Acute arteriovenous access failure: long-term outcomes of endovascular salvage and assessment of co-variates affecting patency.
This study reports long-term outcomes after endovascular salvage (EVS) for acute dialysis fistula/graft dysfunction. All patients presenting with acute fistula or graft dysfunction, excluding primary failures, referred for endovascular salvage were included in this single-centre prospective study. Altogether, 410 procedures were carried out in 232 patients. Overall, the incidence of thrombosis/occlusion (per patient-year) was 0.12 for fistulae and 0.9 for grafts. The anatomical success rate for EVS was 94% for fistulae and 92% for grafts. Primary patency rates for fistulae at 1, 6, 12, 24 and 36 months were 82, 64, 44, 34 and 26%, respectively, whereas secondary patency rates were 88, 84, 74, 69 and 61%, respectively. Primary patency rates for grafts at 1, 6 and 12 months were 50, 14 and 8%. The overall rate of complications was 6% with no incidence of symptomatic pulmonary embolism. In a Cox regression model, upper-arm location of fistula (HR 1.9, p = 0.04, n = 144) was associated with lower primary patency, whereas the presence of thrombosis was associated lower primary (HR 1.9, p = 0.004, n = 144) and secondary patency (HR 3.7, p < 0.001, n = 144). Aspirin therapy was associated with longer primary patency (HR 0.6, p = 0.02, n = 144) and secondary patency (HR 0.58, p = 0.08, n = 144). EVS is effective but longer-term outcomes are poor. Presence of thrombosis portends poor fistula survival and strategies for prevention need attention. Balloon maceration, our preferred declotting technique, is safe and the most cost-effective method. Aspirin therapy for patients presenting with failure of fistulae deserves further investigation.


A review of the evidence supporting melatonin's role as an antioxidant.
This survey summarizes the findings, accumulated within the last 2 years, concerning melatonin's role in defending against toxic free radicals. Free radicals are chemical constituents that have an unpaired electron in their outer orbital and, because of this feature, are highly reactive. Inspired oxygen, which sustains life, also is harmful because up to 5% of the oxygen (O2) taken in is converted to oxygen-free radicals. The addition of a single electron to O2 produces the superoxide anion radical (O2-.); O2-. is catalytic-reduced by superoxide dismutase, to hydrogen peroxide (H2O2). Although H2O2 is not itself a free radical, it can be toxic at high concentrations and, more importantly, it can be reduced to the hydroxyl radical (.OH). The .OH is the most toxic of the oxygen-based radicals and it wreaks havoc within cells, particularly with macromolecules. In recent in vitro studies, melatonin was shown to be a very efficient neutralizer of the .OH; indeed, in the system used to test its free radical scavenging ability it was found to be significantly more effective than the well known antioxidant, glutathione (GSH), in doing so. Likewise, melatonin has been shown to stimulate glutathione peroxidase (GSH-Px) activity in neural tissue; GSH-PX metabolizes reduced glutathione to its oxidized form and in doing so it converts H2O2 to H2O, thereby reducing generation of the .OH by eliminating its precursor. More recent studies have shown that melatonin is also a more efficient scavenger of the peroxyl radical than is vitamin E. The peroxyl radical is generated during lipid peroxidation and propagates the chain reaction that leads to massive lipid destruction in cell membranes. In vivo studies have demonstrated that melatonin is remarkably potent in protecting against free radical damage induced by a variety of means. Thus, DNA damage resulting from either the exposure of animals to the chemical carcinogen safrole or to ionizing radiation is markedly reduced when melatonin is co-administered. Likewise, the induction of cataracts, generally accepted as being a consequence of free radical attack on lenticular macromolecules, in newborn rats injected with a GSH-depleting drug are prevented when the animals are given daily melatonin injections. Also, paraquat-induced lipid peroxidation in the lungs of rats is overcome when they also receive melatonin during the exposure period. Paraquat is a highly toxic herbicide that inflicts at least part of its damage by generating free radicals.(ABSTRACT TRUNCATED AT 400 WORDS)


Carrier scattering in quasi-free standing graphene on hexagonal boron nitride.
Graphene, a two-dimensional material with a honeycomb lattice, has been promoted as a next generation material because of its ultrafast charge carriers and superior electrical properties. Hexagonal boron nitride (h-BN) is an insulator explored as an ideal substrate for graphene with lattice-matching. Using raido-frequency (RF) transmission measurement which provides specific characteristics of carrier scattering in a device, we profoundly investigated the electrical properties of quasi-free standing graphene on h-BN. RF devices with graphene supported and encapsulated with h-BN were fabricated to analyze the RF signal at low temperatures from 100 to 300 K. We demonstrated the carrier behavior in graphene with thermally excited carriers and acoustic photon scattering according to heat energy. Both h-BN supported and encapsulated graphene showed a significant enhancement in RF transmission, which is close to a gold interconnector. Our device with graphene on h-BN exhibited concealed nonlinear characteristics at a specific temperature of 180 K due to the internal effects of acoustic phonon scattering, while a usual device with graphene on SiO2/Si provided a linear variation. To anticipate the potential for electronic applications, the electrical circuit properties such as impedance, resistance, and inductance were extracted from the results of RF measurement.


New Acridine Thiourea Gold(I) Anticancer Agents: Targeting the Nucleus and Inhibiting Vasculogenic Mimicry.
Two new 1-acridin-9-yl-3-methylthiourea Au(I) DNA intercalators [Au(ACRTU)2]Cl (2) and [Au(ACRTU) (PPh3)]PF6 (3) have been prepared. Both complexes were highly active in the human ovarian carcinoma cisplatin-sensitive A2780 cell line, exhibiting IC50 values in the submicromolar range. Compounds 2 and 3 are also cytotoxic toward different phenotypes of breast cancer cell lines MDA-MB-231 (triple negative), SK-BR-3 (HER2+, ERα-, and ERβ-), and MCF-7 (ER+). Both complexes induce apoptosis through activation of caspase-3 in vitro. While inhibition of some proteins (thiol-containing enzymes) seems to be the main mechanism of action for cytotoxic gold complexes, 2 and 3 present a DNA-dependent mechanism of action. They locate in the cell nucleus according to confocal microscopy and transmission electronic microscopy. The binding to DNA resulted to be via intercalation as shown by spectroscopic methods and viscometry, exhibiting a dose-dependent response on topoisomerase I mediated DNA unwinding. In addition, 2 and 3 exhibit potent antiangiogenic effects and are also able to inhibit vasculogenic mimicry of highly invasive MDA-MB-231 cells.


Does honey have any salutary effect against streptozotocin - induced diabetes in rats?
Diabetes is a global, growing and costly public health problem. In the literature, there are conflicting reports on the effect of consumption of bee honey on diabetes. We assessed the possible effect of a commercially available bee honey (given orally by gavage at doses of 1 g/kg/day for 4 weeks) on the blood concentrations of glucose, insulin and leptin and body weight of rats with streptozotocin-induced diabetes. Thirty-six rats were allocated randomly into six groups equally and treated for 4 weeks as follows: Group.1: non-diabetic rats given distilled water, group.2: non-diabetic rats given honey (1 g/kg), group.3: Diabetic rats given distilled water, group.4: Diabetic rats given honey, group.5: Diabetic rats given insulin (10 IU/kg), and group.6: Diabetic rats given combination of insulin (10 IU/kg) with honey (1 g/kg). The body weight, blood glucose, insulin and leptin concentrations of each rat were measured. Honey treatment did not significantly affect the glucose, leptin and insulin concentrations of diabetic rats. It did not significantly affect the excessive water intake or urinary output in diabetic rats when compared to the insulin-treated groups. Neither honey nor insulin improved body weight in diabetic rats. Contrary to the reports of a salutary effect of honey in diabetic humans and rodents, our results showed that consumption of honey caused no significant changes in body weight, or glucose and insulin concentrations. However, further studies with different doses and durations of treatment are warranted.


Judgement bias in goats (Capra hircus): investigating the effects of human grooming.
Animal emotional states can be investigated by evaluating their impact on cognitive processes. In this study, we used a judgement bias paradigm to determine if short-term positive human-animal interaction (grooming) induced a positive affective state in goats. We tested two groups of goats and trained them to discriminate between a rewarded and a non-rewarded location over nine training days. During training, the experimental group (n = 9) was gently groomed by brushing their heads and backs for five min over 11 days (nine training days, plus two testing days, total time 55 min). During training, the control group (n = 10) did not experience any direct interaction with the experimenter, but was kept unconstrained next to him for the same period of time. After successful completion of the training, the responses (latency time) of the two groups to reach ambiguous locations situated between the two reference locations (i.e., rewarded/non-rewarded) were compared over two days of testing. There was not a positive bias effect after the animals had been groomed. In a second experiment, 10 goats were tested to investigate whether grooming induced changes in physiological activation (i.e., heart rate and heart rate variability). Heart rate increased when goats were groomed compared to the baseline condition, when the same goats did not receive any contact with the experimenter. Also, subjects did not move away from the experimenter, suggesting that the grooming was positively accepted. The very good care and the regular positive contacts that goats received from humans at the study site could potentially account for the results obtained. Good husbandry outcomes are influenced by animals' perception of the events and this is based on current circumstances, past experiences and individual variables. Taking into account animals' individual characteristics and identifying effective strategies to induce positive emotions could increase the understanding and reliability of using cognitive biases paradigms to investigate and promote animal welfare.


Dynamic expression of imprinted genes associates with maternally controlled nutrient allocation during maize endosperm development.
In angiosperms, the endosperm provides nutrients for embryogenesis and seed germination and is the primary tissue where gene imprinting occurs. To identify the imprintome of early developing maize (Zea mays) endosperm, we performed high-throughput transcriptome sequencing of whole kernels at 0, 3, and 5 d after pollination (DAP) and endosperms at 7, 10, and 15 DAP, using B73 by Mo17 reciprocal crosses. We observed gradually increased expression of paternal transcripts in 3- and 5-DAP kernels. In 7-DAP endosperm, the majority of the genes tested reached a 2:1 maternal versus paternal ratio, suggesting that paternal genes are nearly fully activated by 7 DAP. A total of 116, 234, and 63 genes exhibiting parent-specific expression were identified at 7, 10, and 15 DAP, respectively. The largest proportion of paternally expressed genes was at 7 DAP, mainly due to the significantly deviated parental allele expression ratio of these genes at this stage, while nearly 80% of the maternally expressed genes (MEGs) were specific to 10 DAP and were primarily attributed to sharply increased expression levels compared with the other stages. Gene ontology enrichment analysis of the imprinted genes suggested that 10-DAP endosperm-specific MEGs are involved in nutrient uptake and allocation and the auxin signaling pathway, coincident with the onset of starch and storage protein accumulation.


