Structured education using Dose Adjustment for Normal Eating (DAFNE) reduces long-term HbA1c and HbA1c variability.

AIMS: Previous evidence has demonstrated that participation in the Dose Adjustment for Normal Eating (DAFNE) education programme can reduce HbA1c and severe hypoglycaemia in people with Type 1 diabetes. In a number of studies, increased HbA1c variability has been associated with higher diabetic morbidity and mortality. No studies have examined the impact of structured education on HbA1c variability in Type 1 diabetes. METHODS: People with Type 1 diabetes who had attended DAFNE were identified for inclusion from the Scottish Care Information-Diabetes dataset. HbA1c median and variability, expressed as coefficient of variation (CV) before and after DAFNE was calculated. RESULTS: Some 1061 individuals participated in DAFNE education and 687 met the inclusion criteria. A significant median reduction in HbA1c [-3.5 mmol/mol (-0.3%)] was seen at 12 months with a significant reduction [-1.5 mmol/mol (-0.1%)] still seen at 60 months of follow-up. HbA1c variability as measured by CV was significantly lower during the post-DAFNE period: 0.08 (IQR 0.05-0.12) reduced to 0.07 (IQR 0.05-0.10); P = 0.002. CONCLUSION: The data confirm that DAFNE participation improves glycaemic control in Type 1 diabetes with benefits being sustained for 5 years. This study is the first to demonstrate reduced HbA1c variability after completion of structured education. This is new evidence of the beneficial impact of DAFNE on glycaemic profile.

HbA1c variability is associated with increased mortality and earlier hospital admission in people with Type 1 diabetes.

AIM: Despite evidence of morbidity, no evidence exists on the relationship between HbA1c variability and mortality in Type 1 diabetes. We performed an observational study to investigate whether the association between HbA1c variability and mortality exists in a population of people with Type 1 diabetes. As a secondary outcome, we compared onset of first hospital admission between groups. METHODS: People with Type 1 diabetes were identified for inclusion from the Scottish Care Information - Diabetes data set. This database includes data of all people known to have diabetes who live within Scotland. A survival analysis was carried out over a 47-month period comparing two groups; group 1 with a HbA1c coefficient of variation (CV) above the median CV value, and group 2 with a CV below the median value. Time to death or first admission was also analysed. A Cox proportional hazard model was used to compare time to death, adjusting for appropriate covariables. RESULTS: Some 6048 individuals with Type 1 diabetes were included in the analysis. Median HbA1c CV was 7.9. The hazard ratio (HR) for mortality for those with an HbA1c CV above the median value is 1.5 over 47 months of follow-up (P < 0.001). HR for survival to either the first admission to hospital or death for those with an HbA1c CV above the median value was 1.35 (95% confidence interval 1.25-1.45) over 730 days of follow-up (P < 0.001). CONCLUSION: Our results show that people with greater HbA1c variability have a higher rate of mortality and earlier hospital admission in Type 1 diabetes.

Reactive oxygen species generated in the presence of fine pyrite particles and its implication in thermophilic mineral bioleaching.

In the tank bioleaching process, maximising solid loading and mineral availability, the latter through decreasing particle size, are key to maximising metal extraction. In this study, the effect of particle size distribution on bioleaching performance and microbial growth was studied through applying knowledge based on medical geology research to understand the adverse effects of suspended fine pyrite particles. Small-scale leaching studies, using pyrite concentrate fractions (106-75, 75-25, -25 µm fines), were used to confirm decreasing performance with decreasing particle size (D 50 <40 µm). Under equivalent experimental conditions, the generation of the reactive oxygen species (ROS), hydrogen peroxide and hydroxyl radicals from pyrite was illustrated. ROS generation measured from the different pyrite fractions was found to increase with increasing pyrite surface area loading (1.79-74.01 m(2) L(-1)) and Fe(2+) concentration (0.1-2.8 g L(-1)) in solution. The highest concentration of ROS was measured from the finest fraction of pyrite (0.85 mM) and from the largest concentration of Fe(2+) (0.78 mM). No ROS was detected from solutions containing only Fe(3+) under the same conditions tested. The potential of ROS to inhibit microbial performance under bioleaching conditions was demonstrated. Pyrite-free Sulfolobus metallicus cultures challenged with hydrogen peroxide (0.5-2.5 mM) showed significant decrease in both cell growth and Fe(2+) oxidation rates within the concentration range 1.5-2.5 mM. In combination, the results from this study suggest that conditions of large pyrite surface area loading, coupled with high concentrations of dissolved Fe(2+), can lead to the generation of ROS, resulting in oxidative stress of the microorganisms.

