialysis were done on the same time of the day to negate the changes due to circadian variation in body temperature. Axillary and tympanic temperatures were measured before start of the dialysis and dialysis temperature was adjusted as per axillary temperature. Sixty patients were enrolled and completed the study. The mean delivered dialysate temperature in the intervention group was 36.5 ± 0.2 achieving a 0.5 ± 0.2°C between-group separation. The incidence of IDH and intradialytic hypotension while on SHD and IHD were 79/120 (66%) vs 44/120 (37%), odds ratio (OR) 3.3, 95% confidence interval (CI) (1.96-5.65) and 45/120 (38%) vs 14/120 (12%), OR 4.5, 95% CI (2.3-8.7), respectively. The 4 h time averaged mean systolic blood pressure (SBP) at IHD and SHD were 154 ± 1.7 and 157.2 ± 1.1 mmHg, respectively, the mean difference in SBP being -3.4 mmHg to -3.1 mmHg, 95% CI, P < 0.001. The standard deviation, a measure of BP variability was lower at IHD than at SHD (P < 0.001). In a subgroup analysis during IHD there was a significant reduction of both SBP and diastolic BP during the entire duration of dialysis in 35 out of 60 patients (systolic 4 h mean 154.96 ± 2.22 vs 164.32 ± 1.99 mmHg), (diastolic 4 h mean 79.24 ± 0.82 vs 82.54 ± 0.68 mmHg) - (rANOVA for systolic and diastolic <0.001). This phenomenon of cooler dialysis causing reduction of BP was reproduced in the same group of patients when the IHD was repeated another time (systolic 4 h mean 157.95 ± 1.88 vs 160.65 ± 1.47), (diastolic 4 h mean 79.27 ± 0.74 vs 82.03 ± 1.07) rANOVA for systolic and diastolic <0.001. The incidence of IDH can be reduced significantly by reducing the dialysate temperature to patients' body temperature. Hypertension during dialysis is related to heat gain during dialysis.


Synthesis and bioactivity of antitubercular peptides and peptidomimetics: an update.
Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), an infection that has been declared a global public health emergency by the World Health Organization. Current anti-TB therapies are limited in their efficacy and have failed to prevent the spread of TB, due to the long term drug compliance required and the genesis of multidrug-resistant strains (MDR). The number of chemotherapeutic agents currently available to treat MDR is limited, therefore there is a great need for new anti-TB drugs. Anti-TB peptides and peptidomimetics have emerged as an important and growing class of chemotherapeutic agents. This mini-review provides an update on peptides that exhibit very potent anti-TB activity, and their chemical syntheses, which could potentially be included in the pipeline for new anti-TB drug development.


A theoretical study on mixtures of amino acid-based ionic liquids.
Ionic liquid mixtures containing amino acid anions are studied at the microscopic level using molecular dynamics simulations. The analysis of relevant features such as intermolecular forces (hydrogen bonding), molecular level arrangements, and properties of solvation spheres, allowed inferring the structuring of the studied mixtures. The effects of mixture compositions and the number of cations and anions were analysed in detail. The reported results showed even distribution of anions around cations. The absence of microheterogeneities and low deviations from ideality are due to the similar mechanism of interaction between the considered anions and cations. Likewise, the most relevant features are produced by the development of hydrogen bonding between the amino acid carboxylate group and hydrogen bond donor sites in the cations.


CD14(hi)HLA-DR(dim) macrophages, with a resemblance to classical blood monocytes, dominate inflamed mucosa in Crohn's disease.
Intestinal M play an important role in maintaining gut homeostasis. However, little is known about these cells, their precursors, and their role in intestinal inflammation. Here, we characterize the CD14(+) mononuclear cell populations in intestinal mucosa and blood in patients with CD. Among the LP CD14(+) M, we identified three distinct HLA-DR(+)-expressing subsets. Compared with uninflamed, inflamed mucosa contained a marked increase in the proportion of the CD14(hi)HLA-DR(dim) cellular subset. This subset resembled the classical blood monocytes with low CD16, HLA-DR, and CX3CR1 expression. Classical monocytes migrated efficiently toward CCL2 and released the highest levels of MMP-1 and proinflammatory cytokines when stimulated with immune complexes or LPS. Our findings strongly suggest that it is the classical and not the intermediate or nonclassical monocytes that are the precursors to the dominating intestinal CD14(hi)HLA-DR(dim) subset. This enhances our understanding of CD pathology and may provide new options in treatment.


Characteristic patterns of inter- and intra-hemispheric metabolic connectivity in patients with stable and progressive mild cognitive impairment and Alzheimer's disease.
The change in hypometabolism affects the regional links in the brain network. Here, to understand the underlying brain metabolic network deficits during the early stage and disease evolution of AD (Alzheimer disease), we applied correlation analysis to identify the metabolic connectivity patterns using 18F-FDG PET data for NC (normal control), sMCI (stable MCI), pMCI (progressive MCI) and AD, and explore the inter- and intra-hemispheric connectivity between anatomically-defined brain regions. Regions extracted from 90 anatomical structures were used to construct the matrix for measuring the inter- and intra-hemispheric connectivity. The brain connectivity patterns from the metabolic network show a decreasing trend of inter- and intra-hemispheric connections for NC, sMCI, pMCI and AD. Connection of temporal to the frontal or occipital regions is a characteristic pattern for conversion of NC to MCI, and the density of links in the parietal-occipital network is a differential pattern between sMCI and pMCI. The reduction pattern of inter and intra-hemispheric brain connectivity in the metabolic network depends on the disease stages, and is with a decreasing trend with respect to disease severity. Both frontal-occipital and parietal-occipital connectivity patterns in the metabolic network using 18F-FDG PET are the key feature for differentiating disease groups in AD.


Obesity at age 20 and the risk of miscarriages, irregular periods and reported problems of becoming pregnant: the Adventist Health Study-2.
In a group of 46,000 North-American Adventist women aged 40 and above, we investigated the relationships between body mass index (BMI, kg/m(2)) at age 20 and the proportion of women who reported at least one miscarriage, periods with irregular menstruation or failing to become pregnant even if trying for more than one straight year. Approximately 31, 14 and 17 %, respectively, reported the three different problems related to reproduction. Positive age- and marital status adjusted relationships were found between BMI at age 20 and periods with irregular menstruation or failing to become pregnant even if trying for more than 1 year, but not with the risk of miscarriages. Women with BMI ≥ 32.5 kg/m(2) when aged 20 had approximately 2.0 (95 % CI: 1.6, 2.4) and 1.5 (95 % CI: 1.3, 1.9) higher odds for irregular periods or failing to get pregnant, respectively, than women with BMI in the 20-24.9 kg/m(2) bracket. These relationships were consistently found in a number of strata of the population, including the large proportion of the women who never had smoked or never used alcohol. Underweight (BMI < 18.5 kg/m(2)) when aged 20 marginally (approximately 15 %) increased the risk of failing to get pregnant within a year. Thus, obesity at age 20 increases the risk of reporting some specific reproductive problems, but not the risk of miscarriages.


Combination therapy with fluconazole and flucytosine in the murine model of cryptococcal meningitis.
This study elucidates the role of combined fluconazole and flucytosine as therapy for cryptococcosis in the murine model of meningitis. Three strains of Cryptococcus neoformans for which the range of fluconazole MICs was wide--2 microg/ml (susceptible strain), 8 microg/ml (moderately susceptible strain), and 32 microg/ml (resistant strain)--were used for infection. One day postinfection, the mice were randomized into eight treatment groups: placebo; flucytosine (40 mg/kg of body weight/day); fluconazole at 3 mg/kg/day (low dosage), 10 mg/kg/day (moderate dosage), or 20 mg/kg/day (high dosage); and combined flucytosine and fluconazole at low, moderate, or high doses of fluconazole. Three major findings were demonstrated: (i) correlation between the MICs for the isolates and the in vivo effectiveness of fluconazole as assessed by the reduction in cryptococcal brain burden, (ii) a dose-response curve (a higher dose of fluconazole was significantly more efficacious than a lower dose [P < 0.001]), and (iii) synergism between fluconazole and flucytosine (therapy with a combination of fluconazole and flucytosine was superior to therapy with either agent alone [P < 0.01]).


