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Biomedical subjects

A J Cox

Publications and source records attributed to A J Cox.

At least 19 recordsLinked to original sources
PubMed2006

Combination therapy with tranilast and angiotensin-converting enzyme inhibition provides additional renoprotection in the remnant kidney model.

Despite current therapy with agents that block the renin-angiotensin system, renal dysfunction continues to progress in a significant proportion of patients with kidney disease. Several pre-clinical studies have reported beneficial effects of tranilast, an inhibitor of transforming growth factor (TGF)-beta's actions in a range of diseases that are characterized by fibrosis. However, whether such therapy provides additional benefits in renal disease, when added to angiotensin-converting enzyme (ACE) inhibition, has not been explored. We randomized subtotally (5/6) nephrectomized rats to receive vehicle, the ACE inhibitor, perindopril (6 mg/l), tranilast (400 mg/kg/day), or their combination for 12 weeks. When compared with sham-nephrectomized animals, subtotally nephrectomized animals had reduced creatinine clearance, proteinuria, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and evidence of TGF-beta activity, as indicated by the abundant nuclear staining of phosphorylated Smad2. These manifestations of injury and TGF-beta activation were all attenuated by treatment with either tranilast or perindopril, with the latter also attenuating the animals' hypertension. When compared with single-agent treatment, the combination of tranilast and perindopril provided additional, incremental improvements in creatinine clearance, proteinuria, and glomerulosclerosis, and a reduction in nuclear phsopho-Smad2 beyond single-agent treatment. These findings indicate that the combination of tranilast and perindopril was superior to single-agent treatment on kidney structure and function in the remnant kidney model, and suggests the potential for such dual therapy in kidney disease that continues to progress despite blockade of the renin-angiotensin system.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Tranilast attenuates vascular hypertrophy, matrix accumulation and growth factor overexpression in experimental diabetes.

OBJECTIVES: The growth factors transforming growth factor-B (TGF-B) and epidermal growth factor (EGF) have both been implicated in the hypertrophic structural changes in the vasculature that are characteristic features of both human and experimental diabetes. Recently, tranilast (N(3,4-dimethoxycinnamoyl)anthranilic acid), a drug used in the treatment of allergic and dermatological diseases, has also been reported to inhibit transforming growth factor-B (TGF-B)-mediated collagen formation. However, its effects on vascular hypertrophy in diabetes are unknown. The present study thus sought to determine the effects of tranilast on both TGF-B and EGF expression and mast cells in mediating the trophic vascular changes in experimental diabetes. METHODS: Vessel morphology, growth factors and collagen gene expression and matrix deposition were examined in the mesenteric arteries of control rats treated with or without tranilast, and streptozotocin-induced diabetic Sprague-Dawley rats treated with or without tranilast (200 mg/kg/day) during a 3-week period. RESULTS: Compared with control animals, diabetic rats had significantly increased vessel weight, wall: lumen ratio, ECM accumulation, gene expression of TGF-B1, EGF, and both alpha1 (I) and alpha1 (IV) collagen. Tranilast treatment did not influence plasma glucose or systemic blood pressure. However, tranilast significantly reduced mesenteric weight, wall: lumen ratio and matrix deposition and also attenuated the overexpression of TGF-B1, EGF, and both alpha1 (I) and alpha1 (IV) collagen mRNA in diabetic rats. CONCLUSION: These findings indicate that tranilast ameliorates pathological vascular changes observed in experimental diabetes in association with reduced growth factor expression independent of blood glucose or systemic blood pressure.

Animals↗
PubMed2002

Proteinuria and the expression of the podocyte slit diaphragm protein, nephrin, in diabetic nephropathy: effects of angiotensin converting enzyme inhibition.

