Biospecimen Repositories in Low- and Middle-Income Countries: Insights From an American University of Beirut and Memorial Sloan Kettering Collaboration.

PURPOSE: Biobanking helps source tissue and blood for studying cancer genomics. Access to biorepository resources in low- and middle-income countries is lacking. Memorial Sloan Kettering Cancer Center (MSK) and the American University of Beirut (AUB) established a joint tissue biorepository at AUB in Beirut, Lebanon. The undertaking encountered key challenges that were unanticipated. MATERIALS AND METHODS: Patients age 18 years or older were eligible for enrollment at AUB. After consent, biospecimens were obtained at the time of routine diagnostic and/or therapeutic interventions. Both normal and abnormal tissue and solid and/or liquid specimens were collected from varied body sites. Early on, declining consent was frequently observed, and this was highlighted for investigation to understand potential participants reasoning. RESULTS: Of 850 patients approached, 704 (70.8%) elected to consent and 293 (29.5%) declined participation. The number of declined consents led to an amendment permitting the documentation of reasons for same. Of 100 potential participants who declined to consent and to whom outreach was undertaken, 63% indicated lack of research awareness and 27% deferral to their primary physician or family member. A financial gain for AUB was cited as concern by 5%, cultural boundaries in 4%, and 1% expressed concern about confidentiality. Of the patients who elected to consent, 682 biospecimens were procured. CONCLUSION: The AUB-MSK biospecimen repository has provided a unique resource for interrogation. Patient participation rate was high, and analyses of those who elected not to consent (29%) provide important insights into educational need and the local and cultural awareness and norms.

VEGF-A: A Novel Mechanistic Link Between CYP2C-Derived EETs and Nox4 in Diabetic Kidney Disease.

Diabetes is associated with decreased epoxyeicosatrienoic acid (EET) bioavailability and increased levels of glomerular vascular endothelial growth factor A (VEGF-A) expression. We examined whether a soluble epoxide hydrolase inhibitor protects against pathologic changes in diabetic kidney disease and whether the inhibition of the VEGF-A signaling pathway attenuates diabetes-induced glomerular injury. We also aimed to delineate the cross talk between cytochrome P450 2C (CYP2C)-derived EETs and VEGF-A. Streptozotocin-induced type 1 diabetic (T1D) rats were treated with 25 mg/L of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) in drinking water for 6 weeks. In parallel experiments, T1D rats were treated with either SU5416 or humanized monoclonal anti-VEGF-A neutralizing antibody for 8 weeks. Following treatment, the rats were euthanized, and kidney cortices were isolated for further analysis. Treatment with AUDA attenuated the diabetes-induced decline in kidney function. Furthermore, treatment with AUDA decreased diabetes-associated oxidative stress and NADPH oxidase activity. Interestingly, the downregulation of CYP2C11-derived EET formation is found to be correlated with the activation of the VEGF-A signaling pathway. In fact, inhibiting VEGF-A using anti-VEGF or SU5416 markedly attenuated diabetes-induced glomerular injury through the inhibition of Nox4-induced reactive oxygen species production. These findings were replicated in vitro in rat and human podocytes cultured in a diabetic milieu. Taken together, our results indicate that hyperglycemia-induced glomerular injury is mediated by the downregulation of CYP2C11-derived EET formation, followed by the activation of VEGF-A signaling and upregulation of Nox4. To our knowledge, this is the first study to highlight VEGF-A as a mechanistic link between CYP2C11-derived EET production and Nox4. ARTICLE HIGHLIGHTS: Diabetes is associated with an alteration in cytochrome P450 2C11 (CYP2C11)-derived epoxyeicosatrienoic acid (EET) bioavailability. Decreased CYP2C11-derived EET bioavailability mediates hyperglycemia-induced glomerular injury. Decreased CYP2C11-derived EET bioavailability is associated with increased reactive oxygen species production, NADPH oxidase activity, and Nox4 expression in type 1 diabetes. Decreased CYP2C11-derived EET formation mediates hyperglycemia-induced glomerular injury through the activation of the vascular endothelial growth factor A (VEGF-A) signaling pathway. Inhibiting VEGF signaling using anti-VEGF or SU5416 attenuates type 1 diabetes-induced glomerular injury by decreasing NADPH oxidase activity and NOX4 expression.

Sonographic evaluation of normal diaphragmatic thickness and excursion in Malaysia paediatric population: A single-institution cross-sectional study.