Pharmacogenetics in drug development.
Over the last two decades, identification of polymorphisms that influence human diseases has begun to have an impact on the provision of medical care. The promise of genetics lies in its ability to provide insights into an individual's susceptibility to disease, the likely nature of the disease and the most appropriate therapy. For much of its history, pharmacogenetics (PGx-the use of genetic information to impact drug choice) has been limited to comparatively simple phenotypes such as plasma drug levels. Progress in genetics technologies has broadened the scope of PGx efficacy and safety studies that can be implemented, impacting on a broad spectrum of drug discovery and development activities. Recent PGx data show the ability of this approach to generate information that can be applied to dose selection, efficacy determination and safety issues. This in turn will lead to significant opportunities to affect both the approach to clinical development and the probability of success--the latter being an important aspect for pharmaceutical companies and for the patients who will benefit from these new medicines.


Somatosensory Neuron Typing with High-Coverage Single-Cell RNA Sequencing and Functional Analysis.
Different physical and chemical stimuli are detected by the peripheral sensory receptors of dorsal root ganglion (DRG) neurons, and the generated inputs are transmitted via afferent fibers into the central nervous system. The gene expression profiles of DRG neurons contribute to the generation, transmission, and regulation of various somatosensory signals. Recently, the single-cell transcriptomes, cell types, and functional annotations of somatosensory neurons have been studied. In this review, we introduce our classification of DRG neurons based on single-cell RNA-sequencing and functional analyses, and discuss the technical approaches. Moreover, studies on the molecular and cellular mechanisms underlying somatic sensations are discussed.


Pigment patterns in adult fish result from superimposition of two largely independent pigmentation mechanisms.
Dorso-ventral pigment pattern differences are the most widespread pigmentary adaptations in vertebrates. In mammals, this pattern is controlled by regulating melanin chemistry in melanocytes using a protein, agouti-signalling peptide (ASIP). In fish, studies of pigment patterning have focused on stripe formation, identifying a core striping mechanism dependent upon interactions between different pigment cell types. In contrast, mechanisms driving the dorso-ventral countershading pattern have been overlooked. Here, we demonstrate that, in fact, zebrafish utilize two distinct adult pigment patterning mechanisms - an ancient dorso-ventral patterning mechanism, and a more recent striping mechanism based on cell-cell interactions; remarkably, the dorso-ventral patterning mechanism also utilizes ASIP. These two mechanisms function largely independently, with resultant patterns superimposed to give the full pattern.


Comparison of equations for estimating glomerular filtration rate in screening for chronic kidney disease in asymptomatic black Africans: a cross sectional study.
Several equations have been developed to estimate glomerular filtration rate (eGFR). The common equations used were derived from populations predominantly comprised of Caucasians with chronic kidney disease (CKD). Some of the equations provide a correction factor for African-Americans due to their relatively increased muscle mass and this has been extrapolated to black Africans. Studies carried out in Africa in patients with CKD suggest that using this correction factor for the black African race may not be appropriate. However, these studies were not carried out in healthy individuals and as such the extrapolation of the findings to an asymptomatic black African population is questionable. We sought to compare the proportion of asymptomatic black Africans reported as having reduced eGFR using various eGFR equations. We further compared the association between known risk factors for CKD with eGFR determined using the different equations. We used participant and laboratory data collected as part of a global reference interval study conducted by the Committee of Reference Intervals and Decision Limits (C-RIDL) under the International Federation of Clinical Chemistry (IFCC). Serum creatinine values were used to calculate eGFR using the Cockcroft-Gault (CG), re-expressed 4 variable modified diet in renal disease (4v-MDRD), full age spectrum (FAS) and chronic kidney disease epidemiology collaboration equations (CKD-EPI). CKD classification based on eGFR was determined for every participant. A total of 533 participants were included comprising 273 (51.2%) females. The 4v-MDRD equation without correction for race classified the least number of participants (61.7%) as having an eGFR equivalent to CKD stage G1 compared to 93.6% for CKD-EPI with correction for race. Only age had a statistically significant linear association with eGFR across all equations after performing multiple regression analysis. The multiple correlation coefficients for CKD risk factors were higher for CKD-EPI determined eGFRs. This study found that eGFR determined using CKD-EPI equations better correlated with a prediction model that included risk factors for CKD and classified fewer asymptomatic black Africans as having a reduced eGFR compared to 4v-MDRD, FAS and CG corrected for body surface area.


A gradient of childhood self-control predicts health, wealth, and public safety.
Policy-makers are considering large-scale programs aimed at self-control to improve citizens' health and wealth and reduce crime. Experimental and economic studies suggest such programs could reap benefits. Yet, is self-control important for the health, wealth, and public safety of the population? Following a cohort of 1,000 children from birth to the age of 32 y, we show that childhood self-control predicts physical health, substance dependence, personal finances, and criminal offending outcomes, following a gradient of self-control. Effects of children's self-control could be disentangled from their intelligence and social class as well as from mistakes they made as adolescents. In another cohort of 500 sibling-pairs, the sibling with lower self-control had poorer outcomes, despite shared family background. Interventions addressing self-control might reduce a panoply of societal costs, save taxpayers money, and promote prosperity.


Encoding of configural regularity in the human visual system.
The visual system is very efficient in encoding stimulus properties by utilizing available regularities in the inputs. To explore the underlying encoding strategies during visual information processing, we presented participants with two-line configurations that varied in the amount of configural regularity (or degrees of freedom in the relative positioning of the two lines) in a fMRI experiment. Configural regularity ranged from a generic configuration to stimuli resembling an "L" (i.e., a right-angle L-junction), a "T" (i.e., a right-angle midpoint T-junction), or a "+",-the latter being the most regular stimulus. We found that the response strength in the shape-selective lateral occipital area was consistently lower for a higher degree of regularity in the stimuli. In the second experiment, using multivoxel pattern analysis, we further show that regularity is encoded in terms of the fMRI signal strength but not in the distributed pattern of responses. Finally, we found that the results of these experiments could not be accounted for by low-level stimulus properties and are distinct from norm-based encoding. Our results suggest that regularity plays an important role in stimulus encoding in the ventral visual processing stream.


Metalloporphyrin antioxidants ameliorate normal tissue radiation damage in rat brain.
We examined the effects of manganese (III) meso-tetrakis (diethyl-2-5-imidazole) porphyrin, a metalloporphyrin antioxidant (MPA), on neural tissue radiation toxicity in vivo and on tumour cell radiosensitivity in vitro. MPA was administered directly into the right lateral ventricle of young adult, male Sprague-Dawley rats (0 or 3.4 microg) 3 h before treatment with a single fraction, 100 Gy radiation dose delivered to the left brain hemisphere. The effects of treatment on radiation responses were assessed at different time points following irradiation. MPA treatment prior to brain irradiation protected against acute radiation-induced apoptosis and ameliorated delayed damage to the blood-brain barrier and radiation necrosis, but without producing a discernible increase in tissue superoxide disumtase (SOD) activity. In vitro, MPA pretreatment protected against radiation-induced apoptosis in primary neuronal cultures and increased clonogenic survival of irradiated rat glioma C6 cells, but had no discernible effect on radiation-induced DNA double-strand breaks. MPA, a low molecular weight SOD mimic, significantly increased mitochondrial SOD activity in C6 cells, but not total cellular SOD activity. MPA up-regulated C6 expression of heme-oxygenase 1 (HO-1), an endogenous radioprotectant, but had no effect on HO-1 levels in human astrocytoma U-251 cells, human prostatic carcinoma LNCaP cells, or primary rat brain microvascular endothelial cells in vitro, nor on brain tissue HO-1 expression levels in vivo. Metalloporphyrin antioxidants merit further exploration as adjunctive radioprotectants for cranial radiotherapy/radiosurgery applications, although the potential for tumour protection must be carefully considered.


Spatial organization of transcribing loci during early genome activation in Drosophila.
The early Drosophila embryo provides unique experimental advantages for addressing fundamental questions of gene regulation at multiple levels of organization, from individual gene loci to the entire genome. Using 1.5-h-old Drosophila embryos undergoing the first wave of genome activation,1 we detected ∼110 discrete "speckles" of RNA polymerase II (RNA Pol II) per nucleus, two of which were larger and localized to the histone locus bodies (HLBs).2,3 In the absence of the primary driver of Drosophila genome activation, the pioneer factor Zelda (Zld),1,4,5 70% fewer speckles were present; however, the HLBs tended to be larger than wild-type (WT) HLBs, indicating that RNA Pol II accumulates at the HLBs in the absence of robust early-gene transcription. We observed a uniform distribution of distances between active genes in the nuclei of both WT and zld mutant embryos, indicating that early co-regulated genes do not cluster into nuclear sub-domains. However, in instances whereby transcribing genes did come into close 3D proximity (within 400 nm), they were found to have distinct RNA Pol II speckles. In contrast to the emerging model whereby active genes are clustered to facilitate co-regulation and sharing of transcriptional resources, our data support an "individualist" model of gene control at early genome activation in Drosophila. This model is in contrast to a "collectivist" model, where active genes are spatially clustered and share transcriptional resources, motivating rigorous tests of both models in other experimental systems.