AIMS/HYPOTHESIS: Proteinuria, reflecting increased glomerular permeability to macromolecules is a characteristic feature of diabetic nephropathy. Nephrin, a 1241-residue transmembrane protein is a key component of the podocyte slit pore membrane and a major contributor of the glomerular filtration barrier. We investigated the expression of nephrin in human kidney tissue from patients with diabetic nephropathy to elucidate its relationship with proteinuria and the effects of anti-proteinuric therapy with angiotensin converting enzyme inhibition. METHODS: Renal biopsies were examined from 14 patients with Type II (non-insulin-dependent) diabetes mellitus and proteinuria who had been randomised to receive treatment with the ACE inhibitor, perindopril (4 mg/day) or placebo for the preceding 2 years. These specimens were compared with control human tissue sections, obtained from areas of normal renal cortex following nephrectomy for malignancy. Proteinuria was measured, specimens were examined histologically for injury and the expression of nephrin messenger RNA was assessed by quantitative in situ hybridisation. RESULTS: Glomeruli from placebo-treated patients with diabetic nephropathy, showed a 62% reduction in nephrin expression compared with control subjects (p=0.0003). In contrast, nephrin RNA in glomeruli from perindopril treated patients was similar to that in the non-diabetic control group. In both placebo and perindopril treated patients, a close inverse correlation was noted between the magnitude of nephrin gene expression and the degree of proteinuria (placebo: r=0.86, p=0.013, perindopril: r=0.91, p=0.004). CONCLUSION/INTERPRETATION: Modulation in nephrin expression is related to the extent of proteinuria in diabetic nephropathy. These changes define, at a molecular level alterations in the glomerulus that occur in relation to proteinuria in diabetes and the effects of anti-proteinuric treatment with ACE inhibition.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Decreased matrix degradation in diabetic nephropathy: effects of ACE inhibition on the expression and activities of matrix metalloproteinases.

AIMS/HYPOTHESIS: Extracellular matrix accumulation is thought to be involved in the pathogenesis of diabetic nephropathy. Increased matrix synthesis has been well documented but the effects of diabetes on degradative pathways, particularly in the in vivo setting, have not been fully explored. Furthermore, the effect of renoprotective therapies on matrix accumulation through these pathways has not been examined. We investigated the degradative pathway of type IV collagen and the effects of ACE inhibition in experimental diabetic nephropathy. METHODS: Diabetes was induced in 16 rats by administrating streptozocin; 8 of the diabetic rats were allocated at random to receive the ACE inhibitor perindopril (2 mg/l) in their drinking water and 8 age and weight matched rats served as controls. Gene expression of matrix metalloproteinase ( MMP) and tissue inhibitor of metalloproteinase ( TIMP) was measured by RT-PCR and type IV collagen content by immunohistochemistry. MMP activities were determined by degradation of a radiolabelled substrate and by zymography. RESULTS: Six months of diabetes was associated with a decrease in mRNA and enzymatic activity of MMP-9 (21 % and 51 % respectively, p < 0.05 vs control) and a 51 % increase in TIMP-1 mRNA ( p < 0.05 vs control). By contrast, MMP-2 mRNA was increased but its activity decreased (43 % and 43 % respectively, p < 0.05 vs control). Total degradative capacity of kidney tissue from diabetic rats was also lower (Control: 48 +/- 7 %, Diabetic: 33 +/- 6 %, p < 0.05). Activation of latent MMPs with amino-phenylmercuric acetate increased matrix degradation by two-fold. However the relative decrease associated with experimental diabetes still remained. All diabetes-associated changes in MMP and TIMP mRNA and activities were attenuated by perindopril treatment in association with reduced type IV collagen accumulation. CONCLUSIONS/INTERPRETATION: These results indicate that the impairment of matrix degradation contributes to matrix accumulation in diabetic nephropathy and that the beneficial effects of ACE inhibition could in part be mediated by modulation of changes in matrix degradative pathways.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Mapping airborne lead contamination near a metals smelter in Derbyshire, UK: spatial variation of Pb concentration and 'enrichment factor' for tree bark.

