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Biomedical subjects

L Mori

Publications and source records attributed to L Mori.

At least 19 recordsLinked to original sources
PubMed2006

Genetic mutation screening in an italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients.

To assess the prevalence of genetic mutations in nonsyndromic pheochromocytoma/paraganglioma (PHEO/PGL) patients we have performed a systematic search for mutations in the succinate dehydrogenase (SDH) B, C, and D subunits, von Hippel-Lindau (VHL), and RET genes by direct bidirectional sequencing. Patients were selected from the medical records of hypertension centers. After exclusion of syndromic patients, 45 patients with familial (F+, n=3) and sporadic (F-, n=42) cases of isolated PHEO/PGL were considered. They included 35 patients with PHEO, 7 with PGL, and 3 with head/neck PGL (hnPGL). Three patients with PHEO (2F-, 1F+) presented VHL mutations (P86A, G93C, and R167W), six with PGL (4F-, 2F+) were positive for SDH or VHL mutations (SDHB R230G in two patients, SDHB S8F, R46Q, R90Q, and VHL P81L in one subject each), and one with hnPGL carried the SDHD 348-351delGACT mutation. We have also detected missense (SDHB S163P, SDHD H50R and G12S), synonymous (SDHB A6A, SDHD S68S), and intronic mutations that have been considered nonpathological polymorphic variants. No mutation was found in SDHC or RET genes. Our data indicate that germline mutations of VHL and SDH subunits are not infrequent in familial as well as in sporadic cases of nonsyndromic PHEO/PGL (overall, 12 of 45 probands, 22%). Accordingly, screening for such mutations seems to be justified. However, a more precise characterization of the functional relevance of any observed sequence variant and of other genetic and environmental determinants of neoplastic transformation is essential in order to plan appropriate protocols for family screening and follow-up.

Adrenal Gland Neoplasms↗
PubMed2005

Fetal and placental chromosomal mosaicism revealed by QF-PCR in severe IUGR pregnancies.

A number of genetic and environmental factors are taken into account as responsible for intrauterine growth restriction (IUGR); nevertheless, the relevance of genetic alteration in IUGR aetiology remains to be determined. The aim of this study was to investigate using a combined cytogenetic-molecular approach, improved by a new application of QF-PCR method, the presence of mosaic chromosomal changes in fetal/placental samples from 12 pregnancies with unexplained severe IUGR. This multiple approach allowed us to reveal and quantify subtle chromosomal mosaicisms with less than 5% of trisomic cells even in cases in which cytogenetic and FISH analyses failed to reveal them. These are three pregnancies with a mosaic trisomy for chromosomes 7, 2 and 14; the former case presented matUPD7 and was previously described in this journal (Placenta 22 (2001) 813) in association with pre- and postnatal growth restriction. It is intriguing that chromosomes 7, 2 and 14 are known or suspected to harbour imprinted genes, so that an unbalanced gene dosage in a subset of cells during embryonic development could lead to an early impairment of placental function. Our findings indicate that extensive molecular and cytogenetic studies of IUGR fetal and placental tissues are necessary to reveal at least part of the heterogeneous genetic lesions implicated in IUGR phenotypes.

Adult↗
PubMed2002

Presentation of the same glycolipid by different CD1 molecules.

Five CD1 molecules are expressed in humans and it is unclear whether they have specialized or redundant functions. We found that sulfatide is a promiscuous CD1-binding ligand and have isolated T cell clones that are specific for sulfatide and restricted by distinct CD1 molecules. These clones have been used to compare the capacity of different CD1 to present the same glycolipid, to induce effector functions, and to form persistent immunogenic complexes. CD1a, CD1b, and CD1c molecules similarly load sulfatide on the cell surface without processing, and prime Th1 and Th2 responses. Stimulation by sulfatide-loaded CD1a persists much longer than that by CD1b and CD1c in living cells. Use of recombinant soluble CD1a confirmed the prolonged capacity to stimulate T cells. Moreover, other glycosphingolipids bind to all CD1, which suggests the presence of additional promiscuous ligands. Thus, group I CD1 molecules present an overlapping set of self-glycolipids, even though they are quite divergent from an evolutionary point of view.

