Showing papers by "Mark E. Cooper published in 2001"

Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy

Abstract: Background Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin–angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II–receptor antagonist losartan in patients with type 2 diabetes and nephropathy. Methods A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of prog...

Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE)

Abstract: Tubulointerstitial disease, a prominent phenomenon in diabetic nephropathy, correlates with decline in renal function. The underlying pathogenic link between chronic hyperglycemia and the development of tubulointerstitial injury has not been fully elucidated, but myofibroblast formation represents a key step in the development of tubulointerstitial fibrosis. RAGE, the receptor for advanced glycation end products (AGEs), induces the expression of TGF-beta and other cytokines that are proposed to mediate the transdifferentiation of epithelial cells to form myofibroblasts. Here we report specific binding of (125)I-AGE-BSA to cell membranes prepared from a rat proximal tubule cell line and show that the binding site was RAGE. AGE exposure induced dose-dependent epithelial-myofibroblast transdifferentiation determined by morphological changes, de novo alpha smooth-muscle actin expression, and loss of epithelial E-cadherin staining. These effects could be blocked with neutralizing Ab's to RAGE or to TGF-beta. Transdifferentiation was also apparent in the proximal tubules of diabetic rats and in a renal biopsy from a patient with type 1 diabetes. The AGE cross-link breaker, phenyl-4,5-dimethylthiazolium bromide (ALT 711) reduced transdifferentiation in diabetic rats in association with reduced tubular AGE and TGF-beta expression. This study provides a novel mechanism to explain the development of tubulointerstitial disease in diabetic nephropathy and provides a new treatment target.

PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40(phox).

Abstract: The production of reactive oxygen species (ROS) by neutrophils has a vital role in defence against a range of infectious agents, and is driven by the assembly of a multi-protein complex containing a minimal core of five proteins: the two membrane-bound subunits of cytochrome b(558) (gp91(phox) and p22(phox)) and three soluble factors (GTP-Rac, p47(phox) and p67(phox) (refs 1, 2). This minimal complex can reconstitute ROS formation in vitro in the presence of non-physiological amphiphiles such as SDS. p40(phox) has subsequently been discovered as a binding partner for p67(phox) (ref. 3), but its role in ROS formation is unclear. Phosphoinositide-3-OH kinases (PI(3)Ks) have been implicated in the intracellular signalling pathways coordinating ROS formation but through an unknown mechanism. We show that the addition of p40(phox) to the minimal core complex allows a lipid product of PI(3)Ks, phosphatidylinositol 3-phosphate (PtdIns(3)P), to stimulate specifically the formation of ROS. This effect was mediated by binding of PtdIns(3)P to the PX domain of p40(phox). These results offer new insights into the roles for PI(3)Ks and p40(phox) in ROS formation and define a cellular ligand for the orphan PX domain.

Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy.

Abstract: Diabetic nephropathy seems to occur as a result of an interaction of metabolic and haemodynamic factors. Glucose dependent pathways are activated within the diabetic kidney. These include increased oxidative stress, renal polyol formation and accumulation of advanced glycated end-products. Haemodynamic factors are also implicated in the pathogenesis of diabetic nephropathy and include increased systemic and intraglomerular pressure and activation of various vasoactive hormone pathways including the renin-angiotensin system and endothelin. These haemodynamic pathways, independently and with metabolic pathways, activate intracellular second messengers such as protein kinase C and MAP kinase, nuclear transcription factors such as NF-kappaB and various growth factors such as the prosclerotic cytokine, TGF-beta and the angiogenic, permeability enhancing growth factor, VEGF. These pathways ultimately lead to increased renal albumin permeability and extracellular matrix accumulation which results in increasing proteinuria, glomerulosclerosis and tubulointerstitial fibrosis. Therapeutic strategies involved in the management and prevention of diabetic nephropathy include currently available treatments such as intensified glycaemic control and antihypertensive agents, particularly those which interrupt the renin-angiotensin system. More novel strategies to influence vasoactive hormone action or to inhibit various metabolic pathways such as inhibitors of advanced glycation, specific protein kinase C isoforms and aldose reductase are at present under experimental and clinical investigation. It is predicted that multiple therapies will be required to reduce the progression of diabetic nephropathy.

