Adenocarcinoma arising in a retroperitoneal enterogenous cyst.
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Adenocarcinoma↗
Biomedical subjects
P A Hill
Publications and source records attributed to P A Hill.
The effects of serine proteinase inhibitors on bone resorption in vitro.
The aims of this study were to identify the role and sites of action of serine proteinases (SPs) in bone resorption, a process which involves a cascade of events, the central step of which is the removal of bone matrix by osteoclasts (OCs). This resorbing activity, however, is also determined by recruitment of new OCs to future resorption sites and removal of the osteoid layer by osteoblasts (OBs), which enables OCs to gain access to the underlying mineralized bone. The resorption systems we have studied consisted of (i) neonatal calvarial explants, (ii) isolated OCs cultured on ivory slices, (iii) mouse OBs cultured on either radiolabelled type I collagen films or bone-like matrix, (iv) bone marrow cultures to assess OC formation and (v) 17-day-old fetal mouse metatarsal bone rudiments to assess OC migration and fusion. Two separate SP inhibitors, aprotinin and alpha(2)-antiplasmin dose-dependently inhibited (45)Ca release from neonatal calvarial explants: aprotinin (10(-6) M) was the most effective SP inhibitor, producing a maximum inhibitory effect of 55.9%. Neither of the SP inhibitors influenced either OC formation or OC resorptive activity. In contrast, each SP inhibitor dose-dependently inhibited OB-mediated degradation of both type I collagen fibrils and non-mineralized bone matrix. In 17-day-old metatarsal explants aprotinin produced a 55% reduction in the migration of OCs from the periosteum to the mineralized matrix after 3 days in culture but after 6 days in culture aprotinin was without effect on OC migration. Primary mouse osteoblasts expressed mRNA for urokinase type plasminogen activator (uPA), tIssue type plasminogen activator (tPA), the type I receptor for uPA, plasminogen activator inhibitor types I and II and the broad spectrum serine proteinase inhibitor, protease nexin I. In situ hybridization demonstrated expression of tPA and uPA in osteoclasts disaggregated from 6-day-old mouse long bones. We propose that the regulation of these various enzyme systems within bone tIssue determines the sites where bone resorption will be initiated.
Amyloid beta-Protein Precursor↗
Nephrotic syndrome associated with carcinoma of the breast.
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Breast Neoplasms↗
Delayed renal allograft failure due to polyomavirus-associated tubulointerstitial nephritis.
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Acute Kidney Injury↗
Human breast-cancer cells stimulate the fusion, migration and resorptive activity of osteoclasts in bone explants.
A central event in bone resorption is the recruitment of osteoclasts to future resorption sites. Breast-cancer cells invariably metastasise to the skeleton and induce extensive bone destruction by osteoclasts. However, our understanding of the mechanisms by which cancer cells interact with osteoclasts remains unclear. Consequently, we compared the effects of conditioned medium (CM) from 2 human breast-cancer cell lines, MB-MDA-231 and MCF-7, with those of a normal human breast epithelial cell line, HME, on osteoclastic fusion, resorptive activity and migration from the periosteum to the developing marrow cavity of fetal mouse metatarsals in culture. Osteoclastic resorptive activity was assessed by pre-labelling 17-day-old fetal metatarsal explants with 45Ca, whilst fusion and migration were monitored by histomorphometry and osteoclasts were identified by their tartrate-resistant acid phosphatase activity. CM from TPA-stimulated breast-cancer cell lines produced a significant increase in osteoclastic resorptive activity, whilst the normal breast cell line produced a minimal increase. The breast-cancer cell lines also stimulated osteoclastic fusion and migration in the metatarsal explants, but the normal breast cell line was without effect. The stimulatory effect of CM from MDA-MB-231 cells on osteoclastic fusion, but not migration, was partially inhibited by preventing prostaglandin and leukotriene synthesis by cells within the bone explants. In contrast, a synthetic matrix metalloproteinase (MMP) inhibitor, but not a cysteine proteinase inhibitor, prevented the migration of osteoclasts to the calcified centre of the metatarsal explants in response to CM from MDA-MB-231 cells. MDA-MB-231 cells also induced an increase in the expression of MMP-9 by migrating osteoclasts. Fractionation of the TPA-stimulated breast cancer cell CM established that the resorptive activity was associated with factors of m.w. >3 kDa. We determined by immuno-assay that human breast-cancer cells secrete parathyroid hormone-related protein (PTH-rP), tumour necrosis factor-alpha (TNF-alpha) and interleukins (ILs) 6 and 11. Neutralizing experiments with human antibodies to these cytokines established that PTH-rP and TNF-alpha production by MDA-MB-231 cells were responsible for mediating their effects on osteoclastic migration and ultimately bone resorption in the metatarsal explants.
