Technologies and methods used for the detection, enrichment and characterization of cancer stem cells.
Cancer stem cells (CSCs) represent a subclass of tumour cells with the ability for self-renewal, production of differentiated progeny, prolonged survival, resistance to damaging therapeutic agents, and anchorage-independent survival, which together make this population effectively equipped to metastasize, invade and colonize secondary tissues in the face of therapeutic intervention. In recent years, investigators have increasingly focused on the characterization of CSCs to better understand the mechanisms that govern malignant disease progression in an effort to develop more effective, targeted therapeutic agents. The primary obstacle to the study of CSCs, however, is their rarity. Thus, the study of CSCs requires the use of sensitive and efficient technologies for their enrichment and detection. This review discusses technologies and methods that have been adapted and used to isolate and characterize CSCs to date, as well as new potential directions for the enhanced enrichment and detection of CSCs. While the technologies used for CSC enrichment and detection have been useful thus far for their characterization, each approach is not without limitations. Future studies of CSCs will depend on the enhanced sensitivity and specificity of currently available technologies, and the development of novel technologies for increased detection and enrichment of CSCs.


Relationship between relative interdialytic weight gain and serum leptin levels, nutrition, and inflammation in chronic hemodialysis patients.
Excessive relative interdialytic weight gain (RIDWG, %) is an important risk factor for long-term adverse cardiovascular outcomes in chronic hemodialysis (HD) patients. On the other hand, it may also be an index of good appetite and nutritional status. We aimed to assess the relationship between RIDWG and appetite, nutrition, inflammation parameters of chronic HD patients. 100 chronic anuric HD patients were enrolled in this prospective study between January 2013 and January 2014. Patients with hospitalization, major surgery, obvious infectious/inflammatory disease, end-stage liver disease, malignancies, and malabsorption syndromes were excluded. Patients were divided into 3 groups according to their RIDWG levels; group 1 = RIDWG < 3%, group 2 = RIDWG: 3 - 5%, and group 3 = RIDWG > 5%. Group 3 patients were younger (p = 0.011) and had a lower body mass index (BMI) (p = 0.014). Nutrition and inflammation parameters including malnutrition inflammation score (MIS), serum albumin, prealbumin, triceps skinfold thickness, hs-CRP, and TNF-α ere not significantly different between the groups. Leptin and leptin/BMI ratio were significantly lower in group 3 (p = 0.001). RIDWG was negatively correlated with age (p = 0.001, r = -0.371), BMI (p = 0.001, r = -0.372), leptin (p = 0.001, r = -0.369), leptin/BMI (p = 0.001, r = -0.369). After adjustment for BMI in linear regression analyis, leptin/BMI remained significantly correlated with RIDWG (p = 0.024). This study revealed that RIDWG was associated with younger age, lower BMI and dry weight, and lower serum leptin levels. More detailed studies are needed to validate and dissect the mechanisms of these findings.


The global burden of disease attributable to low consumption of fruit and vegetables: implications for the global strategy on diet.
We estimated the global burden of disease attributable to low consumption of fruit and vegetables, an increasingly recognized risk factor for cardiovascular disease and cancer, and compared its impact with that of other major risk factors for disease. The burden of disease attributable to suboptimal intake of fruit and vegetables was estimated using information on fruit and vegetable consumption in the population, and on its association with six health outcomes (ischaemic heart disease, stroke, stomach, oesophageal, colorectal and lung cancer). Data from both sources were stratified by sex, age and by 14 geographical regions. The total worldwide mortality currently attributable to inadequate consumption of fruit and vegetables is estimated to be up to 2.635 million deaths per year. Increasing individual fruit and vegetable consumption to up to 600 g per day (the baseline of choice) could reduce the total worldwide burden of disease by 1.8%, and reduce the burden of ischaemic heart disease and ischaemic stroke by 31% and 19% respectively. For stomach, oesophageal, lung and colorectal cancer, the potential reductions were 19%, 20%, 12% and 2%, respectively. This study shows the potentially large impact that increasing fruit and vegetable intake could have in reducing many noncommunicable diseases. It highlights the need for much greater emphasis on dietary risk factors in public health policy in order to tackle the rise in noncommunicable diseases worldwide, and suggests that the proposed intersectoral WHO/FAO fruit and vegetable promotion initiative is a crucial component in any global diet strategy.


Is There a Future for Nuclear Power? Wind and Emission Reduction Targets in Fossil-Fuel Alberta.
This paper explores the viability of relying on wind power to replace upwards of 60% of electricity generation in Alberta that would be lost if coal-fired generation is phased out. Using hourly wind data from 17 locations across Alberta, we are able to simulate the potential wind power output available to the Alberta grid when modern, 3.5 MW-capacity wind turbines are spread across the province. Using wind regimes for the years 2006 through 2015, we find that available wind power is less than 60% of installed capacity 98% of the time, and below 30% of capacity 74% of the time. There is only a small amount of correlation between wind speeds at different locations, but yet it remains necessary to rely on fossil fuel generation. Then, based on the results from a grid allocation model, we find that CO2 emissions can be reduced by about 30%, but only through a combination of investment in wind energy and reliance on purchases of hydropower from British Columbia. Only if nuclear energy is permitted into the generation mix would Alberta be able to meet its CO2-emissions reduction target in the electricity sector. With nuclear power, emissions can be reduced by upwards of 85%.


Warfarin accelerated vascular calcification and worsened cardiac dysfunction in remnant kidney mice.
Vascular calcification is highly prevalent in end-stage renal disease (ESRD) and is a significant risk factor for future cardiovascular events and death. Warfarin use results in dysfunction of matrix Gla protein, an inhibitor of vascular calcification. However, the effect of warfarin on vascular calcification in patients with ESRD is still not well characterized. Thus we investigated whether arterial calcification can be accelerated by warfarin treatment both in vitro and in vivo using a mouse remnant kidney model. Human aortic smooth muscle cells (HASMC) were cultured in medium supplemented with warfarin and phosphate to investigate the potential role of this drug in osteoblast transdifferentiation. For in vivo study, adult male C57BL/6 mice underwent 5/6 nephrectomy were treated with active vitamin D3 plus warfarin to determine the extent of vascular calcification and parameters of cardiovascular function. We found that the expressions of Runx2 and osteocalcin in HASMC were markedly enhanced in the culture medium containing warfarin and high phosphate concentration. Warfarin induced calcification of cultured HASMC in the presence of high phosphate levels, and this effect is inhibited by vitamin K2. Severe aortic calcification and reduced left ventricular ejection fractions were also noted in 5/6 nephrectomy mice treated with warfarin and active vitamin D3. Warfarin treatment contributes to the accelerated vascular calcification in animal models of advanced chronic kidney disease. Clinicians should therefore be aware of the profound risk of warfarin use on vascular calcification and cardiac dysfunction in patients with ESRD and atrial fibrillation.


Myeloid DLL4 Does Not Contribute to the Pathogenesis of Non-Alcoholic Steatohepatitis in Ldlr-/- Mice.
Non-alcoholic steatohepatitis (NASH) is characterized by liver steatosis and inflammation. Currently, the underlying mechanisms leading to hepatic inflammation are not fully understood and consequently, therapeutic options are poor. Non-alcoholic steatohepatitis (NASH) and atherosclerosis share the same etiology whereby macrophages play a key role in disease progression. Macrophage function can be modulated via activation of receptor-ligand binding of Notch signaling. Relevantly, global inhibition of Notch ligand Delta-Like Ligand-4 (DLL4) attenuates atherosclerosis by altering the macrophage-mediated inflammatory response. However, the specific contribution of macrophage DLL4 to hepatic inflammation is currently unknown. We hypothesized that myeloid DLL4 deficiency in low-density lipoprotein receptor knock-out (Ldlr-/-) mice reduces hepatic inflammation. Irradiated Ldlr-/- mice were transplanted (tp) with bone marrow from wild type (Wt) or DLL4f/fLysMCre+/0 (DLL4del) mice and fed either chow or high fat, high cholesterol (HFC) diet for 11 weeks. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) of DLL4f/fLysMCreWT and DLL4f/fLysMCre+/0 mice. In contrast to our hypothesis, inflammation was not decreased in HFC-fed DLL4del-transplanted mice. In line, in vitro, there was no difference in the expression of inflammatory genes between DLL4-deficient and wildtype bone marrow-derived macrophages. These results suggest that myeloid DLL4 deficiency does not contribute to hepatic inflammation in vivo. Since, macrophage-DLL4 expression in our model was not completely suppressed, it can't be totally excluded that complete DLL4 deletion in macrophages might lead to different results. Nevertheless, the contribution of non-myeloid Kupffer cells to notch signaling with regard to the pathogenesis of steatohepatitis is unknown and as such it is possible that, DLL4 on Kupffer cells promote the pathogenesis of steatohepatitis.


Treatment of social phobia with gabapentin: a placebo-controlled study.
A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the efficacy and safety of gabapentin in relieving the symptoms of social phobia. Sixty-nine patients were randomly assigned to receive double-blind treatment with either gabapentin (dosed flexibly between 900 and 3,600 mg daily in three divided doses) or placebo for 14 weeks. A significant reduction (p < 0.05) in the symptoms of social phobia was observed among patients on gabapentin compared with those on placebo as evaluated by clinician- and patient-rated scales. Results were similar for the intent-to-treat and week-2 completer populations. Adverse events were consistent with the known side effect profile of gabapentin. Dizziness (p = 0.05), dry mouth (p = 0.05), somnolence, nausea, flatulence, and decreased libido occurred at a higher frequency among patients receiving gabapentin than among those receiving placebo. No serious adverse events or deaths were reported. On the basis of these limited data, it seems that gabapentin offers a favorable risk-benefit ratio for the treatment of patients with social phobia. Further studies are required to confirm this effect and to determine whether a dose-response relationship exists.


