Modulation of glycine potency in rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes.
Heteromeric NMDARs are composed of coagonist glycine-binding NR1 subunits and glutamate-binding NR2 subunits. The majority of functional NMDARs in the mammalian central nervous system (CNS) contain two NR1 subunits and two NR2 subunits of which there are four types (A-D). We show that the potency of a variety of endogenous and synthetic glycine-site coagonists varies between recombinant NMDARs such that the highest potency is seen at NR2D-containing and the lowest at NR2A-containing NMDARs. This heterogeneity is specified by the particular NR2 subunit within the NMDAR complex since the glycine-binding NR1 subunit is common to all NMDARs investigated. To identify the molecular determinants responsible for this heterogeneity, we generated chimeric NR2A/2D subunits where we exchanged the S1 and S2 regions that form the ligand-binding domains and coexpressed these with NR1 subunits in Xenopus laevis oocytes. Glycine concentration-response curves for NMDARs containing NR2A subunits including the NR2D S1 region gave mean glycine EC(50) values similar to NR2A(WT)-containing NMDARs. However, receptors containing NR2A subunits including the NR2D S2 region or both NR2D S1 and S2 regions gave glycine potencies similar to those seen in NR2D(WT)-containing NMDARs. In particular, two residues in the S2 region of the NR2A subunit (Lys719 and Tyr735) when mutated to the corresponding residues found in the NR2D subunit influence glycine potency. We conclude that the variation in glycine potency is caused by interactions between the NR1 and NR2 ligand-binding domains that occur following agonist binding and which may be involved in the initial conformation changes that determine channel gating.


Contemporary Management of Acute Aortic Occlusion Has Evolved but Outcomes Have Not Significantly Improved.
Most existing series of acute aortic occlusion (AAO) predate the changes in surgical and endovascular therapy of the last 2 decades. We examined the contemporary management and outcomes of AAO. We reviewed consecutive patients with AAO at a tertiary referral center from 2004 to 2012. Outcomes were stratified and compared according to etiology and procedure performed. AAO in 29 patients was due to in situ thrombosis in 21 (72%) and embolism in 8 (28%) patients. Vascular patients with embolism were on average older (77 ± 7 vs. 66 ± 12 years, P = 0.02) and had higher rates of atrial fibrillation (100% vs. 20%, P = 0.0002) and congestive heart failure (75% vs. 0%, P = 0.0001) in comparison with those with in situ thrombosis. Neurologic deficit was present in 16 (55%) patients. Six patients (21%) presented with bilateral paresis/paralysis secondary to spinal cord or lumbosacral plexus ischemia, and primary neurologic etiology was investigated before vascular consultation was obtained in 4 of these 6 patients. Of the 29 patients, 28 (97%) underwent revascularization including transfemoral embolectomy (n = 6), transperitoneal aortoiliac thrombectomy (n = 2), axillobifemoral bypass (n = 10), aortobifemoral bypass (n = 6), and endovascular therapy including thrombolysis, angioplasty ± stenting (n = 4). In-hospital mortality was 31% and did not vary significantly according to etiology (embolism 38% vs. in situ thrombosis 29%, P = 0.67). In-hospital mortality varied widely according to procedure (transfemoral embolectomy 50%, aortoiliac thrombectomy 100%, axillobifemoral bypass 30%, aortobifemoral bypass 0%, and endovascular therapy 25%, P = 0.08). Major morbidity (59%), length of stay (8.6 ± 8.0 days), and discharge to a rehabilitation facility (50%) did not vary by etiology or procedure. At a media follow-up of 361 ± 460 days (range 3-2014), overall survival was 42%. There were no amputations among 20 survivors of initial hospitalization. AAO is now more commonly caused by in situ thrombosis rather than embolism. A high index of suspicion for AAO is required for prompt diagnosis and treatment, particularly when patients present with profound lower extremity neurologic deficit. In comparison with previous reports, the contemporary management of AAO includes increased use of axillobifemoral bypass and now involves endovascular revascularization, although a variety of open surgical procedures are utilized. However, the in-hospital mortality and morbidity of AAO has not decreased significantly over the last 2 decades and mid-term survival remains limited. Further study is required to identify strategies that improve outcomes after AAO.


Placebo controls for acupuncture studies.
Many studies of acupuncture treatment are seriously flawed by methodological problems. Poor design, inadequate measures and statistical analysis, lack of follow-up data and sub-standard treatment are all too common. However, the major problem, which many investigators consider to be still unresolved, is the definition of an appropriate placebo control. The use of inappropriate placebo controls has bedeviled acupuncture research and led to serious misinterpretation of the results of clinical trials. While a number of different solutions have been proposed there is, as yet, no agreed way of assessing the adequacy of control conditions or of deciding which placebo to use in a particular trial. We propose that assessing the credibility of treatments and control conditions may provide a way forward to a more rigorous, consensus approach.


Rapid detection of antibiotic resistance in positive blood cultures by MALDI-TOF MS and an automated and optimized MBT-ASTRA protocol for Escherichia coli and Klebsiella pneumoniae.
Introduction: For fast and effective antibiotic therapy of serious infections like sepsis, it is crucial with rapid information about antibiotic susceptibility, especially in a time when the number of infections caused by multi resistant bacteria has escalated in the world.Methods: Here, we have used a semi-quantitative MALDI-TOF-MS based method for antibiotic resistance detection, MBT-ASTRA™, which is based on the comparison of growth rate of the bacteria cultivated with and without antibiotics. We demonstrate a new protocol where several parameters have been optimized and automated leading to reduced hands-on time and improved capacity to simultaneously analyse multiple clinical samples and antibiotics.Results: Ninety minutes of incubation at 37 °C with agitation was sufficient to differentiate the susceptible and resistant strains of E. coli and K. pneumoniae, for the antibiotics cefotaxime, meropenem and ciprofloxacin. In total, 841 positive blood culture analyses of 14 reference strains were performed. The overall sensitivity was 99%, specificity 99% and the accuracy 97%. The assay gave no errors for cefotaxime (n = 263) or meropenem (n = 289) for sensitive and resistant strains, whilst ciprofloxacin (n = 289) gave six (0.7%) major errors (false resistance) and four (0.5%) very major errors (false susceptibility). The intermediate strains showed a larger variety compared to the E-test MIC values.Conclusions: The hands-on time and the analysis time to detect antibiotic resistance of clinical blood samples can be substantially reduced and the sample capacity can be increased by using automation and this improved protocol.


Posterior Lumbar Stabilization Surgery under Spinal Anesthesia for High-Risk Patients with Degenerative Spondylolisthesis, Spinal Stenosis and Lumbar Compression Fracture.
Spinal anesthesia is an appropriate technique for lumbar spine surgeries of two to three hours duration. The aim of this study is to document our experience on spinal anesthesia administered to the patients with degenerative lumbar spine. A total of 497 patients underwent spinal stabilization surgery with spinal anesthesia for degenerative lumbar spinal disorders in an 8-year period. Spinal anesthesia was performed at the L3-L4 or L4-L5 level and subarachnoid block was achieved with 15 mg of 0.5% plain bupivacaine with 2 μg of fentanyl and 0.2 mg of epinephrine. There was no failure of anesthesia. The patients were closely monitored for complications associated with the SA technique and especially hypotension and bradycardia but no gross alterations in cardiovascular stability were noted. Among the 497 patients, 139 were male and 358 were female with a median age of 51 years. The average anesthesia duration was 130 minutes and the average operative time was 85 minutes. In the postoperative period 36 patients has nausea (7.2%) and 18 of them had vomiting (3.6%) that required one dose of antiemetic. No spinal headache was observed and 36 (7.2%) patients complained of urinary retention. All recovered with urinary cannulation within 24 hours. No respiratory complication occurred and no patient died. Spinal anesthesia is a safe and effective procedure for the lumbar spinal stabilization surgery, especially in high-riskpatients. Proper precautions should be taken in order to achieve an effective anesthesia for these operations.


Flow cytometry of fine needle aspirations of the Sprague-Dawley rat testis: defining normal maturation and the effects of multiple biopsies.
Quantitative assessment of spermatogenesis by flow cytometry reproducibly correlates with histological examination. Flow cytometry of fine needle aspirates from the testis was used to analyze normal spermatogenesis of Sprague-Dawley rats. Aged matched male weanlings were divided into 3 groups: group 1-5 rats underwent bilateral percutaneous aspiration of the testes with a 22 gauge Chiba needle on postpartum days 19, 24, 30 and 40; group 2-5 rats aspirated on days 24, 30 and 40, and group 3-4 rats aspirated on days 30 and 40. This sequential approach allowed for evaluation of normal spermatogenesis and the effects of repeated fine needle aspiration on spermatogenesis. Deoxyribonucleic acid distribution analysis by flow cytometry correlates with haploid (1N), diploid (2N), tetraploid (4N) and S phase cell populations. These cell populations were evaluated and comparisons among each group were made at all biopsy times. No significant differences in mean 2N, 4N or S phase cell populations in single versus repeat biopsied testes were detected. However, there was a significant increase in the 1N population at 30 days post partum in the repeat biopsy group (p = 0.037), which normalized by day 40. This increase in 1N corresponds to the beginning of meiosis, which is maximal between postpartum days 30 and 40, and occurs earlier in the repeat biopsied testis. Repeat fine needle aspiration of the testis can be performed without significantly affecting spermatogenesis in the "weanling" rat. This provides a useful technique in the future investigations of the time related effects of varicocele, chemotherapy and toxicologic drugs on spermatogenesis.


Mirror, mirror on the wall: which microbiomes will help heal them all?
Clinicians have known for centuries that there is substantial variability between patients in their response to medications-some individuals exhibit a miraculous recovery while others fail to respond at all. Still others experience dangerous side effects. The hunt for the factors responsible for this variation has been aided by the ability to sequence the human genome, but this just provides part of the picture. Here, we discuss the emerging field of study focused on the human microbiome and how it may help to better predict drug response and improve the treatment of human disease. Various clinical disciplines characterize drug response using either continuous or categorical descriptors that are then correlated to environmental and genetic risk factors. However, these approaches typically ignore the microbiome, which can directly metabolize drugs into downstream metabolites with altered activity, clearance, and/or toxicity. Variations in the ability of each individual's microbiome to metabolize drugs may be an underappreciated source of differences in clinical response. Complementary studies in humans and animal models are necessary to elucidate the mechanisms responsible and to test the feasibility of identifying microbiome-based biomarkers of treatment outcomes. We propose that the predictive power of genetic testing could be improved by taking a more comprehensive view of human genetics that encompasses our human and microbial genomes. Furthermore, unlike the human genome, the microbiome is rapidly altered by diet, pharmaceuticals, and other interventions, providing the potential to improve patient care by re-shaping our associated microbial communities.