Animals↗
Recombinant tissue plasminogen activator (alteplase) for restoration of flow in occluded central venous access devices: a double-blind placebo-controlled trial--the Cardiovascular Thrombolytic to Open Occluded Lines (COOL) efficacy trial.
PURPOSE: Central venous access devices (CVADs) are a mainstay of current medical therapy but often become occluded by thrombus. Tissue plasminogen activator (alteplase), at a dose of 2 mg per 2 mL, has been shown to be effective in restoring flow to catheters proven by radiographic contrast injection to be occluded by thrombus. The purpose of this double-blind placebo-controlled multicenter trial was to determine the efficacy of alteplase in occluded catheters without earlier contrast injections or radiographic examinations. MATERIALS AND METHODS: Patients were eligible for inclusion if blood could not be withdrawn from their catheter after a period of normal function of at least 48 hours. Single or multiple catheters, peripherally inserted central catheters, catheters with valves, and implanted ports were eligible; catheters used for hemodialysis were not included. Patients were randomly assigned to one of two groups. In one group, patients received a first dose of 2 mg alteplase followed, if needed, by a second dose of 2 mg alteplase and a third dose of placebo. The other group received placebo first followed by one 2-mg dose of alteplase and then a second, if needed. Each dose was allowed to dwell for 2 hours and ability to withdraw blood from the catheter was reassessed. The endpoint was restoration of the ability to withdraw and infuse through the catheter. One hundred forty-nine patients were randomized: 74 received placebo first, 75 received alteplase first. RESULTS: After the first 2-hour treatment, function was restored to 74% in the alteplase arm and 17% in the placebo arm (P <.0001 compared to placebo). After one or two treatments, function was restored in 90% of patients. There were no serious study-drug-related adverse events, no intracranial hemorrhage, no major hemorrhage, and no embolic events. CONCLUSION: Infusion of alteplase appeared to be safe and effective in restoring flow to occluded catheters without need for pretreatment radiographic evaluation.
Catheterization, Central Venous↗
LF15-0195 prevents the induction and inhibits the progression of rat anti-GBM disease.
BACKGROUND: LF15-0195 is a novel immunosuppressant that is currently in phase II clinical trials for the treatment of vasculitis. This study examined whether LF15-0195 could suppress the induction and progression of rat anti-glomerular basement membrane (anti-GBM) glomerulonephritis. METHODS: Rapidly progressive glomerulonephritis was induced in primed rats by the administration of anti-GBM serum. In the first experiment, LF15-0195 was given daily by subcutaneous injection (days 0 to 14) to treat the induction of anti-GBM disease analyzed at day 14. In a second experiment, rats received LF15-0195 as an intervention treatment from days 7 to 28 (continuous therapy) or days 7 to 12 (pulse therapy) to treat the progression of disease assessed at day 28. RESULTS: Continuous LF15-0195 treatment during the induction of anti-GBM disease (experiment 1) prevented proteinuria and loss of renal function, and markedly reduced histological kidney lesions and renal fibrosis. LF15-0195 also reduced kidney leukocyte infiltrate, urine excretion of interleukin-1beta (IL-1beta) and transforming growth factor-beta (TGF-beta), and the serum antibody response, but not kidney deposition of Ig and C3. When LF15-0195 treatment was initiated at day 7, both continuous and pulse therapy partially inhibited disease progression by suppressing the loss of renal function, interstitial macrophage and T-cell accumulation, tubular cell proliferation, and renal fibrosis. CONCLUSION: LF15-0195 prevents the induction and suppresses the progression of rat anti-GBM disease through multiple mechanisms of action, suggesting that this drug may have significant therapeutic potential in human glomerulonephritis. The similar efficacy of continuous and pulse intervention treatment in this model indicates that short-term LF15-0195 treatment may achieve optimal benefit without prolonged bone marrow suppression.
