The effectiveness of a new dried human amnion derived membrane in addition to standard care in treating diabetic foot ulcers: A patient and assessor blind, randomised controlled pilot study.

Recent reviews suggest that amniotic membrane products may accelerate healing of diabetic foot ulcers. A new dried human amniotic membrane (dHAM) has been used for ocular ulcers but not for diabetic foot ulcers. This was a multi-centre, prospective, patient and observer blind, randomised controlled pilot trial, to investigate whether 2 weekly addition of the dHAM to standard care versus standard care alone increased the proportion of healed participants' index foot ulcers within 12 weeks. Thirty-one people (mean age 59.8 years, 81% male, 87% type 2 diabetes) were randomised (15 dHAM, 16 usual care). Within 12 weeks, healing occurred in 4 (27%) ulcers in the dHAM group versus 1 (6.3%) usual care group (P = .1). Percentage wound area reduction was higher in the dHAM versus control group. (P = .0057). There was no difference in AEs between the two groups. Six participants allocated to dHAM correctly identified their treatment group, although 5 in usual care incorrectly thought they were in the intervention arm. This pilot trial result is encouraging showing that this dHAM preparation is safe and promising treatment. These results will be used to design a statistically powered, definitive double blind randomised controlled trial.

Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring.

BACKGROUND: Genomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance. METHODS: Whole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in NLRP5 have previously been found. RESULTS: We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including NLRP2, NLRP7 and PADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss. CONCLUSION: The identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.

Independent and combined effects of acute physiological hyperglycaemia and hyperinsulinaemia on metabolic gene expression in human skeletal muscle.

Physiological hyperglycaemia and hyperinsulinaemia are strong modulators of gene expression, which underpins some of their well-known effects on insulin action and energy metabolism. The aim of the present study was to examine whether acute in vivo exposure of healthy humans to hyperinsulinaemia and hyperglycaemia have independent or additive effects on expression of key metabolic genes in skeletal muscle. On three randomized occasions, seven young subjects underwent a 4 h (i) hyperinsulinaemic (50 m-units·m⁻²·min⁻¹) hyperglycaemic (10 mmol/l) clamp (HIHG), (ii) hyperglycaemic (10 mmol/l) euinsulinaemic (5 m-units·m⁻²·min⁻¹) clamp (LIHG) and (iii) hyperinsulinaemic (50 m-units·m⁻²·min⁻¹) euglycaemic (4.5 mmol/l) clamp (HING). Muscle biopsies were obtained before and after each clamp for the determination of expression of genes involved in energy metabolism, and phosphorylation of key insulin signalling proteins. Hyperinsulinaemia and hyperglycaemia exerted independent effects with similar direction of modulation on PI3KR1 (phosphatidylinositol 3-kinase, regulatory 1), LXRα (liver X receptor α), PDK4 (pyruvate dehydrogenase kinase 4) and FOXO1 (forkhead box O1A) and produced an additive effect on PI3KR1, the gene that encodes the p85α subunit of PI3K in human skeletal muscle. Acute hyperglycaemia itself altered the expression of genes involved in fatty acid transport and oxidation [fatty acid transporter (CD36), LCAD (long-chain acyl-CoA dehydrogenase) and FOXO1], and lipogenesis [LXRα, ChREBP (carbohydrate-responseelement-binding protein), ABCA1 (ATP-binding cassette transporter A1) and G6PD (glucose-6-phosphate dehydrogenase). Surperimposing hyperinsulinaemia on hyperglycaemia modulated a number of genes involved in insulin signalling, glucose metabolism and intracellular lipid accumulation and exerted an additive effect on PI3KR1. These may be early molecular events that precede the development of glucolipotoxicity and insulin resistance normally associated with more prolonged periods of hyperglycaemia and hyperinsulinaemia.

Oncogenic osteomalacia and metastatic breast cancer: a case report and review of the literature.