Irbesartan normalises the deficiency in glomerular nephrin expression in a model of diabetes and hypertension.

Abstract: Aims/hypothesis. The location of nephrin has been identified as the slit-diaphragm of the glomerular podocyte. Recent evidence suggests that nephrin could play a key role in the function of the glomerular filtration barrier and the development of proteinuria but its status in long-term diabetes is still not understood. We studied the expression of nephrin in a hypertensive model of diabetic nephropathy and investigated the potential influence of angiotensin II blockade on nephrin gene and protein expression. Methods. Streptozotocin-diabetic spontaneously hypertensive rats were given either no treatment or the angiotensin II antagonist, irbesartan, at a dose of 15 mg/kg per day by gavage for 32 weeks. Non-diabetic spontaneously hypertensive rats were used as a control group. Real time RT-PCR and immunohistochemistry were used to assess and quantify gene and protein expression of nephrin. Results. Diabetic spontaneously hypertensive rats developed albuminuria and had a reduction in both gene and protein expression of nephrin when compared with control rats. Irbesartan treatment prevented the development of albuminuria and completely abrogated the down regulation of nephrin in diabetic rats. Conclusion/interpretation. Long-term diabetes in spontaneously hypertensive rats is associated with a reduction in both gene and protein expression of nephrin within the kidney. These changes in nephrin levels were completely prevented by angiotensin II antagonist treatment, suggesting a potential novel mechanism to explain the antiproteinuric effect of agents which interrupt the renin-angiotensin system. [Diabetologia (2001) 44: 874–877]

Breeding for low input conditions and consequences for participatory plant breeding: examples from tropical maize and wheat

Abstract: Participatory plant breeding (PPB) has been suggested as an effective alternative to formal plant breeding (FPB) as a breeding strategy for achieving productivity gains under low input conditions. With genetic progress through PPB and FPB being determined by the same genetic variables, the likelihood of success of PPB approaches applied in low input target conditions was analyzed using two case studies from FPB that have resulted in significant productivity gains under low input conditions: (1) breeding tropical maize for low input conditions by CIMMYT, and (2) breeding of spring wheat for the highly variable low input rainfed farming systems in Australia. In both cases, genetic improvement was an outcome of long-term investment in a sustained research effort aimed at understanding the detail of the important environmental constraints to productivity and the plant requirements for improved adaptation to the identified constraints, followed up by the design and continued evaluation of efficient breeding strategies. The breeding strategies used differed between the two case studies but were consistent in their attention to the key determinants of response to selection: (1) ensuring adequate sources of genetic variation and high selection pressures for the important traits at all stages of the breeding program, (2) use of experimental procedures to achieve high levels of heritability in the breeding trials, and (3) testing strategies that achieved a high genetic correlation between performance of germplasm in the breeding trials and under on-farm conditions. The implications of the outcomes from these FPB case studies for realizing the positive motivations for adopting PPB strategies are discussed with particular reference for low input target environment conditions.

Direct and sensitive detection of a human virus by rupture event scanning

Abstract: We have developed a sensitive, economical method that directly detects viruses by making use of the interaction between type 1 herpes simplex virus (HSV1) and specific antibodies covalently attached to the oscillating surface of a quartz crystal microbalance (QCM). The virions were detached from the surface by monotonously increasing the amplitude of oscillation of the QCM, while using the QCM to sensitively detect the acoustic noise produced when the interactions were broken. We term this process rupture event scanning (REVS). The method is quantitative over at least six orders of magnitude, and its sensitivity approaches detection of a single virus particle.

Renoprotective effects of a novel inhibitor of advanced glycation.