Four-legged friend or foe? Dog walking displaces native birds from natural areas.
Dog walking is among the world's most popular recreational activities, attracting millions of people to natural areas each year with diverse benefits to human and canine health. But conservation managers often ban dog walking from natural areas fearing that wildlife will see dogs as potential predators and abandon their natural habitats, resulting in outcry at the restricted access to public land. Arguments are passionate on both sides and debate has remained subjective and unresolved because experimental evidence of the ecological impacts of dog walking has been lacking. Here we show that dog walking in woodland leads to a 35% reduction in bird diversity and 41% reduction in abundance, both in areas where dog walking is common and where dogs are prohibited. These results argue against access by dog walkers to sensitive conservation areas.


The psycholinguistic and affective structure of words conveying pain.
Despite the flourishing research on the relationships between affect and language, the characteristics of pain-related words, a specific type of negative words, have never been systematically investigated from a psycholinguistic and emotional perspective, despite their psychological relevance. This study offers psycholinguistic, affective, and pain-related norms for words expressing physical and social pain. This may provide a useful tool for the selection of stimulus materials in future studies on negative emotions and/or pain. We explored the relationships between psycholinguistic, affective, and pain-related properties of 512 Italian words (nouns, adjectives, and verbs) conveying physical and social pain by asking 1020 Italian participants to provide ratings of Familiarity, Age of Acquisition, Imageability, Concreteness, Context Availability, Valence, Arousal, Pain-Relatedness, Intensity, and Unpleasantness. We also collected data concerning Length, Written Frequency (Subtlex-IT), N-Size, Orthographic Levenshtein Distance 20, Neighbor Mean Frequency, and Neighbor Maximum Frequency of each word. Interestingly, the words expressing social pain were rated as more negative, arousing, pain-related, and conveying more intense and unpleasant experiences than the words conveying physical pain.


Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: pooled analysis of randomized controlled trials.
Zinc deficiency is prevalent in children in developing countries. Supplemental zinc provides therapeutic benefits in diarrhea. We sought to measure the effect of supplemental zinc given with oral rehydration therapy during recovery from acute or persistent diarrhea. We conducted pooled analyses including all available published and unpublished randomized controlled trials of the effects of supplementary oral zinc in children aged <5 y with acute or persistent diarrhea. We used Cox survival regression analysis to evaluate the overall effect of zinc on continuation of diarrhea and possible differential effects in subgroups divided by sex, age, weight-for-height, and initial plasma zinc concentration. Dichotomous outcomes were analyzed by logistic regression. To assess the effects of excluding studies without original data from the pooled analyses, effect-size was estimated for all studies by using random-effects models. Zinc-supplemented children had a 15% lower probability of continuing diarrhea on a given day (95% CI: 5%, 24%) in the acute-diarrhea trials and a 24% lower probability of continuing diarrhea (95% CI: 9%, 37%) and a 42% lower rate of treatment failure or death (95% CI: 10%, 63%) in the persistent-diarrhea trials. In none of the subgroup analyses were the 2 subgroups of each pair significantly different from each other; however, in persistent diarrhea there tended to be a greater effect in subjects aged <12 mo, who were male, or who had wasting or lower baseline plasma zinc concentrations. Zinc supplementation reduces the duration and severity of acute and persistent diarrhea.


Absolute measurement of surface roughness.
In an interferometer which uses a reference surface, the measured surface heights correspond to the difference between the test and reference surfaces. To accurately determine the rms roughness of supersmooth surfaces, the effects of the reference surface roughness need to be removed. One technique for doing this involves averaging a number of uncorrelated measurements of a mirror to generate a reference surface profile which can then be subtracted from subsequent measurements so that they do not contain errors due to the reference surface. The other technique provides an accurate rms roughness of the surface by taking two uncorrelated measurements of the surface. These two techniques for measurement of supersmooth surfaces are described in detail, and results of the measurement of a 0.7-A rms roughness mirror are presented. The expected error in the rms roughness measurement of a supersmooth mirror due to instrument noise is 0.02 A.


Titania-coated gold nanorods with expanded photocatalytic response. Enzyme-like glucose oxidation under near-infrared illumination.
Gold nanorods coated with a uniform titanium dioxide nanoshell have been prepared and used as glucose-oxidase surrogates. Remarkably, this core-shell photocatalytic nanostructure has been able to induce complete oxidation of glucose at near room temperature (32-34 °C) in a wide range of pH values with the aid of a near-infrared (NIR) irradiation source. In contrast, the uncoated gold nanorods exhibit negligible photo-oxidation response under identical experimental conditions thereby proving the photoactivity of the titania shell towards glucose oxidation. The process takes place via in situ photo-generation of singlet oxygen or hydroxyl radicals as reactive oxidative species (ROS). This underlines the role played by the core nanorods as plasmonic light harvesters in the NIR range and constitutes the first example of a NIR-activated enzyme-like catalyst.


Undersulfated chondroitin sulfate does not increase in osteoarthritic cartilage.
To test whether there is undersulfation of chondroitin sulfate in osteoarthritic bovine articular cartilage to support the hypothesis that sulfate deficiency is involved with the development of osteoarthritis. Cartilage samples from bovine patellae (n = 32) were divided into 3 groups based on their osteoarthritic progression, as assessed by modified Mankin score. Uronic acid contents of the samples were determined. Fragmentation of the proteoglycans due to proteolytic processing was estimated with agarose gel electrophoresis. The molar ratios of chondroitin sulfate isoforms in the extracted proteoglycans were determined with fluorophore-assisted carbohydrate electrophoresis. Loss of proteoglycans and accumulation of tissue water was evident in groups II and III, and progressive OA increased heterogeneity of aggrecan population in groups II and III. Importantly, the molar ratio of nonsulfated disaccharide was decreased in the osteoarthritic articular cartilage. The structure of chondroitin sulfate in degenerated bovine cartilage did not support the hypothesis that sulfate depletion is present in osteoarthritic joint.


Acute mountain sickness is related to nocturnal hypoxemia but not to hypoventilation.
The purpose of the study was to investigate determinants of acute mountain sickness after rapid ascent to high altitude. A total of 21 climbers were studied ascending from <1,200 m to Capanna Regina Margherita, a hut in the Alps at 4,559 m, within <24 h. During their overnight stay at 4,559 m, breathing patterns and ventilation were recorded by calibrated respiratory inductive plethysmography along with pulse oximetry. In the following morning, acute mountain sickness was assessed. Altogether, 11 mountaineers developed pronounced symptoms of acute mountain sickness (Lake Louise score > or =5) and 10 did not (controls). Compared to controls, subjects with acute mountain sickness had lower nocturnal oxygen saturation (mean+/-SD 59+/-13% versus 73+/-6%), higher minute ventilation (7.94+/-2.35 versus 6.06+/-1.34 L x min(-1)), and greater mean inspiratory flow, a measure of respiratory centre drive (0.29+/-0.09 versus 0.22+/-0.05 L x s(-1)). Periodic respiration was prevalent but not significantly different among the two groups (apnoea/hypopnea index 60.1+/-34.6 versus 47.1+/-42.6 events per h). The data suggest that pronounced nocturnal hypoxemia, which was not related to hypoventilation, may have promoted acute mountain sickness. Periodic breathing seems not to play a predominant role in the pathogenesis of acute mountain sickness.


MicroRNA regulation of expression of the cystic fibrosis transmembrane conductance regulator gene.
The CFTR (cystic fibrosis transmembrane conductance regulator) gene shows a complex temporal and spatial pattern of expression that is controlled by multiple cis-acting elements interacting with the basal promoter. Although significant progress has been made towards understanding these genomic elements, there have been no reports of post-transcriptional regulation of CFTR by miRNAs (microRNAs). In the present study, we identify two miRNAs, hsa-miR-145 and hsa-miR-494, which regulate CFTR expression by directly targeting discrete sites in the CFTR 3' UTR (untranslated region). We show that at least 12 miRNAs are capable of repressing endogenous CFTR mRNA expression in the Caco-2 cell line. Ten of these also inhibit expression of a reporter construct containing the CFTR 3' UTR in one or more cell lines, and five repress endogenous CFTR protein expression in Caco-2 cells. Moreover, at least three are expressed in primary human airway epithelial cells, where CFTR expression is maintained at low levels in comparison with intestinal cell lines. Three of the miRNAs that target CFTR, hsa-miR-384, hsa-miR-494 and hsa-miR-1246, also inhibit expression of a reporter carrying the Na(+)-K(+)-Cl(-) co-transporter SLC12A2 [solute carrier family 12 (Na(+)-K(+)-Cl(-) transporters), member 2] 3' UTR, suggesting that these miRNAs may play a more general role in regulating chloride transport in epithelial cells.


Influence of dietary nucleotide restriction on bacterial sepsis and phagocytic cell function in mice.
Although enzyme defects in purine metabolism have revealed the importance of these substrates to maintenance of a normal immune response, the role of exogenous nucleotides on the cells that mediate the host defense system has remained largely unexplored. Recent investigations have revealed that dietary nucleotides are vital to the maintenance of cell-mediated responses to antigen stimulation. To test the influence of dietary nucleotide deprivation on resistance to infection, Balb/c mice were maintained on chow, a nucleotide-free (NF) diet, or an NF diet repleted with adenine, uracil, or RNA. Mice on the NF diet suffered 100% mortality following intravenous challenge with Staphylococcus aureus, while chow-fed and RNA- or uracil-repleted mice demonstrated significantly greater resistance to this bacterial challenge. Macrophages from mice on the NF diet had decreased phagocytic activity as measured by uptake of radiolabeled bacteria compared with mice maintained on the NF diet supplemented with adenine, uracil, or RNA. No change in S aureus antibody response was noted on the various diets. Although the mechanism of this suppression of nonspecific immunity remains unclear, provision of nucleotides to defined diets appears vital to maintain host resistance to bacterial challenge.


