Hypoxia inducible factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML.

Hypoxia-inducible factor (HIF)-1α accumulation promotes hematopoietic stem cells' quiescence and is necessary to maintain their self-renewal. However, the role of HIF-2α in hematopoietic cells is less clear. We investigated the role of HIF-2α in leukemia and lymphoma cells. HIF-2α expression was high in subsets of human and mouse leukemia and lymphoma cells, whereas it was low in normal bone marrow leukocytes. To investigate the role of HIF-2α, we transduced human HIF-2α cDNA in mouse syngeneic models of myeloid preleukemia and a transgenic model of B lymphoma. Ectopic expression of HIF-2α accelerated leukemia cell proliferation in vitro. Mice transplanted with cells transduced with HIF-2α died significantly faster of leukemia or B lymphoma than control mice transplanted with empty vector-transduced cells. Conversely, HIF-2α knockdown in human myeloid leukemia HL60 cells decreased proliferation in vitro and significantly prolonged animal survival following transplantation. In human acute myeloid leukemia (AML), HIF-2α mRNA was significantly elevated in several subsets such as the t(15;17), inv(16), complex karyotype and favorable cytogenetic groups. However, patients with high HIF-2α expression had a trend to higher disease-free survival in univariate analysis. The different effects of HIF-2α overexpression in mouse models of leukemia and human AML illustrates the complexity of this mutliclonal disease.

A randomized controlled trial of postoperative analgesia following total knee replacement: transdermal Fentanyl patches versus patient controlled analgesia (PCA).

BACKGROUND: This randomized controlled trial compared a standard patient controlled analgesic (PCA) regime with a transdermal and oral Fentanyl regime for post-operative pain management in patients undergoing total knee replacement. METHODS: One hundred and ninety-six patients undergoing total knee replacement were recruited. Pre- and post-operatively Visual Analogue Score (VAS), Oxford Knee Score, Health Anxiety and Depression Score and Brief Pain Inventory Score were completed. According to the day 1, VAS score patients were randomly allocated to either a PCA regime or a Fentanyl transdermal/oral regime. Patient reported outcomes were measured until the patients were discharged. RESULTS: The results demonstrate that in terms of analgesic effect, day of discharge and side effect profile the two regimes are comparable. CONCLUSIONS: We conclude that a Fentanyl transdermal regime provides adequate analgesic effect comparable to a standard PCA regime in conjunction with a low side effect profile. Using a transdermal analgesic system provides efficient continuous delivery enabling a smooth transition from hospital to home within the first week. Transdermal Fentanyl provides an alternative analgesic regime that can provide an equivalent analgesic effect so as to enable a satisfactory outcome for the patient in terms of function and pain. LEVEL OF EVIDENCE: II.

BSACI guideline for the management of chronic urticaria and angioedema.

This guidance for the management of patients with chronic urticaria and angioedema has been prepared by the Standards of Care Committee of the British Society for Allergy and Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert opinion and is aimed at both adult physicians and paediatricians practising in allergy. The recommendations are evidence graded. During the development of these guidelines, all BSACI members were included in the consultation process using a Web-based system. Their comments and suggestions were carefully considered by the Standards of Care Committee. Where evidence was lacking, a consensus was reached by the experts on the committee. Included in this management guideline are clinical classification, aetiology, diagnosis, investigations, treatment guidance with special sections on children with urticaria and the use of antihistamines in women who are pregnant or breastfeeding. Finally, we have made recommendations for potential areas of future research.

Surgical smoke - a health hazard in the operating theatre: a study to quantify exposure and a survey of the use of smoke extractor systems in UK plastic surgery units.

