Biomedical subjects
Publications and source records attributed to M Sironi.
We report a case of Leydig cell tumor of the testis in a young man, in whom preoperative diagnosis was achieved by fine-needle aspiration biopsy cytology. Cytology, histology, and ultrastructural examination showed diagnostic Reinke's crystals, both in nuclei and in cytoplasm. Immunohistochemistry displayed strong vimentin and estrogen positivity.
Interleukin 6 (IL-6) is known to inhibit the synthesis of tumour necrosis factor (TNF) in vitro and in vivo. In this study we investigated the possible role of IL-6 as an endogenous inhibitor of TNF production in the brain or in the periphery using IL-6-deficient mice or administering recombinant human IL-6 (rhIL-6). When IL-6-deficient mice were injected intracerebroventricularly (i.c.v.) with lipopolysaccaride (LPS), no differences were observed in the production of TNF in the brain, while in the periphery (serum or spleen) TNF levels were markedly increased (about four-fold). When normal mice were injected i.c.v. with a combination of LPS and rhIL-6, inhibition of TNF production was only slight (about 20%), while IL-6 had a stronger effect (> 80% inhibition) in the periphery. Co-administration of soluble IL-6 receptor (sIL-6R) did not enhance the effect of IL-6 on brain TNF, so this refractoriness cannot be attributed to a lack of IL-6 receptors. Interestingly, IL-6 potently inhibited LPS-induced TNF production by macrophagic cells but not by a microglial cell clone, suggesting that the defective response to IL-6 of the brain lies within the responsiveness TNF producing cells to IL-6. It thus appears that the TNF-inhibitory role of IL-6 is confined to the periphery.
Benzydamine is a non-steroidal antiinflammatory drug, devoid of activity on arachidonic acid metabolism, which is extensively used as a topical drug in inflammatory conditions, particularly for the treatment of bacterial vaginosis and Candida albicans-sustained vaginitis. In the present study the effects of benzydamine on the production of several inflammatory cytokines were examined in cultures of Candida albicans-stimulated human mononuclear cells. Benzydamine (6.25-50 microM) inhibited Candida-induced tumor necrosis factor-alpha and, to a lesser extent, interleukin-1 beta production, whereas it did not affect interleukin-6 release. Benzydamine also blocked monocyte chemotactic protein-1 secretion, but it did not affect interleukin-8 production. Unlike benzydamine, ibuprofen and naproxen, two non-steroidal antiinflammatory drugs also used topically, were unable to suppress inflammatory lymphokine production from Candida-activated mononuclear cells. These data suggest that benzydamine may be effective in local Candida infections at least in part by suppressing inflammatory cytokine and monokine production in the vaginal mucosa and consequently decreasing their levels in vaginal secretions.
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IL-6-/- mice showed impaired leukocyte accumulation in subcutaneous air pouches. Defective leukocyte accumulation was not due to a reduced migratory capacity of IL-6-/- leukocytes and was associated with a reduced in situ production of chemokines. These observations led to a reexamination of the interaction of IL-6 with endothelial cells (EC). EC express only the gp130 signal transducing chain and not the subunit-specific IL-6R and are therefore unresponsive to IL-6. However, EC are responsive to a combination of IL-6 and soluble IL-6R as measured by the activation of STAT3, chemokine expression, and augmentation of ICAM-1. Activation by IL-6-IL-6R complexes was inhibited by an IL-6 receptor antagonist and potentiated by a superagonist. Hence, in vivo and in vitro evidence supports the concept that the IL-6 system plays an unexpected positive role in local inflammatory reactions by amplifying leukocyte recruitment.
We describe the case of a 46-year-old male patient who presented with pain in the left thigh, often accompanied by lumbar pain. These symptoms were sustained by a neoplasm, which was located in the sympathetic ganglia, at the level of the 3rd left lumbar spinal root and which was completely excised. Immunohistochemical positivity for S100, HMB45, and NSE antibodies suggested that the lesion was a melanotic schwannoma (MS), with both schwannian and melanocytic differentiations, the latter containing melanosomes at ultrastructural examination. Non-recurrence after 16 months of follow-up further supports our diagnosis of MS.
