Genetic characterization of the HrpL regulon of the fire blight pathogen Erwinia amylovora reveals novel virulence factors.
The bacterial pathogen Erwinia amylovora is the causal agent of fire blight, an economically significant disease of apple and pear. Disease initiation by E. amylovora requires the translocation of effector proteins into host cells via the hypersensitive response and pathogenicity (hrp) type III secretion system (T3SS). The alternative sigma factor HrpL positively regulates the transcription of structural and translocated components of the T3SS via hrp promoter elements. To characterize genome-wide HrpL-dependent gene expression in E. amylovora Ea1189, wild-type and Ea1189ΔhrpL strains were cultured in hrp-inducing minimal medium, and total RNA was compared using a custom microarray designed to represent the annotated genes of E. amylovora ATCC 49946. The results revealed 24 genes differentially regulated in Ea1189ΔhrpL relative to Ea1189 with fold-change expression ratios greater than 1.5; of these, 19 genes exhibited decreased transcript abundance and five genes showed increased transcript abundance relative to Ea1189. To expand our understanding of the HrpL regulon and to elucidate direct versus indirect HrpL-mediated effects on gene expression, the genome of E. amylovora ATCC 49946 was examined in silico using a hidden Markov model assembled from known Erwinia spp. hrp promoters. This technique identified 15 putative type III novel hrp promoters, seven of which were validated with quantitative polymerase chain reaction based on expression analyses. It was found that HrpL-regulated genes encode all known components of the hrp T3SS, as well as five putative type III effectors. Eight genes displayed apparent indirect HrpL regulation, suggesting that the HrpL regulon is connected to downstream signalling networks. The construction of deletion mutants of three novel HrpL-regulated genes resulted in the identification of additional virulence factors as well as mutants displaying abnormal motility and biofilm phenotypes.


A closer look at the relationship among accelerometer-based physical activity metrics: ICAD pooled data.
Accelerometers are widely used to assess child physical activity (PA) levels. Using the accelerometer data, several PA metrics can be estimated. Knowledge about the relationships between these different metrics can improve our understanding of children's PA behavioral patterns. It also has significant implications for comparing PA metrics across studies and fitting a statistical model to examine their health effects. The aim of this study was to examine the relationships among the metrics derived from accelerometers in children. Accelerometer data from 24,316 children aged 5 to 18 years were extracted from the International Children's Accelerometer Database (ICAD) 2.0. Correlation coefficients between wear time, sedentary behavior (SB), light-intensity PA (LPA), moderate-intensity PA (MPA), vigorous-intensity PA (VPA), moderate- and vigorous-intensity PA (MVPA), and total activity counts (TAC) were calculated. TAC was approximately 22X103 counts higher (p < 0.01) with longer wear time (13 to 18 h/day) as compared to shorter wear time (8 to < 13 h/day), while MVPA was similar across the wear time categories. MVPA was very highly correlated with TAC (r = .91; 99% CI = .91 to .91). Wear time-adjusted correlation between SB and LPA was also very high (r = -.96; 99% CI = -.96, - 95). VPA was moderately correlated with MPA (r = .58; 99% CI = .57, .59). TAC is mostly explained by MVPA, while it could be more dependent on wear time, compared to MVPA. MVPA appears to be comparable across different wear durations and studies when wear time is ≥8 h/day. Due to the moderate to high correlation between some PA metrics, potential collinearity should be addressed when including multiple PA metrics together in statistical modeling.


Designing family-centered male circumcision services: a conjoint analysis approach.
Male circumcision (MC) has become an important weapon in the fight against HIV/AIDS in many Sub-Saharan African countries. The successful implementation of a national MC program requires the design of circumcision services that are attractive to young men of various ages. For many potential clients, mothers and/or fathers will play an important role in the decision to be circumcised, and hence services will need to be designed with the preferences of mothers, fathers, and sons in mind. Our objective was to value multiple design characteristics of potential community-based MC services from the perspectives of mothers, fathers, and sons in Johannesburg, South Africa, and to test for concordance between their values for the design characteristics. Potential design characteristics of MC services were identified through open-ended interviews with key informants (n = 25). Preferences were estimated using conjoint analysis implemented as part of a cluster randomized household survey. Each participant was randomized to receive one of two possible blocks of conjoint analysis, each consisting of six forced-choice tasks comparing two possible MC services varying on 11 design characteristics. With only two levels for each attribute, our experimental design utilized a main effects orthogonal array. Data were analyzed using linear probability models, with tests of concordance of values using Wald tests generated from stratified estimates calculated using restricted least square estimation. A racially and geographically diverse sample consisting of 204 fathers, 204 mothers, and 237 sons completed the survey. In aggregate, requiring a follow-up visit was the most valued design factor (p < 0.001), followed by having a lower infection rate (p < 0.001), having less pain (p = 0.001), and a private waiting room (p = 0.001). Based on stratified analysis, sons also valued having the risks and benefits of MC explained (p = 0.01) and mothers valued requiring an HIV test as part of the procedure. Requiring an HIV test was the most significant difference between the respondents (p = 0.03), with sons finding it somewhat repulsive (p = 0.30). Our findings suggest that valuation of aspects of MC clinic design can diverge by decision maker. To better ensure utilization of services, these variations should be taken into account to prior to implementation of a national strategy in South Africa.


Extending carbon chain length of 1-butanol pathway for 1-hexanol synthesis from glucose by engineered Escherichia coli.
An Escherichia coli strain was engineered to synthesize 1-hexanol from glucose by extending the coenzyme A (CoA)-dependent 1-butanol synthesis reaction sequence catalyzed by exogenous enzymes. The C4-acyl-CoA intermediates were first synthesized via acetyl-CoA acetyltransferase (AtoB), 3-hydroxybutyryl-CoA dehydrogenase (Hbd), crotonase (Crt), and trans-enoyl-CoA reductase (Ter) from various organisms. The butyryl-CoA synthesized was further extended to hexanoyl-CoA via β-ketothiolase (BktB), Hbd, Crt, and Ter. Finally, hexanoyl-CoA was reduced to yield 1-hexanol by aldehyde/alcohol dehydrogenase (AdhE2). Enzyme activities for the C6 intermediates were confirmed by assays using HPLC and GC. 1-Hexanol was secreted to the fermentation medium under anaerobic conditions. Furthermore, co-expressing formate dehydrogenase (Fdh) from Candida boidinii increased the 1-hexanol titer. This demonstration of 1-hexanol production by extending the 1-butanol pathway provides the possibility to produce other medium chain length alcohols using the same strategy.


Sorafenib Induced Hand Foot Skin Rash in FLT3 ITD Mutated Acute Myeloid Leukemia-A Case Report and Review of Literature.
Sorafenib is a novel small molecule multiple kinase inhibitor which has been used for metastatic renal cancer, hepatocellular cancer. Sorafenib induced skin rash has been discussed as a side effect in trials in both, FLT3 wild type and mutated acute myeloid leukemia (AML), as monotherapy or as combination with other chemotherapeutic agents. We describe a patient with FLT 3 ITD mutated AML, who was started on adjunctive Sorafenib therapy. Skin reactions manifested as NCI Grade III palmoplantar erythrodysesthesia (PPE), requiring drug discontinuation. Several pathogenic mechanisms have been implicated in Sorafenib induced skin reactions, but none has been conclusively proven. While treatment options are varied for early stage skin reactions, drug discontinuation remains the only possible therapy presently for severe grade skin reaction.


Variation in both host defense and prior herbivory can alter plant-vector-virus interactions.
While virus-vector-host interactions have been a major focus of both basic and applied ecological research, little is known about how different levels of plant defense interact with prior herbivory to affect these relationships. We used genetically-modified strains of tomato (Solanum lycopersicum) varying in the jasmonic acid (JA) plant defense pathways to explore how plant defense and prior herbivory affects a plant virus (tomato yellow leaf curl virus, 'TYLCV'), its vector (the whitefly Bemisia tabaci MED), and the host. Virus-free MED preferred low-JA over high-JA plants and had lower fitness on high-JA plants. Viruliferous MED preferred low-JA plants but their survival was unaffected by JA levels. While virus-free MED did not lower plant JA levels, viruliferous MED decreased both JA levels and the expression of JA-related genes. Infestation by viruliferous MED reduced plant JA levels. In preference tests, neither virus-free nor viruliferous MED discriminated among JA-varying plants previously exposed to virus-free MED. However, both virus-free and viruliferous MED preferred low-JA plant genotypes when choosing between plants that had both been previously exposed to viruliferous MED. The enhanced preference for low-JA genotypes appears linked to the volatile compound neophytadiene, which was found only in whitefly-infested plants and at concentrations inversely related to plant JA levels. Our findings illustrate how plant defense can interact with prior herbivory to affect both a plant virus and its whitefly vector, and confirm the induction of neophytadiene by MED. The apparent attraction of MED to neophytadiene may prove useful in pest detection and management.


The study of capacitive deionization behavior of a carbon nanotube electrode from the perspective of charge efficiency.
In this work, the capacitive deionization (CDI) performance of a single-walled carbon nanotube (CNT) electrode has been studied from the point view of charge efficiency theory. It is revealed here that the charge efficiency of a CNT electrode is strongly dependent upon the cell voltage and solution concentration. Either the high cell voltage or the low ionic strength results in a high charge efficiency, implying that CDI is expected to be a promising technique for an aqueous solution with low ionic strength. Additionally, it is found that the high decay constant and high electrical double-layer capacity are beneficial to enhance electrosorption performance.


Flow stabilizer on a syringe tip for hand-powered microfluidic sample injection.
Precise, portable, low-cost sample injection is strongly demanded for use in point-of-care testing devices in resource-poor settings; however, current microfluidic sample injection techniques are often expensive, bulky and electricity-powered. To address this issue, we propose a novel syringe flow-stabilizer for hand-powered, precise, continuous-flow microfluidic sample injection. Our syringe flow-stabilizer applies the principle of passive flow-resistance compensation to stabilize the unstable sample flow and has the special advantages of easy-to-use, simple structure, low cost and high stability. The flow stabilizing performance of the stabilizer is characterized via a series of experiments and the results show that our stabilizer is capable of outputting a constant flow rate up to several milliliters per minute under a low threshold pressure. Finally, the fabricated syringe flow-stabilizer is integrated with an inertial microfluidic cell concentrator for high-throughput continuous concentration of trace blood cells from large-volume biofluids. The use of our stabilizer makes the concentration performance totally independent of operation. We envision wide applications of our syringe flow-stabilizer as a hand-powered sample injection unit in various point-of-care testing devices in resource-poor settings.


