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T D Hewitson

Publications and source records attributed to T D Hewitson.

At least 37 records · Page 2Linked to original sources
PubMed1997

Apoptosis is increased in a model of diabetes-impaired wound healing in genetically diabetic mice.

Impaired wound healing is a common complication of diabetes mellitus. The underlying pathophysiology of diabetes-impaired healing is poorly understood. In the present study we have compared cell proliferation rates, apoptosis (programmed cell death), the myofibroblast marker alpha-smooth muscle actin and procollagen I mRNA expression, between diabetic and control mice. Full-thickness skin wounds were made in non-obese diabetic (NOD) mice and C57B6 controls. NOD mice showed a marked retardation of wound healing at both 7 and 14 days after wounding. Comparison of cell proliferation rates 7 days after wounding, using 5-bromo-2'-deoxy-Uridine incorporation, showed higher rates of cell proliferation in controls (88.1 +/- 12.8) than in NOD wounds (52.1 +/- 9.9, p < 0.02, n = 4). Immunohistochemical detection of alpha-smooth muscle actin, showed a later onset in diabetic wounds, suggesting that wound contraction may be delayed in the diabetic animals. In situ hybridisation for alpha 1 (I) procollagen mRNA expression, showed reduced procollagen I expression in the diabetic wounds when compared with controls. Lastly, there appeared to be higher levels of apoptosis in diabetic wounds, shown by the terminal transferase mediated UTP nick end-labelling technique. Apoptotic cells were rare in control wounds confirming previous studies, which showed that apoptosis occurs late in normal wound healing as the wound matures into scar tissue. In conclusion, we hypothesize that reduced cell proliferation, retarded onset of the myofibroblast phenotype, reduced procollagen I mRNA expression and aberrant control of apoptotic cell death may contribute to impaired wound healing seen in this diabetic model.

Animals↗
PubMed1996

The phenotype and fate of the antibody-forming cells of the splenic foci.

The first product of the humoral response to antigen is low-affinity antibody, produced by extrafollicular foci of antibody-forming cells (AFC) in organs such as spleen and lymph node. These cells proliferate rapidly but then undergo an equally rapid decline, so that they are present in only small numbers 14 days after immunization. We have used 6-parameter flow cytometry to isolate and examine the characteristics of (4-hydroxy-5-nitrophenyl)acetyl-specific AFC, looking in particular for those markers that might differentiate them from cells of the intrafollicular (germinal center) arm of the T-dependent immune response. At day 7 of the primary response, most AFC were found to express surprisingly low levels of B220, high levels of syndecan, and retain significant levels of surface IgG1. We then used enzyme-linked immunospot assays to demonstrate that the rapid decline of these cells was not likely to be due to migration to organs such as the bone marrow. Their decline could, however, be explained by apoptosis in situ, which was demonstrated immunohistologically by nick-end labeling.

Animals↗
PubMed1996

The significance of focal and segmental hyalinosis and sclerosis (FSHS) and nephrotic range proteinuria in IgA nephropathy.

Between 1971 and 1991, 845 patients were diagnosed as having IgA glomerulonephritis on renal biopsy performed. These patients were followed for a mean period of 53 months post biopsy (range 0-336 months). By the end of follow up 147 (17%) of patients have developed chronic renal failure (Cr > 0.2 mmol/l) or end-stage renal failure. Presenting creatinine > 0.12 mmol/l, hypertension, nephrotic range, age > 40 years and male gender, all correlated strongly on univariate analysis with the development of chronic renal failure or kidney disease (all p < 0.0001). However, a number of patients developing chronic renal failure or end-stage renal failure already had renal impairment (creatinine > 0.12 mmol/l at presentation). A separate comparison was performed of patients presenting with creatinine < 0.12 mmol/l and either developing chronic failure or end-stage renal failure within 5 years of biopsy (n = 18) and those with creatinine still < 0.12 mmol/l after 5 years follow up (n = 186). Of the 18 patients who deteriorated 6 (35%) were nephrotic at presentation and 9 (56%) had focal hyalinosis and sclerosis on renal biopsy. This compared with 5 (3%) patients with nephrotic range proteinuria and 16 (10%) patients with focal hyalinosis and sclerosis among the 186 patients who did not deteriorate (p < 0.0001). The sensitivity and specificity of the presence of either or both factors in predicting deterioration was calculated at 65% and 87% respectively. Thus in patients with normal renal function at presentation the presence of nephrotic range or focal hyalinosis and sclerosis are strong predictors of adverse clinical outcome.

