Surface degradation of laminated metal226Ra foils used in school sealed sources in the UK.

In the few years leading up to this research, CLEAPSS noticed a small but steadily increasing number of calls from UK schools regarding a red-brown discolouration on the surface of the foil of their radium source. There were no reports of this type of discolouration on foils of other radionuclides. CLEAPSS and the University of Liverpool collaborated to investigate the nature and cause of this discolouration and the likelihood that the foils were becoming unsafe. The evidence indicates that the discolouration is principally caused by some combination of silicon, sulfur and possibly lead from within the foil diffusing into the face layer. There is no indication currently that the face layers are fragmenting on these foils, but the longer-term integrity of the discoloured foils now becomes questionable. Given the age of the foils and the radiotoxicity of radium, the recommendation from this research is that discoloured foils should be taken out of service and disposed.

Testing General Relativity with Stellar Orbits around the Supermassive Black Hole in Our Galactic Center.

We demonstrate that short-period stars orbiting around the supermassive black hole in our Galactic center can successfully be used to probe the gravitational theory in a strong regime. We use 19 years of observations of the two best measured short-period stars orbiting our Galactic center to constrain a hypothetical fifth force that arises in various scenarios motivated by the development of a unification theory or in some models of dark matter and dark energy. No deviation from general relativity is reported and the fifth force strength is restricted to an upper 95% confidence limit of |α|<0.016 at a length scale of λ=150 astronomical units. We also derive a 95% confidence upper limit on a linear drift of the argument of periastron of the short-period star S0-2 of |ω[over ˙]_{S0-2}|<1.6×10^{-3} rad/yr, which can be used to constrain various gravitational and astrophysical theories. This analysis provides the first fully self-consistent test of the gravitational theory using orbital dynamic in a strong gravitational regime, that of a supermassive black hole. A sensitivity analysis for future measurements is also presented.

Assessing the Acceptability of Science Operations Concepts and the Level of Mission Enhancement of Capabilities for Human Mars Exploration Extravehicular Activity.

The Biologic Analog Science Associated with Lava Terrains (BASALT) research project is investigating tools, techniques, and strategies for conducting Mars scientific exploration extravehicular activity (EVA). This has been accomplished through three science-driven terrestrial field tests (BASALT-1, BASALT-2, and BASALT-3) during which the iterative development, testing, assessment, and refinement of concepts of operations (ConOps) and capabilities were conducted. ConOps are the instantiation of operational design elements that guide the organization and flow of personnel, communication, hardware, software, and data products to enable a mission concept. Capabilities include the hardware, software, data products, and protocols that comprise and enable the ConOps. This paper describes the simulation quality and acceptability of the Mars-forward ConOps evaluated during BASALT-2. It also presents the level of mission enhancement and acceptability of the associated Mars-forward capabilities. Together, these results inform science operations for human planetary exploration.

Genetic variants of microsomal epoxide hydrolase and glutamate-cysteine ligase in COPD.

The genetic factors that contribute to the development of chronic obstructive pulmonary disease (COPD) are poorly understood. Many candidate genes have been proposed, including enzymes that protect the lung against oxidative stress, such as microsomal epoxide hydrolase (EPHX1) and glutamate-cysteine ligase (GCL). To date, most reported findings have been for EPHX1, particularly in relation to functional variants associated with fast and slow metabolism of epoxide intermediates. The present study aimed to identify any association of variation in these genes with COPD susceptibility or severity. In total, 1,017 white COPD patients and 912 nondiseased age and sex matched smoking controls were genotyped for six single nucleotide polymorphisms (SNPs) in EPHX1 (including the fast and slow variants and associated haplotypes), and eight SNPs in the two genes encoding GCL. GCL is a rate-limiting enzyme in the synthesis of glutathione, a major contributor to anti-oxidant protection in the lung. No association of variation was found in EPHX1 or GCL with susceptibility to COPD or disease severity. This is the largest reported study to date and is well powered to detect associations that have been previously suggested. The current data indicate that these genetic variants are unlikely to be related to susceptibility or disease severity in white chronic obstructive pulmonary disease patients.

c-Myc protein synthesis is initiated from the internal ribosome entry segment during apoptosis.