Effects of non-equilibrium angle fluctuation on F1-ATPase kinetics induced by temperature increase.
F1-ATPase (F1) is an efficient rotary protein motor, whose reactivity is modulated by the rotary angle to utilize thermal fluctuation. In order to elucidate how its kinetics are affected by the change in the fluctuation, we have extended the reaction-diffusion formalism [R. Watanabe et al., Biophys. J., 2013, 105, 2385] applicable to a wider range of temperatures based on experimental data analysis of F1 derived from thermophilic Bacillus under high ATP concentration conditions. Our simulation shows that the rotary angle distribution manifests a stronger non-equilibrium feature as the temperature increases, because ATP hydrolysis and Pi release are more accelerated compared with the timescale of rotary angle relaxation. This effect causes the rate coefficient obtained from dwell time fitting to deviate from the Arrhenius relation in Pi release, which has been assumed in the previous activation thermodynamic quantities estimation using linear Arrhenius fitting. Larger negative correlation is also found between hydrolysis and Pi release waiting time in a catalytic dwell with the increase in temperature. This loss of independence between the two successive reactions at the catalytic dwell sheds doubt on the conventional dwell time fitting to obtain rate coefficients with a double exponential function at temperatures higher than 65 °C, which is close to the physiological temperature of the thermophilic Bacillus.


Honey, I shrunk the bubbles: microfluidic vacuum shrinkage of lipid-stabilized microbubbles.
We present a microfluidic technique that shrinks lipid-stabilized microbubbles from O(100) to O(1) μm in diameter - the size that is desirable in applications as ultrasound contrast agents. We achieve microbubble shrinkage by utilizing vacuum channels that are adjacent to the microfluidic flow channels to extract air from the microbubbles. We tune a single parameter, the vacuum pressure, to accurately control the final microbubble size. Finally, we demonstrate that the resulting O(1) μm diameter microbubbles have similar stability to microfluidically generated microbubbles that are not exposed to vacuum shrinkage. We anticipate that, with additional scale-up, this simple approach to shrink microbubbles generated microfluidically will be desirable in ultrasound imaging and therapeutic applications.


Sleep-related migraine occurrence increases with aging.
A preferential occurrence of attacks at night-time or during early morning is documented in migraine without aura, suggesting a relationship between migraine and sleep and an impairment of circadian rhythms. The objective of this study was to verify the occurrence of sleep-related migraine in a large sample of migraineurs divided in different age groups and to evaluate the possible role of physiological variables (i.e., aging, gender) and comorbidities (i.e., psychiatric diseases). 734 patients (519 women and 215 males), aged 21-70 years, fulfilling IHS criteria (2004) for migraine without aura, were enrolled. The population was divided into five groups according to decades of life and it was evaluated the percentage of sleep-related migraine (at least 75% migraine attacks occurring during night sleep and/or upon awakening) in the different age groups. Headache clinical diary, Pittsburgh Sleep Quality Index and Beck Depression Inventory were also used. The preferential emergence of attacks during night sleep and/or upon awakening progressively increased with aging, without gender predilection; the percentage of patients with sleep-related migraine was: 16% between 20 and 30 years, 27% between 31 and 40 years, 38% between 41 and 50 years, 45% between 51 and 60 years, and 58% between 61 and 70 years, respectively. Poor sleep quality and depression did not account for night-time and/or awakening migraine collocation. These data suggest the main role of aging in order to favor nocturnal/early morning emergence of migraine without aura and support the hypothesis of an involvement of impaired chronobiological mechanisms and sleep regulation.


Primary Prevention with a Capital P.
The survival of large segments of human populations to advanced ages is a crowning achievement of improvements in public health and medicine, but in the 21st century, our continued desire to extend life brings forth a unique dilemma. The risk of death from chronic fatal diseases has declined, but even if it continues to do so in the future, the resulting longevity benefits are likely to diminish. It is even possible that unhealthy life expectancy could rise in the future as major fatal diseases wane. The reason for this is that the longer we live, the greater the influence of biological aging on the expression of fatal and disabling diseases. Research in gerontology has already demonstrated that aging is inherently modifiable, and that a therapeutic intervention that slows aging in people is a plausible target for science and public health. Given the speed with which population aging is progressing and chronic fatal and disabling conditions are challenging health-care costs across the globe, the case is now being made that delayed aging could be one of the most efficient and promising ways to combat disease, extend healthy life, compress morbidity, and reduce health-care costs.


Alcohol content in declared non-to low alcoholic beverages: implications to pregnancy.
Alcohol consumption in pregnancy may result in serious adverse fetal outcome. Non- or low alcoholic wines and beers may be a risk-reduction strategy to help alcohol-dependent individuals to prevent or limit ethanol consumption. The objective of this study was to quantify ethanol concentrations in Canadian beverages claiming to contain no or low alcohol content. Forty-five different beverages claiming to contain no or low alcohol content in the Canadian market were tested for ethanol concentration using gas chromatography. Thirteen (29%) of the beverages contained ethanol levels higher than the declared concentration on their label. Six beverages claiming to contain no alcohol were found to contain greater than 1% ethanol. Pregnant women seeking replacement to alcoholic beverages may be misled by these labels, unknowingly exposing themselves and their unborn babies to ethanol.


Response inhibition on the stop signal task improves during cardiac contraction.
Motor actions can be facilitated or hindered by psychophysiological states of readiness, to guide rapid adaptive action. Cardiovascular arousal is communicated by cardiac signals conveying the timing and strength of individual heartbeats. Here, we tested how these interoceptive signals facilitate control of motor impulsivity. Participants performed a stop signal task, in which stop cues were delivered at different time points within the cardiac cycle: at systole when the heart contracts (T-wave peak, approximately 300 ms following the R-wave), or at diastole between heartbeats (R-wave peak). Response inhibition was better at systole, indexed by a shorter stop signal reaction time (SSRT), and longer stop signal delay (SSD). Furthermore, parasympathetic control of cardiovascular tone, and subjective sensitivity to interoceptive states, predicted response inhibition efficiency, although these cardiovascular and interoceptive correlations did not survive correction for multiple comparisons. This suggests that response inhibition capacity is influenced by interoceptive physiological cues, such that people are more likely to express impulsive actions during putative states of lower cardiovascular arousal, when frequency and strength of cardiac afferent signalling is reduced.


Endothelial Nogo-B regulates sphingolipid biosynthesis to promote pathological cardiac hypertrophy during chronic pressure overload.
We recently discovered that endothelial Nogo-B, a membrane protein of the ER, regulates vascular function by inhibiting the rate-limiting enzyme, serine palmitoyltransferase (SPT), in de novo sphingolipid biosynthesis. Here, we show that endothelium-derived sphingolipids, particularly sphingosine-1-phosphate (S1P), protect the heart from inflammation, fibrosis, and dysfunction following pressure overload and that Nogo-B regulates this paracrine process. SPT activity is upregulated in banded hearts in vivo as well as in TNF-α-activated endothelium in vitro, and loss of Nogo removes the brake on SPT, increasing local S1P production. Hence, mice lacking Nogo-B, systemically or specifically in the endothelium, are resistant to the onset of pathological cardiac hypertrophy. Furthermore, pharmacological inhibition of SPT with myriocin restores permeability, inflammation, and heart dysfunction in Nogo-A/B-deficient mice to WT levels, whereas SEW2871, an S1P1 receptor agonist, prevents myocardial permeability, inflammation, and dysfunction in WT banded mice. Our study identifies a critical role of endothelial sphingolipid biosynthesis and its regulation by Nogo-B in the development of pathological cardiac hypertrophy and proposes a potential therapeutic target for the attenuation or reversal of this clinical condition.


Survival of the fattest: fat babies were the key to evolution of the large human brain.
In the past 2 million years, the hominid lineage leading to modern humans evolved significantly larger and more sophisticated brains than other primates. We propose that the modern human brain was a product of having first evolved fat babies. Hence, the fattest (infants) became, mentally, the fittest adults. Human babies have brains and body fat each contributing to 11-14% of body weight, a situation which appears to be unique amongst terrestrial animals. Body fat in human babies provides three forms of insurance for brain development that are not available to other land-based species: (1) a large fuel store in the form of fatty acids in triglycerides; (2) the fatty acid precursors to ketone bodies which are key substrates for brain lipid synthesis; and (3) a store of long chain polyunsaturated fatty acids, particularly docosahexaenoic acid, needed for normal brain development. The triple combination of high fuel demands, inability to import cholesterol or saturated fatty acids, and dependence on docosahexaenoic acid puts the mammalian brain in a uniquely difficult situation compared with other organs and makes its expansion in early humans all the more remarkable. We believe that fresh- and salt-water shorelines provided a uniquely rich, abundant and accessible food supply, and the only viable environment for evolving both body fat and larger brains in human infants.


PLEK: a tool for predicting long non-coding RNAs and messenger RNAs based on an improved k-mer scheme.
High-throughput transcriptome sequencing (RNA-seq) technology promises to discover novel protein-coding and non-coding transcripts, particularly the identification of long non-coding RNAs (lncRNAs) from de novo sequencing data. This requires tools that are not restricted by prior gene annotations, genomic sequences and high-quality sequencing. We present an alignment-free tool called PLEK (predictor of long non-coding RNAs and messenger RNAs based on an improved k-mer scheme), which uses a computational pipeline based on an improved k-mer scheme and a support vector machine (SVM) algorithm to distinguish lncRNAs from messenger RNAs (mRNAs), in the absence of genomic sequences or annotations. The performance of PLEK was evaluated on well-annotated mRNA and lncRNA transcripts. 10-fold cross-validation tests on human RefSeq mRNAs and GENCODE lncRNAs indicated that our tool could achieve accuracy of up to 95.6%. We demonstrated the utility of PLEK on transcripts from other vertebrates using the model built from human datasets. PLEK attained >90% accuracy on most of these datasets. PLEK also performed well using a simulated dataset and two real de novo assembled transcriptome datasets (sequenced by PacBio and 454 platforms) with relatively high indel sequencing errors. In addition, PLEK is approximately eightfold faster than a newly developed alignment-free tool, named Coding-Non-Coding Index (CNCI), and 244 times faster than the most popular alignment-based tool, Coding Potential Calculator (CPC), in a single-threading running manner. PLEK is an efficient alignment-free computational tool to distinguish lncRNAs from mRNAs in RNA-seq transcriptomes of species lacking reference genomes. PLEK is especially suitable for PacBio or 454 sequencing data and large-scale transcriptome data. Its open-source software can be freely downloaded from https://sourceforge.net/projects/plek/files/.


