Access to statistical support for medical imaging research: questionnaire survey of UK radiology trainees.

AIM: To investigate the level of statistical support available to UK radiology trainees, and to gather opinions regarding how support may affect their current and future research aspirations. MATERIALS AND METHODS: An online survey was developed, piloted, and distributed to radiology trainees via the UK Radiology Academic Network for Trainees and training programme directors. Research experience, research aspirations, available and desired statistical support, and attitudes to statistics were surveyed and responses were collated. RESULTS: Seventy-nine responses were received, only two (3%) of whom had allocated time for research. Only three (4%) respondents were content with their statistical support whereas 25 (32%) reported insufficient statistical support; 13 (52%) of these believed this impacted "considerably" on research aspirations. Sixty-six (84%) respondents desired dedicated statistical support, 40 (61%) of whom stated the amount required would likely be "moderate" and 26 (39%) "significant". Respondents believed support would be most helpful to analyse data already collected (41 responses, 54%) rather than research planning (25, 33%). Most respondents (60, 76%) had used self-help methods to learn research statistics but only 21 (35%) found this useful. CONCLUSION: Training schemes must improve the provision, access to, and awareness of statistical support so that any research efforts are performed to a high standard. Trainees should not be expected to participate in research without sufficient time, mentorship, and statistical support.

The effect of soil type on the extraction of insensitive high explosive constituents using four conventional methods.

Explosive contamination is commonly found at military and manufacturing sites (Hewitt et al., 2005; Clausen et al., 2004; Walsh et al., 2013). Under current environmental legislation the extent of the contamination must be characterized by soil sampling and subsequent separation of the explosive contaminants from the soil matrix by extraction to enable chemical analysis and quantification (Dean, 2009). It is essential that the extraction method can consistently recover explosive residue from a variety of soil types i.e. all materials that have not degraded or irreversibly bound to the matrix, so that any resultant risk is not underestimated. In this study, five different soil types with a range of organic content, particle size and pH, were spiked with a mixture of RDX, DNAN, NQ and NTO at 50 mg/kg and were extracted using one of four one-step extraction methods: stirring, shaking, sonication, and accelerated solvent extraction (ASE). Analysis of the extraction efficiencies of the four methods found that they were broadly successful for the extraction of all IHE constituents from all five soils (an average of 84% ±â€¯14% recovery across 80 extractions). However, soils with high organic content (Total Organic Content (TOC) ≥ 2%) were found to significantly affect extraction efficiency and reproducibility. NTO and DNAN were the least consistent in extraction efficiency with poorest recovery of NTO as low as 37% ±â€¯2%. Of the four tested methods shaking was found to be the most reproducible, though less efficient than stirring (64%-91%). ASE was found to have the most variable results for extraction of IHE constituents suggesting that ASE was the most affected by the different soil types. Therefore, it is recommended that the efficiency and reproducibility of the selected extraction method should be validated by extracting known concentrations of the IHE from the soil of interest and that any required correction factors are reported.

Refining Liver Safety Risk Assessment: Application of Mechanistic Modeling and Serum Biomarkers to Cimaglermin Alfa (GGF2) Clinical Trials.

Cimaglermin alfa (GGF2) is a recombinant human protein growth factor in development for heart failure. Phase I trials were suspended when two cimaglermin alfa-treated subjects experienced concomitant elevations in serum aminotransferases and total bilirubin, meeting current US Food and Drug Administration criteria for a serious liver safety signal (i.e., "Hy's Law"). We assayed mechanistic biomarkers in archived clinical trial serum samples which confirmed the hepatic origin of the aminotransferase elevations in these two subjects and identified apoptosis as the major mode of hepatocyte death. Using a mathematical model of drug-induced liver injury (DILIsym) and a simulated population, we estimated that the maximum hepatocyte loss in these two subjects was <13%, which would not result in liver dysfunction sufficient to significantly increase serum bilirubin levels. We conclude that the two subjects should not be considered Hy's Law cases and that mechanistic biomarkers and modeling can aid in refining liver safety risk assessment in clinical trials.

Effects of treadmill training on combined goserelin acetate and doxorubicin-induced osteopenia in female rats.