The role of action control in implementing intentions during the first weeks of behaviour change.
Prevailing social cognition models consider behavioural intentions as immediate precursors of actions. This view ignores the role of more proximal self-regulatory processes, such as action control. The latter emerges after an intention has been formed and is supposed to maintain the level of intentions over time and to translate them into action. Three facets of action control were examined in terms of their predictive power for changes in intentions and for physical exercise: (a) awareness of standards, (b) self-monitoring, and (c) self-regulatory effort. A parsimonious 6-item instrument was administered to 122 cardiac patients at six weekly measurement points in time following rehabilitation. A distinction was made between the level of action control and the degree of change in action control, applying a latent growth model. While awareness of standards remained stable, the other two facets exhibited a linear change over the six-week period. Level and change were distinct predictors of physical exercise and changes in intentions. These findings emphasize the importance of self-regulatory mechanisms in the first weeks of trying to overcome a sedentary lifestyle. Action control may be a promising construct to narrow the intention-behaviour gap.


Bioinformatic Resources of microRNA Sequences, Gene Targets, and Genetic Variation.
Variation in quantitative gene expression has been observed in natural populations and associated with various complex traits/phenotypes such as risks for common diseases and drug response. MicroRNAs (miRNAs), a family of small, non-coding RNA molecules, have been demonstrated to be an important class of gene regulators that mostly downregulate gene expression at the post-transcriptional level. A comprehensive and reliable catalogue of miRNAs and miRNA gene targets is critical to understanding the gene regulatory networks. Though experimental approaches have been used to identify many miRNAs and their gene targets, due to cost and efficiency, currently miRNA and target identification still largely relies on computational algorithms. We reviewed several widely used bioinformatic resources of miRNA sequences and gene targets that take advantage of the unique characteristics of miRNA-mRNA interactions, experimental validation, as well as the integration of sequence-based evidence and microarray expression data. Furthermore, given the importance of miRNAs in regulating gene expression, elucidating expression quantitative trait loci involved with miRSNPs or miR-polymorphisms will help improve our understanding of complex traits. We reviewed the available resources of miRNA genetic variation, and the current progress (e.g., the 1000 Genomes Project) in detailing the genetic variation in miRNA-related single nucleotide polymorphisms (SNPs). We also provided our perspectives of the potential impact of next-generation sequencing on the research of miRNAs, gene targets, and miRSNPs. These bioinformatic resources may help interpret experimental and association study results, thus enhancing our knowledge of the dynamic gene regulatory networks and the physiological pathways for complex traits/phenotypes. Prospectively, these bioinformatic resources of miRNAs will need to address the challenges raised by the application of next-generation sequencing in miRNA research.


Current and future systemic treatment options in metastatic pancreatic cancer.
Although pancreatic adenocarcinoma is the fourth leading cause of cancer death, only modest improvement has been observed in the past two decades, single agent gemcitabine has been the only standard treatment in patients with advanced disease. Recently newer agents such as nab-paclitaxel, nimotuzumab and regimens such as FOLFIRINOX have been shown to have promising activity being superior to gemcitabine as a single agent. With better understanding of tumour biology coupled with the improvements in targeted and immunotherapies, there is increasing expectation for better response rates and extended survival in pancreatic cancer.


Expansion and preferential activation of the CD14(+)CD16(+) monocyte subset during multiple sclerosis.
Multiple sclerosis (MS) is an immune-driven, demyelinating disease of the central nervous system (CNS). Although many types of immune cells are involved in disease progression, activated monocytes are believed to be one of the first to arrive to the brain and initiate inflammation. However, little is known about how the two main monocyte subsets, CD14(++)CD16(-) and CD14(+)CD16(+), are involved in MS. To understand how the phenotype and responses of these monocyte subsets are altered during MS, total monocytes and the purified monocyte subsets from healthy subjects (n=29) and MS patients (n=20) were characterized ex vivo and stimulated in vitro with lipopolysaccharide (LPS). The ex vivo analyses showed that total monocytes from MS patients had significantly elevated levels of CD40, CD86, HLA-DR, CD64 and C-C motif chemokine receptor 2 (CCR2), and this elevation was most marked on CD16(+) monocytes. In vitro stimulation with LPS led to an increase in CD86, HLA-DR, CD64 and IL-6 production by monocytes from MS patients. Furthermore, in purified cultures, CD14(+) monocytes were found to be the main producers of IL-10 while CD16(+) monocytes produced more IL-12. In monocytes from MS patients, both subsets produced substantially more IL-6, and the production of IL-10 by the CD16(+) subset was also significantly elevated compared with healthy monocytes. Together these findings highlight the important contribution of the CD16(+) monocyte subset in driving inflammatory responses during MS.


An axial Hox code controls tissue segmentation and body patterning in Nematostella vectensis.
Hox genes encode conserved developmental transcription factors that govern anterior-posterior (A-P) pattering in diverse bilaterian animals, which display bilateral symmetry. Although Hox genes are also present within Cnidaria, these simple animals lack a definitive A-P axis, leaving it unclear how and when a functionally integrated Hox code arose during evolution. We used short hairpin RNA (shRNA)-mediated knockdown and CRISPR-Cas9 mutagenesis to demonstrate that a Hox-Gbx network controls radial segmentation of the larval endoderm during development of the sea anemone Nematostella vectensis. Loss of Hox-Gbx activity also elicits marked defects in tentacle patterning along the directive (orthogonal) axis of primary polyps. On the basis of our results, we propose that an axial Hox code may have controlled body patterning and tissue segmentation before the evolution of the bilaterian A-P axis.


Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene.
Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4alpha) and HNF1A/TCF1 (encoding HNF-1alpha), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice. We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001); 56% (30/54) of HNF4A-mutation carriers were macrosomic compared with 13% (7/54) of non-mutation family members (p < 0.001). Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003). There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic beta-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth. HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and diabetes later in life.


Effects of nitric oxide donors on non-pregnant and pregnant rat uterine and aortic smooth muscle.
To compare the effects of nitric oxide (NO) donors, diethylamine/nitric oxide (DEA/NO) and nitroglycerin (NTG), on isolated uterine and aortic tissues from non-pregnant, mid and late pregnant rats. The uterus and thoracic aorta were obtained from non-pregnant (estrous cycle) and pregnant Sprague-Dawley rats on day 14 and day 21. The uterine and aortic rings were incubated in organ chambers filled with Krebs-Henseleit solution bubbled with 5% CO2 in air for isometric tension recordings. Cumulative concentration-response relationships to DEA/NO and NTG were obtained in the aortic rings contracted with phenylephrine and in spontaneously contracting uterine rings. The sensitivity and the maximal inhibitory effects of DEA/NO did not differ in aortic tissues of any group. DEA/NO-induced Maximal inhibition of spontaneous contractions of uterine tissues from mid-pregnant rats was greater (although not significantly) than in the tissues from non-pregnant animals (with similar sensitivity), but it was significantly depressed in tissues from late pregnant rats. The sensitivity to and maximal inhibitory effects of NTG were less in aortic tissues from late pregnant versus mid-pregnant and non-pregnant rats. In uterine tissues from late pregnant rats the effect of NTG was negligible. The inhibitory action of both NO donors was much more pronounced in aortic versus uterine tissues. Uterine smooth muscle is less sensitive than vascular smooth muscle to NO. Uterine smooth muscle from late pregnant animals demonstrates refractoriness to both DEA/NO and NTG, while vascular smooth muscle from late pregnant animals demonstrates refractoriness to NTG, but not to DEA/NO.


Neuroprotection by gene therapy targeting mutant SOD1 in individual pools of motor neurons does not translate into therapeutic benefit in fALS mice.
A major challenge in neurological gene therapy is delivery of the transgene to sufficient cell numbers in an atraumatic manner. This is particularly difficult for motor neuron (MN) diseases that have cells located across the entire spinal cord, brain stem, and cortex. We have used the familial mouse model of amyotrophic lateral sclerosis (ALS) to examine the feasibility of body-wide intramuscular injections of adeno-associated virus serotype 6 (AAV6), a vector capable of axonal retrograde transport, to deliver therapeutic genetic information across the lower MN axis. Neonatal muscle delivery of AAV expressing small hairpin RNAs (shRNAs) against the toxic transgene in this model, human mutant superoxide dismutase 1 (mSOD1), led to significant mSOD1 knockdown in the muscle as well as innervating MNs. This knockdown conferred neuroprotection and halted muscle atrophy in individually targeted MN pools. However, despite the vector being targeted to MNs that innervate muscle groups controlling eating, breathing, and locomotion, this approach was unable to therapeutically impact on disease progression in the ALS mouse model. These results stress the complexity of gene delivery for mSOD1 silencing and suggest that critical thresholds of protein knockdown and transduction across various cell types are required to translate local neuroprotective effects into functional improvements.


Dermal absorption of chemicals: estimation by IH SkinPerm.
This article describes the IH SkinPerm mathematical tool for estimating dermal absorption. The first part provides the scientific background of the IH SkinPerm model, including the QSARs and the developed differential equations. Then the practical value of the tool is demonstrated through example dermal absorption assessments for substances with skin notations. IH SkinPerm simulates three types of dermal absorption scenarios relevant to occupational environments. The first is dermal absorption from instantaneous splash type exposures onto bare skin for pure liquids. The second estimates dermal absorption from the deposition of pure liquids over time. The third enables estimation of dermal uptake from an airborne vapor concentration. A simulation with IH SkinPerm was made using vapor absorption data published from volunteer exposure studies. Comparison of measured and estimated dermal absorbed dose showed IH SkinPerm estimated dermal absorbed dose was within a factor of 3 compared to the reported study values. IH SkinPerm accounts for substance volatility and evaporated mass and provides real-time description of dermal absorption with graphical displays and numerical outputs. To assess absorption resulting from dermal exposure scenarios, the mass of the substance loaded onto the skin, substance physical chemical properties, exposure duration, and the skin surface area affected are the only required input parameters.


Resveratrol for prenatal-stress-induced oxidative damage in growing brain and its consequences on survival of neurons.
Prenatal-stress-induced neuronal damage in offspring is multifactorial, including oxidative damage in the developing brain. Resveratrol is known to exert its neuroprotective potentials by upregulating several antioxidant systems. Hence, the study was undertaken to evaluate the neuroprotective effect of resveratrol against prenatal-stress-induced hippocampal damage and oxidative damage in neonate rat brains. Pregnant rats were subjected to restraint stress during early or late gestational period. Another set of rats received resveratrol during the entire gestational period along with early or late gestational stress. The study parameters included several antioxidant studies directly from rat brain homogenate on the 40th postnatal day and hippocampal neuronal assay on the 21st postnatal day. Early as well as late gestational stress resulted in a significant increase in lipid peroxidation and advanced oxidation protein products and decrease in total antioxidant activity and nitric oxide levels in rat brain homogenate. The neurons of the dentate gyrus were severely affected in early and late gestational stress, and only the neurons of the CA3 region were adversely affected in late gestational stress. Administration of resveratrol reversed the prenatal-stress-induced oxidative damage and neurons of dentate gyrus but not the CA3 hippocampal neurons. These results show the neuroprotective abilities of resveratrol against prenatal-stress-induced oxidative damage in neonatal rat brain.


