Search

The four papers in this document are centered around several themes in education reform: (1) the need to reimagine and recreate strategies; (2) the need to approach familiar obstacles innovatively; (3) the need to utilize all available resources; and (4) and the need to engage in this work cooperatively and with courage and vision. In the first paper, "National and Local Strategies for Building Teacher Expertise: A Necessary Relationship"(Sharon Robinson), education is seen as the way to acquire knowledge for with knowledge comes power. The second paper, "Race Matters" (Cornel West) offers hope and justice, loyalty, commitment, and trust to the most vulnerable members of the community, who often are blamed for the downward mobility that leads to rage. The third paper, "Organizing Communities for Student Achievement" (Ernesto J. Cortes, Jr.), suggests that the future lies in individual capacity and collaboration, and in the power that teaching ordinary people about public life and public skills brings. The fourth paper, "A Call to Action: Thinking-and-Acting K-16" (Kati P. Haycock), also looks at the educational needs of poor and minority children and urges development of new systems from elementary through higher education. A brief section describing the American Association for Higher Education and its Education Trust is appended. (CH)

This book is intended to provide insights into the role that the mass media play in the broad educational process, especially in the ways that young people develop their beliefs and feelings about human diversity. The book also offers insights and ideas for grappling with the media teaching-learning process and for understanding its implications for diversity-related education. The chapters are: (1) "Holly and Melissa's Multicultural Curriculum"; (2) "The Societal Curriculum"; (3) "Mediamakers as Multicultural Curriculum Developers"; (4) "Media Products as Multicultural Textbooks"; (5) "Mass Media and Multicultural Learning"; (6) "October 1997: A Multicultural Media Journal"; (7) "The Contemporary Media Curriculum as School Context"; (8) "Mass Media, Multiculturalism, and Schools"; (9) "Struggling with Stereotypes: Uses and Abuses of a Critical Concept"; and (10) "Multicultural Education in the Cyberspace Era." An epilogue, "She's Black, I'm White," discusses the racial awareness of the author's grandchildren. (Contains 372 references.) (SLD)

Offering practical tips for K-12 teachers and other curriculum planners, this booklet presents a comprehensive view of how ethnicity should be treated in the curriculum, suggests a number of activities for ethnic studies, identifies resources and materials available in ethnic studies, and describes a number of instruments available for evaluating the outcomes of ethnic studies. Focusing on the nature of ethnicity in the curriculum, the first of four chapters defines ethnic studies, describes where ethnic studies education occurs, and identifies the goals of ethnic studies. In addition, "do and don't" guidelines of teaching about ethnicity are provided. The last section in chapter one discusses multiethnic teaching concepts. The major portion of the document, chapter two, offers activities designed to introduce the concept of ethnicity and enrich students' knowledge and understanding of their ethnic origins and the ethnic origins of others. Chapter three provides suggestions about how to identify available ethnic studies materials and select those that best suit the needs of a particular class. Chapter four presents an annotated list of existing instruments for evaluating various aspects of ethnic studies programs. The book is also included in an Ethnic Heritage Studies Kit, along with other books, a filmstrip, and cassette, which is available from the Social Science Education Consortium for $29.00. (Author/JR)

Reviews some of the current children's literature and films that address the Latino immigration experience from the Americas and that introduce children to the issues confronting them. Each work is briefly described, including the immigration theme(s) it presents. (GR)

This book aims to help educators improve their understanding of minority students within the American social context. It contains seven chapters, each written by different authors. The introductory chapter, "The Education of Language Minority Students: A Contextual Interaction Model" by C. Cortes, provides an overview of a theory for how the many sociocultural factors influence language minority education. The next chapter, "Ethnic Minority Issues in the United States: Challenges for the Educational System" by S. Sue and A. Padilla, looks at historical explanations for why some groups do better in school than others. "Understanding Sociocultural Factors: Knowledge, Identity, and School Adjustment" by J. Ogbu and M. Matute-Bianchi analyzes sociocultural factors such as group attitudes toward education, self-identity, historical experiences, cultural values, and job ceiling. The next chapter, "Sociocultural Contexts of Language Development" by S. Heath, stresses the inclusion of mother tongue and second language education in language minority educational reform. "Sociocultural Resources in Instruction: A Context-Specific Approach" by S. Diaz, L. Moll and H. Mehan provides a detailed illustration of how language development (reading and writing) can be improved, based on a positive link between the home and school. "Cooperative Learning and Sociocultural Factors in Schooling" by S. Kagan describes cooperative learning as an educational innovation for improving students' acquisition of both academic and humanistic skills. The concluding chapter, "Educators' Responses to Sociocultural Diversity" by M. McGroarty facilitates educators' understanding and use of the hypotheses and approaches proposed in the earlier chapters. The book contains approximately 200 references. (KS)