Abstract: Aims/hypothesis. ALT-946, an inhibitor of advanced glycation with a minimal inhibitory effect on nitric oxide synthase, was compared with aminoguanidine in experimental diabetic nephropathy.¶Methods. In vitro and in vivo assays were used to assess the ability of ALT-946 to inhibit AGE-protein cross-link formation. Diabetic animals were randomly allocated into groups receiving aminoguanidine for 32 weeks, ALT-946 or vehicle (untreated). As a delayed intervention protocol, an additional diabetic group was treated with ALT-946 from week 16 to week 32 of the study. Non-diabetic rats were studied concurrently. Systolic blood pressure, body weight, plasma glucose, glycated haemoglobin and urinary albumin excretion were measured serially. Accumulation of advanced-glycation end products in the kidney was assessed by immunohistochemistry.¶Results. The ALT-946 inhibitor was more potent than aminoguanidine in inhibiting AGE-protein cross-linking both in vitro and in vivo. Increased albuminuria observed in diabetic rats was attenuated in all three treatment groups. We found no difference in body weight, blood pressure or glycaemic control with any of the treatments. The untreated diabetic group had a twofold increase in glomerular staining for advanced-glycation end products compared with the diabetic groups which received treatment.¶Conclusion/interpretation. ALT-946 is a potent inhibitor of advanced renal glycation end-product accumulation and reproduces the renoprotective effects of aminoguanidine. Therefore, ALT-946 should be considered as a treatment for preventing or retarding diabetic nephropathy. [Diabetologia (2001) 44: 108–114]

A comparison of formal and participatory breeding approaches using selection theory

Abstract: Progress from plant breeding has been slow in some marginal environments Conventional or formal plant breeding (FPB) programs conducted by international agricultural research centres or national programs in developing countries have been criticized for ignoring indigenous germplasm, failing to breed for conditions facing poor farmers, and emphasizing selection for broad versus local adaptation A suite of techniques, referred to as participatory plant breeding (PPB) and including farmer-participatory or farmer-led selection, on-farm evaluation, and use of local landraces, has been advocated in response to this critique PPB programs are diverse in scope and approach, but often rely heavily on farmer visual evaluation or phenotypic mass selection to select for simply-inherited traits, with limited replicated yield testing in multiple-environment trials (MET), one of the main tools of FPB Prediction equations derived from selection theory can be used to examine the conditions under which idealized versions of FPB and PPB may be expected to achieve genetic progress for traits such as yield The effectiveness of any selection environment is determined by both the genetic correlation between genotype performance in it and the target environment (r G) and the heritability of genotypic differences in the selection environment (H s) r is a measure of the accuracy with which performance of genotypes in the selection environment predicts performance in the target environment; H s is a measure of the precision with which performance differences among genotypes can be measured in the selection environment We compare FPB and PPB with respect to these determinants of selection response, using examples from self-pollinated species Particular areas examined include: (i) selection for broad versus specific adaptation; (ii) on-station versus on-farm selection; and (iii) selection under high-yield versus low-yield conditions In general, PPB systems attempt to maximize gains through the use of on-farm evaluation and the skills of farmer-selectors to maximize r G FPB exploits METs to maximize H s PPB is most likely to develop cultivars that out-perform the products of FPB when it is applied in low-yield cropping systems, because it is in such situations that r G between high-yield breeding nurseries and low-yield target environments is likely to be low or negative To make continued gains, and to compete with internationally-supported FPB programs, PPB systems will need to counter the obscuring effects of uncontrollable within-field, site-to-site, and year-to-year heterogeneity Simple and robust designs for on-farm METs are needed for this purpose

Podocyte foot process broadening in experimental diabetic nephropathy: amelioration with renin-angiotensin blockade.

Abstract: Aims/hypothesis. Changes in podocyte number and morphology have been implicated in the pathogenesis of proteinuria and the progression of human and experimental kidney disease. This study sought to examine podocyte foot process and slit pore architecture in experimental diabetic nephropathy and to determine whether such changes were modified with renoprotective intervention by blockade of the renin-angiotensin system. Methods. The number of filtration slits per 100 μm of glomerular basement membrane was assessed by transmission electron microscopy and quantitated histomorphometrically in control animals and in rats with 24 weeks of streptozotocin-induced diabetes. Diabetic rats were either untreated or received the angiotensin converting enzyme inhibitor ramipril, or the angiotensin II type 1 receptor antagonist, valsartan. Results. When compared with control animals, diabetes was associated with a decrease in the number of slit pores per unit length of glomerular basement membrane, indicative of podocyte foot process broadening. Both ramipril and valsartan attenuated these ultrastructural changes to a similar degree. These differences remained after correcting for glomerular volume as a possible confounding variable. Conclusion/interpretation. Preservation of podocyte architecture could contribute to the renoprotective effects of renin-angiotensin system blockade in diabetic nephropathy. [Diabetologia (2001) 44: 878–882]

