Demonstration of improved laser preheat with a cryogenically cooled magnetized liner inertial fusion platform.

We report on progress implementing and testing cryogenically cooled platforms for Magnetized Liner Inertial Fusion (MagLIF) experiments. Two cryogenically cooled experimental platforms were developed: an integrated platform fielded on the Z pulsed power generator that combines magnetization, laser preheat, and pulsed-power-driven fuel compression and a laser-only platform in a separate chamber that enables measurements of the laser preheat energy using shadowgraphy measurements. The laser-only experiments suggest that ∼89% ± 10% of the incident energy is coupled to the fuel in cooled targets across the energy range tested, significantly higher than previous warm experiments that achieved at most 67% coupling and in line with simulation predictions. The laser preheat configuration was applied to a cryogenically cooled integrated experiment that used a novel cryostat configuration that cooled the MagLIF liner from both ends. The integrated experiment, z3576, coupled 2.32 ± 0.25 kJ preheat energy to the fuel, the highest to-date, demonstrated excellent temperature control and nominal current delivery, and produced one of the highest pressure stagnations as determined by a Bayesian analysis of the data.

Development of a deuterium-ice extruder for inertial confinement fusion experiments on the Z Facility.

A deuterium-ice extruder has been developed for inertial confinement fusion experiments on the Sandia National Laboratories Z Facility. The screw-driven extruder is filled via desublimation, where a slow flow of deuterium gas enters the extruder cavity and freezes to the walls without entering the liquid phase. Ice generated in this manner is optically clear, demonstrating its high uniformity. When the extruder cavity is filled with ice, the screw is driven downward, closing off the gas-fill line. With the ice cavity isolated, further screw rotation compresses the deuterium through a nozzle, extruding a fiber. Fiber diameters ranging from 200 to 500 µm have been extruded to lengths of 1.5 feet before hitting the vacuum chamber floor. The fiber straightness improves with the nozzle length-to-diameter aspect ratio. Deuterium-ice fibers can persist in high vacuum for more than 10 min before breaking free from the nozzle. The peripheral infrastructure required for Z experimental operations is under development. An in-vacuum stepper-motor-based drive system will allow remote operation, and a translating cathode will ensure proper placement of the fiber in the powerflow hardware.

Retinoblastoma-binding protein 2 (RBP2) is frequently expressed in neuroendocrine tumors and promotes the neoplastic phenotype.

Neuroendocrine tumors (NETs), which can have survival rates as low as 4%, currently have limited therapeutic interventions available highlighting the dire need for the identification of novel biological targets for use as new potential drug targets. One such potential target is retinoblastoma-binding protein 2 (RBP2), an H3K4 demethylase whose overexpression has been linked to cancer formation and metastasis in non-endocrine tumor types. We measured RBP2 mRNA and protein levels in enteropancreatic NETs by measuring RBP2 in matched human normal and NET tissue samples. Further, proliferation, migration, invasion and colony formation assays were performed in the physiologically relevant NET cell lines ßlox5, H727 and QGP-1 to understand the role of RBP2 and its demethylase activity on end points of tumorigenesis. Our data indicate a strong correlation between RBP2 mRNA and protein expression in NET specimens. RBP2 was overexpressed relative to tissue-matched normal controls in 80% of the human tumors measured. In vitro studies showed RBP2 overexpression significantly increased proliferation, migration, invasion and colony formation, whereas knockdown significantly decreases the same parameters in a demethylase-independent manner. The cell cycle inhibitors p21 and p57 decreased with RBP2 overexpression and increased upon its depletion, suggesting a regulatory role for RBP2 in cellular proliferation. Taken together, our results support the hypothesis that the aberrant overexpression of RBP2 is a frequent contributing factor to tumor formation and metastasis in enteropancreatic NETs.

The effectiveness of person-centred planning for people with intellectual disabilities: A systematic review.

OBJECTIVES: To evaluate the effectiveness of Person-Centred Planning (PCP) on outcomes for individuals with intellectual disabilities (ID) across the age range. METHOD: The electronic databases PsycInfo, Embase, CINHAL, PubMed, Web of Science, Scopus and Medline were searched for studies evaluating the impact of PCP on people with ID, published between 1990 and 2014; these were supplemented by manual searches of reference lists. Studies were considered irrespective of methodology, sample size and publication source, if outcomes reflected the impact of PCP on individuals with ID. RESULTS: Seven quantitative, five qualitative and four mixed methods studies were included in the review. The overall quality of the evidence was low but suggestive that PCP may have a positive, yet moderate, impact on some outcomes for individuals with ID, particularly community-participation, participation in activities and daily choice-making. For other outcomes such as employment the findings were inconsistent. CONCLUSION: The evidence supporting the effectiveness of PCP is limited and does not demonstrate that PCP can achieve radical transformations in the lives of people with ID. Clearer descriptions of PCP and its components are needed. Small-scale successful demonstrations of effectiveness exist, but its clinical, cost-effectiveness and wider implementation must be investigated in large scale studies.