Experiences of fathers shortly after the birth of their preterm infants.
To explore the experiences of fathers shortly after the birth of their preterm infants. A focused ethnography conducted over 33 months (2003–2006) in the neonatal intensive care unit (NICU) of a large U.K. National Health Trust (NHS) teaching hospital. Data were collected through participant observation, in-depth interviews with fathers (n = 10), and an ethnographic survey distributed to NICU staff (n = 87). Practices and relationships with fathers were concurrently analyzed thematically through the conceptual perspective of emotion work. Fathers' emotional reactions to their experiences were described in three themes: emotional withdrawal and control, stereotyping, and mixed feelings. Fathers' emotional behaviors were governed by complex, culturally determined conventions and expectations. Fathers engaged in considerable effort to manage their emotions as they attempted to reconcile the tension between what they wanted to feel and what they thought others expected them to feel. The results of this study support the view that focusing on emotional externalities alone tends to underplay the amount of emotion work carried out by less expressive individuals; this "silent emotion work" was characteristic of the fathers in this study.


Comparison of the upper airways from cephalometric radiographs of children with and without finger-sucking habit.
Finger-sucking in early childhood can induce morphologic changes in the oropharynx and upper airways, which could arise even in children without reported oral breathing. The aim of this study was to compare cephalometric findings in children with and without finger sucking habit with respect to oral breathing. Fifty-six children aged 4 to 12 years (28 with diagnosis of finger sucking and 28 controls) treated at the Port Colombia Dental Clinic underwent cephalometric radiographs, from which morphologic (n=11, whole skull), upper airways (n=10), hyoid bone (n=3) and postural (n=5) measurements were performed. The unpaired t-test was used for comparison between groups. Both groups had similar age and gender distribution (7.9 yrs ± 2.9; M/F: 14/14). Patients with finger-sucking habit had a higher hard palate length from the anterior nasal spine to the posterior nasal spine (finger-sucking subjects: 50.18 mm; controls: 46.91 mm; p = 0.0001) and distance from the epiglottic vallecula to the posterior pharyngeal wall (finger-sucking subjects: 15.55 mm; controls: 13.36 mm; p = 0.0231) than control subjects. Patients with finger-sucking habits also had a shorter distance from the posterior nasal spine to the adenoids (14.91 mm vs. 17.82 mm; p = 0.0173), wider cranial-cervical angles (105.64 mm vs. 101.6 mm; p = 0.05) and lower hyoid bone positioning (14.55 mm vs. 11.82 mm; p = 0.0125) than controls. Finger-sucking habit is associated with characteristic cephalometric changes even in children without oral breathing, especially at the hyoid bone and postural measurements.


The short-term stability of life satisfaction judgments.
Life satisfaction judgments are thought to reflect people's overall evaluation of the quality of their lives as a whole. Because the circumstances of these lives typically do not change very quickly, life satisfaction judgments should be relatively stable over time. However, some evidence suggests that these judgments can be easily manipulated, which leads to low stability even over very short intervals. The current study uses a unique data set that includes multiple assessments of life satisfaction over both long (up to 4 years) and short (over the course of a single interview) intervals to assess whether information that is made salient during the course of an interview affects life satisfaction judgments at the end of the interview. Results suggest that this intervening information has only small effects on the final judgment and that placement within an interview has little influence on the judgment that people provide. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Role of chemoradiotherapy in oesophageal cancer -- adjuvant and neoadjuvant therapy.
Despite low postoperative mortality rates, the long-term outcomes from surgical-based treatment for oesophageal cancer remain poor. Chemoradiotherapy (CRT), either given before surgical resection as neoadjuvant therapy or after resection as adjuvant therapy, has been postulated to improve these outcomes. This systematic review examines the evidence for these approaches. The evidence for postoperative radiotherapy is limited and conclusions are difficult, but it may have a role in patients at high risk of local relapse (positive margins). The addition of chemotherapy is recommended when possible. Patient selection is important due to the associated toxicities. The evidence for neoadjuvant treatment is stronger and based on the current evidence neoadjuvant CRT can be recommended as a treatment approach in T2-T4, N1-3 oesophageal cancer for both adenocarcinoma and squamous cell carcinoma, but further work is needed to establish its superiority over neoadjuvant chemotherapy alone, particularly for adenocarcinoma. We recommend that further studies divide the two histologies and they should be treated as two separate diseases.


Neural progenitor cell-mediated delivery of osteoprotegerin limits disease progression in a preclinical model of neuroblastoma bone metastasis.
Osteoprotegerin (OPG) inhibits osteoclast activation and reduces osteolysis in bone tumors. We hypothesized that tumor-tropic neural progenitor cells (NPCs) engineered to express OPG would reduce neuroblastoma disease burden in the bone. Stable expression of green fluorescent protein (NPC-GFP) and OPG (NPC-OPG) was established in human NPCs by lentivirus-mediated transduction. Bone disease was established by intrafemoral injection of luciferase-expressing human neuroblastoma (CHLA-255) cells into 20 SCID mice. Three weeks later, mice began receiving intravenous injection of 2 x 10(6) NPC-OPG or NPC-GFP (control) every 10 days x 3 doses. Disease was monitored with quantitative bioluminescence imaging and x-ray images, which were evaluated on a scale of 0 to 4. These studies were approved by the Institutional Animal Care and Use Committee. Osteoprotegerin treatment in vitro produced no direct toxicity to tumor cells. Coculture of tumor cells with bone marrow significantly increased activation of bone marrow-derived osteoclasts as assessed by tartrate-resistant acid phosphatase staining (156 +/- 10.8 osteoclasts per well) compared to bone marrow culture alone (91.67 +/- 4.7, P = .005). This increase was abrogated by adding OPG-containing media (68.3 +/- 2.8, P = .001). NPC-OPG slowed tumor progression (108-fold increase from pretreatment) compared to mice treated with NPC-GFP (538-fold), as judged by bioluminescence imaging. X-rays subjectively demonstrated less bone disease in NPC-OPG-treated mice (2.27 +/- 0.25) compared to NPC-GFP-treated mice (3.25 +/- 0.22, P = .04). Neural progenitor cell-mediated delivery of OPG slowed disease progression in a preclinical model of neuroblastoma bone metastasis. The decrease in bone disease was not from direct tumor cell toxicity but likely occurred indirectly through inhibition of osteoclast-directed bone resorption. Thus, targeted delivery of OPG by NPCs may be effective in the treatment of neuroblastoma bone metastasis.


Genetically-encoded tools for cAMP probing and modulation in living systems.
Intracellular 3'-5'-cyclic adenosine monophosphate (cAMP) is one of the principal second messengers downstream of a manifold of signal transduction pathways, including the ones triggered by G protein-coupled receptors. Not surprisingly, biochemical assays for cAMP have been instrumental for basic research and drug discovery for decades, providing insights into cellular physiology and guiding pharmaceutical industry. However, despite impressive track record, the majority of conventional biochemical tools for cAMP probing share the same fundamental shortcoming-all the measurements require sample disruption for cAMP liberation. This common bottleneck, together with inherently low spatial resolution of measurements (as cAMP is typically analyzed in lysates of thousands of cells), underpin the ensuing limitations of the conventional cAMP assays: (1) genuine kinetic measurements of cAMP levels over time in a single given sample are unfeasible; (2) inability to obtain precise information on cAMP spatial distribution and transfer at subcellular levels, let alone the attempts to pinpoint dynamic interactions of cAMP and its effectors. At the same time, tremendous progress in synthetic biology over the recent years culminated in drastic refinement of our toolbox, allowing us not only to bypass the limitations of conventional assays, but to put intracellular cAMP life-span under tight control-something, that seemed scarcely attainable before. In this review article we discuss the main classes of modern genetically-encoded tools tailored for cAMP probing and modulation in living systems. We examine the capabilities and weaknesses of these different tools in the context of their operational characteristics and applicability to various experimental set-ups involving living cells, providing the guidance for rational selection of the best tools for particular needs.


Multiple ribosomal proteins are expressed at high levels in developing zebrafish endoderm and are required for normal exocrine pancreas development.
Ribosomal protein L (rpl) genes are essential for assembly of the 60S subunit of the eukaryotic ribosome and may also carry out additional extra-ribosomal functions. We have identified a common expression pattern for rpl genes in developing zebrafish larvae. After initially widespread expression in early embryos, the expression of multiple rpl genes becomes increasingly restricted to the endoderm. With respect to the pancreas, rpl genes are highly expressed in ptf1a-expressing pancreatic progenitors at 48 hpf, suggesting possible functional roles in pancreatic morphogenesis and/or differentiation. Utilizing two available mutant lines, rpl23a(hi2582) and rpl6(hi3655b), we found that ptf1a-expressing pancreatic progenitors fail to properly expand in embryos homozygous for either of these genes. In addition to these durable homozygous phenotypes, we also demonstrated recoverable delays in ptf1a-expressing pancreatic progenitor expansion in rpl23a(hi2582) and rpl6(hi3655b) heterozygotes. Disruptions in ribosome assembly are generally understood to initiate a p53-dependent cellular stress response. However, concomitant p53 knockdown was unable to rescue normal pancreatic progenitor expansion in either rpl23a(hi2582) or rpl6(hi3655b) mutant embryos, suggesting required and p53-independent roles for rpl23a and rpl6 in pancreas development.


Carcinogenic risk of N-Nitrosamines in Shanghai Drinking Water: Indications for the Use of Ozone Pretreatment.
N-Nitrosamines are drinking water disinfection byproducts that pose a high carcinogenic risk. We hypothesized that raw water treatment processes influence the types and concentrations of nitrosamines in drinking water, thereby posing differential health risks. We compared the finished water of two water treatment plants (WTP-A, WTP-B) serving Shanghai, China. Both plants use the Qingcaosha reservoir as a water source to generate drinking water with conventional but distinct treatment processes, namely preoxidation with sodium hypochlorite (WTP-A) vs ozone (WTP-B). Average nitrosamine concentrations, especially that of the probable human carcinogen (2A) N-nitrosodimethylamine, were higher in finished (drinking) water from WTP-A (35.83 ng/L) than from WTP-B (5.07 ng/L). Other differences in mean nitrosamines in drinking water included N-nitrosodipropylamine (42.62 ng/L) and N-nitrosomethylethylamine (26.73 ng/L) in WTP-A in contrast to N-nitrosodiethylamine (7.26 ng/L) and N-nitrosopyrrolidine (59.12 ng/L) in WTP-B. The estimated adult cancer risk from exposure to mixed nitrosamines was 1.83 times higher from WTP-A than from WTP-B drinking water. Children exposed to nitrosamines had a significantly higher cancer risk than adults ( p < 0.05). Disease burden exceeded 106 person-years. Taken together, these data suggest that use of ozone in the preoxidation step can reduce nitrosamine formation in drinking water and thereby lower the population cancer health risk.