OBJECTIVES: This study examined individual and combined effects of the cancer treatments goserelin acetate (GA) and doxorubicin (DOX) on bone and determined if treadmill running (TM) provides osteoprotection. METHODS: Ten-week-old female Sprague-Dawley rats were randomly assigned to sedentary (SED) or TM groups. SED received GA, DOX, combined GA and DOX (GA+DOX), or placebo and maintained normal cage activity. TM received GA, DOX, GA+DOX, or placebo and participated in a progressive motorized treadmill protocol. After 8 weeks, tibiae were evaluated using micro computed tomography. RESULTS: Negative drug effects were observed in cancellous bone (bone volume/tissue volume, trabecular number, trabecular thickness, trabecular spacing; P<0.05). An additive bone volume/tissue volume and trabecular spacing effect was observed in SED GA+DOX (vs. SED+GA and SED+DOX, P<0.05) but not in TM GA+DOX (vs. TM+GA and TM+DOX, P>0.05). Negative drug effects were observed in cortical bone (cross-sectional volume, cortical volume, marrow volume; P<0.05), but combined GA+DOX did not exacerbate these effects. Additionally, there were no protective cortical bone effects observed in TM. CONCLUSIONS: Combined GA+DOX exacerbates cancellous osteopenia in the tibia, and treadmill running provided only minor protection.

Remifentanil target-controlled infusion vs propofol target-controlled infusion for conscious sedation for awake fibreoptic intubation: a double-blinded randomized controlled trial.

BACKGROUND: Awake fibreoptic intubation (AFOI) is a technique used in patients with difficult airways. This study compares the suitability of remifentanil target-controlled infusion (TCI) to propofol TCI for conscious sedation during AFOI in patients with bona fide difficult airways. METHODS: We recruited 24, ASA I-III patients, who were undergoing sedation for elective AFOI. Patients were randomized to one of the two groups, Group P (n=10) received propofol TCI and Group R (n=14) received remifentanil TCI. Primary outcome measures were conditions achieved at endoscopy, intubation, and post-intubation, which were graded using scoring systems. Other parameters measured were the endoscopy time, intubation time, and number of attempts at intubation. A postoperative interview was conducted to determine recall of events and level of patient satisfaction. RESULTS: Endoscopy scores (0-5) and intubation scores (0-5) were significantly different [Group P 3 (1-4) vs Group R 1 (0-3) P<0.0001, Group P 3 (2-4) vs Group R 1 (0-3) P<0.0001, respectively]; with much better conditions in Group R, endoscopy times and intubation times were also significantly different, being shorter in Group R (P<0.007 and P<0.023, respectively). Patient tolerance of the procedure, judged by the discomfort scores (P<0.004) and the post-intubation scores (P<0.08), was significantly better in Group R. The level of recall for events was higher in Group R. However, there were no significant differences in the patient satisfaction scores. CONCLUSIONS: Remifentanil TCI appears to provide better conditions for AFOI when compared with propofol TCI. The disadvantage of remifentanil in this setting may be a higher incidence of recall.

On the mutagenic action of adenine.

The deamination of cytosine and adenine is mutagenic; the deamination of guanine is not. The deamination of cytosine leads to G=C-->A=T point mutation and to G-->A and C-->T transition in the DNA molecule; the deamination of adenine leads to the opposite A-->G and T-->C transition. It is shown that adenine lack could be as mutagenic as adenine deamination and it is also shown schematically that adenine lack through defective adenine synthesis could give rise to a population of genetically abnormal cells incapable of any degree of differentiation, a state perhaps reminiscent of the most acute of leukaemias and the most anaplastic of cancers.

Urotensin-II induces ear flushing in rats.

BACKGROUND AND PURPOSE: While investigating the effects of systemic urotensin II (U-II), a potent vasoactive peptide acting at the UT receptor, we observed ear pinna flushing after systemic administration to conscious rats. In the present study, U-II-induced ear flushing was quantified in terms of ear pinna temperature change and potential mechanisms were explored. EXPERIMENTAL APPROACH: U-II-induced ear flushing was quantified by measuring lateral ear pinna temperature changes and compared to that of calcitonin gene-related peptide (CGRP), a known cutaneous vasodilator. Further, the effects of a variety of pharmacological agents on U-II-induced ear flushing were explored. KEY RESULTS: Subcutaneous injection of U-II (9 microg kg(-1))produced localized ear pinna flushing with an onset of approximately 15 min, a duration of approximately 30 min and a maximal temperature change of 9 degrees C. In contrast, CGRP caused cutaneous flushing within multiple cutaneous beds including the ear pinna with a shorter onset and greater duration than U-II. A potent UT receptor antagonist, urantide, blocked U-II-induced ear flushing but did not affect CGRP-induced ear flushing. Pretreatment with indomethacin or L-Nomega-nitroarginine methylester (L-NAME) abolished U-II-induced ear flushing. Mecamylamine or propranolol did not affect this response to U-II. Direct intracerebroventricular injection studies suggested that the ear flushing response to U-II was not mediated directly by the CNS. CONCLUSION AND IMPLICATIONS: Our results suggest that U-II-induced ear flushing and temperature increase is mediated by peripheral activation of the UT receptor and involves prostaglandin- and nitric oxide-mediated vasodilation of small capillary beds in the rat ear pinna.