Comparative transcriptomic analysis reveals the oncogenic fusion protein PAX3-FOXO1 globally alters mRNA and miRNA to enhance myoblast invasion.

Rhabdomyosarcoma, one of the most common childhood sarcomas, is comprised of two main subtypes, embryonal and alveolar (ARMS). ARMS, the more aggressive subtype, is primarily characterized by the t(2;13)(p35;p14) chromosomal translocation, which fuses two transcription factors, PAX3 and FOXO1 to generate the oncogenic fusion protein PAX3-FOXO1. Patients with PAX3-FOXO1-postitive tumors have a poor prognosis, in part due to the enhanced local invasive capacity of these cells, which leads to the increased metastatic potential for this tumor. Despite this knowledge, little is known about the role that the oncogenic fusion protein has in this increased invasive potential. In this report we use large-scale comparative transcriptomic analyses in physiologically relevant primary myoblasts to demonstrate that the presence of PAX3-FOXO1 is sufficient to alter the expression of 70 mRNA and 27 miRNA in a manner predicted to promote cellular invasion. In contrast the expression of PAX3 alters 60 mRNA and 23 miRNA in a manner predicted to inhibit invasion. We demonstrate that these alterations in mRNA and miRNA translate into changes in the invasive potential of primary myoblasts with PAX3-FOXO1 increasing invasion nearly 2-fold while PAX3 decreases invasion nearly 4-fold. Taken together, these results allow us to build off of previous reports and develop a more expansive molecular model by which the presence of PAX3-FOXO1 alters global gene regulatory networks to enhance the local invasiveness of cells. Further, the global nature of our observed changes highlights the fact that instead of focusing on a single-gene target, we must develop multi-faceted treatment regimens targeting multiple genes of a single oncogenic phenotype or multiple genes that target different oncogenic phenotypes for tumor progression.

A method for isolating and culturing placental cells from failed early equine pregnancies.

Early pregnancy loss occurs in 6-10% of equine pregnancies making it the main cause of reproductive wastage. Despite this, reasons for the losses are known in only 16% of cases. Lack of viable conceptus material has inhibited investigations of many potential genetic and pathological causes. We present a method for isolating and culturing placental cells from failed early equine pregnancies. Trophoblast cells from 18/30 (60%) failed equine pregnancies of gestational ages 14-65 days were successfully cultured in three different media, with the greatest growth achieved for cells cultured in AmnioChrome™ Plus. Genomic DNA of a suitable quality for molecular assays was also isolated from 29/30 of these cases. This method will enable future investigations determining pathologies causing EPL.

Review of seven cases of granulosa cell tumour of the equine ovary.

This paper reviews the equine granulosa cell tumour (GCT) and describes the clinicopathological features, treatment and outcome in seven cases of GCT in mares. Mares were presented with unilateral ovarian enlargement during the 2007 to 2010 breeding seasons. The mean (sd) age of the mares was 11.7 (5.96) years. Three mares were multiparous barren, three were nulliparous and one was primigravida. Behaviour at presentation was 57 per cent anoestrus, 28 per cent with stallion-like behaviour and 14 per cent with persistent oestrus. All mares had unilateral ovarian enlargement. Six non-pregnant mares had a small and inactive contralateral ovary; the pregnant mare had a single small corpus luteum on the contralateral ovary and was at three-and-a-half months' gestation. Enlarged ovaries measured 7 cm to an estimated 30 cm in diameter. 28 per cent had a multicystic ultrasound appearance, 57 per cent were dense structures and 14 per cent were of mixed appearance. Mean concentrations of progesterone were <1 ng/ml, oestrone sulphate 3.06 (2.32) ng/ml and testosterone 0.58 (0.64) nmol/l in non-pregnant mares. Inhibin was elevated in all non-pregnant cases at 7.6 (12.45) ng/ml. The pregnant mare had concentrations of progesterone 2.5 ng/ml, oestrone sulphate 81.0 ng/ml, testosterone 1.9 nmol/l and inhibin 1.31 ng/ml. Mares demonstrating stallion-like behaviour had a significantly higher (P<0.001) testosterone concentration (1.85 [0.07] nmol/l) than those that did not (0.34 [0.26] nmol/l). Three mares underwent unilateral ovariectomy and resumed cyclic ovarian activity within nine months of surgery.

International variation in Helicobacter pylori infection and rates of oesophageal cancer.