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Available information suggests that the type II IL-1 receptor (RII) is a nonsignaling molecule which acts as a decoy for IL-1. The decoy function model for RII was supported by gene transfer experiments in fibroblasts and keratinocytes. Therefore, inhibition of IL-1 responsiveness after decoy RII gene transfer could reflect a non-physiological cellular context and receptor number. In the present study, constructs encoding RII or a cytoplasmic deletion mutant (delta 372-398) were transfected into U937 cells which express only low levels of RI detectable by RT-PCR. Gene transfer resulted in receptor numbers (approximately equal to 10(3)/cell) of the same order of magnitude as that found in normal myelomonocytic cells. Transfer of RII or a cytoplasmic deletion mutant into U937 did not increase responsiveness to IL-1, as assessed by IL-8 expression and production; it actually considerably dampened it. These results are consistent with the view that in a myelomonocytic cellular context, RII does not contribute to signaling and represents a unique pathway of negative regulation of the IL-1 system.
Cockroaches are known to harbour intracellular bacteria in specialised cells (mycetocytes, or bacteriocytes) of the fat body. In termites, mycetocyte bacteria have been observed only in Mastotermes darwiniensis. These symbionts are thought to have originated from a bacterium that infected an ancestor common to cockroaches and termites. Thus, loss of the infection should have occurred during evolution in all termite lineages, with the exception of that leading to M. darwiniensis. One might suspect that traces of the ancient infection may be present in some termites, in the form of non-mycetocyte intracellular bacteria (e.g. a small number of bacteria within normal cells). Indeed, circumstantial evidence for the presence of intracellular bacteria in two termite species has been reported. However, no data are available on the actual distribution of these bacteria in termites, or on their relationships with the mycetocyte bacteria of cockroaches and M. darwiniensis. In this paper we report results indicating that non-mycetocyte intracellular bacteria are widespread in termites. These results were obtained by electron microscopy on representatives of nine termite species. In addition, sequence analysis of the 16S rRNA genes indicated that the non-mycetocyte bacteria of termites belong to the wolbachia group of the alpha-2 subclass of the proteobacteria. These latter bacteria are not related to the mycetocyte bacteria of cockroaches and M. darwiniensis, which belong to the blattabacterium group of the flavobacteria-bacteroides. PCR analyses with primers specific for wolbachia or blattabacterium provided further support for the identification of the observed non-mycetocyte bacteria as members of the wolbachia group.
Here we report the use of random amplified polymorphic DNAs (RAPDs) and sequence analysis of the genes encoding for the small subunit ribosomal RNA (16S rDNA) for the characterisation of Borrelia burgdorferi sensu lato strains recovered from Ixodes ricinus and from Lyme disease patients. All strains examined were assigned to the species Borrelia garinii. However, both RAPDs and 16S rDNAs revealed a level of genetic variation among the strains which appears higher than expected for a bacterial species. In addition, the data obtained agree with the clonal theory applied to Borrelia burgdorferi s.l. for explaining some traits of its epidemiology. According to this theory, particular strains should spread rapidly, leading to the diffusion of bacteria with a particular chromosomal genotype. Our results reveal high genetic variation even among strains isolated in the same period from a restricted geographic area. Moreover, the data here reported indicate that clonal diffusion of antigenic characteristics could also occur.
Renal oncocytoma is a neoplasm which rarely occurs in patients with solitary kidney, the other being absent because of a previous nephrectomy performed for renal cancer. We present two case reports and a literature review. We have studied some important problems such as the histogenesis, the potential for malignancy, the diagnosis, the treatment and the follow up. The high incidence of coexistence of renal oncocytoma and renal cell carcinoma has important clinical implications. We would like to emphasize the importance of preoperatory FNAB, nephron sparing surgery and very careful follow up.
Tumors of the epididymis are very rare. They are benign tumors in 75 per cent of the cases. Papillary cystadenoma represents 4-9 per cent of epididymal benign tumors. Often associated with the syndrome of von Hippel Lindau and infertility, histologically it can be confused with metastatic renal cell carcinoma. We report two cases of papillary cystadenoma located in the head of the right epididymis, with no concomitance with the syndrome of von Hippel Lindau, cured by the removal of the neoplastic nodule. There was no recidivation, in confirmation of the neoplastic benignity.
