Genome sequences of the biotechnologically important Bacillus megaterium strains QM B1551 and DSM319.
Bacillus megaterium is deep-rooted in the Bacillus phylogeny, making it an evolutionarily key species and of particular importance in understanding genome evolution, dynamics, and plasticity in the bacilli. B. megaterium is a commercially available, nonpathogenic host for the biotechnological production of several substances, including vitamin B(12), penicillin acylase, and amylases. Here, we report the analysis of the first complete genome sequences of two important B. megaterium strains, the plasmidless strain DSM319 and QM B1551, which harbors seven indigenous plasmids. The 5.1-Mbp chromosome carries approximately 5,300 genes, while QM B1551 plasmids represent a combined 417 kb and 523 genes, one of the largest plasmid arrays sequenced in a single bacterial strain. We have documented extensive gene transfer between the plasmids and the chromosome. Each strain carries roughly 300 strain-specific chromosomal genes that account for differences in their experimentally confirmed phenotypes. B. megaterium is able to synthesize vitamin B(12) through an oxygen-independent adenosylcobalamin pathway, which together with other key energetic and metabolic pathways has now been fully reconstructed. Other novel genes include a second ftsZ gene, which may be responsible for the large cell size of members of this species, as well as genes for gas vesicles, a second β-galactosidase gene, and most but not all of the genes needed for genetic competence. Comprehensive analyses of the global Bacillus gene pool showed that only an asymmetric region around the origin of replication was syntenic across the genus. This appears to be a characteristic feature of the Bacillus spp. genome architecture and may be key to their sporulating lifestyle.


The zebrafish klf gene family.
The Krüppel-like factor (KLF) family of genes encodes transcriptional regulatory proteins that play roles in differentiation of a diverse set of cells in mammals. For instance, the founding member KLF1 (also known as EKLF) is required for normal globin production in mammals. Five new KLF genes have been isolated from the zebrafish, Danio rerio, and the structure of their products, their genetic map positions, and their expression during development of the zebrafish have been characterized. Three genes closely related to mammalian KLF2 and KLF4 were found, as was an ortholog of mammalian KLF12. A fifth gene, apparently missing from the genome of mammals and closely related to KLF1 and KLF2, was also identified. Analysis demonstrated the existence of novel conserved domains in the N-termini of these proteins. Developmental expression patterns suggest potential roles for these zebrafish genes in diverse processes, including hematopoiesis, blood vessel function, and fin and epidermal development. The studies imply a high degree of functional conservation of the zebrafish genes with their mammalian homologs. These findings further the understanding of the KLF genes in vertebrate development and indicate an ancient role in hematopoiesis for the Krüppel-like factor gene family.


From whole body to cellular models of hepatic triglyceride metabolism: man has got to know his limitations.
The liver is a main metabolic organ in the human body and carries out a vital role in lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, encompassing a spectrum of conditions from simple fatty liver (hepatic steatosis) through to cirrhosis. Although obesity is a known risk factor for hepatic steatosis, it remains unclear what factor(s) is/are responsible for the primary event leading to retention of intrahepatocellular fat. Studying hepatic processes and the etiology and progression of disease in vivo in humans is challenging, not least as NAFLD may take years to develop. We present here a review of experimental models and approaches that have been used to assess liver triglyceride metabolism and discuss their usefulness in helping to understand the aetiology and development of NAFLD.


Plant community response to loss of large herbivores differs between North American and South African savanna grasslands.
Herbivory and fire shape plant community structure in grass-dominated ecosystems, but these disturbance regimes are being altered around the world. To assess the consequences of such alterations, we excluded large herbivores for seven years from mesic savanna grasslands sites burned at different frequencies in North America (Konza Prairie Biological Station, Kansas, USA) and South Africa (Kruger National Park). We hypothesized that the removal of a single grass-feeding herbivore from Konza would decrease plant community richness and shift community composition due to increased dominance by grasses. Similarly, we expected grass dominance to increase at Kruger when removing large herbivores, but because large herbivores are more diverse, targeting both grasses and forbs, at this study site, the changes due to herbivore removal would be muted. After seven years of large-herbivore exclusion, richness strongly decreased and community composition changed at Konza, whereas little change was evident at Kruger. We found that this divergence in response was largely due to differences in the traits and numbers of dominant grasses between the study sites rather than the predicted differences in herbivore assemblages. Thus, the diversity of large herbivores lost may be less important in determining plant community dynamics than the functional traits of the grasses that dominate mesic, disturbance-maintained savanna grasslands.


Novel method for evaluation of the oligomeric structure of membrane proteins.
Assessment of the quaternary structure of membrane proteins by PAGE has been problematic owing to their relatively poor solubility in non-dissociative detergents. Here we report that several membrane proteins can be readily solubilized in their native quaternary structure with the use of the detergent perfluoro-octanoic acid (PFO). Further, PFO can be used with PAGE, thereby providing a novel, accessible tool with which to assess the molecular mass of homo-multimeric protein complexes.


Black-hair follicular dysplasia in a New Zealand Huntaway Dog.
A 6-year-old intact male New Zealand Huntaway dog had slowly progressive alopecia that was first observed at 12 weeks of age. Patchy alopecia was confined to the black-haired areas of the body, and was most evident on the head and dorsum of the body; tan-haired areas of skin appeared normal. Histological examination of black-haired skin revealed distended melanocytes and large aggregates of melanin within, and surrounding, the hair follicles and the epidermis. Macrophages distended with melanin were also visible within the peri-follicular and superficial dermis, and follicular lumina were often plugged by keratin that contained aggregates of melanin. The follicles were dysplastic and few hair shafts were visible emerging from follicular infundibula within the sections. The clinical and histological findings were consistent with black-hair follicular dysplasia (BHFD). This is the first report of BHFD in a dog in New Zealand, and is the first report in a Huntaway. The most significant effect of BHFD is a predisposition to follicular plugging and secondary bacterial skin infections. Due to the hereditary nature of the follicular dysplasias, breeding from affected dogs should be discouraged. Histological examination of the skin is required to differentiate between the different follicular dysplasias as well as differentiating between follicular dysplasia and follicular atrophy due to endocrinopathy.


Effect of serum proteins on haem uptake and metabolism in primary cultures of liver cells.
A role of haemopexin in transporting haem to hepatocytes for degradation has been inferred from the high affinity of haemopexin for haem. We have examined this question in primary cultures of chick-embryo and adult rat liver cells. We present here the results of four sets of experiments which indicate that haemopexin retarded haem uptake by hepatocytes in culture. (1) Haem bound to bovine serum albumin is known to repress the activity of delta-aminolaevulinate synthase in chick cultures as indicated by decreased porphyrin accumulation. When haem-albumin was added in the presence of excess purified or freshly secreted chicken haemopexin, no haem-mediated repression of porphyrin production was observed. The haem-mediated repression of porphyrin accumulation was partially prevented when human, but not chicken, albumin was added to cultures. This finding reflected the higher affinity of human albumin for haem compared with that of chicken albumin. (2) Haemopexin inhibited the ability of haem to be incorporated into cytochrome P-450 induced in the chick cultures in the presence of the iron chelator desferrioxamine. (3) The rate of association of [55Fe]haem with cultured rat hepatocytes when [55Fe]haem-haemopexin was added was one-eighth of the rate observed when [55Fe]haem-bovine serum albumin was used as the haem donor. (4) The presence of haemopexin also diminished the catabolism of haem by both rat and chick-embryo liver cell cultures. It is concluded that the uptake and subsequent metabolic effects of haem are inhibited in cultured hepatocytes by proteins such as haemopexin which have a high affinity for haem.


Economic aspects of global warming in a post-Copenhagen environment.
The science of global warming has reached a consensus on the high likelihood of substantial warming over the coming century. Nations have taken only limited steps to reduce greenhouse gas emissions since the first agreement in Kyoto in 1997, and little progress was made at the Copenhagen meeting in December 2009. The present study examines alternative outcomes for emissions, climate change, and damages under different policy scenarios. It uses an updated version of the regional integrated model of climate and the economy (RICE model). Recent projections suggest that substantial future warming will occur if no abatement policies are implemented. The model also calculates the path of carbon prices necessary to keep the increase in global mean temperature to 2 degrees C or less in an efficient manner. The carbon price for 2010 associated with that goal is estimated to be $59 per ton (at 2005 prices), compared with an effective global average price today of around $5 per ton. However, it is unlikely that the Copenhagen temperature goal will be attained even if countries meet their ambitious stated objectives under the Copenhagen Accord.


Macrophage-specific transgenic expression of cholesteryl ester hydrolase significantly reduces atherosclerosis and lesion necrosis in Ldlr mice.
Accumulation of cholesteryl esters (CEs) in macrophage foam cells, central to atherosclerotic plaque formation, occurs as a result of imbalance between the cholesterol influx and efflux pathways. While the uptake, or influx, of modified lipoproteins is largely unregulated, extracellular acceptor-mediated free cholesterol (FC) efflux is rate limited by the intracellular hydrolysis of CE. We previously identified and cloned a neutral CE hydrolase (CEH) from human macrophages and demonstrated its role in cellular CE mobilization. In the present study, we examined the hypothesis that macrophage-specific overexpression of CEH in atherosclerosis-susceptible Ldlr(-/-) mice will result in reduction of diet-induced atherosclerosis. Transgenic mice overexpressing this CEH specifically in the macrophages (driven by scavenger receptor promoter/enhancer) were developed and crossed into the Ldlr(-/-) background (Ldlr(-/-)CEHTg mice). Macrophage-specific overexpression of CEH led to a significant reduction in the lesion area and cholesterol content of high-fat, high-cholesterol diet-induced atherosclerotic lesions. The lesions from Ldlr(-/-)CEHTg mice did not have increased FC, were less necrotic, and contained significantly higher numbers of viable macrophage foam cells. Higher CEH-mediated FC efflux resulted in enhanced flux of FC from macrophages to gall bladder bile and feces in vivo. These studies demonstrate that by enhancing cholesterol efflux and reverse cholesterol transport, macrophage-specific overexpression of CEH is antiatherogenic.


