Showing papers by "Mark E. Cooper published in 1998"
TL;DR: Specific inhibitors of the various pathways are now available, enabling investigation of the role of these processes in the pathogenesis of diabetic nephropathy and potentially to provide new therapeutic approaches for the prevention and treatment of diabetic nephropathy.
530 citations
TL;DR: High dietary salt led to widespread fibrosis and increased TGF-beta1 in the heart and kidney in normotensive and hypertensive rats, and further suggest that excessive salt intake may be an important direct pathogenic factor for cardiovascular disease.
Abstract: Background—The detrimental effects of high dietary salt intake may not only involve effects on blood pressure and organ hypertrophy but also lead to tissue fibrosis independently of these factors. Methods and Results—The effect of a normal (1%) or high (8%) sodium chloride diet on myocardial and renal fibrosis was assessed by quantitative histomorphometry in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKYs). The effect of salt on transforming growth factor-β1 (TGF-β1) gene expression was assessed by Northern blot hybridization. A high-salt diet from 8 to 16 weeks of age resulted in increased blood pressure and left ventricular and renal hypertrophy in both WKYs and SHRs. Marked interstitial fibrosis was demonstrated in the left ventricle (LV), glomeruli, and renal tubules and in intramyocardial arteries and arterioles but not in the right ventricle. The collagen volume fraction increased significantly after high-salt diet in the LV, intramyocardial arteries and arterioles, g...
335 citations
TL;DR: The observed beneficial effects of ramipril on the tubulointerstitium in experimental diabetes suggest that this mechanism may contribute to the therapeutic effect of ACE inhibitors in diabetic nephropathy.
Abstract: Transforming growth factor-beta (TGF-beta) and the renin-angiotensin system (RAS) have both been implicated in the pathogenesis of glomerulosclerosis in diabetic kidney disease. However, tubulointerstitial pathology may also be an important determinant of progressive renal dysfunction in diabetic nephropathy. In the present study, we investigated tubulointerstitial injury, TGF-beta1 expression, and the effect of blocking the RAS by inhibition of ACE. We randomized 36 male SD rats to control and diabetic groups. Diabetes was induced in 24 rats by administration of streptozotocin; 12 diabetic rats were further randomized to receive the ACE inhibitor ramipril (3 mg/l drinking water). At 6 months, experimental diabetes was associated with tubulointerstitial damage, a 70% increase in expression of TGF-beta1 (P < 0.05 vs. control), and a 120% increase in alpha1 (IV) collagen gene expression (P < 0.01 vs. control). In situ hybridization demonstrated a diffuse increase in both TGF-beta1 and alpha1 (IV) collagen mRNA in renal tubules. In addition, intense expression of both transcripts was noted in regions of focal tubular dilatation. Administration of the ACE inhibitor ramipril prevented tubulointerstitial injury and the overexpression of TGF-beta1 and alpha1 (IV) collagen mRNA. Changes in gene expression were accompanied by parallel changes in immunostaining for TGF-beta1 and type IV collagen. The observed beneficial effects of ramipril on the tubulointerstitium in experimental diabetes suggest that this mechanism may contribute to the therapeutic effect of ACE inhibitors in diabetic nephropathy.
204 citations
Journal Article•
TL;DR: The changes in retinal expression of VEGF and VEGFR-2 in association with diabetes suggest a role for this pathway in diabetic retinopathy.
175 citations
TL;DR: The E(N:K) framework enables the generation of families of genetic models that incorporate the effects of genotype-by-environment (G x E) interactions and epistasis and the structure of the QU-GENE simulation software is explained and demonstrated.
