Interventions for preventing obesity in children.
Prevention of childhood obesity is an international public health priority given the significant impact of obesity on acute and chronic diseases, general health, development and well-being. The international evidence base for strategies to prevent obesity is very large and is accumulating rapidly. This is an update of a previous review. To determine the effectiveness of a range of interventions that include diet or physical activity components, or both, designed to prevent obesity in children. We searched CENTRAL, MEDLINE, Embase, PsychINFO and CINAHL in June 2015. We re-ran the search from June 2015 to January 2018 and included a search of trial registers. Randomised controlled trials (RCTs) of diet or physical activity interventions, or combined diet and physical activity interventions, for preventing overweight or obesity in children (0-17 years) that reported outcomes at a minimum of 12 weeks from baseline. Two authors independently extracted data, assessed risk-of-bias and evaluated overall certainty of the evidence using GRADE. We extracted data on adiposity outcomes, sociodemographic characteristics, adverse events, intervention process and costs. We meta-analysed data as guided by the Cochrane Handbook for Systematic Reviews of Interventions and presented separate meta-analyses by age group for child 0 to 5 years, 6 to 12 years, and 13 to 18 years for zBMI and BMI. We included 153 RCTs, mostly from the USA or Europe. Thirteen studies were based in upper-middle-income countries (UMIC: Brazil, Ecuador, Lebanon, Mexico, Thailand, Turkey, US-Mexico border), and one was based in a lower middle-income country (LMIC: Egypt). The majority (85) targeted children aged 6 to 12 years.Children aged 0-5 years: There is moderate-certainty evidence from 16 RCTs (n = 6261) that diet combined with physical activity interventions, compared with control, reduced BMI (mean difference (MD) -0.07 kg/m2, 95% confidence interval (CI) -0.14 to -0.01), and had a similar effect (11 RCTs, n = 5536) on zBMI (MD -0.11, 95% CI -0.21 to 0.01). Neither diet (moderate-certainty evidence) nor physical activity interventions alone (high-certainty evidence) compared with control reduced BMI (physical activity alone: MD -0.22 kg/m2, 95% CI -0.44 to 0.01) or zBMI (diet alone: MD -0.14, 95% CI -0.32 to 0.04; physical activity alone: MD 0.01, 95% CI -0.10 to 0.13) in children aged 0-5 years.Children aged 6 to 12 years: There is moderate-certainty evidence from 14 RCTs (n = 16,410) that physical activity interventions, compared with control, reduced BMI (MD -0.10 kg/m2, 95% CI -0.14 to -0.05). However, there is moderate-certainty evidence that they had little or no effect on zBMI (MD -0.02, 95% CI -0.06 to 0.02). There is low-certainty evidence from 20 RCTs (n = 24,043) that diet combined with physical activity interventions, compared with control, reduced zBMI (MD -0.05 kg/m2, 95% CI -0.10 to -0.01). There is high-certainty evidence that diet interventions, compared with control, had little impact on zBMI (MD -0.03, 95% CI -0.06 to 0.01) or BMI (-0.02 kg/m2, 95% CI -0.11 to 0.06).Children aged 13 to 18 years: There is very low-certainty evidence that physical activity interventions, compared with control reduced BMI (MD -1.53 kg/m2, 95% CI -2.67 to -0.39; 4 RCTs; n = 720); and low-certainty evidence for a reduction in zBMI (MD -0.2, 95% CI -0.3 to -0.1; 1 RCT; n = 100). There is low-certainty evidence from eight RCTs (n = 16,583) that diet combined with physical activity interventions, compared with control, had no effect on BMI (MD -0.02 kg/m2, 95% CI -0.10 to 0.05); or zBMI (MD 0.01, 95% CI -0.05 to 0.07; 6 RCTs; n = 16,543). Evidence from two RCTs (low-certainty evidence; n = 294) found no effect of diet interventions on BMI.Direct comparisons of interventions: Two RCTs reported data directly comparing diet with either physical activity or diet combined with physical activity interventions for children aged 6 to 12 years and reported no differences.Heterogeneity was apparent in the results from all three age groups, which could not be entirely explained by setting or duration of the interventions. Where reported, interventions did not appear to result in adverse effects (16 RCTs) or increase health inequalities (gender: 30 RCTs; socioeconomic status: 18 RCTs), although relatively few studies examined these factors.Re-running the searches in January 2018 identified 315 records with potential relevance to this review, which will be synthesised in the next update. Interventions that include diet combined with physical activity interventions can reduce the risk of obesity (zBMI and BMI) in young children aged 0 to 5 years. There is weaker evidence from a single study that dietary interventions may be beneficial.However, interventions that focus only on physical activity do not appear to be effective in children of this age. In contrast, interventions that only focus on physical activity can reduce the risk of obesity (BMI) in children aged 6 to 12 years, and adolescents aged 13 to 18 years. In these age groups, there is no evidence that interventions that only focus on diet are effective, and some evidence that diet combined with physical activity interventions may be effective. Importantly, this updated review also suggests that interventions to prevent childhood obesity do not appear to result in adverse effects or health inequalities.The review will not be updated in its current form. To manage the growth in RCTs of child obesity prevention interventions, in future, this review will be split into three separate reviews based on child age.


Purification, crystallization and preliminary X-ray crystallographic analysis of the ETS domain of human Ergp55 in complex with the cfos promoter DNA sequence.
The Ergp55 protein belongs to the Ets family of transciption factors. The Ets transcription factors are involved in various developmental processes and the regulation of cancer metabolism. They contain a highly similar DNA-binding domain known as the ETS domain and have diverse functions in oncogenesis and physiology. The Ets transcription factors differ in their DNA-binding preference at the ETS site and the mechanisms by which they target genes are not clearly understood. To understand its DNA-binding mechanism, the ETS domain of Ergp55 was expressed and purified. The ETS domain was crystallized in the native form and in complex forms with DNA sequences from the E74 and cfos promoters. An X-ray diffraction data set was collected from an ETS-cfos DNA complex crystal at a wavelength of 0.9725 Å on the BM14 synchrotron beamline at the ESRF, France. The ETS-cfos DNA complex crystal belonged to space group C222(1), with four molecules in the asymmetric unit. For structure analysis, initial phases for the ETS-cfos DNA complex were obtained by the molecular-replacement technique with Phaser in the CCP4 suite using the coordinates of Fli-1 protein (PDB entry 1fli) and cfos DNA (PDB entry 1bc7) as search models. Structure analysis of the ETS-cfos DNA complex may possibly explain the DNA-binding specificity and its mechanism of interaction with the ETS domain of Ergp55.


Role of excess inorganic pyrophosphate in primer-extension genotyping assays.
We have developed and genotyped >15,000 SNP assays by using a primer extension genotyping assay with fluorescence polarization (FP) detection. Although the 80% success rate of this assay is similar to those of other SNP genotyping assays, we wanted to determine the reasons for the failures and find ways to improve the assay. We observed that the failed assays fell into three general patterns: PCR failure, excess of heterozygous genotypes, and loss of FP signal for one of the dye labels. After analyzing several hundred failed assays, we concluded that 5% of the assays had PCR failure and had to be redesigned. We also discovered that the other two categories of failures were due to misincorporation of one of the dye-terminators during the primer extension reaction as a result of primer shortening with a reverse reaction involving inorganic pyrophosphate, and to the quenching of R110-terminator after its incorporation onto the SNP primer. The relatively slow incorporation of R110 acycloterminators by AcycloPol compounds the problem with the R110 label. In this report, we describe the source of the problems and simple ways to correct these problems by adding pyrophosphatase, using quenching as part of the analysis, and replacing R110 by Texas red as one of the dye labels. With this new protocol, we have achieved approximately 95% success rate in assay development without the need for optimization.


Whisper: Tracing the Spatiotemporal Process of Information Diffusion in Real Time.
When and where is an idea dispersed? Social media, like Twitter, has been increasingly used for exchanging information, opinions and emotions about events that are happening across the world. Here we propose a novel visualization design, "Whisper", for tracing the process of information diffusion in social media in real time. Our design highlights three major characteristics of diffusion processes in social media: the temporal trend, social-spatial extent, and community response of a topic of interest. Such social, spatiotemporal processes are conveyed based on a sunflower metaphor whose seeds are often dispersed far away. In Whisper, we summarize the collective responses of communities on a given topic based on how tweets were retweeted by groups of users, through representing the sentiments extracted from the tweets, and tracing the pathways of retweets on a spatial hierarchical layout. We use an efficient flux line-drawing algorithm to trace multiple pathways so the temporal and spatial patterns can be identified even for a bursty event. A focused diffusion series highlights key roles such as opinion leaders in the diffusion process. We demonstrate how our design facilitates the understanding of when and where a piece of information is dispersed and what are the social responses of the crowd, for large-scale events including political campaigns and natural disasters. Initial feedback from domain experts suggests promising use for today's information consumption and dispersion in the wild.


Climate change: could it help develop 'adaptive expertise'?
Preparing health practitioners to respond to the rising burden of disease from climate change is emerging as a priority in health workforce policy and planning. However, this issue is hardly represented in the medical education research. The rapidly evolving wide range of direct and indirect consequences of climate change will require health professionals to have not only broad content knowledge but also flexibility and responsiveness to diverse regional conditions as part of complex health problem-solving and adaptation. It is known that adaptive experts may not necessarily be quick at solving familiar problems, but they do creatively seek to better solve novel problems. This may be the result of an acquired approach to practice or a pathway that can be fostered by learning environments. It is also known that building adaptive expertise in medical education involves putting students on a learning pathway that requires them to have, first, the motivation to innovatively problem-solve and, second, exposure to diverse content material, meaningfully presented. Including curriculum content on the health effects of climate change could help meet these two conditions for some students at least. A working definition and illustrative competencies for adaptive expertise for climate change, as well as examples of teaching and assessment approaches extrapolated from rural curricula, are provided.