Adult↗
PubMed1995

Interstitial myofibroblasts in IgA glomerulonephritis.

We examined renal biopsy specimens from patients with mesangial IgA glomerulonephritis (n = 25; plasma creatinine 0.05-0.30 mmol/l) to ascertain whether the myofibroblast has a role in progressive renal interstitial fibrosis. Myofibroblasts were identified by morphology and alpha smooth muscle actin (alpha-SMA) immunostaining at the light and electron microscope level. Results were related to staining for interstitial leukocytes and collagen III. A control group consisted of 6 normal renal transplant donors from whom biopsy specimens were taken at the time of vascular anastomosis. The fractional volume of interstitial alpha-SMA staining was greater in patients with mesangial IgA glomerulonephritis than in the control group (17.2 vs. 1.3%; p < 0.001). alpha-SMA staining was increased in areas of interstitial fibrosis with prominent periglomerular and peritubular distribution. Ultrastructural studies established that alpha-SMA staining in the renal interstitium was intracellular, cytoplasmic, and confined to myofibroblast-like cells and processes. The alpha-SMA expression correlated with fractional volume of tubular atrophy/dilation (r = 0.79, p < 0.001), interstitial connective tissue (r = 0.66, p < 0.001), leucocytes (r = 0.72, p < 0.005), and collagen III (r = 0.71, p < 0.001). Staining correlated with renal function at the time of biopsy (r = 0.64, p < 0.005) and after 2 years of follow-up (r = 0.77, p < 0.01). In conclusion, cells with a myofibroblast-like phenotype have a significant role in the progression of tubulointerstitial injury.

Actins↗
PubMed1995

Interstitial myofibroblasts in experimental renal infection and scarring.

We have examined the temporal and spatial distribution of myofibroblast-like cells, a phenotype with fibroblast and smooth muscle features, in an experimental model of renal infection. Escherichia coli organisms (10(5)) were inoculated directly into the renal cortex of Sprague-Dawley rats weighing 270 g. Saline was substituted in a control group. The animals were sacrificed at five time points up to day 24 (E. coli n = 8, controls n = 3 each interval). Myofibroblasts were identified by morphology and immunohistochemistry for alpha smooth muscle actin (alpha-SMA) and compared with staining for monocytes (ED-1), collagen III, and bromodeoxyuridine incorporation. Histological changes included a focal lesion in E. coli infected animals. Interstitial alpha-SMA staining was confined to spindle-shaped cells resembling myofibroblasts. The percent fractional area of alpha-SMA staining in the lesion increased from 0.12 +/- 0.09 at day 1 to 20.0 +/- 7.1 at day 3 (p < 0.005), decreasing progressively to 2.0 +/- 2.6 by day 24. This paralleled bromodeoxyuridine incorporation in myofibroblasts: 0.4 +/- 0.5 cells/0.25 mm2 at day 1, 105.0 +/- 36.3 at day 3, and 2.6 +/- 2.2 cells/0.25 mm2 at day 24. ED-1-positive cells increased from 374 +/- 200/0.25 mm2 at day 1 to 894 +/- 88 at day 3 (p < 0.01), declining to 230 +/- 108/0.25 mm2 by day 24. Intracellular collagen III and alpha-SMA stainings were colocalized at day 3. The fractional area of collagen III increased by day 24 (p < 0.05). In conclusion, myofibroblasts accumulate transiently during renal interstitial fibrosis and are derived at least in part from local proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1994

Clinical and histological correlations of decline in renal function in diabetic patients with proteinuria.

