Biomedical subjects

A K House

Publications and source records attributed to A K House.

At least 37 records · Page 2Linked to original sources

PubMed1997

Morphometric changes seen in balloon-injured porcine iliac arteries: the influence of sympathectomy on intimal hyperplasia and remodelling.

OBJECTIVES: To assess the influence of lumbar sympathectomy on intimal thickening and arterial remodelling following balloon de-endothelialisation. DESIGN: Experimental animal model with control and treated (sympathectomy) groups. METHODS: Unilateral common iliac artery de-endothelialisation was performed in 36 male pigs using a 5F balloon catheter introduced via the profunda femoris artery. Bilateral lumbar sympathectomies were performed in 18 animals. Both iliac arteries were perfusion-fixed and harvested 4 weeks later. Arterial morphometry was assessed using computer image analysis. RESULTS: Area measurements are expressed as median (interquartile range) in mm2. Balloon injury resulted in significant intimal thickening but no loss of lumen due to compensatory enlargement of the injured artery. Sympathectomy resulted in significant lumen enlargement (4.8 (2.6-6.3) vs. 1.9 (1.7-2.9)) in balloon-injured arteries. Although intimal thickening was reduced (0.9 (0.6-1.7) vs. 1.5 (0.9-2.0)), this was not statistically significant. CONCLUSIONS: Sympathectomy increases lumen area 4 weeks after balloon injury to porcine iliac arteries. This effect is due to a combination of reduced arterial wall thickening and increased arterial size.

Angioplasty, Balloon↗

PubMed1997

Hypothermic ischaemia of the liver: a re-perfusion phenomenon.

BACKGROUND: The effects of hypothermic injury to the liver were investigated on an isolated perfusion circuit by comparing porcine livers with varying degrees of preservation injury. METHODS: A group of unstored livers (n = 5) were compared to livers stored in University of Wisconsin (UW) solution for 18 h (n = 5), and a group of livers stored in Hartmann's solution for 18 h (n = 5). RESULTS: We observed that the degree of platelet sequestration was directly related to the severity of the preservation injury. After 2 h of isolated liver perfusion, the perfusate platelet count fell from 148 +/- 14 x 10(9)/L to 84 +/- 13 x 10(9)/L for control livers. In comparison for livers stored in UW solution, the platelet count fell from 173 +/- 43 x 10(9)/L to 61 +/- 14 x 10(9)/L representing a 64.8% fall, while for those stored in Hartmann's solution, an even more profound fall from 152 +/- 36 x 10(9)/L to 19 +/- 9 x 10(9)/L (87.5% fall) was observed. The difference between the UW-stored and Hartmann's-stored livers was significant (P < 0.05). However, using this model, the degree of leukocyte sequestration did not differentiate the groups. Both histological and ultrastructural examination of liver biopsies taken immediately following revascularization demonstrated that for mild degrees of preservation injury following hypothermic storage, changes occur to the sinusoidal lining cells well before changes to the parenchymal elements. CONCLUSIONS: These findings substantiate the hypothesis that the primary injury associated with hypothermia involves the sinusoidal lining cells (non-parenchymal elements), that it is predominantly a reperfusion phenomenon and that efforts at improving preservation should therefore be targeted primarily at these cells and not the hepatocytes.

Adenosine↗

PubMed1997

Intra-abdominal fluid collections after liver transplantation.

Fluid collections are commonly seen following orthotopic liver transplantation. The majority of these collections are not infected and resolve spontaneously. However, infected collections are associated with significant morbidity and mortality and usually require drainage. Clinical signs of infection are frequently masked following transplantation due to immunosuppression. Intrahepatic collections usually represent abscesses or bilomas and invariably require intervention. Altered anatomical relationships result in signs that frequently help to differentiate these from loculated fluid within hepatic fissures. Other imaging features indicating infection include the presence of gas where none was seen previously, the development of a discrete wall and changes in the surrounding liver.

Ascites↗

PubMed1996

Monocyte chemoattractant protein-1 gene expression in injured pig artery coincides with early appearance of infiltrating monocyte/macrophages.

Monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) are potent chemokines which attract circulating monocytes and neutrophils respectively to inflamed tissues. JE/MCP-1 gene expression has been previously studied in rabbit aortae after endothelial denudation and the rapid appearance of this transcript was thought to precede emigration of phagocytes. We now report MCP-1 gene expression following de-endothelialization of iliac arteries in the pig, a species which can develop spontaneous atherosclerosis. Using Northern blot analysis, we demonstrated that MCP-1 mRNA was rapidly induced in pig arteries at 2 h and continued to increase to reach a maximum at 8 h before returning to low levels at 16-24 h after injury. The increase seen for MCP-1 mRNA at 8 h was also observed for IL-8 mRNA but was not apparent for growth-related gene expressions, urokinase-type plasminogen activator (u-PA), and plasminogen activator inhibitor-1 (PAI-1). Since smooth muscle cells, endothelial cells, and phagocytes are all capable of expressing MCP-1, we examined pig arteries for immunostaining using a monoclonal antibody to human MCP-1 (5D3-F7). At 8 h after injury, the predominant cell type staining positive for MCP-1 was the monocyte/macrophage. Staining was also observed in occasional scattered neutrophils, but MCP-1 protein could not be detected in smooth muscle cells or on extracellular matrix within the sensitivity constraints posed by our methodology. Our results are consistent with invading monocyte/macrophages having a major input into the production of this chemokine in the arterial wall following injury. The fact that MCP-1 expression accompanied monocyte/macrophage presence in damaged artery, rather than preceding it, is suggestive that continued MCP-1 expression is required for functions other than chemoattraction.

Animals↗

PubMed1996

p53 accumulation and mutation are prognostic indicators of poor survival in human gastric carcinoma.

The aim of our study was to examine the prognostic significance of p53 protein accumulation and gene mutation in a series of 116 gastric carcinomas from a low incidence population. Formalin-fixed, paraffin-embedded tumour sections were used to investigate p53 protein accumulation by immunostaining with monoclonal antibody (MAb) DO-7 and p53 gene mutation by single-strand conformation polymorphism analysis of exons 5-8. Nuclear p53 accumulation was detected in 23% of tumours and mutation in 28%. Concordance between the 2 alterations was observed in 73% of cases. p53 protein accumulation was more frequent in tumours with lymph node metastasis, while p53 mutations were more frequent in tumours from older patients. The histopathological parameters of depth of invasion, grade and histological type showed no significant associations with either p53 alteration. In univariate analysis, both alterations were associated with significantly shortened patient survival. The 5-year survival rate for patients with a p53 mutation was 9% compared to 42% for those without a mutation. In multivariate analysis adjusted for the other histopathological parameters, p53 gene mutation but not immunohistochemically-detected p53 protein accumulation was an independent prognostic indicator of poor survival in gastric carcinoma.

Adult↗

PubMed1996

Role of cimetidine in the prevention of intimal hyperplasia in rat carotid artery.

In vitro studies have revealed that histamine increases smooth muscle cell proliferation and migration, an effect abolished by the H2 antagonist cimetidine. This study examined the effect of cimetidine on intimal hyperplasia in vivo. Thirty male Wistar rats underwent endothelial denudation of the left carotid artery; 15 received cimetidine 350 mg per kg per day for four weeks and 15 received vehicle only. Four weeks after injury the left carotid arteries were perfusion fixed and harvested. Morphometric analysis revealed that there was no significant difference between the intima:media ratio of rats treated with cimetidine (median (interquartile range (i.q.r.)) 1.69 (0.59)) and those treated with vehicle (median (i.q.r.) 1.59 (0.59), P = 0.28). Similarly, the percentage luminal reduction was not significantly different between the groups (median (i.q.r.) 54.7 (19.9) per cent and 45.8 (13.4) per cent respectively, P = 0.30). It is concluded that treatment with cimetidine does not reduce the formation of intimal hyperplasia in rat carotid arteries de-endothelialized with a balloon catheter.

Animals↗

PubMed1996

Vitamin D3 exacerbates intimal hyperplasia in balloon-injured arteries.

Although a high dose of vitamin D3 is known to cause arterial calcification and degeneration, its effect on intimal hyperplasia has never been studied. The aim of this study was to examine the influence of a moderate supplement of vitamin D3 on intimal hyperplasia in the balloon-injured rat carotid artery. Forty-four rats had balloon injury to the carotid artery; 22 were given oral vitamin D3 supplementation (0.25 microgram kg-1 day-1). Animals were killed at 4 weeks and the carotid arteries were perfusion fixed and assessed morphometrically by means of computerized image analysis of transverse sections. Mean (s.e.m.) intimal area was significantly greater in the vitamin D3-treated animals than in controls: 0.92(0.05) versus 0.71(0.07) mm2 (P = 0.02). The area of the media of both injured and uninjured arteries was not influenced by vitamin D3 administration. A small dose of vitamin D3 resulted in significant exacerbation of intimal hyperplasia in this rat carotid artery model and raises the question of the role of dietary vitamin D3 in restenosis following vascular intervention.