Transcription of the hypersensitive site HS2 enhancer in erythroid cells.
In the human genome, the erythroid-specific hypersensitive site HS2 enhancer regulates the transcription of the downstream beta-like globin genes 10-50 kilobases away. The mechanism of HS2 enhancer function is not known. The present study employs RNA protection assays to analyze the transcriptional status of the HS2 enhancer in transfected recombinant chloramphenicol acetyltransferase (CAT) plasmids. In erythroid K562 cells in which the HS2 enhancer is active, the HS2 sequence directs the synthesis of long enhancer transcripts that are initiated apparently from within the enhancer and elongated through the intervening DNA into the cis-linked CAT gene. In nonerythroid HL-60 cells in which the HS2 enhancer is inactive, long enhancer transcripts are not detectable. Splitting the HS2 enhancer between two tandem Ap1 sites abolishes the synthesis of a group of long enhancer transcripts and results in loss of enhancer function and transcriptional silencing of the cis-linked CAT gene. In directing the synthesis of RNA through the intervening DNA and the gene by a tracking and transcription mechanism, the HS2 enhancer may (i) open up the chromatin structure of a gene domain and (ii) deliver enhancer binding proteins to the promoter sequence where they may stimulate the transcription of the gene at the cap site.


SWOG S1400B (NCT02785913), a Phase II Study of GDC-0032 (Taselisib) for Previously Treated PI3K-Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Sub-Study).
S1400B is a biomarker-driven Lung-MAP substudy evaluating the phosphatidylinositol 3-kinase (PI3K) inhibitor taselisib (GDC-0032) in patients with PI3K pathway-activated squamous NSCLC (sqNSCLC). Eligible patients had tumoral phosphatidylinositol-4,5-biphosphate 3 kinase catalytic subunit alpha (PIK3CA) alterations by next-generation sequencing and disease progression after at least one line of platinum-based therapy. Patients received 4-mg taselisib orally daily. The primary analysis population (PAP) was a subset of patients having substitution mutations believed to be associated with clinical benefit of PI3K inhibitors. Primary endpoint was response by Response Evaluation Criteria in Solid Tumors version 1.1; secondary endpoints included progression-free survival, overall survival and duration of response. Twenty-six patients treated with taselisib comprised the full evaluable population (FEP); 21 patients comprised the PAP. Median age for patients in the FEP was 68 years (range: 53-83 years), 19 were male (73%). The study was closed for futility at interim analysis with one responder in the PAP (5% response rate, 95% confidence interval [CI]: 0%-24%). Two possibly treatment-related deaths (one respiratory failure, one cardiac arrest) were observed; one patient had grades 4 and 11 had grade 3 adverse events. Median progression-free survival and overall survival in the PAP group were 2.9 months (95% CI: 1.8-4.0 mo) and 5.9 months (95% CI: 4.2-7.8 mo), respectively. These numbers were nearly the same in the FEP. Study S1400B evaluating taselisib in PIK3CA-altered sqNSCLC failed to meet its primary endpoint and was closed after an interim futility analysis. The trial is unique in cataloguing the diversity of PIK3CA mutations in sqNSCLC.


Physician supply and distribution in Georgia.
Physician supply in Georgia must be considered an urgent issue. Several important points must be recognized and addressed. The lowest physicians rates are in the more rural county population groupings. The only county population grouping with a surplus of physicians is in the over 150,000 population. The majority of physicians are concentrated in the metropolitan counties. Sixteen percent of all physicians practice in the 134 counties having less than 50,000 population. The majority of physicians are in primary care specialties. Family practice is the most dominant specialty in rural areas. By the year 2000, Georgia can expect to add 5,600 physicians due to growth. By the year 2000, Georgia can expect to lose 2,600 physicians due to retirement. Family practitioners are the most uniformly distributed of the specialties examined. They are also the specialty most needed. The average age of Georgia physicians is 46. General surgeons are in the oldest average age group (50), whereas internists are in the youngest (44). Older physicians are concentrated in the more rural areas. A significant number of all physicians are over age 55. The majority of these will be retired by the year 2000. Physicians over age 65 represent 9.2% of all physicians from the survey. In Georgia, 13.6% of all physicians were Foreign Medical School Graduates. They tend to locate their practices in medically underserved areas. The specialty choices most frequently favored by FMGs are: pediatrics, internal medicine, family practice, and obstetrics/gynecology. A total of 71.2% of all physicians accept Medicare patients; 83.8% accept Medicare patients. Ninety-two percent of all obstetricians accept obstetric patients, but this participation is threatened by problems with malpractice insurance.


Effect of galantamine on acetylcholinesterase and butyrylcholinesterase activities in the presence of L-carnitine in rat selected brain and peripheral tissues.
The alkaloid galantamine (GAL), which exhibits a combined anticholinesterase and direct parasympathomimetic mechanism of action, is employed in conjunction with therapeutic interventions in the stimulation of central cholinergic transfer in cognitive diseases. We attempted to achieve pharmacologically-induced enhancement of the parasympathomimetic activity of GAL in the key areas of rat brain, using an interactive combination of the alkaloid with the transmembrane enhancer L-carnitine (CAR). We investigated activities of acetylcholinesterase (AChE) in brain areas (frontal cortex, basal ganglia, septum and hippocampus) and the hypophysis, and that of butyrylcholinesterase (BuChE) in plasma and liver. Following administration of the highest of the GAL doses used (2.5; 5; 10 mg/kg i.m.), AChE activity decreased mainly in the frontal cortex, hippocampus and hypophysis. In the interaction of GAL and CAR, AChE inhibition was stronger but without any statistical significance. The peripheral inhibition of BuChE was found to be dose-dependent. Premedication by CAR led to a slight change in the values of the activities monitored. CAR in terms of positive modulation of GAL targeting to the central nervous system had no statistically significant effect.


Total serum cholesterol levels and mortality risk as a function of age. A report based on the Framingham data.
To evaluate the relationship between serum cholesterol level and all-cause, coronary heart disease (CHD), and non-CHD mortality as a function of age. The data source was the biennial examination data from 1948 through 1980 for the 5209 men and women enrolled in the Framingham Heart Study. Age-specific analyses by the Cox proportional hazards regression model were performed of survival subsequent to ages 40, 50, 60, 70, and 80 years for all subjects enrolled and alive at each of the stated ages. Complementary models were studied that used high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, or total cholesterol level as predictors of survival subsequent to the examination at which lipoprotein subfractions were determined (1968) through 1973). The relationship between total cholesterol level and all-cause mortality was positive (ie, higher cholesterol level associated with higher mortality) at age 40 years, negative at age 80 years, and negligible at ages 50 to 70 years. The relationship with CHD mortality was significantly positive at ages 40, 50, and 60 years but attenuated with age until the relationship was positive, but not significant, at age 70 years and negative, but not significant, at age 80 years. Results for the relationship between low-density lipoprotein cholesterol and high-density lipoprotein cholesterol and mortality help explain these findings. Non-CHD mortality was significantly negatively related to cholesterol level for ages 50 years and above. The negative results in the oldest age group for all-cause and CHD morality appeared to be due to a negative relationship with low-density lipoprotein cholesterol levels rather than the protective effect of high high-density lipoprotein cholesterol levels. Similar results from several modified analyses make low cholesterol level due to severe illness an unlikely explanation for our results. Physicians should be cautious about initiating cholesterol-lowering treatment in men and women above 65 to 70 years of age. Only randomized clinical trials in older people can settle the debate over the efficacy and cost-effectiveness of lipid-lowering interventions for reducing mortality and morbidity in this population.


Challenges for the effective molecular imprinting of proteins.
Molecular imprinting is a technique that is used to create artificial receptors by the formation of a polymer network around a template molecule. This technique has proven to be particularly effective for molecules with low molecular weight (<1500 Da), and during the past five years the number of research articles on the imprinting of larger (bio)templates is increasing considerably. However, expanding the methodology toward imprinted materials for selective recognition of proteins, DNA, viruses and bacteria appears to be extremely challenging. This paper presents a critical analysis of data presented by several authors and our own experiments, showing that the molecular imprinting of proteins still faces some fundamental challenges. The main topics of concern are proper monomer selection, washing method/template removal, quantification of the rebinding and reproducibility. Use of charged monomers can lead to strong electrostatic interactions between monomers and template but also to undesired high aspecific binding. Up till now, it has not been convincingly shown that electrostatic interactions lead to better imprinting results. The combination of a detergent (SDS) and AcOH, commonly used for template removal, can lead to experimental artifacts, and should ideally be avoided. In many cases template rebinding is unreliably quantified, results are not evaluated critically and lack statistical analysis. Therefore, it can be argued that presently, in numerous publications the scientific evidence of molecular imprinting of proteins is not convincing.


Isolation and characterization of extragenic suppressors of mutations in the SSA hsp70 genes of Saccharomyces cerevisiae.
Saccharomyces cerevisiae strains that contain null alleles of two hsp70 genes, SSA1 and SSA2, are temperature sensitive for growth. In this study, extragenic suppressors of ssa1 ssa2 have been isolated. Suppression is due to mutations at nuclear loci designated EXA1, EXA2 and EXA3 for EXtragenic suppressor hsp70 subfamily A. Two of the four EXA1 alleles are dominant as is EXA3-1. The other two EXA1 alleles as well as the sole EXA2 allele are recessive. EXA1 mutations lead to accumulation of a previously uncharacterized form of hsp70. EXA2 and EXA3 mutations affect the regulation of the stress response. In exa2-1 ssa1 ssa2 strains the gene products of the remaining SSA hsp70 genes, SSA3 and SSA4 (Ssa3/4p), accumulate to higher levels. The EXA3-1 mutation results in increased accumulation of both Ssa3/4p and the hsp70s encoded by the SSB1 and SSB2 genes (Ssb1/2p), suggesting that the EXA3 gene product plays a central role in the yeast stress response. Consistent with this hypothesis, EXA3-1 is tightly linked to HSF1, the gene encoding the transcriptional regulatory protein known as "heat shock factor." All of the genes identified in this study seem to be involved in regulating the expression of SSA3 and SSA4 or the activity of their protein products.