Gastrobronchial fistula following laparoscopic sleeve gastrectomy.
Acquired fistulas between the tracheobronchial tree and the gastrointestinal tract are rare but serious complications of laparoscopic sleeve gastrectomies with significant morbidity and mortality. With the rising popularity and widespread acceptance of bariatric surgery techniques, the occurrence of gastrobronchial fistulas is being increasingly recognised. We present the case of a 26-year-old woman who underwent laparoscopic sleeve gastrectomy for morbid obesity and presented later with a history of chronic productive cough. Upper gastrointestinal series showed the presence of a communicating fistula between the stomach and the lung, with extravasation of contrast into the lung. The aim of this paper is to highlight the importance of considering the diagnosis of a gastrobronchial fistula in cases of persistent respiratory infections in the postoperative period following bariatric surgery and to review its incidence, clinical manifestations and treatment.


Mechanical cloak design by direct lattice transformation.
Spatial coordinate transformations have helped simplifying mathematical issues and solving complex boundary-value problems in physics for decades already. More recently, material-parameter transformations have also become an intuitive and powerful engineering tool for designing inhomogeneous and anisotropic material distributions that perform wanted functions, e.g., invisibility cloaking. A necessary mathematical prerequisite for this approach to work is that the underlying equations are form invariant with respect to general coordinate transformations. Unfortunately, this condition is not fulfilled in elastic-solid mechanics for materials that can be described by ordinary elasticity tensors. Here, we introduce a different and simpler approach. We directly transform the lattice points of a 2D discrete lattice composed of a single constituent material, while keeping the properties of the elements connecting the lattice points the same. After showing that the approach works in various areas, we focus on elastic-solid mechanics. As a demanding example, we cloak a void in an effective elastic material with respect to static uniaxial compression. Corresponding numerical calculations and experiments on polymer structures made by 3D printing are presented. The cloaking quality is quantified by comparing the average relative SD of the strain vectors outside of the cloaked void with respect to the homogeneous reference lattice. Theory and experiment agree and exhibit very good cloaking performance.


Tissue-specific distribution and dynamic changes of 5-hydroxymethylcytosine in mammalian genomes.
Cytosine residues in the vertebrate genome are enzymatically modified to 5-methylcytosine, which participates in transcriptional repression of genes during development and disease progression. 5-Methylcytosine can be further enzymatically modified to 5-hydroxymethylcytosine by the TET family of methylcytosine dioxygenases. Analysis of 5-methylcytosine and 5-hydroxymethylcytosine is confounded, as these modifications are indistinguishable by traditional sequencing methods even when supplemented by bisulfite conversion. Here we demonstrate a simple enzymatic approach that involves cloning, identification, and quantification of 5-hydroxymethylcytosine in various CCGG loci within murine and human genomes. 5-Hydroxymethylcytosine was prevalent in human and murine brain and heart genomic DNAs at several regions. The cultured cell lines NIH3T3 and HeLa both displayed very low or undetectable amounts of 5-hydroxymethylcytosine at the examined loci. Interestingly, 5-hydroxymethylcytosine levels in mouse embryonic stem cell DNA first increased then slowly decreased upon differentiation to embryoid bodies, whereas 5-methylcytosine levels increased gradually over time. Finally, using a quantitative PCR approach, we established that a portion of VANGL1 and EGFR gene body methylation in human tissue DNA samples is indeed hydroxymethylation.


The strength of weak connections in the macaque cortico-cortical network.
Examination of the cortico-cortical network of mammals has unraveled key topological features and their role in the function of the healthy and diseased brain. Recent findings from social and biological networks pinpoint the significant role of weak connections in network coherence and mediation of information from segregated parts of the network. In the current study, inspired by such findings and proposed architectures pertaining to social networks, we examine the structure of weak connections in the macaque cortico-cortical network by employing a tract-tracing dataset. We demonstrate that the cortico-cortical connections as a whole, as well as connections between segregated communities of brain areas, comply with the architecture suggested by the so-called strength-of-weak-ties hypothesis. However, we find that the wiring of these connections is not optimal with respect to the aforementioned architecture. This configuration is not attributable to a trade-off with factors known to constrain brain wiring, i.e., wiring cost and efficiency. Lastly, weak connections, but not strong ones, appear important for network cohesion. Our findings relate a topological property to the strength of cortico-cortical connections, highlight the prominent role of weak connections in the cortico-cortical structural network and pinpoint their potential functional significance. These findings suggest that certain neuroimaging studies, despite methodological challenges, should explicitly take them into account and not treat them as negligible.


Searching for new options for treating insomnia: are melatonin and ramelteon beneficial?
Insomnia is one of the most common complaints faced in clinical practice. The limited pharmacological options available make the treatment of this complaint a challenge. All of the available benzodiazepines and non-benzodiazepine hypnotics have the potential to induce addiction, cause withdrawal symptoms, or trigger rebound insomnia. Further, the evidence supporting the utility of commonly prescribed options such as antidepressants and antipsychotics is limited. Melatonin is a hormone that has been associated with soporific effects. Based on this premise, a melatonin receptor agonist was created. Ramelteon was approved by the Food and Drug Administration in 2005 and is the only medication indicated for the long-term treatment of insomnia. A critical review with a clinical perspective of randomized, placebo-controlled clinical trials was conducted to determine the efficacy of melatonin and ramelteon for the treatment of insomnia. Based on this review, it appears that more placebo-controlled trials are indicated before valid judgments concerning the efficacy of both melatonin and ramelteon can be made. In the meantime, there is some support for the use of melatonin for the treatment of insomnia, and findings concerning ramelteon also appear promising. Nevertheless, clinicians who prescribe melatonin or ramelteon should be cautious and carefully monitor both potential benefits and adverse effects, since data on melatonin are based on studies with multiple limitations and only three controlled trials have been done with ramelteon.


Fringe visibility, irradiance, and accuracy in common path interferometers for visualization of phase disturbances.
Common-path interferometers have been used to perform phase visualization for over 40 years. A number of techniques have been proposed, including dark central ground, phase contrast (π/2 and π), and field-absorption interferometers. The merits of the interferometers have been judged ad hoc by either tests with a small number of phase objects or by computer simulation. Three standardized criteria, which consolidate the work of others, are proposed to evaluate common-path interferometers: fringe visibility, fringe irradiance, and fringe accuracy. The interferometers can be described as one generic class of Fourier-plane filters and can be analyzed for all input conditions. Closed-form expressions are obtained for visibility and irradiance under the forced condition that little inaccuracy is tolerated. This analysis finds that the π-phase-contrast interferometer is a good choice if the optical phase disturbance is at least 2π; for smaller disturbances, the Π/2 filter selected by Zernike is near optimum. It is shown mathematically that the resulting fringe visibility is highly object dependent, and good results are not ensured. By allowing the optical beam to be 50% larger than the phase object, the interferometer performs well under all conditions. With this approach and a combination π-phase/field-absorption filter, interference fringe visibility is greater than 0.8 for all phase objects.


Real teams and their effect on the quality of care in nursing homes.
Use of teams has shown to be an important factor for organizational performance. However, research has shown that a team has to meet certain criteria and operate in a certain way to realize the potential benefits of team organizing. There are few studies that have examined how teams operate in the nursing home sector and their effect on quality of care. This study investigates the relationship between teams that meet an academic definition of the team concept and quality of care in nursing homes. A cross-sectional survey of forty nursing home wards throughout Norway was used to collect the data. Five sources of data were utilized to test our research question: (1) self-report questionnaires to 444 employees, (2) interviews with 40 ward managers, (3) self-report questionnaires to 40 ward managers, (4) telephone interviews with 378 relatives, and (5) 900 hours of field observations. Use of teams in nursing home wards was assessed by field observations and by interviews with ward mangers. Quality of care was assessed by data from surveys and interviews with relatives and staff and through field observations. All data were aggregated to the ward level and two-level analyses were used to assess the relationships. The multi-level analyses showed that teams - as operationalized in the present study - were significantly positively related to two out of the three quality of care indices when controlled for ward size, days of sick leave and care level. One significant interaction effect was found between teams and days of sick leave, implying that the effect of teams decreased with higher numbers of days of sick leave. The results suggest that teams are related to higher levels of quality of care in nursing homes. However, the study shows that there is a substantial difference between real, functional teams that meet an academic definition of the concept and quasi teams, the latter having a significantly lower effect on quality of care. Hence, nursing home leaders, directors and ward leaders should be aware of the substantial differences betweens dysfunctional - or quasi - teams and real teams, and encourage the development of real functional teams to take advantage of the potential benefits of team organizing.


Binding-, intracellular transport-, and biosynthesis-defective mutants of vasopressin type 2 receptor in patients with X-linked nephrogenic diabetes insipidus.
Nephrogenic diabetes insipidus (NDI) is most often an X-linked disorder in which urine is not concentrated due to renal resistance to arginine vasopressin. We recently identified four vasopressin type 2 receptor gene mutations in unrelated X-linked NDI families, including R143P, delta V278, R202C, and 804insG. All these mutations reduced ligand binding activity to < 10% of the normal without affecting mRNA accumulation. To elucidate whether the receptors are expressed on the cell surface, we analyzed biosynthesis and localization of tagged or untagged receptors stably expressed in Chinese hamster ovary (CHO) cells, using two antibodies directed against distinct termini. Whole-cell and surface labeling studies revealed that the R202C clone had both surface-localized (50-55 kD) and intracellular proteins (40 and 75 kD), similar to the wild-type AVPR2 clone, whereas the R143P and delta V278 clones lacked the surface receptors, despite relatively increased intracellular components. The 804insG mutant cell produced no proteins despite an adequate mRNA level. Immunofluorescence staining confirmed that the R202C mutant reaches the cell surface, whereas the R143P and delta V278 mutants are retained within the cytoplasmic compartment. Thus, R202C, R143P/delta V278, and 804insG result in three distinct phenotypes, that is, a simple binding impairment at the cell surface, blocked intracellular transport, and ineffective biosynthesis or/and accelerated degradation of the receptor, respectively, and therefore are responsible for NDI. This phenotypic classification will help understanding of molecular pathophysiology of this disorder.


