A preliminary evaluation of bardoxolone methyl for the treatment of diabetic nephropathy

INTRODUCTION: The coordinated activation of Nrf-2-dependent signaling pathway is currently being investigated in a range of chronic diseases. Bardoxolone methyl is a potent, orally bioavailable Nrf-2 agonist. In a recent 52-week study, treatment with bardoxolone methyl improved renal function in patients with chronic kidney disease (CKD) and type 2 diabetes. This improvement was sustained for the duration of the treatment. Such agonists potentially offer new options for the complex management of renal impairment. AREAS COVERED: A literature search was performed to analyze the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of bardoxolone methyl in both healthy volunteers and patients. Updated information about bardoxolone methyl, either after single administration or after chronic administration is also included. A special focus has been put on the putative mechanisms of action and potential toxicity profiles as well as an ongoing trials in patients with CKD and type 2 diabetes. EXPERT OPINION: The development of an agent that leads to sustained improvement in renal function comes as a welcome relief to the millions of individuals with diabetes and CKD. However, much remains to be established regarding its actions in a complex and pleiotropic signalling cascade. Other triterpenoids with different PK/PD profiles are currently under development.     

Changes in bacterial isolates from burn wounds and their antibiograms: A 20-year study (1986–2005)

BackgroundOur aim is to elucidate shifts in the bacterial spectrum colonising burn wounds and corresponding antibiotic susceptibilities during a 20-year study period.MethodsMicrobiological results from burn patients collected between 1986 and 2005 were analysed retrospectively.ResultsStaphylococcus aureus was isolated most frequently (20.8%), followed by Escherichia coli (13.9%), Pseudomonas aeruginosa (11.8%), coagulase-negative staphylococci (CNS) (10.9%), Enterococcus sp. (9.7%), Enterobacter cloacae (5.6%), Klebsiella pneumoniae (5%), Acinetobacter sp. (3.2%), Proteus mirabilis (2%) and Stenotrophomonas maltophilia (1.4%). Susceptibility of S. aureus to broad-spectrum substances such as ciprofloxacin or penicillinase-stable penicillins has waned, others such as cotrimoxazole or netilmicin remained effective. Not a single resistance against vancomycin was recorded. Increases in methicillin-resistant S. aureus (MRSA) were pronounced (3% in 1986–1997 (the first of the three study periods) to 16% in 1998–2001 and 13% in 2002–2005). Results for methicillin-resistant CNS (MRCNS) show an even greater increase. P. aeruginosa has shown increasing susceptibility against netilmicin (1986–1989: 84%, 2002–2005: 95%). Susceptibility of P. aeruginosa to ceftazidime has decreased markedly. S. maltophilia has shown clinically relevant susceptibility mainly against ciprofloxacin. Acinetobacter sp. have shown little susceptibility to most antibiotics. Imipenem or meropenem have been very reliable reserve antibiotics throughout the study period for the fermenting Enterobacteriaceae (E. coli, K. pneumoniae, E. cloacae and P. mirabilis), with susceptibilities of or near 100%.ConclusionIn-depth knowledge of the bacteria causing infectious complications and of their antibiotic susceptibilities is a prerequisite for treating burn patients. Our study shows shifts in the microbial spectrum and their antibiogram, which mandate frequent reassessments.     

Stool DNA analysis detects premorphological colorectal neoplasia: a case report

We found, in an asymptomatic patient with familial occurrence of malignancy, that mutations in the oncogene Kras could be detected in stool 18 months before a premalignant polyp was detected and removed endoscopically. Colorectal cancers usually develop from benign adenomas in a lengthy period of 5-10 years. During this period, several major biochemical pathways are involved, each characterized by one or several genetic alterations. Our patient did not present any signs or symptoms of colorectal disease during his two visits to the endoscopist. This case report shows that the use of genetic markers in stool testing has the potential to detect colon cancer in its very early stages when treatment is simple and often successful.     

