Biomedical subjects
Publications and source records attributed to P K Donnelly.
Though milky nipple discharge is frequently seen in neonates, blood stained discharge from the nipple is an exceptionally rare phenomenon. We noted a case of a three-month-old baby girl who presented with bilateral blood stained nipple discharge without signs of inflammation; engorgement or hypertrophy and which subsided without any intervention. This case is reported along with literature review about managing this rare condition.
Alpha2-Macroglobulin receptor/low-density lipoprotein receptor-related protein is a multifunctional cell surface receptor known to bind and internalize a large number of ligands. alpha2-Macroglobulin receptor-associated protein acts as an intracellular "chaperone" for this receptor, and it has been shown to inhibit binding of all its known ligands. In this paper, we characterize the expression of the receptor-associated protein in both normal human epidermal melanocytes and in six different human melanoma cell lines, by the use of flow cytometry and Western blotting analysis. We show that all the melanoma cell lines and the normal melanocytes express the receptor-associated protein at similar levels, with most located intracellularly. No receptor-associated protein was detected at the cell surface in the melanocytes or in three of the cell lines. However, in two of the melanoma cell lines, large amounts of receptor-associated protein were found on the cell surface, these having the largest amounts of it reported to date; in a further melanoma cell line, there was a small amount at the cell surface. We have also shown that the melanocytes and all the melanoma cell lines express the receptor itself at a wide range of levels, the highest levels of both the cell surface receptor and the cell surface receptor-associated protein being found in one particular melanoma cell line. By growing the cell lines under controlled conditions, we have demonstrated that, although the total cellular content of the receptor is markedly increased at high cell culture density, this treatment has no effect on the level of expression of the receptor-associated protein.
alpha2-Macroglobulin receptor/low density lipoprotein receptor-related protein (alpha2 MR/LRP) is a multifunctional cell surface receptor that binds and endocytoses several structurally and functionally distinct ligands. Very little is known about the expression and function of alpha2 MR/LRP in tumour cells. The aim of this study was to quantify the number of alpha2 MR/LRP on surfaces of human tumour cells by flow cytometry. Using human alpha2 MR/LRP monoclonal antibody 8G1, human peripheral blood lymphocytes (negative control cells), monocytes (positive control cells), human neonatal foreskin fibroblast cells (NFF) (positive control cells), three human breast cancer cell lines (BT-20, T-47D, and MCF-7), two human ovarian tumour cell lines (JAM, and CI80-13S), and five human melanomas (MM418c1, MM253c1, A2058, MM138, MM370) were indirectly labelled with goat anti-mouse IgFITC. The fluorescent signals of stained cells were measured by flow cytometry. Using Quantum Simply Cellular bead standards, the number of alpha2 MR/LRP binding sites per cell was assessed. The flow cytometric method to quantify of alpha2 MR/LRP described here is simple and reliable. All the human tumour cell lines so far examined express alpha2 MR/LRP at different levels from approximately 300 to approximately 10000 sites per cell.
The aim of this study was to test the hypothesis that nifedipine will improve graft survival in cyclosporin A (CyA)-treated renal transplant recipients. One hundred and forty-seven patients were randomised to one of three regimens. Group A received CyA, 7 mg/kg per day, and prednisolone; group B followed the same regimen as group A plus oral nifedipine and group C received CyA, 4 mg/kg per day, prednisolone and azathioprine. Calcium channel blockers were avoided in groups A and C. The crude 2-year (P = 0.0223) and 4-year (P = 0.0181) graft survival was significantly better in group B (86% and 81%, respectively) than in group A (75% and 63%, respectively). Delayed initial function was seen least frequently in group B (10.2%) compared to groups A (31%) and C (28%; P < 0.01). Group B also experienced fewer rejection episodes than groups A and C (P < 0.05). We conclude that the combination of oral nifedipine and CyA significantly improves initial graft function, rejection frequency and long term graft survival.
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Explore the source record for details and available documents.
