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.

Cytocompatibility assessment of chemical surface treatments for phosphate glass to improve adhesion between glass and polyester.

Fully resorbable phosphate glass fiber reinforced polymer composites have shown real potential for replacing some of the existing metallic bone fracture fixation devices. However, some of these composites have not provided suitable mechanical strength profiles over the required healing period for bone. Typically, it has been seen that these composites can lose up to 50% or more of their strength within the first week of degradation. Functionalizing the glass surface to promote polymer adhesion or to introduce hydrophobicity at the glass surface could potentially introduce control over the mechanical properties of the composite and their retention. In this study eight chemical agents namely, Glycerol 2-phosphate disodium salt; 3-phosphonopropionic acid; 3-aminopropyltriethoxy silane; etidronic acid; hexamethylene diisocyanate; sorbitol/sodium ended PLA oligomers and amino phosphonic acid, were selected to functionalise the bulk phosphate glass surface. Selected chemical agents had one functional group (-OH or O C N) to react with the glass and another functionality (either -OH, NH2, or Na) to react with the polymer matrix and/or produce hydrophobicity at the fiber surface. Bulk phosphate glass surface-treated with the above agents were assessed for the cytotoxicity of degradation products cell-material interaction in short- and long-term direct cytocompatibility studies. Results obtained from these cytocompatibility studies (using human osteosarcoma (MG63) and primary human osteoblast cell lines) revealed no cytotoxicity from the degradation products and a response comparable to controls in terms of cell functions (attachment, viability, metabolic activity, proliferation, and differentiation) and morphology.

The influence of coupling agents on mechanical property retention and long-term cytocompatibility of phosphate glass fibre reinforced PLA composites.

Completely resorbable composites are an attractive alternative for metallic bone-fracture fixation devices. However, failure of their interfacial integrity within aqueous environments, which can lead to a rapid loss of overall mechanical properties, has been reported in the literature. In this study coupling agents were investigated for phosphate glass fibre reinforced poly(lactic acid) composites. Three coupling agents with varying wettability were employed to improve initial mechanical properties and their retention in vitro via improvement of the interfacial bond between polymer matrix and fibres. Coupling agents were grafted onto the glass fibres by dip-coating in coupling agent solution at optimised concentrations. Three-aminopropyltriethoxy silane and sorbitol ended PLA oligomer treatments improved the initial flexural properties (27% strength with APS and 17% modulus via SPLA treatment) of the composites and 3-aminopropyltriethoxy silane and hexamethylene diisocyanate (HDI) treatments also decreased the loss of flexural strength and modulus during degradation. HDI treated samples retained 57.2% and 64.7% of their initial strength and modulus, respectively compared to control where only 34% of initial strength and 52% of initial modulus was retained after 28 days of degradation in PBS solution. Initial improvements in flexural properties were associated with improved shear bond strength at the interface due to covalent bonding between the glass fibres and polymer matrix provided by the coupling agents. Delay in mechanical property loss with degradation was suggested to be due to the hydrophobicity at the interface, which could have hindered the interfacial integrity loss and consequently loss of mechanical integrity of the composites. All coupling agent treated and control composites were tested for cytocompatibility using a primary human osteoblast cell line. A comparable response to the control, in terms of cell adhesion, proliferation and differentiation was observed supporting the use of these agents within implantable devices.

Material characterisation and cytocompatibility assessment of quinternary phosphate glasses.