The complex relationship between self-reported 'personal recovery' and clinical recovery in schizophrenia.
Self-reported 'personal recovery' and clinical recovery in schizophrenia (SRPR and CR, respectively) reflect different perspectives in schizophrenia outcome, not necessarily concordant with each other and usually representing the consumer's or the therapist's point of view. By means of a cluster analysis on SRPR-related variables, we identified three clusters. The first and third cluster included subjects with the best and the poorest clinical outcome respectively. The second cluster was characterized by better insight, higher levels of depression and stigma, lowest self-esteem and personal strength, and highest emotional coping. The first cluster showed positive features of recovery, while the third cluster showed negative features. The second cluster, with the most positive insight, showed a more complex pattern, a somewhat 'paradoxical' mixture of positive and negative personal and clinical features of recovery. The present results suggest the need for a characterization of persons with schizophrenia along SRPR and CR dimensions to design individualized and integrated treatment programs aimed to improve insight and coping strategies, reduce stigma, and shape recovery styles.


Brain immune cell composition and functional outcome after cerebral ischemia: comparison of two mouse strains.
Inflammatory cells may contribute to secondary brain injury following cerebral ischemia. The C57Bl/6 mouse strain is known to exhibit a T helper 1-prone, pro-inflammatory type response to injury, whereas the FVB strain is relatively T helper 2-prone, or anti-inflammatory, in its immune response. We tested whether stroke outcome is more severe in C57Bl/6 than FVB mice. Male mice of each strain underwent sham surgery or 1 h occlusion of the middle cerebral artery followed by 23 h of reperfusion. Despite no difference in infarct size, C57Bl/6 mice displayed markedly greater functional deficits than FVB mice after stroke, as assessed by neurological scoring and hanging wire test. Total numbers of CD45(+) leukocytes tended to be larger in the brains of C57Bl/6 than FVB mice after stroke, but there were marked differences in leukocyte composition between the two mouse strains. The inflammatory response in C57Bl/6 mice primarily involved T and B lymphocytes, whereas neutrophils, monocytes and macrophages were more prominent in FVB mice. Our data are consistent with the concept that functional outcome after stroke is dependent on the immune cell composition which develops following ischemic brain injury.


Current-use and organochlorine pesticides and polychlorinated biphenyls in the biodegradable fraction of source separated household waste, compost, and anaerobic digest.
Several current-use (≤ 80 ng g⁻¹ dry weight) and organochlorine pesticides (≤ 15 ng g⁻¹ dry weight) and polychlorinated biphenyls (≤ 18 ng g⁻¹ dry weight) were found in the biodegradable fraction of source separated household waste, compost, and/or anaerobic digestate. The degradation rates of individual compounds differ depending on the treatment. Dieldrin and pentachloroaniline, e.g., degrade more rapidly than the waste is mineralized and accumulates in the products after all treatments. Many organochlorines degrade at the same rate as the waste and have the same concentrations in the waste and products. Chlorpyrifos degrades slower than the waste and accumulates in all products and ethion during anaerobic digestion. The polychlorinated biphenyls and some pesticides show different degradations rates relative the waste during different processes. Understanding the degradation of the contaminants under different conditions is necessary to develop quality criteria for the use of compost and digest.


Hybrid vertex-midline modelling of elongated plant organs.
We describe a method for the simulation of the growth of elongated plant organs, such as seedling roots. By combining a midline representation of the organ on a tissue scale and a vertex-based representation on the cell scale, we obtain a multiscale method, which is able to both simulate organ growth and incorporate cell-scale processes. Equations for the evolution of the midline are obtained, which depend on the cell-wall properties of individual cells through appropriate averages over the vertex-based representation. The evolution of the organ midline is used to deform the cellular-scale representation. This permits the investigation of the regulation of organ growth through the cell-scale transport of the plant hormone auxin. The utility of this method is demonstrated in simulating the early stages of the response of a root to gravity, using a vertex-based template acquired from confocal imaging. Asymmetries in the concentrations of auxin between the upper and lower sides of the root lead to bending of the root midline, reflecting a gravitropic response.


Effects of blueberry and cranberry consumption on type 2 diabetes glycemic control: A systematic review.
The metabolic effects of cranberry and blueberry consumption on glycemic control have been evaluated in vitro and in animal models as well as in human studies, although findings have not been systematically reviewed yet. Therefore, a systematic review was carried out of relevant randomized clinical trials (RCTs) in order to assess the effect of berries (blueberry and cranberry) consumption on type 2 diabetes (T2DM) glycemic control. Some evidences were also discussed on the anti-diabetic mechanisms exerted by berries polyphenols. Studies were identified by searching electronic databases: LILACS, PubMed/MEDLINE, Scopus, The Cochrane Library and Web of Science. Three authors independently searched and extracted RCTs in which the effect of berries (cranberry or blueberry) consumption on T2DM glycemic control was assessed. A total of 7 RCTs, involving 270 adults with type 2 diabetes were included. Despite the heterogeneity of the administration forms (in natura, dried, extract, preparations - juice), dosage, duration of the intervention and type of population of the studies involving these two berries some studies highlight the potential benefit of berries, especially of blueberry, on glucose metabolism in T2DM subjects. Daily cranberry juice (240 mL) consumption for 12 weeks and blueberry extract or powder supplementation (9.1 to 9.8 mg of anthocyanins, respectively) for 8 to 12 weeks showed a beneficial effect on glucose control in T2DM subjects. Those results indicate a promising use of these berries in T2DM management; although more studies are required to better understand the mechanisms involved.


Patterns in the use of benzodiazepines in British Columbia: examining the impact of increasing research and guideline cautions against long-term use.
We examined changes in patterns of benzodiazepine use in British Columbia over a period of increasing evidence of harms associated with long-term use. Using linked administrative databases for the years 1996 and 2006, we performed logistic regression to examine how socio-economic and health factors affect the likelihood of benzodiazepine use and long-term use, and to test for changes in rates of use and long-term use over time. In 2006, 8.4% of British Columbians used benzodiazepines, 3.5% long-term. Use was positively related with being female, lower income, older, and of poorer health status. Long-term use was positively associated with being in the lowest income quintile, of poorest health, and over the age of 65. While the rate of long-term use decreased from 1996 to 2006 for those over age 70, it increased in middle-aged populations. Our results suggest, despite increased awareness of and cautions regarding risks associated with long-term use of benzodiazepines, rates of potentially inappropriate use have changed very little over a decade. Given that early use of benzodiazepines is positively associated with later long-term use, policies targeting populations younger than conventionally studied (i.e. those under age 65) may be needed to decrease rates of long-term use.


NO• /RUNX3/kynurenine metabolic signaling enhances disease aggressiveness in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is refractory to available treatments. Delineating the regulatory mechanisms of metabolic reprogramming, a key event in pancreatic cancer progression, may identify candidate targets with potential therapeutic significance. We hypothesized that inflammatory signaling pathways regulate metabolic adaptations in pancreatic cancer. Metabolic profiling of tumors from PDAC patients with a high- (>median, n = 31) and low-NOS2 (inducible nitric oxide synthase; <median, n = 32) mRNA expression was performed. Differentially abundant metabolites were analyzed and linked with patient survival. The functional role of the prognostically significant metabolite and the mechanism of its regulation by NOS2/NO• (nitric oxide)-mediated signaling pathway was elucidated. The level of kynurenine, a tryptophan metabolite, was associated with high NOS2 expression, and a higher level of kynurenine predicted poor survival in patients (n = 63, p = 0.01). Gene expression analysis in PDAC tumors (n = 63) showed a positive correlation between the expression of NOS2 and the tryptophan/kynurenine pathway genes, including indoleamine-2,3-dioxygenase 1 (IDO1) and several aryl hydrocarbon receptor (AHR)-target genes including NFE2L2 (NRF2), SERPINB2, IL1b, IL6 and IL8, which are implicated in pancreatic cancer. Consistently, treatment of pancreatic cancer cell lines with NO• donor induced IDO1, kynurenine production and the expression of AHR-target genes. Furthermore, kynurenine treatment enhanced spheroid growth and invasive potential of pancreatic cancer cell lines. Mechanistically, NO• -induced IDO1/Kynurenine/AHR signaling was mediated by RUNX3 transcription factor. Our findings identified a novel NO• /RUNX3/Kynurenine metabolic axis, which enhances disease aggressiveness in pancreatic cancer and may have potential translational significance in improving disease outcome.


Lunar thermal anomalies: infrared observations.
The lunar craters Tycho, Copernicus, and Aristarchus have been observed during lunar night at wavelengths between 3 and 14 microns. After an initial fast decrease to a color temperature of 220 degrees K, the temperature remains nearly constant through the lunar night. The data suggest that these thermal anomalies (craters) contain hot and cold regions with the hot portions constituting 2 to 10 percent of the area and probably thermally connected to a subsurface temperatuer of about 200 degrees K.


The Wnt/beta-catenin pathway regulates cardiac valve formation.
Truncation of the tumour suppressor adenomatous polyposis coli (Apc) constitutively activates the Wnt/beta-catenin signalling pathway. Apc has a role in development: for example, embryos of mice with truncated Apc do not complete gastrulation. To understand this role more fully, we examined the effect of truncated Apc on zebrafish development. Here we show that, in contrast to mice, zebrafish do complete gastrulation. However, mutant hearts fail to loop and form excessive endocardial cushions. Conversely, overexpression of Apc or Dickkopf 1 (Dkk1), a secreted Wnt inhibitor, blocks cushion formation. In wild-type hearts, nuclear beta-catenin, the hallmark of activated canonical Wnt signalling, accumulates only in valve-forming cells, where it can activate a Tcf reporter. In mutant hearts, all cells display nuclear beta-catenin and Tcf reporter activity, while valve markers are markedly upregulated. Concomitantly, proliferation and epithelial-mesenchymal transition, normally restricted to endocardial cushions, occur throughout the endocardium. Our findings identify a novel role for Wnt/beta-catenin signalling in determining endocardial cell fate.