Abstract: Classical quantitative genetics theory makes a number of simplifying assumptions in order to develop mathematical expressions that describe the mean and variation (genetic and phenotypic) within and among populations, and to predict how these are expected to change under the influence of external forces. These assumptions are often necessary to render the development of many aspects of the theory mathematically tractable. The availability of high-speed computers today provides opportunity for the use of computer simulation methodology to investigate the implications of relaxing many of the assumptions that are commonly made. QU-GENE (QUantitative-GENEtics) was developed as a flexible computer simulation platform for the quantitative analysis of genetic models. Three features of the QU-GENE software that contribute to its flexibility are (i) the core E(N:K) genetic model, where E is the number of types of environment, N is the number of genes, K indicates the level of epistasis and the parentheses indicate that different N:K genetic models can be nested within types of environments, (ii) the use of a two-stage architecture that separates the definition of the genetic model and genotype-environment system from the detail of the individual simulation experiments and (iii) the use of a series of interactive graphical windows that monitor the progress of the simulation experiments. The E(N:K) framework enables the generation of families of genetic models that incorporate the effects of genotype-by-environment (G x E) interactions and epistasis. By the design of appropriate application modules, many different simulation experiments can be conducted for any genotype-environment system. The structure of the QU-GENE simulation software is explained and demonstrated by way of two examples. The first concentrates on some aspects of the influence of G x E interactions on response to selection in plant breeding, and the second considers the influence of multiple-peak epistasis on the evolution of a four-gene epistatic network. QU-GENE is available over the Internet at (http://pig.ag.uq.edu.au/qu-gene/) m.cooper@mailbox.uq.edu. au
174 citations
TL;DR: A role for an activated renal RAS in the acceleration of diabetic renal disease is suggested and the benefit of drugs that inhibit this system is confirmed.
164 citations
TL;DR: Conditions for the formation of lipid monolayers have been optimised with respect to lipid type, chemical and buffer compatibility, ligand stability and reproducibility.
123 citations
TL;DR: Local proliferation is an important mechanism in both macrophage and myofibroblast accumulation during the development of renal injury in the rat remnant kidney and is postulated as a mechanism for amplifying kidney damage in nonimmune renal injury.
Abstract: BACKGROUND We have recently shown that blockade of angiotensin II activity inhibits local macrophage and myofibroblast proliferation in progressive non-immune renal injury in the rat remnant kidney. However, it is not known whether this local proliferation contributes to macrophage and myofibroblast accumulation and the development of renal injury. Therefore, we examined this issue in a detailed time-course study of the rat remnant kidney. METHODS Groups of five rats were killed 4, 8,12 or 16 weeks after 5/6 subtotal nephrectomy (STNx) or a sham operation. Macrophage and myofibroblast proliferation was assessed by two-colour immunostaining for ED1+ macrophages or alpha-smooth muscle actin (alpha-SMA)-positive myofibroblasts with the proliferating cell nuclear antigen (PCNA) or bromodeoxyuridine. RESULTS All parameters of renal function and histology remained normal in the sham-operated controls, and no macrophage or myofibroblast accumulation was evident. In contrast, prominent macrophage accumulation developed in both the glomerulus and tubulointerstitium in STNx animals, peaking at week 12. Many ED1+ macrophages showed PCNA expression, accounting for 19-34% of the total macrophage population. There was a highly significant correlation between proliferating macrophages and total macrophage accumulation in the glomerulus (r = 0.82, P < 0.0001) and tubulointerstitium (r = 0.70, P < 0.001). Macrophage proliferation was largely restricted to focal areas of renal damage, such as glomerular segmental lesions and severe tubulointerstitial damage. Also, the subpopulation of proliferating macrophages gave a highly significant correlation with loss of renal function, proteinuria, and glomerular and tubulointerstitial lesions. In addition, many alpha-SMA myofibroblasts were evident within expanded mesangial areas and the tubulointerstitium following STNx. Interestingly, active lesions contained many large alpha-SMA+ cells double-stained for PCNA, accounting for 24-29% of total myofibroblasts. There was a highly significant correlation between the number of proliferating myofibroblasts and total myofibroblast accumulation during the evolution of this disease, and both populations correlated with progressive renal injury. CONCLUSIONS This study has shown that local proliferation is an important mechanism in both macrophage and myofibroblast accumulation during the development of renal injury in the rat remnant kidney. In addition, local macrophage proliferation is postulated as a mechanism for amplifying kidney damage in nonimmune renal injury.