Cyclic loading of tendon fascicles using a novel fatigue loading system increases interleukin-6 expression by tenocytes.

Repetitive strain or 'overuse' is thought to be a major factor contributing to the development of tendinopathy. The aims of our study were to develop a novel cyclic loading system, and use it to investigate the effect of defined loading conditions on the mechanical properties and gene expression of isolated tendon fascicles. Tendon fascicles were dissected from bovine-foot extensors and subjected to cyclic tensile strain (1 Hz) at 30% or 60% of the strain at failure, for 0 h (control), 15 min, 30 min, 1 h, or 5 h. Post loading, a quasi-static test to failure assessed damage. Gene expression at a selected loading regime (1 h at 30% failure strain) was analyzed 6 h post loading by quantitative real-time polymerase chain reaction. Compared with unloaded controls, loading at 30% failure strain took 5 h to lead to a significant decrease in failure stress, whereas loading to 60% led to a significant reduction after 15 min. Loading for 1 h at 30% failure strain did not create significant structural damage, but increased Collagen-1-alpha-chain-1 and interleukin-6 (IL6) expression, suggesting a role of IL6 in tendon adaptation to exercise. Correlating failure properties with fatigue damage provides a method by which changes in gene expression can be associated with different degrees of fatigue damage.

Detection of companion galaxies around hot dust-obscured hyper-luminous galaxy W0410-0913.

The phase transition between galaxies and quasars is often identified with the rare population of hyper-luminous, hot dust-obscured galaxies. Galaxy formation models predict these systems to grow via mergers, that can deliver large amounts of gas toward their centers, induce intense bursts of star formation and feed their supermassive black holes. Here we report the detection of 24 galaxies emitting Lyman-α emission on projected physical scales of about 400 kpc around the hyper-luminous hot dust-obscured galaxy W0410-0913, at redshift z = 3.631, using Very Large Telescope observations. While this indicates that W0410-0913 evolves in a very dense environment, we do not find clear signs of mergers that could sustain its growth. Data suggest that if mergers occurred, as models expect, these would involve less massive satellites, with only a moderate impact on the internal interstellar medium of W0410-0913, which is sustained by a rotationally-supported fast-rotating molecular disk, as Atacama Large Millimeter Array observations suggest.

AMP-activated protein kinase is activated in adipose tissue of individuals with type 2 diabetes treated with metformin: a randomised glycaemia-controlled crossover study.