Six phosphate glass formulations (in the system P(2)O(5)-CaO-MgO-Na(2)O-Fe(2)O(3)) were produced with fixed magnesium and calcium content at 24 and 16 mol%, respectively. P(2)O(5) and Fe(2)O(3) were varied between 40-50 and 0-4 mol% respectively, with the balance being Na(2)O. EDX analyses confirmed the final composition of the glasses investigated to within a 1-2 % error margin. Thermal analyses showed a linear increase in T(g) with increasing Fe(2)O(3) and P(2)O(5) contents, with Fe(2)O(3) showing a greater effect than P(2)O(5). This was proposed to be due to the formation of Fe-O-P bonds and an increase in the cross-link density of the glass network enhancing the durability of the glass. The glasses that were investigated revealed a decrease in degradation rate with increasing Fe(2)O(3) and P(2)O(5) contents and again the effect of Fe(2)O(3) was greater. All the above characteristics correlated well with structural changes measured by IR and XPS analyses. Cytocompatibility studies showed good cellular (MG63) response to the glasses up to 168 h in terms of cell viability, proliferation and differentiation. Statistical analysis revealed that all the formulations with the exception of P50Fe4 gave a comparable response to the control (TCP), which suggested that after a threshold level of glass durability is achieved the degradation rate has no or minimal effect on biocompatibility. However, it was seen that the glass chemistry can also affect cellular response, since increasing the P(2)O(5) content promoted phenotypic expression that was not related to degradation rate but to the degradation products. This was supported using an elution assay.

In vitro degradation, flexural, compressive and shear properties of fully bioresorbable composite rods.

Several studies have investigated self-reinforced polylactic acid (SR-PLA) and polyglycolic acid (SR-PGA) rods which could be used as intramedullary (IM) fixation devices to align and stabilise bone fractures. This study investigated totally bioresorbable composite rods manufactured via compression moulding at ~100 °C using phosphate glass fibres (of composition 50P(2)O(5)-40CaO-5Na(2)O-5Fe(2)O(3) in mol%) to reinforce PLA with an approximate fibre volume fraction (v(f)) of 30%. Different fibre architectures (random and unidirectional) were investigated and pure PLA rods were used as control samples. The degradation profiles and retention of mechanical properties were investigated and PBS was selected as the degradation medium. Unidirectional (P50 UD) composite rods had 50% higher initial flexural strength as compared to PLA and 60% higher in comparison to the random mat (P50 RM) composite rods. Similar initial profiles for flexural modulus were also seen comparing the P50 UD and P50 RM rods. Higher shear strength properties were seen for P50 UD in comparison to P50 RM and PLA rods. However, shear stiffness values decreased rapidly (after a week) whereas the PLA remained approximately constant. For the compressive strength studies, P50 RM and PLA rods remained approximately constant, whilst for the P50 UD rods a significantly higher initial value was obtained, which decreased rapidly after 3 days immersion in PBS. However, the mechanical properties decreased after immersion in PBS as a result of the plasticisation effect of water within the composite and degradation of the fibres. The fibres within the random and unidirectional composite rods (P50 RM and P50 UD) degraded leaving behind microtubes as seen from the SEM micrographs (after 28 days degradation) which in turn created a porous structure within the rods. This was the main reason attributed for the increase seen in mass loss and water uptake for the composite rods (~17% and ~16%, respectively).

Composites for bone repair: phosphate glass fibre reinforced PLA with varying fibre architecture.

Internal fixation for bone fractures with rigid metallic plates, screws and pins is a proven operative technique. However, refracture's have been observed after rigid internal fixation with metal plates and plate fixation has been known to cause localised osteopenia under and near the plate. In the present study, resorbable composites comprising a PLA matrix reinforced with iron doped phosphate glass fibres were investigated. Non-woven random mat laminates of approximately 30% and 45% fibre volume fraction (V(f)) were produced, along with unidirectional and 0°-90° samples of approximately 20% V(f). The non-woven composite laminates achieved maximum values of 10 GPa modulus and 120 MPa strength. The 0-90º samples showed unexpectedly low strengths close to matrix value (~50 MPa) although with a modulus of 7 GPa. The UD specimens exhibited values of 130 MPa and 11.5 GPa for strength and modulus respectively. All the modulus values observed were close to that expected from the rule of mixtures. Samples immersed in deionised water at 37°C revealed rapid mechanical property loss, more so for the UD and 0-90º samples. It was suggested that continuous fibres wicked the degradation media into the composite plates which sped up the deterioration of the fibre-matrix interface. The effect was less pronounced in the non-woven random mat laminates due to the discontinuous arrangement of fibres within the composite, making it less prone to wicking. Random mat composites revealed a higher mass loss than the UD and 0°-90° specimens, it was suggested this was due to the higher fibre volume fractions of these composites and SEM studies revealed voidage around the fibres by day 3. Studies of pH of the degradation media showed similar profiles for all the composites investigated. An initial decrease in pH was attributed to the release of phosphate ions into solution followed by a gradual return back to neutral.