102 citations
TL;DR: Findings support the hypothesis that biologically active TGF- β plays a pathogenetic role in diabetic kidney disease and suggest that β ig-h3 may be a useful index of T GF- β 1 bioactivity in the kidney.
83 citations
TL;DR: The importance of the various components, particularly with regard to the progression of DN, is currently being explored with the assistance of targeted drug intervention studies.
Abstract: Diabetic nephropathy (DN) is now the commonest cause of end-stage renal failure in the Western world. Recent studies examining the pathogenesis of diabetic complications have focused on the complex interaction between genetic and hemodynamic mechanisms in addition to metabolic factors such as advanced glycation, protein kinase C (PKC) activation, and polyol production. The importance of the various components, particularly with regard to the progression of DN, is currently being explored with the assistance of targeted drug intervention studies.
68 citations
TL;DR: The data suggest that advanced glycation may participate in atherogenesis and raise the possibility that inhibitors of advanced glycoxylation may retard this process.
TL;DR: The results suggest that after binding to M. sexta APN, the Cry1Ac toxin undergoes a rate-limiting step leading to a high-affinity state, and this inability to form an irreversible association with the APN-lipid monolayer helps explain the lack of toxicity of this protein towards M. Sexta larvae and its deficient membrane-permeabilizing activity.
Abstract: The Bacillus thuringiensis Cry1Ac δ-endotoxin was shown to bind in a biphasic manner to Manduca sexta aminopeptidase N (APN) present in a novel model membrane. Surface plasmon resonance analysis allowed the quantification of toxin binding to M. sexta APN in a supported lipid monolayer. The initial binding was rapid and reversible, with an affinity constant of 110 nM. The second phase was slower and resulted in an overall affinity constant of 3.0 nM. Reagents used to disrupt protein–protein interactions did not dissociate the toxin after high-affinity binding was attained. The initial association between Cry1Ac and APN was inhibited by the sugar GalNAc, but the higher-affinity state was resistant to GalNAc-induced dissociation. The results suggest that after binding to M. sexta APN, the Cry1Ac toxin undergoes a rate-limiting step leading to a high-affinity state. A site-directed Cry1Ac mutant, N135Q, exhibited a similar initial binding affinity for APN but did not show the second slower phase. This inability to form an irreversible association with the APN-lipid monolayer helps explain the lack of toxicity of this protein towards M. sexta larvae and its deficient membrane-permeabilizing activity on M. sexta midgut brush border membrane vesicles.
TL;DR: It is suggested that the action of AG in restoring the number of nNOS-containing retinal neurons is mediated by the inhibition of AGE formation, which may contribute to alterations in the autoregulation of blood flow which occurs in diabetes.
Abstract: A close association of neuronal nitric oxide synthase-immunoreactive (nNOS-IR) neurons with the retinal vasculature has been reported and it is proposed that activation of these neurons could be the mechanism by which retinal blood flow and metabolism are linked. Further, advanced glycation end products (AGEs) have previously been shown to be increased in the diabetic retina and aminoguanidine (AG), an inhibitor of advanced glycation, has been shown to attenuate the development of AGE accumulation as well as the progression of experimental diabetic retinopathy. This study examined the effects of short (1 and 3 weeks) and long term (32 weeks) diabetes on nNOS-containing neurons of the retina using NADPH diaphorase (NADPHd) histochemistry. In addition, the effect of aminoguanidine (an inhibitor of advanced glycation and NOS) and NG-nitro-L-arginine methyl ester (L-NAME) (a non-selective NOS inhibitor) on retinal nNOS-containing neurons was examined in short and long term control and diabetic rats. In a separate study, the effect of 2,3 diamino-phenazine (NN0028) (an inhibitor of advanced glycation, but not NOS) was examined in short term (3 weeks) diabetic rats. The number of NADPHd-positive neurons per retina was reduced after one week of diabetes and remained decreased in long term diabetic rats, an effect not observed in diabetic rats rendered euglycaemic by intensified insulin treatment. Treatment of diabetic animals with aminoguanidine or NN0028 prevented the depletion in the nNOS-containing neuron number, an effect not reproduced by L-NAME. These studies suggest that the action of AG in restoring the number of nNOS-containing retinal neurons is mediated by the inhibition of AGE formation. The depletion of nNOS-containing neurons may contribute to alterations in the autoregulation of blood flow which occurs in diabetes. [Diabetologia (1998) 41: 1419–1425]
TL;DR: This is the first study to determine the ED50 of intrathecal sufentanil in spontaneously laboring nulliparous patients, and as dose‐response curves are determined for other labor analgesics, future studies can compare equianalgesic doses or dose combinations.