Samples of tree bark, collected over an area of 4 km2 near a small non-ferrous metals smelter in Derbyshire, UK, were analysed for Pb and Al by inductively coupled plasma atomic emission spectroscopy (ICP-AES). Analyte concentrations varied from 100 to over 25,000 mg kg-1 and 5 to 1000 mg kg-1, respectively. While an inverse relationship between the Pb content of bark and distance from the smelter was observed, concentrations fluctuated, indicating a variability in sample collection efficiency and problems in standardization. To overcome these effects, the Pb/Al ratio was calculated and subsequently normalized to the average Pb/Al ratio in continental crust (0.00015). On the assumption that the time-averaged concentration of airborne Al in this area is relatively constant and derived principally from wind-blown soil, the measurement represents an anthropogenic 'enrichment factor' (PbEF). PbEF varied from 10,000 to over 1,000,000, and showed a consistent reduction with distance from the smelter. Isolines of equal PbEF were subsequently defined on a map of the sampled area. Pb contamination was greatest in the vicinity of the smelter, and preferential transport along the NW-SE axis of the valley (in which the smelter is situated) was observed. The use of enrichment factors thus proved valuable in defining the relative level of airborne-derived Pb pollution.

Air Pollutants↗
PubMed2001

Colonization, extinction, and phylogeographic patterning in a freshwater crustacean.

Phylogeographic analyses have revealed the importance of Pleistocene vicariance events in shaping the distribution of genetic diversity in freshwater fishes. However, few studies have examined the patterning of variation in freshwater organisms with differing dispersal syndromes and life histories. The present investigation addresses this gap, examining the phylogeography of Sida crystallina, a species whose production of diapausing eggs capable of passive dispersal was thought to constrain its regional genetic differentiation. By contrast, the present analysis has revealed deep allozyme and cytochrome oxidase I mitochondrial DNA divergence between populations from North America and Europe. Moreover, North American populations are separated into four allopatric assemblages, whose distribution suggests their derivation from different Pleistocene refugia. These lineages show higher haplotype diversity and deeper sequence divergence than those of any fish from temperate North America. Its distinctive life history traits have evidently sheltered lineages of Sida from extinction, contributing to a remarkably comprehensive and high resolution phylogeographic record.

Animals↗
PubMed2001

SSAHA: a fast search method for large DNA databases.

We describe an algorithm, SSAHA (Sequence Search and Alignment by Hashing Algorithm), for performing fast searches on databases containing multiple gigabases of DNA. Sequences in the database are preprocessed by breaking them into consecutive k-tuples of k contiguous bases and then using a hash table to store the position of each occurrence of each k-tuple. Searching for a query sequence in the database is done by obtaining from the hash table the "hits" for each k-tuple in the query sequence and then performing a sort on the results. We discuss the effect of the tuple length k on the search speed, memory usage, and sensitivity of the algorithm and present the results of computational experiments which show that SSAHA can be three to four orders of magnitude faster than BLAST or FASTA, while requiring less memory than suffix tree methods. The SSAHA algorithm is used for high-throughput single nucleotide polymorphism (SNP) detection and very large scale sequence assembly. Also, it provides Web-based sequence search facilities for Ensembl projects.

Algorithms↗
PubMed2000

Characterisation of a Pasteurella multocida esterase gene which confers a hemolytic phenotype in Escherichia coli under anaerobic conditions.

Investigation of the hemolytic phenotype under anaerobic growth conditions of an avian Pasteurella multocida strain, PBA100, resulted in the identification and characterisation of a gene encoding an esterase enzyme, mesA, that conferred a hemolytic phenotype in Escherichia coli under anaerobic conditions. MesA appeared to be expressed and functional under anaerobic and aerobic conditions in both E. coli and P. multocida. A P. multocida mesA mutant was generated which resulted in the loss of acetyl esterase activity under anaerobic conditions. However, this mutation did not cause any attenuation of virulence for mice nor a detectable change to the anaerobic hemolytic phenotype of P. multocida. In E. coli MesA appeared to cause hemolysis indirectly by the induction of the latent E. coli K-12 cytolysin, sheA.