Recent studies have shown that during apoptosis protein synthesis is inhibited and that this is in part due to the proteolytic cleavage of eukaryotic initiation factor 4G (eIF4G). Initiation of translation can occur either by a cap-dependent mechanism or by internal ribosome entry. The latter mechanism is dependent on a complex structural element located in the 5' untranslated region of the mRNA which is termed an internal ribosome entry segment (IRES). In general, IRES-mediated translation does not require eIF4E or full-length eIF4G. In order to investigate whether cap-dependent and cap-independent translation are reduced during apoptosis, we examined the expression of c-Myc during this process, since we have shown previously that the 5' untranslated region of the c-myc proto-oncogene contains an IRES. c-Myc expression was determined in HeLa cells during apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. We have demonstrated that the c-Myc protein is still expressed when more than 90% of the cells are apoptotic. The presence of the protein in apoptotic cells does not result from either an increase in protein stability or an increase in expression of c-myc mRNA. Furthermore, we show that during apoptosis initiation of c-myc translation occurs by internal ribosome entry. We have investigated the signaling pathways that are involved in this response, and cotransfection with plasmids which harbor either wild-type or constitutively active MKK6, a specific immediate upstream activator of p38 mitogen-activated protein kinase (MAPK), increases IRES-mediated translation. In addition, the c-myc IRES is inhibited by SB203580, a specific inhibitor of p38 MAPK. Our data, therefore, strongly suggest that the initiation of translation via the c-myc IRES during apoptosis is mediated by the p38 MAPK pathway.

Chemoradiotherapy with Brachytherapy or Electron Therapy Boost for Locally Advanced Squamous Cell Carcinoma of the Anus-Reducing the Colostomy Rate.

PURPOSE: The aim of this study is to determine overall survival, disease-specific survival and stoma-free survival after treatment of squamous cell carcinoma of the anus with chemoradiotherapy followed by brachytherapy or electron boost in a recent cohort of patients. METHODS: Fifty-two patients (median age 62 years) were treated with radical chemoradiotherapy (mitomycin C, infusional 5-fluorouracil concurrently with conformal radical radiotherapy 45 Gy in 25 fractions over 5 weeks) followed by a radiotherapy boost between 1 December 2000 and 30 April 2011. Follow-up was to 30 November 2014. Thirty-six patients received a boost (15-20 Gy) over 2 days with 192Ir needle brachytherapy for anal canal tumours, and 16 patients received electron beam therapy (20 Gy in 10 fractions in 2 weeks) for anal margin tumours. A defunctioning stoma was only created prior to chemoradiotherapy for fistula or severe anal pain. RESULTS: The overall survival for the 36 patients treated with chemoradiotherapy followed by brachytherapy was 75 % (95 % CI, 61-89) at 5 years, the disease-specific survival was 91 % (95 % CI, 81-101 %), and the stoma-free survival was 97 % (95 % CI, 91-103 %) all at 5 years. For the 16 patients treated with an electron boost for anal margin tumours, the 5-year overall survival, disease-specific survival and stoma-free survival were 68 % (95 % CI, 44-92 %), 78 % (95 % CI, 56-100 %) and 80 % (95 % CI, 60-100 %), respectively. CONCLUSIONS: A very low stoma formation rate can be obtained with radical chemoradiotherapy followed by a brachytherapy boost for squamous cell carcinoma of the anal canal but not with an electron boost for anal margin tumours.

Longitudinal study of CTX-M ESBL-producing E. coli strains on a UK dairy farm.