Enhanced basal lubrication and the contribution of the Greenland ice sheet to future sea-level rise.
We assess the effect of enhanced basal sliding on the flow and mass budget of the Greenland ice sheet, using a newly developed parameterization of the relation between meltwater runoff and ice flow. A wide range of observations suggest that water generated by melt at the surface of the ice sheet reaches its bed by both fracture and drainage through moulins. Once at the bed, this water is likely to affect lubrication, although current observations are insufficient to determine whether changes in subglacial hydraulics will limit the potential for the speedup of flow. An uncertainty analysis based on our best-fit parameterization admits both possibilities: continuously increasing or bounded lubrication. We apply the parameterization to four higher-order ice-sheet models in a series of experiments forced by changes in both lubrication and surface mass budget and determine the additional mass loss brought about by lubrication in comparison with experiments forced only by changes in surface mass balance. We use forcing from a regional climate model, itself forced by output from the European Centre Hamburg Model (ECHAM5) global climate model run under scenario A1B. Although changes in lubrication generate widespread effects on the flow and form of the ice sheet, they do not affect substantial net mass loss; increase in the ice sheet's contribution to sea-level rise from basal lubrication is projected by all models to be no more than 5% of the contribution from surface mass budget forcing alone.


Collagen-induced rapid morphogenesis of human mammary epithelial cells: the role of the alpha 2 beta 1 integrin.
The cell line MTSV1-7, originally derived by immortalizing mammary epithelial cells cultured from human milk was able to form three-dimensional structures in collagen gel. We have now found that these cells, cultured as a monolayer, are able to undergo rapid morphogenesis forming ridges and balls around collagen fibres, when soluble collagen type I is added to the medium. Monoclonal antibodies to the alpha 2 (P1E6) and beta 1- (mAB13) subunits of VLA-2, but not to the alpha 3-subunit (P1B5) of VLA-3, could block this collagen-induced rapid morphogenesis (CIRM). The effect of the antibodies on cell attachment, spreading, and migration on collagen gels was analyzed to identify alpha 2 beta 1 dependent steps which might be involved in CIRM. The results suggest that while other proteins, besides alpha 2 beta 1, are also involved in cell attachment and migration, cell spreading was specifically blocked by antibodies to the VLA-2, but not to the VLA-3 integrin. The results demonstrate that the alpha 2 beta 1 integrin plays a crucial role in the collagen-induced morphogenesis of human mammary epithelial cells and implicate the process of VLA-2-dependent cell spreading as an important step in this morphogenesis.


Suicide by persons with foreign background in Japan.
This study examined trends in the suicide rates of persons with foreign background in Japan. Using the nationwide death records in the Vital Statistics of Japan, we first reported the age-adjusted suicide rates of 8 foreign nationals (Brazil, China, Korea, Peru, the Philippines, Thailand, the United Kingdom, and the United States) in Japan by sex from 1980 to the mid-2010s. We also computed rate ratios to compare the suicide rate of each group with those of the Japanese population. Second, we focused on Koreans, who had the highest suicide rate in Japan. We compared the suicide rates of Koreans in Japan with Koreans in South Korea to examine whether their suicide rates were more closely related to those of their country of origin or those of their host country. We found that the suicide rates of Koreans and Chinese in Japan were similar to or higher than those of Japanese, while other groups tended to show lower suicide rates. Most notably, Koreans displayed consistently high suicide rates from 1980 to the mid-2010s, which were nearly twice as high as those of the Japanese population. Korean males and females in Japan had higher suicide rates than those in South Korea. Immigrants in Japan were not necessarily influenced by the suicide rates of the host country. The high suicide rates among Korean residents in Japan might be explained by various disadvantages and adversities that they face in Japan.


Tocilizumab is clinically, functionally, and radiographically effective and safe either with or without low-dose methotrexate in active rheumatoid arthritis patients with inadequate responses to DMARDs and/or TNF inhibitors: a single-center retrospective cohort study (KEIO-TCZ study) at week 52.
To explore the effectiveness and safety of tocilizumab (TCZ) with or without methotrexate (MTX) in active rheumatoid arthritis (RA) patients showing inadequate responses to DMARDs and/or TNF inhibitors in clinical practice. We observed consecutive 115 RA patients initiating TCZ treatment in Keio University Hospital, dividing them into two groups with (TCZ + MTX group) or without MTX (TCZ group), and evaluated clinical, functional and structural outcomes besides safety at week 52. Overall mean age, RA duration, and DAS28-ESR were 55.4, 8.4 years, and 5.0, respectively. Proportions of the prior use of TNF inhibitors and concomitant MTX were 45.5% and 57.4%, respectively. Mean dose of concomitant MTX was 8.4 mg/week. Baseline characteristics were comparable between the groups. TCZ improved disease activity measured by DAS28-ESR to 2.1 at week 52 overall, without significant difference between the groups. Clinical (DAS28-ESR < 2.6), functional (HAQ-DI ≤ 0.5), and structural (ΔTSS ≤ 0.5) remission rates in the TCZ group and the TCZ + MTX group were 79.1%/63.8% (P = 0.10), 62.8%/54.4% (P = 0.40), and 70.0%/53.8% (P = 0.61), respectively. Retention rates were 81.0% in the TCZ + MTX group and 88.5% in the TCZ group (P = 0.47). The rate of serious adverse events was comparable between the groups. TCZ was clinically, functionally, and radiographically effective and safe either with or without low-dose MTX.


Heterogeneous Cu-Pd binary interface boosts stability and mass activity of atomic Pt clusters in the oxygen reduction reaction.
A ternary metallic CuPdPt nanocatalyst (NC) is synthesized using a wet chemical reduction method, which is sequentially designed, in the presence of acid treated carbon nanotubes. This NC is a nanocrystal with a configuration of a Cu@Pd core and atomic Pt clusters (∼9 wt%) on the top (Cu@Pd/Pt). A residual current of 92.6%, 5.2 times higher than that of commercial Pt catalysts (at 0.85 V vs. RHE), is retained after 40 000 cycles of an accelerated degradation test (ADT). Atomic and electronic structure analyses show that such exclusive stability mainly results from electron localization at Pt clusters in heterogeneous interfaces of the Cu-Pd core. Most importantly, we develop a robust ternary NC, which shows outstanding MA, superior chemical durability, and ∼90 wt% lower Pt loading than commercial Pt NCs in the oxygen reduction reaction.


In humans IL-6 is released from the brain during and after exercise and paralleled by enhanced IL-6 mRNA expression in the hippocampus of mice.
Plasma interleukin-6 (IL-6) increases during exercise by release from active muscles and during prolonged exercise also from the brain. The IL-6 release from muscles continues into recovery and we tested whether the brain also releases IL-6 in recovery from prolonged exercise in humans. Additionally, it was evaluated in mice whether brain release of IL-6 reflected enhanced IL-6 mRNA expression in the brain as modulated by brain glycogen levels. Nine healthy male subjects completed 4 h of ergometer rowing while the arterio-jugular venous difference (a-v diff) for IL-6 was determined. The IL-6 mRNA and the glycogen content were determined in mouse hippocampus, cerebellum and cortex before and after 2 h treadmill running (N = 8). At rest, the IL-6 a-v diff was negligible but decreased to -2.2 ± 1.9 pg ml(-1) at the end of exercise and remained low (-2.1 ± 2.1 pg ml(-1) ) 1 h into the recovery (P < 0.05 vs. rest). IL-6 mRNA was expressed in the three parts of the brain with the lowest content in the hippocampus (P < 0.05) coupled to the highest glycogen content (3.2 ± 0.8 mmol kg(-1) ). Treadmill running increased the hippocampal IL-6 mRNA content 2-3-fold (P < 0.05), while the hippocampal glycogen content decreased to 2.6 ± 0.6 mmol kg(-1) (P < 0.05) with no significant changes in the two other parts of the brain. Human brain releases IL-6 both during and in recovery from prolonged exercise and mouse data suggest that concurrent changes in IL-6 mRNA and glycogen levels make the hippocampus a likely source of the IL-6 release from the brain.


Brace evaluation in children with diplegic cerebral palsy with a jump gait pattern.
Brace prescription for children with diplegic cerebral palsy challenges the clinician with a variety of options and little evidence for rational decisions. Previous studies have indicated that ankle-foot orthoses improve toe-walking, but it is unclear if any brace is better than another. The goal of the present study was to compare the effectiveness of hinged and dynamic ankle-foot orthoses in terms of improving gait and motor function in a homogeneous group of children with diplegic cerebral palsy exhibiting a jump gait pattern. Fifteen children (mean age, 7.5 years) with spastic diplegic cerebral palsy who were able to walk independently with a jump gait pattern and twenty children (mean age, 10.6 years) with normal gait participated in the study. Standardized Gross Motor Function Classification System scores, Pediatric Outcomes Data Collection Instrument scores, and gait data were collected, analyzed, and compared. The subjects were tested while barefoot and while wearing hinged and dynamic ankle-foot orthoses. Data were analyzed to detect differences among these conditions. Significant improvements in gait metrics were seen during brace wear. No significant differences were seen between the two different braces used. The barefoot and braced conditions differed most significantly in terms of ankle kinematics and kinetics. Among the patients with cerebral palsy, no significant differences in the standardized outcome measurements were found between the braced and unbraced conditions or between the two braced conditions. Our data suggest that gait improves with brace wear in children with cerebral palsy with a level-I Gross Motor Function Classification System score. The Pediatric Outcomes Data Collection Instrument and the Gross Motor Function Measure were not sensitive to brace treatment in the population studied. The hinged and dynamic braces were equally effective for improving ankle kinematics and kinetics in these relatively highly functioning children with cerebral palsy.