Surgeons and operating theatre personnel are routinely exposed to the surgical smoke plume generated through thermal tissue destruction. This represents a significant chemical and biological hazard and has been shown to be as mutagenic as cigarette smoke. It has previously been reported that ablation of 1 g of tissue produces a smoke plume with an equivalent mutagenicity to six unfiltered cigarettes. We studied six human and 78 porcine tissue samples to find the mass of tissue ablated during 5 min of monopolar diathermy. The total daily duration of diathermy use in a plastic surgery theatre was electronically recorded over a two-month period. On average the smoke produced daily was equivalent to 27-30 cigarettes. Our survey of smoke extractor use in UK plastic surgery units revealed that only 66% of units had these devices available. The Health and Safety Executive recommend specialist smoke extractor use, however they are not universally utilised. Surgical smoke inhalation is an occupational hazard in the operating department. Our study provides data to quantify this exposure. We hope this evidence can be used together with current legislation to make the use of surgical smoke extractors mandatory to protect all personnel in the operating theatre.

NOD2 polymorphisms in clinical phenotypes of common variable immunodeficiency disorders.

Common variable immunodeficiency disorders (CVIDs) are a heterogeneous group of diseases characterized by hypogammaglobulinaemia and consequent susceptibility to infection. CVID patients commonly develop a variety of additional manifestations for which the causative factors are not fully understood. Two such manifestations are granulomatous disease and enteropathy. Because the ability to predict complications would aid clinical management, we continue to search for possible disease modifier genes. NOD2 acts a microbial sensor and is involved in proinflammatory signalling. Particular mutations of the NOD2 gene are associated with Crohn's disease including gly908arg, leu1007finsc and arg702trp polymorphisms. We hypothesized that NOD2 polymorphisms may be a disease modifier gene towards an enteropathic or granulomatous phenotype within CVIDs. Sequence-specific primers returned genotypes for 285 CVID patients from centres across the United Kingdom and Europe. We present the frequencies of the different phenotypes of patients within our international cohort. Arg702trp polymorphisms were significantly less frequent than wild-type (WT) (P = 0·038) among international CVID patients with splenomegaly. Gly908arg polymorphisms were more prevalent than WT in UK patients with autoimmune disorders (P = 0·049) or enteropathy (P = 0·049). NOD2 polymorphisms were not more prevalent than WT in CVID patients with clinical phenotypes of granulomata. UK allele frequencies of 0·014, 0·056 and 0·026 were found for gly908arg, arg702trp and leu1007finsc NOD2 polymorphisms, respectively. These do not differ significantly from UK immunocompetent controls confirming, as expected, that in addition these NOD2 polymorphisms do not confer susceptibility to CVIDs per se.

Morphological study of tracheal shape in donkeys with and without tracheal obstruction.

REASON FOR PERFORMING STUDY: There is limited information on the gross tracheal morphology of donkeys with or without tracheal abnormalities. OBJECTIVES: To: 1) examine the morphology of tracheas of donkeys with and without clinical and/or post mortem evidence of tracheal obstruction; 2) record the cross-sectional dimensions and shapes of tracheal rings at fixed sites; and 3) document prevalence, sites and characteristics of detected tracheal abnormalities. METHODS: The tracheas of 75, predominantly aged (median age 30 years, range 7-48 years) donkeys that died or were subjected to euthanasia on humane grounds were examined. Five had severe dyspnoea due to tracheal obstruction (with intercurrent lung disease in 3), while 7 had post mortem evidence of severe tracheal airway obstruction. Every 5th tracheal ring was dissected free and the inner and outer vertical and transverse dimensions and cross sectional areas were measured. Each dissected ring was photographed and the shape of the trachea was classified as normal or, in one of 6 abnormal grades, according to the type and degree of structural abnormality present. RESULTS: The tracheas had a mean of 43 (range 34-50) tracheal rings that tended to be more oval in shape in the distal cervical region. Only 31.2% of rings examined had a circular to oval shape. Dorso-ventral flattening was present in 0.9% of tracheal rings, dorsal ligament separation in 24.4%, slight cartilage deformity in 26.0%, moderate cartilage deformity in 10.4%, marked cartilage deformity in 1.9% and miscellaneous other abnormalities in 4.9% of tracheal rings. The 12 donkeys with ante or post mortem evidence of tracheal obstruction had significantly increased tracheal abnormality grade in comparison to the remaining donkeys. CONCLUSIONS AND POTENTIAL RELEVANCE: Structural tracheal abnormalities are present in most old donkeys, but generally do not cause clinical problems in these sedentary animals unless intercurrent pulmonary disease is present.