In 47 patients with diabetic nephropathy (29 type I, 18 type II) renal function and blood pressure (BP) (treated with or without an angiotensin-converting enzyme [ACE] inhibitor, enalapril [10 mg], in 38 hypertensive patients) were followed over 4 years. A percutaneous renal biopsy was performed in all patients initially and repeated in a representative 19 patients with treated hypertension after 4 years. Mean glomerular volume (MGV), interstitial fibrosis (IF), capillary volume, and sclerosed glomeruli (GS) were measured histomorphometrically. Mean fall in creatinine clearance (CCr) was 11.8% after 4 years with no difference between treatment groups or type of diabetes. BP both initially and during treatment correlated with initial and final serum creatinine and CCr (P < 0.01). There were no histomorphometric differences between type I and type II patients or hypertension treatment groups. Initial IF correlated with initial and final serum creatinine and CCr (P < 0.05) in all patients and type I patients alone, MGV correlated inversely with CCr in type I patients (P < 0.05). After 4 years, IF (24.8 vs. 30.0%, P < 0.01) and GS (26 vs. 37%, P < 0.05) increased significantly, and increase in IF correlated with fall in CCr (P < 0.01). Proteinuria and HbA1 did not correlate with indexes of function or structure. In this longitudinal study of patients with diabetic nephropathy, there was a close relation between BP and renal function but no difference between treatment with enalapril and other hypertensive agents. The correlations between renal function and histology at entry and after 4 years suggest that IF is a co-determinant of renal function in diabetic nephropathy.

Adolescent↗
PubMed1994

Acute renal failure in IgA nephropathy.

Twenty-five (3%) of 865 patients with IgA nephropathy presented with acute renal failure (ARF). These patients were matched with 25 patients in the same series who presented with irreversible renal impairment. Patients with acute renal failure had a significantly higher incidence of macroscopic hematuria and red blood cells in tubules. Conversely, a greater percentage of patients with irreversible renal failure had > or = 40% sclerosed glomeruli. The long-term prognosis for patients presenting with ARF appears excellent with only 1 (4%) patient developing chronic renal failure after a mean follow-up of 65 months. Mechanisms of acute renal failure in IgA nephropathy are discussed.

Acute Kidney Injury↗
PubMed1992

Corticotropin effects on blood pressure and fluid and electrolyte homeostasis in five strains of rats.

The hemodynamic and metabolic effects of 11 days of sham (saline) and corticotropin injection were examined in five different strains of rats: Sprague-Dawley, spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), Brattleboro, and Long Evans. Corticotropin significantly increased systolic blood pressure (SBP) compared with sham injection in all strains: final SBP in Sprague-Dawley was 108 +/- 5 mm Hg corticotropin, 94 +/- 4 mm Hg sham; SHR 146 +/- 6 mm Hg corticotropin, 141 +/- 3 mm Hg sham; WKY 117 +/- 3 mm Hg corticotropin, 103 +/- 3 mm Hg sham; Brattleboro 108 +/- 5 mm Hg corticotropin, 93 +/- 2 mm Hg sham; and Long Evans 103 +/- 5 mm Hg corticotropin, 90 +/- 4 mm Hg sham (P less than .001). Corticotropin also produced a decrease in body weight and increases in water intake and urine output. Increases in urine electrolyte excretion were seen in some, but not all strains. The rise in pressure in the Brattleboro rats indicated that vasopressin is not essential for the corticotropin-induced rise in pressure. Blood pressure rises in SHR were not exaggerated. Withdrawal of corticotropin in Sprague-Dawley rats led to rapid reversal of the corticotropin-induced hemodynamic and metabolic changes. Thus, strain does not appear to be an important factor in corticotropin hypertension in the rat, in contrast to deoxycorticosterone hypertension.

Adrenocorticotropic Hormone↗
PubMed1992

Glomerulosclerosis and hyalinosis in rabbits.

Histological appearances of remnant kidney in female New Zealand white rabbits undergoing left nephrectomy at 6 mths were studied. All 20 rabbits had evidence of previous Encephalitozoon cuniculi (E. cuniculi) infection. Half of the 10 uninephrectomized and 10 control animals completed 3 pregnancies before sacrifice (15 mths). Twelve of 30 kidneys at sacrifice showed focal and segmental hyalinosis and sclerosis (FSHS), a lesion not previously reported in rabbits. Four of 5 kidneys in both uninephrectomized pregnant and uninephrectomized virgin animals showed FSHS compared with 2 of 10 in both control pregnant and non-pregnant rabbits (p = 0.0026). More glomeruli were sclerosed in control pregnant (median 3.5%) than non pregnant animals (median 0.4%) (p < 0.005). Median right kidney weights per kilogram body weight were greater in previously nephrectomized animals (3.9 gm/kg) than controls (2.6 gm/kg), (p < 0.001). Absolute glomerular area was increased in hypertrophied kidneys, however, after correction for kidney weight, glomerular area was smaller in previously uninephrectomized animals than controls (p < 0.0001).

Animals↗
PubMed1992

Urinary platelet factor four (Pf4) levels in mesangial IgA glomerulonephritis and thin basement membrane disease.