The aim of this study was to investigate the bacterial strains and farm environment that may contribute to the persistence of ESBL-producing E. coli on a single UK dairy farm. A longitudinal study was conducted comprising 6 visits, between August and October 2010, followed by a further visit at approximately 69weeks after the initial visit. Faecal and environmental samples were collected from different parts of the farm. The persistence and extent of faecal shedding of ESBL E. coli by individual calves was also determined. Twenty two different PFGE types were identified. Four of these were persistent during the study period and were associated with serotypes: O98, O55, O141 and O33. The counts suggest that shedding in calf faeces was an important factor for the persistence of strains, and the data will be useful for parameterising mathematical models of the spread and persistence of ESBL strains within a dairy farm.

C-Myc 5' untranslated region contains an internal ribosome entry segment.

Translation in eukaryotic cells is generally initiated by ribosome scanning from the 5' end of the capped mRNA. However, initiation of translation may also occur by a mechanism which is independent of the cap structure and in this case ribosomes are directed to the start codon by an internal ribosome entry segment (IRES). Picornaviruses represent the paradigm for this mechanism, but only a few examples exist which show that this mechanism is used by eukaryotic cells. In this report we show data which demonstrate that the 5' UTR of the proto-oncogene c-myc contains an IRES. When a dicistronic reporter vector, with c-myc 5' UTR inserted between the two cistrons, was transfected into both HepG2 and HeLa cells, the translation of the downstream cistron was increased by 50-fold, demonstrating that translational regulation of c-myc is mediated through cap-independent mechanisms. This is the first example of a proto-oncogene regulated in this manner and suggests that aberrant translational regulation of c-myc is likely to play a role in tumorigenesis.

A mutation in the c-myc-IRES leads to enhanced internal ribosome entry in multiple myeloma: a novel mechanism of oncogene de-regulation.

The 5' untranslated region of the proto-oncogene c-myc contains an internal ribosome entry segment (IRES) (Nanbru et al., 1997; Stoneley et al., 1998) and thus c-myc protein synthesis can be initiated by a cap-independent as well as a cap-dependent mechanism (Stoneley et al., 2000). In cell lines derived from patients with multiple myeloma (MM) there is aberrant translational regulation of c-myc and this correlates with a C-T mutation in the c-myc-IRES (Paulin et al., 1996). RNA derived from the mutant IRES displays enhanced binding of protein factors (Paulin et al., 1998). Here we show that the same mutation is present in 42% of bone marrow samples obtained from patients with MM, but was not present in any of 21 controls demonstrating a strong correlation between this mutation and the disease. In a tissue culture based assay, the mutant version of the c-myc-IRES was more active in all cell types tested, but showed the greatest activity in a cell line derived from a patient with MM. Our data demonstrate that a single mutation in the c-myc-IRES is sufficient to cause enhanced initiation of translation via internal ribosome entry and represents a novel mechanism of oncogenesis.

Effect of lipid feeding on endothelium dependent relaxation in rabbit aortic preparations.

The effect of a cholesterol enriched diet on concentration responses to 5-hydroxytryptamine, ergometrine, and acetylcholine and on endothelium dependent relaxation was investigated in rabbit aortic strip preparations. Sensitivity to ergometrine was slightly reduced after both two and 10 weeks of cholesterol feeding. Sensitivity to 5-hydroxytryptamine was slightly reduced after two but not after 10 weeks of cholesterol feeding. Sensitivity to acetylcholine was not altered at two or 10 weeks in the absence of endothelium, but the endothelium dependent lowering of the constrictor concentration-response was almost abolished after 10 weeks of cholesterol feeding. Likewise the endothelium dependent relaxant response of preconstricted preparations to acetylcholine was almost abolished after 10 weeks of cholesterol feeding. Thus this model of hyperlipidaemia leads after 10 weeks to loss of endothelium dependent relaxation.

Myocardial reoxygenation damage: can it be circumvented?