INTRODUCTION: Diaphragmatic dysfunction is often underdiagnosed as clinical presentation is non-specific and reference values for normal diaphragmatic excursion are inadequate. The rationale of this study is to provide a normal reference value of diaphragmatic excursion and thickness in Malaysia's paediatric population using M-mode sonography, as no previous local data are available to our knowledge. MATERIALS AND METHODS: A total of 119 healthy infants and children fulfilling our inclusion and exclusion criteria were recruited. They were divided into three groups according to age - 0-2 years old in group 1; 2-6 years old in group 2; 6- 12 years old in group 3. Sonography B-mode was used to assess bilateral diaphragmatic thickness and M-mode to assess diaphragmatic excursion during quiet spontaneous respiration. RESULTS: In our paediatric population, the normal right and left diaphragmatic thickness were 2.0 mm ± 0.5 and 2.0 mm ± 0.5 for group 1; 2.5 mm ± 0.8 and 2.4 mm ± 0.6 for group 2; 2.7 mm ± 0.7 and 2.5 mm ± 0.5 for group 3, respectively. The normal right and left diaphragmatic excursion were 7.7 mm ± 2.5 and 7.3 mm ± 2.6 for group 1; 11.5 mm ± 3.8 and 10.6 mm ± 3.8 for group 2; 13.8 mm ± 3.9 and 12.9 mm ± 3.3 for group 3, respectively (data presented in mean ± standard deviation). There were no significant differences between two genders for each group. Significant positive correlation between age, weight, height, and body surface area with bilateral diaphragmatic thickness and excursion were detected in all studied population. The percentage difference between excursions of both hemidiaphragm was below 40%. CONCLUSIONS: M-mode sonography is the modality of choice for diaphragmatic kinetics especially in paediatric population. This study provides normal sonographic reference value of diaphragmatic excursion and thickness in the Malaysian paediatric population as well as percentile curves for right diaphragmatic excursion plotted against body weight. The availability of this data will aid in the diagnosis of diaphragmatic dysfunction and hence immediate intervention for better recovery.

Mode-locked ytterbium-doped fiber laser with zinc phthalocyanine thin film saturable absorber.

A stable mode-locked laser was demonstrated using a newly developed zinc phthalocyanine (ZnPc) thin film as passive saturable absorber (SA) in ytterbium-doped fiber laser (YDFL). The ZnPc thin film was obtained using a casting method and then inserted between the two fiber ferrules of a YDFL ring cavity to generate mode-locked pulses. The resulting pulsed laser operated at a wavelength of 1034.5 nm having a repetition rate of 3.3 MHz. At pump power of 277 mW, the maximum output power and pulse energy are achieved at 4.92 mW and 1.36 nJ, respectively. ZnPc has a high chemical and photochemical stability, and its significance for use as a potential SA in a mode-locked laser is reported in this work.

Modulation of Neuro-Inflammatory Signals in Microglia by Plasma Prekallikrein and Neuronal Cell Debris.

Microglia, the resident phagocytes of the central nervous system and one of the key modulators of the innate immune system, have been shown to play a major role in brain insults. Upon activation in response to neuroinflammation, microglia promote the release of inflammatory mediators as well as promote phagocytosis. Plasma prekallikrein (PKall) has been recently implicated as a mediator of neuroinflammation; nevertheless, its role in mediating microglial activation has not been investigated yet. In the current study, we evaluate the mechanisms through which PKall contributes to microglial activation and release of inflammatory cytokines assessing PKall-related receptors and their dynamics. Murine N9-microglial cells were exposed to PKall (2.5 ng/ml), lipopolysaccharide (100 ng/ml), bradykinin (BK, 0.1 µM), and neuronal cell debris (16.5 µg protein/ml). Gene expression of bradykinin 2 receptor (B2KR), protease-activated receptor 2 (PAR-2), along with cytokines and fibrotic mediators were studied. Bioinformatic analysis was conducted to correlate altered protein changes with microglial activation. To assess receptor dynamics, HOE-140 (1 µM) and GB-83 (2 µM) were used to antagonize the B2KR and PAR-2 receptors, respectively. Also, the role of autophagy in modulating microglial response was evaluated. Data from our work indicate that PKall, LPS, BK, and neuronal cell debris resulted in the activation of microglia and enhanced expression/secretion of inflammatory mediators. Elevated increase in inflammatory mediators was attenuated in the presence of HOE-140 and GB-83, implicating the engagement of these receptors in the activation process coupled with an increase in the expression of B2KR and PAR-2. Finally, the inhibition of autophagy significantly enhanced the release of the cytokine IL-6 which were validated via bioinformatics analysis demonstrating the role of PKall in systematic and brain inflammatory processes. Taken together, we demonstrated that PKall can modulate microglial activation via the engagement of PAR-2 and B2KR where PKall acts as a neuromodulator of inflammatory processes.