Antigen Presentation↗
PubMed2002

A new aspect in glycolipid biology: glycosphingolipids as antigens recognized by T lymphocytes.

T cells may recognize a large variety of ligands with different chemical structures. Recently, glycosphingolipids have also been shown to stimulate human T lymphocytes. Recognition of glycosphingolipids is restricted by the nonpolymorphic CD1 molecules, expressed by professional antigen-presenting cells and by macrophages infiltrating inflammatory sites. CD1 molecules have a structure resembling that of classical MHC class I molecules, with the terminal extracellular domains characterized by two antiparallel alpha helices placed on two hydrophobic pockets. The glycosphingolipids bound to CD1 insert the lipid tails in the two pockets and position the hydrophilic head on the external part of CD1. The TCR interacts with aminoacids present in the two alpha helices and with residues provided by the carbohydrate moiety of glycosphingolipids and discriminates their structural variations. T cells recognizing self-glycosphingolipids release proinflammatory cytokines and may have a pathogenetic role in autoimmune diseases such as multiple sclerosis.

Animals↗
PubMed2001

Interaction of mite allergens Der p3 and Der p9 with protease-activated receptor-2 expressed by lung epithelial cells.

The respiratory epithelium represents the first barrier encountered by airborne Ags. Two major dust mite Ags, Der p3 and Der p9, are serine proteases that may activate lung epithelial cells by interaction with the protease-activated receptor 2 (PAR-2). In this study both Der p3 and Der p9 cleaved the peptide corresponding to the N terminus of PAR-2 at the activation site. Both Ags sequentially stimulated phosphoinositide hydrolysis, transient cytosolic Ca(2+) mobilization, and release of GM-CSF and eotaxin in human pulmonary epithelial cells. These responses were similar to those observed with trypsin and a specific PAR-2 agonist and were related to the serine protease activity of Der p3 and Der p9. Cell exposure to the Ags resulted in a refractory period, indicating that a PAR had been cleaved. Partial desensitization to Der p3 and Der p9 by the PAR-2 agonist suggested that PAR-2 was one target of the Ags. However, PAR-2 was not the only target, because the PAR-2 agonist caused less desensitization to Der p3 and Der p9 than did trypsin. A phospholipase C inhibitor prevented the cytokine-releasing effect of the PAR-2 agonist and abolished or reduced (>70%) the cytokine-releasing effects of Der p3 and Der p9. Our results suggest that Der p 3 and Der p9 may induce a nonallergic inflammatory response in the airways through the release of proinflammatory cytokines from the bronchial epithelium and that this effect is at least in part mediated by PAR-2.

Allergens↗
PubMed2001

Surgical treatment of iatrogenic lesions of the proximal common bile duct.

Between January 1979 and September 1999 a series of 96 patients were operated on at our institution for iatrogenic biliary injuries, and among them 62 involved the proximal biliary tract. Injuries, according to the Strasberg classification, were type E2 in 18 patients, type E3 in 29 patients, and type E4 in 15 patients. The most frequent primary surgical procedures were laparoscopic cholecystectomy in 27 of the 62 patients (43.6%) and open cholecystectomy in 30 patients (48.3%). Previous repair had been attempted in 25 patients (40.3%). A total of 58 cholangiojejunostomies were performed. Repair had been performed directly, and a T-tube had been left in the main bile duct in four patients with E2 Strasberg lesions. Postoperative death occurred in four patients (6.4%). Outcome was graded as excellent, good, or poor depending on clinical symptoms, liver function tests, and the need for reintervention due to anastomotic stricture. The final outcome was evaluated in 54 patients. The mean follow-up was 5.9 +/- 0.3 years, with the longest follow-up 10.2 years. Following our first repair 49 of the 54 patients (90.7%) had excellent results, 1 (1.9%) had good results, and 4 (7.4%) had poor results. None of the patients who underwent immediate or early repair had complications. Diagnostic and therapeutic courses are given on the basis of the type of lesion and the timing of repair. We emphasize the importance of timing (i.e., carrying out surgical repair as soon as possible) and of cholangiojejunostomy reconstruction in respect to defined technical principles. Moreover, we believe that repair treatment at a hepatobiliary center with multidisciplinary competence greatly influences the final long-term outcome.