Pharmacological characterization of the putative cADP-ribose receptor.
cADP-ribose (cADPR), a naturally occurring metabolite of NAD(+), has been shown to be an important regulator of intracellular Ca(2+) release. Considerable evidence suggests that cADPR is the endogenous modulator of the ryanodine receptor (RyR), which mediates Ca(2+)-induced Ca(2+) release (CICR). Indeed, cADPR-mediated Ca(2+) release is subject to functional regulation by other modulators of CICR, including Ca(2+), caffeine and calmodulin. However, the underlying basis behind the effect of such agents on cADPR activity (in particular whether they regulate cADPR binding), as well as the precise nature of the cADPR receptor remains unclear. In the present study, use of (32)P-radiolabelled cADPR has enabled a detailed pharmacological characterization of cADPR-binding sites in sea urchin egg homogenates. We report that cADPR binds specifically to a single class of high affinity receptor. Retainment of binding to membranes after a high-salt wash suggests the involvement of either an integral membrane protein (possibly the RyR itself) or a peripheral protein tightly associated to the membrane. Insensitivity of [(32)P]cADPR binding to either FK506 or rapamycin suggests that this does not concern the FK506-binding protein. Significantly, binding is highly robust, being relatively insensitive to both endogenous and pharmacological modulators of RyR-mediated CICR. In turn, this suggests that such agents modulate cADPR-mediated Ca(2+) release primarily by tuning the 'gain' of the CICR system, upon which cADPR acts, rather than influencing the interaction of cADPR with its target receptor. The exception to this is calmodulin, for which our results indicate an additional role in facilitating cADPR binding.


Characterization of biomaterials intended for use in the nucleus pulposus of degenerated intervertebral discs.
Biomaterials for regeneration of the intervertebral disc must meet complex requirements conforming to biological, mechanical and clinical demands. Currently no consensus on their characterization exists. It is crucial to identify parameters and their method of characterization for accurate assessment of their potential efficacy, keeping in mind the translation towards clinical application. This review systematically analyses the characterization techniques of biomaterial systems that have been used for nucleus pulposus (NP) restoration and regeneration. Substantial differences in the approach towards assessment became evident, hindering comparisons between different materials with respect to their suitability for NP restoration and regeneration. We have analysed the current approaches and identified parameters necessary for adequate biomaterial characterization, with the clinical goal of functional restoration and biological regeneration of the NP in mind. Further, we provide guidelines and goals for their measurement. STATEMENT OF SIGNIFICANCE: Biomaterials intended for restoration of regeneration of the nucleus pulposus within the intervertebral disc must meet biological, biomechanical and clinical demands. Many materials have been investigated, but a lack of consensus on which parameters to evaluate leads to difficulties in comparing materials as well as mostly partial characterization of the materials in question. A gap between current methodology and clinically relevant and meaningful characterization is prevalent. In this article, we identify necessary methods and their implementation for complete biomaterial characterization in the context of clinical applicability. This will allow for a more unified approach to NP-biomaterials research within the field as a whole and enable comparative analysis of novel materials yet to be developed.


The influence and interactions of hydrostatic and osmotic pressures on the intracellular milieu of chondrocytes.
The intracellular milieu of chondroctyes is regulated by an array of proteins in the cell membrane which operate as transport pathways, allowing ions and nutrients such as glucose and amino acids and metabolites such as lactate to cross the plasma membrane. Here we investigated the influence of hydrostatic pressure on intracellular calcium concentrations ([Ca(2+)](i)) in isolated bovine articular chondrocytes. We found that short applications of high hydrostatic pressures led to a significant increase in [Ca(2+)](i). The pressure-induced rise was abolished for long (240 sec) but not short (30 sec) pressure applications by removal of extracellular Ca(2+). The rise in pressure was also blocked by the inhibitors neomycin and thapsigargin confirming that pressure, by generating IP(3), led to an increase in [Ca(2+)](i) by mobilising the pool of Ca(2+) ions contained within intracellular stores. We also found that intracellular [Na(+)] was affected by a rise in osmotic pressure and further affected by application of hydrostatic pressure. The effect of hydrostatic pressure on sulphate incorporation depended strongly on extracellular osmolality. Since significant gradients in extracellular osmolality exist across intact cartilage, the results imply that responses of chondrocytes to the same pressure will vary depending on location in the joint. The results also indicate that hydrostatic pressures can affect several different transporter systems thus influencing the intracellular milieu and chondrocyte metabolism.


Ceramide and ceramide 1-phosphate in health and disease.
Sphingolipids are essential components of cell membranes, and many of them regulate vital cell functions. In particular, ceramide plays crucial roles in cell signaling processes. Two major actions of ceramides are the promotion of cell cycle arrest and the induction of apoptosis. Phosphorylation of ceramide produces ceramide 1-phosphate (C1P), which has opposite effects to ceramide. C1P is mitogenic and has prosurvival properties. In addition, C1P is an important mediator of inflammatory responses, an action that takes place through stimulation of cytosolic phospholipase A2, and the subsequent release of arachidonic acid and prostaglandin formation. All of the former actions are thought to be mediated by intracellularly generated C1P. However, the recent observation that C1P stimulates macrophage chemotaxis implicates specific plasma membrane receptors that are coupled to Gi proteins. Hence, it can be concluded that C1P has dual actions in cells, as it can act as an intracellular second messenger to promote cell survival, or as an extracellular receptor agonist to stimulate cell migration.


Dietary preference in dairy calves for feed ingredients high in energy and protein.
In 3 experiments, we assessed preference of recently weaned dairy calves for (1) 8 high-energy feed types [barley meal, corn meal, corn gluten feed (CGF), oat meal, rice meal, sorghum meal, wheat meal, and wheat middlings meal]; (2) 6 high-protein feed types [corn gluten meal (CGM), wheat distillers dried grains, rapeseed meal, soybean meal (SBM), sunflower meal, and pea meal]; and (3) 4 mixtures (50:50) of the highest- and lowest-ranked high-energy and high-protein feeds, to assess whether calves maintain preference for feed ingredients that are included in a mixture. In all experiments, pairwise preference tests were conducted between all feed types (28 different pairwise preference tests in experiment 1, 15 tests in experiment 2, and 6 tests in experiment 3). Each pairwise preference test was conducted by offering ad libitum access to both feed types for 6h. All tests were repeated with 20 Holstein calves. Before this study, calves were offered milk replacer at a rate of 4 L/d and a pelleted starter feed ad libitum. After weaning at 62 d of age, each calf was involved in a pairwise preference test at 3 and 5d postweaning. A preference ratio was calculated for each calf in each test as (intake of feed type A)/(intake of feed type A + intake of feed type B). Preference for feed types was ranked across tests in each experiment using pairwise comparison charts. In experiment 1, the highest-ranked high-energy feed type was wheat meal and the lowest ranked were rice meal and CGF. In experiment 2, the highest-ranked high-protein feed type was SBM and the lowest ranked was CGM. According to the preference rankings from experiments 1 and 2, experiment 3 evaluated (50:50) mixtures of SBM + wheat meal, SBM + CGF, CGM + wheat meal, and CGM + CGF. The mixture of SBM + wheat meal was highest ranked, CGM + CGF was lowest ranked, and the mixtures containing one high-ranked and one low-ranked feed ingredient (SBM + CGF and CGM + wheat meal) were ranked equally. The results of this study indicate that young calves exhibit clear preferences for certain high-energy and high-protein feeds that may be considered highly palatable. Further, preference ranking of feed types provided as 50:50 mixtures was consistent with ranking of individual feed types, suggesting that palatability of mixed starter rations can be improved by inclusion of a preferred feed type.


Impact of errors in paper-based and computerized diabetes management with decision support for hospitalized patients with type 2 diabetes. A post-hoc analysis of a before and after study.
Most preventable adverse drug events and medication errors occur during medication ordering. Medication order entry and clinical decision support are available on paper or as computerized systems. In this post-hoc analysis we investigated frequency and clinical impact of blood glucose (BG) documentation- and user-related calculation errors as well as workflow deviations in diabetes management. We aimed to compare a paper-based protocol to a computerized medication management system combined with clinical workflow and decision support. Seventy-nine hospitalized patients with type 2 diabetes mellitus were treated with an algorithm driven basal-bolus insulin regimen. BG measurements, which were the basis for insulin dose calculations, were manually entered either into the paper-based workflow protocol (PaperG: 37 patients) or into GlucoTab(®)-a mobile tablet PC based system (CompG: 42 patients). We used BG values from the laboratory information system as a reference. A workflow simulator was used to determine user calculation errors as well as workflow deviations and to estimate the effect of errors on insulin doses. The clinical impact of insulin dosing errors and workflow deviations on hypo- and hyperglycemia was investigated. The BG documentation error rate was similar for PaperG (4.9%) and CompG group (4.0%). In PaperG group, 11.1% of manual insulin dose calculations were erroneous and the odds ratio (OR) of a hypoglycemic event following an insulin dosing error was 3.1 (95% CI: 1.4-6.8). The number of BG values influenced by insulin dosing errors was eightfold higher than in the CompG group. In the CompG group, workflow deviations occurred in 5.0% of the tasks which led to an increased likelihood of hyperglycemia, OR 2.2 (95% CI: 1.1-4.6). Manual insulin dose calculations were the major source of error and had a particularly strong influence on hypoglycemia. By using GlucoTab(®), user calculation errors were entirely excluded. The immediate availability and automated handling of BG values from medical devices directly at the point of care has a high potential to reduce errors. Computerized systems facilitate the safe use of more complex insulin dosing algorithms without compromising usability. In CompG group, missed or delayed tasks had a significant effect on hyperglycemia, while in PaperG group insufficient precision of documentation times limited analysis. The use of old BG measurements was clinically less relevant. Insulin dosing errors and workflow deviations led to measurable changes in clinical outcome. Diabetes management systems including decision support should address nurses as well as physicians in a computerized way. Our analysis shows that such systems reduce the frequency of errors and therefore decrease the probability of hypo- and hyperglycemia.