The aim of this study was to assess the significance of platelet factor four (Pf4) excretion in the urine of patients with mesangial IgA glomerulonephritis (IgAGN) and thin basement membrane disease (TBMD), and ascertain if Pf4 is a useful parameter to distinguish these diseases. The concentration of Pf4 in urine (Pf4) was determined by an enzyme linked immunoabsorbent assay (ELISA) in patients with IgAGN (n = 80), TBMD (n = 37), membranous nephropathy (MN) (n = 12), minimal change nephrotic syndrome (MCNS) (n = 3), crescentic glomerulonephritis (CGN) (n = 6) and in healthy controls (n = 20), and then compared with urinalysis and renal function. An immunoperoxidase method was used to examine urine sediments for the presence of platelets. Urinary Pf4 was detected in 35 out of 80 patients with IgAGN (median 0.15, range 0.07-2.5 ng/ml, n = 35), in only 2 out of 37 patients with TBMD (p less than 0.005), in all patients with CGN and in no patients from MN, MCNS or control groups. A positive correlation between urinary Pf4 levels and red blood cell counts was observed in patients with IgAGN (r = 0.876, p less than 0.001), but not in TBMD. Pf4 did not correlate with proteinuria or plasma creatinine in either group. Platelets were detected in urine in 10 out of 15 patients with IgAGN but in only 1 out of 9 patients with TBMD. Urinary red blood cell counts in all of these 24 patients were over 100,000/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Caffeine potentiation of mefenamic acid-induced lesions in the rat renal medulla.

The effect of caffeine given in combination with mefenamic acid on the renal medulla was examined. Sprague-Dawley rats were divided into four groups and gavage fed either vehicle suspension (control), mefenamic acid, mefenamic acid+caffeine or caffeine only for 4 months. Renal tissue taken from the corticomedullary junction was processed for electron microscopy. Ultrathin sections were cut after identification of vasa rectae on survey sections. On subsequent morphometric analysis, percentage interstitial tissue was calculated from the total area of vasa recta less the non-interstitial tissue. The median percentage of interstitial tissue in the mefenamic acid and caffeine group was 41 (range 33-50; n = 15) compared with 34 (20-48; n = 20) in mefenamic acid (P less than 0.01), 29 (15-42; n = 15) in caffeine only (P less than 0.001) and 32 (20-46; n = 18) in vehicle-treated animals (P less than 0.001). There were no significant differences between mefenamic acid alone and vehicle or caffeine-only groups or between caffeine-only and vehicle-treated controls. This suggests that caffeine potentiates the effect of the non-steroidal anti-inflammatory drug, mefenamic acid, on the rat renal medulla, resulting in a quantitative increase in the interstitial tissue between adjacent afferent and efferent vasa recta.

Animals↗
PubMed1991

Localisation of complement components in association with glomerular extracellular particles in various renal diseases.

Intraglomerular extracellular microparticles including so-called virus-like particles and striated membranous structures have been observed in various renal diseases. The presence and localisation of complement components in these extracellular bodies was studied using the protein A-gold electron microscopy method. Ultrastructurally these particles were differentiated into microspherical structures (MSS) and thread-like structures (TS). Both structures showed weak to moderate diffuse labelling with C1s, whilst the intense labelling found with C3d and C9 was confined to individual membrane-like structures of both MSS and TS. Labelling with IgA, IgG, fibrinogen and the complement components C1q, C1r, C3c C4 and C5 showed negative or trace results. There were no differences between the immunolabelling patterns of MSS and TS, nor among different renal diseases in which these structures were found. These findings raise the possibility that formation of so-called virus-like particles such as MSS and TS may be associated with complement activation.

Complement System Proteins↗
PubMed1991

Platelet-derived growth factor mesangial deposits in mesangial IgA glomerulonephritis.