Analysis of histone gene expression in adult tissues of the sea urchins Strongylocentrotus purpuratus and Lytechinus pictus: tissue-specific expression of sperm histone genes.
We analyzed the histone mRNA population found in several adult tissues of the sea urchin Strongylocentrotus purpuratus and in testis of Lytechinus pictus. Unique species of H1 and H2b mRNAs encoding the sperm-specific histone subtypes can be found exclusively in testis RNA. S. purpuratus contains two distinct testis-specific H1 transcripts, while L. pictus contains one such transcript. Each of these mRNAs is larger than either early or late embryonic H1 mRNAs. Other somatic adult tissues contain transcripts derived from members of the late embryonic H1 histone gene family. S. purpuratus contains one H2b transcript found exclusively in testis, while L. pictus contains two such H2b mRNAs. Similarly, in tissues other than testis, late H2b transcripts were found. While there is no sperm-specific H2a protein, a limited set of late histone H2a genes encoding primarily the H2a-beta subtype is expressed in testis. The majority of the H2a protein found in diploid adult tissues is also the H2a-beta subtype; however, the size of the H2a transcripts differs between testis and other tissues. We conclude that different members of the late H2a gene family are differentially expressed in embryos and adult tissues. We prepared and characterized cDNA clones encoding the sperm-specific H2b protein as well as the H2a-beta protein found in testis.


In vitro activities of antifungal drugs against environmental Exophiala isolates and review of the literature.
Exophiala is a genus of black fungi isolated worldwide from environmental and clinical specimens. Data on antifungal susceptibility of Exophiala isolates are limited and the methodology on susceptibility testing is not yet standardised. In this study, we investigated in vitro antifungal susceptibilities of environmental Exophiala isolates. A total of 87 Exophiala isolated from dishwashers or railway ties were included. A CLSI M38-A2 microdilution method with modifications was used to determine antifungal susceptibility for fluconazole, voriconazole, posaconazole, itraconazole, amphotericin B and terbinafine. Minimum inhibitory concentration (MIC) values were determined visually at 48 hours, 72 hours and 96 hours. MIC-0 endpoint (complete inhibition of growth) was used for amphotericin B and azoles, except fluconazole, for which MIC-2 endpoint (~50% inhibition compared to growth control) was used. Both MIC-0 and MIC-1 (~80% inhibition compared to growth control) results were analysed for terbinafine to enable comparison with previous studies. Fungal growth was sufficient for determination of MICs at 48 hours for all isolates except two Exophiala dermatitidis strains. At 72 hours, most active antifungal agents according to GM MIC were voriconazole and terbinafine, followed by posaconazole, itraconazole and amphotericin B in rank order of decreasing activity. While amphotericin B displayed adequate in vitro activity despite relatively high MICs, fluconazole showed no meaningful antifungal activity against Exophiala.


Caenorhabditis elegans: A Model System for Anti-Cancer Drug Discovery and Therapeutic Target Identification.
The nematode Caenorhabditis elegans (C. elegans) offers a unique opportunity for biological and basic medical researches due to its genetic tractability and well-defined developmental lineage. It also provides an exceptional model for genetic, molecular, and cellular analysis of human disease-related genes. Recently, C. elegans has been used as an ideal model for the identification and functional analysis of drugs (or small-molecules) in vivo. In this review, we describe conserved oncogenic signaling pathways (Wnt, Notch, and Ras) and their potential roles in the development of cancer stem cells. During C. elegans germline development, these signaling pathways regulate multiple cellular processes such as germline stem cell niche specification, germline stem cell maintenance, and germ cell fate specification. Therefore, the aberrant regulations of these signaling pathways can cause either loss of germline stem cells or overproliferation of a specific cell type, resulting in sterility. This sterility phenotype allows us to identify drugs that can modulate the oncogenic signaling pathways directly or indirectly through a high-throughput screening. Current in vivo or in vitro screening methods are largely focused on the specific core signaling components. However, this phenotype-based screening will identify drugs that possibly target upstream or downstream of core signaling pathways as well as exclude toxic effects. Although phenotype-based drug screening is ideal, the identification of drug targets is a major challenge. We here introduce a new technique, called Drug Affinity Responsive Target Stability (DARTS). This innovative method is able to identify the target of the identified drug. Importantly, signaling pathways and their regulators in C. elegans are highly conserved in most vertebrates, including humans. Therefore, C. elegans will provide a great opportunity to identify therapeutic drugs and their targets, as well as to understand mechanisms underlying the formation of cancer.


Acetylation of nuclear hormone receptor-interacting protein RIP140 regulates binding of the transcriptional corepressor CtBP.
CtBP (carboxyl-terminal binding protein) participates in regulating cellular development and differentiation by associating with a diverse array of transcriptional repressors. Most of these interactions occur through a consensus CtBP-binding motif, PXDLS, in the repressor proteins. We previously showed that the CtBP-binding motif in E1A is flanked by a Lys residue and suggested that acetylation of this residue by the p300/CBP-associated factor P/CAF disrupts the CtBP interaction. In this study, we show that the interaction between CtBP and the nuclear hormone receptor corepressor RIP140 is regulated similarly, in this case by p300/CBP itself. CtBP was shown to interact with RIP140 in vitro and in vivo through a sequence, PIDLSCK, in the amino-terminal third of the RIP140 protein. Acetylation of the Lys residue in this motif, demonstrated in vivo by using an acetylated RIP140-specific antibody, dramatically reduced CtBP binding. Mutation of the Lys residue to Gln resulted in a decrease in CtBP binding in vivo and a loss of transcriptional repression. We suggest that p300/CBP-mediated acetylation disrupts the RIP140-CtBP complex and derepresses nuclear hormone receptor-regulated genes. Disruption of repressor-CtBP interactions by acetylation may be a general mode of gene activation.


Human adipose derived stromal cells heal critical size mouse calvarial defects.
Human adipose-derived stromal cells (hASCs) represent a multipotent cell stromal cell type with proven capacity to differentiate along an osteogenic lineage. This suggests that they may be used to heal defects of the craniofacial or appendicular skeleton. We sought to substantiate the use of undifferentiated hASCs in the regeneration of a non-healing mouse skeletal defect. Human ASCs were harvested from female lipoaspirate. Critical-sized (4 mm) calvarial defects were created in the parietal bone of adult male nude mice. Defects were either left empty, treated with an apatite coated PLGA scaffold alone, or a scaffold with human ASCs. MicroCT scans were obtained at stratified time points post-injury. Histology, in situ hybridization, and histomorphometry were performed. Near complete healing was observed among hASC engrafted calvarial defects. This was in comparison to control groups that showed little healing (*P<0.01). Human ASCs once engrafted differentiate down an osteogenic lineage, determined by qRT-PCR and histological co-expression assays using GFP labeled cells. ASCs were shown to persist within a defect site for two weeks (shown by sex chromosome analysis and quantified using Luciferase+ ASCs). Finally, rBMP-2 was observed to increase hASC osteogenesis in vitro and osseous healing in vivo. Human ASCs ossify critical sized mouse calvarial defects without the need for pre-differentiation. Recombinant differentiation factors such as BMP-2 may be used to supplement hASC mediated repair. Interestingly, ASC presence gradually dissipates from the calvarial defect site. This study supports the potential translation for ASC use in the treatment of human skeletal defects.


Interaction of influenza virus with mouse macrophages.
Mouse peritoneal and alveolar macrophages differed substantially in their response to influenza in vitro. Immunofluorescent and infectious-center techniques showed that viral proteins were produced in only a small subpopulation (17%) of peritoneal macrophages and that these infected cells were removed from culture by 3 days postinfection. In contrast, alveolar macrophages were highly susceptible to influenza, and viral antigens were produced in all cells. This was accompanied by a cytopathic effect and cell death. However, no infectious virus was released and the infection was considered abortive. With mouse cytomegalovirus, however, both alveolar and peritoneal macrophages were equally restrictive, and viral antigens were produced in only 1 to 5% of either cell population. No significant differences were observed between mouse-virulent and -avirulent strains of influenza in their interaction with macrophages either in vitro or in vivo. In vivo, both strains induced an influx of cells to the alveolar spaces by 3 to 4 days postinfection, and this was reflected by a 5- to 10-fold increase in the number of "macrophages" in harvest fluids at this time. Many of these cells had an altered morphology compared with alveolar macrophages from uninfected mice, and the cell population as a whole was not susceptible to influenza. However, this resistance was lost by 7 days of in vitro culture.


Combining data from primary and ancillary surveys to assess the association between neighborhood-level characteristics and health outcomes: the Multi-Ethnic Study of Artherosclerosis.
There is increasing interest in understanding the role of neighborhood-level factors on the health of individuals. Many large-scale epidemiological studies that accurately measure health status of individuals and individual risk factors exist. Sometimes these studies are linked to area-level databases (e.g. census) to assess the association between crude area-level characteristics and health. However, information from such databases may not measure the neighborhood-level constructs of interest. More recently, large-scale epidemiological studies have begun collecting data to measure specific features of neighborhoods using ancillary surveys. The ancillary surveys are composed of a separate, typically larger, set of individuals. The challenge is then to combine information from these two surveys to assess the role of neighborhood-level factors. We propose a method for combining information from the two data sources using a likelihood-based framework. We compare it with currently used ad hoc approaches via a simulation study. The simulation study shows that the proposed approach yields estimates with better sampling properties (less bias and better coverage probabilities) compared with the other approaches. However, there are cases where some ad hoc approaches may provide adequate estimates. We also compare the methods by applying them to the Multi-Ethnic Study of Atherosclerosis and its Neighborhood Ancillary Survey.