Animals↗

PubMed1996

Concordance between p53 protein overexpression and gene mutation in a large series of common human carcinomas.

Immunohistochemical (IHC) detection of p53 protein was compared with the presence of p53 gene mutation in many colorectal (n = 100), breast (n = 92), endometrial (n = 122), and gastric (n = 116) carcinomas. Two commercially available antibodies, DO7 and CM1, were used for IHC analysis of paraffin-embedded tissue sections. Screening for gene mutations in frozen and paraffin-embedded tumor samples was carried out using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP). The frequency of nuclear staining with DO7 or CM1 for each tumor type, respectively, was colorectal (36%, 23%); breast (15%, 19%); endometrial (21%, 33%); and gastric (23%,-). Overall correlation between the two antibodies for nuclear staining was 90% for the 314 tumors analyzed. Cytoplasmic staining was observed with DO7 in 7% of breast and 5% of gastric carcinomas and with CM1 in 17% of breast and 54% of endometrial carcinomas. p53 gene mutation was found in 39% of colorectal, 28% of breast, 13% of endometrial, and 25% of gastric cancers. The concordance between p53 nuclear overexpression and gene mutation (both positive or both negative) was 68% for colorectal, 79% for breast, 76% for endometrial, and 73% for gastric carcinomas. This study provides further evidence that IHC detection of p53 protein accumulation does not always indicate the presence of a gene mutation and vice versa. Discordant results were observed in approximately 20% to 30% of the tumors studied, highlighting the need for careful characterization of both p53 gene and protein alterations when assessing the relationship between p53 status and tumor behavior.

Breast Neoplasms↗

PubMed1996

Expression of transforming growth factor-beta1 (TGF-beta1) and urokinase-type plasminogen activator (u-PA) genes during arterial repair in the pig.

OBJECTIVE: The transition from quiescence to proliferation in vitro is accompanied by early expression of proliferation-associated genes encoding products including cytokines and enzymes. We aimed to investigate TGF-beta1, u-PA and PAI-1 gene expressions in relation to proliferation and extracellular matrix (ECM) protein gene expressions in porcine arteries following injury. METHODS: Right iliac arteries of juvenile pigs were de-endothelialised and harvested at fixed times after injury. RNA was then extracted and analysed by Northern blot analysis. RNA transcripts in thickened neointima of arteries were examined by in situ hybridisation using digoxygenin-labelled cDNA probes. RESULTS: TGF-beta1, u-PA and PAI-1 transcripts were rapidly elevated (2-8h) and preceded a peak in histone mRNA at 24h after arterial injury. A second prolonged rise in TGF-beta1 mRNA at 4d coincided with elevated ECM protein gene expression. TGF-beta1 gene expression was detected in neointimal cells lining the arterial lumen at 4wk after injury. CONCLUSIONS: The timings of increases in TGF-beta1, u-PA and PAI-1 mRNAs in injured arteries are consistent with contributions to processes prior to proliferation. The observation of a second protracted elevation in TGF-beta1 expression is supportive of an additional role in stimulation of ECM protein synthesis. Functional specialisation exists within the thickened intima of arteries late in repair.

Animals↗

PubMed1995

Short-term and long-term outcome following renovascular reconstruction.

Experience with renovascular reconstruction at the authors' institution over the past 16 years has been reviewed. A total of 76 patients underwent surgical intervention for renovascular disease during that time. This included 62 patients with atherosclerosis and 11 with fibromuscular hyperplasia. Indications for intervention were uncontrolled hypertension in 42 patients and to restore renal impairment in eight. The procedure was performed for both indications in 26 patients. Ten patients (13%) died in the perioperative interval, which correlated strongly with comorbidity. With the exception of one patient, all deaths occurred in the elderly (> 65 years). While an increased mortality rate (P < 0.05) was observed in those undergoing concomitant surgical procedures (20%) as opposed to those undergoing renovascular reconstruction alone (6%), this was not an independent risk factor. Both the short term and long term response of hypertension control to renovascular reconstruction were favourable, with age < 60 years, shorter duration of hypertension (< 5 years) and diagnosis of fibromuscular hyperplasia predictive of a better response. Renovascular reconstruction, while successful in stabilizing or even improving renal function in the short term, was poor at restoring function long term, especially in the subgroup of patients whose serum creatinine was > 200 mumol/l at the time of reconstruction.