We present several results related to ranking. We give a general margin-based bound for ranking based on the L∞ covering number of the hypothesis space. Our bound suggests that algorithms that maximize the ranking margin generalize well. We then describe a new algorithm, Smooth Margin Ranking, that precisely converges to a maximum ranking-margin solution. The algorithm is a modification of RankBoost, analogous to Approximate Coordinate Ascent Boosting. We also prove a remarkable property of AdaBoost: under very natural conditions, AdaBoost maximizes the exponentiated loss associated with the AUC and achieves the same AUC as RankBoost. This explains the empirical observations made by Cortes and Mohri, and Caruana and Niculescu-Mizil, about the excellent performance of AdaBoost as a ranking algorithm, as measured by the AUC. [ABSTRACT FROM AUTHOR]

Managing patients with myelodysplastic syndrome (MDS) is a highly challenging endeavor. MDS appears to arise from intrinsic or acquired genetic defects in stem cells that confer a proliferative advantage to the malignant clone over normal stem cells. Recurrent chromosomal abnormalities are present in 40% to 70% of patients at diagnosis and in 95% of patients with treatment-related MDS. Until now, allogeneic stem cell transplantation and occasionally high-dose chemotherapy have been viewed as possibly curative options for patients with MDS disorders, but they are limited by the advanced age of most patients, concomitant co-morbidities, and/or in the case of stem cell transplantation the lack of donors. The escalating unraveling of numerous pathogenetic pathways in MDS has spurred development of novel targeted approaches for the treatment of these complex disorders. The recognition of the importance that epigentic phenomena play in the regulation of gene transcription led to the development of methylation inhibitors and histone deacetylase inhibitors in hematologic malignancies. Currently, these agents constitute the mainstay of therapy for MDS. Several agents with antiangiogenic properties have also been evaluated for the treatment of MDS, and immunotherapeutic approaches are under investigation for patients with MDS. Identifying the genes that are associated with recurrent chromosomal deletions and numerical abnormalities in patients with MDS, including studies and tests for haplo-insufficiency, are important directions to pursue in the future. [ABSTRACT FROM AUTHOR]

The successful introduction of the tyrosine kinase inhibitors (TKIs) has revolutionized the outcome of patients with chronic myeloid leukemia (CML). Imatinib mesylate therapy induced high rates of complete cytogenetic and major molecular responses and improved survival for patients with CML. A small proportion of patients in chronic phase CML and more patients in advanced phases are resistant to imatinib or develop resistance during treatment through BCR-ABL-dependent and BCR-ABL-independent mechanisms. Novel, more potent TKIs can overcome imatinib resistance, including dasatinib (a potent dual Src and Bcr-Abl inhibitor), nilotinib (a selective potent Bcr-Abl inhibitor), bosutinib and INNO406 (both Src-Abl inhibitors), among others. Other approaches are exploring combination therapy, agents affecting various oncogenic pathways, and immune modulation. This chapter reviews some of these targeted therapies, particularly those for which clinical data are already available. [ABSTRACT FROM AUTHOR]

Despite the excellent clinical results with imatinib in chronic myeloid leukemia, most patients have minimal residual disease and others will develop resistance and may eventually progress. Thus there is a need for developing approaches to overcome and prevent resistance to imatinib. The "second generation" of more potent tyrosine kinase inhibitors have shown significant activity in the laboratory and in the clinic. However, there is considerable interest in developing agents that may act on different pathways that could either be combined with these inhibitors to better overcome and eventually prevent the development of resistance, to deal with mechanisms of resistance common to all inhibitors, or to deal with the problem of residual disease, that could be mediated by a stem cell insensitive to tyrosine kinase inhibitors. To this effect, many agents have been developed and have already entered the clinical arena, such as hypomethylating agents, farnesyl transferase inhibitors, and homoharringtonine, with promising preclinical and clinical results. Others may have been tested only at a preclinical level but have shown important activity. In addition, the use of immune modulation, for example, in the form of "vaccines," is evolving as a major strategy to achieve eradication of minimal residual disease. This chapter will discuss some of the different agents currently under development, with particular attention to those already in clinical trials. The challenge for the future is to incorporate them into effective strategies that can eliminate the disease and cure all patients with chronic myeloid leukemia. [ABSTRACT FROM AUTHOR]