Does Place of Residence or Time of Year Affect the Risk of Stroke Hospitalization and Death? A Descriptive Spatial and Temporal Epidemiologic Study.
Identifying geographic areas with significantly high risks of stroke is important for informing public health prevention and control efforts. The objective of this study was to investigate geographic and temporal patterns of stroke hospitalization and mortality risks so as to identify areas and seasons with significantly high burden of the disease in Florida. The information obtained will be useful for resource allocation for disease prevention and control. Stroke hospitalization and mortality data from 1992 to 2012 were obtained from the Florida Agency for Health Care Administration. Age-adjusted stroke hospitalization and mortality risks for time periods 1992-94, 1995-97, 1998-2000, 2001-03, 2004-06, 2007-09 and 2010-12 were computed at the county spatial scale. Global Moran's I statistics were computed for each of the time periods to test for evidence of global spatial clustering. Local Moran indicators of spatial association (LISA) were also computed to identify local areas with significantly high risks. There were approximately 1.5 million stroke hospitalizations and over 196,000 stroke deaths during the study period. Based on global Moran's I tests, there was evidence of significant (p<0.05) global spatial clustering of stroke mortality risks but no evidence (p>0.05) of significant global clustering of stroke hospitalization risks. However, LISA showed evidence of local spatial clusters of both hospitalization and mortality risks with significantly high risks being observed in the north while the south had significantly low risks of stroke deaths. There were decreasing temporal trends and seasonal patterns of both hospitalization and mortality risks with peaks in the winter. Although stroke hospitalization and mortality risks have declined in the past two decades, disparities continue to exist across Florida and it is evident from the results of this study that north Florida may, in fact, be part of the stroke belt despite not being in any of the traditional stroke belt states. These findings are useful for guiding public health efforts to reduce/eliminate inequities in stroke outcomes and inform policy decisions. There is need to continually identify populations with significantly high risks of stroke to better guide the targeting of limited resources to the highest risk populations.


Effects of subchronic exposure to radio frequency from a conventional cellular telephone on testicular function in adult rats.
We investigated the effects of subchronic exposure to radio frequency emitted from a conventional cellular telephone on the testicular function in adult rats. A total of 16 male Wistar rats at age 30 days were randomly divided into 2 groups, including experimental and control groups. The experimental group was exposed to radio frequency emitted from a conventional GSM (global system for mobile communications) cellular telephone (1,835 to 1,850 MHz) for 1 hour daily during 11 weeks. Rectal temperature was measured before and after the exposure period. Testicular and epididymal weight, lipid peroxidation levels in these organs, serum total testosterone and the epididymal sperm count were evaluated. Maturation phase spermatid retention at stage IX-X, interstitial infiltration, cellular vacuolation and multinucleate giant cells were among the qualitative testicular histopathological end points analyzed. Each rat had 10 consecutive round seminiferous tubules at stage VII-VIII evaluated for the mean seminiferous tubular diameter measurement, the crude histological count of round spermatids, pachytene spermatocytes and Sertoli's cells with evident nucleoli, and the true histological count (Abercrombie's correction factor) of round spermatids and pachytene spermatocytes. Mean rectal temperature did not alter following exposure. There was no statistical difference between the control and experimental groups in any end points evaluated. The current study shows that the low intensity pulsed radio frequency emitted by a conventional cellular telephone does not impair testicular function in adult rats.


Does Asian race affect hepatitis B virus recurrence or survival following liver transplantation for hepatitis B cirrhosis?
To assess whether Asian race is an independent variable affecting survival and hepatitis B virus (HBV) recurrence after liver transplantation, the results of 27 consecutive liver transplants performed between June 1994 and April 1997 for HBV cirrhosis were analysed. In the group of 13 Asians, 38% had associated hepatocellular carcinoma and 62% had positive hepatitis B virus early antigen (HBeAg) or elevated HBV-DNA before transplant. Prophylactic hepatitis B immunoglobulin (HBIG) was administered perioperatively and long term at 4-6 weekly interval. Four patients with elevated HBV-DNA received lamivudine before transplantation. The 3 year actuarial patient survival rate was 100% in both Asian and non-Asian patients. Twenty-six patients remained seronegative for hepatitis B virus surface antigen after transplantation. The incidence of post-transplant HBV recurrence was similar: 0% in Asians compared with 7% in non-Asians. There was no recurrence in the group of 12 patients who were HBV-DNA or HBeAg negative pretransplant.


Simulation of organ patterning on the floral meristem using a polar auxin transport model.
An intriguing phenomenon in plant development is the timing and positioning of lateral organ initiation, which is a fundamental aspect of plant architecture. Although important progress has been made in elucidating the role of auxin transport in the vegetative shoot to explain the phyllotaxis of leaf formation in a spiral fashion, a model study of the role of auxin transport in whorled organ patterning in the expanding floral meristem is not available yet. We present an initial simulation approach to study the mechanisms that are expected to play an important role. Starting point is a confocal imaging study of Arabidopsis floral meristems at consecutive time points during flower development. These images reveal auxin accumulation patterns at the positions of the organs, which strongly suggests that the role of auxin in the floral meristem is similar to the role it plays in the shoot apical meristem. This is the basis for a simulation study of auxin transport through a growing floral meristem, which may answer the question whether auxin transport can in itself be responsible for the typical whorled floral pattern. We combined a cellular growth model for the meristem with a polar auxin transport model. The model predicts that sepals are initiated by auxin maxima arising early during meristem outgrowth. These form a pre-pattern relative to which a series of smaller auxin maxima are positioned, which partially overlap with the anlagen of petals, stamens, and carpels. We adjusted the model parameters corresponding to properties of floral mutants and found that the model predictions agree with the observed mutant patterns. The predicted timing of the primordia outgrowth and the timing and positioning of the sepal primordia show remarkable similarities with a developing flower in nature.


Evidence for linkage of stature to chromosome 3p26 in a large U.K. Family data set ascertained for type 2 diabetes.
We have analyzed data from 573 pedigrees from the United Kingdom for evidence for linkage to loci influencing adult stature. Our data set comprised 1,214 diabetic and 163 nondiabetic siblings for whom height data were available. We used variance-components analysis implemented in GENEHUNTER 2 and a modification of the Haseman-Elston regression method, HE-COM. We found evidence for a locus on 3p26 (LOD score 3.17) influencing height in this adult sample, with less-significant evidence for loci on chromosomes 7, 10, 15, 17, 19, and 20. Our findings extend similar recent studies in Scandinavian and Quebecois populations, adding further evidence that height is indeed under the control of multiple genes.


Tc-99m TRODAT-1 SPECT is a Potential Biomarker for Restless Leg Syndrome in Patients with End-Stage.
Rationales: Restless leg syndrome (RLS) is a common complication in patients with end-stage renal disease (ESRD). However, there is a lack of biomarkers linking uremic RLS to dopaminergic neurons. Previous studies demonstrated that Tc-99m TRODAT-1 SPECT was a biomarker for RLS but the correlation between the physiologic parameter was lacking. Overall, 32 patients were enrolled in the study and divided into the following 3 groups: (1) control (n = 13), (2) ESRD without RLS (n = 8) and (3) ESRD with RLS (n = 11). All patients had a clinical diagnosis of RLS and received Tc-99m TRODAT-1 SPECT. A subgroup analysis was performed to compare differences between the control and ESRD with RLS groups. Tc-99m TRODAT-1 SPECT was performed and activities in the striatum and occipital areas were measured using manually delineated regions of interest (ROIs) by an experienced nuclear medicine radiologist who was blinded to clinical data. The total ratio of Tc-99m TRODAT SPECT was lower in the ESRD with RLS group (p = 0.046). The uptake ratio of TRODAT negatively correlated with serum parathyroid hormone (r = -0.577, p = 0.015) and ferritin (r = -0.464, p = 0.039) concentrations. However, the uptake positively correlated with the hemoglobin concentration (r = 0.531, p = 0.011). The sensitivity and specificity of the total TRODAT ratio for predicting RLS in the overall population were 95.0% and 67.7%, respectively, at a cutoff value of 0.980 (area under the curve of receiver operating characteristic curve was 0.767, p = 0.024). In patients with ESRD and RLS, Tc-99m TRODAT might be a potential biomarker. Dysregulated hemoglobin, serum parathyroid hormone and serum ferritin concentrations might influence the uptake of the TRODAT ratio.


Impact of Information Technology-Based Interventions for Type 2 Diabetes Mellitus on Glycemic Control: A Systematic Review and Meta-Analysis.
Information technology-based interventions are increasingly being used to manage health care. However, there is conflicting evidence regarding whether these interventions improve outcomes in people with type 2 diabetes. The objective of this study was to conduct a systematic review and meta-analysis of clinical trials, assessing the impact of information technology on changes in the levels of hemoglobin A1c (HbA1c) and mapping the interventions with chronic care model (CCM) elements. Electronic databases PubMed and EMBASE were searched to identify relevant studies that were published up until July 2016, a method that was supplemented by identifying articles from the references of the articles already selected using the electronic search tools. The study search and selection were performed by independent reviewers. Of the 1082 articles retrieved, 32 trials (focusing on a total of 40,454 patients) were included. A random-effects model was applied to estimate the pooled results. Information technology-based interventions were associated with a statistically significant reduction in HbA1c levels (mean difference -0.33%, 95% CI -0.40 to -0.26, P<.001). Studies focusing on electronic self-management systems demonstrated the largest reduction in HbA1c (0.50%), followed by those with electronic medical records (0.17%), an electronic decision support system (0.15%), and a diabetes registry (0.05%). In addition, the more CCM-incorporated the information technology-based interventions were, the more improvements there were in HbA1c levels. Information technology strategies combined with the other elements of chronic care models are associated with improved glycemic control in people with diabetes. No clinically relevant impact was observed on low-density lipoprotein levels and blood pressure, but there was evidence that the cost of care was lower.