Vascular Cells Proteome Associated with Bradykinin and Leptin Inflammation and Oxidative Stress Signals.

Among the primary contributors to cardiovascular diseases are inflammation and oxidative imbalance within the vessel walls as well as the fibrosis of rat aortic smooth muscle cell (RASMC). Bradykinin (BK) and leptin are inflammatory modulators that are linked to vascular injury. In this study, we employed tandem LC-MS/MS to identify protein signatures that encompass protein abundance in RASMC treated with BK or leptin followed by systems biology analyses to gain insight into the biological pathways and processes linked to vascular remodeling. In the study, 1837 proteins were identified in control untreated RASMC. BK altered the expression of 72 (4%) and 120 (6.5%) proteins, whereas leptin altered the expression of 189 (10.2%) and 127 (6.5%) proteins after 24 and 48 h, respectively, compared to control RASMC. BK increased the protein abundance of leptin receptor, transforming growth factor-ß. On the other hand, leptin increased the protein abundance of plasminogen activator inhibitor 1 but decreased the protein abundance of cofilin. BK and leptin induced the expression of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-1ß (IL-1ß) and pathway analysis revealed the activation of mitogen-activated protein kinases (MAPKs) and AKT pathways. The proteome profile in response to BK and leptin revealed mechanistic interplay of multiple processes that modulate inflammation and oxidative stress signals in the vasculature.

Modulation of proteomic and inflammatory signals by Bradykinin in podocytes.

Podocyte damage is one of the hallmarks of diabetic nephropathy leading to proteinuria and kidney damage. The underlying mechanisms of podocyte injury are not well defined. Bradykinin (BK) was shown to contribute to diabetic kidney disease. Here, we evaluated the temporal changes in proteome profile and inflammatory signals of podocytes in response to BK (10-7M). Protein profile was evaluated by liquid chromatography mass Spectrometry (LC-MS/MS) analysis. Proteome profile analysis of podocytes treated with BK (10-7M) for 3 and 6 h, revealed 61 proteins that were differentially altered compared to unstimulated control podocytes. Pathway enrichment analysis suggested inhibition of cell death pathways, engagement of cytoskeletal elements and activation of inflammatory pathways. One of the inflammatory proteins that was identified to be induced by BK treatment is Prostaglandin (PG) H Synthase-2 (Cyclooxygenase-2, COX-2). In addition, BK significantly induced the production and release of PGE2 and this effect was inhibited by both COX-2 and MEK Kinase inhibitors, demonstrating that the production of PGE2 by BK is mediated via COX-2 and MAPK-dependent mechanisms. These findings provide a global understanding of the effector modulated proteome in response to BK and also reveal BK as an important modulator of inflammation and a potential player in podocyte injury.

Sonographic nomogram of paediatric renal size in Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM).

INTRODUCTION: A person's childhood is an important period of growth, and also one's most vulnerable, as one can be exposed to various pathologies, for example those that could affect the growth of one's kidney. Asians are physiologically different from Caucasians, and the nomogram renal size obtained from a Western population (mostly of Caucasians) is not be suitable for representing Asian children. As such a nomogram on paediatric renal size derived from Malaysia is needed. METHODS: A total of 109 (64 males and 45 females) aged 0-12 in Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM) took part in this study. They underwent ultrasonography of both kidneys, and their demographic and anthropometric data were collected. The mean and standard deviations of the renal length and renal volume according to their age groups was calculated, and the final data was compared to the ones reported by Rosenbaum et al. (1984). RESULT: Body weight and Body Surface Area (BSA) of the children reported the strongest correlation with renal size. Significant differences were found between local and the data from Rosenbaum et al (1984). A nomogram on paediatric renal size based on children in PPUKM was then created. DISCUSSION: Ultrasonography is regarded as the standard method for determining renal size. Body weight and BSA were both strongly correlated with renal size. It was shown that the widely used nomograms derived from data obtained from Caucasian was not suitable to represent the population of Malaysian children.