Mutagenic mechanisms in leukemia and cancer: a new concept Cytosine lack could be as mutagenic as cytosine deamination.

The molecular mechanisms involved in mutagenesis caused by nitrous acid, ultraviolet light and cytosine methylation are reviewed. All three mutagens lead to a G=C --> A=T point mutation in the DNA molecule and the biochemical basis of these mutations in each case is the deamination of cytosine to uracil. It is shown that the lack of cytosine could be as mutagenic as the deamination of cytosine and it is shown schematically how cytosine lack could give rise to a population of genetically abnormal cells which are completely incapable of any degree of differentiation; a state perhaps reminiscent of the most acute of leukemias and the most anaplastic of cancers. A metabolic block in the amination of uracil to cytosine is suggested as a possible cause of the cytosine lack, a block which is unique in that it incorporates a mutagenic mechanism.

Children's cortisol levels and quality of child care provision.

BACKGROUND: Cortisol levels are increasingly being used as an indicator of stress levels. Research suggests that children who attend child care demonstrate higher cortisol levels than children in their homes, suggesting that child care acts as a risk factor for poor child outcomes. However, it is also suggested that quality influences outcomes. METHODS: Cortisol levels were measured through samples of saliva taken from children (3-5 years of age) attending long-day care centres in Perth, Western Australia. Quality of the programme was measured using industry national quality assurance indicators designed for child care centres. The analysis employed a 2 (time of collection: average am cortisol, average pm cortisol) by 3 (centre quality: high, satisfactory, unsatisfactory) split plot ANOVA with repeated measures on the time factor. RESULTS: Cortisol levels of children attending high-quality programmes demonstrated a decline across the child care day. Levels in children attending unsatisfactory programmes demonstrated an increase across the day. CONCLUSIONS: Although we do not yet know how high, and for how long, cortisol levels need to be elevated for risk of undesirable outcomes to increase, this research signals the importance of emphasizing the need for high-quality care for young children.

On the pathogenesis of erythroleukaemia (H0493).

In erythroleukaemia megaloblastic changes can co-exist with leukaemic changes in the marrow. The cause of the disease must therefore be such as can cause megaloblastosis and at the same time be mutagenic. Failure of the thymidylate synthelase reaction, the commonest cause of megaloblastic anaemia, can be eliminated in erythroleukaemia because (a) the dU suppression test is normal in the disease and (b) failure of the thymidylate synthelase reaction is not mutagenic. The deamination of both cytosine and adenine is mutagenic but the deamination of cytosine alone is apparent and the nucleotide of cytosine is the prime mutagenic nucleotide in leukaemia and cancer. Megaloblastic changes can result from an inadequate supply of any one of the four nucleotides that enter into the composition of DNA and it is suggested that an inadequate supply of the mutagenic nucleotide of cytosine, possibly through impaired synthesis, could cause both the megaloblastic and leukaemic changes in erythroleukaemia.

Subclinical rhythmic EEG discharge of adults: SREDA in two children.

Subclinical rhythmic electroencephalogram (EEG) discharge is an uncommon rhythmic EEG pattern that has been reported to occur in adults. It is thought to be a nonspecific finding with little clinical significance. This article reports this EEG pattern in two children and suggests it be called subclinical rhythmic EEG discharge of adults and children.

Pharmacokinetics and immunological effects of exogenously administered recombinant human B lymphocyte stimulator (BLyS) in mice.