Using genomics to understand the origin and dispersion of multidrug and extensively drug resistant tuberculosis in Portugal.
Portugal is a low incidence country for tuberculosis (TB) disease. Now figuring among TB low incidence countries, it has since the 1990s reported multidrug resistant and extensively drug resistant (XDR) TB cases, driven predominantly by two strain-types: Lisboa3 and Q1. This study describes the largest characterization of the evolutionary trajectory of M/XDR-TB strains in Portugal, spanning a time-period of two decades. By combining whole-genome sequencing and phenotypic susceptibility data for 207 isolates, we report the geospatial patterns of drug resistant TB, particularly the dispersion of Lisboa3 and Q1 clades, which underly 64.2% and 94.0% of all MDR-TB and XDR-TB isolates, respectively. Genomic-based similarity and a phylogenetic analysis revealed multiple clusters (n = 16) reflecting ongoing and uncontrolled recent transmission of M/XDR-TB, predominantly associated with the Lisboa3 and Q1 clades. These clades are now thought to be evolving in a polycentric mode across multiple geographical districts. The inferred evolutionary history is compatible with MDR- and XDR-TB originating in Portugal in the 70's and 80's, respectively, but with subsequent multiple emergence events of MDR and XDR-TB particularly involving the Lisboa3 clade. A SNP barcode was defined for Lisboa3 and Q1 and comparison with a phylogeny of global strain-types (n = 28 385) revealed the presence of Lisboa3 and Q1 strains in Europe, South America and Africa. In summary, Portugal displays an unusual and unique epidemiological setting shaped by >40 years of uncontrolled circulation of two main phylogenetic clades, leading to a sympatric evolutionary trajectory towards XDR-TB with the potential for global reach.


Neonatal brain structure on MRI and diffusion tensor imaging, sex, and neurodevelopment in very-low-birthweight preterm children.
The neurological basis of an increased incidence of cerebral palsy (CP) in preterm males is unknown. This study examined neonatal brain structure on magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) at term-equivalent age, sex, and neurodevelopment at 1 year 6 months on the basis of the Amiel-Tison neurological examination, Gross Motor Function Classification System, and Bayley Scales of Infant Development in 78 very-low-birthweight preterm children (41 males, 37 females; mean gestational age 27.6 wks, SD 2.5; mean birthweight 1021 g, SD 339). Brain abnormalities on MRI and DTI were not different between males and females except in the splenium of the corpus callosum, where males had lower DTI fractional anisotropy (p=0.025) and a higher apparent diffusion coefficient (p=0.013), indicating delayed splenium development. In the 26 infants who were at higher risk on the basis of DTI, males had more abnormalities on MRI (p=0.034) and had lower fractional anisotropy and a higher apparent diffusion coefficient in the splenium (p=0.049; p=0.025) and right posterior limb of the internal capsule (PLIC; p=0.003; p=0.033). Abnormal neurodevelopment was more common in males (n=9) than in females (n=2; p=0.036). Children with abnormal neurodevelopment had more abnormalities on MRI (p=0.014) and reduced splenium and right PLIC fractional anisotropy (p=0.001; p=0.035). In children with abnormal neurodevelopment, right PLIC fractional anisotropy was lower than left (p=0.035), whereas in those with normal neurodevelopment right PLIC fractional anisotropy was higher than left (p=0.001). Right PLIC fractional anisotropy correlated to neurodevelopment (rho=0.371, p=0.002). Logistic regression predicted neurodevelopment with 94% accuracy; only right PLIC fractional anisotropy was a significant logistic coefficient. Results indicate that the higher incidence of abnormal neurodevelopment in preterm males relates to greater incidence and severity of brain abnormalities, including reduced PLIC and splenium development.


A new paradigm for navigating compound property related drug attrition.
Improving the efficiency of drug discovery remains a major focus for the pharmaceutical industry. Toxicity accounts for 90% of withdrawals and major early-stage terminations relate to suboptimal efficacy and safety. Traditional oral drug space is well defined with respect to physicochemical properties and ADMET risks but increased focus on ligand-lipophilicity efficiency, maximizing enthalpy contributions and new target classes challenge this paradigm. A hybrid space has been identified that combines physical properties and key interactions attributable to drug transporters. A novel algorithm is proposed that incorporates drug-transporter interactions and its utility evaluated against popular ligand efficiency indices. Simply reducing the bulk properties of compounds can exchange one problem for another and creates high-risk areas that challenge the successful delivery from a balanced portfolio.


Shift Work: A Perspective on Shift Work Disorder-Is Prevention the Answer?
The prevalence of shift work in the United States is nearly 20%, but recognition of shift work disorder (SWD) among shift workers is still a challenge. The health care sector is no exception. While a substantial portion of shift workers are physicians and nurses, expertise in identifying SWD is lacking. Shift work adjustment occurs spontaneously in some individuals, but for others, it poses difficulties, including both sleep disturbance and insufficient sleep, leading to chronic excessive sleepiness and other long-term morbidities. Treatment is multifaceted and often requires pharmacologic therapy to address acute sleep-wake symptoms, as well as circadian interventions to realign intrinsic biological rhythms to the externally imposed shift-work schedule. The complexity and myriad obstacles of treating maladjustment to shift work after its manifestation, including determination of circadian phase, risk-benefit considerations in pharmacologic treatment, and behavioral/health risks associated with delaying intervention, suggest that prevention of SWD should be a priority. This article presents the personal experience of one author (Amit Gupta), identifies some of the issues faced by shift workers, especially medical trainees, and suggests a preventive approach to this complex problem that should be considered for future research and practical implementation in the clinic.


CD28 engagement and proinflammatory cytokines contribute to T cell expansion and long-term survival in vivo.
To mount a productive response to Ag, CD4+ T cells in mice must divide, differentiate, and survive at least until the Ag has been eliminated. It has been suggested that to accomplish this, T cells must receive two signals, one through their TCRs and a second through CD28. The second signal through CD28 has been thought to fulfill two roles, to stimulate T cell proliferation and to promote T cell survival. In this paper we confirm that CD28 engagement can contribute to vigorous T cell expansion in mice injected with superantigens. However, CD28 engagement does not protect T cells produced during a superantigen-specific proliferative response from undergoing subsequent deletion. Even if CD28 is bound, 4 days after superantigen exposure, the majority of T cells produced in response to superantigen exposure are eliminated in vivo. In contrast, this loss of superantigen-stimulated T cells can be prevented by the inflammatory stimuli created by injection of bacterial LPS. This protection does not require engagement of CD28 by its ligands, B7-1 and B7-2. These data suggest that productive T cell responses in mice involve a number of signals, including those initiated through TCR and CD28, which are primarily involved in the activation and expansion of T cells, and others delivered by proinflammatory cytokines that protect an activated T cell from subsequent deletion.


Is accurate routine cancer prognostication psychologically harmful? 5-year outcomes of life expectancy prognostication in uveal melanoma survivors.
Prognostication in cancer is growing in importance as increasingly accurate tools are developed. Prognostic accuracy intensifies ethical concerns that a poor prognosis could be psychologically harmful to survivors. Uveal melanoma (UM) prognostication allows survivors to be reliably told that life expectancy is either normal (good prognosis) or severely curtailed because of metastatic disease (poor prognosis). Treatment cannot change life expectancy. To identify whether prognosis is associated with psychological harm, we compared harm in UM survivors with good and poor prognoses and those who declined testing and compared these outcomes to general population norms. Non-randomized 5-year study of a consecutive series of 708 UM survivors (51.6% male, mean age 69.03, SD=12.12) with observations at 6, 12, 24, 36, 48 and 60 months. We operationalized psychological harm as anxiety and depression symptoms, worry about cancer recurrence (WREC) and poor quality of life (QoL). Compared to other groups, survivors with poor prognoses showed initially elevated anxiety and depression and consistently elevated worry about local or distant recurrence over 5 years. Good prognoses were not associated with outcomes. Generally, no prognostic groups reported anxiety, depression and WREC or QoL scores that exceeded general population norms. Using a large sample, we found that harm accruing from a poor prognosis was statistically significant over 5 years, but did not exceed general non-cancer population norms. Survivors desire prognostic information. At a population level, we do not believe that our findings show sufficiently strong links between prognostication outcome and psychological harm to deny patients the option of knowing their prognosis. Nonetheless, it is important that patients are informed of potential adverse psychological consequences of a poor prognosis.


Bridging the gap: parkour athletes provide new insights into locomotion energetics of arboreal apes.
The tree canopy is an energetically challenging environment to traverse. Along with compliant vegetation, gaps in the canopy can prove energetically costly if they force a route-extending detour. Arboreal apes exhibit diverse locomotion strategies, including for gap crossing. Which one they employ in any given scenario may be influenced by the energy costs to do so, which are affected by the details of the immediate environment in combination with their body size. Measuring energetics of arboreal apes is not tractable; thus our knowledge in this area is limited. We devised a novel, custom-made experimental set-up to record the energy expenditure of parkour athletes tree-swaying, jumping and vertical climbing. The latter strategy was vastly more expensive, indicating that when energy economy is the focus arboreal apes will prioritize routes that limit height changes. Whether tree-swaying or jumping was most economical for the athletes depended upon interactions between tree stiffness, the distance to cross, number of tree-sways required and their own mass. Updated analysis of previous interspecific correlations suggests that whether the relative costs to vertical climb are size-invariant across primate species is complicated by details of the climbing context.


Systematic Review: Characteristics and Preclinical Uses of Bladder Cancer Cell Lines.
Bladder cancer (BC) cell lines are indispensable in basic and preclinical research. Currently, an up-to-date and comprehensive overview of available BC cell lines is not available. To provide an overview and resources on the origin, pathological and molecular characteristics of commonly used human, murine and canine BC cell lines. A PubMed search was performed for relevant articles published between 1980 and 2017 according to the following MeSH terms: cell line; cell line, tumor; urinary bladder neoplasms; carcinoma, transitional cell. The Cellosaurus database was searched, using the term "bladder" and/or "urothelial carcinoma". We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We provide information on 157 human, murine and canine BC cell lines. 103 human BC cell lines have molecular data available, of which 69 have been profiled by at least one "omic" technology. We outline how these cell lines are currently being used for in vitro and in vivo experimental models. These results allow direct comparison of BC cell lines to patient samples, providing information needed to make informed decisions on the most genomically appropriate cell line to answer research questions. Furthermore, we show that cross-contamination remains an issue and describe guidelines for prevention. In the BC field, multiple human, murine and canine BC cell lines have been developed and many have become indispensable for in vitro and in vivo research. High-throughput -omic technologies have dramatically increased the amount of molecular data on these cell lines. We synthesized a comprehensive overview of these data as a resource for the BC scientific community.