If you want a quick kiss, make it count: How choice of syntactic construction affects event construal.
When we hear an event description, our mental construal is not only based on lexical items, but also on the message's syntactic structure. This has been well-studied in the domains of causation, event participants, and object conceptualization. Less studied are the construals of temporality and numerosity as a function of syntax. We present a theory of how syntax affects the construal of event similarity and duration in a way that is systematically predictable from the interaction of mass/count syntax and verb semantics, and test these predictions in six studies. Punctive events in count syntax (give a kiss) and durative events in mass syntax (give advice) are construed as taking less time than in transitive frame (kiss and advise). Durative verbs in count syntax (give a talk), however, result in a semantic shift, orthogonal to duration estimates. These results demonstrate how syntactic and semantic structure together systematically affect event construal.


The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute megakaryoblastic leukemia: a Pediatric Oncology Group Study.
We report the nonrandom occurrence and frequency of the t(1;22)(p13;q13) in acute myeloid leukemia (AML) and its close association with the French-American-British M7 subtype of AML in infants (less than 1 year). This chromosomal abnormality occurred in 6 of 252 (2.4%) children and adolescents with AML (6 of 28 infants, 22%; 6 of 18 M7 AML cases overall, 33%; and 6 of 6 M7 cases in infants). Infants with AML of M7 subtype and the t(1;22) often presented with prominent abdominal masses. Two of these infants were not treated and died early. Three of four treated infants entered complete remission with therapy for AML; the remaining infant died of hemorrhage on day 8. Of the three infants who entered remission, only one remains alive and disease free at 5+ months. The other two infants relapsed in the bone marrow at 5 and 2 months from the start of therapy, respectively. We conclude that M7 AML with the t(1;22) usually presents in infants with extensive infiltration of abdominal organs by leukemic cells and may confer a poor prognosis despite intensive AML-directed treatment. Identification of this nonrandom translocation exclusively in infants with acute megakaryoblastic leukemia (AMkL) implies that it may serve as an additional diagnostic marker for this disease and links it to the pathogenesis of AMkL in infants.


Exosomal secretion of a psychosis-altered miRNA that regulates glutamate receptor expression is affected by antipsychotics.
The ability of small secretory microvesicles known as exosomes to influence neuronal and glial function via their microRNA (miRNA) cargo has positioned them as a novel and effective method of cell-to-cell communication. However, little is known about the role of exosome-secreted miRNAs in the regulation of glutamate receptor gene expression and their relevance for schizophrenia (SCZ) and bipolar disorder (BD). Using mature miRNA profiling and quantitative real-time PCR (qRT-PCR) in the orbitofrontal cortex (OFC) of SCZ (N = 29; 20 male and 9 female), BD (N = 26; 12 male and 14 female), and unaffected control (N = 25; 21 male and 4 female) subjects, we uncovered that miR-223, an exosome-secreted miRNA that targets glutamate receptors, was increased at the mature miRNA level in the OFC of SCZ and BD patients with positive history of psychosis at the time of death and was inversely associated with deficits in the expression of its targets glutamate ionotropic receptor NMDA-type subunit 2B (GRIN2B) and glutamate ionotropic receptor AMPA-type subunit 2 (GRIA2). Furthermore, changes in miR-223 levels in the OFC were positively and negatively correlated with inflammatory and GABAergic gene expression, respectively. Moreover, miR-223 was found to be enriched in astrocytes and secreted via exosomes, and antipsychotics were shown to control its cellular and exosomal localization in a cell-specific manner. Furthermore, addition of astrocytic exosomes in neuronal cultures resulted in a significant increase in miR-223 expression and a notable reduction in Grin2b and Gria2 mRNA levels, which was strongly inversely associated with miR-223 expression. Lastly, inhibition of astrocytic miR-223 abrogated the exosomal-mediated reduction in neuronal Grin2b expression. Taken together, our results demonstrate that the exosomal secretion of a psychosis-altered and glial-enriched miRNA that controls neuronal gene expression is regulated by antipsychotics.


The outcome of neurology outpatients with medically unexplained symptoms: a prospective cohort study.
In a previous cross sectional study of 300 consecutive new attenders at neurology outpatient clinics, 90 were detected with symptoms that were rated as "not at all" or only "somewhat" explained by organic disease. To report a follow up study of this cohort. Patients were reinterviewed by telephone eight months after their initial assessment. They were asked to rate their overall improvement on a clinical global improvement scale, and their health status on the medical outcome short form 36 item scale (SF-36). The PRIME MD interview was administered to determine psychiatric diagnoses. Neurological and primary care records were reviewed for any changes in diagnostic opinion during the follow up period. Of the 90 eligible patients, 66 (73%) participated in follow up. Among these, five (8%) rated themselves as "much worse," four (6%) as "somewhat worse," 27 (40%) as "just the same," 15 (23%) as "somewhat better," and 15 (23%) as "much better." There were no cases in which an organic cause for the presenting complaint was uncovered during the follow up period. Poorer physical function at baseline was the only predictor of poorer outcome at follow up. Over half the patients who presented to neurologists with symptoms that were rated as largely or completely medically unexplained had not improved eight months later. In no case was a disease explanation for the original presenting symptoms subsequently identified.


Tofu intake is associated with poor cognitive performance among community-dwelling elderly in China.
Tofu is a soy product which is commonly consumed in Asian countries, such as China and Indonesia. Several studies found negative associations of high tofu consumption with cognitive function in older Asian populations. However, the effect of tofu on cognitive function remains disputed as it was not found in Western populations. In the present study, the effect of weekly tofu intake on cognitive performance was investigated in an observational cross sectional study of 517 Chinese elderly from Shanghai. Similar to earlier studies, results showed that a higher weekly intake of tofu was associated with worse memory performance using the Hopkins Verbal Learning Test (β = -0.10, p = 0.01) after controlling for age, gender, education, being vegetarian, and weekly intake of fruit/juice, green vegetables, and orange/red vegetables. Furthermore, among older elderly (≥68 years of age), high tofu intake increased the risk of cognitive impairment indicative of dementia (OR = 1.27, 95% CI = 0.99-1.64, p = 0.04), after adjusting for all covariates. Consumption of meat and green vegetables independently also reduced risk of dementia. To conclude, high intake of tofu was negatively related to cognitive performance among community-dwelling elderly in China. Similar findings were reported in Indonesia and in Japanese Americans in the US. These findings suggest that the effect of tofu on cognition in elderly should be further investigated.


The Wnt signaling antagonist Kremen1 is required for development of thymic architecture.
Wnt signaling has been reported to regulate thymocyte proliferation and selection at several stages during T cell ontogeny, as well as the expression of FoxN1 in thymic epithelial cells (TECs). Kremen1 (Krm1) is a negative regulator of the canonical Wnt signaling pathway, and functions together with the secreted Wnt inhibitor Dickkopf (Dkk) by competing for the lipoprotein receptor-related protein (LRP)-6 co-receptor for Wnts. Here krm1 knockout mice were used to examine krm1 expression in the thymus and its function in thymocyte and TEC development. Krm1 expression was detected in both cortical and medullary TEC subsets, as well as in immature thymocyte subsets, beginning at the CD25+CD44+ (DN2) stage and continuing until the CD4+CD8+(DP) stage. Neonatal mice show elevated expression of krm1 in all TEC subsets. krm1(-/-) mice exhibit a severe defect in thymic cortical architecture, including large epithelial free regions. Much of the epithelial component remains at an immature Keratin 5+ (K5) Keratin 8(+)(K8) stage, with a loss of defined cortical and medullary regions. A TOPFlash assay revealed a 2-fold increase in canonical Wnt signaling in TEC lines derived from krm1(-/-) mice, when compared with krm1(+/+) derived TEC lines. Fluorescence activated cell sorting (FACS) analysis of dissociated thymus revealed a reduced frequency of both cortical (BP1(+)EpCAM(+)) and medullary (UEA-1(+) EpCAM(hi)) epithelial subsets, within the krm1(-/-) thymus. Surprisingly, no change in thymus size, total thymocyte number or the frequency of thymocyte subsets was detected in krm1(-/-) mice. However, our data suggest that a loss of Krm1 leads to a severe defect in thymic architecture. Taken together, this study revealed a new role for Krm1 in proper development of thymic epithelium.


Comparative analysis of brain proteins from p53-deficient mice by two-dimensional electrophoresis.
p53 is a tumor suppressor protein that regulates many cellular processes including the cell cycle, DNA repair, and apoptosis. It also serves as a critical regulator of neuronal apoptosis in the central nervous system (CNS). To elucidate the role of p53 in the CNS, brain proteins of p53 knock-out mice (p53-/-) were analyzed by two-dimensional gel electrophoresis (2-DE) and compared with those from p53 wild type (p53+/+) mice. Six types of brain tissue (temporal cortex, cerebellum, hippocampus, striatum, olfactory bulb, and cervical spinal cord) and other control tissues (lung and blood) from 18-week-old non-stress-induced mice were analyzed. The morphology of brains from p53-/- mice appeared to be normal and identical to that of p53+/+ mice, although lungs showed diffuse tumors that may have been caused by p53 deficiency. Comparative 2-D gel analysis showed that, on average, 7 of 886 spots from brain tissue were p53-/- specific, whereas 12 of 1008 spots from lung tissue were p53-/- specific. N-terminal amino acid sequence was determined for p53-/- specific proteins. In all brain tissues from p53-/- mice, a newly identified mouse mitochondrial NADH-ubiquinone oxidoreductase 24 kDa subunit showed decreased expression, and apolipoprotein A1 acidic forms showed increased expression. In addition, brain-type creatine kinase B chain and tubulin beta-5 N-terminal fragment were increased in the p53-/- cerebellum, and a new protein in mouse, hydroxyacylglutathione hydrolase (glyoxalase II) was decreased in the temporal cortex of p53-/- mice. The alterations in protein expression identified in this study may imply a p53-related brain function. This is the first proteomic analysis on the p53-/- mouse brain, and further information based on this study will provide new insights into the p53 function in the CNS.