Passive integrated transponder (PIT) technology was used to study the behaviour of fishes during the summer season in two headwater streams of northeastern Portugal. A total of 71 PIT tags (12 mm long × 2.1 mm diameter) were surgically implanted in 1+ stocked (39) and native (32) brown trout of two size classes (<20.0 and ≥20.0 cm). Eight independent antennae, connected to a multi-point decoder (MPD reader) unit, were placed in different microhabitats, selected randomly every 3 days during the observation period (29 August-9 September in Baceiro stream and 19 September-4 October in Sabor stream). The results confirmed this method as a suitable, labour efficient tool to assess the movement and habitat use of sympatric stocked and native trout populations. About 76.9% of stocked and 59.4% of native PIT tagged trouts were detected. Multivariate techniques (CCA, DFA and classification tree) showed a separation in habitat use between the two sympatric populations. Stocked trout mainly used the microhabitats located in the middle of the channel with higher depths and without cover. Furthermore, these fishes displayed a greater mobility and a diel activity pattern different to native trout populations. [ABSTRACT FROM AUTHOR]

We present a general study of learning and linear separability with rational kernels, the sequence kernels commonly used in computational biology and natural language processing. We give a characterization of the class of all languages linearly separable with rational kernels and prove several properties of the class of languages linearly separable with a fixed rational kernel. In particular, we show that for kernels with transducer values in a finite set, these languages are necessarily finite Boolean combinations of preimages by a transducer of a single sequence. We also analyze the margin properties of linear separation with rational kernels and show that kernels with transducer values in a finite set guarantee a positive margin and lead to better learning guarantees. Creating a rational kernel with values in a finite set is often non-trivial even for relatively simple cases. However, we present a novel and general algorithm, double-tape disambiguation, that takes as input a transducer mapping sequences to sequence features, and yields an associated transducer that defines a finite range rational kernel. We describe the algorithm in detail and show its application to several cases of interest. [ABSTRACT FROM AUTHOR]

This paper examines in detail an alternative ranking problem for search engines, movie recommendation, and other similar ranking systems motivated by the requirement to not just accurately predict pairwise ordering but also preserve the magnitude of the preferences or the difference between ratings. We describe and analyze several cost functions for this learning problem and give stability bounds for their generalization error, extending previously known stability results to non-bipartite ranking and magnitude of preference-preserving algorithms. We present algorithms optimizing these cost functions, and, in one instance, detail both a batch and an on-line version. For this algorithm, we also show how the leave-one-out error can be computed and approximated efficiently, which can be used to determine the optimal values of the trade-off parameter in the cost function. We report the results of experiments comparing these algorithms on several datasets and contrast them with those obtained using an AUC-maximization algorithm. We also compare training times and performance results for the on-line and batch versions, demonstrating that our on-line algorithm scales to relatively large datasets with no significant loss in accuracy. [ABSTRACT FROM AUTHOR]

Because G-protein-coupled receptors (GPCRs) constitute excellent putative therapeutic targets, functional characterization of orphan GPCRs through identification of their endogenous ligands has great potential for drug discovery. In an attempt to identify a receptor specific for angiotensin III, we have cloned, by homology from a rat brain cDNA library, a GPCR that shares 90% amino acid sequence identity with the human orphan APJ (putative receptor protein related to the angiotensin receptor AT1) receptor and 31% with the rat AT1A angiotensin receptor. In 1998, the endogenous ligand for the human orphan APJ receptor, i.e., apelin, was isolated from bovine stomach extracts. Apelin, a bioactive peptide, naturally occurs in the brain and plasma as 13 (pE13F) and 17 amino acid (K17F) fragments of a 77 amino acid precursor. The APJ receptor binds with high affinity K17F and pE13F but not the shorter N-terminal-deleted apelin fragments. This receptor is negatively coupled to adenylate cyclase and internalizes following stimulation with K17F and pE13F. Apelin and its receptor are both widely distributed in the brain and are highly expressed in the supraoptic and paraventricular hypothalamic nuclei. Dual labeling studies demonstrate that, within these two types of nuclei, apelin and its receptor co-localize with vasopressin (AVP) in magnocellular neurons. In lactating rodents, characterized by increases in synthesis and release of AVP, central injection of apelin inhibits the phasic electrical activity of AVP neurons and reduces the secretion of AVP in the bloodstream, resulting in aqueous diuresis. Apelin may thus be considered as a natural inhibitor of the anti-diuretic effect of AVP. Moreover, water deprivation, which increases systemic AVP release, decreases plasma apelin concentrations and induces apelin storage inside magnocellular neurons, thereby avoiding the inhibitory action of apelin on AVP release. Thus apelin and AVP are conversely regulated to optimize systemic AVP release and prevent additional water loss at the kidney level. In addition, apelin and its receptor are present in the cardiovascular system, i.e., in heart, kidney and vessels. Given systemically, apelin reduces arterial blood pressure, increases cardiac contractility and reduces cardiac loading. Apelin may therefore play a crucial role in the control of body fluid homeostasis and cardiovascular functions. A clinical study in healthy volunteers to determine whether apelin controls water balance in humans is in progress. If this hypothesis is confirmed, the development of non-peptide agonists of the apelin receptor may therefore represents new therapeutic avenues for the treatment of water/sodium retention, heart and kidney failure. [ABSTRACT FROM AUTHOR]