The pet as an anxiolytic intervention.
The effect of a pet on psychological consequences of stress (i.e., state and trait anxiety levels) of college students was examined under three test conditions (i.e., reading aloud, reading quietly, and interacting with a friendly but unknown dog). A repeated-measures analysis of variance with three covariates was used to examine the effect of the treatment on each dependent variable (state and trait anxiety). Reading aloud differed from baseline measure under all treatment conditions (p less than .001). Reading quietly and interacting with the dog were slightly below baseline for variables, with more effect seen by reading quietly than by interacting with the dog. Examination of interactions among variables showed no significant differences. Effects upon state anxiety were significant, while trait anxiety levels remained fairly constant throughout the treatments. Baseline differences in trait anxiety scores indicate a potentially greater benefit for pet owners than nonowners. Selected social network and relationship data related to the role of the pet during anxiety-producing times were also analyzed. While interaction with the pet produced a decrease in anxiety level, pet owners did not report the use of their own pet as a social support (i.e., as confidant) significantly more than did previous owners. Results indicated that interacting with a pet for some individuals does affect both physiological and psychological responses by lowering response levels. However, a parallel effect was also seen by reading quietly. Given the effect of pet interaction upon selected social support indicators of health in well college students, these data suggest the importance of examining this treatment with an "at-risk" group in which it is possible to control for ownership characteristics.


Block-copolymer ordering with a spatiotemporally heterogeneous mobility.
Motivated by recent zone annealing measurements on stripe-forming block-copolymer films [B. C. Berry, Nano Lett. 7, 2789 (2007)], we study block-copolymer ordering with a spatiotemporally heterogeneous mobility. Specifically, we implement a time- and space-dependent mobility field in the relaxation of a diblock copolymer self-consistent field theory. The model includes a gradient in the local mobility and intrinsic nanoscale mobility variations characteristic of glass phenomenology. The simulations demonstrate that a spatiotemporally heterogeneous mobility can have a significant influence on microdomain ordering in block-copolymer systems, and that nanoscale dynamic heterogeneities associated with glass formation can impact the structure of the ordered block-copolymer microphase.


Development and Validation of a Multidimensional Measure of Family Supportive Supervisor Behaviors (FSSB).
Due to growing work-family demands, supervisors need to effectively exhibit family supportive supervisor behaviors (FSSB). Drawing on social support theory and using data from two samples of lower wage workers, the authors develop and validate a measure of FSSB, defined as behaviors exhibited by supervisors that are supportive of families. FSSB is conceptualized as a multidimensional superordinate construct with four subordinate dimensions: emotional support, instrumental support, role modeling behaviors, and creative work-family management. Results from multilevel confirmatory factor analyses and multilevel regression analyses provide evidence of construct, criterion-related, and incremental validity. The authors found FSSB to be significantly related to work-family conflict, work-family positive spillover, job satisfaction, and turnover intentions over and above measures of general supervisor support.


Toward Understanding How Social Factors Shaped a Behavioral Intervention on Healthier Infant Formula-Feeding.
As part of a process evaluation, we explored in semi-structured interviews the experiences of 19 mothers who had taken part in a trial to reduce infant formula-milk intake and promote healthy weight gain, and reflections of three facilitators who delivered the intervention and control group protocols. Mothers appreciated the nonjudgmental support provided during the trial, after experiencing stigma and receiving limited advice on how, how much, and how often formula-milk should be given. The information mothers had previously found, printed on formula-milk tins, or provided by family, friends, and health professionals was often perceived as contradictory; the trial guidance also conflicted with social norms relating infant health positively with weight gain. For those recruited into the trial with older infants, who had already exceeded the recommendations, reducing formula-milk amounts was difficult. The findings highlight the difficulties of addressing a highly stigmatized, complex social practice with an individual, behavioral intervention approach.


In vitro evaluation of three curettes with edge retention technology after extended use.
This study assessed the edge cutting efficiency of three new curettes with different edge retention technologies after simulated wear in vitro. Three test curettes (two with a titanium nitride coating and one without coating, but made of a cryogenically treated stainless steel alloy) were used to root plane prepared bovine dentin specimens. Nine curettes of each type were used to instrument one dentin sample each. Dentin removal was determined after the first ten strokes and again cumulatively for the strokes 500-510 and 1,000-1,010 by means of atomic absorption spectrophotometry (AAS). The effects of chemical and thermal stress were analysed after repeated disinfection and sterilization of the instruments then followed by a final 10-stroke sequence of dentin removal to determine cutting efficacy. A standard, untreated stainless steel curette was used as a control. Test and control instruments showed no statistical evidence of diminished dentin removal over 1010 strokes. Dentin surface roughness also displayed insignificant differences for all instruments. However, sterilization negatively affected the test and control instruments to an equal degree. Sterilization procedures appear to be an important factor in the dulling of curettes, which affected dentin removal efficacy but not surface roughness.


Midwifery workforce profile in Limpopo Province referral hospitals.
In sub-Saharan Africa including South Africa, maternal mortality rates remain unacceptably high due to a shortage of registered nurses with advanced midwifery diplomas. To determine the profile of registered nurses (RNs) involved in maternity care in public referral hospitals of the Limpopo Province, South Africa. A cross-sectional descriptive study was conducted in all maternity units of Limpopo's public referral hospitals. The study population comprised of 210 registered nurses, who became the study sample. Data on their educational profile and work experience in midwifery was analysed using STATA version 9.0. The mean age of the 210 registered nurses was 44.5 ± 9.1 years (range 21 to 62). The majority (152/210; 70%) were 40 years and older, 56% (117/210) had been working for more than 10 years, and 63/210 (30%) were due to retire within 10 years. Only 22% (46/210) had advanced midwifery diplomas, i.e. after their basic undergraduate training. Only six (2.9%) of the RNs providing maternity care in these referral hospitals were studying for advanced midwifery diplomas at the time of the study. This study demonstrated a shortage of registered nurses with advanced midwifery training/diplomas in referral hospitals of the Limpopo Province. This has a potentially negative effect in reducing the high maternal mortality rate in the province.


Complex Machine-Learning Algorithms and Multivariable Logistic Regression on Par in the Prediction of Insufficient Clinical Response to Methotrexate in Rheumatoid Arthritis.
The goals of this study were to examine whether machine-learning algorithms outperform multivariable logistic regression in the prediction of insufficient response to methotrexate (MTX); secondly, to examine which features are essential for correct prediction; and finally, to investigate whether the best performing model specifically identifies insufficient responders to MTX (combination) therapy. The prediction of insufficient response (3-month Disease Activity Score 28-Erythrocyte-sedimentation rate (DAS28-ESR) > 3.2) was assessed using logistic regression, least absolute shrinkage and selection operator (LASSO), random forest, and extreme gradient boosting (XGBoost). The baseline features of 355 rheumatoid arthritis (RA) patients from the "treatment in the Rotterdam Early Arthritis CoHort" (tREACH) and the U-Act-Early trial were combined for analyses. The model performances were compared using area under the curve (AUC) of receiver operating characteristic (ROC) curves, 95% confidence intervals (95% CI), and sensitivity and specificity. Finally, the best performing model following feature selection was tested on 101 RA patients starting tocilizumab (TCZ)-monotherapy. Logistic regression (AUC = 0.77 95% CI: 0.68-0.86) performed as well as LASSO (AUC = 0.76, 95% CI: 0.67-0.85), random forest (AUC = 0.71, 95% CI: 0.61 = 0.81), and XGBoost (AUC = 0.70, 95% CI: 0.61-0.81), yet logistic regression reached the highest sensitivity (81%). The most important features were baseline DAS28 (components). For all algorithms, models with six features performed similarly to those with 16. When applied to the TCZ-monotherapy group, logistic regression's sensitivity significantly dropped from 83% to 69% (p = 0.03). In the current dataset, logistic regression performed equally well compared to machine-learning algorithms in the prediction of insufficient response to MTX. Models could be reduced to six features, which are more conducive for clinical implementation. Interestingly, the prediction model was specific to MTX (combination) therapy response.


Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone.
Cholinergic excitation of vertebrate neurones is frequently mediated through the action of acetylcholine on muscarinic (atropine-sensitve) receptors. This type of excitation differs substantially from the better known nicotinic excitation. One difference is that, instead of an increased membrane conductance, a decreased conductance (to K+ ions) frequently accompanies muscarinic depolarisation. This has been detected in sympathetic, cortical and hippocampal neurones. Using voltage-clamped frog sympathetic neurones we have now identified a distinctive voltage-sensitive K+-current, separate from the delayed rectifier current, as the prime target for muscarinic agonists. We have termed this current the M-current, IM.


Opposing Timing Constraints Severely Limit the Use of Pupillometry to Investigate Visual Statistical Learning.
Majority of visual statistical learning (VSL) research uses only offline measures, collected after the familiarization phase (i.e., learning) has occurred. Offline measures have revealed a lot about the extent of statistical learning (SL) but less is known about the learning mechanisms that support VSL. Studies have shown that prediction can be a potential learning mechanism for VSL, but it is difficult to examine the role of prediction in VSL using offline measures alone. Pupil diameter is a promising online measure to index prediction in VSL because it can be collected during learning, requires no overt action or task and can be used in a wide-range of populations (e.g., infants and adults). Furthermore, pupil diameter has already been used to investigate processes that are part of prediction such as prediction error and updating. While the properties of pupil diameter have the potentially to powerfully expand studies in VSL, through a series of three experiments, we find that the two are not compatible with each other. Our results revealed that pupil diameter, used to index prediction, is not related to offline measures of learning. We also found that pupil differences that appear to be a result of prediction, are actually a result of where we chose to baseline instead. Ultimately, we conclude that the fast-paced nature of VSL paradigms make it incompatible with the slow nature of pupil change. Therefore, our findings suggest pupillometry should not be used to investigate learning mechanisms in fast-paced VSL tasks.