Animals↗
PDGF signal transduction inhibition ameliorates experimental mesangial proliferative glomerulonephritis.
BACKGROUND: Platelet-derived growth factor (PDGF) has been consistently implicated in the cell proliferation and extracellular matrix accumulation, which characterize progressive glomerular disease. In the present study, the effects of a potent and selective inhibitor of PDGF receptor tyrosine kinase, STI 571, were examined in vitro and in vivo. METHODS: Cultured mesangial cells were incubated with PDGF (50 ng/mL) and fibroblast growth factor-2 (FGF-2; 50 ng/mL) and treated with STI 571 (0.13 to 2.0 micromol/L). Experimental mesangial proliferative glomerulonephritis was induced in male Wistar rats with monoclonal OX-7, anti-rat Thy-1.1 antibody with rats randomized to receive either STI 571 (50 mg/kg intraperitoneally daily) or vehicle. Animals were examined six days later. RESULTS: In vitro, both PDGF and FGF-2 induced a threefold increase in mesangial cell 3H-thymidine incorporation. STI 571 reduced PDGF but not FGF-2-stimulated mesangial cell proliferation in a dose-dependent manner, with complete abolition at 0.4 micromol/L. In animals with Thy-1.1 glomerulonephritis, PDGF receptor tyrosine kinase blockade was associated with significant reductions in mesangial cell proliferation (P < 0.001), the number of activated (alpha-smooth muscle positive) mesangial cells, and glomerular type IV collagen deposition (P < 0.001). CONCLUSION: The amelioration of the pathological findings of experimental mesangial proliferative glomerulonephritis by blockade of PDGF receptor activity suggests the potential clinical utility of this approach as a therapeutic strategy in glomerular disease.
Animals↗
Tubules are the major site of M-CSF production in experimental kidney disease: correlation with local macrophage proliferation.
BACKGROUND: Local proliferation of macrophages occurs within both the glomerulus and the interstitium in severe forms of human and experimental glomerulonephritis and plays an important role in amplifying renal injury. Macrophage colony-stimulating factor (M-CSF) is thought to be the growth factor driving this local macrophage proliferation. Previous studies have found that glomeruli are the predominant source of M-CSF production. However, this is difficult to reconcile with the prominent macrophage accumulation and proliferation seen in the interstitial compartment in glomerulonephritis. To address this issue, we localized M-CSF expression in rat models of glomerular versus tubulointerstitial injury and examined its relationship to local macrophage proliferation. METHODS: M-CSF expression (Northern blotting, in situ hybridization, immunostaining, Western blotting) and local macrophage proliferation (double immunostaining) was examined in normal rat kidney on days 1 and 14 of rat anti-glomerular basement membrane (anti-GBM) glomerulonephritis and on day 5 following unilateral ureteric obstruction. RESULTS: M-CSF mRNA and protein expression were identified in small numbers of glomerular podocytes, approximately 25% of cortical tubules, and most medullary tubules in normal rat kidney. Northern blotting showed a significant increase in whole kidney M-CSF mRNA in rat anti-GBM glomerulonephritis. Up-regulation of glomerular and, most prominently, tubular M-CSF production was confirmed by three independent methods: in situ hybridization, immunostaining, and Western blotting. The increase in M-CSF expression colocalized with local macrophage proliferation (ED1+PCNA+ cells) in both the glomerulus and tubulointerstitium. On day 5 after ureter ligation, there was a significant increase in tubular M-CSF mRNA and protein expression in the obstructed kidney, with no change in glomerular M-CSF. In parallel with M-CSF expression, macrophage accumulation and proliferation was prominent in the interstitium, but was absent from glomeruli. CONCLUSIONS: The tubular epithelial cell is the major site of M-CSF production within the injured kidney. Indeed, substantial macrophage accumulation and local proliferation can occur in the tubulointerstitium in the absence of glomerular inflammation. These results suggest that M-CSF production within the kidney, particularly by tubular epithelial cells, plays an important role in regulating local macrophage proliferation in experimental kidney disease.