The scientific status of childhood dissociative identity disorder: a review of published research.
Dissociative identity disorder (DID) remains a controversial diagnosis due to conflicting views on its etiology. Some attribute DID to childhood trauma and others attribute it to iatrogenesis. The purpose of this article is to review the published cases of childhood DID in order to evaluate its scientific status, and to answer research questions related to the etiological models. I searched MEDLINE and PsycINFO records for studies published since 1980 on DID/multiple personality disorder in children. For each study I coded information regarding the origin of samples and diagnostic methods. The review produced a total of 255 cases of childhood DID reported as individual case studies (44) or aggregated into empirical studies (211). Nearly all cases (93%) emerged from samples of children in treatment, and multiple personalities was the presenting problem in 23% of the case studies. Four US research groups accounted for 65% of all 255 cases. Diagnostic methods typically included clinical evaluation based on Diagnostic and Statistical Manual of Mental Disorder criteria, but hypnosis, structured interviews, and multiple raters were rarely used in diagnoses. Despite continuing research on the related concepts of trauma and dissociation, childhood DID itself appears to be an extremely rare phenomenon that few researchers have studied in depth. Nearly all of the research that does exist on childhood DID is from the 1980s and 1990s and does not resolve the ongoing controversies surrounding the disorder.


Management and clinical outcome of stable coronary artery disease in Austria : Results from 5 years of the CLARIFY registry.
The population of patients with established coronary artery disease (CAD) is growing because of an improvement in outcomes and survival from acute disease episodes. Nevertheless, these patients remain at high risk of cardiovascular events. Thus, CAD management is important in prevention of disease progression. The objective of this analysis was to describe disease management and clinical outcome of Austrian outpatients with stable CAD over 5 years by using data from the international CLARIFY registry. CLARIFY was an international prospective observational registry of outpatients with stable CAD, defined as prior myocardial infarction or revascularization (CABG or PCI), coronary stenosis of more than 50% by coronary angiography or chest pain with myocardial ischemia. We analyzed demographic characteristics, risk factors, treatments and clinical outcomes of 424 Austrian outpatients with established CAD who were enrolled between November 2009 and July 2010 and observed until September 2015. The primary risk factors in Austrian outpatients with stable CAD were smoking (current smokers: 13.2%), overweight (77.1%), hypertension (78.5%), raised low-density lipoprotein (LDL) cholesterol plasma levels (81.4% ≥ 0.7 g/l or 1.8 mmol/l), elevated heart rate (≥70 bpm: 60.9% in patients with anginal symptoms) and poor physical activity (none or light activity: 63.4%). Patients received lipid-lowering drugs (predominantly statins), aspirin, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors according to current recommendations. After 5 years a systolic blood pressure (SBP) < 140 mm Hg and diastolic blood pressure (DBP) < 90 mm Hg was reached in 58.5% of patients. Of the patients 70.4% had LDL cholesterol plasma levels below 1.0 g/l (2.6 mmol/l), 42.1% of smokers had stopped smoking, 42.9% of patients with anginal symptoms had a heart rate ≤60 bpm and 26.0% of diabetic patients had brought their HbA1c levels below 6.5%. Cardiovascular death, myocardial infarction or stroke occurred in 30 patients (7.1%), all-cause death in 25 cases (5.9%) and cardiovascular death in 15 cases (3.5%). Myocardial infarction was reported in 14 patients (fatal and non-fatal: 3.3%) and stroke in 8 patients (fatal and non-fatal: 1.9%), 39 patients (9.2%) underwent myocardial revascularization and 124 patients (29.2%) experienced cardiovascular hospitalization. Characteristics of Austrian outpatients with stable CAD corresponded to those of patients with CAD in other developed countries. Medical treatments following the recommendations of the European guidelines were prescribed in the majority of patients; however, recommended goals of life style interventions including a heart rate less than 60 bpm and general risk factor management were not achieved by a high proportion of patients. Heart rate control and life style changes remain unmet needs of cardiovascular care in Austria.


Centriole polarisation to the immunological synapse directs secretion from cytolytic cells of both the innate and adaptive immune systems.
Cytolytic cells of the immune system destroy pathogen-infected cells by polarised exocytosis of secretory lysosomes containing the pore-forming protein perforin. Precise delivery of this lethal hit is essential to ensuring that only the target cell is destroyed. In cytotoxic T lymphocytes (CTLs), this is accomplished by an unusual movement of the centrosome to contact the plasma membrane at the centre of the immunological synapse formed between killer and target cells. Secretory lysosomes are directed towards the centrosome along microtubules and delivered precisely to the point of target cell recognition within the immunological synapse, identified by the centrosome. We asked whether this mechanism of directing secretory lysosome release is unique to CTL or whether natural killer (NK) and invariant NKT (iNKT) cytolytic cells of the innate immune system use a similar mechanism to focus perforin-bearing lysosome release. NK cells were conjugated with B-cell targets lacking major histocompatibility complex class I 721.221 cells, and iNKT cells were conjugated with glycolipid-pulsed CD1-bearing targets, then prepared for thin-section electron microscopy. High-resolution electron micrographs of the immunological synapse formed between NK and iNKT cytolytic cells with their targets revealed that in both NK and iNKT cells, the centrioles could be found associated (or 'docked') with the plasma membrane within the immunological synapse. Secretory clefts were visible within the synapses formed by both NK and iNKT cells, and secretory lysosomes were polarised along microtubules leading towards the docked centrosome. The Golgi apparatus and recycling endosomes were also polarised towards the centrosome at the plasma membrane within the synapse. These results reveal that, like CTLs of the adaptive immune system, the centrosomes of NK and iNKT cells (cytolytic cells of the innate immune system) direct secretory lysosomes to the immunological synapse. Morphologically, the overall structure of the immunological synapses formed by NK and iNKT cells are very similar to those formed by CTLs, with both exocytic and endocytic organelles polarised towards the centrosome at the plasma membrane, which forms a focal point for exocytosis and endocytosis within the immunological synapse. We conclude that centrosomal polarisation provides a rapid, responsive and precise mechanism for secretory lysosome delivery to the immunological synapse in CTLs, NK cells and iNKT cells.


Blockade of membrane transport and disassembly of the Golgi complex by expression of syntaxin 1A in neurosecretion-incompetent cells: prevention by rbSEC1.
The t-SNAREs syntaxin1A and SNAP-25, i.e. the members of the complex involved in regulated exocytosis at synapses and neurosecretory cells, are delivered to their physiological site, the plasma membrane, when transfected into neurosecretion-competent cells, such as PC12 and AtT20. In contrast, when transfection is made into cells incompetent for neurosecretion, such as those of a defective PC12 clone and the NRK fibroblasts, which have no endogenous expression of these t-SNAREs, syntaxin1A (but neither two other syntaxin family members nor SNAP-25) remains stuck in the Golgi-TGN area with profound consequences to the cell: blockade of both membrane (SNAP-25, GAT-1) and secretory (chromogranin B) protein transport to the cell surface; progressive disassembly of the Golgi complex and TGN; ultimate disappearance of the latter structures, with intermixing of their markers (mannosidase II; TGN-38) with those of the endoplasmic reticulum (calreticulin) and with syntaxin1A itself. When, however, syntaxin 1A is transfected together with rbSec1, a protein known to participate in neurosecretory exocytosis via its dynamic interaction with the t-SNARE, neither the blockade nor the alterations of the Golgi complex take place. Our results demonstrate that syntaxin1A, in addition to its role in exocytosis at the cell surface, possesses a specific potential to interfere with intracellular membrane transport and that its interaction with rbSec1 is instrumental to its physiological function not only at the plasma membrane but also within the cell. At the latter site, the rbSec1-induced conversion of syntaxin1A into a form that can be transported and protects the cell from the development of severe structural and membrane traffic alterations.


