Biomedical subjects
Publications and source records attributed to F Moro.
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We studied 34 apparently healthy children and 2 propositi from kindreds with familial juvenile hyperuricaemic nephropathy (FJHN) - a disorder characterised by early onset, hyperuricaemia, gout, familial renal disease and a similarly low urate clearance relative to glomerular filtration rate (GFR) [fractional excretion of uric acid (FEur) 5.1+/-1.6%] in young men and women. In addition to the propositi, 17 asymptomatic children were hyperuricaemic -- mean plasma urate (368+/-30 micromol/l), twice that of controls (154+/-41 micromol/l). Eight of them had a normal GFR ( > 80 ml/min per 1.73 m2), and 11 renal dysfunction, which was severe in 5. The FEur in the 14 hyperuricaemic children with a GFR > 50 ml/min was 5.0+/-0.5% and in the 5 with a GFR < or =50 ml/min was still low (11.5+/-0.2%) compared with controls (18.4+/-5.1%). The 17 normouricaemic children (185+/-37 micromol/l) had a normal GFR (>80 ml/min) and FEur (14.0+/-5.3%). The results highlight the dominant inheritance, absence of the usual child/adult difference in FEur in FJHN and presence of hyperuricaemia without renal disease in 42% of affected children, but not vice versa. Since early allopurinol treatment may retard progression to end-stage renal failure, screening of all relatives in FJHN kindreds is essential.
We describe a case of basal cell carcinoma (BCC) situated on the external upper margin of the right eyelid in a young man aged 28 years. The tumor was diagnosed as an "extended wart in a degenerative phase" and removed during reconstructive plastic surgery. No pathologic examination was performed. Seven years later, the operation was followed by a first recurrence. Pathologic examination was then performed, and the diagnosis was BCC. Therapy was with radiotherapy and chemotherapy. Subsequent recurrences were treated with radiotherapy and surgery (enucleation, exenteration of the orbit), but the evolution of the tumor was not halted. It ended 25 years after its first manifestation with the death of the patient of a hemorrhage of the upper airways during an operation, the aim of which was to reexamine the orbital cavity. The autopsy revealed intracranial extension of the tumor, and all the histological examinations confirmed the diagnosis. No histopathological feature was found that could differentiate a particularly aggressive nature of the tumor. Basal cell carcinoma is a tumor more frequently encountered in elderly patients. Its appearance in a young subject may cause grounds for suspicion, requiring initial radical surgical treatment and careful surveillance of the evolution of the lesion. This case documents the fatal consequences that may arise from the failure to recognize BCC in its first manifestation and highlights the ineffectiveness of repeated radiation and surgical therapy against continual recurrence.
The effect of potential mediators of mucus secretion was investigated in the isolated vascularly perfused rat colon by using a sandwich enzyme-linked immunosorbent assay for rat colonic mucin and by histochemical analysis. Bethanechol (100-200 microM), bombesin (100 nM), and vasoactive intestinal peptide (VIP, 100 nM) provoked a dramatic mucin discharge (maximal response at 900, 900, and 600% of control loops, respectively). VIP-stimulated mucin secretion was abolished by tetrodotoxin, whereas atropine was without effect. In contrast, both tetrodotoxin and atropine significantly decreased mucin release induced by bombesin. Isoproterenol or calcitonin gene-related peptide was without effect. Serotonin (1-5 microM) and peptide YY (10 nM) evoked mucin discharge, whereas glucagon-like peptide-1 did not release mucin. Finally, bromolasalocid (20 microM), interleukin-1beta (0.25 nM), sodium nitroprusside (1 mM), and dimethyl-PGE2 (2.5 microM) induced mucus discharge. The results demonstrated a good correlation between the immunological method and histological analysis. In conclusion, these findings suggest a role for the enteric nervous system, the enteroendocrine cells, and resident immune cells in mediation of colonic mucus release.
