External beam radiotherapy for primary and adjuvant management of aggressive fibromatosis

PURPOSE: To review a large single-institution experience in the management of aggressive fibromatosis to determine the effectiveness of external beam radiotherapy (EBRT) and identify the presentation and treatment variables predictive of locoregional control. METHODS AND MATERIALS: Between 1975 and 2000, 72 patients were treated with EBRT for a pathologically confirmed diagnosis of aggressive fibromatosis. Thirty patients were treated at the primary presentation and 42 at the time of a locoregional recurrence. Minimal 2-year follow-up data were available for 65 patients (median 6 years). Megavoltage irradiation with 60Co to 20 MV photons or electron therapy was used for all patients. Most patients were treated after attempted complete surgical resection; 16 patients underwent pretreatment biopsy alone. The prescribed treatment was standard (1.8 Gy) daily fractions in 42 cases and 1.2 Gy fractions b.i.d. in 23 cases. The median prescribed dose was 54 Gy. The prognostic variables and treatment results were evaluated by Kaplan-Meier actuarial analysis. RESULTS: Locoregional control was achieved in 52 of 65 patients. The 5-year actuarial locoregional control was 83%. Locoregional failure occurred in 13 patients (11 in patients with recurrent tumors). Only two failures occurred within the irradiation fields; nine failures occurred at the field margins. Eleven patients were salvaged by surgery: wide excision in nine and amputation in two. The only prognostic factor significant for locoregional control was primary vs. recurrent presentation (p = 0.0193). The 5-year locoregional control rates for irradiation at initial presentation and at recurrence were 96% and 75%, respectively. The variables without significance for locoregional control included primary tumor location, surgical procedures performed, resection margins, and gross vs. microscopic residual tumor at irradiation. Lymphedema was the most common late effect, occurring in 7 patients, 5 with prior treatment. Bone fracture occurred in 3 patients; all 3 had fibromatosis involving the bone at presentation but without recurrence at the time of fracture. CONCLUSION: EBRT is effective treatment for aggressive fibromatosis. The probability of locoregional control decreases with multiple prior recurrences.     

Expression of matrix metalloproteinases and their inhibitors during the resorption of schistosome egg-induced fibrosis in praziquantel-treated mice

Schistosomiasis mansoni is a tropical helminthic disease characterized by parasite egg-induced granulomatous inflammation and cumulative fibrosis. Because fibrosis is influenced by the imbalance between degradative matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), we analysed the resorption of fibrous tissue and MMP/TIMP expression in the livers of S. mansoni-infected and praziquantel-cured mice. Worm elimination significantly enhanced survival rate, ameliorated the granulomatous pathology and reduced collagen I, III and IV gene expression at 6 and 12 months post-treatment. Compared to 6 months infected, untreated controls, liver fibrous tissue was resorbed by 71.4% at 12 months after treatment. At 3 months post-treatment, expression of the MMP-2, -3, -8, -10, -13, -14 and -16 genes decreased compared with untreated controls. By 6 months, a highly significant increase in MMP-10 gene expression was manifest. At 12 months, messages for all MMP genes decreased in relation to untreated controls. TIMP-1, -2 and -3 gene expression drastically decreased between 3 and 6 months. At 1 year, only TIMP-1 expression was significantly diminished. Overall, profibrogenic tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta and inducible nitric oxide synthase (iNOS) gene expression decreased. Antigen-stimulated splenocytes secreted significantly higher levels of interleukin (IL)-4, IL-5, IL-10 and IL-13 cytokines between 3 and 12 months after treatment. Production of interferon (IFN)-gamma was higher than in untreated controls 3 and 6 months after treatment. In conclusion, praziquantel-treated mice showed a slow resorption of liver fibrous tissue. Resorption is attributed to the precipitous drop in TIMP-1 gene expression level, which shifted the balance in favour of MMP message expression and presumed enhanced collagenase activity.     

Interaction of Dr adhesin with collagen type IV is a critical step in Escherichia coli renal persistence

The pathogenic mechanism of recurrent or chronic urinary tract infection is poorly understood. Escherichia coli cells bearing Dr fimbriae display unique tropism to the basement membrane (BM)-renal interstitium that enables the bacteria to cause chronic pyelonephritis in experimental mice. The renal receptors for Dr-fimbriated E. coli are type IV collagen and decay-accelerating factor (DAF). We hypothesized that type IV collagen receptor-mediated BM-interstitial tropism is essential for E. coli to cause chronic pyelonephritis. To test the role of the type IV collagen tropism of Dr-fimbriated E. coli in renal persistence, we constructed an isogenic mutant in the DraE adhesin subunit that was unable to bind type IV collagen but retained binding to DAF and examined its virulence in the mouse model. The collagen-binding mutant DrI113T was eliminated from the mouse renal tissues in 6 to 8 weeks, while the parent strain caused persistent renal infection that lasted at least 14 weeks (P < or = 0.02). Transcomplementation with the intact Dr operon restored collagen-binding activity, BM-interstitial tropism, and the ability to cause persistent renal infection. We conclude that type IV collagen binding mediated by DraE adhesin is a critical step for the development of persistent renal infection in a murine model of E. coli pyelonephritis.     

