Biomedical subjects

I J Franklin

Publications and source records attributed to I J Franklin.

6 recordsLinked to original sources

PubMed2001

Provocation of experimental aortic inflammation and dilatation by inflammatory mediators and Chlamydia pneumoniae.

BACKGROUND: The macrophage appears to have a key role in the inflammation and proteolysis associated with the growth and development of abdominal aortic aneurysms. The role of inflammatory mediators and Chlamydia pneumoniae in stimulating the influx of macrophages and dilatation of the abdominal aorta was investigated in an experimental model. METHODS: Periaortic application of calcium chloride solution (and monocyte chemoattractant protein (MCP) 1, a cocktail of cytokines or C. pneumoniae) to the abdominal aorta of New Zealand White rabbits was performed at laparotomy. Some animals were fed a cholesterol-rich diet. The diameter of the aorta was measured by ultrasonography and after perfusion fixation, 3 weeks after laparotomy. Aortic sections were stained with RAM-11 to identify macrophages for counting. The presence of C. pneumoniae DNA was confirmed using the polymerase chain reaction. RESULTS: Aortic macrophage influx in response to MCP-1, thioglycollate or C. pneumoniae was more than doubled in the cholesterol-fed animals. In response to human recombinant MCP-1 (1 microg) the mean(s.d.) macrophage count increased from 79(19) to 340(215) per unit area (P < 0.02). Even in cholesterol-fed animals, application of MCP-1 (recombinant human or rabbit form) was not associated with aortic dilatation. Application of thioglycollate 0.1 mol/l, or live or formalin-inactivated C. pneumoniae (0.5 x 108 organisms), was associated with a similar increase in macrophages to that caused by MCP-1 and a significant (approximately twofold) increase in aortic diameter after 3 weeks. CONCLUSION: Macrophage influx into rabbit abdominal aorta, without macrophage activation, is insufficient to cause experimental aortic dilatation. C. pneumoniae antigens appeared to stimulate aortic dilatation, probably by specific activation of macrophages.

Animals↗

PubMed1999

Inhibition of prostaglandin E2 synthesis in abdominal aortic aneurysms: implications for smooth muscle cell viability, inflammatory processes, and the expansion of abdominal aortic aneurysms.

BACKGROUND: There is no treatment proven to limit the growth of abdominal aortic aneurysms, in which the histological hallmarks include inflammation and medial atrophy, with apoptosis of smooth muscle cells and destruction of elastin. METHODS AND RESULTS: Aneurysm biopsies were used for explant cultures, the preparation of smooth muscle cell cultures, and isolation of macrophages. Tissue macrophages stained strongly for cyclooxygenase 2. Prostaglandin E2 (PGE2) concentrations in aneurysm tissue homogenates, conditioned medium from explants, and isolated macrophages were 49+/-22 ng/g, 319+/-38 ng/mL, and 22+/-21 ng/mL, respectively. PGE2 inhibited DNA synthesis and proliferation in normal aortic smooth muscle cells (IC50, 23.2+/-3.8 and 23.6+/-4.5 ng/mL, respectively). In smooth muscle cells derived from aneurysmal aorta, PGE2 also caused cell death, with generation of oligonucleosomes. Conditioned medium from the mixed smooth muscle and monocyte cultures derived from explants also had potent growth-inhibitory effects, and fractionation of this medium showed that the growth-inhibitory molecule(s) coeluted with PGE2. In explants, indomethacin 10 micromol/L or mefenamic acid 10 micromol/L abolished PGE2 secretion and significantly reduced IL-1beta and IL-6 secretion. In a separate case-control study, the expansion of abdominal aortic aneurysms was compared in 15 patients taking nonsteroidal anti-inflammatory drugs and 63 control subjects; median growth rates were 1.5 and 3.2 mm/y, respectively, P=0.001. CONCLUSIONS: The adverse effects of PGE2 on aortic smooth muscle cell viability and cytokine secretion in vitro and the apparent effect of anti-inflammatory drugs to lower aneurysm growth rates suggest that selective inhibition of PGE2 synthesis could be an effective treatment to curtail aneurysm expansion.

Adolescent↗

PubMed1999

Uptake of tetracycline by aortic aneurysm wall and its effect on inflammation and proteolysis.

BACKGROUND: Proteolytic degradation of the aortic wall by matrix metalloproteinases (MMPs) is considered important in the pathogenesis of abdominal aortic aneurysms (AAAs). Many of these MMPs are inhibited by tetracycline derivatives, which may have the potential to retard aneurysm growth. METHODS: Patients undergoing elective repair of an AAA (n = 5) received an intravenous bolus of tetracycline (500 mg) on induction of anaesthesia and levels of tetracycline in serum, aneurysm wall and mural thrombus were assessed by microbiological assay. In a separate series of patients (n = 7) aneurysm biopsies were placed into explant culture (with and without tetracyline) and the accumulation of protein, hydroxyproline, MMP-9, interleukin (IL) 6 and monocyte chemoattractant protein (MCP) 1 in the medium was assessed by colorimetric assay or immunoassay. RESULTS: At aortic cross-clamping the median concentration of tetracycline was 8.3 microg/ml in serum, 2.9 microg per g tissue in aortic wall and zero in mural thrombus. Tetracycline inhibited, in a concentration-dependent manner, both MMP-9 and MCP-1 secretion (P = 0.022 and P = 0.018 respectively), but did not alter hydroxyproline or IL-6 secretion. At the highest concentration of tetracycline (100 microg/ml) median MMP-9 secretion was reduced from 27 to 5 ng/ml (P = 0.007) and median MCP-1 secretion was reduced from 50 to 10 ng/ml (P = 0.008). CONCLUSION: Tetracycline rapidly penetrates the aortic wall, but the concentration achieved may be insufficient to alter collagen turnover through limitation of MMP production or activity.