Adolescent↗

PubMed1995

Clonal analysis of colorectal tumors using K-ras and p53 gene mutations as markers.

Mutations to the K-ras oncogene and p53 tumor suppressor gene are two of the most common genetic lesions in human cancers. In the present study we examined the clonality of colorectal tumors with respect to each of these genetic alterations. Screening for mutations was carried out using the polymerase chain reaction-based technique of single-strand conformation polymorphism. Eleven primary colorectal adenocarcinomas and two secondary adenocarcinomas were analyzed at four different sites within the tumor. Involved pericolic lymph nodes were collected from nine of these cases, a metastatic deposit in the liver was obtained in one case, and adjacent adenomatous lesions were collected in two cases. Seven tumors contained mutations in either the K-ras or p53 genes. In all cases, DNA derived from multiple sites within an individual tumor or metastatic deposits arising from that tumor showed the same pattern of gene mutation. Immunohistochemical staining for p53 protein overexpression also showed similar patterns of reactivity within individual tumors and their metastatic deposits. These results suggest that the major clonal expansion of colorectal carcinomas occurs after the acquisition of mutations in these genes. Our results also indicate that sampling errors are unlikely to occur in molecular studies aimed at defining the role of these genes in colorectal cancer progression.

Carcinoma↗

PubMed1995

A method for the treatment of ureteric complications following renal transplantation.

Over an 8-year period, 117 renal transplants (97 cadaveric and 20 living related) were performed at the Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. Ureteric complications following renal transplantation occurred following seven transplants (6%). The technique of using a multiply fenestrated vesicocutaneous stent/drain to manage this problem is described. This was uncomplicated in all cases with the exception of one case in which the stent/drain was removed early because of blockage and sepsis, but most importantly on no occasion was the graft lost. We therefore recommend this technique for the management of this complication, whether early or late. We observed a disproportionate number of ureteric complications in living related transplants, a feature not described previously.

Adult↗

PubMed1995

Radiological predictors of response to renovascular reconstructive surgery.

The aim of this study was to identify preoperative angiographic criteria which could be used to predict the response to renovascular reconstruction. A cohort of 49 patients who survived for more than 6 months after renovascular reconstruction was studied. All preoperative angiograms were reviewed independently and the renal size, degree of stenosis and the length of the lesion recorded. The response of blood pressure and renal function to surgery were correlated with the angiographic findings. We found that 58% of patients had long-term improvement in blood pressure control, though the response was significantly better where both kidneys were >12 cm in size (82%) compared with when both kidneys were < 12 cm (25%), P < 0.02. The degree of stenosis, while showing a trend towards a better blood pressure response with increasing stenosis, was not a statistically significant factor. None of the angiographic criteria examined could be used to predict the response in renal function. We have shown that the preoperative renal size is the only angiographic factor that may have some role in predicting the response of blood pressure to renovascular reconstruction.

Adult↗

PubMed1994

The common molecular genetic alterations in Dukes' B and C colorectal carcinomas are not short-term prognostic indicators of survival.

Our study was undertaken to determine the prognostic significance of several common genetic alterations observed in colorectal carcinomas. We have previously analysed loss of heterozygosity of the MCC, APC, p53 and DCC tumour suppressor gene loci as well as p53 gene mutations and protein over-expression in a series of 100 Dukes' stage B and C colorectal tumours obtained at surgery. To extend our observations of alterations that may occur in these tumours, mutations to the c-Ki-ras oncogene and APC tumour suppressor gene were detected by PCR single-strand conformation polymorphism analysis. Short-term follow-up revealed no significant association between overall patient survival and any single, or combination of, genetic alteration(s). Surprisingly, patients whose tumours showed evidence of p53 protein over-expression/accumulation by immunocytochemistry (ICC) had a significantly better prognosis (p = 0.039) than those whose tumours had no p53 ICC reactivity.

Adenocarcinoma↗

PubMed1994

A comparison of flushing solutions for liver procurement using an isolated perfused porcine model.