Intraoperative dexamethasone does not increase the risk of postoperative wound infection: a propensity score-matched post hoc analysis of the ENIGMA-II trial (EnDEX).
In a post hoc analysis of the ENIGMA-II trial, we sought to determine whether intraoperative dexamethasone was associated with adverse safety outcomes. Inverse probability weighting with estimated propensity scores was used to determine the association of dexamethasone administration with postoperative infection, quality of recovery, and adverse safety outcomes for 5499 of the 7112 non-cardiac surgery subjects enrolled in ENIGMA-II. Dexamethasone was administered to 2178 (40%) of the 5499 subjects included in this analysis and was not associated with wound infection [189 (8.7%) vs 275 (8.3%); propensity score-adjusted relative risk (RR) 1.10; 95% confidence interval (CI) 0.89-1.34; P=0.38], severe postoperative nausea and vomiting on day 1 [242 (7.3%) vs 189 (8.7%); propensity score-adjusted RR 1.06; 95% CI 0.86-1.30; P=0.59], quality of recovery score [median 14, interquartile range (IQR) 12-15, vs median 14, IQR 12-16, P=0.10), length of stay in the postanaesthesia care unit [propensity score-adjusted median (IQR) 2.0 (1.3, 2.9) vs 1.9 (1.3, 3.1), P=0.60], or the primary outcome of the main trial. Dexamethasone administration was associated with a decrease in fever on days 1-3 [182 (8.4%) vs 488 (14.7%); RR 0.61; 95% CI 0.5-0.74; P<0.001] and shorter lengths of stay in hospital [propensity score-adjusted median (IQR) 5.0 (2.9, 8.2) vs 5.3 (3.1, 9.1), P<0.001]. Neither diabetes mellitus nor surgical wound contamination status altered these outcomes. Dexamethasone administration to high-risk non-cardiac surgical patients did not increase the risk of postoperative wound infection or other adverse events up to day 30, and appears to be safe in patients either with or without diabetes mellitus. NCT00430989.


Efficacy of yogurt drink with added plant stanol esters (Benecol®, Colanta) in reducing total and LDL cholesterol in subjects with moderate hypercholesterolemia: a randomized placebo-controlled crossover trial NCT01461798.
Cardiovascular diseases have become the leading cause of death from chronic diseases in the world. Main risk factors include hypercholesterolemia, which is caused in most cases by a high saturated fat diet. Plant stanol esters partly block cholesterol absorption in the digestive tract and thereby reduce total cholesterol and low-density lipoprotein (LDL) cholesterol serum levels. Based on epidemiological data, a 10 percent reduction of LDL cholesterol leads to a 20 percent decrease in the coronary heart disease risk throughout life. The aim of this study was to evaluate the efficacy of yogurt drink with added plant stanol esters (Benecol® yogurt drink) in higher doses than the typically used (2g/d stanols), in lowering blood lipids in moderately hypercholesterolemic subjects. A randomized double-blind crossover, placebo-controlled study in moderately hypercholesterolemic subjects (n = 40) aged between 20 and 50 years old. Yogurt drink with added plant stanols (4 g) as esters (Benecol®, Colanta) consumption compared to regular yogurt drink caused a statistically significant decrease in total cholesterol and low density lipoprotein cholesterol by 7.2% and 10.3%. During the two periods and compared to controls, high-density lipoprotein cholesterol and triglycerides were not significantly different. Yogurt drink with an active ingredient in Benecol®, plant stanol esters, reduced total cholesterol and LDL cholesterol in moderately hypercholesterolemic subjects. NCT01461798.


Intentional replantation for the management of maxillary sinusitis.
To present a case that emphasizes the importance of the use of intentional replantation as a technique to successfully treat a periapical lesion and an odontogenic maxillary sinusitis through the alveolus at the same time. This case report presents a patient with odontogenic maxillary sinusitis secondary to periapical disease of a maxillary molar that had previously received root canal treatment. The molar was extracted, with drainage and rinsing of the maxillary sinus. The apices were resected extra-orally, the retrograde cavities prepared with ultrasound and retrograde fillings of silver amalgam placed. The tooth was then replanted. After 2 years, the patient was asymptomatic, periapical radiography showed no evidence of root resorption and computed tomography scanning demonstrated the resolution of maxillary sinusitis. *When root canal treatment or periapical surgery cannot be undertaken or has failed, intentional replantation may be considered. *This alternative treatment may be predictable in certain cases.


Pharmacological evidence for tumor necrosis factor as a mediator of allergic inflammation in the airways.
Tumor necrosis factor (TNF) has been implicated in the pathophysiology of a number of inflammatory diseases of the lung. Using the TNF receptor fusion protein, Ro 45-2081, our study investigated the involvement of TNF in allergic inflammatory responses in the airways of sensitized guinea pigs and Brown-Norway rats. Sensitized guinea pigs exhibited an enhanced airway reactivity to substance P (1-10 micrograms/kg, i.v.) at 6 hr after antigen challenge which was inhibited (P < .05) by Ro 45-2081 (3 mg/kg, i.p.). Treatment with Ro 45-2081 (1-3 mg/kg, i.p.) dose-dependently inhibited (P < .05) the accumulation of neutrophils and total cells in bronchoalveolar lavage fluid in sensitized guinea pigs examined at 6 and 24 hr postchallenge. Ro 45-2081 (3 mg/kg, i.p.) also significantly (P < .05) reduced the number of eosinophils in bronchoalveolar lavage at both time points whereas a lower dose (1 mg/kg, i.p.) had no effect. Ro 45-2081 (1 or 3 mg/kg, i.p.) abolished antigen-induced microvascular leakage (quantified by tissue content of Evans blue dye) in the trachea and main bronchi in sensitized guinea pigs. In the Brown-Norway rat, Ro 45-2081 (1-3 mg/kg, i.p.) caused a dose-dependent inhibition of neutrophil and eosinophil infiltration into bronchoalveolar lavage fluid at 24 hr after antigen challenge. In both guinea pig and Brown-Norway rat models, treatment with dexamethasone (30 mg/kg, i.p., for guinea pig and 0.3 mg/kg, i.p., for Brown-Norway rat) produced virtually identical results to those obtained with Ro 45-2081. The ability of Ro 45-2081 to inhibit antigen-induced responses in sensitized animals suggests that TNF is a mediator of allergic inflammation in the lung.


Mortality in vegetarians and comparable nonvegetarians in the United Kingdom.
Vegetarians and others who do not eat meat have been observed to have lower incidence rates than meat eaters of some chronic diseases, but it is unclear whether this translates into lower mortality. The purpose of this study was to describe mortality in vegetarians and comparable nonvegetarians in a large United Kingdom cohort. The study involved a pooled analysis of data from 2 prospective studies that included 60,310 persons living in the United Kingdom, comprising 18,431 regular meat eaters (who ate meat ≥5 times/wk on average), 13,039 low (less-frequent) meat eaters, 8516 fish eaters (who ate fish but not meat), and 20,324 vegetarians (including 2228 vegans who did not eat any animal foods). Mortality by diet group for each of 18 common causes of death was estimated with the use of Cox proportional hazards models. There were 5294 deaths before age 90 in >1 million y of follow-up. There was no significant difference in overall (all-cause) mortality between the diet groups: HRs in low meat eaters, fish eaters, and vegetarians compared with regular meat eaters were 0.93 (95% CI: 0.86, 1.00), 0.96 (95% CI: 0.86, 1.06), and 1.02 (95% CI: 0.94, 1.10), respectively; P-heterogeneity of risks = 0.082. There were significant differences in risk compared with regular meat eaters for deaths from circulatory disease [higher in fish eaters (HR: 1.22; 95% CI: 1.02, 1.46)]; malignant cancer [lower in fish eaters (HR: 0.82; 95% CI: 0.70, 0.97)], including pancreatic cancer [lower in low meat eaters and vegetarians (HR: 0.55; 95% CI: 0.36, 0.86 and HR: 0.48; 95% CI: 0.28, 0.82, respectively)] and cancers of the lymphatic/hematopoietic tissue [lower in vegetarians (HR: 0.50; 95% CI: 0.32, 0.79)]; respiratory disease [lower in low meat eaters (HR: 0.70; 95% CI: 0.53, 0.92)]; and all other causes [lower in low meat eaters (HR: 0.74; 95% CI: 0.56, 0.99)]. Further adjustment for body mass index left these associations largely unchanged. United Kingdom-based vegetarians and comparable nonvegetarians have similar all-cause mortality. Differences found for specific causes of death merit further investigation.


Functional Richness and Identity Do Not Strongly Affect Invasibility of Constructed Dune Communities.
Biotic effects are often used to explain community structure and invasion resistance. We evaluated the contribution of functional richness and identity to invasion resistance and abiotic resource availability using a mesocosm experiment. We predicted that higher functional richness would confer greater invasion resistance through greater resource sequestration. We also predicted that niche pre-emption and invasion resistance would be higher in communities which included functional groups similar to the invader than communities where all functional groups were distinct from the invader. We constructed communities of different functional richness and identity but maintained constant species richness and numbers of individuals in the resident community. The constructed communities represented potential fore dune conditions following invader control activities along the Australian east coast. We then simulated an invasion event by bitou (Chrysanthemoides monilifera ssp. rotundata DC. Norl.), a South African shrub invader. We used the same bitou propagule pressure across all treatments and monitored invasion success and resource availability for 13 months. Contrary to our predictions, we found that functional richness did not mediate the number of bitou individuals or bitou cover and functional identity had little effect on invasion success: there was a trend for the grass single functional group treatment to supress bitou individuals, but this trend was obscured when grasses were in multi functional group treatments. We found that all constructed communities facilitated bitou establishment and suppressed bitou cover relative to unplanted mesocosms. Abiotic resource use was either similar among planted communities, or differences did not relate to invasion success (with the exception of light availability). We attribute invasion resistance to bulk plant biomass across planted treatments rather than their functional group arrangement.


Comparative genomics of IncP-1ε plasmids from water environments reveals diverse and unique accessory genetic elements.
The goal of this study was to determine and compare the complete genome sequences of three new broad-host-range conjugative plasmids. Plasmids pMLUA1, pMLUA3 and pMLUA4 were previously recovered from estuarine water by exogenous plasmid isolation and ranged in size from ∼55 to 59 kb. Comparative genomics showed that their backbone region was identical to the prototype pKJK5 and other IncP1-ε plasmids captured from soils. The accessory region was inserted between the tra region and parA, and presented the typical IncP-1ε ISPa17 and Tn402-like transposon modules. Nevertheless, new class 1 integrons were identified (In794, carrying aadA5 and In795, carrying qacF5-aadA5), as well as a composite transposon IS26-msr(E)-mph(E)-IS26 carrying genes that confer resistance to macrolides. A new insertion sequence, termed ISUnCu17, was also identified on pMLUA3. The architecture of the accessory regions implies the occurrence of multiple insertions and deletions. These data support the notion that IncP-1 plasmids from the ε subgroup are proficient in the capture of diverse genetic elements, including antibiotic resistance genes, and thus may contribute to the co-selection of several resistance determinants. This study constitutes the first report of completely sequenced IncP-1ε plasmids from water environments, and enhances our understanding of the geographic distribution and genetic diversity of these replicons.