Animals↗
The incidence of biopsy-proven glomerulonephritis in Australia.
BACKGROUND: There is limited population-based epidemiological data on renal disease. An insight into the spectrum of clinically significant glomerulonephritis can be obtained from renal biopsy diagnoses. This is a descriptive report of biopsy-proven glomerulonephritis within a defined population. METHODS: A retrospective review of the pathology reports of all native renal biopsies performed in the Australian state of Victoria in 1995 and 1997 was undertaken. Trends in the average annual age- and sex-specific incidence rates for biopsy-proven glomerulonephritis were calculated. Comparisons were made with the incidence of end-stage renal disease due to glomerulonephritis confirmed on renal biopsy. RESULTS: The most common glomerulonephritides in adults are IgA disease, focal glomerulosclerosis, lupus nephritis and vasculitis, and in children are lupus nephritis, focal glomerulosclerosis, IgA disease and minimal change disease. A male predominance is seen for all glomerulonephritides, except lupus nephritis, in both adults and children. An increase in incidence of disease with age, particularly in males, is seen for vasculitis and focal glomerulosclerosis. The most common glomerulonephritides on renal biopsy are reflected in the most common causes of end-stage renal disease due to glomerulonephritis. CONCLUSIONS: This review has provided population-based descriptive epidemiological data on clinically significant glomerulonephritis. This data provides important clues for further studies relating to the identification of risk factors for the various types of glomerulonephritis.
Adult↗
Local macrophage proliferation correlates with increased renal M-CSF expression in human glomerulonephritis.
BACKGROUND: Macrophage accumulation is a prominent feature in many forms of glomerulonephritis. Local proliferation of macrophages within the kidney has been described in human and experimental glomerulonephritis and may have an important role in augmenting the inflammatory response. The current study examined the relationship between local macrophage proliferation and renal expression of macrophage colony-stimulating factor (M-CSF). METHODS: A total of 118 renal biopsies of patients with a wide range of glomerulonephridities were examined for M-CSF protein and macrophage proliferation (KP1+PCNA+cells) by single and double immunohistochemistry staining, respectively. RESULTS: Biopsies of thin membrane disease (TMD) with histologically normal kidney showed M-CSF protein expression by 33% of cortical tubules, while glomerular M-CSF expression was limited to resident macrophages and some podocytes. Glomerular M-CSF expression increased significantly in proliferative forms of glomerulonephritis, with M-CSF staining of infiltrating macrophages, podocytes and some mesangial cells. Segmental areas of strong M-CSF expression, particularly in crescents, co-localized with KP1+PCNA+ proliferating macrophages. There was also an increase in tubular M-CSF expression in most types of glomerulonephritis. Tubular M-CSF staining was strongest in areas of tubular damage and co-localized with KP1+ macrophages, including KP1+PCNA+ proliferating macrophages. Many interstitial macrophages and alpha-smooth muscle actin-positive myofibroblasts showed strong M-CSF staining. Statistical analysis showed a highly significant correlation between M-CSF expression and local macrophage proliferation in both the glomerulus and tubulointerstitium. Glomerular and tubular M-CSF expression gave a significant correlation with renal dysfunction. CONCLUSIONS: Glomerular and tubulointerstitial M-CSF expression is up-regulated in human glomerulonephritis, being most prominent in proliferative forms of disease. This correlated with local macrophage proliferation, suggesting that increased renal M-CSF production plays an important role in regulating local macrophage proliferation in human glomerulonephritis.
Adult↗
Membranous nephropathy and anti-neutrophil cytoplasmic antibody-associated glomerulonephritis: a report of 2 cases.