Are there differences in individual-level needle and syringe coverage across Australian jurisdictions related to program policy? A preliminary analysis.
Services provided by needle and syringe programs (NSP) within Australia are easily accessible by international standards. However, important variation in NSP policy remains across Australian jurisdictions. The potential impacts of these variations on program operation for clients have not been systematically analysed in Australia. In this paper we conduct a preliminary examination to compare individual-level syringe coverage between and within Australian capital cities. Participants were 2498 people who inject drugs (PWID) recruited from all Australian capital cities as part of the annual Illicit Drug Reporting System PWID survey over the period 2014-2016. Insufficient coverage was defined when <100% of a participant's injecting episodes were 'covered' by sterile needles and syringes. We report the percentage of insufficient coverage for each capital city for each year, and present descriptive statistics for coverage parameters, and an alternative measure for insufficient coverage, as Supporting Information. Differences in behaviours that have the potential to impact syringe coverage were highly variable over time and place leading to variations in levels of insufficient coverage between and within all cities. Overall, insufficient coverage was most evident in larger cities where insufficient coverage varied between 19% and 23% (Sydney) over time, compared to smaller cities with variation from 9% to 12% (Adelaide). We found no consistent pattern of differences in individual-level needle and syringe coverage between and within Australian capital cities. Further work is needed to fully evaluate whether policy variation between Australian jurisdictions impacts on NSP coverage.


Patterns of Regional Cerebral Blood Flow as a Function of Obesity in Adults.
While obesity has been shown to be a risk factor for Alzheimer's disease, the potential mechanisms underlying this risk may be clarified with better understanding of underlying physiology in obese persons. To identify patterns of cerebral perfusion abnormality in adults as a function of body mass index (BMI) defined weight categories, including overweight or obese status. A large psychiatric cohort of 35,442 brain scans across 17,721 adults (mean age 40.8±16.2 years, range 18-94 years) were imaged with SPECT during baseline and concentration scans, the latter done after each participant completed the Connors Continuous Performance Test II. ANOVA was done to identify patterns of perfusion abnormality in this cohort across BMI designations of underweight (BMI < 18.5), normal weight (BMI = 18.5 to 24.9), overweight (BMI 24.9 to 29.9), obesity (BMI≥30), and morbid obesity (BMI≥40). This analysis was done for 128 brain regions quantifying SPECT perfusion using the automated anatomical labeling (AAL) atlas. Across adulthood, higher BMI correlated with decreased perfusion on both resting and concentration brain SPECT scans. These are seen in virtually all brain regions, including those influenced by AD pathology such as the hippocampus. Greater BMI is associated with cerebral perfusion decreases in both resting and concentration SPECT scans across adulthood.


Plant growth-promoting rhizobacteria allow reduced application rates of chemical fertilizers.
The search for microorganisms that improve soil fertility and enhance plant nutrition has continued to attract attention due to the increasing cost of fertilizers and some of their negative environmental impacts. The objectives of this greenhouse study with tomato were to determine (1) if reduced rates of inorganic fertilizer coupled with microbial inoculants will produce plant growth, yield, and nutrient uptake levels equivalent to those with full rates of the fertilizer and (2) the minimum level to which fertilizer could be reduced when inoculants were used. The microbial inoculants used in the study were a mixture of plant growth-promoting rhizobacteria (PGPR) strains Bacillus amyloliquefaciens IN937a and Bacillus pumilus T4, a formulated PGPR product, and the arbuscular mycorrhiza fungus (AMF), Glomus intraradices. Results showed that supplementing 75% of the recommended fertilizer rate with inoculants produced plant growth, yield, and nutrient (nitrogen and phosphorus) uptake that were statistically equivalent to the full fertilizer rate without inoculants. When inoculants were used with rates of fertilizer below 75% of the recommended rate, the beneficial effects were usually not consistent; however, inoculation with the mixture of PGPR and AMF at 70% fertility consistently produced the same yield as the full fertility rate without inoculants. Without inoculants, use of fertilizer rates lower than the recommended resulted in significantly less plant growth, yield, and nutrient uptake or inconsistent impacts. The results suggest that PGPR-based inoculants can be used and should be further evaluated as components of integrated nutrient management strategies.


Exposure to traumatic events and the behavioral health of children enrolled in an early childhood system of care.
Children may be exposed to numerous types of traumatic events that can negatively affect their development. The scope to which studies have examined an array of events among young children has been limited, thereby restricting our understanding of exposure and its relationship to behavioral functioning. The current cross-sectional study describes traumatic event exposure in detail and its relationship to behavioral health among an at-risk sample of young children (N = 184), under 6 years of age, upon enrollment into an early childhood, family-based, mental health system of care. Caregivers completed home-based semistructured interviews that covered children's exposure to 24 different types of traumatic events and behavioral and emotional functioning. Findings indicated that nearly 72% of young children experienced 1 or more types of traumatic events. Multiple regression model results showed that exposure was significantly associated with greater behavioral and emotional challenges with children's age, gender, race/ethnicity, household income, and caregiver's education in the model. These findings highlight the prevalence of traumatic exposures among an at-risk sample of young children in a system of care and suggest that this exposure is associated with behavioral and emotional challenges at a young age.


VEGF-c expression in an in vivo model of orthotopic endometrial cancer and retroperitoneal lymph node metastasis.
Retroperitoneal lymph node (RLN) metastasis is an important indicator of endometrial cancer (EC) prognosis. Because vascular endothelial growth factor c (VEGF-c) is known to influence lymphangiogenesis and thereby lymph node metastasis, this study assessed the relationship of VEGF-c mRNA expression with RLN metastasis in EC. The uterine muscularis mucosae of New Zealand white rabbits were inoculated with a VX2 tumor cell suspension after which they were sacrificed at 15, 18, 21, 24, 27 and 30 days. Control groups consisted of those receiving no treatment or an injection of saline. EC and metastatic RLN tissues along with peripheral blood samples were collected, and VEGF-c mRNA expression was evaluated using fluorescence real-time quantitative PCR. The establishment of an in vivo model of EC with complete RLN metastasis was pathologically confirmed at day 21 post-injection with VX2 cells. As compared to the control groups, VEGF-c mRNA expression increased significantly over time in the tumor site, RLN, and peripheral white blood cells of EC rabbits. Significantly higher VEGF-c mRNA expression was observed in metastatic RLNs as compared to those without metastasis (P < 0.001). In addition, increased VEGF-c mRNA expression was observed in peripheral white blood cells of rabbits with RLN metastasis (P < 0.002). Injection of a VX2 cell suspension is a simple method of establishing an in vivo EC model. VEGF-c may play an important role in the development of EC and its metastasis to RLN and may be useful marker to predict RLN metastasis.


Deterministic composite nanophotonic lattices in large area for broadband applications.
Exotic manipulation of the flow of photons in nanoengineered materials with an aperiodic distribution of nanostructures plays a key role in efficiency-enhanced broadband photonic and plasmonic technologies for spectrally tailorable integrated biosensing, nanostructured thin film solarcells, white light emitting diodes, novel plasmonic ensembles etc. Through a generic deterministic nanotechnological route here we show subwavelength-scale silicon (Si) nanostructures on nanoimprinted glass substrate in large area (4 cm2) with advanced functional features of aperiodic composite nanophotonic lattices. These nanophotonic aperiodic lattices have easily tailorable supercell tiles with well-defined and discrete lattice basis elements and they show rich Fourier spectra. The presented nanophotonic lattices are designed functionally akin to two-dimensional aperiodic composite lattices with unconventional flexibility- comprising periodic photonic crystals and/or in-plane photonic quasicrystals as pattern design subsystems. The fabricated composite lattice-structured Si nanostructures are comparatively analyzed with a range of nanophotonic structures with conventional lattice geometries of periodic, disordered random as well as in-plane quasicrystalline photonic lattices with comparable lattice parameters. As a proof of concept of compatibility with advanced bottom-up liquid phase crystallized (LPC) Si thin film fabrication, the experimental structural analysis is further extended to double-side-textured deterministic aperiodic lattice-structured 10 μm thick large area LPC Si film on nanoimprinted substrates.


Dependence of kidney morphogenesis on the expression of nerve growth factor receptor.
Nerve growth factor receptor (NGFR) serves as the binding site for the neurotrophic growth factors. Although NGFR has been found in several embryonic tissues outside the nervous system, the function of NGFR in embryogenesis of non-neuronal organs remains unknown. NGFR is transiently synthesized by embryonic rat kidney and disappears from nephrons upon their terminal differentiation. Anti-sense oligonucleotide inhibition of NGFR expression inhibits kidney morphogenesis. Therefore, NGFR is required not only for development of the nervous system, but also for differentiation of the kidney tubules.


Health promotion in the office.
Occupational therapists have the training and skill to modify office environments in order to promote employee health. Minor changes in the ways tasks are performed can improve work performance, decrease the incidence of minor health complaints, and help prevent repetition injury. Two employee health promotion education programs are described. They were conducted by an occupational therapist and can be replicated in other settings. One program was a seven-session series for bank employees; the other was a luncheon presentation to office workers employed by a health science university.