Platelets may play a role in the pathogenesis of IgA glomerulonephritis (IgAGN). Ultrastructural labelling of platelet antigens might identify activated platelets, and localisation of platelet antigens may assist in understanding the role of platelets in glomerular disease. We examined renal biopsies from eight patients with mesangial IgAGN using protein A-gold immunoelectron microscopy. Serial sections were stained with antisera against platelet-derived growth factor (PDGF), platelet factor 4, beta-thrombolglobulin, platelet glycoprotein IIb-IIIa complex, and fibrinogen, as well as antisera against IgA, IgG, IgM and C3c. Platelets, including activated and degranulated platelets, were detected in capillaries in five of eight biopsies. PDGF was detected in mesangial deposits in five of eight cases. In one case immunolabelling was as intense as IgA labelling. Fibrinogen labelling was present in six of eight. Less intense labelling or negative results were obtained with the other antisera. There was no correlation between intensity of immunolabelling and any clinical or morphological features reflecting severity of glomerular lesions. The role of platelets in the pathogenesis of IgAGN remains unclear. The documentation of frequent deposit of PDGF should stimulate further interest in PDGF participation in this condition.

Blood Platelets↗
PubMed1991

ACTH hypertension in the rat: role of kidney and gonads.

1. Adrenocorticotrophin (ACTH) administration produces an adrenally dependent rise in blood pressure in rats. 2. The haemodynamic and metabolic effects of ACTH were examined in nephrectomized, 5/6 nephrectomized and orchidectomized male Sprague-Dawley rats and sham operated controls. 3. Reduction in renal mass did not increase the blood pressure rise produced by ACTH. 4. Gonadectomy did not reduce the blood pressure rise produced by ACTH, which was slightly higher in castrated animals.

Adrenocorticotropic Hormone↗
PubMed1991

Atypical structured glomerular deposits: an immunohistochemical study.

Atypical structured glomerular deposits were identified in sub-epithelial, sub-endothelial and mesangial areas in biopsy tissue from a female, aged 33, who presented with anaemia and was found to have proteinuria and microscopic haematuria. Histological examination showed that the deposits were periodic acid Schiff positive and silver negative whilst stains for amyloid were negative. Immunofluorescent staining for all immunoglobulins was negative, and only C3 showed moderate labelling. Conventional electron microscopy revealed that all deposits contained microtubular structures of variable length but with an average diameter of 25 nm and a periodicity of approximately 16 nm. The glomerular basement membrane was interrupted in many areas by deposits, and also contained 'myelin-like' structures. Free microtubular structures were also seen in the urinary space. Immunoelectron microscopy using protein-A-gold confirmed the immunofluorescent findings with immunoglobulins and fibrinogen, showed marked positive labelling of deposits with C1s and C3d and also intense labelling of coiled microtubular structures with C9. Other complement components C1q, C1r, C3c, C4 and C5 showed weak or negative results. Although these organised glomerular deposits contain complement components, their pathogenesis remains uncertain.

Adult↗
PubMed1990

Adrenocorticotrophin-induced hypertension in the rat: haemodynamic, metabolic and morphological characteristics.

Adrenocorticotrophin (ACTH) administration has been systematically studied in man and sheep. It raises systolic blood pressure (SBP) in the rat, but this has been little studied. ACTH was injected once daily at 0.5 mg/kg for 12 days in male Sprague-Dawley rats (n = 19). Sham-injected animals were studied in parallel (n = 15). ACTH increased SBP from 94 +/- 4 to 121 +/- 4 mmHg (P less than 0.001), significantly greater (P less than 0.02) than sham injection. The SBP of ACTH-treated rats was significantly higher than that of sham-injected rats when the same animals were measured by both the tail-cuff method (ACTH, 126 +/- 3 mmHg; sham, 99 +/- 3 mmHg) and direct arterial cannulation (ACTH, 137 +/- 2 mmHg; sham, 123 +/- 3 mmHg): P less than 0.005 and P less than 0.001, respectively. There was a loss of body weight, and increased water intake and urine output in ACTH-treated animals compared with both control (P less than 0.001) and sham treatments (P less than 0.02). ACTH increased plasma [Na] (sham, 140 +/- 1 mmol/l; ACTH, 145 +/- 1 mmol/l; P less than 0.001) and urinary Na excretion compared with control (P less than 0.01) and sham injection (P less than 0.05), and also decreased plasma [K] (sham, 4.6 +/- 0.2 mmol/l; ACTH, 3.3 +/- 0.8 mmol/l; P less than 0.01) and increased urinary K excretion (P less than 0.01) compared with control. SBP in adrenalectomized animals (n = 10) was unchanged by ACTH. ACTH increased adrenal, renal, cardiac and brain weights compared with sham injection (P less than 0.05). There were no significant changes in vascular morphology, although ACTH treatment increased glomerular epithelial cell droplets and abolished the adrenal zona glomerulosa.

Adrenal Glands↗