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Aged↗
Inhibition of heparin-binding epidermal growth factor-like growth factor increases albuminuria in puromycin aminonucleoside nephrosis.
BACKGROUND: Our previous work in the acute puromycin aminonucleoside nephrosis (PAN) model has demonstrated up-regulation of heparin-binding epidermal growth factor-like growth factor (HB-EGF) mRNA and protein within glomerular epithelial cells (GECs) prior to the onset of proteinuria. METHODS: To determine whether increased HB-EGF expression in the acute PAN model contributes to the pathogenesis of proteinuria, a monoclonal antibody (DE10) was produced against recombinant human HB-EGF. RESULTS: The specificity of DE10 for human HB-EGF was confirmed by enzyme-linked immunosorbent assay, immunohistochemical staining, and flow cytometry of transfected cells expressing human and rat HB-EGF, and inhibition of cell proliferation. DE10 also reacted with cells transfected with rat HB-EGF cDNA. Administration of 0.5 mg affinity-purified DE10 to normal rats did not cause significant albuminuria compared with controls. Five days after the induction of the acute PAN model, albuminuria was significantly greater in animals treated with 0.5 mg DE10 than a control mAb (162.6 +/- 32.4 vs. 64.8 +/- 10.2 mg/day, respectively, P < 0.01). Rats treated with DE10 had an earlier onset of severe albuminuria, but no increase in maximal albuminuria at later time points. Electron microscopy showed marked podocyte effacement in both DE10-treated and control animals, but no obvious difference between groups. However, adhesion of the human GEC line 56/10 A1 to laminin and fibronectin, but not to collagens I or IV, was reduced by DE10. CONCLUSIONS: This study suggests that HB-EGF contributes to the integrity of the glomerular filtration barrier, particularly when the podocyte has been injured. Following podocyte injury, adhesion to laminin in the glomerular basement membrane by HB-EGF may be important in reducing albuminuria.
3T3 Cells↗
CD44-mediated neutrophil apoptosis in the rat.
BACKGROUND: Apoptosis is an important mechanism by which neutrophils are removed from sites of inflammation, including the kidney. This study investigated whether ligation of the cell-surface adhesion molecule, CD44, can trigger neutrophil apoptosis. METHODS: The anti-rat CD44 antibody OX-50 was used to induce apoptosis of cultured blood neutrophils, as determined by flow cytometry using annexin V staining and by transmission electron microscopy. The functional consequences of OX-50-mediated neutrophil depletion were examined in a rat model of accelerated antiglomerular basement membrane glomerulonephritis. RESULTS: Flow cytometric analysis using the OX-50 antibody, which recognizes the common amino terminal domain of CD44, showed that rat blood neutrophils express very high levels of CD44. The addition of OX-50, but not control antibodies, rapidly induced neutrophil apoptosis in cultured rat blood leukocytes, as demonstrated by annexin V staining and by electron microscopy. Cross-linking of CD44 was essential since F(ab) fragments of the OX-50 antibody failed to induce neutrophil apoptosis. The CD44 ligand hyaluronan and an antibody to the CD44v6 isoform failed to induce neutrophil apoptosis, indicating that OX-50 antibody-mediated neutrophil apoptosis is epitope specific. This effect was specific to neutrophils since the OX-50 antibody did not induce apoptosis in other CD44-expressing cell types (lymphocytes, mesangial cells, or tubular epithelial cells). An injection of OX-50 antibody into normal rats caused a rapid and profound neutropenia, and apoptotic neutrophils could be seen in the blood by electron microscopy. Furthermore, the administration of OX-50 antibody abrogated neutrophil-dependent glomerular injury (proteinuria) on day 1 of rat antiglomerular basement membrane glomerulonephritis, whereas injury on day 10 of the disease (neutrophil independent) was largely unaffected. CONCLUSIONS: The cross-linking of specific epitopes of the CD44 molecule can rapidly induce neutrophil apoptosis in vitro and inhibit neutrophil-dependent renal injury in vivo. This finding suggests that physiological ligands of the CD44 molecule may play an important role in eliminating neutrophils from sites of inflammation, including inflammatory kidney disease.