Aminoguanidine Ameliorates Overexpression of Prosclerotic Growth Factors and Collagen Deposition in Experimental Diabetic Nephropathy

Abstract: Profibrotic cytokines and the formation of advanced-glycation end products (AGE) have both been implicated in the pathogenesis of glomerulosclerosis in diabetic kidney disease. However, tubulointerstitial pathology is also an important determinant of progressive renal dysfunction in diabetic nephropathy. This study sought to investigate the expression of profibrotic growth factors and matrix deposition in the glomerulus and the tubulointerstitium and to examine the effect of blocking AGE formation in experimental diabetic nephropathy. Thirty-six male Sprague-Dawley rats were randomized into control and diabetic groups. Diabetes was induced in 24 rats by streptozotocin. Twelve diabetic rats were further randomized to receive the inhibitor of AGE formation, aminoguanidine (1 g/l drinking water). At 6 mo, experimental diabetes was associated with a three-fold increase in expression of transforming growth factor (TGF)-beta1 (P < 0.01 versus control) and five-fold increase in platelet-derived growth factor (PDGF)-B gene expression (P < 0.01 versus control) in the tubulointerstitium. In situ hybridization demonstrated a diffuse increase in both TGF-beta1 and PDGF-B mRNA in renal tubules. Aminoguanidine attenuated not only the overexpression of TGF-beta1 and PDGF-B but also reduced type IV collagen deposition in diabetic rats (P < 0.05). TGF-beta1 and PDGF mRNA within glomeruli were also similarly increased with diabetes and attenuated with aminoguanidine. The observed beneficial effects of aminoguanidine on the tubulointerstitium in experimental diabetes suggest that AGE-mediated expression of profibrotic cytokines may contribute to tubulointerstitial injury and the pathogenesis of diabetic nephropathy.

FENS-1 and DFCP1 are FYVE domain-containing proteins with distinct functions in the endosomal and Golgi compartments.

Abstract: FENS-1 and DFCP1 are recently discovered proteins containing one or two FYVE-domains respectively. We show that the FYVE domains in these proteins can bind PtdIns3P in vitro with high specificity over other phosphoinositides. Exogenously expressed FENS-1 localises to early endosomes: this localisation requires an intact FYVE domain and is sensitive to wortmannin inhibition. The isolated FYVE domain of FENS-1 also localises to endosomes. These results are consistent with current models of FYVE-domain function in this cellular compartment. By contrast, exogenously expressed DFCP1 displays a predominantly Golgi, endoplasmic reticulum (ER) and vesicular distribution with little or no overlap with FENS-1 or other endosomal markers. Overexpression of DFCP1 was found to cause dispersal of the Golgi compartment defined by giantin and gpp130-staining. Disruption of the FYVE domains of DFCP1 causes a shift to more condensed and compact Golgi structures and overexpression of this mutant was found to confer significant protection to the Golgi against brefeldin-induced dispersal. These properties of DFCP1 are surprising, and suggest FYVE domain-localisation and function may not be exclusively endosomal.

New constraints on the origin of the Australian Great Barrier Reef: results from an international project of deep coring