Systemic regulation of vascular NAD(P)H oxidase activity and nox isoform expression in human arteries and veins.
Impaired endothelial function, characterized by nitric oxide scavenging by increased superoxide production, is a hallmark of vascular disease states. However, molecular mechanisms regulating superoxide production in human blood vessels remain poorly defined. We compared endothelial function, vascular superoxide production, and the expression of NAD(P)H oxidase subunits in arteries and veins from patients undergoing coronary bypass surgery (n=86). Superoxide release was similar in arteries and veins. Inhibitor studies revealed that the NAD(P)H oxidase system was a quantitatively and proportionately greater source of superoxide in veins, whereas xanthine oxidase also contributed significantly to superoxide production in arteries. Moreover, NAD(P)H oxidase molecular composition differed in veins and arteries; veins expressed more nox2 and p22phox, whereas the relative expression of nox4 was greater in arteries. However, there were strong correlations between p22phox and nox4 expression and between superoxide production, NAD(P)H oxidase activity, and endothelial function in arteries and veins from the same patient. In individuals with coronary artery disease, changes in vascular superoxide production, endothelial function, and NAD(P)H oxidase activity and expression are related in veins and arteries. These findings highlight the importance of systemic effects on the molecular regulation of the NAD(P)H oxidases in human vascular disease. Endothelial dysfunction is characterized by increased superoxide production. NAD(P)H oxidase activity and endothelial function are correlated in veins and arteries in coronary artery disease, suggesting regulation by systemic factors. The expression of the NAD(P)H oxidase subunits p22phox and nox4, although different in veins and arteries, are also correlated.


Multi-Criteria Decision Analysis Model for Assessing the Risk from Multi-Ingredient Dietary Supplements (MIDS).
Military personnel use dietary supplements (DS) for performance enhancement, bodybuilding, weight loss, and to maintain health. Adverse events, including cardiovascular (CV) effects, have been reported in military personnel taking supplements. Previous research determined that ingestion of multi-ingredient dietary supplements (MIDS), can lead to signals of safety concerns. Therefore, to assess the safety of MIDS, the Department of Defense via a contractor explored the development of a model-based risk assessment tool. We present a strategy and preliminary novel multi-criteria decision analysis (MCDA)-based tool for assessing the risk of adverse CV effects from MIDS. The tool integrates toxicology and other relevant data available on MIDS; likelihood of exposure, and biologic plausibility that could contribute to specific aspects of risk.Inputs for the model are values of four measures assigned based on the available evidence supplemented with the opinion of experts in toxicology, modeling, risk assessment etc. Measures were weighted based on the experts' assessment of measures' relative importance. Finally, all data for the four measures were integrated to provide a risk potential of 0 (low risk) to 100 (high risk) that defines the relative risk of a MIDS to cause adverse reactions.We conclude that the best available evidence must be supplemented with the opinion of experts in medicine, toxicology and pharmacology. Model-based approaches are useful to inform risk assessment in the absence of data. This MCDA model provides a foundation for refinement and validation of accuracy of the model predictions as new evidence becomes available.


A systematic review of patient heart failure self-care strategies.
Self-care is at the foundation for living with a chronic condition such as heart failure (HF). Patients with HF express difficulty with translating self-care knowledge into understanding "how" to engage in these activities and behaviors. Understanding the strategies that patients develop to engage in self-care will help healthcare providers (HCPs) improve support for unmet self-care needs of HF patients. The purpose of this systematic review was to highlight strategies that HF patients use to accommodate self-care recommendations into the reality of their daily lives. A systematic review using qualitative meta-synthesis was carried out. Included studies had to contain a qualitative component and data pertaining to self-care of HF from adults older than 18 years and be published as full papers/theses beginning 1995. Ten databases were searched until March 19, 2012. Of 1421 papers identified by the search, 47 were included. Studies involved the following: 1377 patients, 45% women, mean age of 67 years (range, 25-98 years), 145 caregivers, and 15 HCPs. Approaches to self-care reflected both perception- and action-based strategies and were a means to effectively manage HF. Although HF patients often expressed difficulty on how to integrate self-care recommendations into their daily lives, they developed intentional, planned strategies that harnessed previous experiences. Healthcare providers must appreciate that patients view self-care as an "adaptation" that they undertake to maintain their independence and quality of life. In addition, HCPs must recognize that because self-care is a process of learning over time from experience, an individualized approach that emphasizes how to self-care must be adopted for patients to develop the necessary HF self-care skills.


Hebbian learning of recurrent connections: a geometrical perspective.
We show how a Hopfield network with modifiable recurrent connections undergoing slow Hebbian learning can extract the underlying geometry of an input space. First, we use a slow and fast analysis to derive an averaged system whose dynamics derives from an energy function and therefore always converges to equilibrium points. The equilibria reflect the correlation structure of the inputs, a global object extracted through local recurrent interactions only. Second, we use numerical methods to illustrate how learning extracts the hidden geometrical structure of the inputs. Indeed, multidimensional scaling methods make it possible to project the final connectivity matrix onto a Euclidean distance matrix in a high-dimensional space, with the neurons labeled by spatial position within this space. The resulting network structure turns out to be roughly convolutional. The residual of the projection defines the nonconvolutional part of the connectivity, which is minimized in the process. Finally, we show how restricting the dimension of the space where the neurons live gives rise to patterns similar to cortical maps. We motivate this using an energy efficiency argument based on wire length minimization. Finally, we show how this approach leads to the emergence of ocular dominance or orientation columns in primary visual cortex via the self-organization of recurrent rather than feedforward connections. In addition, we establish that the nonconvolutional (or long-range) connectivity is patchy and is co-aligned in the case of orientation learning.


Evaluation of low-dose proton beam radiation efficiency in MIA PaCa-2 pancreatic cancer cell line vitality and H2AX formation.
The aim of this study was to evaluate the efficiency of proton beam irradiation in pancreatic cancer cell line MIA PaCa-2 and its role in the cell cycle, apoptosis, and formation of histone γH2AX in different reparation times (72-h follow-up). The MIA PaCa-2 pancreatic carcinoma cell line was irradiated with 1.6-Gy proton beam. After irradiation, cell viability was measured colorimetrically, and the cell cycle, apoptosis, and γH2AX expression were evaluated on a FACScan cytometer. Low-dose proton beam irradiation had an effect on the MIA PaCa-2 tumor cell line already 1h after exposure, but maximal lethality was reached after 72h postirradiation with a cell viability rate of 24%. The cell cycle went into partial G1/0 arrest, and was released after 72h. The expression of γH2AX was strong and its levels were significantly elevated as late as 48h post radiation. The apoptosis levels increased with post radiation incubation time to reach 79% after 72h. Our data demonstrate that low-doses proton beam irradiation had an effect on MIA PaCa-2 pancreatic carcinoma cell line. Full extent of irradiation had an impact only 24h postirradiation, triggering DNA arrested cell cycle in G1/0 phase. Formed DNA DSBs were found to be repaired via the NHEJ pathway mechanism within 72h. Unsuccessful repaired DSBs induced apoptotic cell death. After 72h reparation processes were completed, and cell cycle was released from arrest in G1/0 phase.


The Profile of Long-term Parkinson's Disease Survivors with 20 Years of Disease Duration and Beyond.
Parkinson's disease (PD) patients with 20 years or more survival (PD-20) are not well characterized. To evaluate PD-20 patient characteristics and identify areas for improvement of their health care. The international, multicenter National Parkinson's Foundation Quality Improvement Initiative (NPF-QII) study database was queried to identify PD-20 subjects. Demographic and clinical data were analyzed. We identified 187 PD-20 subjects (55% men) representing 4% (187/4,619) of all NPF-QII participants. Subjects were mean age 69.5 years; mean age at PD onset was 44.0 years. The majority (75% ) had 20-25 years of PD duration, the longest duration being 49 years. They were median Hoehn and Yahr stage 3, and 75% had motor fluctuations. Half (54% ) reported exercising. The majority (89% ) were living at home and required a caregiver (88% ). They were mildly cognitively impaired for age (Montreal Cognitive Assessment estimate 22.6±3.7), with most deficits in verbal fluency and delayed recall. Quality of life (Parkinson's Disease Quality of Life Questionnaire index 36±15% ) was mild to moderately impaired, with most impairment in mobility and activities of daily living. Caregiver strain measured by the Multidimensional Caregiver Strain Index (27±16% ), recorded highest subscores in social constraint. PD-20 subjects aged <70 years versus ≥70 only differed significantly by worse cognition (P < 0.0001). PD-20 subjects reflect an elite group of PD survivors with early-onset disease and relatively mild cognitive disability despite long disease duration. Interventions for caregivers, mobility, and activities of daily living are areas that could improve caregiver burden and patient quality of life.


Averaging Trials Versus Averaging Trial Peaks: Impact on Study Outcomes.
Gait data are commonly presented as an average of many trials or as an average across participants. Discrete data points (eg, maxima or minima) are identified and used as dependent variables in subsequent statistical analyses. However, the approach used for obtaining average data from multiple trials is inconsistent and unclear in the biomechanics literature. This study compared the statistical outcomes of averaging peaks from multiple trials versus identifying a single peak from an average profile. A series of paired-samples t tests were used to determine whether there were differences in average dependent variables from these 2 methods. Identifying a peak value from the average profile resulted in significantly smaller magnitudes of dependent variables than when peaks from multiple trials were averaged. Disagreement between the 2 methods was due to temporal differences in trial peak locations. Sine curves generated in MATLAB confirmed this misrepresentation of trial peaks in the average profile when a phase shift was introduced. Based on these results, averaging individual trial peaks represents the actual data better than choosing a peak from an average trial profile.