AIMS/HYPOTHESIS: The hypoglycaemic actions of metformin have been proposed to be mediated by hepatic AMP-activated protein kinase (AMPK). As the effects of metformin and the role of AMPK in adipose tissue remain poorly characterised, we examined the effect of metformin on AMPK activity in adipose tissue of individuals with type 2 diabetes in a randomised glycaemia-controlled crossover study. METHODS: Twenty men with type 2 diabetes (aged 50-70 years) treated with diet, metformin or sulfonylurea alone were recruited from North Glasgow University National Health Service Trusts' diabetes clinics and randomised to either metformin or gliclazide for 10 weeks. Randomisation codes, generated by computer, were put into sealed envelopes and stored by the hospital pharmacist. Medication bottles were numbered, and allocation was done in sequence. The participants and investigators were blinded to group assignment. At the end of each phase of therapy adipose biopsy, AMPK activity (primary endpoint) and levels of lipid metabolism and signalling proteins were assessed. In parallel, the effect of metformin on AMPK and insulin-signalling pathways was investigated in 3T3-L1 adipocytes. RESULTS: Ten participants were initially randomised to metformin and subsequently crossed over to gliclazide, while ten participants were initially randomised to gliclazide and subsequently crossed over to metformin. No participants discontinued the intervention and the adipose tissue AMPK activity was analysed in all 20 participants. There were no adverse events or side effects in the study group. Adipose AMPK activity was increased following metformin compared with gliclazide therapy (0.057 ± 0.007 vs 0.030 ± 0.005 [mean ± SEM] nmol min(-1) [mg lysate](-1); p < 0.005), independent of AMPK level, glycaemia or plasma adiponectin concentrations. The increase was associated with reduced levels of acetyl-CoA carboxylase (ACC) protein and increased ACC Ser80 phosphorylation. In 3T3-L1 adipocytes, metformin reduced levels of ACC protein and stimulated phosphorylation of AMPK Thr172 and hormone-sensitive lipase Ser565. CONCLUSIONS: These results provide the first evidence that metformin activates AMPK and reduces ACC protein levels in human adipose tissue in vivo. Future studies are required to assess the role of adipose AMPK activation in the pharmacological effects of metformin. TRIAL REGISTRATION: ISRCTN51336867.

Partial control of an ion-molecule reaction by selection of the internal motion of the polyatomic reagent ion.

The ion-molecule reaction NH(3)(+) + ND(3) has been studied at various collision energies (1 to 5 electron volts in the center of mass) with preparation of the NH(3)(+) reagent in two nearly isoenergetic vibrational states. One state corresponds to pure out-of-plane bending of the planar NH(3)(+) ion (0.60 electron volts), whereas the other state is a combination of in-plane and out-of-plane motion (0.63 electron volts). The product branching ratios differ markedly for these two vibrational-state preparations. The differences in reactivity suggest that the in-plane totally symmetric stretching mode is essentially inactive in controlling the branching ratio of this reaction.

The multi-element content of the lichen Parmelia sulcata, soil, and oak bark in relation to acidification and climate.

Understanding how biodiversity is influenced by changing atmospheric conditions is important for conservation, public policy and environmental health. In a recent study, an impact on two of the most abundant lichens in Europe (Parmelia sulcata and Hypogymnia physodes) was recorded at Burnham Beeches lying 40 km west of London (UK) during unusual atmospheric conditions whilst other species remained unaffected. Bark and soil chemistry also influence lichen vitality and community composition. Correlations between element concentrations and element ratios in different samples help understand element cycling. To study this further, the multi-element content of the lichen P. sulcata and bark sampled in 2000 from 16 oak (Quercus robur) trees at Burnham Beeches was compared with the same elements determined in 24 surface soils sampled in 2005 from beneath the same trees. Soil pH ranged from 4.1 to 6.7. Highly significant correlations (p<0.001) for Mn/Ca ratios in lichen versus bark, soil versus bark and soil versus lichen samples confirmed cycling via the soil-tree-lichen system. Similar Mn/Ca ratios were reported in coniferous forests where high Mn concentrations were shown to limit epiphytic lichen abundance. Soil acidification influences element bioavailability and bark chemistry in Burnham Beeches with implications for lichen diversity and health. Recovery was recorded in P. sulcata, including regeneration within monitoring quadrats. Biological systems are well known to be influenced by pollution episodes.

Biomonitoring using the lichen Hypogymnia physodes and bark samples near Zlatna, Romania immediately following closure of a copper ore-processing plant.