Retrospective Analysis of 255 Papillary Thyroid Carcinomas ≤2 cm: Clinicohistological Features and Prognostic Factors.
Papillary thyroid carcinoma (PTC) is the most common thyroid cancer. The widespread use of neck ultrasound (US) and US-guided fine-needle aspiration cytology is triggering an overdiagnosis of PTC. To evaluate clinical behavior and outcomes of patients with PTCs ≤2 cm, seeking for possible prognostic factors. Clinical records of cases with histological diagnosis of PTC ≤2 cm followed at the Endocrine Department of Instituto Português de Oncologia, Lisbon between 2002 and 2006 were analyzed retrospectively. We identified 255 PTCs, 111 were microcarcinomas. Most patients underwent near-total thyroidectomy, with lymph node dissections in 55 cases (21.6%). Radioiodine therapy was administered in 184 patients. At the last evaluation, 38 (14.9%) had evidence of disease. Two deaths were attributed to PTC. Median (±SD) follow-up was 74 (±23) months. Multivariate analysis identified vascular invasion, lymph node and systemic metastases significantly associated with recurrence/persistence of disease. In addition, lymph node involvement was significantly associated with extrathyroidal extension and angioinvasion. Median (±SD) disease-free survival (DFS) was estimated as 106 (±3) months and the 5-year DFS rate was 87.5%. Univariate Cox analysis identified some relevant parameters for DFS, but multivariate regression only identified lymph node and systemic metastases as significant independent factors. The median DFS estimated for lymph node and systemic metastases was 75 and 0 months, respectively. In the setting of small PTCs, vascular invasion, extrathyroidal extension and lymph node and/or systemic metastases may confer worse prognosis, perhaps justifying more aggressive therapeutic and follow-up approaches in such cases.


A DNA repair complex functions as an Oct4/Sox2 coactivator in embryonic stem cells.
The transcriptional activators Oct4, Sox2, and Nanog cooperate with a wide array of cofactors to orchestrate an embryonic stem (ES) cell-specific gene expression program that forms the molecular basis of pluripotency. Here, we report using an unbiased in vitro transcription-biochemical complementation assay to discover a multisubunit stem cell coactivator complex (SCC) that is selectively required for the synergistic activation of the Nanog gene by Oct4 and Sox2. Purification, identification, and reconstitution of SCC revealed this coactivator to be the trimeric XPC-nucleotide excision repair complex. SCC interacts directly with Oct4 and Sox2 and is recruited to the Nanog and Oct4 promoters as well as a majority of genomic regions that are occupied by Oct4 and Sox2. Depletion of SCC/XPC compromised both pluripotency in ES cells and somatic cell reprogramming of fibroblasts to induced pluripotent stem (iPS) cells. This study identifies a transcriptional coactivator with diversified functions in maintaining ES cell pluripotency and safeguarding genome integrity.


Receptor for hyaluronic acid-mediated motility (RHAMM, CD168) expression is prognostically important in both nodal negative and nodal positive large cell lung cancer.
Despite advances in therapy, lung cancer is still the leading cause of cancer-related mortality in the world. Further prognostic tools are warranted for risk-adapted therapeutic decisions. We analysed a cohort of primary surgically treated non-small cell lung cancers (NSCLCs) to determine the prognostic role of CD44 and associated molecules (receptor for hyaluronic acid-mediated motility (RHAMM), CD95, osteopontin (OPN), P-glycoprotein (P-gp) and caspase 3 (Casp3)). CD44 is a cell adhesion molecule. While the standard form (CD44s) is ubiquitously expressed, its variant isoforms are claimed to play an important role in invasion and metastasis in various cancers. Three-hundred and eighty-three primary surgically resected NSCLC specimens were brought into a standardised tissue microarray platform. Immunohistochemistry for CD44, CD95, RHAMM, OPN, P-gp and Casp3 was performed. The clinical correlation was made with known histopathological, phenotypical and genotypical variables; clinical data were available for a postoperative follow-up period of up to 15 years. RHAMM expression in the subgroup of large cell carcinomas (LCC) was associated with inferior survival (p=0.000223). Median overall survival was 92 versus 18 months for RHAMM-negative and positive patients, respectively. This survival difference remained significant in both nodal negative and positive patients (pN0: p=0.013 and pN≥1: p=0.007, respectively). P-gp expression was associated with inferior survival in adenocarcinomas (ACA; p=0.013) and appeared to be a postsurgical Union International Contre le Cancer (pUICC)- stage and gender-independent prognostic factor, irrespective of adjuvant chemotherapy, in the multivariable analysis; considering nodal status, this survival difference applied to pN0 cancers (p=0.026). Analysis of RHAMM expression is a valuable predictor of survival in LCC. RHAMM-positive patients may benefit from a targeted therapy even in early nodal negative stages. Expression of P-gp identifies a subset of pN0 ACA patients with poor outcome independent of stage, gender and adjuvant chemotherapy.


Lack of N regions in fetal and neonatal mouse immunoglobulin V-D-J junctional sequences.
Much of T and B lymphocyte receptor diversity derives from the addition of nontemplated N regions at the junctions of receptor gene elements, although fetal T cells expressing gamma/delta receptors lack N regions. I have sequenced immunoglobulin H chain variable regions of PCR-amplified DNA and cDNA from fetal and newborn mouse liver and spleen cells. These sequences showed an absence of N regions. Only 1/87 DNA sequences and 17/146 RNA sequences contained N regions, in striking contrast to adult Ig sequences. These data show that N region insertion is a developmentally regulated process in B cells as well as in T cells, and demonstrate that receptor diversity in neonatal B cells is limited by the absence of N regions as well as by biased usage of Vh genes.


Effects of zinc exposure on zinc transporter expression in human intestinal cells of varying maturity.
Zinc (Zn) homeostasis in adults is achieved principally through a balance between intestinal absorption and excretion involving adaptive mechanisms programmed by levels of dietary Zn. Zn absorption in infants is not as tightly regulated as that in adults, which may induce potential toxicity in infants due to the relatively high capacity of Zn absorption. We hypothesized that intestinal Zn homeostasis is developmentally regulated and depends on intestinal maturation, which in turn affects Zn transporter regulation. Cultured human fetal (FHs 74 Int, F) and adult (Caco-2: undifferentiated, U; differentiated, D) intestinal cells were used to determine developmental differences in Zn uptake and effects of Zn exposure on Zn transporters. Zn uptake rates in F and U cells were higher compared with D cells (F, 9-fold; U, 3-fold). F cells were more intolerant to Zn exposure than were U or D cells (LD50 = 67.9 +/- 5.3; 117.0 +/- 5.2; 224.4 +/- 3.7 micromol/L, respectively). Two mechanisms were involved in developmental regulation of Zn homeostasis: differential Zn transporter expression and differential response to Zn exposure. In F cells, zinc-regulated transporter (ZRT)/iron-regulated transporter (IRT)-like protein (Zip)4 expression was undetectable; Zn (50 micromol/L) increased levels of Zn transporter (ZnT)1, ZnT2, and metallothionein-1 mRNA and ZnT1 protein. U and D cells had higher mRNA expression of ZnT1 (U: 5-fold; D: 7-fold, respectively) and ZnT2 (U: 2-fold; D: 9-fold, respectively) than F cells, and D cells also had higher Zip4 expression (3-fold) than U cells. In U cells, Zn exposure increased Zip4 protein level, but not membrane-associated abundance. However, in D cells, Zn exposure decreased both the Zip4 protein level and membrane-associated abundance. Zn absorption is developmentally regulated through intestinal Zn efflux and sequestration and import mechanisms, which may be responsible for differences in Zn absorption observed between infants and adults.


Changes in Drosophila melanogaster Sleep-Wake Behavior Due to Lotus (Nelumbo nucifera) Seed and Hwang Jeong (Polygonatum sibiricum) Extracts.
We evaluated the sleep enhancement activity of the medicinal herbs valerian (Valeriana officinalis), jujube (Ziziphus jujube), lotus seed (Nelumbo nucifera), Gastrodia elata, Polygonatum sibiricum, and baekbokryung (Poria cocos), which can relieve insomnia in a Drosophila model. Locomotor activity was measured in the Drosophila model to evaluate the sleep activity of Korean medicinal herbs traditionally used as sleep aids. The group treated with lotus seed extract showed less nocturnal activity. Treatment with 10 or 20 mg/mL of P. sibiricum significantly reduced nocturnal activity compared to the control group (P<0.05). The activity and sleep bouts of fruit flies were significantly decreased by a high-dose treatment (10 mg/mL) of lotus or P. sibiricum extracts at night. Caffeine-treated Drosophila showed increased nocturnal activity and decreased total sleep time (P<0.05). Flies receiving the 10 mg-doses of lotus seed or P. sibiricum extract showed significantly different nocturnal locomotor activity and total sleep time compared to caffeine-treated Drosophila. Lotus seed and P. sibiricum extracts are attractive and valuable sleep-potentiating nutraceuticals.


Presentation of Neurolytic Effect of 10% Lidocaine after Perineural Ultrasound Guided Injection of a Canine Sciatic Nerve: A Pilot Study.
Phenol and alcohol have been used to ablate nerves to treat pain but are not specific for nerves and can damage surrounding soft tissue. Lidocaine at concentrations > 8% injected intrathecal in the animal model has been shown to be neurotoxic. Tests the hypothesis that 10% lidocaine is neurolytic after a peri-neural blockade in an ex vivo experiment on the canine sciatic nerve. Under ultrasound, one canine sciatic nerve was injected peri-neurally with 10 cc saline and another with 10 cc of 10% lidocaine. After 20 minutes, the sciatic nerve was dissected with gross inspection. A 3 cm segment was excised and preserved in 10% buffered formalin fixative solution. Both samples underwent progressive dehydration and infusion of paraffin after which they were placed on paraffin blocks. The sections were cut at 4 µm and stained with hemoxylin and eosin. Microscopic review was performed by a pathologist from Henry Ford Hospital who was blinded to which experimental group each sample was in. The lidocaine injected nerve demonstrated loss of gross architecture on visual inspection while the saline injected nerve did not. No gross changes were seen in the surrounding soft tissue seen in either group. The lidocaine injected sample showed basophilic degeneration with marked cytoplasmic vacuolation in the nerve fibers with separation of individual fibers and endoneurial edema. The saline injected sample showed normal neural tissue. Ten percent lidocaine causes rapid neurolytic changes with ultrasound guided peri-neural injection. The study was limited by only a single nerve being tested with acute exposure.