Abstract: BACKGROUND Intrathecal sufentanil provides effective analgesia during the first stage of labor. A range of doses has been reported to provide adequate pain relief. This study determined the dose of intrathecal sufentanil that produced acceptable pain relief in 50% of nulliparous patients (ED50) who requested labor analgesia. METHODS With institutional review board approval, 50 nulliparous patients requesting spinal opioid labor analgesia were enrolled into this prospective, randomized, double-blinded study. Each patient was in spontaneous labor at <5 cm cervical dilation. Patients received one of the following doses of intrathecal sufentanil: 1, 2, 3, 5, or 10 microg in 3 ml preservative-free saline (n = 10 for each dose). Pain, pain relief, hemodynamic, respiratory, and side effect data were collected at times 0, 2, 5, 10, 15, 20, 25, and 30 min. Probit analysis of the number of patients in each group who requested additional pain medicine at 30 min was used to determine the ED50. RESULTS The groups were demographically similar. The ED50 of intrathecal sufentanil was 1.8 microg (SE, 0.6 microg; 95% CI, 2.96 to 0.54 microg). The incidence of side effects was similar among the groups. CONCLUSIONS This is the first study to determine the ED50 of intrathecal sufentanil in spontaneously laboring nulliparous patients. As dose-response curves are determined for other labor analgesics, future studies can compare equianalgesic doses or dose combinations.
TL;DR: The results indicate that the move to midge resistant hybrids has been associated with a narrowing of the genetic diversity and average heterozygosity of commercial sorghum hybrids, which may have implications for the genetic vulnerability of Sorghum in Australia.
Abstract: In recent years, hybrids with levels of resistance to sorghum midge (Stenodiplosis sorghicola Coquillett) have become available to Australian sorghum producers. These hybrids have been readily accepted to the extent that more than 80% of the sorghum growing area was planted to hybrids with some level of midge resistance by 1995. Since selection for resistance to sorghum midge is one of the primary objectives of Australian sorghum breeding programs, the relationship between resistance and genetic diversity was investigated. Genetic diversity and heterozygosity were assessed using restriction fragment length polymorphism analysis among 26 grain sorghum hybrids grown commercially in Australia. The genetic distances between each sorghum hybrid and a standard highly resistant hybrid were found to be strongly negatively correlated to hybrid midge resistance ratings (r = - 0.77, p < 0.001). In addition, the average heterozygosity of each hybrid was correlated with their midge resistance ratings (r = - 0.54, p < 0.01). The results indicate that the move to midge resistant hybrids has been associated with a narrowing of the genetic diversity and average heterozygosity of commercial sorghum hybrids. Repeated use of particular elite parent lines, linkage drag and genetic drift are likely to have contributed to this decline. This reduction in genetic diversity may have implications for the genetic vulnerability of sorghum in Australia and the rate of progress in breeding for yield.
TL;DR: It is suggested that amylin peptide is biosynthesized in the developing proximal tubules, acts in an autocrine fashion to promote the proliferation and differentiation of brush border epithelial cells and hence plays an important role as a growth factor in the development of the kidney.