Aortic Aneurysm, Abdominal↗

PubMed1999

The influence of indomethacin on the metabolism and cytokine secretion of human aneurysmal aorta.

INTRODUCTION: inflammation and proteolysis are important processes in the development of abdominal aortic aneurysms (AAAs). Prostaglandin E2 (PGE2) (a product of cyclo-oxygenase 2), other inflammatory mediators and proteolytic enzymes are produced in high quantities in the aneurysm wall. We developed an explant culture system for AAA tissue to assess the effects of potential drug therapies. METHODS: full thickness biopsies of human AAA were established in culture in the presence or absence of indomethacin (a cyclo-oxygenase-2 inhibitor). The conditioned medium was collected at 48 h intervals and analysed for products of collagen breakdown, matrix metalloproteinases, PGE2 and inflammatory cytokines. Explant viability was assessed by histology, glucose consumption, lactate dehydrogenase release and demonstration of protein synthesis in the tissue. RESULTS: nuclear morphology was maintained for 4 or more days and this, together with biochemical assays, indicated that AAA explants were viable in short-term culture. Indomethacin (10 microM) markedly reduced AAA explant production of prostaglandin E2 from 320 ng/ml to 3.3 ng/ml (p=0.028, n=6). Indomethacin also reduced the release of interleukin-1beta (IL-1beta) (from 166 pg/ml to 9.8 pg/ml, p =0.04, n=5) and interleukin-6 (IL-6) (from 119 ng/ml to 57 ng/ml, p=0.028, n=6), but had no effect on monocyte chemotactic protein 1 or matrix metalloproteinase-9 secretion. CONCLUSIONS: short-term explants of AAA are a novel method to assess the effects of drugs on aneurysm tissue. Indomethacin reduces the production of PGE2, IL-1beta and IL-6, suggesting that cyclo-oxygenase-2 inhibitors may control the inflammation in the aneurysm wall and potentially limit AAA growth.

Aorta, Abdominal↗

PubMed1998

Protocol violation in deep vein thrombosis prophylaxis.

This study aimed to determine how closely deep vein thrombosis (DVT) prophylactic policies are adhered to in routine general surgical practice, to identify reasons for policy violations and to assess the effects of policy modification. Eight adult patients, sixty of whom had undergone an operation, under the care of six general surgeons, each with their own written DVT protocol, were studied on one weekday. Thirty patients (50%) did not receive DVT prophylaxis according to the policy of the relevant consultant. Most violations occurred for unacceptable reasons, mainly starting low-dose subcutaneous heparin or using thromboembolic stockings postoperatively. However, 43% of protocol violations occurred for acceptable clinical reasons. Following the initial study, a uniform departmental DVT prophylaxis policy was introduced. Nursing and medical staff were thoroughly appraised of the new policy. In a repeat study of 75 patients 1 year later, there were 15 protocol violations among 58 patients who had undergone an operation (27%). However, there were no violations for acceptable reasons. The number of unacceptable protocol violations in the two studies was similar (24/60 and 17/56). The number of patients at moderate or high DVT risk who received no preoperative prophylaxis was the same in both studies (8/48 in both audits). DVT protocol violations are common in routine general surgical practice. Policy modification and unification results in fewer violations, but made little impact on the level of thromboprophylactic care.

Adolescent↗

PubMed1996

Assessment of peritonism in appendicitis.

The aim of this study was to evaluate the accuracy of different methods of demonstrating right iliac fossa peritonism in appendicitis. The methods used were cat's eye symptom (pain on going over a bump in the road), cough sign, right iliac fossa tenderness, percussion tenderness, rebound tenderness and guarding. A series of 100 consecutive patients with a median age of 25 years (range 4-81 years), presenting with right iliac fossa pain were studied prospectively; the male:female ratio was 39:61. In all, 58 patients underwent operation, 44 had appendicitis confirmed on histology. Fourteen patients had a normal appendix removed; 11 were women aged between 16 and 45 years. Cat's eye symptom and cough sign were sensitive indicators of appendicitis (sensitivity 0.80 and 0.82, respectively), but were not specific (specificity 0.52 and 0.50, respectively) and therefore inaccurate (accuracy 64%). Percussion tenderness was less sensitive (sensitivity 0.57) but more specific (specificity 0.86). Rebound tenderness proved to be sensitive (sensitivity 0.82), specific (specificity 0.89) and accurate (accuracy 86%). Thus, rebound tenderness had a positive predictive value of 86% compared with 56% and 57% for cough sign and cat's eye symptom, respectively. In the difficult diagnostic group of young women, the positive predictive value of rebound tenderness was 88% compared with 58% and 56% for cat's eye symptom and cough sign. Appendicitis remains a difficult diagnosis, particularly in young women. Rebound tenderness still has an important role to play in clinical assessment.

Abdominal Pain↗