Some ado about a polymorphism.
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Adolescent↗
Biomedical subjects
M Molteni
Publications and source records attributed to M Molteni.
Graves' disease: a host defense mechanism gone awry.
In this report we summarize evidence to support a model for the development of Graves' disease. The model suggests that Graves' disease is initiated by an insult to the thyrocyte in an individual with a normal immune system. The insult, infectious or otherwise, causes double strand DNA or RNA to enter the cytoplasm of the cell. This causes abnormal expression of major histocompatibility (MHC) class I as a dominant feature, but also aberrant expression of MHC class II, as well as changes in genes or gene products needed for the thyrocyte to become an antigen presenting cell (APC). These include increased expression of proteasome processing proteins (LMP2), transporters of antigen peptides (TAP), invariant chain (Ii), HLA-DM, and the co-stimulatory molecule, B7, as well as STAT and NF-kappaB activation. A critical factor in these changes is the loss of normal negative regulation of MHC class I, class II, and thyrotropin receptor (TSHR) gene expression, which is necessary to maintain self-tolerance during the normal changes in gene expression involved in hormonally-increased growth and function of the cell. Self-tolerance to the TSHR is maintained in normals because there is a population of CD8- cells which normally suppresses a population of CD4+ cells that can interact with the TSHR if thyrocytes become APCs. This is a host self-defense mechanism that we hypothesize leads to autoimmune disease in persons, for example, with a specific viral infection, a genetic predisposition, or even, possibly, a TSHR polymorphism. The model is suggested to be important to explain the development of other autoimmune diseases including systemic lupus or diabetes.
Animals↗
Endothelial tissue factor induction by T lymphocytes in systemic sclerosis.
We evaluated the ability of circulating T lymphocytes obtained from patients with systemic sclerosis (SSc) to induce the expression of tissue factor (TF) by human umbilical vein endothelial cells (HUVECs), and compared the results with those obtained from healthy controls. Nine patients with SSc and 10 sex- and age-matched healthy subjects were studied. Peripheral T lymphocytes obtained from SSc patients induced TF activity from HUVECs in a dose-dependent manner. A significant induction of endothelial TF was observed when 2 x 10(6) lymphocytes per well (TF values, mean+/-SD: 0.34+0.21U/microg of cell protein vs 0.04+/-0.03; n = 9, p = 0.001) or 1 x 10(6) lymphocytes per well (0.13+/-0.06 vs 0.04+/-0.04; n = 8, p<0.001) were added to HUVEC cultures. Lower concentrations of T lymphocytes were ineffective. Similar results were obtained with control lymphocytes. There were no differences in endothelial TF induction between patients and controls at any lymphocyte concentration tested. Within the SSc group, there were no correlations between TF activity and clinical features or disease duration.
Adult↗
Increased interferon-gamma (IFN-gamma) levels produced in vitro by alloactivated T lymphocytes in systemic sclerosis and Raynaud's phenomenon.
The aim of the present study was to analyse the in vitro proliferation and cytokine production by alloantigen-stimulated peripheral blood mononuclear cells (PBMC) obtained from patients affected by systemic sclerosis (SSc) and patients with Raynaud's phenomenon (RP). In SSc patients the proliferation of PBMC stimulated in vitro with alloantigens was significantly increased compared with healthy subjects, while no differences were observed for RP patients. Lymphocytes from SSc patients also produced larger amounts of IFN-gamma compared with healthy controls. However, patients with clinically active disease had lower IFN-gamma levels than those found in clinically stable patients. Patients affected by RP showed significantly higher levels of IFN-gamma than healthy subjects. Analysis at the clonal level of the lymphocyte subsets involved in alloantigen stimulation in one patient affected by active SSc, and one subject with RP confirmed the results obtained using PBMC. In particular, in the RP patient but not in the SSc patient, we observed a population of CD4+ T cells which proliferated to alloantigens in vitro and produced high levels of IFN-gamma. We suggest that T lymphocytes producing high levels of IFN-gamma might play a protective role in RP patients and in established scleroderma.
Adult↗
Effects of serotonin transporter promoter genotype on platelet serotonin transporter functionality in depressed children and adolescents.