From small subunit ribosomal RNA gene sequences, a pair of PCR primers were designed to amplify a portion of this gene from five species of microsporidia. The amplified fragments encompass polymorphic restriction sites for the Hphl enzyme, resulting in different restriction patterns in the different species. We tested this identification method both on cultured microsporidia and on clinical samples. On cultured microsporidia the expected amplification bands were obtained even when DNA preparations from only ten spores were analysed. On clinical samples, identification of microsporidia was obtained from crude DNA preparations. This method allows for a rapid and easy diagnosis of human microsporidioses.
The aim of this work was to study the relative role of the two TNF receptors (p55 and p75) in the central actions of TNF, studying the elevation of serum corticosterone (CS) and IL-6 levels after injection of recombinant murine (rm)TNF (intracerebroventricularly (i.c.v.)) in normal or p55-deficient (p55 -/-) mice. rmTNF induced high serum IL-6 levels and doubled serum CS in normal mice, whereas no elevation of serum IL-6 or CS was induced in p55 -/- mice. However, a normal CS response was observed in p55 -/- mice after LPS (2.5 microg, i.c.v.). p55 -/- mice also responded, although to a lesser extent than p55 +/+, in terms of LPS-induced IL-6 production. We also injected two agonist Abs specific for the two receptors, alpha p55 and alpha p75. While alpha p55 injected i.c.v. induced a marked elevation in CS and IL-6, alpha p75 induced CS (although less than alpha p55) but no IL-6. rmTNF, which binds both receptors, was more potent in inducing IL-6 and CS than injection of rhTNF, which in mice binds only p55. Finally, we investigated the role of p55 and p75 in IL-6 induction by TNF in a murine brain endothelioma. The results resembled closely those obtained in vivo: rmTNF was more potent than rhTNF and only alpha p55, and not alpha p75, induced IL-6 production. These data indicate that p55 plays a major role in TNF activation of the hypothalamus-pituitary-adrenal axis and in the centrally mediated induction of peripheral IL-6 by TNF, but p75, despite having little IL-6 inductive properties by itself, seems to potentiate p55 induction of IL-6.
Production of inflammatory cytokines, including tumor necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6), in the brain is increased in various diseases. To investigate the relationships between the effect of overproduction of IL-6 in the brain on central and peripheral production of TNF, IL-1 beta and IL-6 itself, we used transgenic mice (NSE-hIL-6) where neuronal human IL-6 expression under the control of the neuronal specific enolase promoter results in astrocytosis and gliosis. These mice had higher cerebral endogenous IL-6 (12-fold), IL-1 beta (12-fold) and TNF (4-fold) production measured in brain homogenates after intracerebroventricular (i.c.v.) injection of 2.5 micrograms LPS, lipopolysaccharide (LPS) than wild-type mice (no TNF or IL-1 were detectable in saline-injected NSE or control mice). Cerebral cytokines production was also increased in NSE-hIL-6 mice treated i.p. with LPS doses that do not normally induce cytokines in the brain. The induction of peripheral (serum or spleen) TNF, IL-1 beta or IL-6 was the same in all these experiments in NSE-hIL-6 and wild-type mice. Furthermore, using microglial cell clone pretreated in vitro with IL-6, we noted an increase in LPS-induced TNF and IL-6 production and proliferation of pretreated cells than control. This study indicates that overproduction of IL-6 in the central nervous system (CNS) may ultimately result in increased central production of inflammatory cytokines, probably due to increased proliferation and activation of the cells which produce cytokine in the CNS.