Transcriptional evidence for the "Reverse Warburg Effect" in human breast cancer tumor stroma and metastasis: similarities with oxidative stress, inflammation, Alzheimer's disease, and "Neuron-Glia Metabolic Coupling".
Caveolin-1 (-/-) null stromal cells are a novel genetic model for cancer-associated fibroblasts and myofibroblasts. Here, we used an unbiased informatics analysis of transcriptional gene profiling to show that Cav-1 (-/-) bone-marrow derived stromal cells bear a striking resemblance to the activated tumor stroma of human breast cancers. More specifically, the transcriptional profiles of Cav-1 (-/-) stromal cells were most closely related to the primary tumor stroma of breast cancer patients that had undergone lymph-node (LN) metastasis. This is consistent with previous morphological data demonstrating that a loss of stromal Cav-1 protein (by immuno-histochemical staining in the fibroblast compartment) is significantly associated with increased LN-metastasis. We also provide evidence that the tumor stroma of human breast cancers shows a transcriptional shift towards oxidative stress, DNA damage/repair, inflammation, hypoxia, and aerobic glycolysis, consistent with the "Reverse Warburg Effect". Finally, the tumor stroma of "metastasis-prone" breast cancer patients was most closely related to the transcriptional profiles derived from the brains of patients with Alzheimer's disease. This suggests that certain fundamental biological processes are common to both an activated tumor stroma and neuro-degenerative stress. These processes may include oxidative stress, NO over-production (peroxynitrite formation), inflammation, hypoxia, and mitochondrial dysfunction, which are thought to occur in Alzheimer?s disease pathology. Thus, a loss of Cav-1 expression in cancer-associated myofibroblasts may be a protein biomarker for oxidative stress, aerobic glycolysis, and inflammation, driving the "Reverse Warburg Effect" in the tumor micro-environment and cancer cell metastasis.


Functional connectivity change across multiple cortical networks relates to episodic memory changes in aging.
A major task of contemporary cognitive neuroscience of aging is to explain why episodic memory declines. Change in resting-state functional connectivity (rsFC) could be a mechanism accounting for reduced function. We addressed this through 3 studies. In study 1, 119 healthy participants (20-83 years) were followed for 3.5 years with verbal recall testing and magnetic resonance imaging. Independent of atrophy, recall change was related to change in rsFC in anatomically widespread areas. Striking age-effects were observed in that a positive relationship between rsFC and memory characterized older participants while a negative relationship was seen among the younger and middle-aged. This suggests that cognitive consequences of rsFC change are not stable across age. In study 2 and 3, the age-dependent differences in rsFC-memory relationship were replicated by use of a simulation model (study 2) and by a cross-sectional experimental recognition memory task (study 3). In conclusion, memory changes were related to altered rsFC in an age-dependent manner, and future research needs to detail the mechanisms behind age-varying relationships.


SU-E-T-434: Use of Deformable Registration for Cumulated Dose Calculation in Image-Guided Intracavitary Bracytherapy for Cervical Cancer.
The minimum dose to 2 cc of tissue receiving the highest dose (D2cc) has been suggested as a surrogate measurement for risk of developing toxicity in organs at risk (OARs) in patients receiving image-guided cervical intracavitary brachytherapy. Conventional D2cc is typically calculated by simple summation, assuming the locations of the hot spots do not vary substantially. This study explores the effect of deformable image registration in determining a more accurate D2cc of rectum, sigmoid colon, bladder and small bowel. Five patients, with 2 pelvic CT scans each performed at the time of brachytherapy planning, were evaluated. The first scan was performed with an empty bladder (an indwelling catheter was in place) and the second with a full bladder (with 180-cc sterile water). OARs were contoured on each scan. A symmetric demons algorithm with weighted sub-area approach was used to register images from different fractions. A pelvic prostate phantom was used to verify the method. After registration, the cumulated D2cc (ND2cc) was compared to the conventional D2cc (OD2cc) without deformable registration. In all cases, the ND2cc was lower than the OD2cc. For full bladder scans, the average difference (range) for rectum, sigmoid colon, bladder and small bowel between ND2cc and OD2cc were 28.9 (1.6 - 56.6)%, 34.7 (5.7 -68.4)%, 12.1 (0.0 -27.7)%, 7.2 (1.1 -22)% respectively. For empty bladder scans, the average differences (range) for the above organs between the ND2cc and the OD2cc were 30.7 (0.75-56.3%, 20.6 (6.3-39.6)%, 7.5 (0.88-13.1)%, 12.2(0.0-22.2)% respectively. A significant difference was observed between the ND2cc and the OD2cc with rectum and sigmoid being the most variable and bladder the least variable. While further studies are needed to evaluate which D2cc method is more useful in predicting late toxicity, we found the conventional method often overestimates dose to OARs.


Assessment of voiding function in inhabitants infected with Schistosoma haematobium.
Voiding function of Schistosoma haematobium infected students was evaluated in 45 schoolboys in Kwale district, Coast province, Kenya, using a questionnaire and uroflowmetry. Sixty-eight schoolboys who were S. haematobium negative were also examined. Symptoms related to the lower urinary tract were qualitatively assessed using the International Prostate Symptoms Score (I-PSS) questionnaire. The I-PSS showed that S. haematobium infected boys felt the need to strain to urinate and post voiding some urine still remained. To examine the disturbances revealed by I-PSS quantitatively, voiding was assessed by a portable uroflowmeter and a bladder scanner. Unexpectedly, no significant residual urine post voiding and no decline in urine flow rates were found in S. haematobium infected boys. However, volume-corrected maximum and average flow rates in S. haematobium infected boys were higher than in those not infected. These results suggest that cystitis associated with S. haematobium infection causes irritation and hypercontraction of the bladder.


Crowding by a single bar: probing pattern recognition mechanisms in the visual periphery.
Whereas visual crowding does not greatly affect the detection of the presence of simple visual features, it heavily inhibits combining them into recognizable objects. Still, crowding effects have rarely been directly related to general pattern recognition mechanisms. In this study, pattern recognition mechanisms in visual periphery were probed using a single crowding feature. Observers had to identify the orientation of a rotated T presented briefly in a peripheral location. Adjacent to the target, a single bar was presented. The bar was either horizontal or vertical and located in a random direction from the target. It appears that such a crowding bar has very strong and regular effects on the identification of the target orientation. The observer's responses are determined by approximate relative positions of basic visual features; exact image-based similarity to the target is not important. A version of the "standard model" of object recognition with second-order features explains the main regularities of the data.


Direct surface force measurements of polyelectrolyte multilayer films containing nanocrystalline cellulose.
Polyelectrolyte multilayer films containing nanocrystalline cellulose (NCC) and poly(allylamine hydrochloride) (PAH) make up a new class of nanostructured composite with applications ranging from coatings to biomedical devices. Moreover, these materials are amenable to surface force studies using colloid-probe atomic force microscopy (CP-AFM). For electrostatically assembled films with either NCC or PAH as the outermost layer, surface morphology was investigated by AFM and wettability was examined by contact angle measurements. By varying the surrounding ionic strength and pH, the relative contributions from electrostatic, van der Waals, steric, and polymer bridging interactions were evaluated. The ionic cross-linking in these films rendered them stable under all solution conditions studied although swelling at low pH and high ionic strength was inferred. The underlying polymer layer in the multilayered film was found to dictate the dominant surface forces when polymer migration and chain extension were facilitated. The precontact normal forces between a silica probe and an NCC-capped multilayer film were monotonically repulsive at pH values where the material surfaces were similarly and fully charged. In contrast, at pH 3.5, the anionic surfaces were weakly charged but the underlying layer of cationic PAH was fully charged and attractive forces dominated due to polymer bridging from extended PAH chains. The interaction with an anionic carboxylic acid probe showed similar behavior to the silica probe; however, for a cationic amine probe with an anionic NCC-capped film, electrostatic double-layer attraction at low pH, and electrostatic double-layer repulsion at high pH, were observed. Finally, the effect of the capping layer was studied with an anionic probe, which indicated that NCC-capped films exhibited purely repulsive forces which were larger in magnitude than the combination of electrostatic double-layer attraction and steric repulsion, measured for PAH-capped films. Wherever possible, DLVO theory was used to fit the measured surface forces and apparent surface potentials and surface charge densities were calculated.


Weekly iron-folic acid supplements containing 2.8 mg folic acid are associated with a lower risk of neural tube defects than the current practice of 0.4 mg: a randomised controlled trial in Malaysia.
Weekly iron-folic acid (IFA) supplements are recommended for all menstruating women in countries where anaemia prevalence is >20%. Anaemia caused by folate deficiency is low worldwide, and the need to include folic acid is in question. Including folic acid might reduce the risk of a neural tube defect (NTD) should a woman become pregnant. Most weekly supplements contain 0.4 mg folic acid; however, WHO recommends 2.8 mg because it is seven times the daily dose effective in reducing NTDs. There is a reluctance to switch to supplements containing 2.8 mg of folic acid because of a lack of evidence that this dose would prevent NTDs. Our aim was to investigate the effect of two doses of folic acid, compared with placebo, on red blood cell (RBC) folate, a biomarker of NTD risk. We conducted a three-arm double-blind efficacy trial in Malaysia. Non-pregnant women (n=331) were randomised to receive 60 mg iron and either 0, 0.4, or 2.8 mg folic acid once weekly for 16 weeks. At 16 weeks, women receiving 0.4 mg and 2.8 mg folic acid per week had a higher mean RBC folate than those receiving 0 mg (mean difference (95% CI) 84 (54 to 113) and 355 (316 to 394) nmol/L, respectively). Women receiving 2.8 mg folic acid had a 271 (234 to 309) nmol/L greater mean RBC folate than those receiving 0.4 mg. Moreover, women in the 2.8 mg group were seven times (RR 7.3, 95% CI 3.9 to 13.7; p<0.0001) more likely to achieve an RBC folate >748 nmol/L, a concentration associated with a low risk of NTD, compared with the 0.4 mg group. Weekly IFA supplements containing 2.8 mg folic acid increases RBC folate more than those containing 0.4 mg. Increased availability and access to the 2.8 mg formulation is needed. This trial is registered with the Australian New Zealand Clinical Trial Registry (ACTRN12619000818134).