Amino Acid Sequence↗
PubMed2000

Cloning and characterisation of the Pasteurella multocida ahpA gene responsible for a haemolytic phenotype in Escherichia coli.

Haemolysins are membrane-damaging agents which have been described as bacterial virulence factors due to their ability to lyse erythrocytes and other host cells, and therefore inducing a greater inflammatory response (Elliott et al., 1998). Pasteurella multocida was found to be haemolytic under anaerobic conditions. In this study, we cloned and characterised a P. multocida gene, designated ahpA, which conferred a haemolytic phenotype on Escherichia coli when incubated under anaerobic conditions. A deletion was introduced into the ahpA open reading frame which abolished the haemolytic phenotype. The clone containing ahpA showed erythrocyte specificity, causing haemolysis of bovine and equine erythrocytes, and demonstrated weak haemolysis on ovine erythrocytes. Upon further investigation, AhpA was found to affect the expression of the E. coli K-12 latent haemolysin, SheA, under anaerobic conditions.

Amino Acid Sequence↗
PubMed2000

Endothelin receptor antagonism ameliorates mast cell infiltration, vascular hypertrophy, and epidermal growth factor expression in experimental diabetes.

Vascular hypertrophy, a feature of experimental and human diabetes, has been implicated in the pathogenesis of the microvascular and macrovascular complications of the disease. In the present study, we sought to examine the role of endogenous endothelin and its relation to vascular growth factors in the mediation of vascular hypertrophy in experimental diabetes and to examine the contribution of mast cells to this process. Vessel morphology, endothelin, growth factor gene expression, and matrix deposition were studied in the mesenteric arteries of control and streptozotocin-induced diabetic Sprague-Dawley rats treated with or without the dual endothelin(A/B) receptor antagonist bosentan (100 mg x kg(-1) x d(-1)) during a 3-week period. Compared with control animals, diabetic animals had significant increases in vessel weight, wall-to-lumen ratio, mast cell infiltration, extracellular matrix deposition, and gene expression of epidermal growth factor (EGF) and transforming growth factor-beta(1). In diabetic, but not control, vessels, not only were EGF mRNA and endothelin present in endothelial cells, but also their expression was observed in adventitial mast cells. Immunoreactive endothelin was present in the media of mesenteric vessels of diabetic, but not control, animals. Bosentan treatment significantly reduced mesenteric weight, wall-to-lumen ratio, mast cell infiltration, matrix deposition, and EGF mRNA but did not prevent the overexpression of transforming growth factor-beta(1) mRNA in diabetic rats. These findings suggest that endogenous endothelin and EGF may play a role in diabetes-induced vascular hypertrophy and that mast cells may be pathogenetically involved in this process.

Animals↗
PubMed2000

SPARC gene expression is increased in diabetes-related mesenteric vascular hypertrophy.

The anti-adhesive extracellular matrix protein SPARC (secreted protein and rich in cysteine; osteonectin or BM-40) has been implicated in the regulation of matrix turnover, cell migration, and proliferation. The present study sought to examine whether modulation in the expression of this protein may play a role in diabetes-associated vascular remodeling. SPARC mRNA and protein were measured in mesenteric vessels of diabetic rats and controls. Hypertrophy of mesenteric vessels was noted after 3 and 32 weeks of diabetes as revealed by the increase in mesenteric vessel wet weight and an increased wall/lumen ratio. SPARC mRNA was sparsely present in intima and adventitia of control vessels. There was a marked increase in SPARC gene expression in the intima and adventitia of mesenteric vessels after 1, 3, and 32 weeks of diabetes. SPARC protein was demonstrated in the vessel wall in control animals and was increased in the mesenteric vessels of diabetic rats after 1 and 32 weeks of diabetes. Administration of the inhibitor of advanced glycation end-product formation, aminoguanidine, to diabetic rats attenuated both the hypertrophic response in mesenteric vessels and the overexpression of SPARC mRNA and protein without affecting glycemic control or food intake. In summary, diabetes-related mesenteric vascular hypertrophy is associated with an increase in SPARC expression in the vessel wall. The modulation of SPARC expression in mesenteric vessels of diabetic rats might be of pathogenetic significance in the development of vascular remodeling in diabetes.