Treatment with yttrium 90 ibritumomab tiuxetan at early relapse is safe and effective in patients with previously treated B-cell non-Hodgkin's lymphoma.
Yttrium 90 ((90)Y) ibritumomab tiuxetan (Zevalin), a radiolabeled monoclonal antibody against the CD20 antigen, is indicated for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL), including patients with rituximab-refractory follicular NHL. Data on 211 patients treated in four clinical trials were analysed to compare the efficacy and safety of (90)Y ibritumomab tiuxetan when it was used after the first relapse of NHL and when it was used after two or more prior therapies. Sixty-three patients (30%) were treated with (90)Y ibritumomab tiuxetan after their first relapse and 148 (70%) after two or more prior therapies. Demographics, disease characteristics and the frequency of adverse events were similar in all groups, with the exception of a higher rate of marrow involvement in first-relapse patients than in patients with two or more prior therapies (57% vs. 39%; P < 0.05). The complete response rate [confirmed (CR) and unconfirmed (Cru)] was higher in first-relapse patients (49% vs. 28%; P < 0.01), and the median time to progression (TTP) was longer (12.6 vs. 7.9 months; P < 0.05). In patients with follicular NHL, the differences were even more pronounced (CR/CRu: 51% vs. 28%; P < 0.01; TTP: 15.4 vs. 9.2 months; P < 0.05). (90)Y ibritumomab tiuxetan has substantial clinical benefits as a second-line therapy, especially in patients with follicular NHL. The quality of disease remissions obtained when (90)Y ibritumomab tiuxetan is administered after first relapse appears to be comparable with that observed with most chemotherapy regimens in first-relapse patients.


Growth, cell division and sporulation in mycobacteria.
Bacteria have the ability to adapt to different growth conditions and to survive in various environments. They have also the capacity to enter into dormant states and some bacteria form spores when exposed to stresses such as starvation and oxygen deprivation. Sporulation has been demonstrated in a number of different bacteria but Mycobacterium spp. have been considered to be non-sporulating bacteria. We recently provided evidence that Mycobacterium marinum and likely also Mycobacterium bovis bacillus Calmette-Guérin can form spores. Mycobacterial spores were detected in old cultures and our findings suggest that sporulation might be an adaptation of lifestyle for mycobacteria under stress. Here we will discuss our current understanding of growth, cell division, and sporulation in mycobacteria.


Pathological non-response to chemotherapy in a neoadjuvant setting of breast cancer: an inter-institutional study.
To identify markers of non-response to neoadjuvant chemotherapy (NAC) that could be used in the adjuvant setting. Sixteen pathologists of the European Working Group for Breast Screening Pathology reviewed the core biopsies of breast cancers treated with NAC and recorded the clinico-pathological findings (histological type and grade; estrogen, progesterone receptors, and HER2 status; Ki67; mitotic count; tumor-infiltrating lymphocytes; necrosis) and data regarding the pathological response in corresponding surgical resection specimens. Analyses were carried out in a cohort of 490 cases by comparing the groups of patients showing pathological complete response (pCR) and partial response (pPR) with the group of non-responders (pathological non-response: pNR). Among other parameters, the lobular histotype and the absence of inflammation were significantly more common in pNR (p < 0.001). By ROC curve analyses, cut-off values of 9 mitosis/2 mm(2) and 18% of Ki67-positive cells best discriminated the pNR and pCR + pPR categories (p = 0.018 and < 0.001, respectively). By multivariable analysis, only the cut-off value of 9 mitosis discriminated the different response categories (p = 0.036) in the entire cohort. In the Luminal B/HER2- subgroup, a mitotic count <9, although not statistically significant, showed an OR of 2.7 of pNR. A lobular histotype and the absence of inflammation were independent predictors of pNR (p = 0.024 and <0.001, respectively). Classical morphological parameters, such as lobular histotype and inflammation, confirmed their predictive value in response to NAC, particularly in the Luminal B/HER2- subgroup, which is a challenging breast cancer subtype from a therapeutic point of view. Mitotic count could represent an additional marker but has a poor positive predictive value.


Reporting methods in studies developing prognostic models in cancer: a review.
Development of prognostic models enables identification of variables that are influential in predicting patient outcome and the use of these multiple risk factors in a systematic, reproducible way according to evidence based methods. The reliability of models depends on informed use of statistical methods, in combination with prior knowledge of disease. We reviewed published articles to assess reporting and methods used to develop new prognostic models in cancer. We developed a systematic search string and identified articles from PubMed. Forty-seven articles were included that satisfied the following inclusion criteria: published in 2005; aiming to predict patient outcome; presenting new prognostic models in cancer with outcome time to an event and including a combination of at least two separate variables; and analysing data using multivariable analysis suitable for time to event data. In 47 studies, prospective cohort or randomised controlled trial data were used for model development in only 33% (15) of studies. In 30% (14) of the studies insufficient data were available, having fewer than 10 events per variable (EPV) used in model development. EPV could not be calculated in a further 40% (19) of the studies. The coding of candidate variables was only reported in 68% (32) of the studies. Although use of continuous variables was reported in all studies, only one article reported using recommended methods of retaining all these variables as continuous without categorisation. Statistical methods for selection of variables in the multivariate modelling were often flawed. A method that is not recommended, namely, using statistical significance in univariate analysis as a pre-screening test to select variables for inclusion in the multivariate model, was applied in 48% (21) of the studies. We found that published prognostic models are often characterised by both use of inappropriate methods for development of multivariable models and poor reporting. In addition, models are limited by the lack of studies based on prospective data of sufficient sample size to avoid overfitting. The use of poor methods compromises the reliability of prognostic models developed to provide objective probability estimates to complement clinical intuition of the physician and guidelines.


Examining the Cascade of Participant Attrition in a Genomic Medicine Research Study: Barriers and Facilitators to Achieving Diversity.
Recent genomic medicine initiatives underscore the importance of including diverse participants in research. Considerable literature has identified barriers to and facilitators of increasing diversity, yet disparities in recruiting and retaining adequate numbers of participants from diverse groups continue to limit the generalizability of clinical genomic research. The North Carolina Clinical Genomic Evaluation by Next-gen Exome Sequencing study employed evidence-based strategies to enhance the participation of under-represented minority patients. In this study, we evaluate the impact of our efforts by systematically analyzing the "cascade" of attrition of participants throughout study interactions. Although successful in recruiting a cohort that included ~30% non-Caucasian patients overall, the study still enrolled and retained a lower proportion of minorities compared to the pool of eligible patients who were nominated. We evaluated sociodemographic characteristics and related variables as potential factors associated with attrition throughout these phases of the study. These results suggest that varied approaches will be needed to increase participation in genomic medicine research. Our findings highlight factors to consider when developing strategies to address this critical need. Failing to include a broad range of populations in research studies will exacerbate existing disparities in the translation of genomic sequencing to medical care.


Toward New Classification Criteria for Juvenile Idiopathic Arthritis: First Steps, Pediatric Rheumatology International Trials Organization International Consensus.
To revise the current juvenile idiopathic arthritis (JIA) International League of Associations for Rheumatology (ILAR) classification criteria with an evidence-based approach, using clinical and routine laboratory measures available worldwide, to identify homogeneous clinical groups and to distinguish those forms of chronic arthritis typically seen only in children from the childhood counterpart of adult diseases. The overall project consists of 4 steps. This work represents Step 1, a Delphi Web-based consensus and Step 2, an international nominal group technique (NGT) consensus conference for the new provisional Pediatric Rheumatology International Trials Organization JIA classification criteria. A future large data collection of at least 1000 new-onset JIA patients (Step 3) followed by analysis and NGT consensus (Step 4) will provide data for the evidence-based validation of the JIA classification criteria. In Step 1, three Delphi rounds of interactions were implemented to revise the 7 ILAR JIA categories. In Step 2, forty-seven questions with electronic voting were implemented to derive the new proposed criteria. Four disorders were proposed: (a) systemic JIA; (b) rheumatoid factor-positive JIA; (c) enthesitis/spondylitis-related JIA; and (d) early-onset antinuclear antibody-positive JIA. The other forms were gathered under the term "others." These will be analyzed during the prospective data collection using a list of descriptors to see whether the clustering of some of them could identify homogeneous entities. An international consensus was reached to identify different proposed homogeneous chronic disorders that fall under the historical term JIA. These preliminary criteria will be formally validated with a dedicated project.


[Role of the pineal body in reproduction and in gynecologic tumors].
According to the current view, the main function of the pineal gland and its hormone melatonin is to convey information on environmental photoperiods to the endocrine, central nervous and immune systems, allowing their optimal adjustment to the time of the day and season. Within the endocrine system, the gonads are a major target; maturation of the female reproductive organs during pubertal development is inhibited by the pineal hormone. During the reproductive phase, melatonin seems to act as a coordinating signal for the menstrual cycle by timing the LH-peak and supporting progesterone production. A gradual decline of circulating melatonin with age suggests a role in age-associated endocrine changes, e.g. during menopause. Due to its important role in the female reproductive system, the pineal gland has been implicated in the aetiology of human breast cancer. Serum melatonin is depressed in patients with primary mammary cancer and experimental tumours are inhibited, a finding suggesting a therapeutic potential of melatonin. In addition, other potent antineoplastic substances exist in the pineal gland, which may become useful tools for future anti-cancer therapies.


Macrophage Differentiation from Monocytes Is Influenced by the Lipid Oxidation Degree of Low Density Lipoprotein.
LDL plays an important role in atherosclerotic plaque formation and macrophage differentiation. However, there is no report regarding the oxidation degree of LDL and macrophage differentiation. Our study has shown that the differentiation into M1 or M2 macrophages is related to the lipid oxidation level of LDL. Based on the level of lipid peroxidation, LDL is classified into high-oxidized LDL (hi-oxLDL) and low-oxidized LDL (low-oxLDL). The differentiation profiles of macrophages were determined by surface receptor expression and cytokine secretion profiles. Low-oxLDL induced CD86 expression and production of TNF-α and IL-12p40 in THP-1 cells, indicating an M1 macrophage phenotype. Hi-oxLDL induced mannose receptor expression and production of IL-6 and monocyte chemoattractant protein-1, which mostly match the phenotype of M2 macrophages. Further supporting evidence for an M2 polarization by hi-oxLDL was the induction of LOX-1 in THP-1 cells treated with hi-oxLDL but not with low-oxLDL. Similar results were obtained in primary human monocytes. Therefore, our results strongly suggest that the oxidation degree of LDL influences the differentiation of monocytes into M1 or M2 macrophages and determines the inflammatory fate in early stages of atherosclerosis.