TL;DR: The late-∞owering hybrids escaped the major impact of the pre-anthesis water stress, had reduced damage to panicle development, and had higher N utilisation, consequently producing higher grain yield.
Abstract: Sorghum (Sorghum bicolor (L.) Moench) is often grown under nitrogen- or water-limited conditions, but there is little information on genotypic variation for grain yield and grain nitrogen (N) concentration under these conditions. This study examined the expression of speciflc adaptation of hybrids to these stress conditions and, secondly, the efiect of N fertiliser application on yield and grain N concentration of the hybrids. Two experiments, one irrigated and the other under rainfed conditions, were conducted in 2 seasons to examine 14 hybrids grown under 3 levels of fertiliser N supply (0, 60, and 240 kg/ha). Genotypic variation for yield and grain N concentration was generally larger than the in∞uence of genotype£environment (predominantly N and water) interactions. Genotypic variation for phenology was important in determining variation for yield and grain N concentration in high-input and rainfed conditions when N was not the limiting factor, but not under N-limiting conditions. Under high-input conditions (240 kg/ha of N fertiliser and irrigated), maturity date accounted for about 50% of the genotypic variation for grain yield (798{1049 g/m 2 ), with later maturing hybrids having a higher yield. Maturity date had little efiect on plant N content at maturity or N harvest index, and hence grain N concentration (1¢67{2¢01%) was negatively correlated with grain yield. Under N-limiting conditions, N fertiliser application had large efiects on yield and/or grain N concentration in both well-watered and pre-anthesis water stress conditions. In the irrigated experiment, when N was limiting (0 and 60 kg/ha of N fertiliser), genotypic variation for grain yield (225{729 g/m 2 ) was not related to that for maturity date. It was, however, related to the variation in N uptake and dry matter growth by anthesis in the non-fertilised treatment. There was signiflcant genotypic variation for grain N concentration (0¢94{1¢26%), which was not explained by variation for grain yield. Under rainfed conditions, where severe pre-anthesis water stress occurred, phenology was important in determining about 40% of the genotypic variation for yield (69{286 g/m 2 ). The late-∞owering hybrids escaped the major impact of the pre-anthesis water stress, had reduced damage to panicle development, and had higher N utilisation, consequently producing higher grain yield. Grain N concentration (1¢09{2¢85%) was again negatively related with grain yield. Genetic improvement of N uptake is identifled as a possible breeding strategy for raising productivity and quality of grain sorghum under N-limiting conditions.
TL;DR: The concept that TGF-β is involved in the changes associated with diabetic vascular disease is supported, and a mechanism by which angiotensin converting enzyme inhibitors exert their antitrophic effects is suggested.
Abstract: OBJECTIVE The purpose of this study was to assess the role of transforming growth factor (TGF)-beta1 in the development of diabetes-associated mesenteric vascular hypertrophy and in the antitrophic effect of angiotensin converting enzyme inhibitors. DESIGN AND METHODS Streptozotocin-induced diabetic and control Sprague-Dawley rats were randomly allocated to treatment with the angiotensin converting enzyme inhibitor ramipril or to no treatment and were killed 1 or 3 weeks after the streptozotocin injection. Blood was collected and mesenteric vessels removed. Mesenteric vascular weight was measured and TGF-beta1 and alpha1 (type IV) collagen messenger (m)RNA levels were analysed by Northern analysis. Immunohistochemical analyses for TGF-beta1 and type IV collagen were also performed. RESULTS The diabetic rats had increased mesenteric vessel weight at 3 weeks but not at 1 week and a concomitant rise in mesenteric TGF-beta1 and in alpha1 (type IV) collagen mRNA levels. Ramipril treatment attenuated mesenteric vessel hypertrophy and prevented the increase in TGF-beta1 and alpha1 (type IV) collagen mRNA levels after 3 weeks of diabetes. The immunohistochemical analysis revealed that diabetes was associated with increased TGF-beta1 and type IV collagen protein and extracellular matrix accumulation in mesenteric vessels, and this increase was reduced by ramipril treatment. CONCLUSIONS These results support the concept that TGF-beta is involved in the changes associated with diabetic vascular disease, and suggest a mechanism by which angiotensin converting enzyme inhibitors exert their antitrophic effects.