Psychological and educational interventions for atopic eczema in children.
Psychological and educational interventions have been used as an adjunct to conventional therapy for children with atopic eczema to enhance the effectiveness of topical therapy. This is an update of the original Cochrane review. To assess the effect of psychological and educational interventions for atopic eczema in children. We updated our searches of the following databases to January 2013: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, Issue 12), MEDLINE (from 1946), EMBASE (from 1974), OpenGrey, and PsycINFO (from 1806). We also searched six trials registers and checked the reference lists of included and excluded studies for further references to relevant randomised controlled trials (RCTs). Randomised controlled trials of psychological or educational interventions, or both, used to assist children and their carers in managing atopic eczema. Three authors independently applied eligibility criteria, assessed trial quality, and extracted data. A lack of comparable data prevented data synthesis, and we were unable to conduct meta-analysis because there were insufficient data. We included 10 RCTs, of which 5 were new to this update; all interventions were adjuncts to conventional therapy and were delivered in primary- and secondary-care settings. There were 2003 participants in the 9 educational interventions and 44 participants in the 1 psychological study. Some included studies had methodological weaknesses; for example, we judged four studies to have high risk of detection bias, attrition bias, or other bias. Our primary outcomes were participant-rated global assessment, reduction in disease severity (reported as objective SCORAD (SCORing Atopic Dermatitis)), and improvement in sleep and quality of life. No study reported participant-rated global assessment or improvement of sleep.The largest and most robust study (n = 992) demonstrated significant reduction in disease severity and improvement in quality of life, in both nurse- and dermatologist-led intervention groups. It provided six standardised, age-appropriate group education sessions. Statistically significant improvements in objective severity using the SCORAD clinical tool were recorded for all intervention groups when compared with controls. Improvements in objective severity (intervention minus no intervention) by age group were as follows: age 3 months to 7 years = 4.2, 95% confidence interval (CI) 1.7 to 6.8; age 8 to 12 years = 6.7, 95% CI 2.1 to 11.2; and age 13 to 18 years = 9.9, 95% CI 4.3 to 15.5. In three of five studies, which could not be combined because of their heterogeneity, the objective SCORAD measure was statistically significantly better in the intervention group compared with the usual care groups. However, in all of the above studies, the confidence interval limits do not exceed the minimum clinically important difference of 8.2 for objective SCORAD.The largest study measured quality of life using the German 'Quality of life in parents of children with atopic dermatitis' questionnaire, a validated tool with five subscales. Parents of children under seven years had significantly better improvements in the intervention group on all five subscales. Parents of children aged 8 to 12 years experienced significantly better improvements in the intervention group on 3 of the 5 subscales. This update has incorporated five new RCTs using educational interventions as an adjunct to conventional treatment for children with atopic eczema. We did not identify any further studies using psychological interventions. The inclusion of new studies has not substantially altered the conclusions from the original review. The educational studies in both the original review and this update lack detail about intervention design and do not use a complex interventions framework. Few use an explicit theoretical base, and the components of each intervention are not sufficiently well described to allow replication. A relative lack of rigorously designed trials provides limited evidence of the effectiveness of educational and psychological interventions in helping to manage the condition of atopic eczema in children. However, there is some evidence from included paediatric studies using different educational intervention delivery models (multiprofessional eczema interventions and nurse-led clinics) that these may lead to improvements in disease severity and quality of life. Educational and psychological interventions require further development using a complex interventions framework. Comparative evaluation is needed to examine their impact on eczema severity, quality of life, psychological distress, and cost-effectiveness. There is also a need for comparison of educational interventions with stand-alone psychosocial self-help.


Personalized Management of Pancreatic Ductal Adenocarcinoma Patients through Computational Modeling.
Phenotypic diversity in pancreatic ductal adenocarcinoma (PDAC) results in a variety of treatment responses. Rapid autopsy studies have revealed a subgroup of PDAC patients with a lower propensity to develop metastatic disease, challenging the common perception that all patients die of widely metastatic disease, but questions remain about root causes of this difference and the potential impact on treatment strategies. In this study, we addressed these questions through the development of a mathematical model of PDAC progression that incorporates the major alteration status of specific genes with predictive utility. The model successfully reproduced clinical outcomes regarding metastatic patterns and the genetic alteration status of patients from two independent cohorts from the United States and Japan. Using this model, we defined a candidate predictive signature in patients with low metastatic propensity. If a primary tumor contained a small fraction of cells with KRAS and additional alterations to CDKN2A, TP53, or SMAD4 genes, the patient was likely to exhibit low metastatic propensity. By using this predictive signature, we computationally simulated a set of clinical trials to model whether this subgroup would benefit from locally intensive therapies such as surgery or radiation therapy. The largest overall survival benefit resulted from complete resection, followed by adjuvant chemoradiation therapy and salvage therapies for isolated recurrence. While requiring prospective validation in a clinical trial, our results suggest a new tool to help personalize care in PDAC patients in seeking the most effective therapeutic modality for each individual. Cancer Res; 77(12); 3325-35. ©2017 AACR.


The effect of 2-methoxyoestrone-3-O-sulphamate on the growth of breast cancer cells and induced mammary tumours.
2-Methoxyoestrogens are emerging as a new class of drug that can inhibit tumour growth and angiogenesis. As sulphamoylation of oestrogens enhances their potency and bioavailability we have synthesized 2-methoxyoestrone-3-O-sulphamate (2-MeOEMATE) and compared its ability to inhibit the proliferation of breast cancer cells with that of 2-methoxyoestrone (2-MeOE1). 2-MeOEMATE (1 microM) inhibited the growth of oestrogen receptor positive MCF-7 breast cancer cells by 52% whereas 2-MeOE1 had little effect at this concentration. 2-MeOEMATE also inhibited the growth of oestrogen receptor negative MDA-MB-231 breast cancer cells. Exposure of cells to 2-MeOEMATE caused them to round up and become detached suggesting that this compound may induce cells to undergo apoptosis. Cell cycle analysis revealed that 2-MeOEMATE caused cells to arrest in the G(2)/M phase with the increase in G(2)/M arrested cells being detectable by 12 hr. Exposure of MCF-7 cells to 2 L-MeOEMATE for 24 hr followed by culture in drug-free medium for 24 hr did not reverse the arrest of cells in the G(2)/M phase. TUNEL analysis confirmed that 2-MeOEMATE induced apoptosis in a significant proportion of treated MCF-7 cells. In an in vivo study, employing nitrosomethylurea-induced mammary tumours in intact rats, 2-MeOE1 (20mg/kg/d, p.o. for 11 days) had little effect on tumour growth. In contrast, the same dose of 2-MeOEMATE resulted in the almost complete regression of 2/3 tumours over an 11-day period. We conclude that 2-MeOEMATE should have considerable therapeutic potential for the treatment of breast tumours.


Determinants of the use of different types of health care provider in urban China: a tracer illness study of URTI.
With the reform of urban health delivery systems in China, concern has been growing about the effect of these changes on health care demand and utilization at basic-level health institutions, especially Community Health Services Centers (CHC). Using data from the fourth China National Health Services Survey (NHSS) that was conducted in 2008, the authors conducted a tracer illness study of urban people with acute upper respiratory tract infections (URTI) to examine the factors that affect their use of different outpatient health care providers. The study addresses the observed demand for both public and private providers and is believed to be the first to attempt this for urban China. The findings indicate that overall private clinics are important sources of medical care for low consumption households, that insured patients are less likely to use private clinics and more likely to use CHC and that children are more likely to see a high-level provider. A number of other factors, including city size and severity of illness were found to play a role in determining provider utilization. We discuss the policy implications of the results in terms of meeting the health care needs of the urban population in China.


Wild blueberry (Vaccinium angustifolium) consumption affects the composition and structure of glycosaminoglycans in Sprague-Dawley rat aorta.
It has been documented that increased intake of polyphenols may provide protection against coronary heart disease and stroke. Blueberries (Vaccinium angustifolium) are one of the richest sources of antioxidants among fruits and vegetables. Phenolic compounds from berry extracts inhibit human low density lipoprotein and liposome oxidation. Glycosaminoglycans (GAGs) and proteoglycans (PGs) are structural components of aortas with great structural diversity. Their interaction with compounds such as enzymes, cytokines, growth factors, proteins and lipoproteins and their subsequent role in degenerative diseases has been documented. We investigated the effects of a diet rich in blueberries on the content and structure of GAGs. Sprague-Dawley rats were fed either a control (C) or a blueberry (B) diet for 13 weeks. Aortic tissue GAGs were isolated with papain digestion, alkaline borohydride treatment and anion-exchange chromatography. Cellulose acetate electrophoresis and treatment of the fractions with specific lyases revealed the presence of three GAG populations, i.e. hyaluronan (HA), heparan sulfate (HS) and galactosaminoglycans (GalAGs). Disaccharide composition was determined by high-performance capillary electrophoresis following enzymatic degradation. A 13% higher amount of total GAGs in aortas of B-fed rats was attributed to a higher content of GalAGs (67%). Determination of the sulfated disaccharides showed an overall lower concentration of oversulfated disaccharides in both HS and GalAG populations in the aortas of the B group. Our results demonstrate for the first time that a diet rich in blueberries results in structural alterations in rat aortic tissue GAGs. These changes may affect cellular signal transduction pathways and could have major consequences for the biological function of GAG molecules within the vascular environment.