Notch ligand Delta-like 1 is essential for postnatal arteriogenesis

Growth of functional arteries is essential for the restoration of blood flow to ischemic organs. Notch signaling regulates arterial differentiation upstream of ephrin-B2 during embryonic development, but its role during postnatal arteriogenesis is unknown. Here, we identify the Notch ligand Delta-like 1 (Dll1) as an essential regulator of postnatal arteriogenesis. Dll1 expression was specifically detected in arterial endothelial cells, but not in venous endothelial cells or capillaries. During ischemia-induced arteriogenesis endothelial Dll1 expression was strongly induced, Notch signaling activated and ephrin-B2 upregulated, whereas perivascular cells expressed proangiogenic vascular endothelial growth factor, and the ephrin-B2 activator EphB4. In heterozygous Dll1 mutant mice endothelial Notch activation and ephrin-B2 induction after hindlimb ischemia were absent, arterial collateral growth was abrogated and recovery of blood flow was severely impaired, but perivascular vascular endothelial growth factor and EphB4 expression was unaltered. In vitro, angiogenic growth factors synergistically activated Notch signaling by induction of Dll1, which was necessary and sufficient to regulate ephrin-B2 expression and to induce ephrin-B2 and EphB4-dependent branching morphogenesis in human arterial EC. Thus, Dll1-mediated Notch activation regulates ephrin-B2 expression and postnatal arteriogenesis.     

Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR downstream pathways in pancreatic cancer cells

MUC1 is a transmembrane glycoprotein which is typically expressed at the apical membrane of normal epithelial cells. In cancer cells, the over-expression of MUC1 and its aberrant localization around the cell membrane and in the cytoplasm favours its interaction with different protein partners such as epidermal growth factor receptor (EGFR) and can promote tumour proliferation through the activation of oncogenic signalling pathways. Our aims were to study the mechanisms inducing MUC1 cytoplasmic localization in pancreatic cancer cells, and to decipher their impact on EGFR cellular localization and activation. Our results showed that galectin-3, an endogenous lectin, is co-expressed with MUC1 in human pancreatic ductal adenocarcinoma, and that it favours the endocytosis of MUC1 and EGFR. Depletion of galectin-3 by RNA interference increased the interaction between MUC1 and EGFR, EGFR and ERK-1,2 phosphorylation, and translocation of EGFR to the nucleus. On the contrary, silencing of galectin-3 led to a decrease of cyclin-D1 levels and of cell proliferation. The galectin-3-dependent regulation of MUC1/EGFR functions may represent an interesting mechanism modulating the EGFR-stimulated cell growth of pancreatic cancer cells.     

Cost and cost-effectiveness of digital mammography compared with film-screen mammography in Australia

Objective: A systematic review assessed the relative safety and effectiveness of digital mammography compared with film-screen mammography. This study utilised the evidence from the review to examine the economic value of digital compared with film-screen mammography in Australia.
Methods: A cost-comparison analysis between the two technologies was conducted for the overall population for the purposes of breast cancer screening and diagnosis. In addition, a cost-effectiveness analysis was conducted for the screening subgroups where digital mammography was considered to be more accurate than film-screen mammography.
Results: Digital mammography in a screening setting is $11 more per examination than film-screen mammography, and $36 or $33 more per examination in a diagnostic setting when either digital radiography or computed radiography is used. In both the screening and diagnostic settings, the throughput of the mammography system had the most significant impact on decreasing the incremental cost/examination/year of digital mammography.
Conclusion: Digital mammography is more expensive than film-screen mammography. Whether digital mammography represents good value for money depends on the eventual life-years and quality-adjusted life-years gained from the early cancer diagnosis.
Implications: The evidence generated from this study has informed the allocation of public resources for the screening and diagnosis of breast cancer in Australia.     

Prevalence and predictors of cardiac hypertrophy and dysfunction in patients with Type 2 diabetes

The aim of the present study was to determine the prevalence and predictors of an abnormal echocardiogram in patients with Type 2 diabetes. Cardiac function and structure were rigorously assessed by comprehensive transthoracic echocardiographic techniques in 229 patients with Type 2 diabetes. Cardiovascular risk factors and diabetic complications were assessed, and predictors of an abnormal echocardiogram were identified using multivariate logistic regression analysis. An abnormal echocardiogram was present in 166 patients (72%). LVH (left ventricular hypertrophy) occurred in 116 patients (51%), and cardiac dysfunction was found in 146 patients (64%), of whom 109 had diastolic dysfunction alone and 37 had systolic+/-diastolic dysfunction. Independent predictors of an abnormal echocardiogram were obesity, age, the number of antihypertensive drugs used (all P<0.001) and creatinine clearance (P<0.05). The risk of an abnormal echocardiogram increased by 9% for each year over 50 years of age {OR (odds ratio), 1.09 [95% CI (confidence interval), 1.04-1.15]}, 3-fold if obesity was present [BMI (body mass index) >30; OR, 4.2 (95% CI, 1.9-9.0)] and by 80% for each antihypertensive agent used [OR, 1.8 (95% CI, 1.3-2.4) per agent]. In conclusion, an abnormal cardiac echocardiogram is common in patients with Type 2 diabetes. Importantly, although cardiac abnormalities can be predicted by traditional risk factors, such as age, obesity and renal function, the absence of micro- or macro-vascular complications does not predict a normal echocardiogram. We suggest that an echocardiogram identifies those with Type 2 diabetes at increased cardiovascular risk due to occult LVH and diastolic dysfunction, and this information may lead to more aggressive management of known risk factors in the clinic.     

Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes

OBJECTIVE—Activation of the receptor for advanced glycation end products (RAGE) in diabetic vasculature is considered to be a key mediator of atherogenesis. This study examines the effects of deletion of RAGE on the development of atherosclerosis in the diabetic apoE^−/− model of accelerated atherosclerosis.RESEARCH DESIGN AND METHODS—ApoE^−/− and RAGE^−/−/apoE^−/− double knockout mice were rendered diabetic with streptozotocin and followed for 20 weeks, at which time plaque accumulation was assessed by en face analysis.RESULTS—Although diabetic apoE^−/− mice showed increased plaque accumulation (14.9 ± 1.7%), diabetic RAGE^−/−/apoE^−/− mice had significantly reduced atherosclerotic plaque area (4.9 ± 0.4%) to levels not significantly different from control apoE^−/− mice (4.3 ± 0.4%). These beneficial effects on the vasculature were associated with attenuation of leukocyte recruitment; decreased expression of proinflammatory mediators, including the nuclear factor-κB subunit p65, VCAM-1, and MCP-1; and reduced oxidative stress, as reflected by staining for nitrotyrosine and reduced expression of various NADPH oxidase subunits, gp91phox, p47phox, and rac-1. Both RAGE and RAGE ligands, including S100A8/A9, high mobility group box 1 (HMGB1), and the advanced glycation end product (AGE) carboxymethyllysine were increased in plaques from diabetic apoE^−/− mice. Furthermore, the accumulation of AGEs and other ligands to RAGE was reduced in diabetic RAGE^−/−/apoE^−/− mice.CONCLUSIONS—This study provides evidence for RAGE playing a central role in the development of accelerated atherosclerosis associated with diabetes. These findings emphasize the potential utility of strategies targeting RAGE activation in the prevention and treatment of diabetic macrovascular complications.The receptor for advanced glycation end products (RAGE) is a multiligand cell surface molecule belonging to the immunoglobulin superfamily (1). It is expressed as full-length, N-truncated, and C-truncated isoforms, generated in humans by alternative splicing (2). Activation of the full-length RAGE receptor has been implicated in a range of chronic diseases, including various diabetic complications and atherosclerosis (1). In particular, studies in RAGE^−/− mice that carry the dominant-negative form of the receptor (2–6) and in RAGE-overexpressing mice (7) have confirmed an important role of RAGE activation in the development of diabetic nephropathy, neuropathy, and impaired angiogenesis. RAGE activation has also been implicated in the acceleration of atherosclerotic lesion formation as well as in the maintenance of proinflammatory and prothrombotic mechanisms, characteristic of diabetes-accelerated atherosclerosis (8,9). RAGE also represents an important mediator of oxidative stress in diabetes. Activation of RAGE in vitro leads to increased NADPH oxidase expression, mitochondrial oxidase activity, and downregulation of endogenous antioxidant activity (10,11). RAGE^−/− mice have a suppression of neointimal proliferation after externally induced arterial injury in the absence of diabetes (12). Moreover, blockade of RAGE-dependent signaling by soluble RAGE (sRAGE) has been shown to inhibit the progression of atherosclerotic changes (8,9) and kidney disease (3) in diabetic mice, possibly by suppressing the activation of nuclear factor-κB (NF-κB) activation and inflammatory cytokine expression. The present study examined the role of RAGE in the development of diabetes-accelerated atherosclerosis in a model of insulin deficiency, the streptozotocin-induced diabetic RAGE^−/−/apoE^−/− mouse. Our aim was to determine the effect of global RAGE deficiency, which includes absence of both the full-length receptor and endogenous sRAGE on the development of vascular lesions in the presence and absence of diabetes. Furthermore, key mediators of the atherosclerotic process in diabetes were examined, and the effects on these pathways were assessed in these RAGE-deficient mice.