Comparative Evaluation of Treatment of Localized Gingival Recessions with Coronally Advanced Flap Using Microsurgical and Conventional Techniques.
Coverage of gingival recession is a very precision-oriented procedure. Employment of operating microscope has proved to be a boon in various surgical procedures and therefore can have positive benefits on the outcome of a procedure. The aim of this study is to find out whether the use of an operating microscope in the surgical treatment of Millers Class I and Class II gingival recession defects could improve the outcome in terms of root coverage and final tissue appearance compared to those done by the conventional technique. This clinical study was carried out on ten patients with the presence of bilateral isolated gingival recession classified as Miller's Class I or Class II recession defect. The split-mouth design was used where coronally advanced flap with the placement of platelet-rich fibrin was done in defects in test (microsurgical) and control (conventional) groups. Various clinical parameters were recorded at baseline and then postoperatively at 3-months and 6-month intervals. The visual analog scale scores showed a statistically significant difference between scores while all other parameters had no statistically significant difference in intergroup comparison after 3 and 6 months. While microscope permitted less traumatic and minimally invasive procedure, both groups showed convincing improvement in clinical parameters.


Empirical oral antibiotic therapy for low risk febrile cancer patients with neutropenia.
For over 30 years, fever and neutropenia in cancer patients has been treated with the utmost urgency, necessitating inpatient evaluation and immediate initiation of empirical broad-spectrum parenteral (i.v.) antibiotics. This practice is based on the recognition that delays in starting antibiotic therapy in febrile neutropenic patients have been associated with life-threatening infections and sometimes fatal consequences. Over the past decade, it has become evident that neutropenic cancer patients are not a homogeneous group and that practice guidelines may vary on their risk status. In fact, attempts have been made to stratify patients into high-risk and low-risk groups and differentiate treatment options respectively. Recent studies suggest that those neutropenic cancer patients who are at low risk may even be successfully treated with oral therapy, thus opening the possibility for ambulatory or home-based management. Oral antibiotic therapy, especially if safely delivered at home, offers a number of advantages including lower cost, improved quality of life (although the impact of shifting the burden of care from the hospital to the home setting on the patient, parent or care provider needs careful assessment) and a decreased risk for nosocomial infection.


Load-relaxation properties of the human trunk in response to prolonged flexion: measuring and modeling the effect of flexion angle.
Experimental studies suggest that prolonged trunk flexion reduces passive support of the spine. To understand alterations of the synergy between active and passive tissues following such loadings, several studies have assessed the time-dependent behavior of passive tissues including those within spinal motion segments and muscles. Yet, there remain limitations regarding load-relaxation of the lumbar spine in response to flexion exposures and the influence of different flexion angles. Ten healthy participants were exposed for 16 min to each of five magnitudes of lumbar flexion specified relative to individual flexion-relaxation angles (i.e., 30, 40, 60, 80, and 100%), during which lumbar flexion angle and trunk moment were recorded. Outcome measures were initial trunk moment, moment drop, parameters of four viscoelastic models (i.e., Standard Linear Solid model, the Prony Series, Schapery's Theory, and the Modified Superposition Method), and changes in neutral zone and viscoelastic state following exposure. There were significant effects of flexion angle on initial moment, moment drop, changes in normalized neutral zone, and some parameters of the Standard Linear Solid model. Initial moment, moment drop, and changes in normalized neutral zone increased exponentially with flexion angle. Kelvin-solid models produced better predictions of temporal behaviors. Observed responses to trunk flexion suggest nonlinearity in viscoelastic properties, and which likely reflected viscoelastic behaviors of spinal (lumbar) motion segments. Flexion-induced changes in viscous properties and neutral zone imply an increase in internal loads and perhaps increased risk of low back disorders. Kelvin-solid models, especially the Prony Series model appeared to be more effective at modeling load-relaxation of the trunk.


[Thrombin-antithrombin complexes and F1+2 prothrombin fragment in coronary revascularization surgery. Relationship with graft occlusion].
To evaluate the possible role played by activation of the coagulation system in the early occlusion of grafts in patients subjected to aortocoronary bypass. This study includes 30 patients subjected to coronary revascularization surgery. The plasma rates of thrombin-anti-thrombin complexes (TAT) and 1+2 prothrombin fragments (F1+2) were measured before and after surgery. The studies were performed by enzyme immunoassay techniques. Selective angiography was performed in every patient on the 10th day after surgery. Descriptive statistics, Student's t test and Mann-Whitney U test were used for comparison of means ans statistical analysis. Occlusive lesion was shown by angiography in 15 of the 30 patients. The TAT and F1+2 levels showed a statistically significant increase (p less than 0.001) along the postoperative period, without any correlation regarding the presence or absence of occlusion. The preoperative concentration of TAT was significantly higher in patients with thrombotic occlusion (p less than 0.05). 1) Marked activation of the coagulation system is present in patients subjected to coronary revascularization surgery. 2) The pre-operative determination of TAT may be of value for predicting early graft occlusion.


Subretinal Visual Implant Alpha IMS--Clinical trial interim report.
A subretinal visual implant (Alpha IMS, Retina Implant AG, Reutlingen, Germany) was implanted in 29 blind participants with outer retinal degeneration in an international multicenter clinical trial. Primary efficacy endpoints of the study protocol were a significant improvement of activities of daily living and mobility to be assessed by activities of daily living tasks, recognition tasks, mobility, or a combination thereof. Secondary efficacy endpoints were a significant improvement of visual acuity/light perception and/or object recognition (clinicaltrials.gov, NCT01024803). During up to 12 months observation time twenty-one participants (72%) reached the primary endpoints, of which thirteen participants (45%) reported restoration of visual function which they use in daily life. Additionally, detection, localization, and identification of objects were significantly better with the implant power switched on in the first 3 months. Twenty-five participants (86%) reached the secondary endpoints. Measurable grating acuity was up to 3.3 cycles per degree, visual acuities using standardized Landolt C-rings were 20/2000, 20/2000, 20/606 and 20/546. Maximal correct motion perception ranged from 3 to 35 degrees per second. These results show that subretinal implants can restore very-low-vision or low vision in blind (light perception or less) patients with end-stage hereditary retinal degenerations.


Use of a modified Robbins device to directly compare the adhesion of Staphylococcus epidermidis RP62A to surfaces.
Staphylococcus epidermidis is a frequent cause of infection associated with the use of biomedical devices. Flow cell studies of the interaction between bacteria and surfaces do not generally allow direct comparison of different materials using the same bacterial suspension. The use of a modified Robbins Device (MRD) to compare the adhesion to different surfaces of Staph. epidermidis RP62A grown in continuous culture was investigated. Adhesion to glass was compared with siliconized glass, plasma-conditioned glass, titanium, stainless steel and Teflon. Attachment to siliconized glass was also compared with glass under differing ionic strength, and divalent cation concentrations. Both the differences in numbers adhering and changes in adhesion (slope) through the MRD were compared. There was a trend towards higher numbers adhering to the discs at the in-flow end of the MRD than at the outflow end, probably reflecting depletion of adherent bacteria in the interacting stream. Adhesion of Staph. epidermidis RP62A to siliconized glass and Teflon was reduced when compared to glass with increasing flow rates. Adhesion to stainless steel was not affected by flow rate and titanium gave a different slope of adhesion through the MRD when compared with glass, suggesting an interaction with different sub-populations within the interacting stream. Differences between siliconized glass and glass at flow rates of 300 ml h-1 were abolished by the addition of calcium or EDTA and reduced by the addition of magnesium. Increasing ionic strength reduced the statistical significance of the differences between glass and siliconized glass. Pre-conditioning of glass with pooled human plasma reduced adhesion compared with untreated glass and again gave a different slope to glass. The MRD linked to a chemostat can be used to compare directly bacterial adhesion to potential biomaterials. Variable depletion of the interacting stream should be taken into account in the interpretation of results. Divalent cation concentration, substrate properties and flow rate were important determinants of the comparative adhesion of Staph. epidermidis RP62A to surfaces.


Nanoparticle-based systems for T(1)-weighted magnetic resonance imaging contrast agents.
Because magnetic resonance imaging (MRI) contrast agents play a vital role in diagnosing diseases, demand for new MRI contrast agents, with an enhanced sensitivity and advanced functionalities, is very high. During the past decade, various inorganic nanoparticles have been used as MRI contrast agents due to their unique properties, such as large surface area, easy surface functionalization, excellent contrasting effect, and other size-dependent properties. This review provides an overview of recent progress in the development of nanoparticle-based T1-weighted MRI contrast agents. The chemical synthesis of the nanoparticle-based contrast agents and their potential applications were discussed and summarized. In addition, the recent development in nanoparticle-based multimodal contrast agents including T1-weighted MRI/computed X-ray tomography (CT) and T1-weighted MRI/optical were also described, since nanoparticles may curtail the shortcomings of single mode contrast agents in diagnostic and clinical settings by synergistically incorporating functionality.