Coronary angiography after thrombolytic therapy for acute myocardial infarction.
To review the status of emergency, urgent, routine, and selective angiography after intravenous thrombolytic therapy. Relevant English-language articles published from January 1985 to July 1990 were identified through MEDLINE. For emergency angiography, four major randomized studies were reviewed and data from nine studies that incorporated rescue coronary angioplasty were pooled for meta-analysis. For urgent angiography, two controlled trials were reviewed. Comparisons of routine and selective angiography were done using data from two dedicated, large-scale, controlled trials and the ancillary findings of four other studies of reperfusion that incorporated angiography. The review emphasizes the findings from multicenter, randomized, controlled trials. Emergency coronary angiography is done primarily in preparation for primary or rescue angioplasty; the value of rescue angioplasty has yet to be assessed in a randomized trial, but technical success and reocclusion improve significantly after therapy with nonspecific plasminogen activators compared with relatively specific agents (success rate, 86% compared with 75%, respectively; P = 0.03; reocclusion rate, 10.9% compared with 26.8%, respectively; P less than 0.001). Urgent coronary angiography has value for treating recurrent ischemia, but patients who develop this complication after thrombolysis are likely to have a suboptimal outcome despite aggressive care. Studies support the use of either selective or routine angiography in uncomplicated patients after thrombolytic therapy; either approach is acceptable, but the former is more practical and may prove to be cost effective. Optimal follow-up for patients with evolving myocardial infarction who receive thrombolysis may incorporate coronary angiography at various stages. Although our ability to noninvasively detect reperfusion, reocclusion, or viable but ischemic myocardium is limited at present, available data may assist in selecting a catheterization strategy.


Deciding treatment for miscarriage--experiences of women and healthcare professionals.
Women experiencing miscarriage are offered a choice of different treatments to terminate their wanted pregnancy at a time when they are often shocked and distressed. Women's and healthcare professionals' experiences of the decision-making process are not well described. We aimed to gain insight into this process and the circumstances that may affect it. A qualitative study using a grounded theory approach. Data were obtained through semi-structured interviews with six women who had chosen and completed either surgical, medical or expectant treatment for miscarriage and five healthcare professionals involved in the decision-making at an emergency gynaecological department in Denmark. An inductive explorative method was chosen due to limited knowledge about the decision-making process, and a theoretical perspective was not applied until the final analysis. Despite information and pretreatment counselling, choice of treatment was often determined by unspoken emotional considerations, including fear of seeing the foetus or fear of anaesthesia. These considerations were not discussed during the decision-making process, which was a time when the women were under time pressure and experienced emotional distress. Healthcare professionals did not explore women's considerations for choosing a particular treatment and prioritised information differently. We found theory about coping and decision-making in stressful situations useful in increasing our understanding of the women's reactions. In relation to theory about informed consent, our findings suggest that women need more understanding of the treatments before making a decision. This study is limited due to a small sample size, but it generates important findings that need to be examined in a larger sample. Frequently, women did not use information provided about treatment pros and cons in their decision-making process. Because of unspoken thoughts, and women's needs being unexplored by healthcare professionals, information did not target women's needs and their reasoning remained unapparent.


Intact word processing in developmental prosopagnosia.
A wealth of evidence from behavioural, neuropsychological and neuroimaging research supports the view that face recognition is reliant upon a domain-specific network that does not process words. In contrast, the recent many-to-many model of visual recognition posits that brain areas involved in word and face recognition are functionally integrated. Developmental prosopagnosia (DP) is characterised by severe deficits in the recognition of faces, which the many-to-many model predicts should negatively affect word recognition. Alternatively, domain-specific accounts suggest that impairments in face and word processing need not go hand in hand. To test these possibilities, we ran a battery of 7 tasks examining word processing in a group of DP cases and controls. One of our prosopagnosia cases exhibited a severe reading impairment with delayed response times during reading aloud tasks, but not lexical decision tasks. Overall, however, we found no evidence of global word processing deficits in DP, consistent with a dissociation account for face and word processing.


[Identification of Vibrio spp bacteria on skin lesions of fisherman in the county of Raposa-MA].
The study was undertaken aiming at identifying bacteria from the county of Raposa in the state of Maranhão. The clinical sample was collected by using a swab and held in a Cary-Blair transport medium. Enrichment in alkaline peptone water, isolation in TCBS selective indicator medium and biochemical coding of species were used for laboratory processing. Fifty fisherman with age varying from 12-65 years took part on the study. Vibrio bacteria isolated in 21 subjects had been identified. There was a predominance of V. alginolyticus (66.6%) followed by V. parahaemolyticus (42.8%), and V. cholerae non-O1 (9.5%). Lesions predominated on lower limbs, presenting hyperhemia, swelling, secretion, and pain. Some species of gram-negative bacteria of the Serratia, Proteus, Escherichia, Citrobacter, Enterobacter associated to the vibrios were isolated, as well as other non-fermenting bacteria (30.9) and gram-positive bacteria of the genos Staphylococcus.


Ascorbyl stearate inhibits cell proliferation and tumor growth in human ovarian carcinoma cells by targeting the PI3K/AKT pathway.
Ascorbyl stearate is a lipophilic, vitamin C derivative with antitumorigenic properties. The molecular mechanism(s) underlying the anticarcinogenic effect of this compound have not been well documented. The effect of ascorbyl stearate was studied in a panel of human ovarian epithelial cancer cells. Treatment with ascorbyl stearate caused a dose-dependent inhibition of the cell proliferation. The antiproliferative effect was due to the arrest of cells in the S/G2-M-phase of the cell cycle. Treatment of OVCAR-3 cells with ascorbyl stearate also inhibited PI3K/AKT activity. The presence of a constitutively active AKT protected OVCAR-3 cells from the effects of ascorbyl stearate, suggesting that this nutraceutical targets the PI3K/AKT pathway. The administration of ascorbyl stearate by gavage induced involution of human ovarian carcinoma xenografts in nude mice. These studies indicate that the antiproliferative effect of ascorbyl stearate on ovarian epithelial cancer cells is associated with decreased PI3K/AKT activity, and point toward the PI3K/AKT signaling pathway as a target for this drug.


MAR-mediated integration of plasmid vectors for in vivo gene transfer and regulation.
The in vivo transfer of naked plasmid DNA into organs such as muscles is commonly used to assess the expression of prophylactic or therapeutic genes in animal disease models. In this study, we devised vectors allowing a tight regulation of transgene expression in mice from such non-viral vectors using a doxycycline-controlled network of activator and repressor proteins. Using these vectors, we demonstrate proper physiological response as consequence of the induced expression of two therapeutically relevant proteins, namely erythropoietin and utrophin. Kinetic studies showed that the induction of transgene expression was only transient, unless epigenetic regulatory elements termed Matrix Attachment Regions, or MAR, were inserted upstream of the regulated promoters. Using episomal plasmid rescue and quantitative PCR assays, we observed that similar amounts of plasmids remained in muscles after electrotransfer with or without MAR elements, but that a significant portion had integrated into the muscle fiber chromosomes. Interestingly, the MAR elements were found to promote plasmid genomic integration but to oppose silencing effects in vivo, thereby mediating long-term expression. This study thus elucidates some of the determinants of transient or sustained expression from the use of non-viral regulated vectors in vivo.


Phase I/IIa trial of autologous formalin-fixed tumor vaccine concomitant with fractionated radiotherapy for newly diagnosed glioblastoma. Clinical article.
The objective of the present study was analysis of results of the prospective clinical trial directed toward the evaluation of therapeutic efficacy of the administration of autologous formalin-fixed tumor vaccine (AFTV) concomitant with fractionated radiotherapy in cases of newly diagnosed glioblastoma multiforme. Twenty-four patients were enrolled into the clinical trial, while 2 cases were excluded from the final analysis of results. The treatment protocol included aggressive tumor resection, fractionated radiotherapy up to a total dose of 60 Gy, and 3 concomitant courses of AFTV administered with an interval of one week at the late stage of irradiation. Two delayed-type hypersensitivity (DTH) tests were done--one 48 hours before the initial course of vaccination (DTH-1) and one 2 weeks after the third (DTH-2). All but one of the patients received salvage therapy at the time of tumor progression. The defined primary end point was overall survival; secondary end points were progression-free survival and safety of concomitant treatment. The median duration of overall survival was 19.8 [corrected] months (95% CI 13.8-31.3 months). The actuarial 2-year survival rate was 40%. The median duration of progression-free survival was 7.6 months (95% CI 4.3-13.6 months). Overall survival showed a statistically significant association with recursive partitioning analysis class (p < 0.05); progression-free survival showed a statistically significant association with p53 staining index (p < 0.05) and size of DTH-2 response (p < 0.001). AFTV injection concomitant with fractionated radiotherapy was well tolerated by all patients and in no case did treatment-related adverse effects exceed Grade 1 toxicity; adverse effects were limited to local erythema, induration, and swelling at the site of injection. The results of this study demonstrate that AFTV treatment concomitant with fractionated radiotherapy may be effective in patients with newly diagnosed glioblastoma. Further clinical testing is warranted.


CYP4A1 antisense oligonucleotide reduces mesenteric vascular reactivity and blood pressure in SHR.
The cytochrome P-450 4A (CYP4A)-derived arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) affects renal tubular and vascular functions and has been implicated in the control of arterial pressure. We examined the effect of antisense oligonucleotide (ODN) to CYP4A1, the low K(m) arachidonic acid omega-hydroxylating isoform, on vascular 20-HETE synthesis, vascular reactivity, and blood pressure in the spontaneously hypertensive rat (SHR). Administration of CYP4A1 antisense ODN decreased mean arterial blood pressure from 137 +/- 3 to 121 +/- 4 mmHg (P < 0.05) after 5 days of treatment, whereas treatment with scrambled antisense ODN had no effect. Treatment with CYP4A1 antisense ODN reduced the level of CYP4A-immunoreactive proteins along with 20-HETE synthesis in mesenteric arterial vessels. Mesenteric arteries from rats treated with antisense ODN exhibited decreased sensitivity to the constrictor action of phenylephrine (EC(50) 0.69 +/- 0.17 vs. 1.77 +/- 0.40 microM). Likewise, mesenteric arterioles from antisense ODN-treated rats revealed attenuation of myogenic constrictor responses to increases of transmural pressure. The decreased vascular reactivity and myogenic responses were reversible with the addition of 20-HETE. These data suggest that CYP4A1-derived 20-HETE facilitates myogenic constrictor responses in the mesenteric microcirculation and contributes to pressor mechanisms in SHR.