AIM: To examine the association between gastric atrophy, Helicobacter pylori and CagA status, and ratio of oesophageal squamous cell carcinoma to oesophageal adenocarcinoma (OSCC:OAC) amongst international heterogeneous populations. METHODS: Standardised protocols were used to collect and process questionnaire data and serum samples for PgA and PgC levels and H. pylori and CagA serology. The OSCC:OAC were used to construct appropriate models. RESULTS: There were significant correlations between the OSCC:OAC and both rates of low PgA:PgC ratios and serological markers of H. pylori infection, in males, but not females. A significant correlation between OSCC:OAC and overall CagA-seropositivity was seen in males, but not females, but this was not independently associated with increasing OSCC:OAC. CONCLUSIONS: In males, populations with higher rates of gastric atrophy or H. pylori infection have a higher OSCC:OAC. CagA seropositivity rates seem to have no additional effect.

Selected best demonstrated practices in peritoneal dialysis access.

Many burdensome interventions that adversely affect the utilization of peritoneal dialysis as renal replacement therapy and patient satisfaction with this treatment modality can be avoided by early peritoneal access placement with embedded catheters, implantation techniques that preempt common catheter complications, and the use of access devices that provide flexibility in exit site location. Catheter embedding consists of subcutaneously burying the external limb of the catheter tubing at the time of the insertion procedure. Interval exteriorization of the catheter is performed when dialysis is needed. Earlier commitment by patients to peritoneal dialysis can be achieved by elimination of catheter maintenance until dialysis is necessary. Catheter embedding is a practical strategy to avoid temporary hemodialysis with vascular catheters and reduces stress on operating room access by allowing more efficient scheduling as non-urgent procedures. Laparoscopic catheter placement enables proactive techniques not available to other conventional insertion methods. These techniques include rectus sheath tunneling to prevent catheter tip migration, selective prophylactic omentopexy to prevent omental entrapment, selective resection of epiploic appendages to prevent catheter obstruction, adhesiolysis to eliminate compartmentalization, and diagnosis and simultaneous repair of previously undiagnosed abdominal wall hernias. Both standard and extended 2-piece catheter systems are necessary to customize the peritoneal access to a variety of body configurations. Catheters should be able to produce lower abdominal, mid-abdominal, upper abdominal, and upper chest exit site locations that facilitate management by the patient without sacrificing deep pelvic position of the catheter tip or resulting in excessive tubing stress during passage through the abdominal wall.

Gastric histology, serological markers and age as predictors of gastric acid secretion in patients infected with Helicobacter pylori.

BACKGROUND: Acid secretion is intimately associated with most upper gastrointestinal diseases. Helicobacter pylori infection is a major environmental factor modifying acid secretion. AIM: To study the association between the pattern of H pylori gastritis and gastric secretory function in a large number of subjects without specific upper gastrointestinal disease. METHODS AND MATERIALS: Maximal acid output (MAO) was measured in 255 patients with dyspepsia showing normal endoscopy. Activity and severity of gastritis, atrophy and H pylori infection were assessed in body and antral biopsies. The correlations of histological parameters as well as age, sex, height, weight, smoking, serum gastrin, pepsinogen I and II, and their ratio with MAO were determined. Multiple linear regression was used to show the best possible predictors of MAO. RESULTS: Negative relationships: Body atrophy and body-combined (active and chronic) inflammatory scores showed a potent inverse correlation with MAO (correlation coefficients (CC) 0.59 and 0.50, respectively). Body:antral chronic gastritis ratio and body:antral combined inflammation ratio (both with CC = 0.49) and age (CC = 0.44) were also inversely correlated with MAO. Intestinal metaplasia at both antral and body sites had negative relationships with acid output with CC = 0.23 and 0.20, respectively. Positive relationships: Serum pepsinogen I, body H pylori density:combined inflammation ratio and pepsinogen I:II ratio with CC of 0.38, 0.38 and 0.30, respectively, correlated with MAO. The H pylori density: combined inflammation of both antrum and body positively correlated with MAO (CC = 0.29 and 0.38, respectively). Male sex and patient height also positively correlated with acid output. Modelling showed that body combined inflammatory score, body atrophy, age and serum pepsinogen I are independent predictors of acid output (R(2) = 0.62). CONCLUSION: Combination of body gastritis, body atrophy, age and serum pepsinogen I can be used as predictors of acid-secretory state in populations infected with H pylori.

Rescue and salvage procedures for mechanical and infectious complications of peritoneal dialysis.

Mechanical and infectious complications are the two most common reasons for removal of peritoneal dialysis catheters and permanent transfer of patients to in-center hemodialysis. Early and appropriate intervention can save many catheters, often without interrupting peritoneal dialysis. If peritoneal dialysis must be interrupted, other strategies may be employed to minimize the time on temporary hemodialysis and preserve peritoneal dialysis as renal replacement therapy. Procedures for managing dialysate leaks, abdominal wall hernias, infusion pain, and catheter flow dysfunction are described. Salvage techniques for catheter-related infections and peritonitis are presented. Clinical conditions are discussed where urgent removal of the dialysis catheter is indicated to protect the future integrity of the peritoneal membrane.