Weight loss, ion release and initial mechanical properties of a binary calcium phosphate glass fibre/PCL composite.

Composites comprising a biodegradable polymeric matrix and a bioactive filler show considerable promise in the field of regenerative medicine, and could potentially serve as degradable bone fracture fixation devices, depending on the properties obtained. Therefore, glass fibres from a binary calcium phosphate (50P(2)O(5)+50CaO) glass were used to reinforce polycaprolactone, at two different volume fractions (V(f)). As-drawn, non-treated and heat-treated fibres were assessed. Weight loss, ion release and the initial mechanical properties of the fibres and composites produced have been investigated. Single fibre tensile testing revealed a fibre strength of 474MPa and a tensile modulus of 44GPa. Weibull analysis suggested a scale value of 524. The composites yielded flexural strength and modulus of up to 30MPa and 2.5GPa, respectively. These values are comparable with human trabecular bone. An 8% mass loss was seen for the lower V(f) composite, whereas for the two higher V(f) composites an approximate 20% mass loss was observed over the course of the 5week study. A plateau in the degradation profile at 350h indicated that fibre dissolution was complete at this interval. This assertion was further supported via ion release studies. The leaching of fibres from the composite created a porous structure, including continuous channels within the polymer matrix. This offers further scope for tailoring scaffold development, as cells from the surrounding tissue may be induced to migrate into the resulting porous matrix.

A new dehydrogenation mechanism for reversible multicomponent borohydride systems--The role of Li-Mg alloys.

A new dehydrogenation mechanism for LiBH4-MgH2 mixtures revealed that magnesium destabilised the LiBH(4) resulting in complete dehydrogenation of the borohydride phase and the formation of a Li-Mg alloy.

Preparation of poly(epsilon-caprolactone)/continuous bioglass fibre composite using monomer transfer moulding for bone implant.

Poly(epsilon-caprolactone) (PCL)/continuous bioglass fibre composite was prepared using the monomer transfer moulding technique coupled with a surface initiated polymerisation. The bioglass fibres were surface treated with an amine ended silane in order to initiate polymerisation of epsilon-caprolactone from the fibre surface. Surface initiated polymerisation significantly improved the Young's modulus and flexural strength and water resistance of the composite. Initial in vitro biocompatibility assessment suggests that amine ended silane treatment of bioglass fibres before their inclusion in the composite does not have a negative effect on the biological responses in terms of macrophage activation as measured by IL-1beta release and craniofacial osteoblast attachment.

The effect of production regime and crucible materials on the thermal properties of sodium phosphate glasses produced from salts.

Changes in the thermal properties of sodium phosphate glasses during melt production have been investigated using Pt/Au and fused alumina crucibles. Glasses were produced from NaH(2)PO(4) as a starting material, providing an intrinsic Na(2)O:P(2)O(5) ratio of 1:1 and giving an O/P = 3, that is, a metaphosphate. In Pt/Au crucibles, glass transition temperatures rose to a plateau value of 295 degrees C at a rate determined by melt temperature. No contamination of the glass by platinum or gold was detected or indicated in the results. E(a) for the reaction was found to be 66.4 kJ mol(-1). In fused alumina crucibles, glass transition temperatures rose to over 450 degrees C, with these values showing some convergence at higher furnace temperatures. Extensive erosion of the alumina crucibles was observed. The amount of alumina incorporation within the glasses correlated well with the rise in glass transition temperature up to a maximum of 15.5 mol % Al(2)O(3) content. Al(2)O(3) incorporation above this value caused a reduction in the value of the T(g).

Water supply aluminium concentration, dialysis dementia, and effect of reverse-osmosis water treatment.