Heteromerization fingerprints between bradykinin B2 and thromboxane TP receptors in native cells.

Bradykinin (BK) and thromboxane-A2 (TX-A2) are two vasoactive mediators that modulate vascular tone and inflammation via binding to their cognate "class A" G-protein coupled receptors (GPCRs), BK-B2 receptors (B2R) and TX-prostanoid receptors (TP), respectively. Both BK and TX-A2 lead to ERK1/2-mediated vascular smooth muscle cell (VSMC) proliferation and/or hypertrophy. While each of B2R and TP could form functional dimers with various GPCRs, the likelihood that B2R-TP heteromerization could contribute to their co-regulation has never been investigated. The main objective of this study was to investigate the mode of B2R and TP interaction in VSMC, and its possible impact on downstream signaling. Our findings revealed synergistically activated ERK1/2 following co-stimulation of rat VSMC with a subthreshold dose of BK and effective doses of the TP stable agonist, IBOP, possibly involving biased agonist signaling. Single detection of each of B2R and TP in VSMC, using in-situ proximity ligation assay (PLA), provided evidence of the constitutive expression of nuclear and extranuclear B2R and TP. Moreover, inspection of B2R-TP PLA signals in VSMC revealed agonist-modulated nuclear and extranuclear proximity between B2R and TP, whose quantification varied substantially following single versus dual agonist stimulations. B2R-TP interaction was further verified by the findings of co-immunoprecipitation (co-IP) analysis of VSMC lysates. To our knowledge, this is the first study that provides evidence supporting the existence of B2R-TP heteromerization fingerprints in primary cultured VSMC.

Proteome profiling in the aorta and kidney of type 1 diabetic rats.

Diabetes is associated with a number of metabolic and cardiovascular risk factors that contribute to a high rate of microvascular and macrovascular complications. The risk factors and mechanisms that contribute to the development of micro- and macrovascular disease in diabetes are not fully explained. In this study, we employed mass spectrometric analysis using tandem LC-MS/MS to generate a proteomic profile of protein abundance and post-translational modifications (PTM) in the aorta and kidney of diabetic rats. In addition, systems biology analyses were employed to identify key protein markers that can provide insights into molecular pathways and processes that are differentially regulated in the aorta and kidney of type 1 diabetic rats. Our results indicated that 188 (111 downregulated and 77 upregulated) proteins were significantly identified in the aorta of diabetic rats compared to normal controls. A total of 223 (109 downregulated and 114 upregulated) proteins were significantly identified in the kidney of diabetic rats compared to normal controls. When the protein profiles from the kidney and aorta of diabetic and control rats were analyzed by principal component analysis, a distinct separation of the groups was observed. In addition, diabetes resulted in a significant increase in PTM (oxidation, phosphorylation, and acetylation) of proteins in the kidney and aorta and this effect was partially reversed by insulin treatment. Ingenuity pathway analysis performed on the list of differentially expressed proteins depicted mitochondrial dysfunction, oxidative phosphorylation and acute phase response signaling to be among the altered canonical pathways by diabetes in both tissues. The findings of the present study provide a global proteomics view of markers that highlight the mechanisms and putative processes that modulate renal and vascular injury in diabetes.

A blind spot on the global mental health map: a scoping review of 25 years' development of mental health care for people with severe mental illnesses in central and eastern Europe.

Just over 25 years have passed since the major sociopolitical changes in central and eastern Europe; our aim was to map and analyse the development of mental health-care practice for people with severe mental illnesses in this region since then. A scoping review was complemented by an expert survey in 24 countries. Mental health-care practice in the region differs greatly across as well as within individual countries. National policies often exist but reforms remain mostly in the realm of aspiration. Services are predominantly based in psychiatric hospitals. Decision making on resource allocation is not transparent, and full economic evaluations of complex interventions and rigorous epidemiological studies are lacking. Stigma seems to be higher than in other European countries, but consideration of human rights and user involvement are increasing. The region has seen respectable development, which happened because of grassroots initiatives supported by international organisations, rather than by systematic implementation of government policies.

Toward computer-assisted image-guided congenital heart defect repair: an initial phantom analysis.