We investigated whether reoxygenation damage could be prevented by interventions directed towards reducing calcium influx only during the reoxygenation period. We measured reoxygenation contracture and recovery of contractile performance, using isolated papillary muscle preparations from cat and rabbit, pretreated with ouabain so as to exaggerate the phenomenon of reoxygenation contracture. Reoxygenation contracture was abolished and contractile recovery achieved by lowering extracellular calcium during early reoxygenation and then gradually replacing it. Gradual reoxygenation only postponed contracture and contractile failure. The slow channel blocker, diltiazem, but not verapamil or lidoflazine--in similarly negative inotropic concentrations of 10(-4) mol X litre-1, 10(-4) mol X litre-1 and 2 X 10(-5) mol X litre-1 respectively--reduced early reoxygenation contracture, as did Mg2+ (30 mmol X litre-1), Mn2+ (8 mmol X litre-1), or metabolic acidosis (pH 6.5), without in any case allowing contractile recovery. These observations indicate that reoxygenation damage is not an irrevocable consequence of the preceding hypoxic insult. They imply that calcium entry during early reoxygenation contributes both to contracture and contractile failure, that this occurs through paths other than the slow calcium channel, and that diltiazem may have properties additional to those of blocking the slow calcium channel.

Problems and pitfalls in the isolation of an endogenous Na+, K+-ATPase inhibitor.

Plasma from volume-expanded and salt-loaded hypertensive animals and from patients with essential hypertension has been reported to inhibit Na+, K+-adenosine triphosphatase (ATPase). Inhibition of the sodium pump in vascular smooth muscle caused by such a circulating factor could increase vascular tone and sensitivity to vasoactive agents, and thereby result in arterial hypertension. Numerous efforts in the past failed to isolate the putative factor from urine and plasma. Recent studies have suggested that the hypothalamus is an important source of an endogenous Na+, K+-ATPase inhibitor, but its isolation from the tissue extracts has been rendered difficult by the presence of other cellular constituents that cause artifactual interference with the assays and purification procedures. Using an alternative approach of isolating the inhibitor from culture medium, we found that dispersed fetal rat hypothalamic neurons in a capillary culture system release a heat-stable, peptidic, low-molecular-weight, active sodium transport inhibitor that causes a reversible increase in vascular tone, sensitizes vascular smooth muscle to the vasoactive effect of norepinephrine, and possesses several characteristics of the putative endogenous digitalislike factor. This inhibitor may be a chemical mediator linking kidney, brain, and cardiovascular system in the genesis of experimental volume-expanded and salt-loaded hypertension and human essential hypertension.

Vaginal hysterectomy for sterilization.

PIP: Vaginal hysterectomy for sterilization was performed on 115 patients. The Heaney technique was used by nine gynecologists, using lidocaine and adrenaline. The average age of patients was 32.2 years and average parity 3.2. Significant unsuspected pathology was found after surgery in 21 patients. One postoperative death occurred due to a brain stem infarction. Complications after hospitalization were vaginal cuff bleeding and urinary tract infection. Lowered morbidity of patients on oral contraceptives was significant but morbidity in patients with IUD's in place was not statistically significant. Vaginal hysterectomy is recommended for elective sterilization.^ieng

Frequency-dependent depression of myocardial contractility by slow calcium channel blocking drugs.

The negative inotropic effects of two dihydropyridine and two non-dihydropyridine calcium slow channel blocking drugs were studied using ferret isolated papillary muscle preparations contracting both isotonically and isometrically. The degree of inotropic depression was found to be dependent on the frequency of stimulation for all four agents. Frequency dependence of inotropic effect was of the order: nifedipine less than felodipine less than diltiazem less than verapamil.

A comparison of surfactant delivery with conventional mechanical ventilation and partial liquid ventilation in meconium aspiration injury.