Exposure of the ileum to nutrients markedly inhibits several upper gastrointestinal functions. Hormonal peptides of the ileal wall, i.e. peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and neurotensin (NT), are thought to play a role in this negative feedback mechanism. The present study was conducted to comparatively assess the secretion of PYY, GLP-1, and NT upon luminal infusion of a variety of individual luminal factors in the isolated vascularly perfused rat ileum preparation. PYY, GLP-1, and NT were measured in the portal effluent with specific RIAs. Glucose (250 mM) induced a pronounced release of the three peptides, whereas a physiological concentration of 5 mM did not induce peptide secretion. Peptone (5%, wt/vol) evoked a sustained release of PYY, GLP-1, and NT. Only NT secretion was increased upon luminal administration of 100 mM sodium oleate. Short chain fatty acids (20 mM) evoked an early and transient release of the three peptides. In contrast, taurocholate (20 mM) induced a sustained release of PYY, GLP-1, and NT, but the threshold concentration for peptide release was lower for NT than for PYY or GLP-1. Cellulose or pectin (0.5%, wt/vol) did not modify peptide secretion. In conclusion, glucose and peptone are potent stimulants of PYY, GLP-1, and NT release. Only NT is released upon oleic acid stimulation. Finally, taurocholate is a potent stimulant of the release of the three peptides. Overall, PYY, GLP-1, and NT may participate cooperatively in the ileal brake. As relatively high concentrations of the various stimulants were required to elicit peptide release, it seems likely that this mechanism operates in cases of maldigestion or malabsorption.
This study investigates the timing of p53 mutations detected in the malignant cells of a Burkitt's lymphoma cell line (BRG-P) with respect to other maturation or transforming events. The BRG-P cell line, derived from an AIDS patient, was of special value since it displayed subclones that had undergone an isotype switch from IgM to IgA1 (BRG-M and BRG-A cells). BRG-M and BRG-A cells were characterized by the same monoclonal c-myc and VDJ rearrangements and by the expression of Ig receptors with specificity for a 45 kDa protein of human breast cells. Analysis of p53 mutations in the different BRG subclones showed that 1) BRG-M cells displayed 2 different p53 mutations in trans; since the original BL cells also showed the same mutations, this finding indicated that both occurred in vivo; 2) one of the p53 alleles of BRG-A cells was lost, while the other showed a mutation different from those seen in BRG-M cells; and 3) all 3 mutations observed in BRG-M or BRG-A cells resulted in the functional inactivation of the transcriptional activation function of p53. Together, our data demonstrate that p53 mutations were relatively late events during lymphomagenesis. Moreover, in view of the role of p53 in cell apoptosis, it is conceivable that BRG cells were subjected to a strong selective pressure that favored p53 inactivation. Such inactivation was possibly required to counterbalance other potentially apoptotic events, including the presence of a deregulated c-myc oncogene and signals delivered by the host environment in situ.
Alternative splicing of vascular endothelial growth factor (VEGF) mRNA results in three distinct molecular forms of 121 or 165 (V165) amino acids that are released in the conditioned medium of cultured cells and one longer isoform of 189 amino acids (V189) that remains cell-associated. V189 has been expressed in wild type CHO-K1 cells and in glycosaminoglycan-deficient pgsA-745 Chinese hamster ovary (CHO) mutant cells. It could be released from CHO-K1 cell membranes by heparin or a synthetic peptide designed on the sequence encoded by exon 6 but was freely released from CHO mutant cells. In both cases, the immunoreactive V189 was mainly released as a 40-kDa cleaved form, provided that the serine protease urokinase, but not plasmin, was active. Recombinant V189 was purified from insect cells infected with a recombinant baculovirus as a nonmitogenic 50-kDa precursor that binds to the receptor Flt-1 but not to Flk-1. It could be matured by urokinase as a 38-kDa fragment able to bind to Flk-1 and to trigger cell proliferation. V165 and V189, however, could be cleaved by plasmin as 34-kDa fragments that exhibit a decreased mitogenic activity. These findings indicate that the carboxyl-terminal domain of V189 masks its binding domain to Flk-1.
OBJECTIVE: The concept of therapeutic angiogenesis with vascular endothelial growth factor (VEGF) has been validated in peripheral arterial disease. Its use in myocardial ischemia may be delayed as the result of the description in a porcine model of peripheral vasodilation after intraluminal injections of VEGF resulting in a 50% fatality rate by hypotension. We carried out this study to test whether VEGF-induced hypotension (1) is species specific, (2) is mediated by the receptor mediating angiogenesis, (3) is prevented by inhibition of nitric oxide synthase. METHODS: In the rabbit corneal pocket assay we tested whether a previously published anti-idiotypic antibody (AIA) agonist of the VEGF receptor Flk-1/KDR could elicit angiogenesis. Various doses of recombinant VEGF or AIA were injected into anesthetized normotensive Wistar-Kyoto rats and the mean arterial blood pressure (MABP) was recorded. To test the implication of nitric oxide in VEGF-induced hypotension we treated the animals with a competitive inhibitor of nitric oxide synthase prior to the injection of VEGF. RESULTS: Both VEGF and AIA induce angiogenesis but only intravenous injections of VEGF induced a rapid, transient and dose-dependent decrease in MABP. The ED50 was 0.5 micrograms. The interval between two VEGF injections required to lead to a decrease of MABP was 40 minutes. Nitric oxide synthesis inhibitor prevented, in a reversible fashion, the effect of VEGF. CONCLUSION: VEGF-induced hypotension is not species specific. It is prevented by nitric oxide inhibition. VEGF-induced angiogenesis and hypotension are not mediated in vivo by the same VEGF receptor.