Consensus Recommendations for Standardized Data Elements, Scales, and Time Segmentations in Studies of Human Circadian/Diurnal Biology and Stroke.
Increasing evidence indicates that circadian and diurnal rhythms robustly influence stroke onset, mechanism, progression, recovery, and response to therapy in human patients. Pioneering initial investigations yielded important insights but were often single-center series, used basic imaging approaches, and used conflicting definitions of key data elements, including what constitutes daytime versus nighttime. Contemporary methodologic advances in human neurovascular investigation have the potential to substantially increase understanding, including the use of large multicenter and national data registries, detailed clinical trial data sets, analysis guided by individual patient chronotype, and multimodal computed tomographic and magnetic resonance imaging. To fully harness the power of these approaches to enhance pathophysiologic knowledge, an important foundational step is to develop standardized definitions and coding guides for data collection, permitting rapid aggregation of data acquired in different studies, and ensuring a common framework for analysis. To meet this need, the Leducq Consortium International pour la Recherche Circadienne sur l'AVC (CIRCA) convened a Consensus Statement Working Group of leading international researchers in cerebrovascular and circadian/diurnal biology. Using an iterative, mixed-methods process, the working group developed 79 data standards, including 48 common data elements (23 new and 25 modified/unmodified from existing common data elements), 14 intervals for time-anchored analyses of different granularity, and 7 formal, validated scales. This portfolio of standardized data structures is now available to assist researchers in the design, implementation, aggregation, and interpretation of clinical, imaging, and population research related to the influence of human circadian/diurnal biology upon ischemic and hemorrhagic stroke.


Growth inhibition of a B cell leukemia: evidence implicating an anti-idiotype immune response for protective tumor immunity.
BCL1, a spontaneous surface IgM (mu lambda)-positive (sIgM+) B cell leukemia of BALB/c (Igha) origin rarely grows in the Ig heavy chain (Igh) congenic mouse C.B-20 (Ighb) but is highly metastatic and lethal in the host strain of origin. Previous studies indicated that BCL1 tumor immunity in C.B-20 mice was associated with a T cell-mediated immune response against H-40, a minor histocompatibility (H) antigen controlled by a gene linked to the Igh locus. However, we observed that BCL1 leukemia grew progressively in BAB-14 (Igha/b) mice, a strain capable of generating an anti-H-40 immune response. This suggested that anti-H-40 immunity was insufficient for protection and implied that an Igh-V (variable) region gene product was also important for BCL1 growth inhibition. We therefore evaluated the role of two possible Igh-V region-linked gene products in BCL1 growth inhibition; namely, an Igh-V region-linked minor H antigen or alternatively the BCL1 IgM idiotype (Id). We could find no evidence for an Igh-V region-linked minor H antigen because immunosuppressed (500 R) CB-20 mice reconstituted with C.B-20 anti-BAB-14 splenocytes were susceptible to BCL1 growth, whereas recipients reconstituted with C.B-20 anti-BALB/c splenocytes were resistant to BCL1 challenge. In contrast, C.B-20 mice immunized against purified BCL1 IgM protein could adoptively confer BCL1 tumor immunity. C.B-20 mice immunized against other BALB/c IgM myeloma proteins containing either lambda or kappa light chains failed to protect C.B-20 mice suggesting that recognition of a unique determinant (Id) and not an allotype was crucial for tumor immunity. The BCL1 mu-chain appeared to make the major contribution to the idiotypic determinant because a hybridoma product composed of BCL1 mu-chains and BALB/c kappa-chains still elicited BCL1 immunity. Adoptive transfer of C.B-20 anti-BCL1 Id splenocytes into irradiated recipients that prevented an anti-H-40 response due to H-40 tissue expression failed to adoptively confer BCL1 immunity. Thus, these data suggest that BCL1 growth inhibition requires a T cell-mediated response against both H-40 and the BCL1 Id; these responses must be elicited concurrently in the tumor-bearing host to achieve protective BCL1 immunity.


Distinct mobilization of circulating CD271+ mesenchymal progenitors from hematopoietic progenitors during aging and after myocardial infarction.
The specific cell surface markers on mesenchymal stem/progenitor cells (MSCs) have been poorly defined in vivo, but in one recent study, an MSC subpopulation was directly isolated from a CD271-positive fraction of human bone marrow cells. The aim of this study was to identify circulating CD271(+) MSCs in human peripheral blood and investigate whether the cells are mobilized after acute myocardial infarction (MI). A flow cytometric analysis identified CD45(low/-)CD34(+)CD271(+) cells in adult human peripheral blood. The numbers of circulating CD45(low/-)CD34(+)CD133(+) cells (hematopoietic linage progenitors) were significantly lower in elderly subjects without coronary artery disease than in healthy young subjects, whereas the numbers of CD45(low/-)CD34(+)CD271(+) cells were comparable between elderly subjects and younger subjects. The CD45(low/-)CD34(+)CD271(+) and CD133(+) cell counts were both higher in patients with acute MI than in patients with stable coronary artery disease. In our investigation of the time course changes after acute MI, the CD45(low/-)CD34(+)CD133(+) cell counts gradually increased up to day 7. Over the same period, the CD45(low/-)CD34(+)CD271(+) cell counts peaked at day 3 and then declined up to day 7. Importantly, the CD271(+) cell counts at day 3 were positively correlated with the peak concentrations of creatine kinase after acute MI. Results of the present study suggest that the CD271(+) MSCs are mobilized differently from the CD133(+) hematopoietic progenitors and may play a specific role in the tissue repair process during age-related changes and after acute myocardial infarction.


p53 expression in colorectal carcinoma in relation to histopathological features in Ugandan patients.
It has been shown that colorectal carcinoma is increasing in incidence in African countries. This could be due to change in life style. Molecular pathogenesis of colorectal cancer commonly involves mutation in p53 gene which leads to expression of p53 protein in tumor cells. Expression of p53 protein has been associated with poor clinical outcome and reduced survival in patients. This was a retrospective laboratory based study carried out in the Department of Pathology Makerere University, Kampala, Uganda. The aim of the study was to evaluate the expression of p53 protein in colorectal carcinoma in Ugandan patients, specifically its association with histological types, degree of differentiation, sites of the tumor and demographic characteristics of the patients. Immunohistochemistry was carried out on 109 patient's paraffin embedded tissue blocks of colorectal carcinoma diagnosed in the Pathology Department, Faculty of Medicine Makerere University Kampala during the period 1995 to 2005. The indirect immunoperoxidase method using monoclonal antibody p53 DO-7 and Envision (+) Dual link system-HRP to detect p53 expression was used. Haematoxylin and eosin stain was used for evaluation of histological types and degree of differentiation of the tumors. Topography of the tumors and demographic data were obtained from accompanying histological request forms. Out of 109 patient's tissue blocks that were studied, 61 cases (56%) expressed p53 protein in the nucleus of malignant cells. Right sided colonic tumors were commoner (53.2%) than left sided colonic tumors (46.8%). p53 protein was expressed more in left sided colonic tumors with a significant difference (p<0.05), it was also expressed more in well differentiated tumors and non mucinous adenocarcinomas but with no significant difference (p>0.05). p53 expression was not affected by age or sex. Frequency of p53 protein expression in Ugandan patients did not differ from that reported in the other parts of the world. It was expressed more in the left sided colonic tumors and this could support the hypothesis that right and left colonic tumors could have different pathogenesis and probably also responsible for difference in prognosis in these two topographic sites.


Ontogeny of bite force in a validated biomechanical model of the American alligator.
Three-dimensional computational modeling offers tools with which to investigate forces experienced by the skull during feeding and other behaviors. American alligators (Alligator mississippiensis) generate some of the highest measured bite forces among extant tetrapods. A concomitant increase in bite force accompanies ontogenetic increases in body mass, which has been linked with dietary changes as animals increase in size. Because the flattened skull of crocodylians has substantial mediolaterally oriented muscles, crocodylians are an excellent model taxon in which to explore the role of mediolateral force components experienced by the feeding apparatus. Many previous modeling studies of archosaur cranial function focused on planar analysis, ignoring the mediolateral aspects of cranial forces. Here, we used three-dimensionally accurate anatomical data to resolve 3D muscle forces. Using dissection, imaging and computational techniques, we developed lever and finite element models of an ontogenetic series of alligators to test the effects of size and shape on cranial loading and compared estimated bite forces with those previously measured in vivo in A. mississippiensis We found that modeled forces matched in vivo data well for intermediately sized individuals, and somewhat overestimated force in smaller specimens and underestimated force in larger specimens, suggesting that ontogenetically static muscular parameters and bony attachment sites alone cannot account for all the variation in bite force. Adding aponeurotic muscle attachments would likely improve force predictions, but such data are challenging to model and integrate into analyses of extant taxa and are generally unpreserved in fossils. We conclude that anatomically accurate modeling of muscles can be coupled with finite element and lever analyses to produce reliable, reasonably accurate estimate bite forces and thus both skeletal and joint loading, with known sources of error, which can be applied to extinct taxa.


Clinical software development for the Web: lessons learned from the BOADICEA project.
In the past 20 years, society has witnessed the following landmark scientific advances: (i) the sequencing of the human genome, (ii) the distribution of software by the open source movement, and (iii) the invention of the World Wide Web. Together, these advances have provided a new impetus for clinical software development: developers now translate the products of human genomic research into clinical software tools; they use open-source programs to build them; and they use the Web to deliver them. Whilst this open-source component-based approach has undoubtedly made clinical software development easier, clinical software projects are still hampered by problems that traditionally accompany the software process. This study describes the development of the BOADICEA Web Application, a computer program used by clinical geneticists to assess risks to patients with a family history of breast and ovarian cancer. The key challenge of the BOADICEA Web Application project was to deliver a program that was safe, secure and easy for healthcare professionals to use. We focus on the software process, problems faced, and lessons learned. Our key objectives are: (i) to highlight key clinical software development issues; (ii) to demonstrate how software engineering tools and techniques can facilitate clinical software development for the benefit of individuals who lack software engineering expertise; and (iii) to provide a clinical software development case report that can be used as a basis for discussion at the start of future projects. We developed the BOADICEA Web Application using an evolutionary software process. Our approach to Web implementation was conservative and we used conventional software engineering tools and techniques. The principal software development activities were: requirements, design, implementation, testing, documentation and maintenance. The BOADICEA Web Application has now been widely adopted by clinical geneticists and researchers. BOADICEA Web Application version 1 was released for general use in November 2007. By May 2010, we had > 1200 registered users based in the UK, USA, Canada, South America, Europe, Africa, Middle East, SE Asia, Australia and New Zealand. We found that an evolutionary software process was effective when we developed the BOADICEA Web Application. The key clinical software development issues identified during the BOADICEA Web Application project were: software reliability, Web security, clinical data protection and user feedback.