The objective of this study was to compare surfactant (SF) distribution and physiological effects after standard SF delivery during conventional mechanical ventilation (CMV) with that using partial liquid ventilation (PLV). A model of meconium aspiration syndrome (MAS) was developed using two groups of adult rats (n = 14). After meconium instillation of 2.5 ml kg(-1) (20% v/w), SF/CMV: (n = 7) CMV and SF/PLV: (n = 7) PLV, received 14C-labeled surfactant (4 ml kg(-1)) delivered intratracheally in four aliquots over 20 min in both groups. Sequential measurements of arterial blood chemistry and lung mechanics were performed in all animals. At the conclusion of experiments, lungs were inflated (30 cmH2O), dried, sectioned and evaluated for radioactivity in disintegrations per minute (DPM). Surfactant distribution was improved (P< 0.01) with PLV as compared to CMV with 48.8% of the pieces vs. 30.9% of the pieces receiving within 25% of the mean amount of surfactant, respectively. Further, regional distribution was also significantly more uniform with PLV than CMV: left vs right (P<0.01) lung and ventral vs. dorsal (P<0.01) regions. Finally, arterial PO2 and ventilation efficiency index were significantly (P<0.01) greater post-treatment in SF/PLV than SF/CMV. These data demonstrate surfactant delivery with PLV, as compared to CMV alone, to be an improved method of delivering surfactant in MAS and suggest the possible utility of SF/PLV combination therapy for its treatment of other etiologies of neonatal respiratory distress.

Substrate oxidation at rest and during exercise: effects of menstrual cycle phase and diet composition.

The estrogen hormones have been shown to be highly glycogenic as well as lipolytic in nature. It is unknown whether the metabolic actions of estrogens impact upon energy metabolism during exercise. The composition of prior diet, however, does affect exercise energy metabolism. This study examined the influence of menstrual cycle phase (mid-follicular [FP; low estrogen] vs. mid-luteal [LP; high estrogen]) and diet composition on the rate of substrate oxidation for carbohydrate (CHO) and lipid at rest and during various intensities of physical exercise. Nine subjects completed an experimental session under four different menstrual cycle-diet conditions: 1) FP following a 3-day high CHO diet [75% total caloric intake], 2) FP following a 3-day low CHO diet [35% total caloric intake], 3) LP following a 3-day high CHO diet, and 4) LP following a 3-day low CHO diet. In each of the experimental sessions substrate oxidation was determined at rest and during cycle ergometer exercise at intensities of 30, 50, and 70% VO2max, respectively. Statistically significant (p < 0.05) interaction effects on substrate oxidation due to the menstrual cycle phase and diet conditions were found at rest and during 30%-50% exercise. In general, CHO oxidation was lowest and lipid oxidation highest in the LP under a low CHO diet condition.

Antimicrobial resistance in Salmonella isolated from animals and their environment in England and Wales from 1988 to 1999.

Resistance to 16 antimicrobial agents was monitored in 109,125 Salmonella cultures isolated from animals, their environment and feedstuffs between 1988 and 1999. The sensitivity of the 6512 isolates of Salmonella enterica enterica serotype Dublin to all the antimicrobial agents tested varied from 98.2 per cent in 1997 to 99.7 per cent in 1990 and 1996. In contrast, among 28,053 isolates of Salmonella enterica enterica serotype Typhimurium, there was a marked decrease in their sensitivity to all the antimicrobial agents tested, from 57.4 per cent in 1992 to 7.6 per cent in 1995, owing to the widespread occurrence in farm animals of S Typhimurium isolates of the definitive type DT104, resistant to ampicillin, sulphonamides, streptomycin, chloramphenicol and tetracyclines, although the percentage of sensitive isolates increased to 18.4 per cent in 1999, when the incidence of DT104 had decreased. Some isolates of DT104 also showed an increase in resistance to potentiated sulphonamides (2.4 per cent in 1989 to 19.2 per cent in 1999) and nalidixic acid (0 per cent in 1992, 3.8 per cent in 1995 to a peak of 16.9 per cent in 1998). In 1996, 5.1 per cent of 1086 isolates of S Typhimurium from cattle and 35.9 per cent of 192 isolates of S Typhimurium from poultry showed resistance to nalidixic acid. Of the other 74,528 Salmonella isolates, the percentage of strains sensitive to all the antimicrobials tested decreased slightly from 88.2 per cent in 1988 to 70.6 per cent in 1996 and then increased slightly to 73.7 per cent in 1999. The commonest of these other Salmonella serotypes was Salmonella Enteritidis (20,982), which remained predominantly susceptible (ranging from 81.4 to 97.4 per cent) during the study period. Few isolates were resistant to commonly used veterinary antimicrobials, for example, furazolidone, the use of which was banned in 1990, and the aminoglycoside, apramycin.