Animals↗
Resolution of front-back confusion in virtual acoustic imaging systems.
A geometric model of the scattering of sound by the human head is used to generate a model of localization cues based on interaural time delay (ITD). The ITD is calculated in terms of the interaural cross-correlation function (IACC) for sources placed at a series of azimuthal angles in the horizontal plane. This model is used to simulate the pressures generated at the ears of a listener due to real sources and due to a two-channel and a four-channel virtual source imaging system. Results are presented in each case for the variation of ITD with head rotation. The simulations predict that the rate of change of the ITD with head rotation produced by a real source and replicated by the four-channel virtual source imaging system, cannot be replicated by the two-channel system. These changes to the ITD provide cues which allow resolution of front-back confusion. The results of subjective experiments are also presented for the three cases modeled. These results strongly support the findings from the modeling work indicating that, for the systems described here, front-back confusion is resolved through changes to the ITD arising from head motion.
Attention↗
Chronic intestinal pseudo-obstruction in systemic lupus erythematosus due to intestinal smooth muscle myopathy.
We report the case of a woman with systemic lupus erythematosus initially manifesting with fever, rash and arthritis, and two years later with Class IV lupus nephritis. Following treatment with cyclophosphamide she developed symptoms and signs of chronic intestinal pseudo-obstruction (CIPO) that was initially thought to be due to a neutropenic enterocolitis. However, persistence of symptoms resulted in segmental resection of the ileum which showed widespread myocyte necrosis and active inflammation within the muscularis propria. A subsequent, more extensive ileocolic resection showed severe diffuse atrophy and fibrosis of the muscularis propria throughout the resected bowel. The absence of mesenteric vasculitis and the clinical response of the CIPO to the immunosupressive regimen of prednisolone and cyclosporin A suggest that the bowel muscle coat changes reflect an intestinal myopathy secondary to systemic lupus erythematosus, and may have an auto-immune etiology.
Adult↗
Autocrine signals promote osteoblast survival in culture.
We have studied the survival requirements of osteoblasts to test the hypothesis that osteoblasts undergo programmed cell death (PCD) or apoptosis unless they are continuously signalled by other cells not to do so. Osteoblasts survived for 6 days in culture at high cell density in the absence of other cell types, serum or exogenous proteins, but they died with the morphological features of apoptosis in these conditions at low cell density. Osteoblast survival was enhanced during the first 2 days of culture by the addition of the sulphydryl compound, cysteine to the culture medium which was converted intracellularly to the antioxidant glutathione. Catalase, an enzyme decomposing hydrogen peroxide, also protected the cells, whereas superoxide dismutase had no effect. Therefore, osteoblasts in culture are sensitive to toxic compounds derived from molecular oxygen, i.e. hydroxyl radicals or hydrogen peroxide spontaneously generated in CMRL medium containing ascorbate and ferrous ions. Conditioned medium from high density cultures prevented osteoblast apoptosis in low density cultures, as long as antioxidants were also present. The enhancing effect of conditioned medium on osteoblast survival was prevented by neutralizing antibodies to insulin-like growth factor-I (IGF-I) and IGF-II but not by antibodies to either platelet-derived growth factor (PDGF) or basic fibroblast growth factor (bFGF). These results suggest that in addition to regulating cell growth and differentiation, IGF-I and IGF-II also function as survival factors for osteoblasts. Our data also indicate that antioxidants are required for osteoblast survival and that they enhance growth factor mediated osteoblast survival.
Animals↗
Tubulointerstitial nephritis following high-dose ifosfamide in three breast cancer patients.
We report three cases of women with breast cancer who developed renal impairment following treatment with high-dose ifosfamide. All the women underwent renal biopsy, which demonstrated severe interstitial damage with tubular changes by light and electron microscopy. Although reversible acute tubular dysfunction is well recognised with ifosfamide therapy, the long-term outcome of ifosfamide-induced renal injury remains unclear. The results of the current study suggest that ifosfamide can cause severe irreversible renal tubulointerstitial injury and should be used with caution even when there is initially normal renal function.
Adult↗