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To determine whether a correlation exists between aneuploidy and p53 status in astrocytic tumors we analyzed 48 astrocytomas with different grades of malignancy for the presence of p53 mutations and aneuploidy of chromosomes 10 and 17 (Ch10, Ch17), known to be particularly involved with this type of tumor. We used polymerase chain reaction (PCR)-based denaturing gradient gel electrophoresis (DGGE) analysis on exons 5-8 of the p53 gene, and fluorescence in situ hybridization (FISH) analysis on interphase nuclei using chromosome specific pericentromeric probes, respectively. Our results showed that Ch10/Ch17 aneuploidy is a common early event in astrocytomas (90% of low grade tumors are aneuploid). p53 mutations and Ch17 aneuploidy are early events, but their incidence is not dependent on tumor grade. Loss of Ch10 is the only alteration that significantly correlates with tumor progression. No significant correlation between the presence of Ch10/Ch17 aneuploidy and p53 mutations was found. However, the coexistence of p53 mutations and aneuploidy, was observed in a subset of cases. The presence of p53 mutations appeared to be a significant predictor of a poor prognosis. In conclusion, genomic instability may or may not be associated with p53 mutations in astrocytomas, thus suggesting that other cellular determinants can also be responsible for the aneuploidy observed.
Thirty two allogeneic bone marrow transplant (BMT) recipients, aged 16-55 (median 35), with CMV antigenemia (= > 5 positive cells) developing at a median interval from BMT of 49 days, were given combined treatment with foscarnet and ganciclovir for 15 days. Maintenance was given with foscarnet and ganciclovir on alternate days for an additional 2 weeks. 31/32 patients were on cyclosporin 30 on systemic antibiotics and 9 were on intravenous amphotericin Median laboratory values on day 1 and 15 of treatment were respectively creatinine 1.0-1.1 mg%; WBC 5.7-4.1 x 10(9)/l; platelets 78 72 x 10(9)/l. All patients cleared CMV-antigenemia by day +15, though 5 reactivated on and 14 off maintenance: the dose of foscarnet (but not ganciclovir) received in the first 15 days was significantly lower in patients reactivating within 30 days (p = 0.0002). Six patients died, one with i.p., one with multiorgan failure, and four with infections. Eighteen patients survive 119-1051 days post-transplant. The actuarial TRM at 1 year is 23%. This study shows that combined foscarnet-ganciclovir is one therapeutic option for allogeneic BMT recipients developing CMVAg-emia with a high number of CMVAg+ cells: treatment can be given together with cyclosporin and antibiotics with appropriate dose reductions; it produces prompt clearing of CMV infection, and may reduce transplant related mortality when compared to single agent therapy.
Vasculotropin (VAS), also called vascular endothelial growth factor (VEGF) or vascular permeability factor, is a secreted growth factor whose target cell specificity has been reported as restricted to vascular endothelium. Its effects are mediated by at least two distinct membrane-spanning tyrosine kinase receptors, KDR and flt-1; the expression of which also seems restricted to vascular endothelium. We describe here that cultured human retinal pigment epithelial (HRPE) cells express both KDR and flt-1 receptors, bind VAS/VEGF on two high affinity sites (apparent Kd of 9 and 210 pM corresponding to 940 and 18,800 sites per cell) and proliferate or migrate upon recombinant VAS/VEGF addition. HRPE cells also express the mRNA corresponding to the 121 and 165 amino acid forms of VAS/VEGF. HRPE cells release in their own culture medium and store in their extracellular matrix self-mitogenic and chemoattractant factors indistinguishable from 121 and 165 VAS/VEGF isoforms. The autocrine role of VAS/VEGF was confirmed by the inhibition of these bioactivities by neutralizing specific anti-VAS/VEGF antibodies.