De novo genome assembly of Oryza granulata reveals rapid genome expansion and adaptive evolution.
The wild relatives of rice have adapted to different ecological environments and constitute a useful reservoir of agronomic traits for genetic improvement. Here we present the ~777 Mb de novo assembled genome sequence of Oryza granulata. Recent bursts of long-terminal repeat retrotransposons, especially RIRE2, led to a rapid twofold increase in genome size after O. granulata speciation. Universal centromeric tandem repeats are absent within its centromeres, while gypsy-type LTRs constitute the main centromere-specific repetitive elements. A total of 40,116 protein-coding genes were predicted in O. granulata, which is close to that of Oryza sativa. Both the copy number and function of genes involved in photosynthesis and energy production have undergone positive selection during the evolution of O. granulata, which might have facilitated its adaptation to the low light habitats. Together, our findings reveal the rapid genome expansion, distinctive centromere organization, and adaptive evolution of O. granulata.


Alkene-assisted cis-to-trans isomerization of non-conjugated polyunsaturated alkenes.
Complex [Cp*Ru(NCMe)3][PF6], 1a, has been identified as a cis-to-trans isomerization catalyst of various non-conjugated cis-polyalkenes under exceptional kinetic control as no alkene conjugation was observed. According to the experimental and theoretical data, the cis-trans isomerization occurred via an alkene-assisted mechanism in which one cis-double bond always served as an anchoring site. Using a combination of multinuclear NMR spectroscopic evidence and mathematical methods it was possible to determine the extent of trans isomerization.


A portable oligonucleotide-based microfluidic device for the detection of VEGF165 in a three-step suspended-droplet mode.
Vascular endothelial growth factor (VEGF165), an important glycosylated protein from the VEGF family, is a type of signal protein highly associated with the development and progression of cancers. In this work, we designed a G-quadruplex-based aptasensing platform for the sensitive and selective detection of VEGF165 in aqueous solution and red blood cell solution. A long-lived phosphorescence iridium(iii) complex (1) with promising photophysical properties and a large Stokes shift was chosen as a selective G-quadruplex probe. The platform could achieve a limit of detection (LOD) down to the picomolar level using a conventional fluorometer. Furthermore, we successfully applied the platform to a three-step suspended droplet (SD)-based microfluidic device for the monitoring of VEGF165. In contrast to the channel-based and digital microfluidic chips, SD-based chips allow easy introduction of liquid samples, valve-free manipulation of multiple reaction steps and flexible volume range. Importantly, polypropylene (PP), a hydrophobic and thermally stable material, was chosen as a substrate to fabricate the chip for the SD-based microfluidic device. The PP-based chip allows the combination of superhydrophobic force, gravity and surface tension for effective driving of the suspended droplet throughout the channel without reverse migration. After assembling all the major components, including a UV lamp, a rotatable chip holder, a filter and a camera into the portable device, we successfully demonstrated the applicability of the device to detect VEGF165 in aqueous solution with a LOD of 0.33 nM at a signal-to-noise ratio (S/N) of 3 and a linear range of 1-100 nM.


Abstracting Attribute Space for Transfer Function Exploration and Design.
Currently, user centered transfer function design begins with the user interacting with a one or two-dimensional histogram of the volumetric attribute space. The attribute space is visualized as a function of the number of voxels, allowing the user to explore the data in terms of the attribute size/magnitude. However, such visualizations provide the user with no information on the relationship between various attribute spaces (e.g., density, temperature, pressure, x, y, z) within the multivariate data. In this work, we propose a modification to the attribute space visualization in which the user is no longer presented with the magnitude of the attribute; instead, the user is presented with an information metric detailing the relationship between attributes of the multivariate volumetric data. In this way, the user can guide their exploration based on the relationship between the attribute magnitude and user selected attribute information as opposed to being constrained by only visualizing the magnitude of the attribute. We refer to this modification to the traditional histogram widget as an abstract attribute space representation. Our system utilizes common one and two-dimensional histogram widgets where the bins of the abstract attribute space now correspond to an attribute relationship in terms of the mean, standard deviation, entropy, or skewness. In this manner, we exploit the relationships and correlations present in the underlying data with respect to the dimension(s) under examination. These relationships are often times key to insight and allow us to guide attribute discovery as opposed to automatic extraction schemes which try to calculate and extract distinct attributes a priori. In this way, our system aids in the knowledge discovery of the interaction of properties within volumetric data.


Assessing quality of Medicago sativa silage by monitoring bacterial composition with single molecule, real-time sequencing technology and various physiological parameters.
The present study applied the PacBio single molecule, real-time sequencing technology (SMRT) in evaluating the quality of silage production. Specifically, we produced four types of Medicago sativa silages by using four different lactic acid bacteria-based additives (AD-I, AD-II, AD-III and AD-IV). We monitored the changes in pH, organic acids (including butyric acid, the ratio of acetic acid/lactic acid, γ-aminobutyric acid, 4-hyroxy benzoic acid and phenyl lactic acid), mycotoxins, and bacterial microbiota during silage fermentation. Our results showed that the use of the additives was beneficial to the silage fermentation by enhancing a general pH and mycotoxin reduction, while increasing the organic acids content. By SMRT analysis of the microbial composition in eight silage samples, we found that the bacterial species number and relative abundances shifted apparently after fermentation. Such changes were specific to the LAB species in the additives. Particularly, Bacillus megaterium was the initial dominant species in the raw materials; and after the fermentation process, Pediococcus acidilactici and Lactobacillus plantarum became the most prevalent species, both of which were intrinsically present in the LAB additives. Our data have demonstrated that the SMRT sequencing platform is applicable in assessing the quality of silage.


Psychological Benefits of Nonpharmacological Methods Aimed for Improving Balance in Parkinson's Disease: A Systematic Review.
Parkinson's disease (PD) is a serious condition with a major negative impact on patient's physical and mental health. Postural instability is one of the cardinal difficulties reported by patients to deal with. Neuroanatomical, animal, and clinical studies on nonparkinsonian and parkinsonian subjects suggest an important correlation between the presence of balance dysfunction and multiple mood disorders, such as anxiety, depression, and apathy. Considering that balance dysfunction is a very common symptom in PD, we can presume that by its management we could positively influence patient's state of mind too. This review is an analysis of nonpharmacological methods shown to be effective and successful for improving balance in patients suffering from PD. Strategies such as general exercise, robotic assisted training, Tai Chi, Qi Gong, Yoga, dance (such as tango or ballet), box, virtual reality-based, or neurofeedback-based techniques and so forth can significantly improve the stability in these patients. Beside this physical outcome, many methods have also shown effect on quality of life, depression level, enjoyment, and motivation to continue in practicing the method independently. The purpose of this review is to provide information about practical and creative methods designed to improve balance in PD and highlight their positive impact on patient's psychology.


Whole-brain death reconsidered--physiological facts and philosophy.
Four main areas generating confusion in discussion on brain death are identified as a) the relation of criteria of death to concepts of death, b) the argument about whether death is an event or a process, c) the inadequate differentiation of different neurological entities having different cardiac prognoses, and d) insufficient awareness of the separate issues of 'determining death' and 'allowing to die'. It is argued that if by death we mean the dissolution of the human 'organism as a whole', then whole-brain death is death. Behavioural patterns, legitimate in the presence of a cadaver, should be legitimate from the time whole-brain death is diagnosed.