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Some 27 (5.5 per cent) of 492 renal transplant recipients developed de novo cancer between January 1975 and December 1991. Patients administered triple therapy of prednisolone, cyclosporin A and azathioprine had a significantly higher incidence of cancer (seven of 40 patients; 17.5 per cent) than those given prednisolone with cyclosporin (14 of 319; 4.4 per cent) and azathioprine with prednisolone (six of 133; 4.5 per cent) (P = 0.005). In a prospective study between January 1989 and December 1992, 110 renal transplant patients were randomized into three immunosuppressive regimens at the time of transplantation. The incidence of cancer in patients receiving low-dose cyclosporin, azathioprine and prednisolone was three of 45, in those given high-dose cyclosporin and prednisolone none of 23 and in those administered high-dose cyclosporin, nifedipine and prednisolone one of 29. The addition of azathioprine to ongoing maintenance cyclosporin and prednisolone therapy is useful in a subgroup of patients with graft dysfunction, but there are possibly higher risks in the development of de novo carcinoma.
Techniques for vascularized pancreas transplantation are relatively standardized, whereas those for human islet isolation and transplantation are rapidly changing and evolving. The commonest method for transplanting the vascularized pancreas is to use the entire pancreas together with a segment of donor duodenum, and to anastomose this to the recipient bladder. This technique offers the advantages of technical ease, the maximum beta-cell mass is transplanted and graft function can be monitored by measuring urinary amylase levels. Human islet isolation requires that the pancreas is dissociated, the islets purified and then transplanted to a well-vascularized location. The pancreas is dispersed by a combination of the intraductal injection of collagenase and gentle mechanical agitation, and the islets separated from contaminating exocrine tissue by density-gradient centrifugation. Once purified, the islets can be placed into tissue culture or cryopreserved. The commonest site for human islet transplantation is intraportal injection so that the islets are embolized throughout the liver. Alternatives include transplantation to the renal subcapsular space or the spleen.
Nifedipine increases the frequency and severity of gingival hyperplasia associated with CyA therapy in renal transplant recipients and this effect appears to be independent of whole-blood CyA levels. De novo malignancies have been reported arising in areas of gingival hyperplasia, in a group already at high risk of malignancy. Patients receiving CyA and nifedipine should receive advice regarding the need for strict oral hygiene to control the initial development of gingival hyperplasia, with severe cases being promptly referred for gingivectomy and histological examination.
The access of choice for patients receiving regular dialysis therapy remains the surgically created arteriovenous fistula. In a number of such patients as well as those requiring treatment for acute renal failure, plasmapheresis or hemoperfusion alternative techniques of access are used. Of the techniques used subclavian and femoral catheterization are preferred for short-term vascular access while in patients requiring long term vascular access the use of a surgically inserted central venous line is favoured. The technology performance and clinical aspects of the use of large bore and implantable catheters are reviewed.
AIMS: To compare the degree of interstitial fibrosis in renal transplant biopsy specimens from immunosuppressed patients using conventional doses of cyclosporin with and without calcium channel blockade with a combination of low dose cyclosporin and azathioprine; to correlate the degree of interstitial fibrosis with the glomerular filtration rate. METHODS: A single blind histomorphometric assessment was done of cortical interstitial volume fraction from biopsy specimens taken intraoperatively and at one, six, and 12 months after transplantation from three prospectively randomised groups of patients: (A) conventional dose cyclosporin; (B) conventional dose cyclosporin plus nifedipine; (C) low dose cyclosporin plus azathioprine. RESULTS: Interstitial volume increased with time in all groups. No differences in interstitial volume were present at operation or at one month, but at six months interstitial volume was significantly less in group B than group A (p < 0.001) or group C (p < 0.05). More grafts failed in group A than group B leaving only small numbers for comparison at 12 months. At 12 months the differences persisted but did not reach significance. These results strongly reflected the clinical findings, where glomerular filtration rate was significantly lower in group A than groups B or C at six and 12 months; no differences in glomerular filtration rate were found at one month. In a direct comparison glomerular filtration rate showed a significant negative correlation with interstitial volume fraction. CONCLUSIONS: These findings suggest that calcium channel blockade with nifedipine slows the development of interstitial fibrosis in renal transplant recipients treated with cyclosporin. When clinical data are considered, it is suggested that calcium channel blockade may have a mitigating effect on the long term nephrotoxic effects of cyclosporin and should be considered as adjunctive treatment in patients requiring this immunosuppressant following renal transplantation.