B lymphocyte stimulator (BLyS; also known as TNFSF20, BAFF, TALL-1, zTNF4, and THANK), a tumor necrosis factor ligand family member, has recently been identified as a factor that promotes expansion and differentiation of the B cell population, leading to increases in serum immunoglobulin levels. Here, pharmacokinetic parameters for BLyS administered i.v. and s.c. to mice are described, and the effects of different dosing regimens on serum and salivary immunoglobulin levels as well as splenic cell populations are reported. The pharmacokinetics of BLyS following i.v. injection are monophasic with a half-life of 160 min, a clearance of 0.22 ml/min-kg, and a volume of distribution of 53 ml/kg. Systemic administration of BLyS to mice resulted in increased serum IgG, IgA, IgM, and IgE and salivary IgA as well as splenic B cell population expansion and differentiation. The i.v. and s.c. routes of administration were pharmacologically equivalent, even though s.c. bioavailability of BLyS is only 25%. BLyS (s.c.) dramatically elevated serum IgG and IgA levels, and the duration of the responses after cessation of treatment (t(1/2) = 4.4 and 1.3 days, respectively) are similar to the half-lives of endogenous IgG and IgA in mice. The IgM response is more modest than that of IgG and IgA but lasts longer (t(1/2) = 7.0 days) than the half-life of endogenous IgM. A linear pharmacodynamic response was identified between days of dosing x log(dose), and increases in serum IgG, IgA, and IgM indicating that the response is more sensitive to the duration of dosing than to the cumulative dose. The implications of these findings for therapeutic administration of BLyS are discussed.

Acute toxicology and pharmacokinetic assessment of a ribozyme (ANGIOZYME) targeting vascular endothelial growth factor receptor mRNA in the cynomolgus monkey.

The potential acute toxicity of a ribozyme (ANGIOZYME) targeting the flt-1 vascular endothelial growth factor (VEGF) receptor mRNA was evaluated in cynomolgus monkeys following i.v. infusion or s.c. injection. ANGIOZYME was administered as a 4-hour i.v. infusion at doses of 10, 30, or 100 mg/kg or a s.c. bolus at 100 mg/kg. End points included blood pressure, electrocardiogram (ECG), clinical chemistry, hematology, complement factors, coagulation parameters, and ribozyme plasma concentrations. ANGIOZYME was well tolerated, with no drug-associated morbidity or mortality. There was no clear evidence of ANGIOZYME-related adverse effects in this study. Slight increases in spleen weight and lymphoid hyperplasia were observed in several animals. However, these changes were not dose dependent. Steady-state concentrations of ANGIOZYME were achieved during the 4-hour infusion of 10, 30, or 100 mg/kg. Dose-dependent elimination of ANGIOZYME was observed, with faster clearance at the two highest doses. ANGIOZYME was slowly absorbed after s.c. administration, resulting in steady-state concentrations for the 9-hour sampling period. Monkeys in this toxicology study received significant plasma ANGIOZYME exposure by both the s.c. and i.v. routes.

Ribozymes as tools for therapeutic target validation in arthritis.

In this paper we describe a method for validating therapeutic gene targets in arthritic disease. Ribozymes are catalytic oligonucleotides capable of highly sequence-specific cleavage of RNA. We designed ribozymes that cleave the mRNA encoding stromelysin, a matrix metalloproteinase implicated in cartilage catabolism. Ribozymes were initially screened in cultured fibroblasts to identify sites in the mRNA that were accessible for binding and cleavage. Accessible sites for ribozyme binding were found in various regions of the mRNA, including the 5' untranslated region, the coding region, and the 3' untranslated region. Several ribozymes that mediated sequence-specific and dose-dependent inhibition of stromelysin expression were characterized. Site selection in cell culture was predictive of in vivo bioactivity. An assay for measuring cartilage catabolism in rabbit articular cartilage explants was developed. Ribozymes inhibited IL-1-stimulated stromelysin mRNA expression in articular cartilage explants, yet failed to inhibit proteoglycan degradation. This indicated that up-regulation of stromelysin was not essential for IL-1-induced cartilage catabolism. Broad applications of this approach in therapeutic target validation are discussed.

Antitumor and antimetastatic activity of ribozymes targeting the messenger RNA of vascular endothelial growth factor receptors.