Abstract: Two new boreholes provide the first direct evidence of the age of the Australian Great Barrier Reef An inner shelf sequence (total depth, 86 m; basal age = 210 ± 40 ka) comprises a dominantly siliciclastic unit (thickness 52–86 m), overlain by four carbonate units (total thickness 0–34 m) A shelf-edge and slope sequence (total depth 210 m) reveals three major sections: (1) a lower section of resedimented flows deposited on a lower slope, (2) a mid-section including intervals of corals, rhodoliths, and calcarenites with low- angle graded laminae, and (3) an upper section of four shelf- margin coral-reef units separated by karst surfaces bearing paleosols Sr isotope and magnetostratigraphic data indicate that the central Great Barrier Reef is relatively young (post Bruhnes-Matuyama boundary time), and our best estimate for the onset of reef growth on the outer barrier system is ca 600 ± 280 ka This date suggests that reef initiation may have been related to the onset of full eccentricity-dominated glacio-eustatic sea-level oscillation as inferred from large-amplitude “saw-tooth? 100 ky ?18O cycles (after marine isotope stage 17), rather than to some regional environmental parameter A major question raised by our study is whether reef margins globally display a similar growth history The possibility of a global reef initiation event has important implications for basin to shelf partitioning of CaCO3, atmospheric carbon dioxide levels, and global temperature change during Quaternary time

Vascular expression of angiotensin type 2 receptor in the adult rat: influence of angiotensin II infusion.

Abstract: Objective The aim of this study was to investigate the relative role of the angiotensin type 1 (AT 1 ) and type 2 (AT 2 ) receptors in mediating angiotensin II-induced regulation of AT 2 receptor in mesenteric artery. Design Sprague-Dawley rats were infused with either angiotensin II or vehicle for 14 days at a dose of 58.3 ng/ min. Ang II-infused rats were allocated to receive either an AT 1 antagonist, valsartan at a dose of 30 mg/kg per day or the AT 2 receptor antagonist PD123319 at a dose of 830 ng/min. Methods Gene and protein expression of the AT 2 receptor in the mesenteric vasculature was assessed by quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry and by in vitro autoradiography with a specific radioligand, 125 I-CGP 42112B. Results The AT 2 receptor mRNA and protein were detected in the mesenteric artery from adult rats. Both nuclear emulsion and immunohistochemical staining showed expression of the AT 2 receptor in the adventitial and medial layers. Compared to control rats, angiotensin II infusion was associated with a significant increase in the AT 2 receptor expression. Valsartan treatment significantly reduced AT 2 receptor gene expression, with no significant effect of PD123319 on this parameter. Conclusions This study confirms that the presence of the AT 2 receptor in mesenteric arteries in adult rats, shows an up-regulation of the AT 2 receptor following angiotensin II infusion and suggests a role for the AT 1 receptor in this regulation. In view of the recently demonstrated effects of the AT 2 receptor, these findings may be relevant to the role of the AT 2 receptor in the pathophysiology of vascular remodeling.

Some vocabulary and grammar for the analysis of multi-environment trials, as applied to the analysis of FPB and PPB trials

Abstract: For the improvement of genetic material suitable for on farm use under low-input conditions, participatory and formal plant breeding strategies are frequently presented as competing options. A common frame of reference to phrase mechanisms and purposes related to breeding strategies will facilitate clearer descriptions of similarities and differences between participatory plant breeding and formal plant breeding. In this paper an attempt is made to develop such a common framework by means of a statistically inspired language that acknowledges the importance of both on farm trials and research centre trials as sources of information for on farm genetic improvement. Key concepts are the genetic correlation between environments, and the heterogeneity of phenotypic and genetic variance over environments. Classic selection response theory is taken as the starting point for the comparison of selection trials (on farm and research centre) with respect to the expected genetic improvement in a target environment (low-input farms). The variance-covariance parameters that form the input for selection response comparisons traditionally come from a mixed model fit to multi-environment trial data. In this paper we propose a recently developed class of mixed models, namely multiplicative mixed models, also called factor-analytic models, for modelling genetic variances and covariances (correlations). Mixed multiplicative models allow genetic variances and covariances to be dependent on quantitative descriptors of the environment, and confer a high flexibility in the choice of variance-covariance structure, without requiring the estimation of a prohibitively high number of parameters. As a result detailed considerations regarding selection response comparisons are facilitated. The statistical machinery involved is illustrated on an example data set consisting of barley trials from the International Center for Agricultural Research in the Dry Areas (ICARDA). Analysis of the example data showed that participatory plant breeding and formal plant breeding are better interpreted as providing complementary rather than competing information.