Light reflection rheography (LRR) has been developed as a simple, quick and non-invasive test of venous function which reproduces the haemodynamic parameters of venous pressure measurements by recording changes in dermal blood content of the lower limb during exercise. It uses the same principles as photoplethysmography (PPG) but is simpler to use in a clinical context. To assess the comparability of LRR, changes in ambulatory venous pressure measurements were compared to simultaneous recordings of LRR in 40 limbs of 20 individuals with venous stasis during and after a standard exercise. One hundred and twenty paired observations were made with an excellent correlation between venous refill times (VRT) recorded by the two methods (r = 0.85, P < 0.01). There was no significant correlation between exercise induced changes in venous pressure (delta P) and light reflection (delta LR) as measures of venous emptying. LRR also demonstrated differences in VRT and delta LR of the limbs of normal subjects and those with signs of venous stasis (varicose veins) (P < 0.0001). Light reflection rheography is thus a simple accurate test of venous function which may be of value in both the pre- and postoperative assessment of venous function.
Serial ultrasonographic measurements of renal transplant cross-sectional area were used to quantify allograft swelling as a diagnostic test of acute rejection. Eighty consecutive episodes of acute allograft dysfunction (rise in creatinine level > or = 10 per cent or > or = 30 mumol l-1) were investigated. Needle core biopsy was performed in all cases to diagnose acute rejection. Rejecting transplants demonstrated a median (interquartile range) swelling of 16.2 (12.1-25.5) per cent compared with 2.2 (-2.0 to 8.4) per cent for non-rejecting organs (P < 0.001). A > or = 10 per cent increase as the diagnostic threshold for rejection yielded a sensitivity of 80 per cent, specificity of 77 per cent, positive predictive value of 85 per cent, negative predictive value of 71 per cent and overall accuracy of 79 per cent. Using a logistic regression model, predictive probabilities of rejection for individual changes in cross-sectional area were calculated. A 20 per cent increase was associated with a predicted probability of rejection of 87 per cent (95 per cent confidence interval 75-94 per cent). There was a significant correlation between the functional severity of rejection and the degree of transplant swelling (rs = 0.63, P < 0.001). Ultrasonographic measurement of renal transplant cross-sectional area is a simple non-invasive test for the diagnosis of acute rejection.
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Daily ultrasonographic measurements of transplant cross-sectional area were used to quantify allograft swelling as a diagnostic test for acute rejection in a series of 120 renal transplants. Initial graft function (IF) occurred in 86 patients (72%) and primary non-function (PNF) occurred in the remaining 34 (28%). An increase in allograft cross-sectional area greater than or equal to 10% was defined as a positive ultrasound scan suggesting an acute rejection episode and was investigated by needle core biopsy. During periods of PNF, allografts with consistently negative ultrasound scans were submitted to needle core biopsy on a weekly basis. The diagnosis of rejection was based exclusively on the histological findings. In the IF group, agreement between ultrasound and histological diagnosis was good (k = 0.63, sensitivity 81%, specificity 83%, positive predictive value 76%, negative predictive value 86% and overall accuracy 82%). In the PNF group, agreement between ultrasound and histology was only fair (k = 0.46, sensitivity 77%, specificity 70%, positive predictive value 69%, negative predictive value 78% and overall accuracy 73%). It is concluded that a degree of allograft swelling is sometimes associated with acute tubular necrosis, and this makes ultrasound measurements of transplant size a less useful technique of monitoring kidneys with PNF.
Since the introduction of low osmolality non-ionic media, acute reactions to radiographic contrast are uncommon and delayed reactions are especially rare, consisting mostly of mild flu-like symptoms. We report two patients suffering from end-stage renal failure and treated by continuous ambulatory peritoneal dialysis (CAPD) who developed a severe constitutional illness including acute polyarthropathy 6 and 16 h after injection of the low osmolality non-ionic contrast medium, iopamidol. Although the clinical presentation of the reactions was similar to a systemic lupus syndrome there was no immunological evidence to support this as an aetiological mechanism. Since CAPD is a relatively inefficient method of clearing contrast media prolonged high circulating levels of iopamidol may have been a contributory factor to these unusually severe delayed contrast reactions.