Faecal carriage of verocytotoxin-producing Escherichia coli O157 in cattle and sheep at slaughter in Great Britain.

A 12-month abattoir survey was conducted between January 1999 and January 2000, to determine the prevalence of faecal carriage of verocytotoxin-producing Escherichia coli O157 (VTEC O157) in cattle and sheep slaughtered for human consumption in Great Britain. Samples of rectum containing faeces were collected from 3939 cattle and 4171 sheep at 118 abattoirs, in numbers proportional to the throughput of the premises. The annual prevalence of faecal carriage of VTEC O157 was 4.7 per cent (95 per cent confidence interval 4.1 to 5.4) for cattle and 1.7 per cent (1.3 to 2.1) for sheep, values which were statistically significantly different from each other (P < 0.001). The organisms were recovered from both cattle and sheep slaughtered throughout the year and at abattoirs in all regions of the country, but the highest prevalence was in the summer. The most frequency recovered VTEC O157 isolates were phage types 2, 8 and 21/28 in cattle and 4 and 32 in sheep, the five most frequently isolated phage types associated with illness in people in Great Britain during the same period.

Prevalence of faecal excretion of verocytotoxigenic Escherichia coli O157 in cattle in England and Wales.

During the decade to 1999, the incidence of human infections with the zoonotic pathogen verocytotoxin-producing Escherichia coli O157 (VTEC O157) increased in England and Wales. This paper describes the results of a survey of 75 farms to determine the prevalence of faecal excretion of VTEC O157 by cattle, its primary reservoir host, in England and Wales. Faecal samples were collected from 4663 cattle between June and December 1999. The prevalence of excretion by individual cattle was 4.2 per cent (95 per cent confidence interval [CI] 2.0 to 6.4) and 10.3 per cent (95 per cent CI 5.8 to 14.8) among animals in infected herds. The within-herd prevalence on positive farms ranged from 1.1 to 51.4 per cent. At least one positive animal was identified on 29 (38.7 per cent; 95 per cent CI 28.1 to 50.4) of the farms, including dairy, suckler and fattening herds. The prevalence of excretion was least in the calves under two months of age, peaked in the calves aged between two and six months and declined thereafter. The phage types identified most widely were 4, 34 and 2, which were each found on six of the 29 positive farms.

Collegiate coaches' knowledge of eating disorders.

OBJECTIVE: To assess, through exploratory research, 1) collegiate coaches' knowledge of eating disorders, 2) the confidence of collegiate coaches in their response correctness to questions about eating disorders among athletes, and 3) demographic data related to prior education about eating disorders and the role of the athletic department in providing such educational experiences. DESIGN AND SETTING: We distributed a 2-part questionnaire to 258 NCAA Division I-A coaches from 5 universities selected by sampling convenience. SUBJECTS: One hundred thirty-eight collegiate coaches responded to the questionnaire for a response rate of 53.5%. MEASUREMENTS: Our survey consisted of 30 true-false questions that tested knowledge of eating disorders overall and in 5 domains. These domains included etiology, identifying signs and symptoms, management and treatment, risk factors, and education and prevention of eating disorders. Coaches indicated their level of certainty in their responses by rating their confidence level on a 4-item Likert-type scale. Demographic data focused on educational programs attended by coaches and teams. Descriptive statistics were used to analyze all data. RESULTS: Our results suggest a need for coaches to achieve a greater knowledge of eating disorders in all domains. Evidence showed that educational programs about eating disorders were not often sponsored by the athletic department for coaches or athletes. There seemed to be poor communication between athletic departments and coaches regarding the availability of eating disorder educational resources. CONCLUSIONS: Data suggested coaches could benefit from comprehensive education in all domains of eating disorders; however, further study is needed to validate these findings, to determine the actual effectiveness of education in the prevention of eating disorders, and to differentiate coaches' knowledge specific to sport coached and to coach and team sex.