OBJECTIVES: Oncogenic osteomalacia is a rare paraneoplastic metabolic syndrome that is characterised by severe hypophosphataemia, hyperphosphaturia and osteomalacia secondary to renal loss of phosphate. It is commonly caused by overproduction of fibroblast growth factor-23 (FGF23) from benign tumours of mesenchymal origin. Currently, there is no clear evidence on the management of oncogenic osteomalacia in patients with metastatic solid tumours. METHODS: We report a case of breast cancer-induced oncogenic osteomalacia and discuss its diagnosis and management. RESULTS: A 71-year-old woman with advanced breast cancer developed symptomatic oncogenic osteomalacia with raised FGF23, severe hypophosphataemia and hypocalcaemia. The electrolytic disturbances were exacerbated after the administration of bisphosphonates in the context of her oncological treatment. Systemic chemotherapy and maintenance endocrine treatment along with phosphate and calcium supplementation reduced the activity of oncogenic osteomalacia and resolved the electrolytic imbalances. CONCLUSIONS: To our knowledge, this is the first reported case of oncogenic osteomalacia in a patient with breast cancer. Oncogenic osteomalacia constitutes a diagnostic and therapeutic challenge. Pre-clinical and clinical evidence suggest that a possible underlying mechanism is the presence of molecular alterations in the FGF/FGFR signalling pathway leading to overexpression of FGF23. In metastatic setting, anticancer treatment can potentially lead to the normalisation of the electrolytic disturbances and reduction of the activity of oncogenic osteomalacia. The use of antiresorptive therapy in patients with bone metastases can potentially trigger FGF23 overexpression. Its use should be guided by the patients' risk of skeletal-related events and electrolytic disturbances as well as the degree of activity of oncogenic osteomalacia.

Elevated free fatty acids attenuate the insulin-induced suppression of PDK4 gene expression in human skeletal muscle: potential role of intramuscular long-chain acyl-coenzyme A.

AIM: We investigated the effect of elevated plasma free fatty acid and insulin concentrations on PDK4 mRNA transcript and protein content and long-chain acyl-coenzyme A accumulation in human skeletal muscle. METHODS: On two occasions, 10 healthy men underwent hyperinsulinemic-euglycemic clamps for 6 h with (LIPID) and without (CON) iv Intralipid (20% at 90 ml/h) plus heparin (200 U prime + 600 U/h) infusion. RESULTS: Glucose disposal was approximately 50% lower at the end of the clamp in the LIPID compared with the CON trial (37.8 +/- 4.4 and 79.6 +/- 4.0 micromol/kg lean mass.min, respectively; P < 0.01). In the LIPID trial, muscle long-chain acyl-coenzyme A concentration increased after 6 h, but not 3 h of lipid infusion (P < 0.01). Muscle PDK4 mRNA, but not protein, was down-regulated by 2-fold within 3 h in both clamps and decreased further (6-fold; P < 0.01) at 6 h in the CON but not the LIPID clamp. The lipid-induced attenuation in the suppression of PDK4 gene expression was not dependent on the activation of the Akt/FOXO3 pathway. CONCLUSION: Accumulation of im lipids plays a more important role than impaired activation of Akt-mediated pathways in the regulation of muscle PDK4 gene expression in lipid-induced acute insulin-resistant states.

DPP-4 inhibitor therapy and bone fractures in people with Type 2 diabetes - A systematic review and meta-analysis.

AIM: Fracture risk is higher in older adults with Type 2 diabetes mellitus (T2DM). Oral glucose-lowering medications have different effects on bone metabolism. The purpose of this study is to appraise the evidence from literature and determine the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor on the risk of developing bone fractures. METHODS: Using Boolean search terms, the search strategy combined synonyms of 'fracture' and 'DPP-4 inhibitor'. Comprehensive electronic databases which include EMBASE, MEDLINE, the EMA and the WHO ICTRP databases were searched for randomised controlled trial (RCT) studies which compared a DPP-4 inhibitor with an active comparator or placebo amongst patients with T2DM. Meta-analysis was performed to compare DPP-4 inhibitor with either an active comparator or a placebo. The outcome measure was the presence or absence of fracture. RESULTS: The search yielded 5061 records relating to fractures and DPP-4 inhibitor, from which 51 eligible RCTs were selected for meta-analysis (N=36,402). Thirty-seven (37) studies compared DPP-4 inhibitor with placebo (n=23,974), while fourteen (14) studies (n=12,428) compared DPP-4 inhibitor with an active comparator. The mean age of patients was 57.5±5.4years, the average glycated haemoglobin (HbA1c) was 8.2%, while the average BMI was 30±2kg/m(2). Overall, there was no significant association of fracture events with the use of DPP-4 inhibitor when compared with placebo (OR; 0.82, 95% CI 0.57-1.16, P=0.9) or when DPP-4 inhibitor was compared against an active comparator (OR; 1.59, 95% CI 0.91-2.80, P=0.9). CONCLUSION: This study offers a larger, up-to-date review of the subject. The meta-analysis showed that there was no significant association between DPP-4 inhibitor use and the incidence of fractures.