Quantitative assessment of promoter methylation profiles in thyroid neoplasms.
Cancer-specific molecular markers are needed to supplement the cytopathological assessment of thyroid tumors, because a majority of patients with cytologically indeterminate nodules currently undergo thyroidectomy without a definitive diagnosis. The aim of this study was the quantitative assessment of promoter hypermethylation and its relation to the BRAF mutation in thyroid tumors. Quantitative hypermethylation of Rassf1A, TSHR, RAR-beta2, DAPK, S100, p16, CDH1, CALCA, TIMP3, TGF-beta, and GSTpi was tested on a cohort of 82 benign and malignant thyroid tumors and five thyroid cancer cell lines. The study was conducted at a tertiary research hospital. Patients underwent surgical resection for a thyroid tumor from 2000 to 2003 at our institution. There were no interventions. Final surgical pathology diagnosis was the main outcome measure. Thyroid tumors showed hypermethylation for the following markers: Rassf1A, TSHR, RAR-beta2, DAPK, CDH1, TIMP3, and TGF-beta. A trend toward multiple hypermethylation was evident in cancer tissues, with hypermethylation of two or more markers detectable in 25% of hyperplasias, 38% of adenomas, 48% of thyroid cancers, and 100% of cell lines. A rank correlation analysis of marker hypermethylation suggests that a subset of these markers is epigenetically modified in concert, which may reflect an organ-specific regulation process. Furthermore, a positive correlation was found between the BRAF mutation and RAR-beta2, and a negative correlation was found between the BRAF mutation and Rassf1A. Methylation-induced gene silencing appears to affect multiple genes in thyroid tissue and increases with cancer progression. Additional markers with better discriminatory power between benign and malignant samples are needed for the diagnostic assessment of cytologically indeterminate thyroid nodules.


Adrenal axis function after high-dose steroid therapy for childhood acute lymphoblastic leukemia.
A 4-week course of high-dose glucocorticoids may cause prolonged adrenal suppression even after a 9-day tapering phase. In this study, adrenal function and signs and symptoms of adrenal insufficiency were prospectively assessed in children with acute lymphoblastic leukemia (ALL) after induction treatment including high-dose prednisone (PDN) or dexamethasone (DXM). Sixty-four children with ALL, treated according to the AIEOP ALL 2000 Study protocol, underwent low dose ACTH (LD-ACTH) stimulation 24 hr after the last tapered steroid dose. In those with impaired cortisol response, additional LD ACTH tests were performed every 1-2 weeks until cortisol levels normalized. Signs and symptoms of adrenal insufficiency were recorded during the observation period. All patients had normal basal cortisol values at diagnosis. Twenty-four hours after last glucocorticoid dose, morning cortisol was reduced in 40/64 (62.5%) patients. LD-ACTH testing showed adrenal suppression in 52/64 (81.5%) patients. At the following ACTH test 7-14 days later, morning cortisol values were reduced in 8/52 (15.4%) patients and response to the test was impaired in 12/52 (23%). Adrenal function completely recovered in all patients within 10 weeks. No difference was found between patients treated with PDN or DXM. Almost 35% of children with impaired cortisol values at the first test developed signs or symptoms of adrenal insufficiency. One child developed a severe adrenal crisis during adrenal suppression. High-dose glucocorticoid therapy in ALL children may cause prolonged adrenal suppression and related clinical symptoms. Laboratory monitoring of cortisol levels and steroid coverage during stress episodes may be indicated.


Detection of phytoplankton pigments from ocean color: improved algorithms.
Passive ocean-color data at 32 wavelengths in the visible domain and laser-induced fluorescence line heights of chlorophyll and phycoerythrin, measured simultaneously from an aircraft in the New York Bight area, are used to examine the problem of developing algorithms for pigment retrieval from ocean-color data that would be capable of distinguishing between chlorophyll and phycoerythrin. Using factor analysis, it is shown that it is indeed possible to develop such algorithms. Furthermore, the wavelengths used in the algorithms can be reduced from 32 to 6 (similar to the SeaWiFS channels) without much loss in information. These multiwavelength algorithms yield significantly higher correlation coefficients for chlorophyll compared with the conventional blue-green ratio used for retrieval of this pigment. The Coastal Zone Color Scanner wavelengths appear to be inadequate for quantitative retrieval of the phycoerythrin signal.


Prestimulus neural alpha power predicts confidence in discriminating identical auditory stimuli.
When deciding upon a sensory stimulus, the power of prestimulus neural alpha oscillations (~10 Hz) has been shown to hold information on a perceiver's bias, or confidence, as opposed to perceptual sensitivity per se. Here, we test whether this link between prestimulus alpha power and decision confidence, previously established in vision and somatosensation, also holds in the auditory modality. Moreover, confidence usually depends on the physical evidence available in the stimulus as well as on decision accuracy. It is unclear in how far the link between prestimulus alpha power and confidence holds when physical stimulus evidence is entirely absent, and thus accuracy does not vary. We here analysed electroencephalography data from a paradigm where human listeners (N = 17) rated their confidence in the discrimination of the pitch of two tones that were, unbeknownst to the listeners, identical. Lower prestimulus alpha power as recorded at central channel sites was predictive of higher confidence ratings. Furthermore, this link was not mediated by auditory evoked activity. Our results support a direct link between prestimulus alpha power and decision confidence. This effect, first, shows up in the auditory modality similar to vision and somatosensation, and second, is present also in the complete absence of physical evidence in the stimulus and in the absence of varying accuracy. These findings speak to a model wherein low prestimulus alpha power increases neural baseline excitability, which is reflected in enhanced stimulus-evoked neural responses and higher confidence.


Urokinase-type plasminogen activator system in breast cancer: association with tamoxifen therapy in recurrent disease.
The prognostic value of components of the urokinase-type plasminogen activator (uPA) system, its receptor uPAR (CD87), and plasminogen activator inhibitors PAI-1 and PAI-2 is well established. We studied the predictive value of these proteolytic factors by evaluating the association of their tumor expression level and the efficacy of tamoxifen therapy in patients with recurrent breast cancer. The antigen levels of the four factors were determined by ELISA in cytosols prepared from estrogen receptor-positive primary breast tumors of 691 hormone-naive breast cancer patients with recurrent disease and treated with tamoxifen as first-line systemic therapy. High tumor levels of uPA (P < 0.001), uPAR (P < 0.01), and PAI-1 (P = 0.01) were associated with a lower efficacy of tamoxifen therapy. In the multivariable analysis, uPA (P < 0.001) provided additional information independent of the traditional predictive factors to predict benefit from tamoxifen therapy. High levels of uPA, uPAR, and PAI-1 predicted a shorter progression-free survival (PFS) on tamoxifen in an analysis of the first 9 months of therapy. However in the analysis during the total follow-up period, high PAI-2 levels (P = 0.01) showed a longer response to tamoxifen. In conclusion, uPA, uPAR, and PAI-1, components of the urokinase system, are predictive for the efficacy of tamoxifen therapy in patients treated for recurrent breast cancer. Knowledge of their tumor expression levels might be helpful for future individualized therapy protocols, including possible new-targeted therapies based on the interference in the urokinase system.


Replicative senescence in sheep fibroblasts is a p53 dependent process.
Studies on telomere and telomerase biology are fundamental to the understanding of human ageing, and age-related diseases such as cancer. However, human studies are hampered by the lack of fully reflective animal model systems. Here we describe basic studies of telomere length and telomerase activity in sheep tissues and cells. Terminal restriction fragment lengths from sheep tissues ranged from 9 to 23 kb, with telomerase activity present in testis but suppressed in somatic tissues. Sheep fibroblasts had a finite lifespan in culture, after which the cells entered senescence. During in vitro growth the mean terminal restriction fragment lengths decreased in size at a rate of 210 and 350 bp per population doubling (PD). Senescent skin fibroblasts had increased levels of p53 and p21WAF1 compared to young cells. Incubation of senescent cells with siRNA duplexes specific for p53 suppressed p53 expression and allowed the cells to re-enter the cell cycle. Five PDs beyond senescence the siRNA-treated cells reached a second proliferative barrier. This study shows that telomere biology in sheep is similar to that in humans, with senescence in sheep GM03550 fibroblasts being a telomere-driven, p53-(p21WAF1)-dependent process. Therefore sheep may represent an alternative model system for studying telomere biology, replicative senescence, and by implication human ageing.


A standardized citation metrics author database annotated for scientific field.
Citation metrics are widely used and misused. We have created a publicly available database of 100,000 top scientists that provides standardized information on citations, h-index, coauthorship-adjusted hm-index, citations to papers in different authorship positions, and a composite indicator. Separate data are shown for career-long and single-year impact. Metrics with and without self-citations and ratio of citations to citing papers are given. Scientists are classified into 22 scientific fields and 176 subfields. Field- and subfield-specific percentiles are also provided for all scientists who have published at least five papers. Career-long data are updated to end of 2017 and to end of 2018 for comparison.


Spontaneous unilamellar polymer vesicles in aqueous solution.
A unilamellar polymeric vesicle is a self-assembled structure of a block copolymer that forms a spherical single bilayer structure with a hydrophobic interlayer and a hydrophilic surface. Due to their enhanced colloidal stability and mechanical property, controllable surface functionality, or tunable membrane thickness, polymeric vesicles are useful in nano and bio-science, providing potential applications as nanosized carriers for catalysts, drugs, and enzymes. For fabrication of a unilamellar vesicle, however, preparative procedures with a few steps are inherently required. Herein, without complicated preparative procedures, we report spontaneous unilamellar polymeric vesicles with nanometer sizes (<100 nm), which are prepared by simply mixing a triblock copolymer, Pluronic P85 (PEO26PPO40PEO26), and an organic derivative, 5-methyl salicylic acid (5mS), in aqueous solution. Depending on the 5mS concentration and the temperature, the P85-5mS mixtures presented various self-assembled nanostructures such as spherical and cylindrical micelles or vesicles, which were characterized by small angle neutron scattering and cryo-TEM, resulting in a phase diagram drawn as a function of temperature and the 5mS concentration. Interestingly the critical temperature for the micelle-to-vesicle phase transition was easily controlled by varying the 5mS concentration, i.e. it was decreased with increasing the 5mS concentration.