Identification of functions linking quorum sensing with biofilm formation in Burkholderia cenocepacia H111.
Burkholderia cenocepacia has emerged as an important pathogen for patients suffering from cystic fibrosis (CF). Previous work has shown that this organism employs the CepIR quorum-sensing (QS) system to control the expression of virulence factors as well as the formation of biofilms. To date, however, very little is known about the QS-regulated virulence factors and virtually nothing about the factors that link QS and biofilm formation. Here, we have employed a combined transcriptomic and proteomic approach to precisely define the QS regulon in our model strain B. cenocepacia H111, a CF isolate. Among the identified CepR-activated loci, three were analyzed in better detail for their roles in biofilm development: (i) a gene cluster coding for the BclACB lectins, (ii) the large surface protein BapA, and (iii) a type I pilus. The analysis of defined mutants revealed that BapA plays a major role in biofilm formation on abiotic surfaces while inactivation of the type I pilus showed little effect both in a static microtitre dish-based biofilm assay and in flow-through cells. Inactivation of the bclACB lectin genes resulted in biofilms containing hollow microcolonies, suggesting that the lectins are important for biofilm structural development.


High nutrient transport and cycling potential revealed in the microbial metagenome of Australian sea lion (Neophoca cinerea) faeces.
Metagenomic analysis was used to examine the taxonomic diversity and metabolic potential of an Australian sea lion (Neophoca cinerea) gut microbiome. Bacteria comprised 98% of classifiable sequences and of these matches to Firmicutes (80%) were dominant, with Proteobacteria and Actinobacteria representing 8% and 2% of matches respectively. The relative proportion of Firmicutes (80%) to Bacteriodetes (2%) is similar to that in previous studies of obese humans and obese mice, suggesting the gut microbiome may confer a predisposition towards the excess body fat that is needed for thermoregulation within the cold oceanic habitats foraged by Australian sea lions. Core metabolic functions, including carbohydrate utilisation (14%), protein metabolism (9%) and DNA metabolism (7%) dominated the metagenome, but in comparison to human and fish gut microbiomes there was a significantly higher proportion of genes involved in phosphorus metabolism (2.4%) and iron scavenging mechanisms (1%). When sea lions defecate at sea, the relatively high nutrient metabolism potential of bacteria in their faeces may accelerate the dissolution of nutrients from faecal particles, enhancing their persistence in the euphotic zone where they are available to stimulate marine production.


Traumatic brain injury and the Americans with Disabilities Act: implications for the social work profession.
The practice of social work has been greatly affected by the Americans with Disabilities Act of 1990 (ADA). Title I of the statute prohibits discrimination against people with disabilities, including the increasing number of workers who are returning to work after a traumatic brain injury (TBI). This article examines the extent to which the ADA protects those with TBI from being harassed, being denied reasonable workplace accommodations, or suffering other adverse actions related to perceived discrimination. To do so, it relies on judicial decisions from U.S. federal courts involving alleged workplace discrimination of this population. Implications for social work practice are noted with the intent of increasing ADA awareness among professionals providing services to people who meet the criteria for disability under the ADA as well as to those persons who do not. The authors hope to encourage social workers to rely on case law analysis as a mechanism to provide further evidence of the systematic problems faced by people with TBI and thus increase their visibility.


Merozoite surface protein-3: a malaria protein inducing antibodies that promote Plasmodium falciparum killing by cooperation with blood monocytes.
We have previously found that the acquired protection against malaria implicates a mechanism of defense that relies on the cooperation between cytophilic antibodies and monocytes. Accordingly, an assay of antibody-dependent cellular inhibition (ADCI) of parasite growth was used as a means of selecting for molecules capable of inducing protective immunity to malaria. This allowed us to identify in the sera of clinically protected subjects an antibody specificity that promotes parasite killing mediated by monocytes. This antibody is directed to a novel merozoite surface protein (MSP-3) of a molecular mass of 48 kD. Purified IgG from protected subjects are effective in ADCI and those directed against MSP-3 are predominantly cytophilic. In contrast, in nonprotected individuals, whose antibodies are not effective in ADCI, anti-MSP-3 antibodies are mostly noncytophilic. A region in MSP-3 targetted by antibodies effective in the ADCI assay was identified and its sequence was determined; it contains an epitope not defined by a repetitive structure and does not appear to be polymorphic. Antibodies raised in mice against a peptide containing this epitope, as well as human antibodies immunopurified on this peptide, elicit a strong inhibition of Plasmodium falciparum growth in ADCI assay, whereas control antibodies, directed to peptides from other molecules, do not. The correlation between isotypes of antibodies produced against the 48-kD epitopes, clinical protection, and the ability of specific anti-MSP-3 antibodies to block the parasite schizogony in the ADCI assay suggests that this molecule is involved in eliciting protective mechanisms.


Grid-free models of multicellular systems, with an application to large-scale vortices accompanying primitive streak formation.
This paper is comprised of two parts. In the first we provide a brief overview of grid-free methods for modeling multicellular systems. We focus on an approach based on Langevin equations, in which inertia is ignored, and stochastic effects on cell motion are included. The discussion starts with simpler models, in which cells are modeled as adhesive spheres. We then turn to more sophisticated approaches in which nontrivial cell shape is accommodated, including the recently introduced Subcellular Element Model, in which each cell is described as a cluster of adhesively coupled over-damped subcellular elements, representing patches of cytoskeleton. In the second part of the paper we illustrate the use of a standard grid-free cell-based model to computationally probe interesting new features associated with primitive streak formation in the chick embryo. Streak formation is a key developmental step in amniotes (i.e., birds, reptiles, and mammals), and can be observed in detail in the chick embryo, where the streak extends across a tightly-packed two-dimensional sheet (the epiblast) comprised of about 50,000 cells. The Weijer group [Cui, Yang, Chuai, Glazier, and Weijer, Dev. Biol. 284 (2005) 37-47] recently observed that streak formation is accompanied by coordinated cell movement lateral to the streak, resulting in two large counter-rotating vortices. We study a mechanism based on cell polarity (in the plane of the epiblast) that provides an explanation for these vortices, and test it successfully using computer simulations. This mechanism is robust, since the emergent vortex formation depends only on the gross features of the initial spatial distribution of planar polarity in the epiblast.


Expression and contributions of TRPM7 and KCa2.3/SK3 channels to the increased migration and invasion of microglia in anti-inflammatory activation states.
Microglia rapidly respond to CNS injury and disease and can assume a spectrum of activation states. While changes in gene expression and production of inflammatory mediators have been extensively described after classical (LPS-induced) and alternative (IL4-induced) microglial activation, less is known about acquired de-activation in response to IL10. It is important to understand how microglial activation states affect their migration and invasion; crucial functions after injury and in the developing CNS. We reported that LPS-treated rat microglia migrate very poorly, while IL4-treated cells migrate and invade much better. Having discovered that the lamellum of migrating microglia contains a large ring of podosomes--microscopic structures that are thought to mediate adhesion, migration and invasion--we hypothesized that IL4 and IL10 would differentially affect podosome expression, gene induction, migration and invasion. Further, based on the enrichment of the KCa2.3/SK3 Ca2+-activated potassium channel in microglial podosomes, we predicted that it regulates migration and invasion. We found both similarities and differences in gene induction by IL4 and IL10 and, while both cytokines increased migration and invasion, only IL10 affected podosome expression. KCa2.3 currents were recorded in microglia under all three activation conditions and KCNN3 (KCa2.3) expression was similar. Surprisingly then, of three KCa2.3 inhibitors (apamin, tamapin, NS8593), only NS8593 abrogated the increased migration and invasion of IL4 and IL10-treated microglia (and invasion of unstimulated microglia). This discrepancy was explained by the observed block of TRPM7 currents in microglia by NS8593, which occurred under all three activation conditions. A similar inhibition of both migration and invasion was seen with a TRPM7 inhibitor (AA-861) that does not block KCa2.3 channels. Thus, we conclude that TRPM7 (not KCa2.3) contributes to the enhanced ability of microglia to migrate and invade when in anti-inflammatory states. This will be an important consideration in developing TRPM7 inhibitors for treating CNS injury.


Interrelationships between postpartum events, hormonal therapy, reproductive abnormalities and reproductive performance in dairy cows: a path analysis.
Path analysis was used to determine the interrelationships between postpartum administration of gonadotrophin releasing hormone and cloprostenol and the occurrence of reproductive disease and reproductive performance in dairy cows. The data analysed were those collected on 226 Holstein-Friesian cows calving in a commercial dairy herd during a 17 month period (May 1, 1981 to October 1, 1982). Cows administered gonadotrophin releasing hormone at day 15 postpartum experienced an improved rate of uterine involution as determined by rectal palpation nine days later. Although this improved rate of uterine involution reduced the risk of pyometritis, it actually directly delayed conception. Also, gonadotrophin releasing hormone therapy directly resulted in an increased incidence of pyometritis which in turn resulted in an increase incidence of cystic ovarian disease and anestrus. The occurrence of these abnormalities resulted in increased intervals from calving to first observed estrus, first service and conception. In addition to this effect, the administration of gonadotrophin releasing hormone was also associated with increased plasma progesterone concentrations at days 24 and 28 postpartum which delayed conception. Cloprostenol therapy at day 24 postpartum resulted in a decreased plasma progesterone concentration at day 28 postpartum which was directly and indirectly associated with a decrease in the calving to conception interval. The indirect effects were mediated by a reduction in days to first estrus. Cloprostenol therapy also directly resulted in a decreased calving to first observed estrus interval for reasons not attributable to the level of progesterone at day 28.