Investigation and comparison of some models for removing ocular artefacts from EEG signals

An investigation of ocular artefacts (OAs) in the human electroencephalogram (EEG) to quantify the effectiveness of OA removal and to find the most effective model for removing OAs online is described. In Part 1, the models used in the investigation are described and the data analysed. The analysis showed that the ‘true’ EEG exhibited a high degree of serial correlation and so the ordinary least-squares (OLS) method employed to remove OA was inefficient. Efficient alternative methods based on autoregressive models of the ‘true’ EEG are discussed. It is also shown that the EOGs are linearly dependent making some of them redundant. In Part 2, the models are compared.     

Neuroanatomical abnormalities related to dexamethasone exposure in survivors of childhood acute lymphoblastic leukemia

Survivors of childhood acute lymphoblastic leukemia (ALL) treated with chemotherapy only are at risk for neurocognitive impairment. Regions of interest were identified a priori based on glucocorticoid receptor distribution, and sex‐stratified multivariable linear regression models were used to test associations between brain MRI morphology and total number of intrathecal injections, and serum concentration of dexamethasone and methotrexate. Compared with controls, ALL survivors have persistently smaller volumes in the bilateral cerebellum (P < 0.005), hippocampal subregions (P < 0.03), temporal lobe regions (P < 0.03), frontal lobe regions (P < 0.04), and parietal lobe regions (precuneus; P < 0.002). Long‐term problems with learning may be related to residual posttreatment brain differences.     

Degradation of basement membranes by Pseudomonas aeruginosa elastase.

Pseudomonas aeruginosa virulence has been attributed in part to extracellular proteinases. We found that one of these proteinases, elastase, extensively degrades intact basement membranes from bovine anterior-lens capsules, bovine glomeruli, and bovine lung, producing about 9, 14, and 9 fragments, respectively, with Mrs in the range of 15,000 to greater than 200,000, as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (nonreducing conditions). Release of hydroxyproline showed that collagen IV was degraded by elastase. Degradation of the newly discovered alpha 3(IV) collagen chain was shown by immunoblotting of digests with Goodpasture's syndrome serum, which contains antibodies that react with an epitope located in the carboxyl-terminal globular (NCl) domain of alpha 3(IV). Comparison of total protein release with collagen IV release showed that noncollagenous protein components were solubilized to the same extent as collagen IV. The extensive degradation of the basement membranes described here suggests a role for elastase in the pathogenic mechanism at the local level when P. aeruginosa infection is present.     

Transfer of fatty acids across the rabbit placenta.

1. Transfer of fatty acids across the placenta was studied in anaesthetized rabbits at 28-days gestation by measuring umbilical venous-arterial differences, by injection of labelled palmitate into the mother and observing its appearance in the foetus, by injection of labelled palmitate into the foetus and measuring its appearance in the mother and the foetal clearance rate. 2. The release of fatty acids and glycerol by foetal adipose tissues was investigated in vitro by measuring the effect of addition of noradrenaline to the incubation medium and in vivo by measuring the effect of noradrenaline infusion into the foetus on circulating glycerol and free fatty acid concentrations. 3. In anaesthetized rabbits at 28-days gestation the maternal circulating free fatty acid concentrations were high and there was a positive umbilical venous-arterial difference. High maternal free fatty acid concentrations were associated with high umbilical venous-arterial differences. 4. Label was present in the foetus in 2 min and reached a peak in 3 min after injection of labelled palmitate into the mother. Label appeared in the maternal circulation in 1 min after injection into the foetus. The half-life of labelled palmitate was of the order of 30-60 sec in both mother in foetus. 5. Foetal white adipose tissue released both free fatty acids and glycerol into the medium and the rate of release increased four to five fold after addition of noradrenaline. Infusion of noradrenaline in the foetus led to a rise in glucose and glycerol concentrations, but the change in free fatty acid concentrations was not significant. 6. It was concluded that (i) free fatty acids can cross the rabbit placenta in amounts sufficient to provide the fatty acid components of stored triglyceride and structural lipids; (ii) placental transport of free fatty acids depends in part on maternal blood concentration and on foetal uptake; (iii) foetal circulating free fatty acids are continually exchanging with fatty acid pools in the placenta and with the maternal circulating free fatty acids.