There is no agreement on the best technique of in situ flushing of livers prior to storage. In order to study this, porcine livers were stored in the University of Wisconsin (UW) solution for 18 h and then assessed using an isolated perfused porcine model. Livers flushed in situ with UW solution were compared to livers flushed with a non-preservation solution (Hartmann's solution). No statistically significant differences could be found in bile production (18.7 +/- 4.4 vs 17.9 +/- 3.8mL/1000 g per 2 h), aspartate amino-transferase (AST) levels in the perfusate after 2 h of isolated perfusion (687 +/- 101 vs 724 +/- 114 U/L), potassium levels in the perfusate after 2 h on the circuit (5.4 +/- 1.5 vs 5.5 +/- 2.3 mmol/L), weight gain (15.2 +/- 3.7 vs 17.1 +/- 4.0%) or platelet sequestration (41.6 +/- 11.7 vs 37.4 +/- 9.8%) between livers flushed with UW solution as opposed to those flushed with Hartmann's solution, respectively. Of overriding importance was the solution in which the liver was stored, reconfirming the superiority of UW solution over an extracellular solution for preservation. If extrapolated to the clinical situation, these findings would have substantial cost-saving implications.

Adenosine↗

PubMed1993

The cyclophilin component of the unactivated estrogen receptor contains a tetratricopeptide repeat domain and shares identity with p59 (FKBP59).

Using a rapid single-step affinity chromatography procedure we have isolated the unactivated estrogen receptor from bovine uterus. Results of sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western analyses for protein extracts recovered from affinity chromatography of receptor cytosols, either preincubated or untreated with estradiol, suggest a component structure for the intact oligomeric receptor which includes hsp90, hsp70, p59, a 40-kDa cyclophilin-related protein, and an uncharacterized 22-kDa protein species. We have chemically determined the amino acid sequences of eight peptides derived from the 40-kDa component and now report the cloning and primary sequence of a cDNA encoding this protein, which is designated estrogen receptor-binding cyclophilin (ERBC). Homology analyses confirm that ERBC is a new member of the cyclophilin family and contains a C-terminal domain with significant sequence homology to an internal region of p59, a binding protein for the immunosuppressant FK506 (FKBP59). This conserved region includes a 3-unit tetratricopeptide repeat domain bounded at the C terminus by a putative calmodulin binding site. We propose that the tetratricopeptide repeat domain mediates the protein interaction properties of ERBC and p59. Both immunophilins may have important roles in receptor assembly and may represent a new category of ligand- and calcium-dependent modulators of protein function.

Amino Acid Isomerases↗

PubMed1993

The influence of nifedipine on microvascular vein graft intimal thickening.

The influence of high-dose Nifedipine on the intimal thickening seen in experimental vein grafts was studied in an established rat model. The iliolumbar vein was grafted to the common iliac artery in 28 control and 30 Nifedipine-treated animals. There was one death in the control group and 10 deaths due to drug aspiration in the treated group; a further six control and four treated grafts were excluded from analysis due to occlusion or histological artefact. Animals were killed at 3 weeks, at which time a Nifedipine assay was performed. Longitudinal sections of the graft were prepared and the intimal thickness in the proximal, mid and distal graft measured using an eyepiece graticule. Median (range in brackets) intimal thicknesses for the control group were as follows: proximal 50 microns (10-120), mid 30 microns (10-70), and distal 30 microns (10-100). Results for the treated group were: proximal 65 microns (10-110), mid 30 microns (5-90), and distal 35 microns (20-120). There was no statistically significant difference between the two groups suggesting that Nifedipine is not of value in the inhibition of early vein graft intimal thickening.

Animals↗

PubMed1993

Influence of dexamethasone on intimal thickening in experimental vein graft.

The influence of dexamethasone on vein graft intimal hyperplasia was studied in a rat model. The iliolumbar vein was grafted to the common iliac artery in 42 rats. Twenty animals were treated with dexamethasone 0.1 mg/kg per day by injection for 3 weeks; 22 control animals received saline injections. Grafts were harvested at 3 weeks and longitudinal sections prepared. Five deaths and considerable morbidity was seen in the dexamethasone-treated animals. All grafts in the surviving animals in both groups were patent at 3 weeks. Intimal thickening, measured in the proximal, mid and distal graft, was found to be maximal in the proximal graft and least in the mid-portion of the graft. Dexamethasone reduced intimal thickening throughout the graft; the median thickness of the proximal graft was 30 microns (control 50 microns), in the mid-graft 10 microns (control 30 microns) and in the distal graft 20 microns (control 30 microns). This reduction was statistically significant in the mid-graft only (P < 0.05; Mann-Whitney U test). The small effect on anastomotic intimal thickening suggests that dexamethasone is of limited use in the prevention of vein graft intimal hyperplasia in clinical practice.

Anastomosis, Surgical↗