The management of diabetic patients with end-stage renal disease (ESRD) by either dialysis treatment (peritoneal dialysis [PD] or hemodialysis [HD]) is more complicated than in nondiabetic patients, mainly because of the presence of advanced comorbid conditions associated with the long-term course of diabetes. During the last two decades, improvements in dialysis modalities resulted in longer survival rates in diabetic patients. HD is the most commonly used therapy, whereas the role of PD in renal replacement therapy (RRT) in patients with diabetic nephropathy (DN) is well established. The decision regarding the choice for treatment options (PD vs HD) must be individualized as survival and rehabilitation data among the two modalities are comparable, at least for the first 5 yr after initiation. However, the best outcome of diabetic ESRD patients may be obtained by integrated care, starting with PD and switching to HD if problems arise, and keeping suitable patients on the renal or renal-pancreas transplantation waiting list. [ABSTRACT FROM AUTHOR]

Several factors are important in determining the rate of progression of diabetic renal disease always starting from microalbuminuria (1), and elevated blood pressure (BP) seems to be a major factor, both in types 1 and 2 diabetes (1-3). This was confirmed in a new analysis in the follow-up studies of proteinuric patients conducted by Steno Diabetes Center (2,3). Although the prognosis for diabetic nephropathy has improved in the last two decades, it is clear that proteinuric patients still have a poor prognosis (1). For type 1 diabetes, this analysis (2) showed that elevated BP, glycemic control, and albuminuria were major factors in the progression. Serum cholesterol level also seemed to play some role. The rate of progression in patients with albuminuria and type 2 diabetes is quite similar (3), although it should be noted that patients with type 2 diabetes and proteinuria most often die from cardiovascular (CV) disease before progression to end-stage renal disease (ESRD), even more than patients with type 1 diabetes and albuminuria. [ABSTRACT FROM AUTHOR]

Not so long ago, terminal renal failure used to be a death sentence for the diabetic patient. In 1972, in a famous paper entitled ";The Sad Truth About Hemodialysis in Diabetic Nephropathy,"; Ghavamian arrived at the conclusion that "dialysis for such patients — carries little likelihood of long-term survival or improvement in quality of life" (1). Although survival of uremic diabetic patients has improved dramatically in recent years, such historical experience underlines the particular susceptibility of the diabetic patient to cardiovascular (CV) complications and infectious episodes. [ABSTRACT FROM AUTHOR]

The products of nonenzymatic glycation and oxidation of proteins and lipids are enriched in diabetic tissues. Driven by hyperglycemia and oxidative stress, the production and accumulation of these species result in multiple perturbations in the diabetic kidney. One of these, a "gain-of-function" outcome results from the interaction of advanced glycation endproducts (AGEs) with their signal transduction receptor, RAGE (receptor for AGE). Multiple epidemiological studies support the contention that AGEs are increased in diabetic nephropathy (DN) and may be a biomarker of disease activity. Studies in animal models support the premise that blockade of AGE or RAGE pathways results in significant suppression of diabetes-associated nephropathic changes, including decreases in albuminuria, expansion of the mesangial matrix, and production of prosclerotic cytokines and growth factors. First, studies in human clinical trials targeting the AGE axis provide support for the contribution of AGEs to the pathogenesis of DN. Trials to assess the role of RAGE antagonism are on the horizon. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is currently the leading cause of end-stage renal disease (ESRD) in the United States and most other developed nations. Approximately 40% of new patients who entered ESRD programs in the United States in 2003 had DN; the overall rate of ESRD resulting from diabetes in the United States has risen 68% since 1992 (1). Moreover, even the earliest clinically detected stage of renal injury in diabetes (microalbuminuria) is associated with an increased prevalence of macrovascular disease (2-5). Thus, the mortality, morbidity, and costs associated with DN extend far beyond those directly attributable to ESRD per se. They include costs associated with the increased burden of macrovascular disease seen at earlier stages of DN (2-5). Common pathogenic mechanisms operative in both microvascular and macrovascular injury in diabetes may account at least in part for this association (6,7). [ABSTRACT FROM AUTHOR]