OBJECTIVE: To investigate possible associations between serotonin transporter (5-HTT) promoter genotypic variants (l/l, l/s, and s/s) and differential regulation of platelet 5-HTT functionality parameters in a group of drug-naive depressed children and adolescents and healthy controls. METHOD: Children and adolescents with major depression (n = 18) defined by DSM-III-R criteria and normal controls (n = 21) were assessed both for platelet serotonin functionality and for genotypic variants on 5-HTT promoter region. Four parameters were considered: (1) serotonin uptake rate (Vmax); (2) serotonin dissociation constant (K(m)); (3) paroxetine binding and density of site (Bmax); and (4) paroxetine dissociation constant (Kd). RESULTS: Depressed children had lower Vmax and K(m). Control subjects with l/l genotype had significantly higher Vmax than control subjects with l/s and s/s genotype. Control subjects with l/l genotype also had significantly higher Vmax than their depressed homologs. In contrast, Vmax was not significantly different between depressed and nondepressed subjects who carried the other 2 genotypes. The 5-HTT promoter genotype, diagnoses, or their interaction had no effect on the other serotonin parameters. CONCLUSIONS: While showing a significant decrease of Vmax and K(m) in a group of drug-naive depressed children and adolescents, these data suggest that l/l genotype has a substantial effect on the decrease of Vmax during a depressive episode.
Adolescent↗
High frequency of T-cell lines responsive to immunodominant epitopes of thyrotropin receptor in healthy subjects.
In this study we analyzed the proliferative response to the extracellular domain of thyrotropin receptor (TSHR-ECD) of T-cell lines raised from healthy subjects. We found high frequencies of cell lines reactive to TSHR-ECD, ranging from 12% to 37%. The response of the cell lines to a set of overlapping peptides of TSHR-ECD showed that the most recognized epitopes by T lymphocytes are on the C-terminal portion. In particular, the regions of residues 360-396 and 258-277 are immunodominant in T-lymphocyte reactivity. A group of cell lines specific for the peptides of TSHR-ECD lost the response to the peptides during time in culture. However, these lines were still responsive to TSHR extracellular domain. The cloning of one of these lines showed three types of T-cell clones: (1) CD4+ clones (n = 4) highly responsive to the TSHR-ECD; (2) CD4+ clones (n = 4) low responsive to TSHR-ECD; (3) CD8+ clones (n = 9) not responsive to TSHR-ECD. The first group of clones was stable during time in culture, while the second group was characterized by the loss of the specific response to TSHR-ECD after some weeks from the first analysis. The observation of a spontaneous anergy in the second group of CD4+ clones suggests that mechanisms of control of the lymphocyte response to TSHR-ECD could be activated in vitro.
Adult↗
Differential effects of cyclo-oxygenase pathway metabolites on cytokine production by T lymphocytes.
Cyclo-oxygenase pathway metabolites released in the microenvironment by activated platelets and endothelial cells are potential local modulators of the immune response. In the present study, we have investigated the modulatory role of PGE2, iloprost (prostacyclin analogue), U-46619 (thromboxane analogue) on the release of IL-2, IFN-gamma, TNF-alpha and IL-6 by T lymphocytes. Our results show that PGE2 and prostacyclin differ in the regulation of cytokine production. PGE2 inhibited the release of IL-2 and IFN-gamma, while iloprost did not affect their production. The addition of PGE2 or iloprost greatly decreased the amount of TNF-alpha measured in the supernatants, although the rates of inhibition differed according to the kind of stimulation. Unlike that of PGE2, inhibition by iloprost was stronger in alloactivated cultures than in PHA-stimulated ones. In vitro IL-6 production was stimulated by PGE2 in alloactivated cultures and by iloprost, whatever the stimulus. These results are probably due to other cellular subsets contaminating the T-lymphocyte preparations. After complete removal of monocytes from cell cultures, there were inhibitory effects of lloprost and PGE2 on IL-6 released in the supernatants. We did not observe any significant effect of thromboxane analogue on the production of either cytokine.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Psychopathological disorders in a population of mentally retarded young adults.
Nosographic, clinical, therapeutic and psychosocial aspects of psychopathological disorders in 43 mentally retarded patients followed from 1988 to 1991 are presented. Mental problems in mentally retarded subjects are linked to mental illness but do not form a continuum with it. The prognosis is generally favourable. Great attention must be given to the psychosocial aspects as social integration is almost always at risk in the mentally retarded.
Adolescent↗
Postoperative radiation therapy for adult soft tissue sarcomas: a retrospective study.
From 1977 to 1988, 81 adult patients with localized soft tissue sarcomas at different sites received postoperative external beam radiotherapy (55 Gy median dose) following primary conservative surgery. Sixty were new referrals after primary surgery and 21 were irradiated after excision of recurrent disease. With a median follow-up of 4 years (range: 2-13) the 5-year overall survival (Kaplan-Meier) and local control were 55.5% and 56% respectively, while 5-year disease-free survival is 49%. There were 26 (32%) local relapses and 22 (27%) distant failures. Local recurrence was the sole pattern of failure in 16 patients (20%). Functional and cosmetic results were good to excellent in most cases. In our series local control is the main prognostic variable influencing survival (P less than 0.0001), and its probability seems to show a link with the type of surgical procedure, with a trend (P less than 0.13) in favor of wide total excision. Postoperative radiation therapy represents an acceptable treatment strategy for ASTS, but further improvements are expected from future controlled clinical trials, aiming at the achievement of the definitive cure of these tumors.