PURPOSE: Radiation exposure in interventional cardiology is an important consideration, due to risk of cancer and other morbidity to the patient and clinical staff. Cardiac catheterizations rely heavily on fluoroscopic imaging exposing both patient and clinician to ionizing radiation. An image-guided surgery system capable of facilitating cardiac catheterizations was developed and tested to evaluate dose reduction. METHODS: Several electromagnetically tracked tools were constructed specifically a 7-Fr catheter with five 5-degree-of-freedom magnetic seeds. Catheter guidance was accomplished using our image guidance system Kit for Navigation by Image-Focused Exploration and fluoroscopy alone. A cardiac phantom was designed and 3D printed to validate the image guidance procedure. In mock procedures, an expert clinician guided and deployed an occluder across the septal defect of the phantom heart. RESULTS: The image guidance method resulted in a dose of 1.26 mSv of radiation dose per procedure, while traditional guidance resulted in a dose of 3.33 mSv. Average overall dose savings for the image-guided method was nearly 2.07 mSv or 62 %. CONCLUSION: The work showed significant ([Formula: see text]) decrease in radiation dose with use of image guidance methods at the expense of a modest increase in procedure time. This study lays the groundwork for further exploration of image guidance applications in pediatric cardiology.

Wavelet packet analysis of EEG signals from dyslexic children with writing disability.

This paper describes Wavelet Packet Analysis of EEG signal of dyslexic children with writing disability. Two activities were carried out during EEG recordings; relax and and writing letters. EEG signals were collected using biosignal gMobilab system and analysed using Wavelet Packet Decomposition to extract alpha and beta brainwave rhythm. Statistical data such as log energy entropy and standard deviation were used to compare the characteristic of EEG signals from dyslexic and normal children. Result showed that the dyslexic children consumed higher energy at left parietal lobe during writing activity especially those who write incorrectly. The alpha band shows higher log energy entropy for dyslexic children compare to normal children at most channel during relax.

20-HETE and EETs in diabetic nephropathy: a novel mechanistic pathway.

Diabetic nephropathy (DN), a major complication of diabetes, is characterized by hypertrophy, extracellular matrix accumulation, fibrosis and proteinuria leading to loss of renal function. Hypertrophy is a major factor inducing proximal tubular epithelial cells injury. However, the mechanisms leading to tubular injury is not well defined. In our study, we show that exposure of rats proximal tubular epithelial cells to high glucose (HG) resulted in increased extracellular matrix accumulation and hypertrophy. HG treatment increased ROS production and was associated with alteration in CYPs 4A and 2C11 expression concomitant with alteration in 20-HETE and EETs formation. HG-induced tubular injury were blocked by HET0016, an inhibitor of CYPs 4A. In contrast, inhibition of EETs promoted the effects of HG on cultured proximal tubular cells. Our results also show that alteration in CYPs 4A and 2C expression and 20HETE and EETs formation regulates the activation of the mTOR/p70S6Kinase pathway, known to play a major role in the development of DN. In conclusion, we show that hyperglycemia in diabetes has a significant effect on the expression of Arachidonic Acid (AA)-metabolizing CYPs, manifested by increased AA metabolism, and might thus alter kidney function through alteration of type and amount of AA metabolites.

Effects of weight reduction regimens and bariatric surgery on chronic kidney disease in obese patients.

Increasing evidence nowadays is showing that obesity by itself, independent of other comorbidities like diabetes and hypertension, is associated with renal functional changes and structural damage. Intentional weight loss demonstrates beneficial reduction in proteinuria and albuminuria in patients with mild to moderate chronic kidney disease, particularly those whose renal damage is likely induced by obesity. The safety of some weight loss interventions, particularly the use of high-protein diets and/or medications, is questionable in this population due to the lack of well-designed randomized controlled studies reporting on their efficacy or harm. Bariatric surgery showed the most promising results with regards to ameliorating glomerular hyperfiltration and albuminuria albeit with a modest risk of increased perioperative complications with advanced stages of chronic kidney disease (CKD).

Overview of the physiology and pathophysiology of leptin with special emphasis on its role in the kidney.

The adipocyte product leptin is a pleiotropic adipokine and hormone, with a role extending beyond appetite suppression and increased energy expenditure. This review summarizes the biology of the leptin system and the roles of its different receptors in a multitude of cellular functions in different organs, with special emphasis on the kidney. Leptin's physiological functions as well as deleterious effects in states of leptin deficiency or hyperleptinemia are emphasized. Chronic hyperleptinemia can increase blood pressure through the sympathetic nervous system and renal salt retention. The concept of selective leptin resistance in obesity is emerging, whereby leptin's effect on appetite and energy expenditure is blunted, with a concomitant increase in leptin's other effects as a result of the accompanying hyperleptinemia. The divergence in response likely is explained by different receptors and post-receptor activating mechanisms. Chronic kidney disease is a known cause of hyperleptinemia. There is an emerging view that the effect of hyperleptinemia on the kidney can contribute to the development and/or progression of chronic kidney disease in selective resistance states such as in obesity or type 2 diabetes mellitus. The mechanisms of renal injury are likely the result of exaggerated and undesirable hemodynamic influences as well as profibrotic effects.