Although anemia is a common problem in patients with chronic kidney disease (CKD), it is only in the last decade that an appreciation of its potential impact in patients with diabetes has emerged (1,2). The prevalence of anemia in patients with diabetes is twice that seen in patients with nondiabetic renal disease and similar renal function. Approximately one in five patients with type 1 or 2 diabetes have hemoglobin (Hb) levels below the gender-specific normal range. Importantly, it is patients with vascular complications that are both at increased risk for anemia, and are most likely to suffer its adverse consequences. [ABSTRACT FROM AUTHOR]

Much of the disease burden in diabetes occurs in patients with diabetic nephropathy (DN), as they have the highest chance of developing cardiovascular disease (CVD) as well as severe retinopathy and neuropathy. Two issues appear crucial in stemming the epidemic of DN and CVD. One is the prevention of diabetes and the solution here from a public health point of view lies in the prevention of obesity. The other is improved understanding of the pathogenesis of renal and vascular disease in diabetes. Here, endothelial dysfunction (ED) is thought to play a key role (1). What is the state of the art regarding this hypothesis? [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (DM) is increasing exponentially; more than 18 million Americans are currently diagnosed, of which more than approx 73% have concomitant hypertension (HTN) (1). Notably, at the time of diagnosis of diabetes, HTN is present in 50% of diabetic patients (2). The presence of diabetic nephropathy (DN) and its clinical hallmark, microalbuminuria (MAU), with concommittant HTN accelerates progression to renal and cardiovascular disease (CVD). CVD risk progresses as DN progresses into chronic kidney disease (CKD) and finally end-stage renal disease (ESRD) requiring renal replacement therapy. Thus, it is then imperative to understand the close relationship that progressive DN has with HTN and concomitant advancing CVD risk. Primary preventive strategies are important to not only prevent DN, but to slow progression once it is present. [ABSTRACT FROM AUTHOR]

Over a nearly 25-yr period beginning in 1979, four "diabetic renal-retinal syndrome" meetings were held in New York City. They were led by Eli Friedman and Francis L'Esperance, who brought together epidemiologists, bench scientists, clinicians, nephrologists, and ophthalmologists involved in research and clinical care of persons with diabetic retinopathy and nephropathy (1-4). The renal-retinal syndrome was defined in these meetings as "coincident kidney and eye diseases resulting from diabetic microvasculopathy in retinal and glomerular arterioles and capillaries" (3). Data from clinical trials over this 25-yr period demonstrated the efficacy of panretinal and focal photocoagulation preventing visual loss owing to proliferative retinopathy and clinically significant macular edema and of intensive glycemic and blood pressure control preventing progression of retinopathy, nephropathy, and other vascular complications associated with diabetes (4-10). Despite this, both retinopathy and nephropathy remain prevalent and are important causes of loss of function and quality of life (11-14). [ABSTRACT FROM AUTHOR]

Prolonged hyperglycemia is the critical etiological factor in the development of the microvascular complications of diabetes including diabetic nephropathy (1-2). The tissues subject to these complications appear to be susceptible by virtue of abundant expression of cell surface facilitative glucose transporters resulting in the transport of glucose down its concentration gradient. The fact that increased glucose uptake and metabolism promotes the pathological changes leading to tissue damage has led to great interest in the pathways of disposition of glucose metabolites and their regulation. There are at least five pathways of glucose metabolism that, either directly or indirectly, appear to contribute to the complications of diabetes. This current concept, reviewed by Brownlee (4), is supported by a number of studies. The increased cellular entry of glucose results first in augmented glycolytic flux and glucose oxidation. A byproduct of mitochondrial substrate metabolism, i.e., electron transport and oxidative phosphorylation, is superoxide, O2-. The increased reactive oxygen species (ROS) production by mitochondria produces oxidative stress, a state in which the formation of ROS exceeds the capacity of cellular endogenous antioxidant removal systems. The excess ROS results in inhibition of the redox-sensitive glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), possibly via activation of poly-ADP-ribose polymerase (5). Poly-ADP-ribose polymerase activation is thought to be owing to ROS-induced DNA damage. [ABSTRACT FROM AUTHOR]