TL;DR: An important role for amylin is described in which it plays a role as a growth factor in the developing kidney and in renal regrowth in the adult kidney and that it stimulates the activity of a local RAS by an intracellular mechanism, leading to the biosynthesis of Ang II.
Abstract: The range of known actions of amylin are reviewed together with the proposal that an important role for amylin may be the hormonal integration of diverse physiological systems activated with feeding.
24 Nov 1998
TL;DR: Simulation methodology was used to compare two selection strategies currently used in plant breeding and investigate their capacity to confront the diffculties associated with the influences of G×E interaction and epistasis.
Abstract: The concept of an adaptation (fitness) landscape has been used to explain evolutionary processes. The landscape is a response surface for the genetic space defined by a genotype-environment system and evolution of populations through natural selection a search for higher peaks in this space. This is an appealing framework for other disciplines interested in issues of search and optimisation. One such application is the genetic improvement of traits in plant breeding. Here, breeding programs can be viewed and analysed as search strategies that are used to explore the surface of an adaptation landscape to find higher adaptive positions. The current theoretical framework considers genetic improvement as a hill climbing process on a smooth single peaked adaptation landscape. However, there is strong evidence to suggest that due to the effects of genotype-by-environment (G×E) interactions and epistasis, the landscapes encountered by plant breeders are in fact rugged and multi-peaked. Simulation methodology was used to compare two selection strategies currently used in plant breeding and investigate their capacity to confront the diffculties associated with the influences of G×E interaction and epistasis: (i) selection of genotypes based on performance in a single environment (mass selection), and (ii) selection of genotypes based on performance in several environments (multi-environment testing). A third selection strategy was proposed for genetic improvement on more complex adaptation landscapes. This selection strategy (shifting search strategy) was based on Wright's 'Shifting Balance Theory'.
TL;DR: It is demonstrated that blockade both of angiotensin II-dependent and of calcium-dependent pathways attenuates mesenteric vascular hypertrophy in experimental diabetes, and the antitrophic effects of these antihypertensive agents may be independent of their hypotensive effects.
Abstract: Objectives To investigate the relative roles of angiotensin II, bradykinin, and calcium-dependent pathways in the genesis of mesenteric vascular hypertrophy in experimental diabetes. Design Streptozotocin-induced diabetic Sprague–Dawley rats were randomly allocated to these treatments for 24 weeks: no treatment; ramipril at a hypotensive dose; ramipril plus the bradykinin type 2 receptor blocker icatibant; icatibant alone; ramipril at a low dose; the angiotensin II type 1 receptor antagonist, valsartan; the dihydropyridine calcium antagonist, lacidipine; and the nondihydropyridine calcium antagonist mibefradil. Methods Systolic blood pressure was serially measured every 4 weeks by tail-cuff plethysmography. We assessed the vascular architecture in sections of mesenteric arteries obtained after in-vivo perfusion, which were stained with an antibody to a-smooth muscle actin. Results Both blood pressure and the mesenteric arterial wall: lumen ratio were reduced by administration of ramipril, at the high dose, either alone or in combination with icatibant, and also by valsartan. Treatment either with the low dose of ramipril or with the calcium antagonists lacidipine and mibefradil was associated with a decrease in the wall: lumen ratio of the mesenteric arteries without influencing blood pressure. Conclusions These findings demonstrate that blockade both of angiotensin II-dependent and of calcium-dependent pathways attenuates mesenteric vascular hypertrophy in experimental diabetes. Furthermore, the antitrophic effects of these antihypertensive agents may be independent of their hypotensive effects.
TL;DR: Analysis of receptor distributions in Macaca fascicularis kidney by in vitro autoradiography revealed distinct patterns of binding for each peptide, suggesting potential roles for amylin, calcitonin, and CGRP in primate renal function.