Photodynamic therapy agent with a built-in apoptosis sensor for evaluating its own therapeutic outcome in situ.
Identifying the extent of apoptosis in cells or tissues after cancer therapy in real time would be a powerful firsthand tool for assessing therapeutic outcome. We combined therapeutic and imaging functions in one agent, choosing photodynamic therapy (PDT) as an appropriate cancer treatment modality. This agent induces photodamage in irradiated cells and simultaneously identifies apoptotic cells by near-infrared fluorescence. This photodynamic therapy agent with a built-in apoptosis sensor (PDT-BIAS) contains a fluorescent photosensitizer used as an anticancer drug, connected to a fluorescence quencher by a caspase-3 cleavable peptide linker. We demonstrated that cleavage of the peptide linker by caspase-3, one of the executioner caspases involved in apoptosis, results in a detectable increase of fluorescence in solution and in cancer cells after PDT treatment. The apoptosis involvement and drug effectiveness were confirmed by Apoptag and cell viability (MTT) assays supporting the ability of PDT-BIAS to induce and image apoptosis in situ.


Does an activity based remuneration system attract young doctors to general practice?
The use of increasingly complex payment schemes in primary care may represent a barrier to recruiting general practitioners (GP). The existing Norwegian remuneration system is fully activity based - 2/3 fee-for-service and 1/3 capitation. Given that the system has been designed and revised in close collaborations with the medical association, it is likely to correspond - at least to some degree - with the preferences of current GPs (men in majority). The objective of this paper was to study which preferences that young doctors (women in majority), who are the potential entrants to general practice have for activity based vs. salary based payment systems. In November-December 2010 all last year medical students and all interns in Norway (n = 1.562) were invited to participate in an online survey. The respondents were asked their opinion on systems of remuneration for GPs; inclination to work as a GP; risk attitude; income preferences; work pace tolerance. The data was analysed using one-way ANOVA and multinomial logistic regression analysis. A total of 831 (53%) responded. Nearly half the sample (47%) did not consider the remuneration system to be important for their inclination to work as GP; 36% considered the current system to make general practice more attractive, while 17% considered it to make general practice less attractive. Those who are attracted by the existing system were men and those who think high income is important, while those who are deterred by the system are risk averse and less happy with a high work pace. On the question of preferred remuneration system, half the sample preferred a mix of salary and activity based remuneration (the median respondent would prefer a 50/50 mix). Only 20% preferred a fully activity based system like the existing one. A salary system was preferred by women, and those less concerned with high income, while a fully activity based system was preferred by men, and those happy with a high work pace. Given a concern about low recruitment to general practice in Norway, and the fact that an increasing share of medical students is women, we were interested in the extent to which the current Norwegian remuneration system correspond with the preferences of potential GPs. This study suggests that an existing remuneration mechanism has a selection effect on who would like to become a GP. Those most attracted are income motivated men. Those deterred are risk averse, and less happy with a high work pace. More research is needed on the extent to which experienced GPs differ along the questions we asked potential GPs, as well as studying the relative importance of other attributes than payment schemes.


Application of mucilage from Dicerocaryum eriocarpum plant as biosorption medium in the removal of selected heavy metal ions.
The ability of mucilage from Dicerocaryum eriocarpum (DE) plant to act as biosorption medium in the removal of metals ions from aqueous solution was investigated. Functional groups present in the mucilage were identified using Fourier transform infrared spectroscopy (FTIR). Mucilage was modified with sodium and potassium chlorides. This was aimed at assessing the biosorption efficiency of modified mucilage: potassium mucilage (PCE) and sodium mucilage (SCE) and comparing it with non-modified deionised water mucilage (DCE) in the uptake of metal ions. FTIR results showed that the functional groups providing the active sites in PCE and SCE and DCE include: carboxyl, hydroxyl and carbonyl groups. The chloride used in the modification of the mucilage did not introduce new functional groups but increased the intensity of the already existing functional groups in the mucilage. Results from biosorption experiment showed that DE mucilage displays good binding affinity with metals ions [Zn(II), Cd(II) Ni(II), Cr(III) and Fe(II)] in the aqueous solution. Increase in the aqueous solution pH, metal ions initial concentration and mucilage concentration increased the biosorption efficiency of DE mucilage. The maximum contact time varied with each species of metal ions. Optimum pH for [Zn(II), Cd(II) Ni(II) and Fe(II)] occurred at pH 4 and pH 6 for Cr(III). Kinetic models result fitted well to pseudo-second-order with a coefficient values of R(2) = 1 for Cd(II), Ni(II), Cr(III), Fe(II) and R(2) = 0.9974 for Zn(II). Biosorption isotherms conforms best with Freundlich model for all the metal ions with correlation factors of 0.9994, 0.9987, 0.9554, 0.9621 and 0.937 for Zn(II), Ni(II), Fe(II), Cr(III) and Cd(II), respectively. Biosorption capacity of DE mucilage was 0.010, 2.387, 4.902, 0688 and 0.125 for Zn(II), Cr(III), Fe(II), Cd(II) and Ni(II) respectively. The modified mucilage was found to be highly efficient in the removal of metal ions than the unmodified mucilage.


Treatment of hemiballismus with stereotactic pallidotomy. Case report and review of the literature.
Hemiballismus is a relatively rare movement disorder that is characterized by uncontrolled, random, large-amplitude movements of the limbs. It is usually caused by a vascular lesion that involves the contralateral subthalamic nucleus (STN) (also known as the nucleus hypothalamicus or corpus luysi) and its afferent and efferent pathways. The authors present a case of medically intractable hemiballismus in a 70-year-old woman who was successfully treated with stereotactic posteroventral pallidotomy. In agreement with the data reported earlier by other groups, the microrecording performed during the pallidotomy showed a decreased rate of firing of the pallidal neurons, supporting the theory of impaired excitatory input from the STN to the internal part of the globus pallidus. Stereotactic pallidotomy may be the procedure of choice in the treatment of medically intractable hemiballismus. Intraoperative microrecording significantly improves the precision of the stereotactic targeting and should be considered a standard part of the pallidotomy protocol.


The Impact of Environmental Stress on Cognitive Performance: A Systematic Review.
In this review, we detail the impact of environmental stress on cognitive and military task performance and highlight any individual characteristics or interventions which may mitigate any negative effect. Military personnel are often deployed in regions markedly different from their own, experiencing hot days, cold nights, and trips both above and below sea level. In spite of these stressors, high-level cognitive and operational performance must be maintained. A systematic review of the electronic databases Medline (PubMed), EMBASE (Scopus), PsycINFO, and Web of Science was conducted from inception up to September 2018. Eligibility criteria included a healthy human cohort, an outcome of cognition or military task performance and assessment of an environmental condition. The search returned 113,850 records, of which 124 were included in the systematic review. Thirty-one studies examined the impact of heat stress on cognition; 20 of cold stress; 59 of altitude exposure; and 18 of being below sea level. The severity and duration of exposure to the environmental stressor affects the degree to which cognitive performance can be impaired, as does the complexity of the cognitive task and the skill or familiarity of the individual performing the task. Strategies to improve cognitive performance in extreme environmental conditions should focus on reducing the magnitude of the physiological and perceptual disturbance caused by the stressor. Strategies may include acclimatization and habituation, being well skilled on the task, and reducing sensations of thermal stress with approaches such as head and neck cooling.


Ultrafiltration in decompensated heart failure with cardiorenal syndrome.
Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function. We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days. Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P=0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was -0.04±0.53 mg per deciliter (-3.5±46.9 μmol per liter) in the pharmacologic-therapy group, as compared with +0.23±0.70 mg per deciliter (20.3±61.9 μmol per liter) in the ultrafiltration group (P=0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg [12.1±11.3 lb] and 5.7±3.9 kg [12.6±8.5 lb], respectively; P=0.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03). In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00608491.).


Logic models as a tool for sexual violence prevention program development.
Sexual violence is a growing public health problem, and there is an urgent need to develop sexual violence prevention programs. Logic models have emerged as a vital tool in program development. The Centers for Disease Control and Prevention funded an empowerment evaluation designed to work with programs focused on the prevention of first-time male perpetration of sexual violence, and it included as one of its goals, the development of program logic models. Two case studies are presented that describe how significant positive changes can be made to programs as a result of their developing logic models that accurately describe desired outcomes. The first case study describes how the logic model development process made an organization aware of the importance of a program's environmental context for program success; the second case study demonstrates how developing a program logic model can elucidate gaps in organizational programming and suggest ways to close those gaps.


Synaptic density in human frontal cortex - developmental changes and effects of aging.
Density of synaptic profiles in layer 3 of middle frontal gyrus was quantitated in 21 normal human brains ranging from newborn to age 90 years. Synaptic profiles could be reliably demonstrated by the phosphotungstic acid method (Bloom and Aghajanian) in tissue fixed up to 36 h postmortem. Synaptic density was constant throughout adult life (ages 16--72 years) with a mean of 11.05 X 10(8) synapses/cu.mm +/- 0.41 S.E.M. There was a slight decline in synaptic density in brains of the aged (ages 74--90 years) with a mean of 9.56 X 10(8) synapses/cu.mm +/- 0.28 S.E.M. in 4 samples (P less than 0.05). Synaptic density in neonatal brains was already high--in the range seen in adults. However, synaptic morphology differed; immature profiles had an irregular presynaptic dense band instead of the separate presynaptic projections seen in mature synapses. Synaptic density increased during infancy, reaching a maximum at age 1--2 years which was about 50% above the adult mean. The decline in synaptic density observed between ages 2--16 years was accompanied by a slight decrease in neuronal density. Human cerebral cortex is one of a number of neuronal systems in which loss of neurons and synapses appears to occur as a late developmental event.


Diagnosis and surgical strategy for sacral meningeal cysts with check-valve mechanism: technical note.
There is agreement that symptomatic sacral meningeal cysts with a check-valve mechanism and/or large cysts representing space-occupying lesions should be treated surgically. This study investigated factors indicating a need for surgical intervention and surgical techniques for sacral meningeal cysts with a check-valve mechanism. In ten patients presenting with sciatica and neurological deficits, myelography, computed tomography (CT) myelography, and magnetic resonance imaging (MR imaging) detected sacral meningeal cysts with a check-valve mechanism. One patient had two primary cysts. Ten cysts were type 2 and one cyst was type 1. Nine of the ten patients had not undergone previous surgery, while the remaining case involved recurrent cyst. For the seven patients with normal (i.e., not huge or recurrent) type 2 cysts and no previous surgery (eight cysts), suture after collapse of the cyst wall was performed. For the recurrent type 2 cyst, duraplasty and suture with collapse of the cyst wall were performed to eliminate the check-valve mechanism. For the remaining type 2 cyst, a primary root was sacrificed because of the huge size of the cyst. For the type 1 cyst, the neck of the cyst was ligated. In all cases, chief complaints disappeared immediately postoperatively and no deterioration of clinical symptoms has been seen after a mean follow-up of 27 months. The presence or absence of a check-valve mechanism is very important in determining the need for surgical intervention for sacral meningeal cysts.