Evaluation of the Effectiveness and Tolerability of Mycophenolate Mofetil and Mycophenolic Acid for the Treatment of Morphea.
First-line systemic therapy for morphea includes methotrexate with or without systemic corticosteroids. When this regimen is ineffective, not tolerated, or contraindicated, a trial of mycophenolate mofetil (MMF) or mycophenolic acid (MPA)-referred to herein as mycophenolate-is recommended; however, evidence to support this recommendation remains weak. To evaluate the effectiveness and tolerability of mycophenolate for the treatment of morphea. A retrospective cohort study was conducted from January 1, 1999, to December 31, 2018, among 77 patients with morphea from 8 institutions who were treated with mycophenolate. The primary outcome was morphea disease activity, severity, and response at 0, 3 to 6, and 9 to 12 months of mycophenolate treatment. A secondary outcome was whether mycophenolate was a well-tolerated treatment of morphea. There were 61 female patients (79%) and 16 male patients (21%) in the study, with a median age at disease onset of 36 years (interquartile range, 16-53 years) and median diagnostic delay of 8 months (interquartile range, 4-14 months). Generalized morphea (37 [48%]), pansclerotic morphea (12 [16%]), and linear morphea of the trunk and/or extremities (9 [12%]) were the most common subtypes of morphea identified. Forty-one patients (53%) had an associated functional impairment, and 49 patients (64%) had severe disease. Twelve patients received initial treatment with mycophenolate as monotherapy or combination therapy and 65 patients received mycophenolate after prior treatment was ineffective (50 of 65 [77%]) or poorly tolerated (21 of 65 [32%]). Treatments prior to mycophenolate included methotrexate (48 of 65 [74%]), systemic corticosteroids (42 of 65 [65%]), hydroxychloroquine (20 of 65 [31%]), and/or phototherapy (14 of 65 [22%]). After 3 to 6 months of mycophenolate treatment, 66 of 73 patients had stable (n = 22) or improved (n = 44) disease. After 9 to 12 months of treatment, 47 of 54 patients had stable (n = 14) or improved (n = 33) disease. Twenty-seven patients (35%) achieved disease remission at completion of the study. Treatments received in conjunction with mycophenolate were frequent. Mycophenolate was well tolerated. Gastrointestinal adverse effects were the most common (24 [31%]); cytopenia (3 [4%]) and infection (2 [3%]) occurred less frequently. This study suggests that mycophenolate is a well-tolerated and beneficial treatment of recalcitrant, severe morphea.


Initial skill assessment of the California Harmful Algae Risk Mapping (C-HARM) system.
Toxic algal events are an annual burden on aquaculture and coastal ecosystems of California. The threat of domoic acid (DA) toxicity to human and wildlife health is the dominant harmful algal bloom (HAB) concern for the region, leading to a strong focus on prediction and mitigation of these blooms and their toxic effects. This paper describes the initial development of the California Harmful Algae Risk Mapping (C-HARM) system that predicts the spatial likelihood of blooms and dangerous levels of DA using a unique blend of numerical models, ecological forecast models of the target group, Pseudo-nitzschia, and satellite ocean color imagery. Data interpolating empirical orthogonal functions (DINEOF) are applied to ocean color imagery to fill in missing data and then used in a multivariate mode with other modeled variables to forecast biogeochemical parameters. Daily predictions (nowcast and forecast maps) are run routinely at the Central and Northern California Ocean Observing System (CeNCOOS) and posted on its public website. Skill assessment of model output for the nowcast data is restricted to nearshore pixels that overlap with routine pier monitoring of HABs in California from 2014 to 2015. Model lead times are best correlated with DA measured with solid phase adsorption toxin tracking (SPATT) and marine mammal strandings from DA toxicosis, suggesting long-term benefits of the HAB predictions to decision-making. Over the next three years, the C-HARM application system will be incorporated into the NOAA operational HAB forecasting system and HAB Bulletin.


Analysis of 3702 patients with acne vulgaris and concomitant comorbidities in Turkey: a multi-centered, prospective, controlled study.
Acne vulgaris is a chronic inflammatory skin disease that affects the pilosebaceous unit. Although it is considered to be a skin-limited disease, different clinical studies have recently been published in which the disease is accompanied by systemic symptoms. In this study, systemic comorbidities accompanying acne vulgaris and the relationship between existing comorbidities and disease severity are investigated. This prospective multicenter study was conducted by the Turkish Society of Dermatology Acne Study Group. Twelve dermatology clinics and 14 clinicians throughout Turkey participated in the study. A structured physician-administered questionnaire was used to collect patient demographics, clinical findings, and lifestyle data. Physicians recorded each participant's medical history, including current and past comorbidities, duration of any comorbidity, smoking, and drinking. Body mass index (BMI) was calculated. There were 3022 patients in the adolescent acne group and 897 in the control group. The incidence of nonmigraine headache in adolescents with acne was significantly higher than in the nonacne group (P = 0.019). There were 680 patients in the postadolescent acne group and 545 in the control group. In the postadolescent group, incidence of metabolic disease was lower than the control group (P = 0.003). In the postadolescent group, premenstrual syndrome (P < 0.001) and PCOS (P = 0.007) were more common than the control group. In this study, we observed that acne vulgaris does not cause systemic comorbidities. There is also a need for new studies involving a large number of patients to illuminate systemic diseases accompanying acne vulgaris.


Production of agglutinating monoclonal antibody against antigen 8 specific for Cryptococcus neoformans serotype D.
A hybridoma (clone CRND-8) that produced agglutinating monoclonal antibody (MAb) against Cryptococcus neoformans serotype D was established by using a soluble capsular polysaccharide-keyhole limpet hemocyanin conjugate for immunization. The isotype was immunoglobulin M(kappa). Specificity was determined by cell slide agglutination and enzyme-linked immunosorbent assay (ELISA). In both tests, the MAb reacted to serotypes D and A-D but not to serotypes A, B, and C. Furthermore, the specificity of the MAb determined by ELISA was the same as that of polyclonal antibody factor serum (PAb factor) 8, which showed high-level reactivity with serotypes D and A-D. These results supported the deduced specificity of the PAb-based antigenic factor 8. A total of 15 isolates of serotypes D and A-D but no serotype A isolates reacted with the MAb in cell slide agglutination tests. CRND-8 MAb can be used in place of PAb factor 8 for serotyping C. neoformans isolates and for the analysis of the antigen 8 epitope.


Effect of collagen-glycosaminoglycan scaffold pore size on matrix mineralization and cellular behavior in different cell types.
We have previously examined osteoblast behavior on porous collagen-glycosaminoglycan (CG) scaffolds with a range of mean pore sizes demonstrating superior cell attachment and migration in scaffolds with the largest pores (325 μm). Scaffolds provide a framework for construct development; therefore, it is crucial to identify the optimal pore size for augmented tissue formation. Utilizing the same range of scaffolds (85 μm - 325 μm), this study aimed to examine the effects of mean pore size on subsequent osteoblast differentiation and matrix mineralization, and to understand the mechanism by which pore size influences behavior of different cell types. Consequently, primary mesenchymal stem cells (MSCs) were assessed and their behavior compared to osteoblasts. Results demonstrated that scaffolds with the largest pore size (325 μm) facilitated improved osteoblast infiltration, earlier expression of mature bone markers osteopontin (OPN) and osteocalcin (OCN), and increased mineralization. MSCs responded similarly to osteoblasts whereby cell attachment and scaffold infiltration improved with increasing pore size. However, MSCs showed reduced cell motility, proliferation, and scaffold infiltration compared to osteoblasts. This was associated with differences in the profile of integrin subunits (α2) and collagen receptors (CD44), indicating that osteoblasts have a stronger affinity for CG scaffolds compared to MSCs. In summary, these results reveal how larger pores promote improved cell infiltration, essential for construct development, however the optimal scaffold pore size can be cell type specific. As such, this study highlights a necessity to tailor both scaffold micro-architecture and cell-type when designing constructs for successful bone tissue engineering applications.


The effects of ingestion of omega-3 fatty acids on perceived pain and external symptoms of delayed onset muscle soreness in untrained men.
The purpose of this study was to examine the effect of ingestion of omega-3 on perceived pain and external symptoms of delayed onset muscle soreness after eccentric exercise in knee extensors. A randomized, double-blinded, repeated measures design was used for this study. The study was performed in the Exercise Physiology Laboratory at the Faculty of Humanities of Urmia University. Twenty-seven men, who had not participated in any training program 60 days before their participation in this study, were recruited. All subjects finished the study. Knee range of motion (ROM), perceived pain, and thigh circumference of the right leg were taken before, immediately, and after 24 and 48 hours after an eccentric exercise. Subjects were assigned to one of the experimental (1.8 g/d omega-3), placebo (R.P. Scherer), or control groups. Subjects self-reported the perceived pain level of the lower limbs using the Talag mentally corrected scale. Thigh circumference was measured by using a Gulick anthropometric tape. Knee ROM was determined by using a Jamar goniometer. No differences among treatments were observed for pain and ROM before, immediately, and 24 hours after the exercise. However, observed differences in perceived pain and ROM were obvious at 48 hours postexercise. In the case of thigh circumference, differences were at 24 and 48 hours postexercise, and there was no difference before and immediately after exercise. Ingestion of omega-3 can be effective in ameliorating delayed onset muscle soreness induced by eccentric exercise.