Comparison of the ETDRS logMAR, 'compact reduced logMar' and Snellen charts in routine clinical practice.

AIM: To compare the performance of the ETDRS logMAR, compact reduced logMAR and Snellen charts in an ophthalmic outpatient setting. METHODS: The reliability and reading times of the charts were compared in a stratified sample of 40 eyes of 40 ophthalmic patients with a variety of stable eye diseases. In order to simulate a clinical setting, forced-choice testing was not used. RESULTS: Similar acuity results were recorded from all three charts, suggesting a lack of a systematic bias as regards chart design. A small practice effect was observed for all charts but was greatest for Snellen and least for ETDRS. The test-retest variability of the charts was similar, with the 95% tolerance limit for change being +/-0.14 logMAR for ETDRS, +/-0.16 for reduced logMAR and +/-0.18 for Snellen. The mean reading times for the subjects were 34.65 s for ETDRS, 21.17 s for reduced logMAR and 18.67 s for Snellen. CONCLUSION: The performance of the compact reduced logMAR chart was intermediate between Snellen and ETDRS. The theoretical advantages of the ETDRS design were still measurable in a clinical setting but the magnitude of the advantage in terms of test-retest reliability was fairly small and the time taken to complete the EDTRS was 1.86 times that of the Snellen chart.

Elbow extension test to rule out elbow fracture: multicentre, prospective validation and observational study of diagnostic accuracy in adults and children.

OBJECTIVE: To determine whether full elbow extension as assessed by the elbow extension test can be used in routine clinical practice to rule out bony injury in patients presenting with elbow injury. DESIGN: Adults: multicentre prospective interventional validation study in secondary care. Children: multicentre prospective observational study in secondary care. SETTING: Five emergency departments in southwest England. PARTICIPANTS: 2127 adults and children presenting to the emergency department with acute elbow injury. INTERVENTION: Elbow extension test during routine care by clinical staff to determine the need for radiography in adults and to guide follow-up in children. MAIN OUTCOME MEASURES: Presence of elbow fracture on radiograph, or recovery with no indication for further review at 7-10 days. RESULTS: Of 1740 eligible participants, 602 patients were able to fully extend their elbow; 17 of these patients had a fracture. Two adult patients with olecranon fractures needed a change in treatment. In the 1138 patients without full elbow extension, 521 fractures were identified. Overall, the test had sensitivity and specificity (95% confidence interval) for detecting elbow fracture of 96.8% (95.0 to 98.2) and 48.5% (45.6 to 51.4). Full elbow extension had a negative predictive value for fracture of 98.4% (96.3 to 99.5) in adults and 95.8% (92.6 to 97.8) in children. Negative likelihood ratios were 0.03 (0.01 to 0.08) in adults and 0.11 (0.06 to 0.19) in children. CONCLUSION: The elbow extension test can be used in routine practice to inform clinical decision making. Patients who cannot fully extend their elbow after injury should be referred for radiography, as they have a nearly 50% chance of fracture. For those able to fully extend their elbow, radiography can be deferred if the practitioner is confident that an olecranon fracture is not present. Patients who do not undergo radiography should return if symptoms have not resolved within 7-10 days.

Road traffic accidents and diabetes: insulin use does not determine risk.