Conformational stability and activity of p73 require a second helix in the tetramerization domain.
p73 and p63, the two ancestral members of the p53 family, are involved in neurogenesis, epithelial stem cell maintenance and quality control of female germ cells. The highly conserved oligomerization domain (OD) of tumor suppressor p53 is essential for its biological functions, and its structure was believed to be the prototype for all three proteins. However, we report that the ODs of p73 and p63 differ from the OD of p53 by containing an additional alpha-helix that is not present in the structure of the p53 OD. Deletion of this helix causes a dissociation of the OD into dimers; it also causes conformational instability and reduces the transcriptional activity of p73. Moreover, we show that ODs of p73 and p63 strongly interact and that a large number of different heterotetramers are supported by the additional helix. Detailed analysis shows that the heterotetramer consisting of two homodimers is thermodynamically more stable than the two homotetramers. No heterooligomerization between p53 and the p73/p63 subfamily was observed, supporting the notion of functional orthogonality within the p53 family.


Social norms shift behavioral and neural responses to foods.
Obesity contributes to 2.8 million deaths annually, making interventions to promote healthy eating critical. Although preliminary research suggests that social norms influence eating behavior, the underlying psychological and neural mechanisms of such conformity remain unexplored. We used fMRI to investigate whether group norms shift individuals' preferences for foods at both behavioral and neural levels. Hungry participants rated how much they wanted to eat a series of healthy and unhealthy foods and, after each trial, saw ratings that ostensibly represented their peers' preferences. This feedback was manipulated such that peers appeared to prefer each food more than, less than, or as much as participants themselves. After a delay, participants rerated each food. Participants' second ratings shifted to resemble group norms. Initial consensus, as compared to disagreement, with peers produced activity in the nucleus accumbens, a region associated with reward prediction errors. Furthermore, the strength of this activity predicted the extent to which participants' ratings conformed to peer ratings, suggesting that the value associated with consensus drives social influence. Ventromedial prefrontal cortex (vMPFC), a region associated with value computation, initially responded more strongly to unhealthy, as compared to healthy, foods. However, this effect was "overwritten" by group norms. After individuals learned their peers' preferences, vMPFC responses tracked the popularity, but not the healthfulness, of foods. Furthermore, changes in vMPFC activity tracked social influence over behavioral ratings. These data provide evidence that group norms can shift food preferences, supporting the use of norms-based interventions to promote healthy eating.


Seasonal variations and source apportionment of complex polycyclic aromatic hydrocarbon mixtures in particulate matter in an electronic waste and urban area in South China.
Complex polycyclic aromatic hydrocarbon (PAH) mixtures including parent PAHs, high molecular weight PAHs (MW 302 PAHs), and halogenated PAHs (HPAHs) were measured in particulate matter (PM) in an urban area and a rural electronic waste area in South China. The concentrations of MW < 302 PAHs at two sites were not significantly different with annual means of 23.2 ± 17.2 and 33.7 ± 29.0 ng/m3, respectively. However the concentrations of both MW 302 PAHs (5.35 ± 3.72 ng/m3) and HPAH (49.9 pg/m3) were significantly higher at the e-waste site than the urban site (2.81 ± 2.36 ng/m3 and 28.2 ± 28.5 pg/m3), suggesting e-waste recycling being a significant source of these PAHs. The majority of PAHs exhibited higher concentrations in winter and spring and lower concentrations in fall and summer. Meteorological conditions and increased emissions of PAHs in northern China due to domestic heating in colder seasons are important factors influencing the PAH seasonal variations. Source apportionment by the chemical mass balance (CMB) model indicated that residential stoves (coal combustion), industrial boilers (coal combustion), biomass burning, and vehicular emission accounted for 38 ± 14%, 30 ± 11%, 22 ± 22%, and 10 ± 7% of the PAHs in the urban PM, respectively. Comparable contributions from these sources were also observed for PM at the e-waste site. PAH emission factors are needed for primitive e-waste recycling to further understand the importance of this source to ambient air.


In vitro lymphocyte proliferation induced by radio-frequency electromagnetic radiation under isothermal conditions.
Whole human blood was exposed or sham-exposed in vitro for 2 h to 27 or 2,450 MHz radio-frequency electromagnetic (RF) radiation under isothermal conditions (i.e., 37 +/- 0.2 degrees C). Immediately after exposure, mononuclear cells were separated from blood by Ficoll density-gradient centrifugation and cultured for 3 days at 37 degrees C with or without mitogenic stimulation by phytohemagglutinin (PHA). Lymphocyte proliferation was assayed at the end of the culture period by 6 h of pulse labeling with 3H-thymidine (3H-TdR). Exposure to radiation at either frequency at specific absorption rates (SARs) below 50 W/kg resulted in a dose-dependent, statistically significant increase of 3H-TdR uptake in PHA-activated or unstimulated lymphocytes. Exposure at 50 W/kg or higher suppressed 3H-TdR uptake relative to that of sham-exposed cells. There were no detectable effects of RF radiation on lymphocyte morphology or viability. Notwithstanding the characteristic temperature dependence of lymphocyte activation in vitro, the isothermal exposure conditions of this study warrant the conclusion that the biphasic, dose-dependent effects of the radiation on lymphocyte proliferation were not dependent on heating.


A seizure attributed to ofloxacine in a woman undergoing detoxification for alcohol dependence.
Objective. To report one case of seizure following administration of ofloxacin. Case Summary. A 38-year-old woman with alcohol dependence but no prior history of seizure disorder admitted in our inpatient alcohol detoxification program was prescribed ofloxacin four days after admission for a lower urinary tract infection. She was currently prescribed diazepam 30 mg per day. This treatment was continued without modification following admission. Forty eight hours after starting ofloxacin and after receiving five doses of oral ofloxacin, the patient experienced a seizure. Ofloxacin treatment was stopped and no further seizures occurred. Neurological examination of the patient, laboratory tests, computerized tomography with contrast enhancement and electroencephalography did not detect any abnormalities. Up to the last consultation, six months after admission, the patient has reported no recurrence of the seizure. Discussion. Quinolone antibiotics vary in their ability to induce seizures, with ofloxacin having one of the least potentials. In the present case, the seizure could be attributed in all probability to taking ofloxacin; since she had no previous history of seizures, she did not present an alcohol withdrawal syndrome, benzodiazepine treatment was not modified, the seizure occurred 48 h after taking ofloxacin, but seven days after stopping drinking, no alternative aetiologies for the seizure could be identified and no seizure recurrence was reported over the following seven months. Of reported cases of seizures in patients treated with fluoroquinolones, none concerned patients with alcohol dependence or patients treated with benzodiazepines. Conclusions. The present case alerts us to the possibility that seizures may occur in alcohol dependent patients treated with benzodiazepines who concomitantly prescribed a fluoroquinolone. These widely-used antibiotics should thus be prescribed with caution to patients undergoing detoxification for alcohol dependence, particularly if they are also taking benzodiazepines, irrespective of whether they have a previous history of seizures or not.


Renal carcinomas with the t(6;11)(p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR.
A highly distinctive subset of renal neoplasms of children and young adults contains a t(6;11)(p21;q12), a translocation recently been shown to result in fusion of Alpha, a gene on 11q12, with the transcription factor gene TFEB on 6p21. To define the clinicopathologic spectrum of this nascent entity and to establish immunohistochemical (IHC) and molecular methods for the detection of the specific Alpha-TFEB fusion, we studied 7 renal neoplasms that showed the t(6;11) by cytogenetic or molecular analysis (patient age: range, 9-33 years; mean, 17 years). While all tumors were confined to the kidney, 3 tumors demonstrated vascular invasion. In limited follow-up, none has metastasized. We postulated that the Alpha-TFEB gene fusion may result in deregulated expression of TFEB protein that would be detectable by IHC. Using a polyclonal antibody to TFEB on formalin-fixed, paraffin-embedded tissue sections, we found that all 7 renal neoplasms with the t(6;11) demonstrated moderate (2 cases) or strong (5 cases) nuclear TFEB immunoreactivity. In contrast, none of 1089 other tumors (of 74 histologic types from 16 sites) labeled significantly for TFEB. Nuclear immunoreactivity for TFEB in normal tissues was extremely rare, limited to weak labeling of scattered benign lymphocytes. We also show that the Alpha-TFEB fusion RNAs are highly variable in size and structure, making detection by reverse-transcriptase polymerase chain reaction (RT-PCR) less reliable than for other gene fusions. Because Alpha is an intronless gene and therefore lacks splice signals, we hypothesized that DNA PCR and RT-PCR products would be identical, allowing for the use of more robust molecular assays based on genomic DNA. Indeed, in 2 cases with available frozen tissue, we showed the genomic Alpha-TFEB junction detected by DNA PCR to be identical to the Alpha-TFEB fusion mRNA detected by RT-PCR. In summary, renal neoplasms with the t(6;11) are a distinctive neoplastic entity with many similarities to the Xp11 translocation carcinomas, and together with the latter form a growing "MiTF/TFE family" of translocation carcinomas. Nuclear immunoreactivity for TFEB protein is a highly sensitive and specific diagnostic marker for these renal neoplasms. Finally, the special molecular features of the Alpha-TFEB gene fusion allow its molecular detection by DNA PCR as a robust alternative to RT-PCR in clinical tumor samples.


Formulating questions and locating primary studies for inclusion in systematic reviews.
Much time and effort are spent on designing primary research studies. Similar care must be given to planning systematic reviews. The review should be based on an important, well-focused question that is relevant to patient care. By formulating the question properly, the criteria that primary studies must meet to be included in the review become clear. These criteria, which comprise the types of persons involved, exposure, control group, outcomes, and study designs of interest, can then be refined so that they are clinically relevant, sensible, and workable. Inclusion criteria that are too narrow will limit the amount of data in the review, thereby increasing the risk for chance results and making the review less useful for the reader. Reviews should include studies whose designs offer the least biased answer to the question being asked. To maximize available data and reduce the risk for bias, as many relevant studies as possible need to be identified, regardless of publication status or language. Multiple overlapping search strategies should therefore be used and must be carefully planned. Strategies include searching the many electronic databases available (after careful consideration of which terms to enter), manually searching journals and conference proceedings, searching bibliographies of articles, searching existing registers of studies, and contacting companies or researchers. The time taken to formulate the question adequately and develop appropriate searches will increase the chance of producing a high-quality, meaningful review.