Glomerular hyperfiltration and proteinuria in transfusion-independent patients with ß-thalassemia intermedia.

BACKGROUND/AIMS: Renal manifestations have been described in ß-thalassemia major and were attributed to transfusional iron overload and chelation therapy. Patients with the milder phenotype, ß-thalassemia intermedia (TI), remain largely transfusion and iron chelation independent while enduring a chronic hemolytic anemia and primary iron overload. Data on renal function in patients with TI is lacking. METHODS: In this cross-sectional study of 50 TI patients, we evaluated the association of estimated glomerular filtration rate (eGFR) and urinary protein to creatinine (UPr/UCr) ratio with relevant patient, disease and laboratory indices. RESULTS: The median age of patients was 28 years (44% males). The eGFR was >90 ml/min/1.73 m(2) in all patients, with a median value of 142.3 ml/min/1.73 m(2). The median UPr/UCr ratio was 213.2 mg/g. There was a negative correlation between age and eGFR, while the UPr/UCr ratio correlated positively with markers of anemia, hemolysis and iron overload. A total of 24 (48%) patients had evidence of glomerular hyperfiltration, while 7 (14%) had proteinuria (UPr/UCr ratio >500 mg/g). Patients with proteinuria were characterized by elevated liver iron concentration (>7 mg Fe/g dry weight), non-transferrin-bound iron levels and nucleated red blood cell counts. CONCLUSIONS: A considerable proportion of TI patients show evidence of abnormally elevated eGFR, with a declining trend towards advancing age. The occurrence of proteinuria is associated with anemia, hemolysis and iron toxicity.

Global renal gene expression profiling analysis in B2-kinin receptor null mice: impact of diabetes.

Diabetic nephropathy (DN), the leading cause of end-stage renal failure, is clinically manifested by albuminuria and a progressive decline in glomerular filtration rate. The risk factors and mechanisms that contribute to the development and progression of DN are still incompletely defined. To address the involvement of bradykinin B(2)-receptors (B(2)R) in DN, we used a genome wide approach to study the effects of diabetes on differential renal gene expression profile in wild type and B(2)R knockout (B(2)R(-/-)) mice. Diabetes was induced with streptozotocin and plasma glucose levels and albumin excretion rate (AER) were measured at predetermined times throughout the 23 week study period. Longitudinal analysis of AER indicated that diabetic B(2)R(-/-)D null mice had a significantly decreased AER levels compared to wild type B(2)R(+/+)D mice (P = 0.0005). Results from the global microarray study comparing gene expression profiles among four groups of mice respectively: (B(2)R(+/+)C, B(2)R(+/+)D, B(2)R(-/-)C and B(2)R(-/-)D) highlighted the role of several altered pathological pathways in response to disruption of B(2)R and to the diabetic state that included: endothelial injury, oxidative stress, insulin and lipid metabolism and inflammatory process with a marked alteration in the pro-apoptotic genes. The findings of the present study provide a global genomics view of biomarkers that highlight the mechanisms and putative pathways involved in DN.

Emerging therapies for diabetic nephropathy patients: beyond blockade of the Renin-Angiotensin system.

Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. The mainstay of treatment has been glycemic control and blood pressure lowering using agents blocking the renin-angiotensin system. Clinical trials are currently under way using novel agents for the treatment of patients with diabetic nephropathy. Promising agents emerging from some of the completed trials include pirfenidone and bardoxolone methyl, which have been shown in two recent randomized controlled trials in patients with diabetic nephropathy to result in an improved estimated glomerular filtration rate compared to placebo. Also, paricalcitol has been shown to decrease the urinary albumin-to-creatinine ratio, whereas sulodexide failed to do so in a large randomized double-blind placebo-controlled trial. Of note, pyridoxamine has also shown promise in the treatment of diabetic nephropathy if started early in the disease course. These preliminary trials have shown significant promise for managing patients with diabetic nephropathy, sparking active research in this field and providing the rationale for further clinical testing in long-term, hard-outcomes trials.