Isolation, characterization and total regioselective synthesis of the novel μO-conotoxin MfVIA from Conus magnificus that targets voltage-gated sodium channels.
The μO-conotoxins are notable for their unique selectivity for Na(v)1.8 over other sodium channel isoforms, making them attractive drug leads for the treatment of neuropathic pain. We describe the discovery of a novel μO-conotoxin, MfVIA, from the venom of Conus magnificus using high-throughput screening approaches. MfVIA was found to be a hydrophobic 32-residue peptide (amino acid sequence RDCQEKWEYCIVPILGFVYCCPGLICGPFVCV) with highest sequence homology to μO-conotoxin MrVIB. To overcome the synthetic challenges posed by μO-conotoxins due to their hydrophobic nature and difficult folding, we developed a novel regioselective approach for the synthesis of μO-conotoxins. Performing selective oxidative deprotections of the cysteine side-chain protecting groups of the fully protected peptide allowed manipulations in organic solvents with no chromatography required between steps. Using this approach, we obtained correctly folded MfVIA with increased synthetic yields. Biological activity of MfVIA was assessed using membrane potential-sensitive dyes and electrophysiological recording techniques. MfVIA preferentially inhibits Na(v)1.8 (IC₅₀ 95.9±74.3 nM) and Na(v)1.4 (IC₅₀ 81±16 nM), with significantly lower affinity for other Na(v) subtypes (IC₅₀ 431-6203 nM; Na(v)1.5>1.6∼1.7∼1.3∼1.1∼1.2). This improved approach to μO-conotoxin synthesis will facilitate the optimization of μO-conotoxins as novel analgesic molecules to improve pain management.


Ostwald ripening of clays and metamorphic minerals.
Analyses of particle size distributions indicate that clay minerals and other diagenetic and metamorphic minerals commonly undergo recrystallization by Ostwald ripening. The shapes of their particle size distributions can yield the rate law for this process. One consequence of Ostwald ripening is that a record of the recrystallization process is preserved in the various particle sizes. Therefore, one can determine the detailed geologic history of clays and other recrystallized minerals by separating, from a single sample, the various particle sizes for independent chemical, structural, and isotopic analyses.


In vitro starch digestibility and in vivo glycemic response of foxtail millet and its products.
Foxtail millet, as a leading variety in arid and semi-arid areas of Asia and Africa, can provide broad potential benefits to human health. However, its digestion properties have not been reported. So in this study, the in vitro starch digestibilities and in vivo glycemic indices (GI) of foxtail millet and pure millet products were investigated. The results showed that starch digestibility of the foxtail millet flour is obviously lower than that of wheat flour. However, deproteinization and heating significantly increased its rapidly digestible starch and decreased its slowly digestible starch and resistant starch. The GIs of pure millet products were in the following order: millet porridge (93.6 ± 11.3) > millet steamed bread (89.6 ± 8.8) > No. 1 millet pancake (75.0% millet flour and 25.0% extrusion flour, 83.0 ± 9.6) > No. 2 millet pancake (without extrusion flour, 76.2 ± 10.7) > cooked millet (64.4 ± 8.5). They were significantly positively correlated with the rapidly digestible starch (r = 0.959), degree of gelatinization (r = 0.967) and estimated glycemic index (r = 0.988). Both in vitro and in vivo tests suggested that boiling, steaming and extrusion enhanced the formation of digestible starch and subsequently increased the GI values. Additionally, the No. 1 millet pancake and cooked millet had a relatively gentle stimulation on β-cell. Therefore, foxtail millet, especially the cooked millet, may serve as a potential source of nutraceutical and functional food that could delay the development of type 2 diabetes.


Have the oldest old adults ever been frail in the past? A hypothesis that explains modern trends in survival.
Three important results concerning the shape and the trends of the human mortality rate were discussed recently in demographic and epidemiological literature. These are the deceleration of the mortality rate at old ages, the tendency to rectangularization of the survival curve, and the decline of the old age mortality observed in the second part of the 20th century. In this paper we show that all these results can be explained by using a model with a new type of heterogeneity associated with individual differences in adaptive capacity. We first illustrate the idea of such a model by considering survival in a mixture of two subpopulations of individuals (called "labile" and "stable"). These subpopulations are characterized by different Gompertz mortality patterns, such that their mortality rates cross over. The survival chances of individuals in these subpopulations have different sensitivities to changes in environmental conditions. Then we develop a more comprehensive model in which the mortality rate is related to the adaptive capacity of an organism. We show that the trends in survival patterns experienced by a mixture of such individuals resemble those obtained in an analysis of empirical data on survival in developed countries. Lastly, we present evidence of the existence of subpopulations of phenotypes in both humans and experimental organisms, which were used as prototypes in our models. The existence of such phenotypes provides the possibility that at least part of today's centenarians originated from an initially frail part of the cohort.


MetaSim: a sequencing simulator for genomics and metagenomics.
The new research field of metagenomics is providing exciting insights into various, previously unclassified ecological systems. Next-generation sequencing technologies are producing a rapid increase of environmental data in public databases. There is great need for specialized software solutions and statistical methods for dealing with complex metagenome data sets. To facilitate the development and improvement of metagenomic tools and the planning of metagenomic projects, we introduce a sequencing simulator called MetaSim. Our software can be used to generate collections of synthetic reads that reflect the diverse taxonomical composition of typical metagenome data sets. Based on a database of given genomes, the program allows the user to design a metagenome by specifying the number of genomes present at different levels of the NCBI taxonomy, and then to collect reads from the metagenome using a simulation of a number of different sequencing technologies. A population sampler optionally produces evolved sequences based on source genomes and a given evolutionary tree. MetaSim allows the user to simulate individual read datasets that can be used as standardized test scenarios for planning sequencing projects or for benchmarking metagenomic software.


Omnifocus laparoscope.
The depth of focus of the latest-model "Chip-on-the-Tip" laparoscopes is limited to 10 cm. The proposed omnifocus laparoscope stretches this depth of focus to 160 cm. The proposed laparoscope is omnifocus, which means that all spots in the picture are in focus, not just certain designated spots as in autofocus devices. This is important because the entire scene needs to be focused during surgery. The omnifocus laparoscope is equipped with an array of color video cameras, each focused at a different distance. The distance information from the laparoscopic profilometer is used to generate a single omnifocused image.


Fluoride varnishes for preventing dental caries in children and adolescents.
Topically-applied fluoride varnishes have been used extensively as an operator-applied caries-preventive intervention for over three decades. This review updates the first Cochrane review of fluoride varnishes for preventing dental caries in children and adolescents, which was first published in 2002. To determine the effectiveness and safety of fluoride varnishes in preventing dental caries in children and adolescents, and to examine factors potentially modifying their effect. We searched the Cochrane Oral Health Group's Trials Register (to 13 May 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 4), MEDLINE via OVID (1946 to 13 May 2013), EMBASE via OVID (1980 to 13 May 2013), CINAHL via EBSCO (1980 to 13 May 2013), LILACS and BBO via the BIREME Virtual Health Library (1980 to 13 May 2013), ProQuest Dissertations and Theses (1861 to 13 May 2013), and Web of Science Conference Proceedings (1945 to 13 May 2013). A search for ongoing trials was undertaken on ClinicalTrials.gov on 13 May 2013. There were no restrictions on language or date of publication in the search of the electronic databases. Randomised or quasi-randomised controlled trials with blind outcome assessment used or indicated, comparing topically-applied fluoride varnish with placebo or no treatment in children up to 16 years during at least one year. The main outcome was caries increment measured by the change in decayed, missing and filled tooth surfaces in both permanent (D(M)FS) and primary (d(e/m)fs) teeth. At least two review authors assessed all search results, extracted data and undertook risk of bias independently. Study authors were contacted for additional information. The primary measure of effect was the prevented fraction, that is the difference in mean caries increments between the treatment and control groups expressed as a percentage of the mean increment in the control group. The caries increments nearest to three years were used from each included study. Random-effects meta-analyses were performed where data could be pooled. Potential sources of heterogeneity were examined in random-effects meta-regression analyses. Adverse effects information was collected from the included trials. Twenty-two trials with 12,455 participants randomised (9595 used in analyses) were included. For the 13 that contributed data for the permanent tooth surfaces meta-analysis, the pooled D(M)FS prevented fraction estimate comparing fluoride varnish with placebo or no treatment was 43% (95% confidence interval (CI) 30% to 57%; P < 0.0001). There was substantial heterogeneity, confirmed statistically (P < 0.0001; I(2) = 75%), however this body of evidence was assessed as of moderate quality. The pooled d(e/m)fs prevented fraction estimate was 37% (95% CI 24% to 51%; P < 0.0001) for the 10 trials that contributed data for the primary tooth surfaces meta-analysis, also with some heterogeneity (P = 0.009; I(2) = 59%). Once again this body of evidence was assessed as of moderate quality. No significant association between estimates of D(M)FS or d(e/m)fs prevented fractions and the pre-specified factors of baseline caries severity, background exposure to fluorides, application features such as prior prophylaxis, concentration of fluoride, frequency of application were found. There was also no significant association between estimates of D(M)FS or d(e/m)fs prevented fractions and the post hoc factors: whether a placebo or no treatment control was used, length of follow-up, or whether individual or cluster randomisation was used, in the meta-regression models. A funnel plot of the trials in the main meta-analyses indicated no clear relationship between prevented fraction and study precision. In both methods, power is limited when few trials are included. There was little information concerning possible adverse effects or acceptability of treatment. The conclusions of this updated review remain the same as those when it was first published. The review suggests a substantial caries-inhibiting effect of fluoride varnish in both permanent and primary teeth, however the quality of the evidence was assessed as moderate, as it included mainly high risk of bias studies, with considerable heterogeneity.