Lichen transplants were established along a 40km transect centred on a large mine waste dump close to Zlatna town centre, two weeks after closure of a major industrial source, to compare spatial patterns of element concentrations in lichen and bark samples. After 3 months of exposure, spatial patterns of 4 element concentrations (Pb, Cu, Zn and Fe) in transplants confirmed deposition due to a point source 'Zlatna influence'. Cu and Pb reached concentrations 8 and 4 times, respectively, higher than samples transplanted in the 'background' site, and over 200 (Cu) and 2000 (Pb) times higher relative to 'background' bark. Ten out of 15 elements analysed reached highest concentrations in bark. Spatial patterns confirmed long-term pollution for 6 elements (Pb, S, Fe, Cu, Zn and Ba). The study provides a model baseline to monitor recovery following closure of major industrial sources and highlights the importance of considering biogeochemical processes when interpreting metal concentrations.

Biogeochemical signatures in the lichen Hypogymnia physodes in the mid Urals.

Multi-element content and uranium (U) isotopes were investigated in the lichen Hypogymnia physodes (native and transplants) sampled across a 60-km transect, centred on Karabash smelter town, from Turgoyak Lake (SW) to Kyshtym (NE) to investigate the origin of U. Kyshtym was the site of a major nuclear accident in 1957. (234)U/(238)U activity ratios in native thalli sampled during July 2001 were within the natural isotopic ratio in minerals. Uranium/thorium (U/Th) ratios were higher in native thalli towards the NE (average 0.73) than those in the SW (average 0.57). Element signatures in native thalli and transplants suggest U was derived from fossil fuel combustion from Karabash and sources lying further to the east. Systematic and significant U enrichment indicative of a nuclear fuel cycle source was not detected in any sample. Element signatures in epiphytic lichen transplants and native thalli provide a powerful method to evaluate U deposition.

Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats.

The role of glucocorticoids in obesity is poorly understood. Observations in obese men suggest enhanced inactivation of cortisol by 5alpha-reductase and altered reactivation of cortisone to cortisol by 11betahydroxysteroid dehydrogenase type 1 (11betaHSD1). These changes in glucocorticoid metabolism may influence corticosteroid receptor activation and feedback regulation of the hypothalamic-pituitary-adrenal axis (HPA). We have compared corticosterone metabolism in vivo and in vitro in male obese and lean Zucker rats, aged 9 weeks (n = 8/group). Steroids were measured in 72-h urine and 0900 h trunk blood samples. 5alpha-Reductase type 1 and 11betaHSD activities were assessed in dissected tissues. Obese animals were hypercorticosteronemic and excreted more total corticosterone metabolites (2264+/-623 vs. 388+/-144 ng/72 h; P = 0.003), with a greater proportion being 5alpha-reduced or 11-oxidized. 11-Dehydrocorticosterone was also elevated in plasma (73+/-9 vs. 18+/-2 nM; P = 0.001) and urine (408+/-111 vs. <28 ng/72 h; P = 0.01). In liver of obese rats, 5alpha-reductase type 1 activity was greater (20.6+/-2.7% vs. 14.1+/-1.5%; P<0.04), but 11betaHSD1 activity (maximum velocity, 3.43+/-0.56 vs. 6.57+/-1.13 nmol/min/mg protein; P = 0.01) and messenger RNA levels (0.56+/-0.08 vs. 1.03+/-0.15; P = 0.02) were lower. In contrast, in obese rats, 11betaHSD1 activity was not different in skeletal muscle and sc fat and was higher in omental fat(36.4+/-6.2 vs. 19.2+/-6.6; P = 0.01), whereas 11betaHSD2 activity was higher in kidney (16.7+/-0.6% vs. 11.3+/-1.5%; p = 0.01). We conclude that greater inactivation of glucocorticoids by 5alpha-reductase in liver and 11betaHSD2 in kidney combined with impaired reactivation of glucocorticoids by 11betaHSD1 in liver may increase the MCR of glucocorticoids and decrease local glucocorticoid concentrations at these sites. By contrast, enhanced 11betaHSD1 in omental adipose tissue may increase local glucocorticoid receptor activation and promote obesity.

Endothelium-derived hyperpolarizing factor and potassium use different mechanisms to induce relaxation of human subcutaneous resistance arteries.