Abstract: Analysis of receptor distributions for125I-labeled amylin,125I-labeled calcitonin, and125I-labeled calcitonin gene-related peptide (CGRP) inMacaca fascicularis kidney by in vitro autoradiography re...
TL;DR: In this article, the influence of genotype × N environment interactions on yield and grain N concentration was examined using 3-6 hybrids with similar phenology, and two experiments were conducted using three N fertiliser application rates (0, 60, and 240 kg/ha).
Abstract: In Australia, grain sorghum [Sorghum bicolor (L.) Moench] hybrids are often grown under conditions of low soil nitrogen (N) availability with suboptimal levels of N fertiliser supplied. However, little is known about the traits that contribute to sorghum hybrid performance in environments with low available N. We examined plant traits that may contribute to adaptation of sorghum to low soil N conditions, and the influence of genotype × N environment interactions on yield and grain N concentration. Two experiments were conducted using 3–6 hybrids with similar phenology. Three N fertiliser application rates (0, 60, and 240 kg/ha) were used in Expt 1, and 2 application rates (0 and 60 kg/ha) were used in Expt 2. Hybrid yield was associated with plant N content at maturity. The ability of a hybrid to take up N continuously during grain filling, under N limiting conditions, was identified as an important component contributing to high yield. In the non-fertilised treatment of Expt 2, where plants suffered the most severe N limitation before anthesis (e.g. total plant N content at anthesis <3 g/m2), hybrid yield was associated with biomass production and duration of effective grain filling. The dependence of the expression of the higher N uptake trait on N availability and other environmental factors resulted in genotype × environment interactions for yield. Differences among hybrids in leaf senescence and grain growth rate had little effect on yield. Genotypic variation for grain N concentration was consistent across experiments for hybrids with and without the staygreen attribute. In Expt 2 the magnitude of leaf senescence and amount of N mobilised from leaf to grain were greater at 60 kg N/ha than in the non-fertilised treatment. In addition, the staygreen hybrid 72389–1-1–3/QL36 had a slower rate of leaf senescence, took up larger amounts of N after anthesis, and had higher grain N concentration (1·07%) than the senescent hybrids ATx623/RTx430 (0·95%) and QL41/69264–2-2–2 (0·90%).
01 Jan 1998
TL;DR: In NIDDM the relationship between nephropathy and hypertension is more complex than in IDDM, since hypertension is not necessarily linked to the presence of renal disease, and often precedes the diagnosis of diabetes.
Abstract: The deleterious effects of systemic blood pressure on glomerular structure were reported more than twenty years ago in a patient with NIDDM and unilateral renal artery stenosis, in which characteristic nodular diabetic glomerulosclerosis was present in the non-ischaemic kidney only [1]. Nevertheless, to date the impact of antihypertensive therapy on renal injury in NIDDM has received little attention even though the cumulative incidence of persistent proteinuria and microalbuminuria in NIDDM subjects is comparable in frequency to IDDM subjects of similar duration [2–5]. The clinical relevance of these figures is reflected by statistics which now show that over 50% of patients entering renal replacement programs have NIDDM [6–8]. Furthermore, in NIDDM the relationship between nephropathy and hypertension is more complex than in IDDM, since hypertension is not necessarily linked to the presence of renal disease, and often precedes the diagnosis of diabetes.
TL;DR: In addition to the use of drugs for the control of blood glucose, patients with diabetes mellitus are likely to be prescribed medication for associated conditions such as cardiovascular disease, and current evidence suggests that these drugs may be particularly useful in this patient group.
Abstract: Diabetes mellitus is associated with alterations in a number of key metabolic pathways. Despite theoretical concerns, clinically significant alterations in the pharmacokinetic properties of commonly prescribed drugs are relatively uncommon. Indeed, dose adjustment is rarely required in the setting of well controlled diabetes mellitus. However, significant alterations in drug handling may occur in the context of poor metabolic control or in the presence of complications such as nephropathy.