Dialysis dementia appeared in 18 of 258 patients treated by haemodialysis. All Cases developed in patients treated by home dialysis (150) and none in patients treated exclusively by hospital dialysis (108). Analyses of the domestic water supply for each month on dialysis showed that dementia occurred only in those whose water supply had a high aluminium concentration (greater than 80 micrograms/l). The significant exponential relation (p less than 0.01) between the mean aluminium concentration in the water used to prepare the dialysate and the time taken to death from dementia indicates that there is probably no safe aluminium concentration and that removal of aluminium from water is essential before haemodialysis, particularly in areas where alum is used in water treatment as a clarifying agent. Reverse osmosis treatment satisfactorily removes aluminium and many other substances from water. Its application had a beneficial effect on 7 of 9 patients previously exposed to dialysate prepared from water with a high aluminium content and prevented the appearance of dementia in 24 patients whose water was so treated from the start of haemodialysis.

Dialysate aluminium concentration and renal bone disease.

We studied 40 patients maintained on regular hemodialysis, using radiology and quantitative bone histology to assess the relationship between renal bone disease and exposure to aluminium. Fractures were significantly more common in patients exposed to high dialysate aluminium concentrations. The histologic indices of osteomalacia were significantly related to the prevailing dialysate aluminium concentration, in such a way that higher aluminium levels were associated with more osteomalacia. Patients who had been exposed to higher concentrations of aluminium also tended to have a lower plasma phosphate concentration, and associated hypercalemia was seen in 6 patients with osteomalacia. These findings suggest that aluminium is a toxic agent associated with a mineralizing defect in the bone of renal failure patients. This may explain the incomplete response of some patients with renal osteomalacia to administration of 1,25-dihydroxy vitamin D.

1-Alpha-hydroxy vitamin D in dialysis bone disease: radiological changes after 6 and 12 months of treatment.

Biochemical, radiological and histological indicators of dialysis bone disease were studied before, 6 months (58 patients) and 12 months (48 patients) after starting treatment with 1 alpha-OH D3. Radiographic healing of subperiosteal erosions was seen after 6 months in 60% and after 12 months in 77% of affected patients. Radiographic improvement, however, was not significantly related to reductions in resorptive surfaces seen on quantitative bone histology, nor to changes in plasma concentrations of immunoreactive parathyroid hormone. Metastatic calcification appeared or increased in 43% of patients after 6 months and 52% after 12 months. Periosteal new bone developed or increased in 14% of patients after 6 months and 17% after 12 months. Both metastatic calcification and periosteal new bone formation were associated with high plasma phosphate concentrations, but not with plasma calcium, alkaline phosphatase or parathyroid hormone concentrations. Treatment with 1 alpha-OH D3 produces radiological improvement in the majority of patients with dialysis bone disease, but the lack of correlation with histological changes confirms the need for regular radiographic examination. Metastatic calcification and periosteal new bone formation probably represent toxicity of 1 alpha-OH D3 but may be minimised by phosphate restriction.

Factors influencing the intestinal absorption of calcium and phosphorus following renal transplantation.

After successful renal transplantation there is continuing malabsorption of calcium and phosphorus. This is due in part to impaired glomerular filtration rate, and in part to the action of steroid on calcium and phosphorus absorption. The effect of steroids is most marked over the first 18 months after transplantation and causes significant malabsorption of calcium and phosphorus even though good graft function is established. Calcium and phosphorus malabsorption can be improved by exogenous 1,25-dihydroxy vitamin D (oral 1 alpha-OH D3 or 1,25-[OH]2D3).

Prophylactic 1alpha-hydroxyvitamin D3 therapy in haemodialysis patients.

Twenty-seven patients starting regular haemodialysis were treated with a 1 microgram daily dose of 1alpha-hydroxyvitamin D3 and concurrent aluminium hydroxide therapy to prevent hyperphosphataemia. There was an increase in plasma calcium, but no significant improvement in plasma alkaline phosphatase activity or parathyroid hormone levels. Metastatic calcification progressed but was never a severe clinical problem. Quantitative bone histology showed a significant decrease in resorptive surfaces confirmed radiologically, but there was no significant decrease in forming surfaces. The expected increase in forming surfaces with length of dialysis was however prevented.