Harmonization of Food-Frequency Questionnaires and Dietary Pattern Analysis in 4 Ethnically Diverse Birth Cohorts.
Canada is an ethnically diverse nation, which introduces challenges for health care providers tasked with providing evidence-based dietary advice. We aimed to harmonize food-frequency questionnaires (FFQs) across 4 birth cohorts of ethnically diverse pregnant women to derive robust dietary patterns to investigate maternal and newborn outcomes. The NutriGen Alliance comprises 4 prospective birth cohorts and includes 4880 Canadian mother-infant pairs of predominantly white European [CHILD (Canadian Healthy Infant Longitudinal Development) and FAMILY (Family Atherosclerosis Monitoring In earLY life)], South Asian [START (SouTh Asian birth cohoRT)-Canada], or Aboriginal [ABC (Aboriginal Birth Cohort)] origins. CHILD used a multiethnic FFQ based on a previously validated instrument designed by the Fred Hutchinson Cancer Research Center, whereas FAMILY, START, and ABC used questionnaires specifically designed for use in white European, South Asian, and Aboriginal people, respectively. The serving sizes and consumption frequencies of individual food items within the 4 FFQs were harmonized and aggregated into 36 common food groups. Principal components analysis was used to identify dietary patterns that were internally validated against self-reported vegetarian status and externally validated against a modified Alternative Healthy Eating Index (mAHEI). Three maternal dietary patterns were identified-"plant-based," "Western," and "health-conscious"-which collectively explained 29% of the total variability in eating habits observed in the NutriGen Alliance. These patterns were strongly associated with self-reported vegetarian status (OR: 3.85; 95% CI: 3.47, 4.29; r2 = 0.30, P < 0.001; for a plant-based diet), and average adherence to the plant-based diet was higher in participants in the fourth quartile of the mAHEI than in the first quartile (mean difference: 46.1%; r2 = 0.81, P < 0.001). Dietary data collected by using FFQs from ethnically diverse pregnant women can be harmonized to identify common dietary patterns to investigate associations between maternal dietary intake and health outcomes.


High-performance field emission of carbon nanotube paste emitters fabricated using graphite nanopowder filler.
Carbon nanotube (CNT) paste emitters were fabricated using graphite nanopowder filler. The CNT paste emitters consist of CNTs as the emitting material, graphite nanopowder as the filler and a graphite rod as the cathode. Rather than metal or inorganic materials, graphite nanopowder was adapted as a filler material to make the CNT paste emitters. After fabricating the emitters, sandpaper treatment was applied to increase the density of emission sites. The CNT paste emitters showed a high field emission performance, for example a high emission current of 8.5 mA from a cylindrical emitter with a diameter of 0.7 mm (corresponding to a current density of 2.2 A cm-2) and an extremely stable emission current at 1 mA (260 mA cm-2 for 20 h). Interestingly, after a number of electrical arcing events, the emitters still showed a high emission current of 5-8 mA (higher than 1 A cm-2). In addition to the sound electrical and thermal properties of the graphite filler, effective mechanical adhesion of the CNTs onto the graphite cathode induced by the use of the graphite nanopowder filler contributed the excellent field emission properties of the CNT paste emitters.


Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF.
Most endocrine hormones are produced in tissues and organs with permeable microvessels that may provide an excess of hormones to be transported by the blood circulation to the distal target organ. Here, we investigate whether leptin, an endocrine hormone, induces the formation of vascular fenestrations and permeability, and we characterize its angiogenic property in the presence of other angiogenic factors. We provide evidence that leptin-induced new blood vessels are fenestrated. Under physiological conditions, capillary fenestrations are found in the leptin-producing adipose tissue in lean mice. In contrast, no vascular fenestrations were detected in the adipose tissue of leptin-deficient ob/ob mice. Thus, leptin plays a critical role in the maintenance and regulation of vascular fenestrations in the adipose tissue. Leptin induces a rapid vascular permeability response when administrated intradermally. Further, leptin synergistically stimulates angiogenesis with fibroblast growth factor (FGF)-2 and vascular endothelial growth factor (VEGF), the two most potent and commonly expressed angiogenic factors. These findings demonstrate that leptin has another new function-the increase of vascular permeability.


Growth and maximum size of tiger sharks (Galeocerdo cuvier) in Hawaii.
Tiger sharks (Galecerdo cuvier) are apex predators characterized by their broad diet, large size and rapid growth. Tiger shark maximum size is typically between 380 & 450 cm Total Length (TL), with a few individuals reaching 550 cm TL, but the maximum size of tiger sharks in Hawaii waters remains uncertain. A previous study suggested tiger sharks grow rather slowly in Hawaii compared to other regions, but this may have been an artifact of the method used to estimate growth (unvalidated vertebral ring counts) compounded by small sample size and narrow size range. Since 1993, the University of Hawaii has conducted a research program aimed at elucidating tiger shark biology, and to date 420 tiger sharks have been tagged and 50 recaptured. All recaptures were from Hawaii except a single shark recaptured off Isla Jacques Cousteau (24°13'17″N 109°52'14″W), in the southern Gulf of California (minimum distance between tag and recapture sites = approximately 5,000 km), after 366 days at liberty (DAL). We used these empirical mark-recapture data to estimate growth rates and maximum size for tiger sharks in Hawaii. We found that tiger sharks in Hawaii grow twice as fast as previously thought, on average reaching 340 cm TL by age 5, and attaining a maximum size of 403 cm TL. Our model indicates the fastest growing individuals attain 400 cm TL by age 5, and the largest reach a maximum size of 444 cm TL. The largest shark captured during our study was 464 cm TL but individuals >450 cm TL were extremely rare (0.005% of sharks captured). We conclude that tiger shark growth rates and maximum sizes in Hawaii are generally consistent with those in other regions, and hypothesize that a broad diet may help them to achieve this rapid growth by maximizing prey consumption rates.


Thrombolysis at 3-4.5 hours after acute ischemic stroke onset--evidence from the Canadian Alteplase for Stroke Effectiveness Study (CASES) registry.
Extending the therapeutic window for thrombolysis is an important strategy in maximizing the proportion of patients treated. ECASS III examined a 3-4.5-hour window and showed a benefit to treated patients. We examined the experience in Canadian centres using intravenous tPA treatment in the 3-4.5-hour time window. The data were obtained from the CASES (Canadian Alteplase for Stroke Effectiveness Study)--a prospective, multicentric cohort study with patient enrollment from 60 centres across Canada over 2.5 years. The 90-day outcome, mortality and symptomatic intracranial hemorrhage of patients thrombolysed between 3 and 4.5 h and within 3 h of symptom onset were compared. A mRS 0-1 (no symptoms at all or no significant disability despite symptoms, able to carry out all usual duties and activities) at 90 days was defined as a favorable outcome. A total of 1,112 patients with complete data were included. 129 (11.6%) patients received tPA between 3 and 4.5 h of symptom onset and 983 (88.4%) patients received tPA within 3 h. At 90 days, 39.4% of the patients in the 3-4.5-hour treatment group and 36.5% of patients in the under 3-hour treatment group attained a mRS ≤1. There were no differences between the two groups regarding their functional status at 3 months. There was a trend towards higher rate of sICH in the 3-4.5-hour group compared to the 0-3-hour group (7.8 vs. 3.8%, p = 0.06). Similarly there was a trend towards higher rate of deaths in the 3-4.5-hour group compared to the 0-3-hour group (28.4 vs. 21.4%, p = 0.09). A χ(2) test for trend demonstrated a rising proportion of symptomatic ICH in later time windows (p = 0.013). A similar trend (non-significant) was observed for mortality. Our study suggests that patients with acute ischemic stroke may be successfully treated with intravenous tPA in the 3-4.5-hour treatment window, but cautions that later time window treatment may result in greater adverse events.


Stress increases susceptibility to pentylenetetrazole-induced seizures in adult zebrafish.
Stress is the body's reaction to any change that requires adaptive responses. In various organisms, stress is a seizure-related comorbidity. Despite the exposure to stressors eliciting aversive behaviors in zebrafish, there are no data showing whether stress potentiates epileptic seizures in this species. Here, we investigated whether a previous exposure to an intense acute stressor positively modulates the susceptibility to seizures in pentylenetetrazole (PTZ)-challenged zebrafish. The conspecific alarm substance (CAS) was used to elicit aversive responses (3.5 mL/L for 5 min), observed by increased bottom dwelling and erratic movements. Then, fish were immediately exposed to 7.5 mM PTZ for 10 min to induce seizure-like behaviors. Stress increased the seizure intensity, the number of clonic-like seizure behaviors (score 4), as well as facilitated the occurrence of score 4 episodes by decreasing the latency in which fish reached the score 4. Moreover, fish with heightened anxiety showed increased susceptibility to PTZ, since positive correlations between anxiety- and seizure-like behaviors were found. Overall, since CAS also increased whole-body cortisol levels in zebrafish, our novel findings show a prominent response to PTZ-induced seizures in previously stressed zebrafish. Moreover, we reinforce the growing utility of zebrafish models to assess seizure-related comorbidities aiming to elucidate how stress can affect epileptic seizures in vertebrates.


The Doctrine of Signatures, Materia Medica of Orchids, and the Contributions of Doctor - Orchidologists.
The heritage of medicine is written in many forms. One repository is to be found in the history of orchids, the world's largest family of flowering plants. Orchids were so named by Theophrastus (c.372-288 BC) who recorded their medicinal use as an aphrodisiac and the promoter of virility, in the context of the Doctrine of Signatures. Such use endured for millennia, and was recorded both by Paracelsus (1493-1551) and Linnaeus (1707-1778). The history of orchidology and medicine are entwined in four domains: (a) orchids and their historical materia medica, within the paradigm of the Doctrine of Signatures; (b) the enduring and extensive contemporary medicinal and culinary use of orchids such as Vanilla and salep extracts of Orchis; (c) the scientific contributions of doctors as orchidologists; and (d) the heritage of more than a hundred doctors' names in the scientific etymology of the Orchidaceae family. Prominent orchidologists have included the Scottish doctor-soldier and botanist, Robert Brown (1773-1858); the Director of the State Herbarium at Leyden and the Rijks Museum, Carl Ludwig Blume (1796-1862); and Dr William Sterling MD (1888-1967). Among the more than 1250 genus names (and 33,000 species) of orchids are the names of more than a hundred doctors, their lives and works perpetuated in the scientific etymology of this family of exotic, beautiful, flamboyant, intriguing and often expensive flowers. Generic names record the lives and works of such as Aristotle (384-322BC) in Aristotelia Loureiro 1790; Cadet de Gassicourt (1769-1821) in Cadetia Gaudichaud 1826; Sir Joseph Dalton Hooker (1817-1911) in Sirhookera O. Kuntze 1891; and Dr Theodore Daniel Vrydag Zynen (fl. 1820-1850) in Vrydagzynea Blume 1858. One of the principal horticultural genera of orchids, Brassavola, records the life and work of the Ferrara and Padua physician and botanist, Antonio Musa Brassavola (1500-1555). The first Slipper Orchid bred as a hybrid, Paphiopedilum harrisianum (by John Dominy [1816-1892], at Exeter in England) was named after his colleague, the Devon surgeon, Dr John Harris (1782-1855).