Update for Anaesthetists on Clinical Features of COVID-19 Patients and Relevant Management.
When preparing for the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the coronavirus infection disease (COVID-19) questions arose regarding various aspects concerning the anaesthetist. When reviewing the literature it became obvious that keeping up-to-date with all relevant publications is almost impossible. We searched for and summarised clinically relevant topics that could help making clinical decisions. This is a subjective analysis of literature concerning specific topics raised in our daily practice (e.g., clinical features of COVID-19 patients; ventilation of the critically ill COVID-19 patient; diagnostic of infection with SARS-CoV-2; stability of the virus; Covid-19 in specific patient populations, e.g., paediatrics, immunosuppressed patients, patients with hypertension, diabetes mellitus, kidney or liver disease; co-medication with non-steroidal anti-inflammatory drugs (NSAIDs); antiviral treatment) and we believe that these answers help colleagues in clinical decision-making. With ongoing treatment of severely ill COVID-19 patients other questions will come up. While respective guidelines on these topics will serve clinicians in clinical practice, regularly updating all guidelines concerning COVID-19 will be a necessary, although challenging task in the upcoming weeks and months. All recommendations during the current extremely rapid development of knowledge must be evaluated on a daily basis, as suggestions made today may be out-dated with the new evidence available tomorrow.


Spontaneous baroreceptor reflex sensitivity for risk stratification of heart failure patients: optimal cut-off and age effects.
Baroreceptor reflex sensitivity (BRS) is an important prognostic factor because a reduced BRS has been associated with an adverse cardiovascular outcome. The threshold for a 'reduced' BRS was established by the ATRAMI study at BRS <3 ms/mmHg in patients with a previous myocardial infarction, and has been shown to improve risk assessment in many other cardiac dysfunctions. The successful application of this cut-off to other populations suggests that it may reflect an inherent property of baroreflex functioning, so our goal is to investigate whether it represents a 'natural' partition of BRS values. As reduced baroreflex responsiveness is also associated with ageing, we investigated whether a BRS estimate <3 ms/mmHg could be the result of a process of physiological senescence as well as a sign of BRS dysfunction. This study involved 228 chronic heart failure patients and 60 age-matched controls. Our novel method combined transfer function BRS estimation and automatic clustering of BRS probability distributions, to define indicative levels of different BRS activities. The analysis produced a fit clustering (cophenetic correlation coefficient 0.9 out of 1) and identified one group of homogeneous patients (well separated from the others by 3 ms/mmHg) with an increased BRS-based mortality risk [hazard ratio (HR): 3.19 (1.73, 5.89), P<0.001]. The age-dependent BRS cut-off, estimated by 5% quantile regression of log (BRS) with age (considering the age-matched controls), provides a similar mortality value [HR: 2.44 (1.37, 4.43), P=0.003]. In conclusion, the 3 ms/mmHg cut-off identifies two large clusters of homogeneous heart failure (HF) patients, thus supporting the hypothesis of a natural cut-off in the HF population. Furthermore, age was found to have no statistical impact on risk assessment, suggesting that there is no need to establish age-based cut-offs because 3 ms/mmHg optimally identifies patients at high mortality risk.


Project hindsight. A Defense Department study of the utility of research.
Recently developed weapon systems were compared with systems of similar function in use 10 to 20 years earlier. The most significant finding was that the improvement in performance or reduction in cost is largely the synergistic effect of a large number of scientific and technological innovations, of which only about 10 percent had been made at the time the earlier system was designed. The common scientific and technological base of the systems was not analyzed. Of the innovations, or Events, 9 percent were classified as science and 91 percent as technology. Ninety-five percent of all Events were funded by the defense sector. Nearly 95 percent were motivated by a recognized defense need. Only 0.3 percent came from undirected science. The results of the study do not call in question the value of undirected science on the 50-year-or-more time scale. In light of our finding that 5 to 10 years are often required before even a piece of highly applied research is "fitted in" as an effective contributing member of a large assembly of other Events, it is not surprising that "fragments" of undirected science are infrequently utilized on even a 20-year time scale. The most obvious way in which undirected science appears to enter into technology and utilization on a substantial scale seems to be in the compressed, highly organized form of a well-established, clearly expressed general theory, or in the evaluated, ordered knowledge of handbooks, textbooks, and university courses.


The human gut chip "HuGChip", an explorative phylogenetic microarray for determining gut microbiome diversity at family level.
Evaluating the composition of the human gut microbiota greatly facilitates studies on its role in human pathophysiology, and is heavily reliant on culture-independent molecular methods. A microarray designated the Human Gut Chip (HuGChip) was developed to analyze and compare human gut microbiota samples. The PhylArray software was used to design specific and sensitive probes. The DNA chip was composed of 4,441 probes (2,442 specific and 1,919 explorative probes) targeting 66 bacterial families. A mock community composed of 16S rRNA gene sequences from intestinal species was used to define the threshold criteria to be used to analyze complex samples. This was then experimentally verified with three human faecal samples and results were compared (i) with pyrosequencing of the V4 hypervariable region of the 16S rRNA gene, (ii) metagenomic data, and (iii) qPCR analysis of three phyla. When compared at both the phylum and the family level, high Pearson's correlation coefficients were obtained between data from all methods. The HuGChip development and validation showed that it is not only able to assess the known human gut microbiota but could also detect unknown species with the explorative probes to reveal the large number of bacterial sequences not yet described in the human gut microbiota, overcoming the main inconvenience encountered when developing microarrays.


Methylation status of CpG-rich islands on active and inactive mouse X chromosomes.
Single copy probes derived from CpG-rich island clones from Eag I and Not I linking libraries and nine rare-cutter restriction endonucleases were used to investigate the methylation status of CpG-rich islands on the inactive and active X chromosomes (Chr) of the mouse. Thirteen of the 14 probes used detected CpG-rich islands in genomic DNA. The majority of island CpGs detected by rare-cutter restriction endonucleases were methylated on the inactive X Chr and unmethylated on the active X Chr, but some heterogeneity within the cell population used to make genomic DNA was detected. The CpG-rich islands detected by two putative pseudoautosomal probes remained unmethylated on both the active and inactive X Chrs. Otherwise, distance from the X Chr inactivation center did not affect the methylation profile of CpG-rich islands. We conclude that methylation of CpG-rich islands is a general feature of X Chr inactivation.


Covalent Atomic Bridges Enable Unidirectional Enhancement of Electronic Transport in Aligned Carbon Nanotubes.
Interconnecting the surfaces of nanomaterials without compromising their outstanding mechanical, thermal, and electronic properties is critical in the design of advanced bulk structures that still preserve the novel properties of their nanoscale constituents. As such, bridging the π-conjugated carbon surfaces of single-walled carbon nanotubes (SWNTs) has special implications in next-generation electronics. This study presents a rational path toward the improvement of the electrical transport in aligned semiconducting SWNT films by deposition of metal atoms. The formation of conducting Cr-mediated pathways between the parallel SWNTs increases the transverse (intertube) conductance while having a negligible effect on the parallel (intratube) transport. In contrast, doping with Li has a predominant effect on the intratube electrical transport of aligned SWNT films. Large-scale first-principles calculations of electrical transport on aligned SWNTs show good agreement with the experimental electrical measurements and provide insight into the changes that different metal atoms exert on the density of states near the Fermi level of the SWNTs and the formation of transport channels.


The vesicular transfer of CLIC1 from glioblastoma to microvascular endothelial cells requires TRPM7.
Chloride intracellular channel 1 (CLIC1) is highly expressed and secreted by human glioblastoma cells and cell lines such as U87, initiating cell migration and tumor growth. Here, we examined whether CLIC1 could be transferred to human primary microvascular endothelial cells (HMEC). We previously reported that the oncogenic microRNA, miR-5096, increased the release of extracellular vesicles (EVs) by which it increased its own transfer from U87 to surrounding cells. Thus, we also examined its effect on the CLIC1 transfer. In homotypic cultures, miR-5096 did not increase the expression of CLIC1 in U87 nor in HMEC. However, the endothelial CLIC1 level increased after exposure to EVs released by U87, and even more by miR-5096-loaded U87. The EVs-transferred CLIC1 was active in HMEC, promoting endothelial sprouting in matrigel. Cell exposure to EVs induced cytosolic Ca2+ spikes which were dependent on the transient receptor potential melastatin member 7 (TRPM7). TRPM7 silencing prevented Ca2+ spikes and the subsequent CLIC1 delivery into HMEC. Our data suggest that the vesicular transfer of CLIC1 between cells requires TRMP7 expression in recipient endothelial cells. How the vesicular transfer of CLIC1 is modulated in cancer therapy is a future challenge.


Metallic Nanodot Patterns with Unique Symmetries Templated from ABC Triblock Terpolymer Networks.
Nanotemplates derived from the self-assembly of AB-type block copolymers provide an elegant route to achieve well-defined metallic dot arrays, even if the variety of pattern symmetries is restricted due to the limited number of structures offered by microphase separated diblock copolymers. A strategy that relies on the use of complex network structures accessible through the self-assembly of linear ABC-type terpolymers is presented for the formation of metallic nanodots arrays with "outside-the-box" symmetries. Patterned templates formed by the cubic Q214 and orthorhombic O70 network structures are used as excellent platforms to build well-ordered gold nanodot arrays with unique p3m1 and p2 symmetries, respectively. A simple yet efficient blending strategy is used to tune the critical dimensions of the p3m1 pattern while laterally ordered gold nanodot arrays are also demonstrated through a directed self-assembly approach. Such highly ordered gold nanodots with tunable particle dimensions and array periods, enabling the control of their plasmonic responses, are attractive probes for biological imaging.


Preclinical Bioavailability, Tissue Distribution, and Protein Binding Studies of Erinacine A, a Bioactive Compound from Hericium erinaceus Mycelia Using Validated LC-MS/MS Method.
Erinacine A, derived from the mycelia of Hericium erinaceus, has attracted much attention due to its neuroprotective properties. However, very few studies have been conducted on the bioavailability, tissue distribution, and protein binding of erinacine A. This study aimed to investigate the bioavailability, tissue distribution, and protein binding of erinacine A in Sprague-Dawley rats. After oral administration (po) and intravenous administration (iv) of 2.381 g/kg BW of the H. erinaceus mycelia extract (equivalent to 50 mg/kg BW of erinacine A) and 5 mg/kg BW of erinacine A, respectively, the absolute bioavailability of erinacine A was estimated as 24.39%. Erinacine A was detected in brain at 1 h after oral dosing and reached the peak at 8 h. Protein binding assay showed unbound erinacine A fractions in brain to blood ratio is close to unity, supporting passive diffusion as the dominating transport. Feces was the major route for the elimination of erinacine A. This study is the first to show that erinacine A can penetrate the blood-brain barrier of rats by the means of passive diffusion and thus support the development of H. erinaceus mycelia for the improvement of neurohealth.