Chemically stabilized hammerhead ribozymes are nuclease-resistant, RNA-based oligonucleotides that selectively bind and cleave specific target RNAs. Due to their potential for specifically inhibiting gene expression, ribozymes are being investigated for therapeutic applications as well as for the elucidation of gene function. In particular, we have investigated ribozymes that target the mRNA of the vascular endothelial growth factor (VEGF) receptors because VEGF signaling is an important mediator of tumor angiogenesis and metastasis. Here we report pharmacodynamic studies testing anti-Flt-1 (VEGFR-1) and anti-KDR (VEGFR-2) ribozymes in animal models of solid tumor growth and metastasis. Ribozymes targeting either Flt-1 or KDR significantly inhibited primary tumor growth in a highly metastatic variant of Lewis lung carcinoma. However, only treatment with the anti-Flt-1 ribozyme resulted in a statistically significant and dose-dependent inhibition of lung metastasis in this model. The anti-Flt-1 ribozyme was then tested in a xenograft model of human metastatic colorectal cancer in which significant inhibition of liver metastasis was observed. Taken together, these data represent the first demonstration that synthetic ribozymes targeting VEGF receptor mRNA reduced the growth and metastasis of solid tumors in vivo.

Ribozyme pharmacokinetic screening for predicting pharmacodynamic dosing regimens.

A significant amount of research has been devoted to the chemical stabilization of synthetic ribozymes, in part, so that applications to systemic disease can be explored. A nuclease-stabilized synthetic hammerhead ribozyme, ANGIOZYME, has been developed which targets the mRNA encoding a vascular endothelial growth factor receptor, Flt-1. Because the stimulation of this receptor may contribute to tumor neovascularization and subsequent tumor growth and metastasis, we have explored the systemic use of ANGIOZYME to down regulate this receptor in a syngeneic model of metastatic cancer. We describe here the application of pharmacokinetic analysis to the selection of a dosing regimen for pharmacodynamic screening in this murine cancer model. These studies demonstrate that the appropriate application of pharmacokinetic analysis is necessary for the optimization of systemic pharmacodynamic studies using synthetic ribozymes.

Utilization of alternative therapies in attention-deficit hyperactivity disorder.

OBJECTIVE: To identify the prevalence of use, the referral patterns and the perceived benefit of alternative therapy in children with attention-deficit hyperactivity disorder (ADHD). METHODOLOGY: A mailed questionnaire survey was undertaken in June 1993, of the use of various therapies by families of 381 children with ADHD. The respondent rate was 76%. RESULTS: Of respondents, 69% were using stimulant medication and 64% had used or were using a non-prescriptional therapy. Diet therapies were the most commonly used alternative therapy (60%). There was no statistical difference in the prevalence of use of other therapies between the medicated and non-medicated groups. The non-medicated group reported more benefit from some alternative therapies. Physicians were commonly involved in the suggestion to try a modified diet. School teachers, family and friends were the main source of suggestion of alternative therapies. CONCLUSION: Clinicians should be aware of the range of alternative therapies and of their frequent use by families of children with attentional problems.

Expanding the phenotype of Filippi syndrome: a report of three cases.

This report is of two brothers and a male singleton with clinical characteristics of Filippi syndrome, born to young, healthy, non-consanguineous parents. Their features, which include borderline to milder developmental delay, particularly of speech and language, primary microdontia and previously unreported radiological findings are described to further delineate and expand the clinical spectrum of the condition.

Pharmacokinetics of an antiangiogenic ribozyme (ANGIOZYME) in the mouse.

Vascular endothelial growth factor (VEGF) is a growth factor that contributes to the angiogenesis of developing tumors. To interfere with the action of VEGF, a nuclease-stabilized ribozyme, ANGIOZYME, has been developed against VEGF receptor subtype Flt-1 mRNA. To determine which routes of administration would be useful for systemic delivery of this ribozyme, a dose of 30 mg/kg [32P]ANGIOZYME was administered as an i.v., i.p., or s.c. bolus. Concentrations of ANGIOZYME in plasma, femur, kidney, liver, and lung were examined. ANGIOZYME was well absorbed after i.p. (90%) or s.c. administration (77%), with peak plasma concentrations occurring 30 minutes after dosing. Total body clearance after a single dose of 30 mg/kg ANGIOZYME was 20 ml/min/kg, and the elimination half-life was 33 minutes. The apparent volume of distribution at steady-state ranged from 0.5 to 1.3 L/kg. ANGIOZYME was detected in the four tissues examined through the 3 hour sampling period after i.v. or i.p. administration. After s.c. administration, ANGIOZYME was detected in femur, kidney, and lung but not in the liver. The highest concentrations of ANGIOZYME were found in kidney and femur with all three routes. Because of the rapid and extensive absorption after extravascular injections, either i.p. or s.c. administration could be considered for use in pharmacodynamic studies examining the effects of ANGIOZYME or other ribozymes with similar chemical modifications.