Animals↗
PubMed2000

Angiotensin converting enzyme inhibition reduces retinal overexpression of vascular endothelial growth factor and hyperpermeability in experimental diabetes.

AIMS/HYPOTHESIS: Angiotensin converting enzyme (ACE) inhibition has been recently suggested to have retinoprotective actions in diabetic patients but the mechanism of this effect is not known. In vitro, angiotensin II stimulates expression of vascular endothelial growth factor (VEGF), a permeability-inducing and endothelial cell specific angiogenic factor which has been implicated in the pathogenesis of diabetic retinopathy in humans and in experimental animals. We sought to determine the effects of ACE inhibition on retinal VEGF expression and permeability in experimental diabetic retinopathy. METHODS: Streptozotocin-induced diabetic rats and control animals were assigned at random to receive ACE inhibitor treatment or vehicle. At 24 weeks the retinal VEGF protein gene expression was assessed by northern blot analysis and in situ hybridisation. Retinal permeability to albumin was measured using a double isotope technique. RESULTS: Experimental diabetes was associated with cell specific two to fourfold increase in retinal VEGF protein gene expression (p < 0.01) and a 2-fold increase in retinal vascular permeability to albumin (p < 0.01). The localization of VEGF expression in the retina was not altered in animals with experimental diabetes. Angiotensin converting enzyme inhibitor treatment of diabetic rats reduced diabetes-associated changes in VEGF gene expression and vascular permeability. CONCLUSION/INTERPRETATION: These findings implicate the renin-angiotensin system in the VEGF overexpression and hyperpermeability which accompany diabetic retinopathy and provide a potential mechanism for the beneficial effects of ACE inhibition in diabetic retinal disease.

Angiotensin II↗
PubMed2000

Effects of endothelin or angiotensin II receptor blockade on diabetes in the transgenic (mRen-2)27 rat.

BACKGROUND: Endothelin (ET) and angiotensin II (Ang II) are vasoactive/trophic peptides that may contribute to the progression of diabetic nephropathy. The transgenic (mRen-2)27 rat exhibits overexpression of Ang II at sites of normal physiological expression. Unlike other rat strains, the streptozotocin-induced diabetic Ren-2 rat develops progressive renal pathology associated with a declining glomerular filtration rate (GFR) and provides a convenient model to evaluate the role of these vasoactive peptides in the nephropathic process. METHODS AND RESULTS: Oral administration of either the endothelin A (ETA) and ETB receptor antagonist bosentan or the angiotensin type 1 (AT1) receptor antagonist valsartan for 12 weeks reduced systolic blood pressure (SBP) of nondiabetic and diabetic Ren-2 rats to normotensive levels. Diabetic renal pathology was associated with intense renin mRNA and protein in the proximal tubules and juxtaglomerular cells along with overexpression of transforming growth factor-beta1 (TGF-beta1) and collagen IV mRNA in glomeruli and tubules. With valsartan but not bosentan, renin mRNA and protein in the proximal tubules were not detected. Valsartan but not bosentan reduced TGF-beta1 and collagen IV mRNA and the severity of diabetic renal pathology. A declining GFR with diabetes was attenuated by both treatments. Albuminuria in diabetic rats rose further with bosentan but was reduced with valsartan. CONCLUSIONS: Despite producing normotension, severe diabetic renal pathology was not prevented by bosentan, suggesting dissociation of ET, albuminuria, and hypertension from the structural injury in this diabetic model. The beneficial effects afforded by valsartan therapy strengthen the importance of the local renin-angiotensin system in mediating progressive diabetic renal injury.

Angiotensin Receptor Antagonists↗
PubMed2000

Blockade of the renin-angiotensin and endothelin systems on progressive renal injury.