Physiological response to membrane protein overexpression in E. coli.
Overexpression represents a principal bottleneck in structural and functional studies of integral membrane proteins (IMPs). Although E. coli remains the leading organism for convenient and economical protein overexpression, many IMPs exhibit toxicity on induction in this host and give low yields of properly folded protein. Different mechanisms related to membrane biogenesis and IMP folding have been proposed to contribute to these problems, but there is limited understanding of the physical and physiological constraints on IMP overexpression and folding in vivo. Therefore, we used a variety of genetic, genomic, and microscopy techniques to characterize the physiological responses of Escherichia coli MG1655 cells to overexpression of a set of soluble proteins and IMPs, including constructs exhibiting different levels of toxicity and producing different levels of properly folded versus misfolded product on induction. Genetic marker studies coupled with transcriptomic results indicate only minor perturbations in many of the physiological systems implicated in previous studies of IMP biogenesis. Overexpression of either IMPs or soluble proteins tends to block execution of the standard stationary-phase transcriptional program, although these effects are consistently stronger for the IMPs included in our study. However, these perturbations are not an impediment to successful protein overexpression. We present evidence that, at least for the target proteins included in our study, there is no inherent obstacle to IMP overexpression in E. coli at moderate levels suitable for structural studies and that the biochemical and conformational properties of the proteins themselves are the major obstacles to success. Toxicity associated with target protein activity produces selective pressure leading to preferential growth of cells harboring expression-reducing and inactivating mutations, which can produce chemical heterogeneity in the target protein population, potentially contributing to the difficulties encountered in IMP crystallization.


Perceptions of barriers and facilitators to cervical cancer screening among low-income, HIV-infected women from an integrated HIV clinic.
Significantly elevated rates of cervical cancer and low rates of Papanicolaou (Pap) smear screening have been documented among HIV-infected women. However, little is known about women's perceptions of cervical cancer screening utilization. Hence, this study describes barriers and facilitators related to cervical cancer screening in a sample of HIV-infected women seeking care at an integrated HIV clinic in Houston, Texas. Using an inductive qualitative methodological approach, data were obtained from five focus group discussions with a total of 33, HIV-infected women. The majority of the study sample consisted of women who self-identified as Black (69.7%), and reported heterosexual contact as the mode of HIV acquisition (75.8%). Barriers to cervical cancer screening were described as pain and discomfort associated with receiving Pap smears and subsequent procedures; lack of awareness of cervical cancer as a preventable disease; limited transportation access; and systemic issues as it relates to scheduling gynecological appointments. Facilitators were described as awareness of HIV-infected women's increased risk of cervical cancer and strong provider-patient relationships. To address disparities in cervical cancer screening among low-income HIV-infected women, programs should capitalize on the identified facilitators and alleviate modifiable barriers using multilevel strategies.


Nanopolymers improve delivery of exon skipping oligonucleotides and concomitant dystrophin expression in skeletal muscle of mdx mice.
Exon skipping oligonucleotides (ESOs) of 2'O-Methyl (2'OMe) and morpholino chemistry have been shown to restore dystrophin expression in muscle fibers from the mdx mouse, and are currently being tested in phase I clinical trials for Duchenne Muscular Dystrophy (DMD). However, ESOs remain limited in their effectiveness because of an inadequate delivery profile. Synthetic cationic copolymers of poly(ethylene imine) (PEI) and poly(ethylene glycol) (PEG) are regarded as effective agents for enhanced delivery of nucleic acids in various applications. We examined whether PEG-PEI copolymers can facilitate ESO-mediated dystrophin expression after intramuscular injections into tibialis anterior (TA) muscles of mdx mice. We utilized a set of PEG-PEI copolymers containing 2 kDa PEI and either 550 Da or 5 kDa PEG, both of which bind 2'OMe ESOs with high affinity and form stable nanoparticulates with a relatively low surface charge. Three weekly intramuscular injections of 5 microg of ESO complexed with PEI2K-PEG550 copolymers resulted in about 500 dystrophin-positive fibers and about 12% of normal levels of dystrophin expression at 3 weeks after the initial injection, which is significantly greater than for injections of ESO alone, which are known to be almost completely ineffective. In an effort to enhance biocompatibility and cellular uptake, the PEI2K-PEG550 and PEI2K-PEG5K copolymers were functionalized by covalent conjugation with nanogold (NG) or adsorbtion of colloidal gold (CG), respectively. Surprisingly, using the same injection and dosing regimen, we found no significant difference in dystrophin expression by Western blot between the NG-PEI2K-PEG550, CG-PEI2K-PEG5K, and non-functionalized PEI2K-PEG550 copolymers. Dose-response experiments using the CG-PEI2K-PEG5K copolymer with total ESO ranging from 3-60 microg yielded a maximum of about 15% dystrophin expression. Further improvements in dystrophin expression up to 20% of normal levels were found at 6 weeks after 10 twice-weekly injections of the NG-PEI2K-PEG550 copolymer complexed with 5 microg of ESO per injection. This injection and dosing regimen showed over 1000 dystrophin-positive fibers. H&E staining of all treated muscle groups revealed no overt signs of cytotoxicity. We conclude that PEGylated PEI2K copolymers are efficient carriers for local delivery of 2'OMe ESOs and warrant further development as potential therapeutics for treatment of DMD.


Longitudinal evaluation of fine motor skills in children with leukemia.
Improved survival for children with acute lymphocytic leukemia (ALL) has allowed investigators to focus on the adverse or side effects of treatment and to develop interventions that promote cure while decreasing the long-term effects of therapy. Although much attention has been given to the significant neurocognitive sequelae that can occur after ALL therapy, limited investigation is found addressing fine motor function in these children and motor function that may contribute to neurocognitive deficits in ALL survivors. Fine motor and sensory-perceptual performances were examined in 82 children with ALL within 6-months of diagnosis and annually for 2 years (year 1 and year 2, respectively) during therapy. Purdue Pegboard assessments indicated significant slowing of fine motor speed and dexterity for the dominant hand, nondominant hand, and both hands simultaneously for children in this study. Mean Visual-Motor Integration (VMI) scores for children with low-risk and high-risk ALL decreased from the first evaluation to year 1 and again at year 2. Mean VMI scores for children with standard risk ALL increased from the first evaluation to year 1 and then decreased at year 2. Significant positive correlations were found between the Purdue and the VMI at both year 1 and year 2, suggesting that the Pegboard performance consistently predicts the later decline in visual-motor integration. Significant correlations were found between the Purdue Pegboard at baseline and the Performance IQ during year 1, though less consistently during year 2. A similar pattern was also observed between the baseline Pegboard performance and performance on the Coding and Symbol Search subtests during year 1 and year 2. In this study, children with ALL experienced significant and persistent visual-motor problems throughout therapy. These problems continued during the first and second years of treatment. These basic processing skills are necessary to the development of higher-level cognitive abilities, including nonverbal intelligence and academic achievement, particularly in arithmetic and written language.


Quantitative proteomics analysis of platelet-derived microparticles reveals distinct protein signatures when stimulated by different physiological agonists.
Platelet-derived MPs (PMPs) are a heterogeneous population of microvesicles released from platelets upon activation and apoptosis. Different platelet activations may affect PMP protein profiles and roles in intercellular communication. Here, we performed a quantitative proteomics study to characterize the protein content of PMPs generated by four differentially activated platelet samples. We selected known physiological agonists for platelet activation such as ADP, thrombin and collagen. Thrombin, which is mostly used to generate PMPs in vitro, was set as control. Platelets were activated by following a known agonist strength scale in which ADP was the weakest activation and thrombin and collagen stimulations were the strongest ones. Our proteomic analysis allowed the quantification of 3383 proteins, of which 428 membrane and 131 soluble proteins were found as significantly different in at least one of the analyzed conditions. Activation with stronger agonists led to the enrichment of proteins related to platelet activation in PMPs. In addition, proteins involved in platelet degranulation and proteins from the electron transport chain were less abundant in PMPs when stronger activation was used. Collectively, our data describe the most detailed characterization of PMPs after platelet physiological activation. Furthermore, we show that PMP protein content is highly dependent on the type of physiological agonist involved in platelet stimulation. Platelet-derived MPs (PMPs) are a population of vesicles generated upon platelet activation by various stimuli known to be involved in several physiological and pathological processes. This manuscript investigates the protein profile of PMPs obtained by performing four different activation protocols using mass spectrometry-based quantitative proteomics. By following a known physiological agonist strength scale our findings suggest a biological link between agonist strength and proteins associated to platelet mediated processes such as activation and degranulation. These data may provide new insights for understanding PMP biological role and formation.


The influence of binary processing additives on the performance of polymer solar cells.
In this study, we report the investigation of the influence of binary processing additives, 1,8-octanedithiol (ODT) and 1-chloronaphthalene (CN) on the performance of polymer solar cells (PSCs). It was found that the power conversion efficiency (PCE) can be enhanced to 8.55% from the PSCs processed with binary processing additives as compared with ∼6.50% from the PSCs processed with either ODT or CN processing additives. With binary processing additives, the crystallinity of the electron donor polymer, poly[[4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b']dithiophene-2,6-diyl][3-fluoro-2-[(2 ethylhexyl)carbonyl]thieno[3,4-b]thiophenediyl]], was elevated, which in turn facilitated charge transport within the bulk heterojunction (BHJ) layer, resulting in a high short-circuit current and large fill factor. By photophysical studies, we further found that the high PCE is majorly attributed to the minimized nongeminate recombination by controlling the kinetic film morphologies of the BHJ composite by binary solvent processing additives.