Adult↗
PubMed2000

Locally inducible CD66a (CEACAM1) as an amplifier of the human intestinal T cell response.

CD66a is an adhesion molecule member of the carcinoembryonic antigen immunoglobulin-like family present on the surface of epithelial cells, granulocytes and IL-2 activated T cells. We studied whether CD66a is expressed in vivo by T lymphocytes and whether it affects TCR-mediated activation. CD66a was detected by histochemistry, flow cytometry analysis, reverse transcription PCR and Western blot on fresh colon biopsies and T cell clones. A fraction of T cells in the lamina propria express CD66a, which is induced by IL-7 and IL-15 cytokines. T cells express four different CD66a splice variants and at least two forms of the protein are glycosylated in a cell type-specific manner. Triggering of CD66a on T cells with physiological ligands or with specific mAb increases TCR-mediated lymphokine release, in an antigen dose-independent manner. This effect requires the presence of the CD66a intracytoplasmic domain, which contains two immunoglobulin receptor family tyrosine-based inhibitory motif-like domains, as shown by stimulation of Jurkat cells transfected with different CD66a isoforms and is associated with increased induction of AP1 and NFkappaB transcription factors. These data indicate that CD66a amplifies T cell activation and thus could facilitate crosstalk between epithelial cells and T lymphocytes in intestinal immune response.

Antigens, CD↗
PubMed2000

Surgery for hilar cholangiocarcinoma: an Italian experience.

From January 1980 to June 1997 we treated 159 patients with carcinoma of the hepatic duct confluence. Seventy-five patients underwent surgical resection (overall resectability rate: 47.2%), and radical resection was attempted in 46 patients (radical resectability rate: 28.9%) classified in the first three stages of our staging system. Perioperative mortality was 10% (16 patients). The 5-year survival rate for 46 patients with curative resection was 17.5% with a median survival of 19 months. The 5-year survival rate for those patients who underwent combined caudate lobectomy (n = 17) was 25%, whereas the survival rate for those who did not was zero. The difference between these two groups' results was statistically significant. The importance of careful preoperative staging is stressed. Preoperative tests should be limited to investigations (ultrasound with Doppler scan, spiral computed tomography, percutaneous transhepatic cholangiography) supplying most information about intra- and extrabiliary diffusion of the tumoral mass. We conclude by highlighting the importance of resection as the only treatment potentially improving long-term survival. On the basis of these results, caudate lobectomy is always recommended in association with resectional treatment of the neoplasm.

Adult↗
PubMed2000

The alphabeta T cell response to self-glycolipids shows a novel mechanism of CD1b loading and a requirement for complex oligosaccharides.

The structural basis for the T cell recognition of lipoglycans remains to be elucidated. We have described autoreactive T cells responsive to GM1 ganglioside presented by CD1b. We show that glycosphingolipids bind to CD1b on the cell surface at neutral pH and are recognized without internalization or processing. Furthermore, soluble GM-CD1b complexes stimulate specific T cells. Oligosaccharide groups containing five or more sugars are required to build a minimal epitope for TCR recognition. This suggests a mechanism for T cell recognition of glycosphingolipids in which much of the CD1b-bound ligand is exposed. Binding to CD1b is a highly reversible process and other ceramide-containing glycosphingolipids displace GM1. These nonantigenic compounds act as blockers and may prevent harmful autoreactivity in vivo.

Antigen Presentation↗
PubMed2000

Treatment of hypertension with valsartan combined with spironolactone.