Circulating Exosomal miRNA Profile During Term and Preterm Birth Pregnancies: A Longitudinal Study.
Despite decades of research in the field of human reproduction, the mechanisms responsible for human parturition still remain elusive. The objective of this study was to describe the changes in the exosomal miRNA concentrations circulating in the maternal plasma between mothers delivering term and preterm neonates, across gestation using a longitudinal study design. This descriptive study identifies the miRNA content in exosomes present in maternal plasma of term and preterm birth (PTB) (n = 20 and n = 10 per each gestational period, respectively) across gestation (i.e., first, second, and third trimesters and at the time of delivery). Changes in exosomal miRNA signature in maternal plasma during term and preterm gestation were determined using the NextSeq 500 high-output 75 cycles sequencing platform. A total of 167 and 153 miRNAs were found to significantly change (P < 0.05) as a function of the gestational age across term and PTB pregnancies, respectively. Interestingly, a comparison analysis between the exosomal miRNA profile between term and PTB reveals a total of 173 miRNAs that significantly change (P < 0.05) across gestation. Specific trends of changes (i.e., increase, decrease, and both) as a function of the gestational age were also identified. The bioinformatics analyses establish that the differences in the miRNA profile are targeting signaling pathways associated with TGF-β signaling, p53, and glucocorticoid receptor signaling, respectively. These data suggest that the miRNA content of circulating exosomes in maternal blood might represent a biomolecular "fingerprint" of the progression of pregnancy.


Hygroscopic Properties and Respiratory System Deposition Behavior of Particulate Matter Emitted By Mining and Smelting Operations.
This study examines size-resolved physicochemical data for particles sampled near mining and smelting operations and a background urban site in Arizona with a focus on how hygroscopic growth impacts particle deposition behavior. Particles with aerodynamic diameters between 0.056-18 μm were collected at three sites: (i) an active smelter operation in Hayden, AZ, (ii) a legacy mining site with extensive mine tailings in Iron King, AZ, and (iii) an urban site, inner-city Tucson, AZ. Mass size distributions of As and Pb exhibit bimodal profiles with a dominant peak between 0.32 and 0.56 μm and a smaller mode in the coarse range (>3 μm). The hygroscopicity profile did not exhibit the same peaks owing to dependence on other chemical constituents. Submicrometer particles were generally more hygroscopic than supermicrometer ones at all three sites with finite water-uptake ability at all sites and particle sizes examined. Model calculations at a relative humidity of 99.5% reveal significant respiratory system particle deposition enhancements at sizes with the largest concentrations of toxic contaminants. Between dry diameters of 0.32 and 0.56 μm, for instance, ICRP and MPPD models predict deposition fraction enhancements of 171%-261% and 33%-63%, respectively, at the three sites.


What cues do ungulates use to assess predation risk in dense temperate forests?
Anti-predator responses by ungulates can be based on habitat features or on the near-imminent threat of predators. In dense forest, cues that ungulates use to assess predation risk likely differ from half-open landscapes, as scent relative to sight is predicted to be more important. We studied, in the Białowieża Primeval Forest (Poland), whether perceived predation risk in red deer (Cervus elaphus) and wild boar (Sus scrofa) is related to habitat visibility or olfactory cues of a predator. We used camera traps in two different set-ups to record undisturbed ungulate behavior and fresh wolf (Canis lupus) scats as olfactory cue. Habitat visibility at fixed locations in deciduous old growth forest affected neither vigilance levels nor visitation rate and cumulative visitation time of both ungulate species. However, red deer showed a more than two-fold increase of vigilance level from 22% of the time present on control plots to 46% on experimental plots containing one wolf scat. Higher vigilance came at the expense of time spent foraging, which decreased from 32% to 12% while exposed to the wolf scat. These behavioral changes were most pronounced during the first week of the experiment but continuous monitoring of the plots suggested that they might last for several weeks. Wild boar did not show behavioral responses indicating higher perceived predation risk. Visitation rate and cumulative visitation time were not affected by the presence of a wolf scat in both ungulate species. The current study showed that perceived predation risk in red deer and wild boar is not related to habitat visibility in a dense forest ecosystem. However, olfactory cues of wolves affected foraging behavior of their preferred prey species red deer. We showed that odor of wolves in an ecologically equivalent dose is sufficient to create fine-scale risk factors for red deer.


Conservation and diversity in the cis-regulatory networks that integrate information controlling expression of Hoxa2 in hindbrain and cranial neural crest cells in vertebrates.
The Hoxa2 and Hoxb2 genes are members of paralogy group II and display segmental patterns of expression in the developing vertebrate hindbrain and cranial neural crest cells. Functional analyses have demonstrated that these genes play critical roles in regulating morphogenetic pathways that direct the regional identity and anteroposterior character of hindbrain rhombomeres and neural crest-derived structures. Transgenic regulatory studies have also begun to characterize enhancers and cis-elements for those mouse and chicken genes that direct restricted patterns of expression in the hindbrain and neural crest. In light of the conserved role of Hoxa2 in neural crest patterning in vertebrates and the similarities between paralogs, it is important to understand the extent to which common regulatory networks and elements have been preserved between species and between paralogs. To investigate this problem, we have cloned and sequenced the intergenic region between Hoxa2 and Hoxa3 in the chick HoxA complex and used it for making comparative analyses with the respective human, mouse, and horn shark regions. We have also used transgenic assays in mouse and chick embryos to test the functional activity of Hoxa2 enhancers in heterologous species. Our analysis reveals that three of the critical individual components of the Hoxa2 enhancer region from mouse necessary for hindbrain expression (Krox20, BoxA, and TCT motifs) have been partially conserved. However, their number and organization are highly varied for the same gene in different species and between paralogs within a species. Other essential mouse elements appear to have diverged or are absent in chick and shark. We find the mouse r3/r5 enhancer fails to work in chick embryos and the chick enhancer works poorly in mice. This implies that new motifs have been recruited or utilized to mediate restricted activity of the enhancer in other species. With respect to neural crest regulation, cis-components are embedded among the hindbrain control elements and are highly diverged between species. Hence, there has been no widespread conservation of sequence identity over the entire enhancer domain from shark to humans, despite the common function of these genes in head patterning. This provides insight into how apparently equivalent regulatory regions from the same gene in different species have evolved different components to potentiate their activity in combination with a selection of core components.


Taste and odorant receptors of the coelacanth--a gene repertoire in transition.
G-protein coupled chemosensory receptors (GPCR-CRs) aid in the perception of odors and tastes in vertebrates. So far, six GPCR-CR families have been identified that are conserved in most vertebrate species. Phylogenetic analyses indicate differing evolutionary dynamics between teleost fish and tetrapods. The coelacanth Latimeria chalumnae belongs to the lobe-finned fishes, which represent a phylogenetic link between these two groups. We searched the genome of L. chalumnae for GPCR-CRs and found that coelacanth taste receptors are more similar to those in tetrapods than in teleost fish: two coelacanth T1R2s co-segregate with the tetrapod T1R2s that recognize sweet substances, and our phylogenetic analyses indicate that the teleost T1R2s are closer related to T1R1s (umami taste receptors) than to tetrapod T1R2s. Furthermore, coelacanths are the first fish with a large repertoire of bitter taste receptors (58 T2Rs). Considering current knowledge on feeding habits of coelacanths the question arises if perception of bitter taste is the only function of these receptors. Similar to teleost fish, coelacanths have a variety of olfactory receptors (ORs) necessary for perception of water-soluble substances. However, they also have seven genes in the two tetrapod OR subfamilies predicted to recognize airborne molecules. The two coelacanth vomeronasal receptor families are larger than those in teleost fish, and similar to tetrapods and form V1R and V2R monophyletic clades. This may point to an advanced development of the vomeronasal organ as reported for lungfish. Our results show that the intermediate position of Latimeria in the phylogeny is reflected in its GPCR-CR repertoire.


Rapid Diagnosis of Imprinting Disorders Involving Copy Number Variation and Uniparental Disomy Using Genome-Wide SNP Microarrays.
Imprinting disorders, such as Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS) and Angelman syndrome (AS), can be detected via methylation analysis, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), or other methods. In this study, we applied single nucleotide polymorphism (SNP)-based chromosomal microarray analysis to detect copy number variations (CNVs) and uniparental disomy (UPD) events in patients with suspected imprinting disorders. Of 4 patients, 2 had a 5.25-Mb microdeletion in the 15q11.2q13.2 region, 1 had a 38.4-Mb mosaic UPD in the 11p15.4 region, and 1 had a 60-Mb detectable UPD between regions 14q13.2 and 14q32.13. Although the 14q32.2 region was classified as normal by SNP array for the 14q13 UPD patient, it turned out to be a heterodisomic UPD by short tandem repeat marker analysis. MS-MLPA analysis was performed to validate the variations. In conclusion, SNP-based microarray is an efficient alternative method for quickly and precisely diagnosing PWS, AS, BWS, and other imprinted gene-associated disorders when considering aberrations due to CNVs and most types of UPD.


Predicting the behavioral impact of transcranial direct current stimulation: issues and limitations.
The transcranial application of weak currents to the human brain has enjoyed a decade of widespread use, providing a simple and powerful tool for non-invasively altering human brain function. However, our understanding of current delivery and its impact upon neural circuitry leaves much to be desired. We argue that the credibility of conclusions drawn with transcranial direct current stimulation (tDCS) is contingent upon realistic explanations of how tDCS works, and that our present understanding of tDCS limits the technique's use to localize function in the human brain. We outline two central issues where progress is required: the localization of currents, and predicting their functional consequence. We encourage experimenters to eschew simplistic explanations of mechanisms of transcranial current stimulation. We suggest the use of individualized current modeling, together with computational neurostimulation to inform mechanistic frameworks in which to interpret the physiological impact of tDCS. We hope that through mechanistically richer descriptions of current flow and action, insight into the biological processes by which transcranial currents influence behavior can be gained, leading to more effective stimulation protocols and empowering conclusions drawn with tDCS.