This investigation examined the hypothesis that release of K(+) accounts for EDHF activity by comparing relaxant responses produced by ACh and KCl in human subcutaneous resistance arteries. Resistance arteries (internal diameter 244+/-12 microm, n=48) from human subcutaneous fat biopsies were suspended in a wire myograph. Cumulative concentration-response curves were obtained for ACh (10(-9) - 3x10(-5) M) and KCl (2.5 - 25 mM) following contraction with noradrenaline (NA; 0.1 - 3 microM). ACh (E(max) 99.07+/-9.61%; -LogIC(50) 7.03+/-0.22; n=9) and KCl (E(max) 74.14+/-5.61%; -LogIC(50) 2.12+/-0.07; n=10)-induced relaxations were attenuated (P<0.0001) by removal of the endothelium (E(max) 8.21+/-5.39% and 11.56+/-8.49%, respectively; n=6 - 7). Indomethacin (10 microM) did not alter ACh-induced relaxation whereas L-NOARG (100 microM) reduced this response (E(max) 61.7+/-3.4%, P<0.0001; n=6). The combination of ChTx (50 nM) and apamin (30 nM) attenuated the L-NOARG-insensitive component of ACh-induced relaxation (E(max): 15.2+/-10.5%, P<0.002, n=6) although these arteries retained the ability to relax in response to 100 microM SIN-1 (E(max) 127.6+/-13.0%, n=3). Exposure to BaCl(2) (30 microM) and Ouabain (1 mM) did not attenuate the L-NOARG resistant component of ACh-mediated relaxation (E(max), 76.09+/-8.92, P=0.16; n=5). KCl-mediated relaxation was unaffected by L-NOARG+indomethacin (E(max); 68.1+/-5.6%, P=0.33; n=5) or the combination of L-NOARG/indomethacin/ChTx/apamin (E(max); 86.61+/-14.02%, P=0.35; n=6). In contrast, the combination of L-NOARG, indomethacin, ouabain and BaCl(2) abolished this response (E(max), 5.67+/-2.59%, P<0.0001, n=6). The characteristics of KCl-mediated relaxation differed from those of the nitric oxide/prostaglandin-independent component of the response to ACh, and were endothelium-dependent, indicating that K(+) does not act as an EDHF in human subcutaneous resistance arteries.

Angiofibroma: treatment trends in 150 patients during 40 years.

A series of 150 patients with histologically confirmed angiofibroma examined from 1945 through 1983 was studied to contrast treatment methods and surgical approaches. From 1945 to 1955, treatment consisted primarily of radiation. From 1955 through 1971, the primary method of treatment was surgical removal; the lateral rhinotomy approach was used to expose the tumor and its extensions in most cases. From 1971 through 1983, all tumors were removed surgically. Trends in diagnosis, treatment, and adjunctive therapy at a single institution were evaluated. Specifically, the trends considered were operative approaches, blood replacement with and without hypotensive anesthesia, adjunctive measures such as hormonal therapy or tumor embolization, mortality, and morbidity. Lateral rhinotomy provides wide exposure of and access to the nose, nasopharynx, paranasal sinuses, elements of the skull base, temporal fossa, and infratemporal fossa. Surgical treatment, specifically the lateral rhinotomy approach and its extensions, is recommended as the best method of managing angiofibroma in most patients.

Juvenile angiofibromas. Behavior and treatment of extensive and residual tumors.

In a 15-year period, 40 juvenile angiofibromas were treated surgically (lateral or extended rhinotomy) at the Mayo Clinic, Rochester, Minn. Tumors were staged according to size and extension by using the Sessions classification. Stage III tumors involved the middle fossa or cavernous sinus or both structures, with or without extension into the orbit. Seven patients had stage I, ten had stage IIA, and six had stage IIB disease. Five tumors extended to the skull base (stage IIC). There were 12 cases that included intracranial extension (stage III), none of which involved the sella. There were eight cases with residual tumor: four (stages IIB [one], IIC [one], and III [two]) were not treated again, and four (stage III) were treated with various methods, including operation, embolization, and irradiation. No patient died. No complications or morbidity was experienced by the four patients who were not treated for residual tumor.