The "Intermediate" CD14++CD16+ monocyte subset increases in severe peripheral artery disease in humans.
Monocytes are key players in atherosclerotic. Human monocytes display a considerable heterogeneity and at least three subsets can be distinguished. While the role of monocyte subset heterogeneity has already been well investigated in coronary artery disease (CAD), the knowledge about monocytes and their heterogeneity in peripheral artery occlusive disease (PAOD) still is limited. Therefore, we aimed to investigate monocyte subset heterogeneity in patients with PAOD. Peripheral blood was obtained from 143 patients suffering from PAOD (Rutherford stage I to VI) and three monocyte subsets were identified by flow cytometry: CD14++CD16- classical monocytes, CD14+CD16++ non-classical monocytes and CD14++CD16+ intermediate monocytes. Additionally the expression of distinct surface markers (CD106, CD162 and myeloperoxidase MPO) was analyzed. Proportions of CD14++CD16+ intermediate monocyte levels were significantly increased in advanced stages of PAOD, while classical and non-classical monocytes displayed no such trend. Moreover, CD162 and MPO expression increased significantly in intermediate monocyte subsets in advanced disease stages. Likewise, increased CD162 and MPO expression was noted in CD14++CD16- classical monocytes. These data suggest substantial dynamics in monocyte subset distributions and phenotypes in different stages of PAOD, which can either serve as biomarkers or as potential therapeutic targets to decrease the inflammatory burden in advanced stages of atherosclerosis.


The Plasmodium falciparum ABC transporter ABCI3 confers parasite strain-dependent pleiotropic antimalarial drug resistance.
Widespread Plasmodium falciparum resistance to first-line antimalarials underscores the vital need to develop compounds with novel modes of action and identify new druggable targets. Here, we profile five compounds that potently inhibit P. falciparum asexual blood stages. Resistance selection studies with three carboxamide-containing compounds, confirmed by gene editing and conditional knockdowns, identify point mutations in the parasite transporter ABCI3 as the primary mediator of resistance. Selection studies with imidazopyridine or quinoline-carboxamide compounds also yield changes in ABCI3, this time through gene amplification. Imidazopyridine mode of action is attributed to inhibition of heme detoxification, as evidenced by cellular accumulation and heme fractionation assays. For the copy-number variation-selecting imidazopyridine and quinoline-carboxamide compounds, we find that resistance, manifesting as a biphasic concentration-response curve, can independently be mediated by mutations in the chloroquine resistance transporter PfCRT. These studies reveal the interconnectedness of P. falciparum transporters in overcoming drug pressure in different parasite strains.


Pleural mesothelioma in a woman whose documented past exposure to asbestos was from smoking asbestos-containing filtered cigarettes: the comparative value of analytical transmission electron microscopic analysis of lung and lymph-node tissue.
Asbestos has had many commercial applications, including its use as a major component in various types of filters. Between 1952 and 1956, crocidolite asbestos was used as a component of filters for cigarettes, reportedly greatly reducing tars and nicotine from mainstream smoke. This case report quantifies asbestos burden in lung and lymph node tissue in a 67-yr-old woman who succumbed to mesothelioma. Her only historically documented exposure to asbestos was from smoking crocidolite asbestos-containing filtered cigarettes between 1952 and 1956. Tissue digestion analysis by analytical transmission electron microscopy (ATEM) identified crocidolite fibers in lungs and thoracic lymph nodes. Combined ATEM data of lung and lymph node tissue clarified the patient's exposure to asbestos and particularly to crocidolite asbestos and thus to the presence of an entity recognized as the causal agent for mesothelioma.


The impact of early exposure to general anesthesia on visual and neurocognitive development.
Every year millions of children are exposed to general anesthesia while undergoing surgical and diagnostic procedures. In the field of ophthalmology, 44,000 children are exposed to general anesthesia annually for strabismus surgery alone. While it is clear that general anesthesia is necessary for sedation and pain minimization during surgical procedures, the possibility of neurotoxic impairments from its exposure is of concern. In animals there is strong evidence linking early anesthesia exposure to abnormal neural development. but in humans the effects of anesthesia are debated. In humans many aspects of vision develop within the first year of life, making the visual system vulnerable to early adverse experiences and potentially vulnerable to early exposure to general anesthesia. We attempt to address whether the visual system is affected by early postnatal exposure to general anesthesia. We first summarize key mechanisms that could account for the neurotoxic effects of general anesthesia on the developing brain and review existing literature on the effects of early anesthesia exposure on the visual system in both animals and humans and on neurocognitive development in humans. Finally, we conclude by proposing future directions for research that could address unanswered questions regarding the impact of general anesthesia on visual development.


Maintenance of Heterochromatin by the Large Subunit of the CAF-1 Replication-Coupled Histone Chaperone Requires Its Interaction with HP1a Through a Conserved Motif.
In eukaryotic cells, the organization of genomic DNA into chromatin regulates many biological processes, from the control of gene expression to the regulation of chromosome segregation. The proper maintenance of this structure upon cell division is therefore of prime importance during development for the maintenance of cell identity and genome stability. The chromatin assembly factor 1 (CAF-1) is involved in the assembly of H3-H4 histone dimers on newly synthesized DNA and in the maintenance of a higher order structure, the heterochromatin, through an interaction of its large subunit with the heterochromatin protein HP1a. We identify here a conserved domain in the large subunit of the CAF-1 complex required for its interaction with HP1a in the Drosophila fruit fly. Functional analysis reveals that this domain is dispensable for viability but participates in two processes involving heterochromatin: position-effect variegation and long range chromosomal interactions during meiotic prophase. Importantly, the identification in the large subunit of CAF-1 of a domain required for its interaction with HP1 allows the separation of its functions in heterochromatin-related processes from its function in the assembly of H3-H4 dimers onto newly synthesized DNA.


Demonstrating the In Vitro and In Situ Antimicrobial Activity of Oxide Mineral Microspheres: An Innovative Technology to Be Incorporated into Porous and Nonporous Materials.
The antimicrobial activity of surfaces treated with zinc and/or magnesium mineral oxide microspheres is a patented technology that has been demonstrated in vitro against bacteria and viruses. This study aims to evaluate the efficiency and sustainability of the technology in vitro, under simulation-of-use conditions, and in situ. The tests were undertaken in vitro according to the ISO 22196:2011, ISO 20473:2013, and NF S90-700:2019 standards with adapted parameters. Simulation-of-use tests evaluated the robustness of the activity under worst-case scenarios. The in situ tests were conducted on high-touch surfaces. The in vitro results show efficient antimicrobial activity against referenced strains with a log reduction of >2. The sustainability of this effect was time-dependent and detected at lower temperatures (20 ± 2.5 °C) and humidity (46%) conditions for variable inoculum concentrations and contact times. The simulation of use proved the microsphere's efficiency under harsh mechanical and chemical tests. The in situ studies showed a higher than 90% reduction in CFU/25 cm2 per treated surface versus the untreated surfaces, reaching a targeted value of <50 CFU/cm2. Mineral oxide microspheres can be incorporated into unlimited surface types, including medical devices, to efficiently and sustainably prevent microbial contamination.


[Profiles of DNA methylation in normal and cancer cells].
In eukaryotes, the epigenetic mark DNA methylation is found exclusively at cytosine residues in the CpG islands of genes, transposons and intergenic DNA. Among functional roles, DNA methylation is essential for mammalian embryonic development, and is classically thought to function by stably silencing promoter activity. However, until recently, understanding of the distribution of cytosine methylation in the whole genome - and hence, identification of its targets - was very limited. High-throughput methodologies, including methylated DNA immunoprecipitation, have recently revealed genome-wide mapping of DNA methylation, and provided new and unexpected data. Clearly DNA methylation is selectively associated with some key promoters- and is not a prerequisite for promoter inactivation, since strong CpG island promoters are mostly unmethylated, even when inactive. Most germline-specific genes are methylated and permanently silenced in somatic cells, suggesting a role of this mark in maintaining somatic cellular identity. These large scale studies will also help understanding the deregulation of DNA methylation associated with cancer, among which unmethylation of germinal cells genes, and recent observtion of large hypomethylated regions in tumoral specimens. The next challenge will be to understand if these methylation changes occur randomly, or more likely are specified by oncogenes or linked to environmental pressure.


Optical tweezers with millikelvin precision of temperature-controlled objectives and base-pair resolution.
In optical tweezers, thermal drift is detrimental for high-resolution measurements. In particular, absorption of the trapping laser light by the microscope objective that focuses the beam leads to heating of the objective and subsequent drift. This entails long equilibration times which may limit sensitive biophysical assays. Here, we introduce an objective temperature feedback system for minimizing thermal drift. We measured that the infrared laser heated the objective by 0.7 K per watt of laser power and that the laser focus moved relative to the sample by approximately 1 nm/mK due to thermal expansion of the objective. The feedback stabilized the temperature of the trapping objective with millikelvin precision. This enhanced the long-term temperature stability and significantly reduced the settling time of the instrument to about 100 s after a temperature disturbance while preserving single DNA base-pair resolution of surface-coupled assays. Minimizing systematic temperature changes of the objective and concurrent drift is of interest for other high-resolution microscopy techniques. Furthermore, temperature control is often a desirable parameter in biophysical experiments.