Adult↗
Cimetidine and zinc sulfate in the treatment of relapsing herpetic infections.
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Adjuvants, Immunologic↗
[Radiotherapy in the treatment of carcinoma of the cervical esophagus: contribution, criteria of integration, limitations].
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Antineoplastic Combined Chemotherapy Protocols↗
[Exclusive radiotherapy of carcinoma of the hypopharynx. Retrospective study of a series of 100 patients].
From January 1980 to December 1987, 100 patients with carcinoma of the hypopharynx, staged according to TNM (UICC-1978) criteria, received exclusive radiation therapy at the Radiotherapy Department of the General Hospital of Varese. The median follow-up is 9 months (range: 1-97). Irradiation was delivered with 60Co or with 10 MV photons and tissue-equivalent bolus. Two opposed parallel lateral fields or rotational technique were used, with progressive shrinking of treated volume in order to spare the spinal cord after 45 Gy. Direct fields of electron beams (6-15 MeV) were employed as boosts on the residual nodes. Median total doses: 64.5 Gy to T and N1-3, 45 Gy to N0. A conventional fractionation (2 Gy once a day, 5 times a week) was used in 37 outpatients, while an accelerated hyperfractionated regimen (1.5 Gy twice a day, 5 times a week, with a six hours' interval between each fraction) was employed in 63 inpatients, in order to shorten hospitalization. The five-year overall survival (Kaplan-Meier) of the 100 treated patients is 10%, while the five-year disease-free survival of the 40 patients in complete clinical remission at the end of radiation therapy is 19.8%. The five-year loco-regional control rate after exclusive radiotherapy is 19.1%. Complete remission at the end of treatment seems to represent the only significant prognostic variable affecting survival: five-year overall survival is 32% for the 40 patients achieving complete remission and only 4.4% for the others (p less than 0.05). On the contrary, tumor extension (T class) seems to affect only the two-year local control rate: 35.2% and 10.9% for T1 + T2 and T3 + T4 respectively (p less than 0.1). The main cause of failure after radiation therapy is represented by the lack of control at the primary site (T) alone or associated with regional adenopathies (N). The analysis of isoeffect parameters, according to CRE model, has not shown any evident dose-response relationship for local control. Late effects were observed in 7% of the patients and were similar to those reported in the literature. The occurrence of both distant metastases, 3% in our experience, and secondary tumors (9%) is lower than those previously reported. The present retrospective study strongly reconfirms the inadequacy of exclusive radiation therapy as the sole treatment modality for carcinoma of the hypopharynx and suggests the need of combination therapy (surgery and radiation) as primary treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
[Radiotherapy of rhinopharyngeal carcinoma: analysis of the caseload of Varese (1979-1986)].
From December 1979 to December 1986, 100 patients affected with nasopharyngeal carcinoma, staged according to TNM (UICC-1978) criteria received exclusive radiation therapy at the Radiotherapy Department of the General Hospital of Varese. The median follow-up is 36 months (range: 1-114). Irradiation was delivered with 10 MV photons (58 patients) or 60Co (42 patients), with two opposed parallel lateral fields and progressive shrinkage, or rotation technique. Direct fields of electron beams (6-15 MeV) were employed as boosts on the residual nodes. Median total dose: 60 Gy to T, 46 Gy to N0, 62 Gy to N1-3. A conventional fractionation (2 Gy once a day, 5 times a week) was used in 43 patients, while an accelerated hyperfractionated regimen (1.5 Gy twice a day, 5 times a week) was employed in 57 patients. Five-year overall survival (Kaplan-Meier) of the 100 treated patients is 54.9%, while 5-year disease-free survival of the 71 patients in complete clinical remission at the end of radiation therapy is 54.7%. The nodal status represents the most important prognostic variable: 5-year overall survival (100 patients) is 77.7% for N0 patients and 40.8% for N1-3 patients, while 5-year disease-free survival for the 71 patients in clinical remission at the end of radiation therapy is 78.9% and 48.8% for N0 and N1-3 patients respectively. Our findings confirm the high rescue rate (approximately 50%) of irradiation failures by re-irradiation and/or salvage surgery. The analysis of loco-regional recurrences and persistent disease, after radiotherapy, strongly suggests the need for an improvement in loco-regional control rates, by means of a more accurate treatment planning (with CT and MR) and more attention to isoeffect parameters (CRE). The incidence of distant metastases (14%) and difficulties in loco-regional control of advanced disease seem to suggest the use of combined chemo-radiotherapy modalities only for selected groups of patients and exclusively in randomized studies.