A programmable triangular neighborhood function for a Kohonen self-organizing map implemented on chip.
An efficient transistor level implementation of a flexible, programmable triangular function (TF) that can be used as a triangular neighborhood function (TNF) in ultra-low power, self-organizing maps (SOMs) realized as application-specific integrated circuit (ASIC) is presented. The proposed TNF block is a component of a larger neighborhood mechanism, whose role is to determine the distance between the winning neuron and all neighboring neurons. Detailed simulations carried out for the software model of such network show that the TNF forms a good approximation of the gaussian neighborhood function (GNF), while being implemented in a much easier way in hardware. The overall mechanism is very fast. In the CMOS 0.18 μm technology, distances to all neighboring neurons are determined in parallel, within the time not exceeding 11 ns, for an example neighborhood range, R, of 15. The TNF blocks in particular neurons require another 6 ns to calculate the output values directly used in the adaptation process. This is also performed in parallel in all neurons. As a result, after determining the winning neuron, the entire map is ready for the adaptation after the time not exceeding 17 ns, even for large numbers of neurons. This feature allows for the realization of ultra low power SOMs, which are hundred times faster than similar SOMs realized on PC. The signal resolution at the output of the TNF block has a dominant impact on the overall energy consumption as well as the silicon area. Detailed system level simulations of the SOM show that even for low resolutions of 3 to 6 bits, the learning abilities of the SOM are not affected. The circuit performance has been verified by means of transistor level Hspice simulations carried out for different transistor models and different values of supply voltage and the environment temperature - a typical procedure completed in case of commercial chips that makes the obtained results reliable.


Reverse total shoulder arthroplasty.
The radical changes in prosthetic design made in the mid 1980s transformed the historically poorly performing reverse ball-and-socket total shoulder prosthesis into a highly successful salvage implant for pseudoparalytic, severely rotator cuff-deficient shoulders. Moving the center of rotation more medial and distal as well as implanting a large glenoid hemisphere that articulates with a humeral cup in 155 degrees of valgus are the biomechanical keys to sometimes spectacular short- to mid-term results. Use of the reverse total shoulder arthroplasty device allows salvage of injuries that previously were beyond surgical treatment. However, this technique has a complication rate approximately three times that of conventional arthroplasty. Radiographic and clinical results appear to deteriorate over time. Proper patient selection and attention to technical details are needed to reduce the currently high complication rate.


Diet composition and the performance of high-intensity exercise.
The crucial role of muscle glycogen as a fuel during prolonged exercise is well established, and the effects of acute changes in dietary carbohydrate intake on muscle glycogen content and on endurance capacity are equally well known. More recently, it has been recognized that diet can also affect the performance of high-intensity exercise of short (2-7 min) duration. If the muscle glycogen content is lowered by prolonged (1-1.5 h) exhausting cycle exercise, and is subsequently kept low for 3-4 days by consumption of a diet deficient in carbohydrate (< 5% of total energy intake), there is a dramatic (approximately 10-30%) reduction in exercise capacity during cycling sustainable for about 5 min. The same effect is observed if exercise is preceded by 3-4 days on a carbohydrate-restricted diet or by a 24 h total fast without prior depletion of the muscle glycogen. Consumption of a diet high in carbohydrate (70% of total energy intake from carbohydrate) for 3-4 days before exercise improves exercise capacity during high-intensity exercise, although this effect is less consistent. The blood lactate concentration is always lower at the point of fatigue after a diet low in carbohydrate and higher after a diet high in carbohydrate than after a normal diet. Even when the duration of the exercise task is kept constant, the blood lactate concentration is higher after exercise on a diet high in carbohydrate than on a diet low in carbohydrate. Consumption of a low-carbohydrate isoenergetic diet is achieved by an increased intake of protein and fat. A high-protein diet, particularly when combined with a low carbohydrate intake, results in metabolic acidosis, which ensues within 24 h and persists for at least 4 days. This appears to be the result of an increase in the circulating concentrations of strong organic acids, particularly free fatty acids and 3-hydroxybutyrate, together with an increase in the total plasma protein concentration. This acidosis, rather than any decrease in the muscle glycogen content, may be responsible for the reduced exercise capacity in high-intensity exercise; this may be due to a reduced rate of efflux of lactate and hydrogen ions from the working muscles. Alternatively, the accumulation of acetyl groups in the carbohydrate-deprived state may reduce substrate flux through the pyruvate dehydrogenase complex, thus reducing aerobic energy supply and accelerating the onset of fatigue.


Extrapulmonary neoplasms in lung cancer screening.
A significant reduction in lung cancer specific mortality rate was demonstrated by the National Lung Screening Trial (NLST) in participants who had annual low-dose computed tomography (LDCT) screening. In addition to early detection of lung cancer, lung cancer screening (LCS) provides an opportunity to detect cardiovascular disease, pulmonary disease (such as chronic obstructive pulmonary disease and interstitial lung disease), and extrapulmonary neoplasms, such as thyroid, breast, kidney, liver, esophageal, pancreatic and mediastinal tumors. Considering the fact that 22.3% of the certified deaths in the computed tomography (CT) arm of the NLST trial were due to extrapulmonary malignancies, compared to 22.9% of deaths from lung cancer, it is possible that early diagnosis and treatment of clinically significant incidental findings may further decrease morbidity and mortality in screening participants. In this article we review prevalence, clinical relevance and management of incidentally detected extrapulmonary malignancies.


Painful dilemmas: A study of the way the public's assessment of animal research balances costs to animals against human benefits.
The conflict between animal costs and human benefits has dominated public as well as academic debates about animal research. However, surveys of public perceptions of animal research rarely focus on this part of attitude formation. This paper traces the prevalence of different attitudes to animal research in the public when people are asked to take benefit and cost considerations into account concurrently. Results from the examination of two representative samples of the Danish public identify three reproducible attitude stances. Approximately 30-35% of people questioned approved of animal research quite strongly, and 15-20% opposed animal research. The remaining 50% were reserved in their views. Further studies will ideally use the measure developed here to make possible relatively fine-grained comparisons and understandings of differences between populations and changes in attitudes over time.


Identification of patients and plaques vulnerable to future coronary events with near-infrared spectroscopy intravascular ultrasound imaging: a prospective, cohort study.
Near-infrared spectroscopy (NIRS) intravascular ultrasound imaging can detect lipid-rich plaques (LRPs). LRPs are associated with acute coronary syndromes or myocardial infarction, which can result in revascularisation or cardiac death. In this study, we aimed to establish the relationship between LRPs detected by NIRS-intravascular ultrasound imaging at unstented sites and subsequent coronary events from new culprit lesions. In this prospective, cohort study (LRP), patients from 44 medical centres were enrolled in Italy, Latvia, Netherlands, Slovakia, UK, and the USA. Patients with suspected coronary artery disease who underwent cardiac catheterisation with possible ad hoc percutaneous coronary intervention were eligible to be enrolled. Enrolled patients underwent scanning of non-culprit segments using NIRS-intravascular ultrasound imaging. The study had two hierarchal primary hypotheses, patient and plaque, each testing the association between maximum 4 mm Lipid Core Burden Index (maxLCBI4mm) and non-culprit major adverse cardiovascular events (NC-MACE). Enrolled patients with large LRPs (≥250 maxLCBI4mm) and a randomly selected half of patients with small LRPs (<250 maxLCBI4mm) were followed up for 24 months. This study is registered with ClinicalTrials.gov, NCT02033694. Between Feb 21, 2014, and March 30, 2016, 1563 patients were enrolled. NIRS-intravascular ultrasound device-related events were seen in six (0·4%) patients. 1271 patients (mean age 64 years, SD 10, 883 [69%] men, 388 [31%]women) with analysable maxLCBI4mm were allocated to follow-up. The 2-year cumulative incidence of NC-MACE was 9% (n=103). Both hierarchical primary hypotheses were met. On a patient level, the unadjusted hazard ratio (HR) for NC-MACE was 1·21 (95% CI 1·09-1·35; p=0·0004) for each 100-unit increase maxLCBI4mm) and adjusted HR 1·18 (1·05-1·32; p=0·0043). In patients with a maxLCBI4mm more than 400, the unadjusted HR for NC-MACE was 2·18 (1·48-3·22; p<0·0001) and adjusted HR was 1·89 (1·26-2·83; p=0·0021). At the plaque level, the unadjusted HR was 1·45 (1·30-1·60; p<0·0001) for each 100-unit increase in maxLCBI4mm. For segments with a maxLCBI4mm more than 400, the unadjusted HR for NC-MACE was 4·22 (2·39-7·45; p<0·0001) and adjusted HR was 3·39 (1·85-6·20; p<0·0001). NIRS imaging of non-obstructive territories in patients undergoing cardiac catheterisation and possible percutaneous coronary intervention was safe and can aid in identifying patients and segments at higher risk for subsequent NC-MACE. NIRS-intravascular ultrasound imaging adds to the armamentarium as the first diagnostic tool able to detect vulnerable patients and plaques in clinical practice. Infraredx.


Magnetic resonance enterography, small bowel ultrasound and colonoscopy to diagnose and stage Crohn's disease: patient acceptability and perceived burden.
To compare patient acceptability and burden of magnetic resonance enterography (MRE) and ultrasound (US) to each other, and to other enteric investigations, particularly colonoscopy. 159 patients (mean age 38, 94 female) with newly diagnosed or relapsing Crohn's disease, prospectively recruited to a multicentre diagnostic accuracy study comparing MRE and US completed an experience questionnaire on the burden and acceptability of small bowel investigations between December 2013 and September 2016. Acceptability, recovery time, scan burden and willingness to repeat the test were analysed using the Wilcoxon signed rank and McNemar tests; and group differences in scan burden with Mann-Whitney U and Kruskal-Wallis tests. Overall, 128 (88%) patients rated MRE as very or fairly acceptable, lower than US (144, 99%; p < 0.001), but greater than colonoscopy (60, 60%; p < 0.001). MRE recovery time was longer than US (p < 0.001), but shorter than colonoscopy (p < 0.001). Patients were less willing to undergo MRE again than US (127 vs. 133, 91% vs. 99%; p = 0.012), but more willing than for colonoscopy (68, 75%; p = 0.017). MRE generated greater burden than US (p < 0.001), although burden scores were low. Younger age and emotional distress were associated with greater MRE and US burden. Higher MRE discomfort was associated with patient preference for US (p = 0.053). Patients rated test accuracy as more important than scan discomfort. MRE and US are well tolerated. Although MRE generates greater burden, longer recovery and is less preferred than US, it is more acceptable than colonoscopy. Patients, however, place greater emphasis on diagnostic accuracy than burden. • MRE and US are rated as acceptable by most patients and superior to colonoscopy. • MRE generates significantly greater burden and longer recovery times than US, particularly in younger patients and those with high levels of emotional distress. • Most patients prefer the experience of undergoing US than MRE; however, patients rate test accuracy as more importance than scan burden.