AIMS: Progressive restrictions placed on insulin-treated patients with diabetes exclude them from driving group 2 and class C1 and D1 vehicles. This reflects an assumption that an increased risk of hypoglycaemia in these patients will cause road traffic accidents. These restrictions have been implemented without any consistent evidence that this is the case. The aim of the study was therefore to investigate whether the rate of road traffic collisions in insulin-treated patients was higher than that of the non-diabetic population using a population register-based study. METHODS: A historical cohort study combined information from the Devon and Cornwall Constabulary database on road traffic collisions with the district wide retinal screening database, to provide an anonymized matched database of road traffic collisions in the diabetic population. Accident rates were calculated in the diabetic population and compared to rates in the non-diabetic population using relative risks. RESULTS: The estimated overall annual accident rate for the non-diabetic population was 1469 per 100,000 vs. 856 per 100,000 for the diabetic population as a whole (Chi-squared, P < 0.001). On stratification of the groups by age, within the insulin-treated group there was no significant difference in the accident rate compared to the non-diabetic population, with relative risks between 0.51 [confidence interval (CI) 0.25-1.05] and 1.13 (CI 0.88-1.46). CONCLUSIONS: Our findings suggest that insulin-treated patients as a group do not pose an increased risk to road safety. They reiterate the need for an individualized risk-based assessment when considering driving restrictions.

Effect of grass pollen immunotherapy with Alutard SQ on quality of life in seasonal allergic rhinoconjunctivitis.

BACKGROUND: Treatment of allergic rhinitis with subcutaneous allergen immunotherapy is effective in terms of reductions in symptoms and seasonal use of reliever medication. Its effect on quality of life (QoL), reflecting the impact of symptoms on work/school performance and leisure activities is, however, important and often overlooked. AIMS OF THE STUDY: To assess effect on QoL of specific immunotherapy with two doses of Alutard SQ Phleum pratense in patients with moderately to severe seasonal allergic rhinoconjunctivitis inadequately controlled by standard drug therapy. METHODS: Double-blind, randomized, placebo-controlled study of 410 patients with seasonal allergic rhinoconjunctivitis. Participants were randomized (2 : 1 : 1) to receive Alutard SQ P. pratense (ALK-Abelló) at maintenance doses of 100,000 SQ-U (203 subjects), 10,000 SQ-U (104 subjects) or placebo (103 subjects) given by subcutaneous injections. The groups were well matched for demographics and baseline symptoms. Quality of life was assessed using the Rhinoconjunctivitis Quality of Life Questionnaire which covers seven domains of health before and in the peak of the pollen season. RESULTS: While all domain scores were significantly improved when comparing 100,000 SQ-U with placebo, two domain scores were significantly improved when comparing 10,000 SQ-U with placebo. When comparing 100,000 SQ-U with 10,000 SQ-U, four domain scores were significantly improved. CONCLUSION: Treatment with Alutard SQ significantly improved the seasonal QoL of patients suffering from allergic rhinoconjunctivitis. The improvement was more pronounced and wider ranging in patients who received the higher 100,000 SQ-U maintenance dose.

BSACI guidelines for the management of chronic urticaria and angio-oedema.

This guidance for the management of patients with chronic urticaria and angio-oedema has been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert opinion and is aimed at both adult physicians and paediatricians practising in allergy. The recommendations are evidence graded. During the development of these guidelines, all BSACI members were included in the consultation process using a web-based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking a consensus was reached by the experts on the committee. Included in this guideline are clinical classification, aetiology, diagnosis, investigations, treatment guidance with special sections on children with urticaria, and the use of antihistamines in women who are pregnant or breastfeeding. Finally, we have made recommendations for potential areas of future research.

The interarm blood pressure difference as predictor of cardiovascular events in patients with hypertension in primary care: cohort study.

Objectives of this study were to measure the prevalence of a difference in blood pressure (BP) between arms and determine whether a difference is associated with increased risk of cardiovascular events or death. A prospective cohort study of 247 patients with hypertension was undertaken in one rural general practice in England. The main outcome measures were mean difference in BP between arms and new episodes of myocardial infarction, cerebrovascular event, onset of angina or peripheral vascular disease or death. A total of 57/247 (23%) patients had a mean difference in systolic BP between arms of >or=10 mm Hg and 8/247 (3%) had a mean difference of >or=20 mm Hg. A total of 15/247 (6%) patients had a mean difference in diastolic BP between arms of >or=10 mm Hg. Survival analysis after 4.7 years (range 3.3-5.9) showed a shorter mean survival time without event or death for patients with a difference in systolic BP of >or=10 mm Hg compared with a difference of <10 mm Hg (3.7 (95% confidence interval, 3.2-4.2) versus 4.8 (4.6-5.1) years; P<0.001; hazard ratio 2.5 (1.5-4.2), P=0.001). Difference in systolic BP of >or=10 mm Hg between arms is common in this primary care population and is associated with a shorter survival time to death or new cardiovascular event. Detection of a difference between arms may identify hypertensive patients at increased risk of cardiovascular events. Such an approach would allow more effective targeting of resources in primary prevention strategies.