Effects of attentional filtering demands on preparatory ERPs elicited in a spatial cueing task.
We used ERP measures to investigate how attentional filtering requirements affect preparatory attentional control and spatially selective visual processing. In a spatial cueing experiment, attentional filtering demands were manipulated by presenting task-relevant visual stimuli either in isolation (target-only task) or together with irrelevant adjacent distractors (target-plus-distractors task). ERPs were recorded in response to informative spatial precues, and in response to subsequent visual stimuli at attended and unattended locations. The preparatory ADAN component elicited during the cue-target interval was larger and more sustained in the target-plus-distractors task, reflecting the demand of stronger attentional filtering. By contrast, two other preparatory lateralised components (EDAN and LDAP) were unaffected by the attentional filtering demand. Similar enhancements of P1 and N1 components in response to the lateral imperative visual stimuli were observed at cued versus uncued locations, regardless of filtering demand, whereas later attentional-related negativities beyond 200 ms post-stimulus were larger the target-plus-distractor task. Our results implicate that the ADAN component is linked to preparatory top-down control processes involved in the attentional filtering of irrelevant distractors; such filtering also affects later attention-related negativities recorded after the onset of the imperative stimulus. ERPs can reveal effects of expected attentional filtering of irrelevant distractors on preparatory attentional control processes and spatially selective visual processing.


Myosin light chain phosphorylation: modulation of basal and agonist-stimulated venular permeability.
We have previously demonstrated that agonists increase microvascular permeability through a phospholipase C-nitric oxide synthase-guanylate cyclase cascade. The aim of this study was to further investigate the downstream end of the signaling pathway with a focus on myosin light chain (MLC) phosphorylation. The apparent permeability coefficient to albumin was measured in isolated coronary venules. Under control conditions, the nitric oxide donor sodium nitroprusside, as well as the guanosine 3',5'-cyclic monophosphate-dependent protein kinase (PKG) activator 8-bromoguanosine 3',5'-cyclic monophosphate, increased venular permeability two- to threefold. Similarly, activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate significantly elevated permeability. Inhibition of MLC phosphorylation with ML-7 significantly attenuated the hyperpermeability responses to the agonists. Furthermore, ML-7 dose dependently reduced basal venular permeability. Consistently, inhibition of dephosphorylation with the protein phosphatase inhibitor calyculin dramatically increased basal permeability. These results suggest that 1) PKG and PKC play an important signaling role in the regulation of endothelial barrier function and 2) MLC phosphorylation contributes to basal and agonist-stimulated microvascular permeability.


Delivery of steric block morpholino oligomers by (R-X-R)4 peptides: structure-activity studies.
Redirecting the splicing machinery through the hybridization of high affinity, RNase H- incompetent oligonucleotide analogs such as phosphoramidate morpholino oligonucleotides (PMO) might lead to important clinical applications. Chemical conjugation of PMO to arginine-rich cell penetrating peptides (CPP) such as (R-Ahx-R)(4) (with Ahx standing for 6-aminohexanoic acid) leads to sequence-specific splicing correction in the absence of endosomolytic agents in cell culture at variance with most conventional CPPs. Importantly, (R-Ahx-R)(4)-PMO conjugates are effective in mouse models of various viral infections and Duchenne muscular dystrophy. Unfortunately, active doses in some applications might be close to cytotoxic ones thus presenting challenge for systemic administration of the conjugates in those clinical settings. Structure-activity relationship studies have thus been undertaken to unravel CPP structural features important for the efficient nuclear delivery of the conjugated PMO and limiting steps in their internalization pathway. Affinity for heparin (taken as a model heparan sulfate), hydrophobicity, cellular uptake, intracellular distribution and splicing correction have been monitored. Spacing between the charges, hydrophobicity of the linker between the Arg-groups and Arg-stereochemistry influence splicing correction efficiency. A significant correlation between splicing correction efficiency, affinity for heparin and ability to destabilize model synthetic vesicles has been observed but no correlation with cellular uptake has been found. Efforts will have to focus on endosomal escape since it appears to remain the limiting factor for the delivery of these splice-redirecting ON analogs.


Estimating Absorbed Dose to Breast Adipose Tissue from Mammograms.
Breast cancer usually originates in the glandular tissue of the breast. However, inflamed adipose tissue surrounding glandular tissue may expedite the local growth of cancerous cells. Exposing adipose tissue to radiation during mammography might cause inflammation in adipose tissue. This inflammation depends on the dose, and thus on the energy deposited from the X-ray mammography. Therefore, estimating the absorbed dose to adipose tissue during mammography is essential in breast cancer research. Absorbed dose to adipose tissue in the breast is determined using a new geometrical (semi-elliptical) model and Monte Carlo N-Particle transport code (MCNP6). X-ray mammogram images of patient breasts were taken as the basis of the new compressed breast geometry. The source probability density used in the MCNP6 code was generated from a published X-ray spectrum corresponding to tube voltage and air kerma. The relationship between various mammogram parameters such as peak tube voltage, compressed breast thickness, and adipose tissue weight fraction versus estimated absorbed dose is established for analysis. Significant influences of adipose tissue weight fraction on absorbed dose were observed. Estimating the absorbed dose to breast adipose tissue during mammography and patients' degree of obesity are important factors in breast cancer research.


Morphine treatment enhances glutamatergic input onto neurons of the nucleus accumbens via both disinhibitory and stimulating effect.
Drug addiction is a chronic brain disorder characterized by the compulsive repeated use of drugs. The reinforcing effect of repeated use of drugs on reward plays an important role in morphine-induced addictive behaviors. The nucleus accumbens (NAc) is an important site where morphine treatment produces its reinforcing effect on reward. However, how morphine treatment produces its reinforcing effect on reward in the NAc remains to be clarified. In the present study, we studied the influence of morphine treatment on the effects of DA and observed whether morphine treatment could directly change glutamatergic synaptic transmission in the NAc. We also explored the functional significance of morphine-induced potentiation of glutamatergic synaptic transmission in the NAc at behavioral level. Our results show that (1) morphine treatment removes the inhibitory effect of DA on glutamatergic input onto NAc neurons; (2) morphine treatment potentiates glutamatergic input onto NAc neurons, especially the one from the basolateral amygdala (BLA) to the NAc; (3) blockade of glutamatergic synaptic transmission in the NAc or ablation of projection neurons from BLA to NAc significantly decreases morphine treatment-induced increase in locomotor activity. These results suggest that morphine treatment enhances glutamatergic input onto neurons of the NAc via both disinhibitory and stimulating effect and therefore increases locomotor activity.


Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics.
Our associated microbial communities play a critical role in human health and predisposition to disease, but the degree to which they also shape therapeutic interventions is not well understood. Here, we integrate results from classic and current studies of the direct and indirect impacts of the gut microbiome on the metabolism of therapeutic drugs and diet-derived bioactive compounds. We pay particular attention to microbial influences on host responses to xenobiotics, adding to the growing consensus that treatment outcomes reflect our intimate partnership with the microbial world, and providing an initial framework from which to consider a more comprehensive view of pharmacology and nutrition.


The benefits of a high-intensity aquatic exercise program (HydrOS) for bone metabolism and bone mass of postmenopausal women.
This study aimed to evaluate the 24-week effects of a high-intensity aquatic exercise program on bone remodeling markers and bone mass of postmenopausal women. In this randomized, controlled trial we studied 108 women (58.8 ± 6.4 years), randomized into Aquatic Exercise Group (AEG), n = 64, performing 24 weeks of aquatic exercises, and Control Group (CG), n = 44, sedentary. They had their fasting morning blood sample collected for the measures of intact parathyroid hormone (iPTH), procollagen type 1 amino-terminal propeptide (P1NP) and carboxy-terminal cross-linking telopeptide of type I collagen (CTx). Bone mass was measured by dual-energy X-ray absorptiometry before and after the intervention. Participants of both groups received a daily supplementation of 500 mg of elementary calcium and 1,000 IU of vitamin D (cholecalciferol). Results showed an augment in bone formation marker (P1NP) only in the AEG (15.8 %; p = 0.001), and although both groups experienced significant enhancements in bone resorption marker (CTx), this increase was less considerable in the AEG (15 % in the AEG and 29 % in the CG). IPTH was increased by 19 % in the CG (p = 0.003) at the end. The femoral trochanter BMD presented a 1.2 % reduction in the CG (p = 0.009), whereas in the AEG no change was observed (p = 0.069). The proposed aquatic exercise program was efficient in attenuating bone resorption raise and enhancing bone formation, which prevented the participants in the AEG from reducing the femoral trochanter BMD, as happened in the CG.


Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose.
T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose-response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways.


The Holocene Asian monsoon: links to solar changes and North Atlantic climate.
A 5-year-resolution absolute-dated oxygen isotope record from Dongge Cave, southern China, provides a continuous history of the Asian monsoon over the past 9000 years. Although the record broadly follows summer insolation, it is punctuated by eight weak monsoon events lasting approximately 1 to 5 centuries. One correlates with the "8200-year" event, another with the collapse of the Chinese Neolithic culture, and most with North Atlantic ice-rafting events. Cross-correlation of the decadal- to centennial-scale monsoon record with the atmospheric carbon-14 record shows that some, but not all, of the monsoon variability at these frequencies results from changes in solar output.


Neurologic manifestations of novel influenza A (H1N1) virus infection in childhood.
The neurologic manifestations and prognoses of a novel influenza A (H1N1) virus infection in previously healthy children were evaluated. Nose and throat swabs were retrieved from all patients who met the criteria of influenza-like illness. A real time reverse-transcriptase polymerase chain reaction assay was used to confirm the novel influenza A (H1N1) virus. This viral infection was evident in 240 children between October 10 and December 22, 2009. Neurologic findings were evident in 17 (7.08%) patients, aged between 4 months and 8 years. Nine were boys. Five patients manifested simple febrile seizures, seven manifested complex febrile seizures or additional afebrile seizures, and three manifested encephalopathy. Febrile status epilepticus and flaccid paralysis were diagnosed in one patient each. All were treated with oseltamivir. Fifteen of 17 patients demonstrated complete recovery. One undergoing follow-up with a diagnosis of Guillain-Barré syndrome manifested sequelae. One patient died because of septic shock and disseminated intravascular coagulation. We suggest that neurologic manifestations occur quite often in children aged less than 5 years with novel influenza A (H1N1) virus infection. Most infections were benign, although a severe course is possible, and sequelae may be encountered.