The effect of cooling on the photodynamic action of hematoporphyrin derivative during interstitial phototherapy of solid tumors. 1983 Second-Place Resident Research Award: basic category.

Hematoporphyrin derivative (HpD), a mixture of compounds chemically prepared from naturally occurring crude hematoporphyrin, is preferentially concentrated in neoplastic cells and produces red fluorescence when irradiated with blue-violet light. In addition, HpD exhibits other photodynamic properties, which, in the presence of oxygen and visible light, result in cytotoxicity. Preliminary reports indicate that early, superficial carcinomas of the upper aerodigestive tract and tracheobronchial tree can be localized and treated successfully with HpD phototherapy (HpD-PT), in which a fiberoptic bundle transmits laser light to the tumors. To assess this modality's potential for treating solid tumors, the cytotoxic effect of HpD-PT was measured in a murine tumor model. We specifically assessed the effect of cooling on the pure photodynamic action of HpD-PT. Adult female mice with typical mammary tumors received interstitial phototherapy 24 hours after HpD was given intraperitoneally. Light from an argon-dye laser was delivered through an optical fiber, along with simultaneous cooling from a cryosurgical probe, for 15 minutes. After being cooled with a cryosurgical probe, tumors were excised 48 hours after treatment and the necrotic area was measured. The results indicate that cooling enhances the tumoricidal action of HpD-PT.

Which factors are responsible for the changing lichen floras of London?

SO(2) is no longer the principal factor influencing the vitality and composition of lichen assemblages in London. We provide direct evidence for an impact on lichen growth during episodic high exhaust emissions coupled with unusual climatic conditions. This suggests a combination of particles and nitrogen plays a major role in influencing lichen growth. Nitrogen from traffic emissions may be at least as important as agriculture in influencing the composition of lichen assemblages.

Effect of bleomycin on hematoporphyrin derivative phototherapy of solid tumors.

Hematoporphyrin derivative phototherapy (HpD-PT) has been successfully used to localize and treat superficial squamous cell cancers. Bleomycin sulfate is a glycopeptide antibiotic that has antineoplastic properties against squamous cell cancers. Because both HpD-PT and bleomycin chemotherapy are accepted forms of treatment for squamous cell cancer and their cytotoxicity is mediated by singlet oxygen and oxygen radicals, we studied the possibility of enhancing the response of solid tumors to HpD-PT by combining this modality with systemic bleomycin chemotherapy in a murine tumor model. Bleomycin did not enhance HpD-PT significantly. Also, we are not confident that HpD-PT alone or in combination with other agents can eradicate solid tumors; it certainly did not in this syngeneic murine tumor model.

Planning the 2001 census: only four years to go.

The first key stage in the build-up to the 2001 Census was reached with the 1997 Census Test on 15 June. As 2001 approaches, Population Trends will carry articles describing the detailed work and analyses that underpin preparations and decisions affecting the Census. In this inaugural article Graham Jones, Director of Census, ONS, explains the principles and issues which underpin the planning process, and the work in hand. A second article, from Dr David Martin, on the geographical information system planned for use in the 1997 Census Test appears later in this issue.

Socializing culturally diverse students: a historically black university's nursing education program.

A convenience sample (N = 83) of RN and non-RN students enrolled at a historically Black university in North Carolina responded to a self-report culturally-relevant socialization questionnaire. The University has a long-standing commitment to the development and socialization of culturally diverse students. As such, the educational plan in both the lower division (general college studies) and the upper division nursing major is culturally sensitive. With the assumption that the process of socialization can be assessed during the course of professional development, the authors designed a culturally relevant socialization model. Using variables from the model, a 19-item questionnaire was administered to determine its efficacy in assessing the level of socialization engendered by the nursing program via the Likert scale. While the results were mixed, the non-RN students reported more socialization than the RNs, and all students perceived themselves as culturally diverse.