Tacrolimus immunosuppression in high-risk corneal grafts.

BACKGROUND: Unlike the immune privilege enjoyed by low-risk corneal grafts, high-risk corneal grafts experience rejection rates comparable to liver and kidney transplants. Systemic immunosuppression reduces the risk of rejection in high-risk corneal grafts. METHODS: Systemic tacrolimus, a specific T cell inhibitor, was used at a mean daily dose of 2.5 mg to immunosuppress 43 patients undergoing high-risk corneal transplantation. Immunosuppression was continued for a period of 18-24 months after the high-risk corneal graft. RESULTS: During a mean follow-up period of 33.7 months, clarity of the graft was maintained in 65% of patients. Eight patients experienced rejection episodes while on tacrolimus, and this led to graft failure in five patients. CONCLUSION: Tacrolimus is relatively safe and effective in reducing rejection and prolonging graft survival in patients with high-risk keratoplasty compared with other series where similar immunosuppression was not used.

Offspring birthweight is not associated with paternal insulin resistance.

AIMS/HYPOTHESIS: Low birthweight is associated with insulin resistance and other insulin resistance-related phenotypes: diabetes, hypertension, and vascular disease in later life. The underlying mechanism is unclear. The foetal insulin hypothesis proposes that a single genetic predisposition to beta cell dysfunction/insulin resistance results in both reduced insulin-dependent foetal growth in utero, hence low birthweight, and predisposition to type 2 diabetes. The aim of this study was to test whether, as predicted by the foetal insulin hypothesis, there is an association between measures of paternal insulin resistance and offspring birthweight. SUBJECTS AND METHODS: The Exeter Family Study of Childhood Health (EFSOCH) is a community-based study within central Exeter (UK), established to test the foetal insulin hypothesis prospectively. Associations were tested between offspring birthweight and paternal insulin resistance, calculated by homeostasis model assessment analysis in 986 families using data relating to singleton, non-diabetic, UK white pregnancies. Ethics approval was given by the North and East Devon local ethics committee. RESULTS: Offspring birthweight was not significantly correlated with log paternal insulin resistance (r=0, p=0.91), log HDL cholesterol concentration (r=-0.02, p=0.47) or log triglyceride concentration (r=0, p=0.99) when corrected for paternal BMI and common confounders. Multiple linear regression analysis confirmed that paternal insulin resistance was not an independent predictor of offspring birthweight. CONCLUSIONS/INTERPRETATION: Results from a young, adult, non-diabetic population do not support the foetal insulin hypothesis as an explanation for the association of low birthweight with insulin resistance.

Paternal insulin resistance and its association with umbilical cord insulin concentrations.

AIMS/HYPOTHESIS: Fetal growth is influenced by genetic factors as well as the intra-uterine environment. We hypothesised that some genetic factors may alter fetal insulin secretion and insulin action. SUBJECTS, MATERIALS AND METHODS: To assess this, we analysed plasma insulin concentration in umbilical cord blood from 644 normal, term, UK Caucasian deliveries from the Exeter Family Study of Childhood Health. We tested for associations between cord insulin and each of parental anthropometry, fasting glucose, insulin and lipids. RESULTS: As expected, cord insulin concentrations correlated with all measures of birth size (weight, length, head and arm circumferences, sum of skinfold thicknesses, ponderal index: r=0.16-0.4, p<0.01 for all) and maternal BMI (r=0.11, p=0.005), maternal glucose (r=0.25, p<0.001) and maternal insulin resistance (r=0.23, p<0.001). Paternal fasting insulin and insulin resistance were correlated with cord insulin (r=0.15, p=0.006; r=0.13, p=0.001, respectively), and this was independent of paternal BMI. Multiple linear regression analysis revealed paternal insulin resistance to be a predictor of cord insulin concentrations, independently of maternal factors. CONCLUSION: Our results show an independent relationship between paternal insulin resistance and cord insulin concentrations. This is consistent with heritability of insulin resistance from father to offspring and a compensatory increase in fetal insulin secretion, the latter occurring pre-natally before the homeostatic feedback loop between glucose and insulin is established.