The International Diabetes Federation estimates that the number of people with diabetes worldwide is 171 million and projects that number will increase to 334 million by the year 2030 (1). Most of the increase will be the result of type 2 diabetes (T2DM) and disadvantaged people and those from transitional populations—people undergoing rapid change in their economies, lifestyles, and health—will be affected disproportionately (Fig. 1). Transitional and disadvantaged populations may include people of any race or ethnicity, but those most at risk for T2DM are Asians, Pacific Islanders, Australian Aborigines, African Americans, Hispanics, and Native Americans. These particular populations are also at higher risk for developing diabetic nephropathy (DN). Factors contributing to the high rate of DN in these transitional and disadvantaged populations may include differences in access to health care, genetic susceptibility, and environmental exposures. [ABSTRACT FROM AUTHOR]

As has been discussed elsewhere in this text, diabetes mellitus is the leading cause of end-stage renal disease (ESRD) and the care of patients with diabetes and ESRD contributes significantly to health care costs. Of patients with type 1 diabetes, approx 20-30% will eventually develop ESRD (1-5), whereas about 10-20% of those with type 2 diabetes will do so (2,5-8). In the past couple of decades, there have been notable advances in our knowledge regarding the early stages of diabetic kidney disease, including the advent of interventions that can significantly slow or even reverse the course of progressive disease. In this chapter, we will review the definition and detection of early diabetic kidney disease, its natural history, current proven therapies, and potential future therapies. [ABSTRACT FROM AUTHOR]

This chapter outlines the histopathology of human diabetic nephropathy (DN). The classical structural changes of DN have been well described and demonstrated in general renal and renal pathology textbooks. The emphasis here is on current and evolving studies and concepts in this field. As renal lesions in type 1 diabetes are believed to be more unique to DN and more uniform and as lesions in type 2 diabetes are more heterogeneous and, perhaps, more frequently complicated by renal diseases other than diabetes, this chapter primarily focuses on the structural changes in type 1 diabetes. We will, however, discuss nephropathy of type 2 diabetes and its differences from type 1 diabetes at the end of this chapter. [ABSTRACT FROM AUTHOR]

We are in the midst of a worldwide epidemic of diabetes and hypertension. In the United States, the overall incidence of end-stage kidney disease (ESKD) is increasing at an alarming rate due to this epidemic. Recently, the incidence of ESKD was estimated at 336 per million per year (1), such that the number of patients with ESKD may approach 2.24 million by 2030. Moreover, approx 11% of the population is estimated to have chronic kidney disease (CKD), with nearly half the patients with a glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 (2). Similar estimates for other countries have been described in Europe (3), Japan (4), and Australia (5). The most common form of CKD in all of these countries is diabetic nephropathy (DN), accounting for approx 40% of the new cases of ESKD in developed countries. [ABSTRACT FROM AUTHOR]

Risks for diabetic kidney disease have traditionally focused on those associated with loss of renal function, particularly glomerular filtration rate (GFR). The ultimate consequence of GFR loss, end-stage renal disease (ESRD), has long been the primary domain for many nephrologists. However, loss of renal function also encompasses many aspects other than GFR. A number of comorbidities result from, or are exacerbated by, damage to the kidney: hypertension, anemia, disordered bone and mineral metabolism, dyslipidemia, and inflammation, among others. Many of these disturbances are more prevalent, occur earlier, and are more severe in diabetes than in other forms of chronic kidney disease (CKD) (1-4). Furthermore, they may contribute to further kidney damage, as well as to cardiovascular disease (CVD). The latter issue is of particular concern because most people with diabetes who develop CKD will die of CVD rather than reach ESRD (5). Therefore, kidney damage and associated comorbidities can be viewed as fundamental participants in a self-perpetuating, positive feedback cycle that produces widespread injury to the circulation with multiple target organ consequences. Because diabetes and CKD pose such a high risk of mortality and major adverse events, the purpose of this chapter is to review major risks indicators. Identification of risks allows for development of improved strategies for detection, intervention, and novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) contributes significantly to morbidity and premature mortality in diabetes mellitus (1,2). Whereas the identification of specific environmental factors involved in the development of proteinuria and progressively declining kidney function have led to clinical measures that modify the natural history of the disease (3,4), available interventions (primarily blood glucose control and treatment with renoprotective and antihypertensive drugs) fall short of the ultimate goal of eradicating this complication. The severity of this deficiency is highlighted best by the fact that an epidemic of end-stage renal disease (ESRD) has developed over the past 20 yr, particularly in patients with type 2 diabetes mellitus (T2DM) in the United States, without any signs of leveling off (5). With T2DM becoming more common among young adults and in pediatric populations (6), one may infer that the burden of ESRD in the US population will increase even further unless more effective clinical measures are found. [ABSTRACT FROM AUTHOR]