Pathogenesis and intervention strategies in diabetic retinopathy

Abstract: Diabetic retinopathy is the leading cause of new blindness in the working-age population. If improved treatment regimens are to be developed it is crucial that the underlying pathophysiological mechanisms responsible for diabetic retinopathy are better understood. The multifactorial nature of the many pathways implicated in diabetic retinopathy requires a very detailed approach to elucidate the key mechanisms involved and their interactions in order to develop logical strategies aimed at therapeutic intervention. Fortunately, the streptozotocin rat model of diabetes displays many of the morphological and functional changes to the retinal vasculature that are evident in human diabetic retinopathy. This study reviews some of the recent experimental work by the authors in the streptozotocin rat, compares their findings to the human pathology and outlines potential new avenues for therapeutic intervention. In particular the improved understanding of which layers of the inner retina have the most stringent metabolic demands has helped identify which retinal layers are most susceptible to metabolic or hypoxic/ischaemic insult. It is concluded that improved treatment outcomes may ensue if the therapy is targeted at the appropriate tissue at specific stages of the disease.

Additive hypotensive and anti-albuminuric effects of angiotensin-converting enzyme inhibition and angiotensin receptor antagonism in diabetic spontaneously hypertensive rats

Abstract: Angiotensin II plays a pivotal role in the development of diabetic nephropathy, but it remains controversial as to the best approach to effectively block the actions of this hormone in the kidney. The aim of the present study was to explore the effects of long-term treatment (8 months) with a combination of an angiotensin type 1 (AT1) receptor antagonist, irbesartan (15 mg/kg per day), and an angiotensin-converting enzyme (ACE) inhibitor, captopril (100 mg/kg per day), in diabetic spontaneously hypertensive rats. Captopril treatment reduced blood pressure (163+/-3 mmHg versus diabetic 201+/-3 mmHg), but not albumin excretion rate (43.8x//1.3 mg/day versus diabetic 46.8x//1.4 mg/day). Irbesartan treatment was associated with a similar reduction in blood pressure (173+/-3 mmHg) to captopril, and albumin excretion rate was reduced (14x//1.5 mg/day). The combination of irbesartan and captopril induced further reductions in blood pressure (140+/-3 mmHg) and albumin excretion rates (4.0x//1.5 mg/day). Gene expression of transforming growth factor beta-1 was reduced by all treatments to a similar level as assessed by in situ hybridization. These results demonstrate the additive hypotensive and anti-albuminuric effects of an ACE inhibitor and an AT1 receptor, suggesting that combination therapy is an approach not only more effective at reducing blood pressure, but also at retarding the development of diabetic nephropathy.

Renoprotective and anti-hypertensive effects of combined valsartan and perindopril in progressive diabetic nephropathy in the transgenic (mRen-2)27 rat.

Abstract: Background We have previously reported that severe glomerulosclerosis progressively develops in the streptozotocin (STZ) diabetic transgenic (mRen-2)27 rat. In this diabetic model, monotherapy with either angiotensin converting enzyme inhibition (ACEI) or angiotensin type 1 (AT(1)) receptor blockade is largely renoprotective. The objective of the present study was to determine if a combination therapy at lower doses than monotherapy would confer greater renoprotection. Methods At 6 weeks of age, non-diabetic control and STZ diabetic female heterozygous Ren-2 rats were randomized to receive vehicle, the AT(1) receptor blocker valsartan (V, 20 mg/kg/day), the ACEI perindopril (P, 6 mg/kg/day), or a combination of low-dose V+P (V, 3 mg/kg/day plus P, 0.5 mg/kg/day) for 12 weeks. Results Systolic blood pressure was lowered with all treatments, but the greatest reductions were observed with V monotherapy and combination V+P therapy. All treatments reduced albuminuria, the decline in glomerular filtration rate, and cortical collagen staining, to the same extent. The glomerulosclerotic index was increased with diabetes and reduced with V and P monotherapy. However, the low-dose combination therapy was more effective than single therapy and reduced severe glomerulosclerosis to levels observed in non-diabetic controls. Conclusions Monotherapy with either V or P reduced blood pressure and retarded the decline in renal function and glomerulosclerosis in the diabetic Ren-2 rat. Combination therapy has the additional benefit of requiring only low doses of AT(1) receptor blockade and ACEI to achieve superior renoprotective effects in this diabetic nephropathy model.