TL;DR: ACE inhibition attenuates many of the vascular changes observed in experimental diabetes and may have important clinical implications as a vasoprotective agent in human diabetes.
Abstract: Vascular disease is now the major cause of morbidity and mortality in the diabetic population. Our group explored the vascular changes associated with experimental diabetes and examined whether these changes can be ameliorated by angiotensin-converting enzyme (ACE) inhibition. The ACE inhibitor perindopril (PE) was administered to streptozotocin-induced diabetic rats for 24 weeks. At death, mesenteric vessels were perfused in vivo followed by assessment of the vascular architecture by quantitative histomorphometry. In a subgroup of animals, RNA was extracted from the mesenteric vasculature for assessment of gene expression of the prosclerotic cytokine, transforming growth factor beta 1 (TGFβ1), and the matrix protein, type IV collagen. Diabetes was associated with smooth muscle hypertrophy and extracellular matrix (ECM) accumulation. ECM accumulation, particularly collagen deposition, was observed in the medial and adventitial layers. ACE inhibition prevented mesenteric vascular hypertrophy after 24 weeks of diabetes. In addition, overexpression of TGFβ1 in the vessels of diabetic animals was prevented by PE treatment. Similarly, type IV collagen mRNA levels were increased in diabetic vessels, and this overexpression was also prevented by PE therapy. In summary, ACE inhibition attenuates many of the vascular changes observed in experimental diabetes and may have important clinical implications as a vasoprotective agent in human diabetes.
TL;DR: In this paper, surface-enhanced binding of depsipeptides to chloroeremomycin (CE) was demonstrated for vancomycin-resistant Staphylococcus aureus and VanB-resistant bacteria.
TL;DR: There are high‐affinity binding sites for amylin in the renal cortex associated with proximal tubules that appear to represent seven transmembrane (heptatopic) receptors that are known to form ternary complexes with G‐proteins and activate second messenger systems.
Abstract: 1. There are high-affinity binding sites for amylin in the renal cortex associated with proximal tubules. These appear to represent seven transmembrane (heptatopic) receptors that are known to form ternary complexes with G-proteins and activate second messenger systems. 2. Amylin stimulates sodium/water reabsorption from the basolateral side of the proximal tubules and plays a role in sodium homeostasis. 3. The transient expression of amylin-like mRNA has been detected perinatally, using in situ hybridization, in the subnephrogenic zone of the metanephros and is associated with proximal tubules of the developing nephron. There it is thought to play a role as a growth factor for brush border epithelial cells in the developing kidney and in renal regrowth in the adult kidney. 4. In two models of hypertension, the spontaneously hypertensive rat (SHR) and one created surgically by subtotal nephrectomy, renal amylin receptors are activated. In the SHR, activation precedes the rise in blood pressure and suggests that activation of the amylin system may be an important event in the development of hypertension.
Journal Article•
TL;DR: There was a significant increase in 125I-AGE binding in the liver of diabetic rats after 3 weeks of experimental diabetes, and it remains speculative as to whether these binding sites represent AGE clearance receptors.
Abstract: Advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of diabetic complications. However, clearance pathways for these products have not been fully delineated. This study investigates changes in AGE binding in the liver in association with experimental diabetes using in vitro and in vivo radioautography techniques. Male Sprague-Dawley rats were randomised into control and diabetic rats and sacrificed after 3 weeks. Frozen liver sections (20 microm) were incubated with 125I-AGE-BSA. To further localise the AGE binding site, in vivo radioautography was performed by injection of 15 microCi of 125I-AGE-BSA into the abdominal aorta of the rat. Specific binding sites for AGEs were detected in the liver by in vitro radioautography. There was a significant increase in 125I-AGE binding in the liver of diabetic rats. Emulsion radioautography revealed that binding was localised primarily in Kupffer and liver endothelial cells. AGE binding sites were increased in the liver after 3 weeks of experimental diabetes. It remains speculative as to whether these binding sites represent AGE clearance receptors.