Stabilizing group treatment for complex posttraumatic stress disorder related to child abuse based on psychoeducation and cognitive behavioural therapy: a multisite randomized controlled trial.
Evidence-based treatments for complex posttraumatic stress disorder (PTSD) related to childhood abuse are scarce. This is the first randomized controlled trial to test the efficacy of psycho-educational and cognitive behavioural stabilizing group treatment in terms of both PTSD and complex PTSD symptom severity. Seventy-one patients with complex PTSD and severe comorbidity (e.g., 74% axis II comorbidity) were randomly assigned to either a 20-week group treatment in addition to treatment as usual or to treatment as usual only. Primary outcome measures were the Davidson trauma scale (DTS) for PTSD and the structured interview for disorders of extreme stress (SIDES) for complex PTSD symptoms. Statistical analysis was conducted in the intention-to-treat (ITT) and in the completer sample. Subjects were considered responders when scoring at 20 weeks at least 1 standard deviation below pretest findings. The 16% attrition was relatively low. After 20 weeks, the experimental condition (large effect sizes) and control condition (medium effect sizes) both showed significant decreases on the DTS and SIDES, but differences between the conditions were not significant. The secondary responder analysis (ITT) revealed significantly more responders on the DTS (45 vs. 21%), but not on the SIDES (61 vs. 42%). Adding psycho-educational and cognitive behavioural stabilizing group treatment for complex PTSD related to child abuse to treatment as usual showed an equivocal outcome. Patients in both conditions improved substantially during stabilizing treatment, and while significant superiority on change scores was absent, responder analysis suggested clinical meaningfulness of adding group treatment.


Enhancing surface heat transfer by carbon nanofins: towards an alternative to nanofluids?
Nanofluids are suspensions of nanoparticles and fibers which have recently attracted much attention because of their superior thermal properties. Nevertheless, it was proven that, due to modest dispersion of nanoparticles, such high expectations often remain unmet. In this article, by introducing the notion of nanofin, a possible solution is envisioned, where nanostructures with high aspect-ratio are sparsely attached to a solid surface (to avoid a significant disturbance on the fluid dynamic structures), and act as efficient thermal bridges within the boundary layer. As a result, particles are only needed in a small region of the fluid, while dispersion can be controlled in advance through design and manufacturing processes. Toward the end of implementing the above idea, we focus on single carbon nanotubes to enhance heat transfer between a surface and a fluid in contact with it. First, we investigate the thermal conductivity of the latter nanostructures by means of classical non-equilibrium molecular dynamics simulations. Next, thermal conductance at the interface between a single wall carbon nanotube (nanofin) and water molecules is assessed by means of both steady-state and transient numerical experiments. Numerical evidences suggest a pretty favorable thermal boundary conductance (order of 107 W·m-2·K-1) which makes carbon nanotubes potential candidates for constructing nanofinned surfaces.


Hydroxyl directed C-arylation: synthesis of 3-hydroxyflavones and 2-phenyl-3-hydroxy pyran-4-ones under transition-metal free conditions.
An efficient, transition-metal free and direct C-arylation of 3-hydroxychromone moieties in the presence of a base, air as an oxidant and arylhydrazines as arylating agents to furnish highly biologically active flavonols or 3-hydroxyflavones has been developed. We have further extended our methodology for the C-arylation of the 5-hydroxy pyran-4-one moiety. The role of the free hydroxyl group towards C-arylation has been delineated.


Complications arising in simple and polycystic liver cysts.
Liver cysts are common, affecting 5%-10% of the population. Most are asymptomatic, however 5% of patients develop symptoms, sometimes due to complications and will require intervention. There is no consensus on their management because complications are so uncommon. The aim of this study was to perform a collected review of how a series of complications were managed at our institutions. Six different patients presenting with rare complications of liver cysts were obtained from Hepatobiliary Units in the United Kingdom and The Netherlands. History and radiological imaging were obtained from case notes and computerised radiology. As a result, 1 patient admitted with inferior vena cava obstruction was managed by cyst aspiration and lanreotide; 1 patient with common bile duct obstruction was first managed by endoscopic retrograde cholangiopancreatography and stenting, followed by open fenestration; 1 patient with ruptured cysts and significant medical co-morbidities was managed by percutaneous drainage; 1 patient with portal vein occlusion and varices was managed by open liver resection; 1 patient with infected cysts was treated with intravenous antibiotics and is awaiting liver transplantation. The final patient with a simple liver cyst mimicking a hydatid was managed by open liver resection. In conclusion, complications of cystic liver disease are rare, and we have demonstrated in this series that both operative and non-operative strategies have defined roles in management. The mainstays of treatment are either aspiration/sclerotherapy or, alternatively laparoscopic fenestration. Medical management with somatostatin analogues is a potentially new and exciting treatment option but requires further study.


Exploratory study on the economic value of a closed farming system on Dutch dairy farms.
A closed farming system may prevent the introduction of infectious diseases on to dairy farms and could be a good starting point for the eradication of these diseases. In order to introduce a closed farming system, farmers need to be made aware of how these diseases are introduced into the herd. Farmers will be more likely to implement a closed farming system when the economic value is quantified and attractive. An exploratory study was carried out to investigate the technical and economic results of closed dairy farms. Farms that purchased cattle and/or shared pasture (defined as 'open' farms) differed in technical results from farms that did not ('closed' farms). The results of the discriminant analysis showed that the 'closed' farms incurred lower costs for veterinary services, had a lower average age at first calving and a higher birth rate per 100 dairy cows. A linear regression analysis was carried out to investigate the influence of the farming system on economic performance. Being 'closed' was found to increase the net profit by 0.31 Pound per 100 kg of milk, or approximately 25 Pounds per cow per year or 5 per cent of the typical net return to labour and management (1 Pound = Dfl 2.80 in November 1996).


Martian Biology: Accumulating evidence favors the theory of life on Mars, but we can expect surprises.
Of all the proposals put forth to account for the observed Martian phenomena, the idea of life on Mars seems to be the most tenable. And if this idea is accepted, we are immediately drawn to the conclusion that this life is a very well-adapted and flourishing one-not the struggle for existence so often suggested in light of the obvious difficulties earthly organisms would have in living on Mars. The suggested criteria seem to eliminate all the known life forms, but of all these forms, a higher plant would require the least modification in order to meet the criteria. The basic shape of the leaf of a higher plant seems suited to conditions on Mars, but the lower gravity might well result in some interesting modifications in morphology. Some life forms on Mars might resemble our own higher plants, but we should be prepared to encounter some interesting surprises in biochemistry.