Power of the joint segregation analysis method for testing mixed major-gene and polygene inheritance models of quantitative traits

Abstract: Understanding the genetic architecture of quantitative traits can greatly assist the design of strategies for their manipulation in plant-breeding programs. For a number of traits, genetic variation can be the result of segregation of a few major genes and many polygenes (minor genes). The joint segregation analysis (JSA) is a maximum-likelihood approach for fitting segregation models through the simultaneous use of phenotypic information from multiple generations. Our objective in this paper was to use computer simulation to quantify the power of the JSA method for testing the mixed-inheritance model for quantitative traits when it was applied to the six basic generations: both parents (P-1 and P-2), F-1, F-2, and both backcross generations (B-1 and B-2) derived from crossing the F-1 to each parent. A total of 1968 genetic model-experiment scenarios were considered in the simulation study to quantify the power of the method. Factors that interacted to influence the power of the JSA method to correctly detect genetic models were: (1) whether there were one or two major genes in combination with polygenes, (2) the heritability of the major genes and polygenes, (3) the level of dispersion of the major genes and polygenes between the two parents, and (4) the number of individuals examined in each generation (population size). The greatest levels of power were observed for the genetic models defined with simple inheritance; e.g., the power was greater than 90% for the one major gene model, regardless of the population size and major-gene heritability. Lower levels of power were observed for the genetic models with complex inheritance (major genes and polygenes), low heritability, small population sizes and a large dispersion of favourable genes among the two parents; e.g., the power was less than 5% for the two major-gene model with a heritability value of 0.3 and population sizes of 100 individuals. The JSA methodology was then applied to a previously studied sorghum data-set to investigate the genetic control of the putative drought resistance-trait osmotic adjustment in three crosses. The previous study concluded that there were two major genes segregating for osmotic adjustment in the three crosses. Application of the JSA method resulted in a change in the proposed genetic model. The presence of the two major genes was confirmed with the addition of an unspecified number of polygenes.

Apoptosis and angiotensin II: yet another renal regulatory system?

Abstract: Apoptosis plays a key role in the regulation of normal renal structure and kidney remodeling in various renal diseases. Angiotensin II plays a prominent role in renal injury through its receptor subtypes, the type 1 (AT1) receptor and the type 2 (AT2) receptor, which involve different molecular mechanisms. In addition to its haemodynamic actions, angiotensin II induces apoptosis. Angiotensin II also increases proliferation in the kidney. A close correlation between renal cell proliferation and apoptosis has been shown in renal diseases as well as in the angiotensin II infusion model. Angiotensin induces upregulation of p53 and other pro-apoptotic proteins. Recent studies suggest that both AT1 and AT2 receptors influence the apoptotic process in the kidney. These apoptotic effects of angiotensin II should be considered as representing another regulatory mechanism that may modulate the balance between cell growth and proliferation within the kidney.

A convenient method for the aromatic amino-Claisen rearrangement of N-(1,1-disubstituted-allyl)anilines

Abstract: N-(1, 1-Disubstituted-allyl)anilines are rearranged cleanly and in high yield to 2-(3,3-disubstituted-allyl)anilines using a catalytic amount of p-toluenesulfonic acid in acetonitrile/water (10:1).

Antibacterial agents comprising conjugates of glycopeptides and peptidic membrane-associating elements

Abstract: The invention concerns agents with anti-bacterial activity and methods and intermediates for their production. The present invention further concerns the use of such agents for the treatment of bacterial infections in animals, including man. The agents are derivatives of vancomycin-type antibiotics, of structure: V-L-W-X; wherein V is a glycopeptide moiety which inhibits peptidoglycan biosynthesis in bacteria; L is a linking group; W is a peptidic membrane-associating element such as an element based on naturally-occurring animal or bacterial peptide antibiotics; and X is hydrogen or a membrane-insertive element.