Cell-nonautonomous effects of dFOXO/DAF-16 in aging.
Drosophila melanogaster and Caenorhabditis elegans each carry a single representative of the Forkhead box O (FoxO) family of transcription factors, dFOXO and DAF-16, respectively. Both are required for lifespan extension by reduced insulin/Igf signaling, and their activation in key tissues can extend lifespan. Aging of these tissues may limit lifespan. Alternatively, FoxOs may promote longevity cell nonautonomously by signaling to themselves (FoxO to FoxO) or other factors (FoxO to other) in distal tissues. Here, we show that activation of dFOXO and DAF-16 in the gut/fat body does not require dfoxo/daf-16 elsewhere to extend lifespan. Rather, in Drosophila, activation of dFOXO in the gut/fat body or in neuroendocrine cells acts on other organs to promote healthy aging by signaling to other, as-yet-unidentified factors. Whereas FoxO-to-FoxO signaling appears to be required for metabolic homeostasis, our results pinpoint FoxO-to-other signaling as an important mechanism through which localized FoxO activity ameliorates aging.


The impact of shared decision making with patient decision aids on the rotavirus vaccination rate in children: A randomized controlled trial.
Rotavirus vaccination reduces the incidence and severity of acute gastroenteritis due to rotavirus infection. However, because of a lack of understanding and private payment for the rotavirus vaccine, the rotavirus vaccination rate is still low in some countries. We intended to assess the impact of shared decision-making (SDM) with the assistance of patient decision aids (PDAs) on the rotavirus vaccination rate, and the knowledge, confidence, and congruence of value among baby's parents when decision-making. The study was a two-group, outcome assessor-blind, randomized, controlled trial. The families of 1-month-old infants for routine vaccination were enrolled; they were divided randomly into non-SDM and SDM groups. The influence of SDM on the acceptance of rotavirus vaccination was assessed when their infants were 2 months old. Outcome measures were decisional conflict, decision-making difficulties, and rotavirus vaccine knowledge, and the overall rotavirus vaccination rate. The study enrolled 180 participants. SDM, parents' education level, and rotavirus vaccination of a previous child were variables that influenced acceptance of rotavirus vaccination. The SDM group scored significantly higher for understanding the information on the oral rotavirus vaccine than the non-SDM group, which helped them to decide whether to vaccinate the baby against rotavirus. The rotavirus vaccination rate was 16.7% higher in the SDM group than the non-SDM group. SDM assisted with PDAs gives more information and helps infants' families understand what they need, reduces their decision conflict, and increases their baby's vaccination against rotavirus, which promotes public health. The clinical trial is registered at ClinicalTrials.gov (NCT03804489).


Ginger for prevention or treatment of drug-induced nausea and vomiting.
In this review, potential benefits of oral ginger for prevention or management of drug- induced nausea and vomiting were evaluated based on the available evidences. By searching medical resources including Scopus, PubMed, Medline, Cochrane central register of controlled trials and Cochrane database systematic reviews, available evidences were collected. Ginger, zingiber, nausea and vomiting were considered as keywords. Various studies have evaluated effects of ginger in prevention and management of nausea and vomiting in different conditions such as pregnancy, chemotherapy, and post-operation. Evidences regarding anti-emetic effect of ginger in prevention and treatment of chemotherapy induced nausea and vomiting are limited and results are conflicting. More randomized clinical trials should be conducted to confirm efficacy of ginger in this regards. Ginger showed promising and attractive effects in preventing post-operative nausea and vomiting at least as add-on therapy. The exact role of ginger as anti-emetic in prevention of post- operative nausea and vomiting can be elucidated by future randomized clinical trials.


Molecular-level understanding of protein adsorption at the interface between water and a strongly interacting uncharged solid surface.
Although protein adsorption on solids is of immense relevance, experimental limitations mean there is still a remarkable lack of understanding of the adsorption mechanism, particularly at a molecular level. By subjecting 240+ molecular dynamics simulations of two peptide/water/solid surface systems to statistical analysis, a generalized molecular level mechanism for peptide adsorption has been identified for uncharged surfaces that interact strongly with the solution phase. This mechanism is composed of three phases: (1) biased diffusion of the peptide from the bulk phase toward the surface; (2) anchoring of the peptide to the water/solid interface via interaction of a hydrophilic group with the water adjacent to the surface or a strongly interacting hydrophobic group with the surface; and (3) lockdown of the peptide on the surface via a slow, stepwise and largely sequential adsorption of its residues, which we term 'statistical zippering'. The adsorption mechanism is dictated by the existence of water layers adjacent to the solid and orientational ordering therein. By extending the solid into the solution by ~8 Å and endowing it with a charged character, the water layers ensure the peptide feels the effect of the solid at a range well beyond the dispersion force that arises from it, thus inducing biased diffusion from afar. The charging of the interface also facilitates anchoring of the peptide near the surface via one of its hydrophilic groups, allowing it time it would otherwise not have to rearrange and lockdown. Finally, the slowness of the lockdown process is dictated by the need for the peptide groups to replace adjacent tightly bound interfacial water.


Scale Trotter: Illustrative Visual Travels Across Negative Scales.
We present ScaleTrotter, a conceptual framework for an interactive, multi-scale visualization of biological mesoscale data and, specifically, genome data. ScaleTrotter allows viewers to smoothly transition from the nucleus of a cell to the atomistic composition of the DNA, while bridging several orders of magnitude in scale. The challenges in creating an interactive visualization of genome data are fundamentally different in several ways from those in other domains like astronomy that require a multi-scale representation as well. First, genome data has intertwined scale levels-the DNA is an extremely long, connected molecule that manifests itself at all scale levels. Second, elements of the DNA do not disappear as one zooms out-instead the scale levels at which they are observed group these elements differently. Third, we have detailed information and thus geometry for the entire dataset and for all scale levels, posing a challenge for interactive visual exploration. Finally, the conceptual scale levels for genome data are close in scale space, requiring us to find ways to visually embed a smaller scale into a coarser one. We address these challenges by creating a new multi-scale visualization concept. We use a scale-dependent camera model that controls the visual embedding of the scales into their respective parents, the rendering of a subset of the scale hierarchy, and the location, size, and scope of the view. In traversing the scales, ScaleTrotter is roaming between 2D and 3D visual representations that are depicted in integrated visuals. We discuss, specifically, how this form of multi-scale visualization follows from the specific characteristics of the genome data and describe its implementation. Finally, we discuss the implications of our work to the general illustrative depiction of multi-scale data.


Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis.
The human kidney contains up to 2 million epithelial nephrons responsible for blood filtration. Regenerating the kidney requires the induction of the more than 20 distinct cell types required for excretion and the regulation of pH, and electrolyte and fluid balance. We have previously described the simultaneous induction of progenitors for both collecting duct and nephrons via the directed differentiation of human pluripotent stem cells. Paradoxically, although both are of intermediate mesoderm in origin, collecting duct and nephrons have distinct temporospatial origins. Here we identify the developmental mechanism regulating the preferential induction of collecting duct versus kidney mesenchyme progenitors. Using this knowledge, we have generated kidney organoids that contain nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells. Within these organoids, individual nephrons segment into distal and proximal tubules, early loops of Henle, and glomeruli containing podocytes elaborating foot processes and undergoing vascularization. When transcription profiles of kidney organoids were compared to human fetal tissues, they showed highest congruence with first trimester human kidney. Furthermore, the proximal tubules endocytose dextran and differentially apoptose in response to cisplatin, a nephrotoxicant. Such kidney organoids represent powerful models of the human organ for future applications, including nephrotoxicity screening, disease modelling and as a source of cells for therapy.


Density of insect-pollinated grassland plants decreases with increasing surrounding land-use intensity.
Pollinator declines have raised concerns about the persistence of plant species that depend on insect pollination, in particular by bees, for their reproduction. The impact of pollinator declines remains unknown for species-rich plant communities found in temperate seminatural grasslands. We investigated effects of land-use intensity in the surrounding landscape on the distribution of plant traits related to insect pollination in 239 European seminatural grasslands. Increasing arable land use in the surrounding landscape consistently reduced the density of plants depending on bee and insect pollination. Similarly, the relative abundance of bee-pollination-dependent plants increased with higher proportions of non-arable agricultural land (e.g. permanent grassland). This was paralleled by an overall increase in bee abundance and diversity. By isolating the impact of the surrounding landscape from effects of local habitat quality, we show for the first time that grassland plants dependent on insect pollination are particularly susceptible to increasing land-use intensity in the landscape.


Electrotonic influences on action potential duration dispersion in small hearts: a simulation study.
Intrinsic spatial variations in repolarization currents in the heart can produce spatial gradients in action potential duration (APD) that serve as possible sites for conduction block and the initiation of reentrant activity. In well-coupled myocardium, however, electrotonic influences at the stimulus site and wavefront collision sites act to modulate any intrinsic heterogeneity in APD. These effects alter APD gradients over an extent larger than that suggested by the length constant associated with propagation and, thus, are hypothesized to play a greater role in smaller hearts used as experimental models of human disease. This study uses computer simulation to investigate how heart size, tissue properties, and the spatial assignment of cell types affect functional APD dispersion. Simulations were carried out using the murine ventricular myocyte model of Pandit et al. or the Luo-Rudy mammalian model in three-dimensional models of mouse and rabbit ventricular geometries. Results show that the spatial extent of the APD dispersion is related to the dynamic changes in transmembrane resistance during recovery. Also, because of the small dimensions of the mouse heart, electrotonic effects on APD primarily determine the functional dispersion of refractoriness, even in the presence of large intrinsic cellular heterogeneity and reduced coupling. APD dispersion, however, is found to increase significantly when the heart size increases to the size of a rabbit heart, unmasking intrinsic cell types.