Myeloid cells limit production of antibody-secreting cells after immunization in the lymph node.
Ab-secreting cell (ASC) expansion and survival are important processes in optimizing vaccines and controlling autoimmunity. The microenvironment of the medullary cords is positioned to control these key processes. Previously, we imaged and characterized ASC differentiation and migration by intravital microscopy in the lymph node (LN) by transferring and activating B cells expressing yellow fluorescent protein only in the ASC compartment. In this study, we observed that yellow fluorescent protein(+) ASCs in the medullary cords migrated along myelomonocytic cells and arrested in contact with them. Acute ablation of myeloid cells using the human diphtheria receptor system (diphtheria toxin receptor [DTR]) expressed in Lysmd1-cre-positive cells increased ASC and Ab production by 2-fold. Increases in ASC numbers were associated with cell proliferation based on Ki-67 staining, rather than reduced apoptosis, or changes in egress from the LN. Using DTR-mediated ablation targeted to Ccr2-expressing myeloid cells also generated increases in ASCs. In contrast, neither the depletion of Gr-1-positive cells with an Ab nor the ablation of cells using a cd11c-DTR resulted in any change in ASCs. IL-6 cytokine signaling can enhance ASC production and has been implicated in dampening ASCs in lupus mouse models through myeloid cells. Using mixed bone marrow chimeras, we observed that IL-6 enhances ASC production, but IL-6 production was not required by myeloid cells to dampen ASCs in the LN. Inhibition of ASCs by these myeloid cells in the LN provides a new regulatory mechanism with implications for tuning Ab responses.


Antiangiogenic therapies for malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM), arises from the mesothelial cells, is difficult to be diagnosed at an early stage, and is refractory to conventional chemotherapy and radiotherapy. Therefore, the establishment of novel effective therapies is necessary to improve the prognosis for many patients with this disease. Recent studies have demonstrated that angiogenesis plays a significant role in MPM progression, suggesting the importance of tumor vessels as therapeutic targets. To explore molecular pathogenesis and evaluate the efficacy of vascular targeting therapy in MPM, we developed orthotopic implantation SCID mouse models of MPM. We found that selective VEGF inhibitors were effective only in the treatment of high-VEGF-producing MPM models. On the other hand, multiple kinase inhibitor E7080, with inhibitory activity against various angiogenic cytokine receptors, suppressed the progression and prolonged survival of both high-VEGF-producing and low-VEGF-producing MPM models. Further understanding of the functional characteristics of tumor angiogenesis may be essential to improve targeting therapies in MPM. In this review, we introduce current status of clinical strategies and novel therapeutic approaches against angiogenesis in MPM.


A Novel Porcine Stomach Tissue Model for Laparoscopic Colpotomy Simulation.
Hysterectomies are the most common benign gynecologic surgical procedures performed in the United States. Currently, there are no tissue models that exist to teach trainees the techniques for colpotomy during laparoscopic hysterectomy. To address this educational gap, we have created a laparoscopic colpotomy model using a porcine stomach attached to a uterine manipulator. A segment of a porcine stomach is secured onto a uterine manipulator to simulate the cervicovaginal junction. A uterus model created with craft materials and reused in subsequent sessions is placed above the porcine stomach onto the uterine manipulator tip. Porcine stomach was obtained from a local butcher or meat market costing less than $1.00 per model. The tissue can be refrigerated or frozen for storage, then thawed before each use. This model can be used with any energy device and any laparoscopic platform to teach and perform the colpotomy. Usability survey showed that trainees responded positively to the model and attendings thought it was a useful teaching tool. Trainees and faculty responded favorably to the model and stated that the use of actual tissue enhanced the realism of a colpotomy simulation. The porcine stomach laparoscopic colpotomy model is an innovative, low-cost teaching tool to add to a gynecologic surgical education simulation toolkit.


An Integrated Metagenome Catalog Reveals New Insights into the Murine Gut Microbiome.
The complexity of host-associated microbial ecosystems requires host-specific reference catalogs to survey the functions and diversity of these communities. We generate a comprehensive resource, the integrated mouse gut metagenome catalog (iMGMC), comprising 4.6 million unique genes and 660 metagenome-assembled genomes (MAGs), many (485 MAGs, 73%) of which are linked to reconstructed full-length 16S rRNA gene sequences. iMGMC enables unprecedented coverage and taxonomic resolution of the mouse gut microbiota; i.e., more than 92% of MAGs lack species-level representatives in public repositories (<95% ANI match). The integration of MAGs and 16S rRNA gene data allows more accurate prediction of functional profiles of communities than predictions based on 16S rRNA amplicons alone. Accompanying iMGMC, we provide a set of MAGs representing 1,296 gut bacteria obtained through complementary assembly strategies. We envision that integrated resources such as iMGMC, together with MAG collections, will enhance the resolution of numerous existing and future sequencing-based studies.


Class and lifestyle 'lock-in' among middle-aged and older men: a Multiple Correspondence Analysis of the British Regional Heart Study.
Health lifestyles are collective patterns of health risk behaviour that develop within a social habitus. An important area for research is the extent to which health lifestyles become more individualised over time and as people age, or whether health lifestyles remain socially structured. This article presents findings from a Multiple Correspondence Analysis of the British Regional Heart Study. Our findings suggest that smoking and alcohol use retain a strong class patterning as men age (suggesting some support for the long-term importance of social structures in old age). This indicates that, in later life, some forms of class-related health lifestyles become fixed or 'locked in'. In contrast there is evidence to suggest that, for exercise, class becomes less important as people age (suggesting either some support for growing individualisation and or important ageing effects). Further studies are required to examine different forms of health lifestyle in later life in relation to forms of cultural and economic capital. This study provides evidence in support of attempts to theorise health lifestyles in terms of collectivities. Furthermore, the concept of selective lifestyle 'lock-in' may be a useful way of understanding the relationship between class and health lifestyles in old age.


Adipose tissue levels of organochlorine pesticides and polychlorinated biphenyls and risk of non-Hodgkin's lymphoma.
In this nested case-control study we examined the relationship between non-Hodgkin's lymphoma (NHL) and organochlorine pesticide exposure. We used a data set originally collected between 1969 and 1983 in the U.S. Environmental Protection Agency National Human Adipose Tissue Survey. Adipose samples were randomly collected from cadavers and surgical patients, and levels of organochlorine pesticide residues were determined. From the original study population, 175 NHL cases were identified and matched to 481 controls; 173 controls were selected from accident victims, and 308 from cases with a diagnosis of myocardial infarction. Cases and controls were mainly from cadavers (> 96%) and were matched on sex, age, region of residence within the United States, and race/ethnicity. Conditional logistic regression showed the organochlorine pesticide residue heptachlor epoxide to be significantly associated with NHL [compared with the lowest quartile: third quartile odds ratio (OR) = 1.82, 95% confidence interval (CI), 1.01-3.28; fourth quartile OR = 3.41, 95% CI, 1.89-6.16]. The highest quartile level of dieldrin was also associated with elevated NHL risk (OR = 2.70; 95% CI, 1.58-4.61), as were higher levels of oxychlordane, p,p'-DDE [p,p'-1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene], and ss-benzene hexachloride (ORs = 1.79, 1.99, and 2.47, respectively). The p-values for trends for these associations were significant. In models containing pairs of pesticides, only heptachlor epoxide and dieldrin remained significantly associated with risk of NHL. Limitations of this study include collection of samples after diagnosis and a lack of information on variables affecting organochlorine levels such as diet, occupation, and body mass index. Given the persistence of pesticides in the environment, these findings are still relevant today.


Physically equivalent temperature and mental and behavioural disorders in Germany in 2009-2011.
We aimed to understand the relationships of the weather as biometeorological and hospital admissions due to common mental and behavioural disorders in a national setting in recent years. This is an ecological study. Ten percent of daily hospital admissions from the included hospitals (n = 1618) across Germany that were available between 1 January 2009 and 31 December 2011 (n = 5,235,600) were extracted from Statistisches Bundesamt, Germany. We identified F01-F51 mental ad behavioural disorders by International Classification of Diseases version 10 as the study outcomes. Daily weather data from 64 weather stations covering 13 German States including air temperature, humidity, wind speed, cloud cover, radiation flux and vapour pressure were obtained and generated into physiologically equivalent temperature (PET). We then plotted two-way fractional-polynomial regression. For the most subtypes, the highest admissions were recorded in spring. There were small peaks in autumn or late winter for a few subtypes as well. Admissions of delirium peaked when PET was at 0 °C. Admissions of personality disorders peaked at the coldest - when PET was at -10 °C. Admissions of schizophrenia and nonorganic sleep disorder peaked when PETs were between 0 and -10 °C while admissions of eating disorders dropped when PETs were above 10 °C. Admissions of depression and anxiety disorder did not vary much across PETs. Moreover, admissions of reaction to stress and dissociate disorder peaked when PETs were between 0 and 10 °C as well. More medical resources could have been needed for mental health on days when PETs were <10 °C than on other days.