Whole genome comparison of the A. fumigatus family.

The availability of the genome sequences of multiple Aspergillus spp. presents the research community with an unprecedented opportunity for discovery. The genomes of Neosartorya fischeri and Aspergillus clavatus have been sequenced in order to extend our knowledge of Aspergillus fumigatus, the primary cause of invasive aspergillosis. Through comparative genomic analysis, we hope to elucidate both obvious and subtle differences between genomes, developing new hypotheses that can be tested in the laboratory. A preliminary examination of the genomes and their predicted proteomes reveals extensive conservation between protein sequences and significant synteny, or conserved gene order. Comparative genomic analysis at the level of these closely related aspergilli should provide important insight into the evolutionary forces at play and their effect on gene content, regulation and expression.

Protection against Helicobacter pylori infection in the Mongolian gerbil after prophylactic vaccination.

Vaccines against Helicobacter pylori could circumvent the problem of increasing antibiotic resistance. They would be particularly useful in developing countries, where re-infection rates are high following standard eradication regimes. The Mongolian gerbil is a good model for H. pylori infection, as the gastric pathology induced by infection is similar to that in humans. The H. pylori-induced inflammatory response in gerbils is considerably greater than in murine models. The aim of this study was to determine if gerbils could be vaccinated against H. pylori. Mongolian gerbils were vaccinated orally with an H. pylori whole cell sonicate preparation and cholera toxin adjuvant. Vaccinated gerbils and controls were challenged with the autologous H. pylori strain 42GX. All infection, and cholera toxin, control gerbils were H. pylori positive 6 weeks post-challenge. By contrast, a significant degree of protection was demonstrated in vaccinated gerbils. Only two of 10 of gerbils were H. pylori positive (P<0.001). Protection was associated with increased serum H. pylori IgG antibodies. Protected gerbils had histologically normal gastric mucosa and, in contrast to mice, no post-immunisation gastritis was evident. In the control groups, the degree of inflammation was variable, with some of the animals having corpus gastritis and corpus mucous metaplasia. The levels of gastric IL-12p40 and IFNgamma transcripts were significantly decreased in vaccinated animals compared to infection and cholera toxin controls (P<0.01). Gastric IL-10 and TGFbeta transcripts were found only at relatively low levels. These results demonstrate that Mongolian gerbils can be successfully vaccinated against H. pylori and protected from H. pylori-induced pathology.

IgG subclass response to Helicobacter pylori and CagA antigens in children.

Specific serum IgG subclass antibodies against Helicobacter pylori antigens and recombinant CagA were analysed in 75 symptomatic children with histologically confirmed H. pylori infection. H. pylori stimulated an IgG1 predominant response, and IgG3 titres showed a positive association with peptic ulcer disease, chronicity of antral inflammation and density of H. pylori colonization. Two methods used for assessing serum IgG CagA antibody status, i.e. Western blotting and enzyme-linked immunosorbent assay (ELISA), were concordant. CagA stimulated an IgG1 and IgG3 predominant humoral response. Total CagA IgG titres were higher in children with active and more severe chronic antral inflammation. These findings suggest that in children the systemic humoral immune response to H. pylori infection may reflect gastroduodenal pathology.

Corynebacterium striatum peritoneal dialysis catheter exit site infection.

BACKGROUND: Regarded as normal flora of the human skin and mucus membranes, non-diphtheria corynebacteria are frequently dismissed as contaminants or harmless colonizers. Recently, the pathogenic potential of C. striatum has been realized in immunocompromised patients with indwelling medical devices and previous antibiotic exposure. OBJECTIVE: We report here the diagnosis, treatment and clinical outcome of a peritoneal dialysis patient with a C. striatum infection of the catheter exit site. The aim is to present important features to assist in identifying clinically significant infections and provide guidelines for treatment. RESULTS: An immunocompromised patient with previous antimicrobial exposure developed an acute dialysis catheter exit site infection. C. striatum was isolated in pure growth. After initial treatment failure with oral antibiotics and intensified wound care, a satisfactory outcome was ultimately achieved without relapse or loss of the catheter with a 1-month course of vancomycin, 1 g intravenously, administered at 5-day intervals. CONCLUSIONS: The virulent capacity of Corynebacterium species should not be underestimated, particularly in high-risk patients. The presence of clinical signs of infection with isolation of the organism in pure culture and the presence of Gram-positive rods on direct Gram stain, especially in association with a leukocyte reaction, supports a cause and effect relationship. Because corynebacteria may be multiresistant, susceptibility testing should be performed on clinically significant isolates. Initial antibiotic selection is influenced by the severity of the infection, however, current experience favors vancomycin in significant infections.