Breathlessness with pulmonary metastases: a multimodal approach.
Case Study Sarah is a 58-year-old breast cancer survivor, social worker, and health-care administrator at a long-term care facility. She lives with her husband and enjoys gardening and reading. She has two grown children and three grandchildren who live approximately 180 miles away. SECOND CANCER DIAGNOSIS One morning while showering, Sarah detected a painless quarter-sized lump on her inner thigh. While she thought it was unusual, she felt it would probably go away. One month later, she felt the lump again; she thought that it had grown, so she scheduled a visit with her primary care physician. A CT scan revealed a 6.2-cm soft-tissue mass in the left groin. She was referred to an oncologic surgeon and underwent an excision of the groin mass. Pathology revealed a grade 3 malignant melanoma. She was later tested and found to have BRAF-negative status. Following her recovery from surgery, Sarah was further evaluated with an MRI scan of the brain, which was negative, and a PET scan, which revealed two nodules in the left lung. As Sarah had attended a cancer support group during her breast cancer treatment in the past, she decided to go back to the group when she learned of her melanoma diagnosis. While the treatment options for her lung lesions included interleukin-2, ipilimumab (Yervoy), temozolomide, dacarbazine, a clinical trial, or radiosurgery, Sarah's oncologist felt that ipilimumab or radiosurgery would be the best course of action. She shared with her support group that she was ambivalent about this decision, as she had experienced profound fatigue and nausea with chemotherapy during her past treatment for breast cancer. She eventually opted to undergo stereotactic radiosurgery. DISEASE RECURRENCE After the radiosurgery, Sarah was followed every 2 months. She complained of shortness of breath about 2 weeks prior to each follow-up visit. Each time her chest x-ray was normal, and she eventually believed that her breathlessness was anxiety-related. Unfortunately, Sarah's 1-year follow-up exam revealed a 2 cm × 3 cm mass in her left lung, for which she had a surgical wedge resection. Her complaints of shortness of breath increased following the surgery and occurred most often with anxiety, heat, and gardening activities, especially when she needed to bend over. Sarah also complained of a burning "pins and needles" sensation at the surgical chest wall site that was bothersome and would wake her up at night. Sarah met with the nurse practitioner in the symptom management clinic to discuss her concerns. Upon physical examination, observable signs of breathlessness were lacking, and oxygen saturation remained stable at 94%, but Sarah rated her breathlessness as 7 on the 0 to 10 Borg scale. The nurse practitioner prescribed duloxetine to help manage the surgical site neuropathic pain and to assist with anxiety, which in turn could possibly improve Sarah's breathlessness. Several nonpharmacologic modalities for breathlessness were also recommended: using a fan directed toward her face, working in the garden in the early morning when the weather is cooler, gardening in containers that are at eye level to avoid the need to bend down, and performing relaxation exercises with pursed lip breathing to relieve anxiety-provoked breathlessness. One month later, Sarah reported relief of her anxiety; she stated that the fan directed toward her face helped most when she started to feel "air hungry." She rated her breathlessness at 4/10 on the Borg scale. SECOND RECURRENCE: MULTIPLE PULMONARY NODULES Sarah's chest x-rays remained clear for 6 months, but she developed a chronic cough shortly before the 9-month exam. An x-ray revealed several bilateral lung lesions and growth in the area of the previously resected lung nodule. Systemic therapy was recommended, and she underwent two cycles of ipilimumab. Sarah's cough and breathlessness worsened, she developed colitis, and she decided to stop therapy after the third cycle. In addition, her coughing spells triggered bronchospasms that resulted in severe anxiety, panic attacks, and air hunger. She rated her breathlessness at 10/10 on the Borg scale during these episodes. She found communication difficult due to the cough and began to isolate herself. She continued to attend the support group weekly but had difficulty participating in conversation due to her cough. Sarah was seen in the symptom management clinic every 2 weeks or more often as needed. No acute distress was present at the beginning of each visit, but when Sarah began to talk about her symptoms and fear of dying, her shortness of breath and anxiety increased. The symptom management nurse practitioner treated the suspected underlying cause of the breathlessness and prescribed oral lorazepam (0.5 to 1 mg every 6 hours) for anxiety and codeine cough syrup for the cough. Opioids were initiated for chest wall pain and to control the breathlessness. Controlled-release oxycodone was started at 10 mg every 12 hours with a breakthrough pain (BTP) dose of 5 mg every 2 hours as needed for breathlessness or pain. Sarah noted improvement in her symptoms and reported a Borg scale rating of 5/10. Oxygen therapy was attempted, but subjective improvement in Sarah's breathlessness was lacking. END OF LIFE Sarah's disease progressed to the liver, and she began experiencing more notable signs of breathlessness: nasal flaring, tachycardia, and restlessness. Opioid doses were titrated over the course of 3 months to oxycodone (40 mg every 12 hours) with a BTP dose of 10 to 15 mg every 2 hours as needed, but her breathlessness caused significant distress, which she rated 8/10. The oxycodone was rotated to IV morphine continuous infusion with patient-controlled analgesia (PCA) that was delivered through her implantable port. This combination allowed Sarah to depress the PCA as needed and achieve immediate control of her dyspneic episodes. Oral lorazepam was also continued as needed. Sarah's daughter moved home to take care of her mother, and hospice became involved for end-of-life care. As Sarah became less responsive, nurses maintained doses of morphine for control of pain and breathlessness and used a respiratory distress observation scale to assess for breathlessness since Sarah could no longer self-report. A bolus PCA dose of morphine was administered by Sarah's daughter if her mother appeared to be in distress. Sarah died peacefully in her home without signs of distress.


An error model for protein quantification.
Quantitative experimental data is the critical bottleneck in the modeling of dynamic cellular processes in systems biology. Here, we present statistical approaches improving reproducibility of protein quantification by immunoprecipitation and immunoblotting. Based on a large data set with more than 3600 data points, we unravel that the main sources of biological variability and experimental noise are multiplicative and log-normally distributed. Therefore, we suggest a log-transformation of the data to obtain additive normally distributed noise. After this transformation, common statistical procedures can be applied to analyze the data. An error model is introduced to account for technical as well as biological variability. Elimination of these systematic errors decrease variability of measurements and allow for a more precise estimation of underlying dynamics of protein concentrations in cellular signaling. The proposed error model is relevant for simulation studies, parameter estimation and model selection, basic tools of systems biology. Matlab and R code is available from the authors on request. The data can be downloaded from our website www.fdm.uni-freiburg.de/~ckreutz/data.


"We do not bury dead livestock like human beings": Community behaviors and risk of Rift Valley Fever virus infection in Baringo County, Kenya.
Rift Valley Fever (RVF), is a viral zoonotic disease transmitted by Aedes and Culex mosquitoes. In Kenya, its occurrence is associated with increased rains. In Baringo County, RVF was first reported in 2006-2007 resulting in 85 human cases and 5 human deaths, besides livestock losses and livelihood disruptions. This study sought to investigate the county's current RVF risk status. A cross-sectional study on the knowledge, attitudes and practices of RVF was conducted through a mixed methods approach utilizing a questionnaire survey (n = 560) and 26 focus group discussions (n = 231). Results indicate that study participants had little knowledge of RVF causes, its signs and symptoms and transmission mechanisms to humans and livestock. However, most of them indicated that a person could be infected with zoonotic diseases through consumption of meat (79.2%) and milk (73.7%) or contact with blood (40%) from sick animals. There was a statistically significant relationship between being male and milking sick animals, consumption of milk from sick animals, consuming raw or cooked blood, slaughtering sick livestock or dead animals for consumption (all at p≤0.001), and handling sick livestock with bare hands (p = 0.025) with more men than women engaging in the risky practices. Only a few respondents relied on trained personnel or local experts to inspect meat for safety of consumption every time they slaughtered an animal at home. Sick livestock were treated using conventional and herbal medicines often without consulting veterinary officers. Communities in Baringo County engage in behaviour that may increase their risk to RVF infections during an outbreak. The authors recommend community education to improve their response during outbreaks.


Reducing Disparities by way of a Cancer Disparities Research Training Program.
For minority populations, there is a continuing disparity in the burden of death and illness from cancer. Research to address this disparity should be conducted by investigators who can best understand and address the needs of culturally diverse communities. However, minorities are under-represented in health-related research. The goal of this project was to develop and evaluate an approach to motivating and preparing master's degree students for careers dedicated to cancer disparities research. A Cancer Disparities Research Training Program (CDRTP) was initiated in 2010. The program consists of coursework, practicum experiences, and research opportunities. Assessment of the curriculum is based on monitoring achievement of evaluation indicators and included a mixed-method approach with included both quantitative and qualitative approach. In its first three years, the program graduated 20 trainees, all of whom were minorities (18 African Americans and two Asians). When asked about career goals, two-thirds of the trainees indicated interest in pursuing careers in research in cancer prevention and control. The trainees expressed high satisfaction with the courses, instructor, materials, and curriculum. Although trainees had suggestions about course details, evaluations overall were positive. Across focus groups, three recurrent themes emerged regarding activities to enhance the trainee experience: having a wider variety of topics, more guest speakers, and field trips. The CDRTP was intended to recruit students - primarily African Americans - into research on prevention and control of cancer disparities. Although final evaluation of the program's overall outcome will not be available for several years, this preliminary evaluation indicates early program success.


Poisson-based self-organizing feature maps and hierarchical clustering for serial analysis of gene expression data.
Serial analysis of gene expression (SAGE) is a powerful technique for global gene expression profiling, allowing simultaneous analysis of thousands of transcripts without prior structural and functional knowledge. Pattern discovery and visualization have become fundamental approaches to analyzing such large-scale gene expression data. From the pattern discovery perspective, clustering techniques have received great attention. However, due to the statistical nature of SAGE data (i.e., underlying distribution), traditional clustering techniques may not be suitable for SAGE data analysis. Based on the adaptation and improvement of Self-Organizing Maps and hierarchical clustering techniques, this paper presents two new clustering algorithms, namely, PoissonS and PoissonHC, for SAGE data analysis. Tested on synthetic and experimental SAGE data, these algorithms demonstrate several advantages over traditional pattern discovery techniques. The results indicate that, by incorporating statistical properties of SAGE data, PoissonS and PoissonHC, as well as a hybrid approach (neuro-hierarchical approach) based on the combination of PoissonS and PoissonHC, offer significant improvements in pattern discovery and visualization for SAGE data. Moreover, a user-friendly platform, which may improve and accelerate SAGE data mining, was implemented. The system is freely available on request from the authors for nonprofit use.