BACKGROUND: Patients with neurofibromatosis demonstrate a very variable clinical picture with signs that are largely age dependent. Rarely a glioma is the first presenting sign of the disease. PATIENTS: Three patients with gliomas of the optic nerve and chiasm with neurofibromatosis 1 (NF1) were followed for 10-20 years. Clinical course and therapy are discussed. CONCLUSION: The correct diagnosis of exophthalmos, papilledema or optic atrophy in childhood is facilitated by family history and examination of an adult member of the family, who is likely to have already developed café-au-lait spots, neurofibromas of the skin, axillary freckles and Lisch nodules as clinical signs of neurofibromatosis.
To answer the question whether the level of p53 expression also reflects the status of a cell, with reference to transformation and genome stability, we have examined, by immunocytochemistry, the presence of p53 protein in a number of cell types including human diploid cells, Chinese hamster embryonal cells at different passages and gene amplified and/or transformed Chinese hamster cell lines. Primary human fibroblasts at early passage (LEO) and an established, non transformed, Chinese hamster cell line at early passage (CHEF/18) did not show any detectable p53 expression, either nuclear or cytoplasmic. All transformed human (Raji) and Chinese hamster cell lines (CHO, V79, V79/B7) showed a nuclear expression of p53, although at different intensities. Two cell lines selected from V79/B7 for their resistance to phosphonacetyl-L-aspartate or methotrexate and previously shown to bear gene amplification, showed p53 expression. In PALA L cells p53 expression was nuclear as in other positive cell lines tested, while in MTX M cells it was cytoplasmic. CHEF/18 cells at late passage in culture showed the typical behaviour of transformed cells and p53 was detected in several cells. Moreover, when transformed CHO cells were treated with compounds known to induce reverse transformation, both the disappearance of hallmarks of transformed phenotype and p53 reduction were observed. These results indicate a strong association within the same cell type between p53 expression and transformed status.
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Twenty-five patients with hematologic malignancies (n = 21) or aplastic anemia (n = 4) undergoing an allogeneic BMT from an HLA-identical sibling developed cytomegalovirus (CMV) antigenemia at a mean interval from BMT of 41 days (range 16-141 days). All patients were treated at the time of antigenemia in the absence of other signs of CMV disease with ganciclovir (n = 13) or foscarnet (n = 12) if the WBC count was < 2.5 x 10(9)/l or the patient had aplastic anemia. The two groups were comparable for age, sex and disease status. There were more patients receiving T cell-depleted grafts in the foscarnet group (58% vs 15%, p = 0.003). The first course of treatment was planned to last a minimum of 10 days: foscarnet was given at 180 mg/kg/day, and ganciclovir at 10 mg/kg/day. Patients still showing pp65-positive cells continued treatment in the absence of adverse effects such as cytopenia and/or increased creatinine levels. Maintenance treatment was given for 3-4 weeks. End-points of the study were (1) clearing of CMV antigenemia, (2) tolerance and side-effects, and (3) progression to CMV disease. Both agents were effective in clearing CMV antigenemia: 14 of 25 patients were CMV antigen-negative by day 14 of treatment and all surviving patients were negative by day +50. Renal toxicity was seen mainly in the foscarnet group but caused discontinuation of the drug only in one patient. Myelotoxicity was seen in the ganciclovir group and again could be controlled in 12 of 13 patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Eleven patients underwent bone marrow transplant (BMT) from an HLA-identical sibling following single dose total body irradiation (TBI), with in vivo and ex vivo T cell depletion (TCD). In spite of CMV prophylaxis with acyclovir and high-dose i.v. Ig, 10 of 11 patients developed CMV antigenemia, at a median interval from BMT of 34 days (range 16-72 days) and five died with CMV disease. Foscarnet was then given prophylactically in 11 additional TCD patients to test whether we could (1) prevent CMV reactivation, and (2) reduce transplant-related mortality. Foscarnet was given daily from days +10 to +15 (180 mg/kg/day), then thrice weekly (90 mg/kg/day) until day +100. Five patients developed CMV antigenemia at a median interval from BMT of 42 days (range 16-65 days); one progressed to CMV pneumonitis and died. The risk of developing CMV antigenemia within day 100 is currently 91% for the historical control group and 45% for the foscarnet group (p = 0.005). At diagnosis of CMV, the median number of CMV antigen-positive cells was 6.5 (range 1-13) vs 1 (range 1-5) in acyclovir vs foscarnet patients (p = 0.02) and the median highest number of CMV antigen-positive cells was 7 (range 3-110) vs 1 (range 1-12), respectively, (p = 0.03). The actuarial 1 year transplant-related mortality (TRM) is 49% and 13% in the two groups (p = 0.08). This study suggests that foscarnet prophylaxis starting on day +10 post-BMT may be helpful in reducing the risk of CMV disease and early mortality following TCD BMT.