The renin-angiotensin system (RAS) and endothelin system may both play a role in the pathogenesis of progressive renal injury. The aims of the present study were 3-fold: first, to explore the possible benefits of dual blockade of the RAS with an ACE inhibitor and an angiotensin type 1(AT1) receptor antagonist; second, to examine the relative efficacy of endothelin A receptor antagonism (ETA-RA) compared with combined endothelin A/B receptor antagonism (ETA/B-RA); and third, to assess whether interruption of both RAS and endothelin system had any advantages over single-system blockade. Subtotally nephrectomized rats were studied as a model of progressive renal injury and randomly assigned to one of the following treatments for 12 weeks: perindopril (ACE inhibitor), irbesartan (AT1 receptor antagonist), BMS193884 (ETA-RA), bosentan (ETA/B-RA), and a combination of irbesartan with either perindopril or BMS193884. Treatment with irbesartan or perindopril was associated with an improved glomerular filtration rate and reductions in blood pressure, urinary protein excretion, glomerulosclerosis, and tubular injury in association with reduced gene expression of transforming growth factor-beta(1) and matrix protein type IV collagen. The combination of irbesartan with perindopril was associated with further reductions in blood pressure and urinary protein excretion. No beneficial effects of either BMS193884 or bosentan were noted. Furthermore, the addition of BMS193884 to irbesartan did not confer any additional benefits. These findings suggest that the RAS but not the endothelin system is a major mediator of progressive renal injury after renal mass reduction and that the combination of an AT1 receptor antagonist with an ACE inhibitor may have advantages over the single agent of RAS blocker treatment.

Angiotensin Receptor Antagonists↗
PubMed2000

Nasal fractures--the details.

Due to the nose's prominent location and functional and cosmetic importance, nasal fractures present a challenge to the facial plastic surgeon to restore all things to normal. Although little groundbreaking news has been reported recently in the literature on nasal fractures, there is ample literature already in print on virtually every topic concerning nasal fractures. This article concentrates on the details of actually managing nasal fractures, with comments on present-day coding of posttraumatic septorhinoplasty.

Anesthesia, General↗
PubMed1999

Role of hyperlipidemia in progressive renal disease: focus on diabetic nephropathy.

BACKGROUND: It has been suggested that lipids promote renal injury and that 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors confer renoprotection in certain renal diseases, including diabetic nephropathy. METHODS: Sprague-Dawley rats were randomized to sham, subtotal nephrectomy (STNx) or STNx + atorvastatin groups. After 12 weeks, proteinuria, renal function, glomerular injury, renal transforming growth factor-beta (TGF-beta) gene expression and macrophage (ED1-positive cells) accumulation were assessed. In addition, the effects of HMG CoA reductase in human diabetic nephropathy were reviewed. RESULTS: Atorvastatin therapy was associated with a modest reduction in proteinuria and glomerulosclerosis without influencing lipid levels or renal function in STNx rats. These effects were associated with decreased renal TGF-beta 1 gene expression and less glomerular and tubulointerstitial macrophage accumulation. The renoprotective effects of HMG CoA reductase inhibitors in both insulin- and non-insulin-dependent diabetic subjects with either incipient or overt nephropathy appear to be highly variable. CONCLUSIONS: HMG CoA reductase inhibition appears to confer renoprotection via effects on prosclerotic cytokines such as TGF-beta and macrophage accumulation, independent of their lipid-lowering properties. The role of lipid-lowering agents in early or overt diabetic nephropathy remains to be fully ascertained.

Animals↗
PubMed1999

Skeletal implants in aesthetic facial surgery.

The features of the nose, mentum, and malar complex define a person's profile and give the essence of character to the visage. Whether profile deficiencies are due to congenital, traumatic, or aging factors, facial plastic surgeons are able to meet patients' and their own exacting demands more thoroughly with skeletal implants. Although the search for the perfect implant continues, today's armamentarium of implant materials is vast and, with appropriate selection and attention to technique, facial skeletal implants can be successful in creating change impossible to obtain with soft tissue techniques alone. This article reviews both the biomaterials used in mandibular and malar complex implants and the techniques.

Biocompatible Materials↗