Determinants of insulin concentrations in healthy 1-week-old babies in the community: applications of a bloodspot assay.

BACKGROUND: Epidemiological research into insulin secretion and insulin action would be helped by improved ability to measure insulin concentrations in large groups of healthy babies in the neonatal period. Such research is often restricted by the invasive nature of blood sampling. AIMS: We assessed the use of an assay that can measure insulin from bloodspots taken during routine Guthrie testing 7 days after delivery. STUDY DESIGN AND SUBJECTS: Insulin and glucose were measured in 366 seven-day-old infants from heel-prick bloodspots. Time since last feed and type of feed were recorded. RESULTS: Bloodspot insulin concentrations in normal 7-day-old infants were much lower (median (IQR): 15.4 pmol/l (<10-28.5)) than fasting insulin concentrations in adult males (44.3 pmol/l (30.6-72.6)) (p<0.001). Insulin and glucose concentrations were correlated (r=0.33, p<0.001). Insulin and glucose fell significantly with time from feed. Bottle fed infants had higher insulin concentrations but similar glucose concentrations compared to breast fed infants. Detailed analysis to account for confounders was limited due to the skewed distribution of time since feed and the lower limit of the assay leading to non-continuous insulin data. CONCLUSIONS: In the largest study of normal 7-day-old children to date we have shown insulin concentrations are low compared to adults and vary with glucose, time from feed, and type of feed. This validates the use of the bloodspot insulin assay as a potential research tool for large-scale epidemiological studies. However, careful study design would be required in future use to reduce the variation caused by timing and type of feeding and the problem of one third of values being at or below the lower limit of this assay.

Systemic cytokine levels and the effects of etanercept in TNF receptor-associated periodic syndrome (TRAPS) involving a C33Y mutation in TNFRSF1A.

OBJECTIVE: To investigate the levels of the pro-inflammatory cytokines IL-6, TNF-alpha, IL-1beta, IL-8, IL-10 and IL-12p70 in the plasma of patients with TNF receptor-associated periodic syndrome (TRAPS) in relation to CRP levels and treatment with etanercept. METHODS: Cytokine concentrations were measured in sequential plasma samples obtained from eight patients with a C33Y mutation in TNFRSF1A and diagnosed with TRAPS, using cytokine bead array. The TRAPS samples were compared with samples from normal controls and rheumatoid arthritis patients. RESULTS: Levels of IL-6 were significantly elevated in C33Y TRAPS patients and these correlated with CRP levels in some of the patients. IL-8 levels were also significantly elevated in the TRAPS patients. However, neither TNF-alpha nor IL-1beta demonstrated a similar increase. This differed from the patients with rheumatoid arthritis, for whom levels of IL-6, IL-8, TNF-alpha, IL-1beta and IL-10 were significantly elevated. The levels of detectable TNF-alpha in the TRAPS patients' plasma were elevated during etanercept treatment. CONCLUSIONS: The cytokine profile of C33Y TRAPS differs from that of a typical autoimmune inflammatory condition such as rheumatoid arthritis, as only IL-6 and IL-8 were elevated in C33Y TRAPS patients, as distinct from a generalized elevation of pro-inflammatory cytokines. However, only some of the C33Y patients tested showed a relationship between elevated IL-6 and CRP. This is consistent with clinical observations that there is marked heterogeneity between individuals with TRAPS, including those in the same family cohort. Although etanercept has a therapeutic effect in some TRAPS patients, it induces increased plasma concentrations of TNF-alpha, possibly by increasing TNF-alpha stability.