["Thus it passes from the patient's purse into that of the doctor without causing displeasure" - Samuel Hahnemann and medical fees].
In 1834, Hahnemann gave the following advice to his pupil Dr. Karl Julius Aegidi: "We are not allopaths who have high medical fees and can legally demand high sums for evil deeds. We must take what we have earned on the spot, since we are not considered worthy of ordinary justice." In an earlier letter to the same addressee, Hahnemann wrote: "No one enters my house if he does not have with him the money to pay me, unless he is paying me monthly, in advance [...]." There can be no doubt that in Hahnemann's times, fees were the most important component in a physician's income. Dependency on fee income meant that the physician always had to worry about delayed and even avoided payments, and patients' reluctance to pay was notorious. Many doctors lost large parts of their nominal income through bad debts. In some cases, installments were accepted by both parties, to avoid costly legal action, which were usually a last resort. In these circumstances it is hardly surprising to find Hahnemann, the founder of a highly disputed new cure, stressing to his colleagues that for a successful medical practice, cash payments at the time of treatment or in advance were preferable to post-facto bills. Having been ostracized by the medical establishment, Hahnemann showed a remarkable professional awareness of patients' propensity to debt. Long before regular physicians propagated cash payment, Hahnemann derived his income solely from ready-money payments. However, he used a sliding fee structure to allow for the different economic circumstances of his patients, who came from all walks of life. The very poor he treated for free, while members of the rural and urban middle class had to pay considerable fees. In some cases, Hahnemann was able to charge very high fees, and his numerous enemies used this against him.


GESA--a two-dimensional processing system using knowledge base techniques.
The successful analysis of two-dimensional (2-D) polyacrylamide electrophoresis gels demands considerable experience and understanding of the protein system under investigation as well as knowledge of the separation technique itself. The present work concerns the development of a computer system for analysing 2-D electrophoretic separations which incorporates concepts derived from artificial intelligence research such that non-experts can use the technique as a diagnostic or identification tool. Automatic analysis of 2-D gel separations has proved to be extremely difficult using statistical methods. Non-reproducibility of gel separations is also difficult to overcome using automatic systems. However, the human eye is extremely good at recognising patterns in images, and human intervention in semi-automatic computer systems can reduce the computational complexities of fully automatic systems. Moreover, the expertise and understanding of an "expert" is invaluable in reducing system complexity if it can be encapsulated satisfactorily in an expert system. The combination of user-intervention in the computer system together with the encapsulation of expert knowledge characterises the present system. The domain within which the system has been developed is that of wheat grain storage proteins (gliadins) which exhibit polymorphism to such an extent that cultivars can be uniquely identified by their gliadin patterns. The system can be adapted to other domains where a range of polymorpic protein sub-units exist. In its generalised form, the system can also be used for comparing more complex 2-D gel electrophoretic separations.


Spatiotemporal maintenance of flora in the Himalaya biodiversity hotspot: Current knowledge and future perspectives.
Mountain ecosystems support a significant one-third of all terrestrial biodiversity, but our understanding of the spatiotemporal maintenance of this high biodiversity remains poor, or at best controversial. The Himalaya hosts a complex mountain ecosystem with high topographic and climatic heterogeneity and harbors one of the world's richest floras. The high species endemism, together with increasing anthropogenic threats, has qualified the Himalaya as one of the most significant global biodiversity hotspots. The topographic and climatic complexity of the Himalaya makes it an ideal natural laboratory for studying the mechanisms of floral exchange, diversification, and spatiotemporal distributions. Here, we review literature pertaining to the Himalaya in order to generate a concise synthesis of the origin, distribution, and climate change responses of the Himalayan flora. We found that the Himalaya supports a rich biodiversity and that the Hengduan Mountains supplied the majority of the Himalayan floral elements, which subsequently diversified from the late Miocene onward, to create today's relatively high endemicity in the Himalaya. Further, we uncover links between this Miocene diversification and the joint effect of geological and climatic upheavals in the Himalaya. There is marked variance regarding species dispersal, elevational gradients, and impact of climate change among plant species in the Himalaya, and our review highlights some of the general trends and recent advances on these aspects. Finally, we provide some recommendations for conservation planning and future research. Our work could be useful in guiding future research in this important ecosystem and will also provide new insights into the maintenance mechanisms underpinning other mountain systems.


'Closing the Gap': how maternity services can contribute to reducing poor maternal infant health outcomes for Aboriginal and Torres Strait Islander women.
The reproductive health outcomes for Aboriginal and Torres Strait Islander mothers and infants are significantly poorer than they are for other Australians; they worsen with increasing remoteness where the provision of services becomes more challenging. Australia has committed to 'Overcoming Indigenous Disadvantage' and 'Closing the Gap' in health outcomes. Fifty-five per cent of Aboriginal and Torres Strait Islander birthing women live in outer regional and remote areas and suffer some of the worst health outcomes in the country. Not all of these women are receiving care from a skilled provider, antenatally, in birth or postnatally while the role of midwives in reducing maternal and newborn mortality and morbidity is under-utilised. The practice of relocating women for birth does not address their cultural needs or self-identified risks and is contributing to these outcomes. An evidence based approach for the provision of maternity services in these areas is required. Australian maternal mortality data collection, analysis and reporting is currently insufficient to measure progress yet it should be used as an indicator for 'Closing the Gap' in Australia. A more intensive, coordinated strategy to improve maternal infant health in rural and remote Australia must be adopted. Care needs to address social, emotional and cultural health needs, and be as close to home as possible. The role of midwives can be enabled to provide comprehensive, quality care within a collaborative team that includes women, community and medical colleagues. Service provision should be reorganised to match activity to need through the provision of caseload midwives and midwifery group practices across the country. Funding to embed student midwives and support Aboriginal and Torres Strait Islander women in this role must be realised. An evidence base must be developed to inform the provision of services in these areas; this could be through the testing of the Rural Birth Index in Australia. The provision of primary birthing services in remote areas, as has occurred in some Inuit and New Zealand settings, should be established. 'Birthing on Country' that incorporates local knowledge, on-site midwifery training and a research and evaluation framework, must be supported.


Evolutionary coupling in the K(V)1.2-β₂ complex.
K(V)1.2 is a potassium channel protein whose electrophysiological properties, including an oxygen sensing response, are modulated by auxiliary beta subunits. The beta subunits are homologous to oxidoreductases, supporting a hypothesis that the coupling of the two subunits helps connect the redox state of the cell to the electrical activity of the membrane. However the exact mechanism of the coupling has not been discovered to-date. We apply evolutionary correlation analysis to infer previously unknown components of the interaction network regulating the response to hypoxia of the K(V)1.2/β₂ complex. Briefly, evolutionary correlation analysis involves finding correlated amino acid substitutions in functionally equivalent proteins (for both subunits) across a range of species. The method thus depends on a reliable method of inferring functionally equivalent (orthologous) proteins in different species, which method we describe in a paper recently published in PLoS ONE. One key finding is the characterization of a network of motif interactions between the α and the β subunits. By significance testing, we show that the likelihood of the correlations shown in the K(V)1.2-β two interaction motifs arising by chance is less than 0.0003, which shows that the correlations are statistically highly significant. We therefore believe that the correlations are likely to be biologically relevant. Other major findings are correlations between specific motifs in the K(V)1.2-β₂ complex and motifs in other proteins such as RACK1 and Eif36sip, which in turn are connected to the hypoxia response. Our paper combines this correlation with the literature evidence on potassium channel inactivation and hypoxia response to identify specific motifs to serve as experimental targets for studies focused on this response. This work aims to add to our general understanding of two major issues in ion channel science: 1) how multi-protein complexes including ion channels function in coordinated fashion, and 2) how ion channels mediate the conversation between the intracellular and extracellular environments. We also aim to apply to ion channel science the principle that domain-domain interactions in proteins can be inferred from correlation of amino-acid substitutions in sets of functionally equivalent proteins.


Thymic stromal lymphopoietin:a potential therapeutic target for allergy and asthma.
Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine that has recently been implicated as central to the microenvironment and is permissive for the immunologic cascade that initiates and propagates allergic immune responses. In humans, TSLP is produced predominantly by epithelial cells and activated mast cells, and stimulates myeloid dendritic cells (mDC), which uniquely express the heterodimeric TSLP receptor. TSLP-activated mDC can promote naïve CD4+ T cells to differentiate into a Th2 phenotype and can promote the expansion of CD4+ Th2 memory cells. Recent evidence implicates TSLP as playing a pivotal role in the pathobiology of allergic asthma and atopic dermatitis. The potential for TSLP to provide a new therapeutic target for the treatment of allergic disorders is compelling, and elucidating the mechanisms that regulate TSLP expression and the effects of TSLP on orchestrating the immune response toward a Th2 phenotype should facilitate this quest.


Effect of alcoholic liver disease and hepatitis C infection on waiting list and posttransplant mortality and transplant survival benefit.
Disease-specific analysis of liver transplant survival benefit, which encompasses both pre- and posttransplant events, has not been reported. Therefore, we evaluated the effect of alcoholic liver disease (ALD) and hepatitis C virus (HCV) infection on waiting list mortality, posttransplant mortality, and the survival benefit of deceased donor liver transplantation using United States data from the Scientific Registry of Transplant Recipients on 38,899 adults placed on the transplant waiting list between September 2001 and December 2006. Subjects were classified according to the presence/absence of HCV and ALD. Cox regression was used to estimate waiting list mortality and posttransplant mortality separately. Survival benefit was assessed using sequential stratification. Overall, the presence of HCV significantly increased waiting list mortality, with a covariate-adjusted hazard ratio (HR) for HCV-positive (HCV+) compared with HCV-negative (HCV-) HR = 1.19 (P = 0.0001). The impact of HCV+ was significantly more pronounced (P = 0.001) among ALD-positive (ALD+) patients (HR = 1.36; P < 0.0001), but was still significant among ALD-negative (ALD-) patients (HR = 1.11; P = 0.02). The contrast between ALD+ and ALD- waiting list mortality was significant only among HCV+ patients (HR = 1.14; P = 0.006). Posttransplant mortality was significantly increased among HCV+ (versus HCV-) patients (HR = 1.26; P = 0.0009), but not among ALD+ (versus ALD-) patients. Survival benefit of transplantation was significantly decreased among HCV+ compared with HCV- recipients with model for end-stage liver disease (MELD) scores 9-29, but was significantly increased at MELD >or=30. ALD did not influence the survival benefit of transplantation at any MELD score. Except in patients with very low or very high MELD scores, HCV status has a significant negative impact on the survival benefit of liver transplantation. In contrast, the presence of ALD does not influence liver transplant survival benefit.