Preliminary observations were made to assess the antihypertensive efficacy and safety of treatment with valsartan plus spironolactone. Thirteen hypertensive patients were studied, 7 were males (54%), and 6 females (46%) with an age range from 61 years to 83 years (mean: 74+/-7.1 years). Patients had a mean daytime SBP/DBP of 164+/-9.2/99+/-9.5 mmHg. Echocardiography showed cardiac hypertrophy and mild cavity enlargement in all patients. After baseline measurements of HR, serum creatinine and electrolytes (potassium and sodium), patients received valsartan 80 mg/day plus spironolactone 100 mg/day for concomitant chronic heart failure due to hypertension. Study parameters were measured at the 30, 60, and 90 day of therapy. Mean ambulatory SBP/DBP monitoring, mean Holter heart rate, mean serum creatinine, and mean serum electrolytes (sodium and potassium) were recorded. These parameters did not show statistically significant changes after 90 days of follow up, except in one patient who had an increase in serum potassium concentration from 4.3 mmol/l to 5.8 mmol/l after 30 days of therapy. Mean BP was reduced up a maximum of 7%. No side effect was seen in the study patients. Combination therapy valsartan and spironolactone seemed to be an effective and safe approach for older hypertensive patients with mild concomitant chronic heart failure.

Aged↗
PubMed1999

Self glycolipids as T-cell autoantigens.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by discrete areas of demyelination. An autoimmune response against components of myelin is thought to contribute to disease pathogenesis. Here we identify glycolipids as new targets recognized by T cells in multiple sclerosis patients. Circulating T cells reactive with glycolipids are more frequent in MS patients than in control donors as shown by enzyme-linked immunospot assay. They specifically recognize different types of glycolipids, such as gangliosides, sulfatide and galactosylceramide and release IFN-gamma and TNF-alpha. T cells specific for gangliosides were found to be CD8+, TCR alphabeta+, restricted by the MHC-like CD1b molecule and specific for epitopes residing in the carbohydrate moiety of gangliosides. Our findings suggest that in addition to self proteins, self glycolipids may represent potential source of autoantigens recognized by T cells in autoimmune diseases.

Adult↗
PubMed1998

Genetic control of susceptibility to collagen-induced arthritis in T cell receptor beta-chain transgenic mice.

OBJECTIVE: To study the genes in the mouse background which predispose to the development of collagen-induced arthritis (CIA). METHODS: T cell receptor beta transgenic (TCRbetaL) mice that have a T cell repertoire that predisposes to the development of CIA were used. Classic genetic studies and microsatellite gene mapping were done in (SWR-betaL x DBA/1)F2 hybrid mice. RESULTS: Besides TCRbeta, major histocompatibility complex class II, and Igh-C, at least 2 other genes are absolutely required for CIA development in these mice. A strict association of CIA with the presence of functional complement C5 allele (Hc1) was found, suggesting that Hc1 or a closely linked gene might be one of these essential genes. CONCLUSION: This study provides new evidence of the pathogenetic role of complement C5 in CIA. Furthermore, these transgenic mice may facilitate molecular identification of other genes that predispose to CIA.

Animals↗
PubMed1997

GB virus C infection in patients with type II mixed cryoglobulinemia.

BACKGROUND: Hepatitis C virus (HCV) infection is present in most but not all patients with type II mixed cryoglobulinemia. OBJECTIVE: To investigate the role of GB virus C (GBV-C) in type II mixed cryoglobulinemia. DESIGN: Retrospective study of serum and cryoprecipitate samples. SETTING: Tertiary care hospital in Bergamo, Italy. PATIENTS: 58 cryoglobulinemic patients, 35 of whom were treated with interferon-alpha. MEASUREMENTS: GB virus C RNA was determined by a reverse-transcription polymerase chain reaction assay done by using primers derived from the conserved GBV-C helicase region. RESULTS: GB virus C RNA was detected in serum specimens from 23 of 58 cryoglobulinemic patients (40% [95% CI, 27% to 53%]) and 1 of 145 healthy blood donors (0.7%) (P < 0.001). Twenty of the 23 patients with GBV-C RNA were simultaneously infected with HCV. Unlike antibodies to HCV and HCV RNA, GBV-C RNA did not concentrate in cryoprecipitate in patients co-infected with GBV-C and HCV. Furthermore, the therapeutic effectiveness of interferon-alpha in patients with coinfection was related to the disappearance of HCV RNA but not GBV-C RNA from serum. None of 3 patients with GBV-C infection alone had detectable GBV-C RNA in cryoprecipitate. CONCLUSIONS: Infection with GBV-C, usually associated with HCV, is common in patients with type II mixed cryoglobulinemia but is unlikely to have a primary role in this disease.