A novel indirect defence in Brassicaceae: structure and function of extrafloral nectaries in Brassica juncea.
While nectaries are commonly found in flowers, some plants also form extrafloral nectaries on stems or leaves. For the first time in the family Brassicaceae, here we report extrafloral nectaries in Brassica juncea. The extrafloral nectar (EFN) was secreted from previously amorphic sites on stems, flowering stalks and leaf axils from the onset of flowering until silique formation. Transverse sections at the point of nectar secretion revealed a pocket-like structure whose opening was surrounded by modified stomatal guard cells. The EFN droplets were viscous and up to 50% of the total weight was sugars, 97% of which was sucrose in the five varieties of B. juncea examined. Threonine, glutamine, arginine and glutamate were the most abundant amino acids. EFN droplets also contained glucosinolates, mainly gluconapin and sinigrin. Nectar secretion was increased when the plants were damaged by chewing above- and belowground herbivores and sap-sucking aphids. Parasitoids of each herbivore species were tested for their preference, of which three parasitoids preferred EFN and sucrose solutions over water. Moreover, the survival and fecundity of parasitoids were positively affected by feeding on EFN. We conclude that EFN production in B. juncea may contribute to the indirect defence of this plant species.


Differential gene expression profiles of metastases in paired primary and metastatic colorectal carcinomas.
Despite the overwhelming clinical significance of metastases, the cellular and molecular mechanisms involved are largely unknown. In order to define significant differences between primary colon carcinomas and their metastases, we analyzed gene expression profiles of 12 sets of triple-paired tissues using 19 K human oligonucleotide microarrays. A total of 36 microarray experiments were analyzed by unsupervised two-way hierarchical clustering and multi-dimensional scaling (MDS). Both methods completely distinguished normal mucosa from carcinoma, but failed to demonstrate a complete classification of primary and metastatic carcinomas. We found a separable tendency to be classified into the primary and metastatic colon carcinomas by MDS. In supervised hierarchical clustering, we identified 80 genes that were differentially expressed between paired primary and metastatic colon carcinomas. The 80 identified genes also successfully distinguished three validation sets of primary and lung-metastatic colon carcinomas. A specific set of genes was identified that distinguished the metastasis from the corresponding primary tumor in nearly half of the metastases analyzed. We suggest that a more accurate model of the metastatic potential is based on a global tumor expression pattern along with the appearance of distinct metastatic variants. This molecular profiling may be useful for the future study of colon cancer metastasis.


Malpractice allegations against vascular surgeons: Prevalence, risk factors, and impact on surgeon wellness.
The contemporary medicolegal environment has been linked to procedure overuse, health care variation, and higher costs. For physicians accused of malpractice, there is also a personal toll. The objective of this study was to evaluate the prevalence of and risk factors for involvement in medical malpractice lawsuits among United States vascular surgeons, and to examine the association between these allegations with surgeon wellness. In 2018, the Society of Vascular Surgery (SVS) Wellness Task Force conducted a confidential survey of active members using a validated burnout assessment (Maslach Burnout Index) embedded into a questionnaire. This survey included questions related to medical errors and malpractice litigation. De-identified demographic, personal, and practice-related characteristics were assessed in respondents who reported malpractice allegations in the preceding 2 years, then compared with those without recent medicolegal litigation. Risk factors for malpractice allegations were identified (χ2, Kruskal-Wallis tests), and the association between malpractice allegations with wellness was examined. Multivariate logistic regression models were developed to identify independent risk factors for malpractice accusations. Of 2905 active SVS members, 871 responses from practicing vascular surgeons were analyzed. A total of 161 (18.5%) were named in a malpractice lawsuit within 2 years. Malpractice allegations were significantly associated with surgeon burnout (odds ratio, 1.47; 95% confidence interval, 1.01-2.15; P = .041), but not with self-reported depression or suicidal ideation. The nature of malpractice claims included procedural errors (23.1%), failure to treat (18.8%), and error/delay in diagnosis (16.9%). Twenty percent of claims were settled prior to trial, and 19% were dismissed. Defendant vascular surgeons reported a "fair" resolution in 26.4% of closed cases. By unadjusted analysis, factors significantly associated with recent malpractice claims included mean age (51.7 ± 10.0 vs 49.3 ± 11.2 years; P = .0044) and mean years in practice (18.0 ± 10.7 vs 15.2 ± 11.8; P = .0007). Multivariate analysis revealed independent variables associated with malpractice allegations, including on-call frequency (P = .0178), recent medical errors (P = .0189), and male surgeons (P = .045). Malpractice allegations are common for vascular surgeons and are significantly associated with surgeon burnout. Nearly 20% of survey respondents reported being named in a lawsuit within the preceding 2 years. Our findings underscore the need for SVS initiatives to provide counseling and peer support for vascular surgeons facing litigation.


Counterion-only electrical double layers: An application of density functional theory.
Within the framework of density functional theory, a self-consistent approach of weighted correlation approximation is developed to give an accurate account of the cross correlations between the Coulombic interaction and the hard-sphere exclusion in the counterion-only electrical double layers. Application of the approach to the cases of practical interest, against the Monte Carlo simulations, shows that it is excellent in describing the structural properties and the pressures of the confined solutions involving both mono- and divalent counterions between two planar charged walls. In particular, the study suggests that the relative importance of electrostatic correlations in comparison to the effects of ionic excluded volume and direct Coulomb interactions depends on the valency of the counterions and the surface charge density. In a clay system with mixed counterions, the competition between the mono- and divalent ions results in a large swelling when the fraction of surface charge compensated by monovalent counterions is greater than 30%. In the opposite situation involving mostly divalent counterions, a limited swelling is found and the attraction between the clay particles favors the formation of stacks incorporating a water layer of about 1.0 nm. These findings are consistent with experimental observations, giving insight into some mechanisms governing the stability of colloidal clay in salt-free or dilute solutions.


Bacterial diversity and White Plague Disease-associated community changes in the Caribbean coral Montastraea faveolata.
Increasing evidence confirms the crucial role bacteria and archaea play within the coral holobiont, that is, the coral host and its associated microbial community. The bacterial component constitutes a community of high diversity, which appears to change in structure in response to disease events. In this study, we highlight the limitation of 16S rRNA gene (16S rDNA) clone library sequencing as the sole method to comprehensively describe coral-associated communities. This limitation was addressed by combining a high-density 16S rRNA gene microarray with, clone library sequencing as a novel approach to study bacterial communities in healthy versus diseased corals. We determined an increase in diversity as well as a significant shift in community structure in Montastraea faveolata colonies displaying phenotypic signs of White Plague Disease type II (WPD-II). An accumulation of species that belong to families that include known coral pathogens (Alteromonadaceae, Vibrionaceae), bacteria previously isolated from diseased, stressed or injured marine invertebrates (for example, Rhodobacteraceae), and other species (for example, Campylobacteraceae) was observed. Some of these species were also present in healthy tissue samples, but the putative primary pathogen, Aurantimonas corallicida, was not detected in any sample by either method. Although an ecological succession of bacteria during disease progression after causation by a primary agent represents a possible explanation for our observations, we also discuss the possibility that a disease of yet to be determined etiology may have affected M. faveolata colonies and resulted in (or be a result of) an increase in opportunistic pathogens.


The ameliorative effects of exercise on cognitive impairment and white matter injury from blood-brain barrier disruption induced by chronic cerebral hypoperfusion in adolescent rats.
Vascular dementia is the progressive change in blood vessels that leads to neuronal injuries in vulnerable areas induced by chronic cerebral hypoperfusion (CCH). CCH induces disruption of blood-brain barrier (BBB), and this BBB disruption can initiate the cognitive impairment and white matter injury. In the present study, we evaluated the effect of treadmill exercise on the cognitive impairment, white matter injury, and BBB disruption induced by CCH. Vascular dementia was induced by permanent bilateral common carotid arteries occlusion (BCCAO) in rats. The rats in the exercise group were made to run on a treadmill for 30min once a day for 14 weeks, starting 4 weeks after birth. Our results revealed that treadmill exercise group was alleviated the cognitive impairment and myelin degradation induced by CCH. The disruption of BBB after CCH indicates degradation of occludin, zonula occluden-1 (ZO-1), and up-regulation of matrix metalloproteinases (MMPs). Treadmill exercise may provide protective effects on BBB disruption from degradation of occludin, ZO-1, and overexpression of MMP-9 after CCH. These findings suggest that treadmill exercise ameliorates cognitive impairment and white matter injury from BBB disruption induced by CCH in rats. The present study will be valuable for means of prophylactic and therapeutic intervention for patients with CCH.


The impact of disease-related knowledge on perceptions of stigma among patients with Hepatitis C Virus (HCV) infection.
Most patients with hepatitis C virus (HCV) infection perceive some degree of disease-related stigma. Misunderstandings about diseases may contribute to disease-related stigma. The objective of this study was to evaluate patient-level knowledge about HCV infection transmission and natural history and its association with HCV-related stigma among HCV-infected patients. We conducted a cross-sectional survey study among 265 patients with HCV in Philadelphia using the HCV Stigma Scale and the National Health and Nutrition Examination Survey (NHANES) Hepatitis C Follow-up Survey (2001-2008). The association between HCV knowledge and HCV-related stigma was evaluated via linear regression. Overall knowledge about HCV transmission and natural history was high, with >80% of participants answering ≥9 of 11 items correctly (median number of correct responses, 9 [82%]), HCV-related knowledge was similar between HIV/HCV-coinfected and HCV-monoinfected participants (p = 0.30). A higher level of HCV-related knowledge was associated with greater perceived HCV-related stigma (β, 2.34 ([95% CI, 0.51-4.17]; p = 0.013). Results were similar after adjusting for age, race, ethnicity, HIV status, education level, stage of HCV management, time since diagnosis, and history of injection drug use. In this study, increased HCV-related knowledge was associated with greater perceptions of HCV stigma. Clinicians may consider allotting time to address common misconceptions about HCV when educating patients about HCV infection, which may counterbalance the stigmatizing impact of greater HCV-related knowledge.


Passive transfer of growth-inhibitory antibodies raised against yeast-expressed recombinant Plasmodium falciparum merozoite surface protein-1(19).
Purified rabbit immunoglobulin raised against yeast-expressed recombinant FVO or 3D7 Plasmodium falciparum merozoite surface protein-1 (MSP-1) 19k-D C terminal fragment (MSP-1(19)) was transfused into malaria-naive Aotus nancymai monkeys that were immediately challenged with FVO asexual stage malaria parasites. Control monkeys received rabbit immunoglobulin raised against the sexual stage antigen Pfs25 or Aotus hyperimmune serum obtained from monkeys immunized by P. falciparum infection and drug cure. Passive transfer of rabbit anti-MSP-1(19) failed to protect against homologous or heterologous challenge and, when compared with negative controls, there were no differences in prepatent periods or time to treatment. Interestingly, rabbit anti-MSP-1(19), but not anti-Pfs25, immunoglobulin, and immune monkey serum prevented the development of antibodies directed against MSP-1(19) fragment by infected monkeys, indicating that the antibodies were reactive with native MSP-1(19) antigen in vivo. The prepatent period and time to treatment was greatly delayed in the two monkeys that received Aotus immune serum, both of which developed a chronic intermittent low level infection. In vitro parasite growth inhibition assays (GIAs) confirmed the presence of inhibitory activity (40% maximum inhibition) in concentrated anti-MSP-1(19) immunoglobulin (4.8 mg/ml), but the peak concentrations we achieved in vivo (1 mg/ml) were not inhibitory in vitro. Subinhibitory levels of anti-MSP-1(19) antibodies achieved by passive transfer were not protective against P. falciparum challenge.