The sulfonylureas (SULF) have long been utilized as oral agents in the treatment of type 2 diabetes mellitus (1). The primary effect of SULF is the stimulation of insulin secretion following binding to specific SULF receptors (SUR) on pancreatic β-cells. However, SUR have extensive representation in a multitude of extrapancreatic tissues. Therefore, it is not unanticipated that SULF may induce metabolic changes aside from that of insulin secretion. These drugs have been shown to increase glucose uptake and glucose transporter (GLUT) expression in myocytes, adipocytes, and skeletal muscle cells (2-5). Moreover, we have documented significant SULF-induced metabolic effects in cultured rat mesangial cells (MCs), including alterations in mesangial matrix metabolism and MC contractility, independent of their effect on the ambient level of glycemia. The latter effect mimicked that provided by other known MC effectors of contractility, for example, atrial natriuretic peptide and angiotensin II. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPARs), originally cloned in an attempt to identify the molecular mediators of peroxisome proliferation in the liver of rodents, are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily (1,2). To date, three isoforms (PPAR-α, -β/δ, and -gg) have been cloned and characterized by their unique expression patterns, different ligand-binding specificity, and distinct metabolic functions (3). On ligand binding, PPARs form heterodimers with retinoid X receptor (RXR) proteins and bind to PPAR response elements within the promoter regions of target genes. A variety of natural and synthetic ligands for PPARs have been identified. As natural ligands for PPAR-α, some polyunsaturated fatty acids (FAs), oxidized phospholipids, and lipoprotein can activate PPAR-α (4). 15-Deoxy-δ-12, 14-prostaglandin J2 (15dPGJ2s) derived from prostaglandin D2 can activate PPAR-γ as a natural ligand (5). Among synthetic ligands, the hypolipidemic fibrate drugs such as fenofibrate and gemfibrozil bind to PPAR-α (6,7). Thiazolidinediones (TZDs) such as troglitazone, pioglitazone, and rosiglitazone, are well-known synthetic ligands for PPAR-γ (8). PPARs have been reported to regulate diverse cell functions, including FA metabolism, adipocyte differentiation, inflammation, atherosclerosis, and cell cycle (9-12). PPAR-α has an important role in lipid metabolism, especially in the liver (7).It is suggested that PPAR-β/δ carries out the effects in cell survival and carcinogenesis in the colon (13). PPAR-γ plays a pivotal role in adipogenesis and its activation by TZDs improves insulin sensitivity through adipocyte differentiation (14). TZDs have been [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is characterized by accumulation of extracellular matrix (ECM) in the kidney. Glomerular mesangial expansion and tubulo-interstitial fibrosis eventually leads to renal failure. The mediators of renal injury in this disease have not been fully identified. The peptide angiotensin (Ang) II has many hemodynamic and biochemical effects that could contribute to DN (Table 1). A prominent role for Ang II has been suggested by experimental and clinical evidence indicating that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have renoprotective effects and that these agents can attenuate the progression of glomerulosclerosis (1). In clinical studies, as well as studies conducted in experimental diabetic animals, it is difficult to separate hemodynamic from nonhemodynamic effects of Ang II. On the other hand, in vitro studies using cultured cells allow study of the specifically nonhemodynamic effects of Ang II and its inhibition (2). These nonhemodynamic effects of Ang II include stimulation of transforming growth factor (TGF)-β1, activation of matrix protein synthesis, and inhibition of matrix degradation (3,4). Ang II also increases generation of reactive oxygen species (ROS) in mesangial cells (MCs) (5) and may contribute to oxidant-induced renal injury. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) develops in about one-third of patients with diabetes, with genetic and environmental factors both contributing to the development of the disease. Clinical studies have established that hypertension, poor glycemic and lipid control, and smoking (1) increase the risk of the development of the disease. It is clear however, that environmental factors alone are not sufficient for the development of this complication (2). In contrast, the prevalence of diabetic retinopathy continues to rise with the duration of diabetes in most populations. Family studies among type 1 diabetics have shown that if one sibling develops nephropathy, the other sibling has a fourfold increased risk of developing it (3). These observations have clearly established the importance of genetic risk factors in the development of DN. It is likely that the genetic response to hyperglycemia varies among individuals and patients who develop a pattern of excessive regulation of nephropathy-related genes will be the ones at greatest risk of developing^DN. [ABSTRACT FROM AUTHOR]