A comparison of two methods of heart rate variability assessment at high altitude.
Heart rate variability (HRV) is a useful index of autonomic function and has been linked to the development of high altitude (HA) related illness. However, its assessment at HA has been undermined by the relative expense and limited portability of traditional HRV devices which have mandated at least a minute heart rate recording. In this study, the portable ithlete™ HRV system, which uses a 55 s recording, was compared with a reference method of HRV which utilizes a 5 min electrocardiograph recording (CheckMyHeart™ ). The root mean squares of successive R-R intervals (RMSSD) for each device was converted to a validated HRV score (lnRMSSD × 20) for comparison. Twelve healthy volunteers were assessed for HRV using the two devices across seven time points at HA over 10 days. There was no significant change in the HRV values with either the ithlete (P = 0·3) or the CheckMyHeart™ (P = 0·19) device over the seven altitudes. There was also a strong overall correlation between the ithlete™ and CheckMyHeart™ device (r = 0·86; 95% confidence interval: 0·79-0·91). The HRV was consistently, though non-significantly higher with ithlete™ than with the CheckMyHeart™ device [mean difference (bias) 1·8 l; 95% CI -12·3 to 8·5]. In summary, the ithlete™ and CheckMyHeart™ system provide relatively similar results with good overall agreement at HA.


A qualitative systematic review of patients' experiences of acupuncture.
To present the results of a systematic review of studies on acupuncture patients' health beliefs and treatment experiences. The search was conducted using CINAHL, PubMed, Ovid MEDLINE, ISI Web of Science, and PsychINFO for qualitative and mixed-methods studies expressing the voice of acupuncture patients. Reference lists of relevant articles were also searched. The review was restricted to studies published in English. Study selection, quality appraisal, and data extraction were performed sequentially. Quality was appraised using the Joanna Briggs Institute Qualitative Assessment and Review Instrument, and the Dedoose mixed methods tool was used in data management and analysis. Four overarching themes were identified: reasons for using acupuncture, treatment experiences, treatment outcomes, and therapeutic model. Patients' reasons for using acupuncture are diverse and include dissatisfaction with conventional medicine and attraction to holistic and empowering models of healthcare. Treatment is thought to relieve symptoms of the presenting concern and a range of other effects that improve well-being. This review highlights the need to improve understanding of patients' health-seeking behaviors and how individually meaningful treatment outcomes may be understood and assessed, particularly within complementary and alternative medicine.


Improving the oral health of older people: the approach of the WHO Global Oral Health Programme.
The proportion of older people continues to grow worldwide, especially in developing countries. Non-communicable diseases are fast becoming the leading causes of disability and mortality, and in coming decades health and social policy-makers will face tremendous challenges posed by the rapidly changing burden of chronic diseases in old age. Chronic disease and most oral diseases share common risk factors. Globally, poor oral health amongst older people has been particularly evident in high levels of tooth loss, dental caries experience, and the prevalence rates of periodontal disease, xerostomia and oral precancer/cancer. The negative impact of poor oral conditions on the quality of life of older adults is an important public health issue, which must be addressed by policy-makers. The means for strengthening oral health programme implementation are available; the major challenge is therefore to translate knowledge into action programmes for the oral health of older people. The World Health Organization recommends that countries adopt certain strategies for improving the oral health of the elderly. National health authorities should develop policies and measurable goals and targets for oral health. National public health programmes should incorporate oral health promotion and disease prevention based on the common risk factors approach. Control of oral disease and illness in older adults should be strengthened through organization of affordable oral health services, which meet their needs. The needs for care are highest among disadvantaged, vulnerable groups in both developed and developing countries. In developing countries the challenges to provision of primary oral health care are particularly high because of a shortage of dental manpower. In developed countries reorientation of oral health services towards prevention should consider oral care needs of older people. Education and continuous training must ensure that oral health care providers have skills in and a profound understanding of the biomedical and psychosocial aspects of care for older people. Research for better oral health should not just focus on the biomedical and clinical aspects of oral health care; public health research needs to be strengthened particularly in developing countries. Operational research and efforts to translate science into practice are to be encouraged. WHO supports national capacity building in the oral health of older people through intercountry and interregional exchange of experiences.


Can intervals enhance the inflammatory response and enjoyment in upper-body exercise?
To investigate the inflammatory and perceptual responses to three different forms of upper-body exercise. Twelve recreationally active, able-bodied males performed three work-matched arm-crank sessions in a randomised order: 30 min moderate-intensity continuous (CON), 30 min moderate-intensity with changes in cadence (CAD) and 20 min high-intensity interval training (HIIT). Blood samples were taken pre, post and 2-h post-exercise to determine plasma concentrations of interleukin (IL)-6 and IL-1ra. Perceptual responses pre, during and following the trials were assessed using the Feeling Scale, Felt Arousal Scale, Ratings of Perceived Exertion (RPE) and the Physical Activity Enjoyment Scale (PACES). All trials were evenly effective in inducing an acute inflammatory response, indicated by similar increases in IL-6 after exercise and in IL-1ra at 2-h post exercise for all trials. More negative affect and higher RPE were reported during HIIT compared to CON and CAD, whereas PACES scores reported after exercise were higher for HIIT and CAD compared to CON. When matched for external work, there was no difference in the inflammatory response to HIIT compared to moderate-intensity upper-body exercise. Although HIIT was (perceived as) more strenuous and affective responses were more negative during this mode, the higher ratings of enjoyment for both HIIT and CAD reported after exercise suggest that the inclusion of variation enhances enjoyment in upper-body exercise. As the fashion in which upper-body exercise is performed does not seem to influence the inflammatory response, it might be advised to prescribe varied exercise to enhance its enjoyment.


A prospective, randomized comparison of a 1940 nm and a 2013 nm thulium: yttrium-aluminum-garnet laser device for Thulium VapoEnucleation of the prostate (ThuVEP): First results.
We report the early postoperative results of the first prospective, randomized comparison of two commercially available thulium lasers with different wavelengths for the treatment of benign prostatic obstruction (BPO). From January to June 2013, 80 consecutive patients were randomized for Thulium VapoEnucleation of the prostate (ThuVEP) with a 2013 nm (RevoLix(®)) (n = 39) or a 1940 nm (Vela(®)XL) (n = 41) thulium laser. Preoperative status, surgical details and the immediate outcome were recorded for each patient. The perioperative complications were assessed and classified according to the modified Clavien classification system. Median operation time, resected tissue, percentage of resected tissue, catheter time, overall operation efficiency and Hb loss differed nonsignificantly between both devices (P > 0.05). At discharge, the median maximum urinary flow rate and postvoiding residual (PVR) urine improved significantly in both groups (P < 0.001). The PVR was lower in the 1940 nm ThuVEP group (P ≤ 0.034). Perioperative complications occurred in 18 (22.5%) patients (Clavien 1: 12.5%; Clavien 2: 5%, Clavien 3b: 2.5%, Clavien 4a: 2.5%), with no differences between the groups (P = 0.5). The 1940 nm and the 2013 nm thulium lasers are both safe and effective for the treatment of BPO with ThuVEP. Both lasers give equivalent and satisfactory immediate micturition improvement with low perioperative morbidity.


Acupuncture versus pharmacological approach to reduce Hyperemesis gravidarum discomfort.
Several reports have suggested the use of acupuncture as a useful treatment for hyperemesis gravidarum (HG), in particular the effects on nausea intensity was underlined. The aim of this study was to compare the efficacy of acupuncture sessions plus acupressure with a metoclopramide/vitamin B12 treatment. In this study we randomized 88 pregnant patients suffering from HG to receive either acupuncture sessions plus acupressure (acupuncture group) or metoclopramide infusion (metoclopramide group) supplemented by vitamin B12 complex. Somatic symptoms and the ability to achieve the daily routine activity (functioning) were evaluated. Acupuncture sessions were performed at the hospital twice a week for 2 weeks according to the traditional Chinese medicine criteria. Acupression was applied for 6-8 h/day. In the metoclopramide group, patients received at hospital metoclopramide infusion (20 mg/500 mL saline for 60 min) twice a week for 2 weeks. An oral supplementation with vitamin B12 complex (30 mg/day) was also prescribed. Both treatments reduced vomiting episodes and then nausea intensity with a consequent improvement in the rate of food intake. The effect of acupuncture seems to be progressive, increasing at the end of treatment whereas pharmacological approach has a prompt effect in responders remaining stable thereafter. Moreover, acupuncture was significantly more effective than drugs in improving functioning. In our study for the first time acupuncture, applied accordingly to Chinese formula, was compared to drugs demonstrating the same effect of both treatments on HG symptoms. Interestingly, functioning was significantly improved just by acupuncture. Even if the effect of acupuncture on HG discomfort remains to be confirmed, the reports on the effect of acupuncture on psychosocial variables could represent a further advantage of acupuncture application and provide an incentive to widen the base of the research.


The reminding effect: presentation of associates enhances memory for related words in a list.
One aspect of successful cognition is the efficient use of prior relevant knowledge in novel situations. Remindings-stimulus-guided retrievals of prior events-allow us to link prior knowledge to current problems by prompting us to retrieve relevant knowledge from events that are distant from the present. Theorizing in research on higher cognition makes much use of the concept of remindings, yet many basic mnemonic consequences of remindings are untested. Here we consider implications of reminding-based theories of the effects of repetition on memory (Benjamin & Tullis, 2010; Hintzman, 2011). Those theories suggest that the spacing of repeated presentations of material benefits memory when the later experience reminds the learner of the earlier one. When applied to memory for related, rather than repeated, material, these theories predict a reminding effect: a mnemonic boost caused by a nearby presentation of a related item. In 7 experiments, we assessed this prediction by having learners study lists of words that contained related word pairs. Recall performance for the first presentation in related pairs was higher than for equivalent items in unrelated pairs, while recognition performance for items in related pairs did not differ from those in unrelated pairs. Remindings benefit only the recollection of the retrieved episodes.