Quantitative measurement of Batrachochytrium dendrobatidis in amphibian skin.
The ability to quantify infections provides a tool with which to perform comparative pathological research. The need exists for a simplistic standard method to compare infection levels of Batrachochytrium dendrobatidis, a major cause of global amphibian declines. Through examination of skin sloughs of the Cape river frog Afrana fuscigula, we present an accessible method that not only provides quantitative measurements of B. dendrobatidis, but also provides information that increases the confidence of detection through histological surveys. The method relies on the availability of live animals that are actively shedding skin. By employing a direct microscopic count of sporangia, it is possible to express infection in terms of density. Micro-spatial infection in the skin of A. fuscigula is characterised by significant differences in sporangium density among the different components of the foot, and by similar differences in site infection frequency. Notably, toe tips and tubercles contain higher infection densities and are more often infected than webbing or the base of the foot. This pattern of infection might facilitate disease transmission due to the increased exposure of these components to abrasion. Density data can be used with the Poisson frequency function to approximate binomial probabilities of detecting B. dendrobatidis through histology. The probability matrix produced for A. fuscigula indicated that foot-site selection for histology markedly influenced the number of sections required to detect B. dendrobatidis at a specific level of probability. Thus, examination of a test sample of skin tissue with direct-count quantification can help in planning the sampling of tissues for histological surveys.


The role of environmental driving factors in historical and projected carbon dynamics of wetland ecosystems in Alaska.
Wetlands are critical terrestrial ecosystems in Alaska, covering ~177,000 km2 , an area greater than all the wetlands in the remainder of the United States. To assess the relative influence of changing climate, atmospheric carbon dioxide (CO2 ) concentration, and fire regime on carbon balance in wetland ecosystems of Alaska, a modeling framework that incorporates a fire disturbance model and two biogeochemical models was used. Spatially explicit simulations were conducted at 1-km resolution for the historical period (1950-2009) and future projection period (2010-2099). Simulations estimated that wetland ecosystems of Alaska lost 175 Tg carbon (C) in the historical period. Ecosystem C storage in 2009 was 5,556 Tg, with 89% of the C stored in soils. The estimated loss of C as CO2 and biogenic methane (CH4 ) emissions resulted in wetlands of Alaska increasing the greenhouse gas forcing of climate warming. Simulations for the projection period were conducted for six climate change scenarios constructed from two climate models forced under three CO2 emission scenarios. Ecosystem C storage averaged among climate scenarios increased 3.94 Tg C/yr by 2099, with variability among the simulations ranging from 2.02 to 4.42 Tg C/yr. These increases were driven primarily by increases in net primary production (NPP) that were greater than losses from increased decomposition and fire. The NPP increase was driven by CO2 fertilization (~5% per 100 parts per million by volume increase) and by increases in air temperature (~1% per °C increase). Increases in air temperature were estimated to be the primary cause for a projected 47.7% mean increase in biogenic CH4 emissions among the simulations (~15% per °C increase). Ecosystem CO2 sequestration offset the increase in CH4 emissions during the 21st century to decrease the greenhouse gas forcing of climate warming. However, beyond 2100, we expect that this forcing will ultimately increase as wetland ecosystems transition from being a sink to a source of atmospheric CO2 because of (1) decreasing sensitivity of NPP to increasing atmospheric CO2 , (2) increasing availability of soil C for decomposition as permafrost thaws, and (3) continued positive sensitivity of biogenic CH4 emissions to increases in soil temperature.


Who consumes whole grains, and how much?
Regular consumption of whole grain foods has been associated with a reduction in the incidence of cardiovascular disease and diabetes, reductions in cancer mortality at certain sites and an overall reduction in premature death. Although benefits are observed at relatively low levels of intake (between two and three servings per d), the consumption of whole grain foods in some Western countries is less than one serving per d. The main sources of whole grain are wholemeal and rye breads and whole grain breakfast cereals. Typical consumers of wholegrain foods tend to be older, from a high socio-economic group, are less likely to smoke and are more likely to exercise than non-consumers. Some of these attributes may contribute to the observed health benefits. However whole grain foods are an important source of a range of nutrients as part of a healthy eating plan. There is considerable scope for strategies to promote increased consumption of whole grain foods to reduce the risk of a variety of chronic diseases.


"Side effects--part of the package": a mixed methods approach to study adverse events among patients being programmatically treated for DR-TB in Gujarat, India.
High rates of Adverse Events (AEs) during treatment is one of the leading causes of unsuccessful treatment outcomes among patients with drug resistant tuberculosis (DR-TB). However, information related to AEs is not systematically collected and managed under programmatic setting. The present study assessed the a) incidence and pattern of adverse events in first three months of DR-TB treatment initiation; b) treatment seeking behaviour for AE management; and c) explore the challenges in seeking treatment and reporting AEs. This mixed methods study included all patients diagnosed and initiated on treatment under RNTCP during July-September 2018 at Ahmedabad DR-TB centre. The patients were interviewed telephonically and assessed for all AEs experienced by them. In-depth interviews and key-informant interviews were conducted among patients, DOTS supervisors and programme staff (treatment supervisors, medical officer and district program managers). Total 207 AEs were reported by the 74 DR-TB patients. All patients experienced at least one AE during initial treatment period. Incidence rate of AEs (experienced) was 3.11 (1st month-4.6, 2nd month-2.7, 3rd month-2.02) per 100 person days. Of the 207 AEs, gastro-intestinal (59, 28.3%), ophthalmic (32, 15.4%) and otolaryngology (25, 11.9%) system related AEs were commonly experienced. Treatment was not sought in two-fifths of the AEs. Themes and sub-themes related to challenges in treatment seeking or reporting of AEs were 1) Patient related-Misconceptions, accessibility and affordability of management, lack of counselling support, stigma and discrimination, and past treatment experience; 2) Health system related- lack of guidelines and training for AE management, 3) Poor coordination between hospital and tuberculosis centre. The incidence of AEs was high among patients with DR-TB in the first three months of treatment and treatment seeking/reporting was low. Adequate health education and counselling of the patient and orientation of the health systems is the need of the hour. An efficient real-time reporting and management of AE should be developed and tested for effective DR-TB control.


Design, objectives, and lessons from a pilot 25 year follow up re-survey of survivors in the Whitehall study of London Civil Servants.
To assess the feasibility of conducting a re-survey of men who are resident in the United Kingdom 25 years after enrollment in the Whitehall study of London Civil Servants. A random sample of 401 study survivors resident in three health authority areas was selected for this pilot study. They were mailed a request to complete a self administered questionnaire, and then asked to attend their general practice to have their blood pressure, weight, and height measured and a blood sample collected into a supplied vacutainer, and mailed to a central laboratory. Using a 2 x 2 factorial design, the impact of including additional questions on income and of an informant questionnaire on cognitive function was assessed. Accurate addresses were obtained from the health authorities for 96% of the sample. Questionnaires were received from 73% and blood samples from 61% of the sample. Questions on income had no adverse effect on the response rate, but inclusion of the informant questionnaire did. Between 1970 and 1995 there were substantial changes within men in the mean blood pressure and blood total cholesterol recorded, as reflected by correlation coefficients between 1970 and 1995 values of 0.26, and 0.30 for systolic and diastolic blood pressure and 0.38 for total cholesterol. This pilot study demonstrated the feasibility of conducting a re-survey using postal questionnaires and mailed whole blood samples. The magnitude of change in blood pressure and blood total cholesterol concentrations within individuals was greater than anticipated, suggesting that such remeasurements may be required at different intervals in prospective studies to help interpret risks associations properly. These issues will be considered in a re-survey of the remaining survivors of the Whitehall study.


Implications of High-Density Cholesterol Metabolism for Oocyte Biology and Female Fertility.
Cholesterol is an essential component of animal cells. Different regulatory mechanisms converge to maintain adequate levels of this lipid because both its deficiency and excess are unfavorable. Low cell cholesterol content promotes its synthesis and uptake from circulating lipoproteins. In contrast, its excess induces the efflux to high-density lipoproteins (HDL) and their transport to the liver for excretion, a process known as reverse cholesterol transport. Different studies suggest that an abnormal HDL metabolism hinders female fertility. HDL are the only lipoproteins detected in substantial amounts in follicular fluid (FF), and their size and composition correlate with embryo quality. Oocytes obtain cholesterol from cumulus cells via gap junctions because they cannot synthesize cholesterol de novo and lack HDL receptors. Recent evidence has supported the possibility that FF HDL play a major role in taking up excess unesterified cholesterol (UC) from the oocyte. Indeed, genetically modified mouse models with disruptions in reverse cholesterol transport, some of which show excessive circulating UC levels, exhibit female infertility. Cholesterol accumulation can affect the egg´s viability, as reported in other cell types, and activate the plasma membrane structure and activity of membrane proteins. Indeed, in mice deficient for the HDL receptor Scavenger Class B Type I (SR-B1), excess circulating HDL cholesterol and UC accumulation in oocytes impairs meiosis arrest and hinders the developmental capacity of the egg. In other cells, the addition of cholesterol activates calcium channels and dysregulates cell death/survival signaling pathways, suggesting that these mechanisms may link altered HDL cholesterol metabolism and infertility. Although cholesterol, and lipids in general, are usually not evaluated in infertile patients, one study reported high circulating UC levels in women showing longer time to pregnancy as an outcome of fertility. Based on the evidence described above, we propose the existence of a well-regulated and largely unexplored system of cholesterol homeostasis controlling traffic between FF HDL and oocytes, with significant implications for female fertility.