Antiviral Agents↗
PubMed1997

Treatment of a newly established transgenic model of chronic arthritis with nondepleting anti-CD4 monoclonal antibody.

We established a novel animal model for rheumatoid arthritis (RA) by following backcrossing to DBA/1 of (SWR/J x DBA/1)F1 TCR-beta Tg mice, previously reported to be highly susceptible to collagen-induced arthritis. These mice evolved, upon collagen type II immunization, into a chronic arthritis that histopathologically resembles RA. The availability of such a model prompted us to study the role of CD4+ T cells throughout the evolution of disease. Here, we show that administration of nondepleting anti-CD4 not only prevented the evolution of disease but also treated established arthritis. Moreover, functional analyses of T cells isolated from anti-CD4-treated mice demonstrated that the mechanism of protection is not achieved by suppression of the Th1 population but is mediated by induction of collagen type II-specific T cell anergy. Our study suggests that: 1) CD4+ T cells have a fundamental role both in the induction and in the perpetuation of disease; 2) targeting T cells may be an appropriate therapeutic option; and 3) a suitable and well-balanced anti-CD4 treatment may be a valid approach to the control of RA.

Animals↗
PubMed1997

Functional inactivation in the whole population of human V gamma 9/V delta 2 T lymphocytes induced by a nonpeptidic antagonist.

Nonpeptidic compounds stimulate human T cells bearing the TCR-gamma delta in the absence of major histocompatibility complex restriction. We report that one of these ligands, 2,3-diphosphoglyceric acid (DPG), which induces expansion of V gamma 9/V delta T cells ex vivo, antagonizes the same cell population after repetitive activation. Stimulation with DPG results in partial early protein tyrosine phosphorylation and a prolonged, but reversible, state of unresponsiveness to agonist ligands in V gamma 9/V delta 2, but not in other T cells. These findings show that TCR antagonism is a general phenomenon of T cells. However, in contrast to the clonal specificity of altered peptides antagonizing alpha beta T cells, all the tested V gamma 9/V delta 2 polyclonal cell lines and clones become unresponsive, a fact that may be relevant for the regulation of their response in vivo.

2,3-Diphosphoglycerate↗
PubMed1996

Attenuation of collagen-induced arthritis in 55-kDa TNF receptor type 1 (TNFR1)-IgG1-treated and TNFR1-deficient mice.

The role of TNF and its type 1 receptor (TNFR1) in the pathogenesis of collagen-induced arthritis (CIA) was investigated in mice using two approaches. First, DBA/1 mice were treated after immunization with type II collagen by injecting TNFR1-IgG1 fusion protein to neutralize systemic TNF. CIA was prevented when treatment was administered shortly before the onset of clinical disease, suggesting that TNF is a crucial mediator in the late initiation phase of the arthritic process. In a second approach, TNFR1-deficient mice, generated by gene targeting and crossed to DBA/1, were used. These mice developed CIA with a low incidence and in a milder form. However, once a joint was afflicted, the disease progressed in this joint to the same end stage as that in wild-type mice. These data suggest that TNFR1 is the main transducer of TNF proinflammatory effects establishing CIA, but the progression of arthritis to tissue destruction and ankylosis is independent of TNFR1.

Animals↗