Chronic renal disease (CRD) has been considered to be irreversible (1). Renal fibrosis, a histological diagnosis of end-stage CRD, is characterized by a loss of renal parenchymal cells that are replaced by extracellular matrix (ECM) proteins, a common final pathway leading to renal dysfunction (1,2). The number of patients affected with CRD is on the increase, and dialysis market estimates indicate that more than 1 million patients worldwide have undergone maintenance dialysis. Thus, many nations are burdened with social and financial problems associated with funding health services for the dialysis of CRD patients (3). Diabetes is now the leading cause of end-stage renal disease (ESRD) in many developed countries, and diabetic nephropathy (DN) has emerged as a silent epidemic worldwide (2,3). This is certainly the case in Japan, in which diabetic kidney disease accounted for 35% of all new patients undergoing dialysis in 2003. To maintain replacement therapy, it now costs nearly $10 million per year in Japan for public financial support. Likewise, in the United States, DN accounted for 35% of all new cases of ESRD in 1997. The physical and monetary costs of diabetic kidney disease to both the patient and society are now enormous. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) remains the major complication of diabetes and the leading cause of end-stage renal disease (ESRD) despite adequate treatment with current available drugs. Better understanding of its pathogenesis and pathophysiology as well as earlier diagnosis is crucial to achieve better therapeutic outcome and to prevent this diabetic complication. Microalbuminuria is the best available noninvasive predictor for the risk of DN (1). However, some patients with microalbuminuria have advanced renal histopathological changes (2-4). Additionally, the conventional assay to detect microalbuminuria measures only immunoreactive form of albumin, whereas the immuno-unreactive albumin is not detectable (5). Therefore, the more sensitive biomarker(s) and/or other laboratory test(s) that can detect all of the albumin isoforms are crucially required. [ABSTRACT FROM AUTHOR]

The pathogenesis of diabetic nephropathy (DN) can be broadly divided into hemodynamic and metabolic causes, but this chapter will focus on the metabolic theories. Among the numerous metabolic derangements in diabetes, the abnormality that plays a central role in the pathogenesis of diabetic renal disease is overactivity of the renal transforming growth factor (TGF)-β system. TGF-β can be thought of as a growth factor or cytokine that causes cellular hypertrophy and stimulates the production of extracellular matrix (ECM), i.e., proteins such as fibronectin, proteoglycans, and several collagen isotypes. These actions are especially relevant to DN, a disease characterized by glomerular and tubular hypertrophy and ECM accumulation. The consequences of matrix buildup manifest as arteriolar hyalinosis, glomerular basement membrane thickening, mesangial matrix expansion (glomerulosclerosis), and tubulo-interstitial fibrosis. In turn, these sclerotic lesions are thought to contribute to progressive renal dysfunction by obliterating the glomerular capillary loops and by displacing or destroying the tubulo-interstitium, causing loss of nephron mass and progressive kidney dysfunction. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is the major cause of end-stage renal disease in the United States and in many other countries (1-3). The development of diabetic nephropathy is thought to occur as a result of an interplay between hemodynamic and metabolic factors (4,5). The various metabolic factors, such as the renal accumulation of advanced glycation end (AGE) products and activation of the polyol pathway, as well as hemodynamic changes, including changes in vasoactive hormones such as the renin-angiotensin system (RAS), act through the stimulation of various intracellular second messengers, cytokines and growth factors to induce end-organ injury (5,6). Vascular endothelial growth factor (VEGF), originally known as vascular permeability factor because of its ability to stimulate vascular permeability, was later shown to have a mitogenic effect in endothelial cells (7,8). Indeed, VEGF was shown to stimulate angiogenesis (8) and has subsequently been postulated to play a role in the pathogenesis of various complications of diabetes (9). In this chapter, we will discuss the role of VEGF, as yet not fully delineated in the development of diabetic nephropathy. [ABSTRACT FROM AUTHOR]