Janus kinase-3 (Jak3) is a nonreceptor tyrosine kinase functionally coupled to cytokine receptors which share a "common" gamma chain (gamma c). Mutations in gamma c and Jak3 genes have been identified in X-linked and autosomal severe combined immuno deficiency (SCID), respectively. Jak3 is expressed and activated in myelomonocytic cells. The present study was designed to define the structural alteration responsible for lack of Jak3 in a patient with autosomal SCID and to characterize monocyte function in the absence of this signal transduction element, as well as to establish the whole exon-intron structure. Polymerase chain reaction analysis, performed with primers designed on exon sequences, identified 20 exons spanning approximately 15 kb. These primers, or others designed on the flanking sequences provided in the present report, can be used to amplify the whole gene, allowing the definition of the molecular defects in all cases, including prenatal diagnosis, in which transcript analysis is not possible. On this basis, the deletion transcript found at the homozygous state in patient CM, with both his consanguineous parents being heterozygous for the deletion, was associated with mutation (T to C) of a splice donor site of intron 16 that was also detected in his mother's DNA. Monocytes from Jak3-SCID showed normal cytokine production in response to interleukin-4 (IL-4) (release of IL-1 receptor antagonist) and IL-2 (release of tumor necrosis factor-alpha and IL-8). Lipopolysaccharide-induced cytokine production was also normal and was blocked by IL-4 in Jak3- SCID monocytes. Interferon-gamma induced augmented expression of major histocompatibility class II in Jak3-SCID monocytes. These data indicate that Jak3, expressed and activated in myelomonocytic cells, is dispensable for monocyte differentiation and responsiveness to cytokines that interact with gamma c receptors as well as to other regulatory signals.
BACKGROUND: The prognostic significance of the histologic and clinical features of medullary thyroid cancer (MTC) and their impact on therapy and outcome have been evaluated infrequently in the same series. METHODS: Fifty-tree patients with MTC (32 females, 21 males; 44 sporadic, 9 familial MTC [4 families]; mean age: 46.11 +/- 14.04 years) who were operated on consecutively between 1970 and 1992 were studied. All pathology slides were reviewed. Patients were followed with clinical examination, serum calcitonin (CT), and carcinoembryonic antigen (CEA) assay, and imaging procedures (median follow-up: 4 years; mean: 5.66 +/- 4.85 years; range: 0-19 years). Impact on survival was evaluated with Kaplan-Meier survival curves compared with the log rank test for these variables: familiarity, sex, age, pT, N, M, stage, histotype, necrosis, calcitonin, gene-related peptide (CGRP), CT, CEA, thyroglobulin, chromogranin A, chromogranin A PHE5, neuron-specific enolase, amyloid, argyrophilia, synaptophysin Y38, external radiotherapy, chemotherapy, 131I therapy, postsurgical serum CT, and postsurgical serum CEA, Multivariate analysis was performed using Cox's proportional hazards model for statistically significant factors (P < 0.05). RESULTS: Ten- and 15-year cause-specific survival were 71% and 54%. Nineteen patients (35.8%) appeared to be cured and 8 (15.1%) were alive with high serum CT levels but no proven metastases. Eight recurrences as distant sites and four at the cervical region were diagnosed. Stage M, N, necrosis, and postsurgical CT and CGRP were significant prognostic factors for survival by univariate analysis, but only the stage was significant by multivariate analysis. CONCLUSIONS: Stage and postsurgical serum CT level are the most powerful and the most useful prognostic factors for MTC, while survival did not correlated significantly with the majority of available immunohistochemical markers.
The hypothesis that the type II receptor (RII) acts as a decoy for interleukin-1 (IL-1) was tested by gene transfer in cells expressing only the type I receptor (8387 fibroblasts). RII-transfected cells showed defective responsiveness to IL-1 in terms of NFkappaB activation, cytokine gene expression and production. Blocking monoclonal antibodies against RII restored the capacity of RII-transfected cells to respond to IL-1 beta. Hence defective IL-1 responsiveness of RII-transfected cells requires surface expression of the molecule. RII-transfected cells showed normal responsiveness to TNF, which shares functional properties and elements in the signal transduction pathway with IL-1. Cells transfected with a deletion mutant of RII missing 26 of 29 amino acids of the cytoplasmic portion of the molecule showed impaired responsiveness to IL-2. Cells transfected with full-length or the cytoplasmic deletion mutant of RII released copious amounts of RII in the supernatant. However, transfected cells showed defective responsiveness to brief exposure to IL-1, in the absence of measurable released RII. These results indicate that impairment of the responsiveness to IL-1 following RII gene transfer was dependent upon surface expression of the molecule, specific for IL-1 and unaffected by truncation of the cytoplasmic portion. Thus, the type II "receptor" is a decoy surface molecule, regulated by antiinflammatory signals, whose only known function is to capture and block IL-1.