A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis.
Mutations in genes involved in lipid metabolism have increasingly been associated with various subtypes of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative motor neuron disorders characterized by spastic paraparesis. Here, we report an unusual autosomal recessive neurodegenerative condition, best classified as a complicated form of hereditary spastic paraplegia, associated with mutation in the ethanolaminephosphotransferase 1 (EPT1) gene (now known as SELENOI), responsible for the final step in Kennedy pathway forming phosphatidylethanolamine from CDP-ethanolamine. Phosphatidylethanolamine is a glycerophospholipid that, together with phosphatidylcholine, constitutes more than half of the total phospholipids in eukaryotic cell membranes. We determined that the mutation defined dramatically reduces the enzymatic activity of EPT1, thereby hindering the final step in phosphatidylethanolamine synthesis. Additionally, due to central nervous system inaccessibility we undertook quantification of phosphatidylethanolamine levels and species in patient and control blood samples as an indication of liver phosphatidylethanolamine biosynthesis. Although this revealed alteration to levels of specific phosphatidylethanolamine fatty acyl species in patients, overall phosphatidylethanolamine levels were broadly unaffected indicating that in blood EPT1 inactivity may be compensated for, in part, via alternate biochemical pathways. These studies define the first human disorder arising due to defective CDP-ethanolamine biosynthesis and provide new insight into the role of Kennedy pathway components in human neurological function.


Neighborhood poverty and allostatic load in African American youth.
This study was designed to determine whether living in a neighborhood in which poverty levels increase across adolescence is associated with heightened levels of allostatic load (AL), a biological composite reflecting cardiometabolic risk. The researchers also sought to determine whether receipt of emotional support could ameliorate the effects of increases in neighborhood poverty on AL. Neighborhood concentrations of poverty were obtained from the Census Bureau for 420 African American youth living in rural Georgia when they were 11 and 19 years of age. AL was measured at age 19 by using established protocols for children and adolescents. When youth were 18, caregivers reported parental emotional support and youth assessed receipt of peer and mentor emotional support. Covariates included family poverty status at ages 11 and 19, family financial stress, parental employment status, youth stress, and youths' unhealthful behaviors. Youth who lived in neighborhoods in which poverty levels increased from ages 11 to 19 evinced the highest levels of AL even after accounting for the individual-level covariates. The association of increasing neighborhood poverty across adolescence with AL was not significant for youth who received high emotional support. This study is the first to show an association between AL and residence in a neighborhood that increases in poverty. It also highlights the benefits of supportive relationships in ameliorating this association.


Aggregation in complex triacylglycerol oils: coarse-grained models, nanophase separation, and predicted x-ray intensities.
Triacylglycerols (TAGs) are biologically important molecules which form crystalline nanoplatelets (CNPs) and, ultimately, fat crystal networks in edible oils. Characterizing the self-assembled hierarchies of these networks is important to understanding their functionality and oil binding capacity. We have modelled CNPs in multicomponent oils and studied their aggregation. The oil comprises (a) a liquid component, and (b) components which phase separately on a nano-scale (nano-phase separation) to coat the surfaces of the CNPs impenetrably, either isotropically or anisotropically, with either liquid-like coatings or crystallites, forming a coating of thickness ?. We modelled three cases: (i) liquid?liquid nano-phase separation, (ii) solid?liquid nano-phase separation, with CNPs coated isotropically, and (iii) CNPs coated anisotropically. The models were applied to mixes of tristearin and triolein with fully hydrogenated canola oil, shea butter with high oleic sunflower oil, and cotton seed oil. We performed Monte Carlo simulations, computed structure functions and concluded: (1) three regimes arose: (a) thin coating regime, Δ < 0.0701 u (b) transition regime, 0.0701 u ≤ Δ ≤ 0.0916 u and (c) thick coating regime, Δ > 0.0916 u. (arbitrary units, u) (2) The thin coating regime exhibits 1D TAGwoods, which aggregate, via DLCA/RLCA, into fractal structures which are uniformly distributed in space. (3) In the thick coating regime, for an isotropic coating, TAGwoods are not formed and coated CNPs will not aggregate but will be uniformly distributed in space. For anisotropic coating, TAGwoods can be formed and might form 1D strings but will not form DLCA/RLCA clusters. (4) The regimes are, approximately: thin coating, 0 < Δ < 7.0 nm transition regime, 7.0 < Δ < 9.2 nm and thick coating, Δ > 9.2 nm (5) The minimum minority TAG concentration required to undergo nano-phase separation is, approximately, 0.29% (thin coatings) and 0.94% (thick coatings). Minority components can have substantial effects upon aggregation for concentrations less than 1%.


Antifungal stewardship in a tertiary hospital.
The inappropriate use of antifungals is an important health problem related to increasing adverse effects, unnecessary cost and promotion of resistant and emerging fungal infections. Despite its relevance, many health institutions assign few resources to improve prescribing practices. To evaluate the efficiency of an antifungal stewardship programme (ASP) centered on restricted antifungal agents. The main activity during the eight-month study was to perform a programmed review of restricted antifungals (lipid formulations of amphotericin B, echinocandins and voriconazole) prescribed in hospitalized patients. In the case of amendable antifungal treatment, a recommendation was included in the electronic medical record. A total of 280 antifungal prescriptions for 262 patients were revised during the study period. The indications were prophylactic in 85 cases (30.4%), pre-emptive in 10 cases (3.5%), empiric in 122 cases (43.6%), and directed in 63 cases (22.5%). A total of 70 prescriptions (25%) in 61 patients were considered to be amendable. In most of these cases, treatment could have been reduced considering the patient's clinical improvement and microbiological results. The most common advice was antifungals change (70%), antifungal withdrawal (21%), removal of one antifungal drug in cases of combined therapy (7%), and switching to oral route (1%). Proposed recommendations were addressed in 28 cases (40%). There was no significant difference in adherence with respect to the type of recommendation (p=0.554). There was a 42% lower use of antifungals during the period of the study compared to that observed during a similar previous period. Mortality among patients who were treated according to the recommendations of the ASP was 17% and in whom treatment was not modified it was 30% (p=0.393). ASPs centered on hospitalized patients may be an efficient strategy to ameliorate antifungal use in hospitals.


Influences on achieving motor milestones: a twin-singleton study.
In order to determine if twinning impacted achievement of motor milestones the attainment of early motor milestones in twins was examined and compared to published data from singletons of the same age from the same culture and birth years. We examined the influence of twinning, sex, zygosity and birth cohort (1987-2001) on the motor development of twins aged 0 to 24 months. Data on the attainment of motor milestones (turn, sit, crawl, stand and walk) of twins were collected from maternal reports. All data were corrected for gestational age. Data from the twin sample were compared to normative data from singletons, which were available from Child Health Clinics (CHC). Analyses across twin data and the CHC singleton data revealed no differences between twins and singletons in achievement of motor milestones. Girls were able to sit without support slightly earlier than boys, otherwise there were no other sex differences. Birth-order analyses revealed minimal but significant differences in turning over from back to belly and for sitting without support between the first- and second-born. Dizygotic (DZ) twins were faster than monozygotic (MZ) twins in achieving the moment of sit, crawl, stand and walk. Twins born in earlier cohorts were faster in reaching the moment of crawl, sit and walk. It is concluded that there are no differences in time of reaching motor milestones between twins and singletons within the normal range. Sex has minimal to no effect on motor development in early childhood. DZ twins achieve motor milestones sooner than MZ twins. Attainment of gross motor milestones (crawl, stand and walk) is delayed in later birth cohorts.


Chemical and optical properties of aerosols and their interrelationship in winter in the megacity Shanghai of China.
A field campaign on air quality was carried out in Shanghai in winter of 2012. The concentrations of NO, NO2, NOx, SO2, CO, and PM2.5 increased during haze formation. The average masses of SO4(2-), NO3(-) and NH4(+) were 10.3, 11.7 and 6.7 μg/m(3) during the haze episodes, which exceeded the average (9.2, 7.9, and 3.4 μg/m(3)) of these components in the non-haze days. The mean values for the aerosol scattering coefficient (bsp), aerosol absorption coefficient (bap) and single scattering albedo (SSA) were 288.7, 27.7 and 0.91 Mm(-1), respectively. A bi-peak distribution was observed for the mass concentrations of CO, NO, NO2, and NOx. More sulfate was produced during daytime than that in the evening due to photochemical reactions. The mass concentration of NH4(+) achieved a small peak at noontime. NO3(-) showed lower concentrations in the afternoon and higher concentrations in the early morning. There were obvious bi-peak diurnal patterns for bsp and bap as well as SSA. bsp and bap showed a positive correlation with PM2.5 mass concentration. (NH4)2SO4, NH4NO3, organic mass, elemental carbon and coarse mass accounted for 21.7%, 19.3%, 31.0%, 9.3% and 12.3% of the total extinction coefficient during non-haze days, and 25.6%, 24.3%, 30.1%, 8.1% and 8.2% during hazy days. Organic matter was the largest contributor to light extinction. The contribution proportions of ammonium sulfate and ammonium nitrate to light extinction were significantly higher during the hazy time than during the non-haze days.


TEOAE suppression in adults with learning disabilities.
The presentation of contralateral noise during the recording of transient evoked otoacoustic emissions (TEOAEs) reduces the amplitude of the TEOAE in normally-hearing adults. This is known as TEOAE suppression. The present study investigated TEOAE suppression in 18 adults with learning disabilities (LDs) compared to 18 adults without LDs. TEOAEs were elicited by 60 dB p.e. SPL clicks and were suppressed by the presentation of 60 dB SPL contralateral broadband noise. Suppression was measured as a change in the overall TEOAE response amplitude, and also analysed in 2-ms epochs representing different TEOAE frequency-response bands. A significant interaction was evident between group type and ear tested. Participants in the control group had right ear dominance for the suppression effect, whereas the left ear was found to be dominant for the LD group. These findings suggest a mechanism of the medial olivary cochlear bundle and efferent auditory pathway that differs in those with LD compared to those with typical learning abilities.