Adolescent↗
[Exclusive radiotherapy of locally advanced carcinoma of the larynx. Analysis of the caseload of Varese (1979-1986)].
The authors analyse a retrospective series of 90 consecutive patients (pts) affected with locally advanced laryngeal carcinoma (T3-4, N0-3--TNM, UICC 1978) who were radically irradiated from November 1979 to December 1986 at the Radiotherapy Department of the General Hospital of Varese. All the patients were treated with 60Co and two opposed parallel lateral fields and progressive shrinkage: 66 with conventional fractionation (2 Gy once a day, 5 times a week), 24 with an accelerated hyperfractionated regimen (1.5 Gy twice a day, 5 times a week). The median total dose delivered to the tumor and clinically involved nodes was 64 Gy (1678 reu, CRE). Median follow-up was 21 months (range: 3-113). The 5-year overall survival (Kaplan-Meier) was 40.5%. The 5-year disease-free survival, for 47 patients in complete remission at the end of radiotherapy, was 51.9% after irradiation alone and 56.7% with salvage surgery. There were no statistically significant differences in survival according to local spread (T3 vs. T4), nodal status (N0 vs. N1-3) and dose fractionation regimen (conventional vs. accelerated hyperfractionated). Isoeffect (CRE) values above 1751 reu obtained a 3-year loco-regional control rate of 65%, while, for isoeffect values under 1600 reu, the 3-year loco-regional control rate was 33.3%. Relevant late sequelae were not observed. Our findings suggest that primary radiotherapy with salvage surgery in reserve could be considered as an effective choice for locally advanced laryngeal carcinoma, at least in selected groups of patients.
Adult↗
Minor psychiatric disorders as possible complication of mental retardation.
In young adult life a large proportion of mentally retarded subjects develop psychiatric complications, both severe and mild, whose origin is undoubtedly multifactorial (biological and psychological). A series of 27 subjects (13 male, 14 female; mean age 27.6 years) with IQ ranging from 70 to 40 were studied in our Institute from 1994 to 1995 and followed up 1 and 2 years later. Paykel scale (life events), FACES III (type of family insight), MFFT and Watkin's test (cognitive styles) were used to evaluate all cases. We found that (1) minor disorders prevailed in mild and moderate mental retardation and severe disorders in profound mental retardation; (2) minor disorders were generally determined by psychological and environmental factors although biological ones may have an important role; (3) psychological factors prevailed in young adult life when the subject had to cope with relatively harder tasks, and (4) the prognosis is generally good if proper care is given.
Adult↗
Lymphocyte-endothelium interaction in systemic sclerosis and Raynaud's phenomenon.
OBJECTIVE: To investigate interactions of immune cells with vascular endothelium in patients with systemic sclerosis (SSc) and in patients with idiopathic or autoimmune Raynaud's phenomenon (RP). METHODS: Lymphocytes obtained from 11 patients with SSc, 9 with RP and 14 control subjects were pre-stimulated in vitro with alloantigens and cultured together with human umbilical vein endothelial cells (HUVECs). Lymphocyte adhesion and induction of endothelial HLA-class 11 molecules were measured by flow cytometry. Lymphocyte cytotoxicity against HUVECs was also evaluated. In some cases cells were cultured under experimental conditions of hypoxia and reoxygenation. RESULTS: Lymphocyte adhesion and induction of endothelial cell expression of HLA-DR molecules were similar in controls and SSc patients, but significantly lower in RP (p < 0.05 and p < 0.03, respectively). Cytotoxic activity of lymphoblasts against endothelial cells was negligible in all patient groups. Under experimental conditions of hypoxia and reoxygenation lymphocyte adhesion was significantly greater than in normoxic conditions in SSc patients, while it was similar to normoxia in control subjects and RP patients. CONCLUSION: These results suggest that in RP patients there may be regulatory mechanisms of lymphocyte response able to control the processes that lead to lymphocyte adhesion and endothelial HLA-DR molecule induction. These mechanisms could play an important role in RP, and might possibly be lost in clinically evident SSc.
Adult↗
Secretion of cytokines upon allogeneic stimulation: effect of aging.
The aim of the present study was to investigate the in vitro mitotic response and cytokine production after allogeneic stimulation of peripheral blood mononuclear cells (PBMC) from healthy elderly subjects. Interleukin-1 (IL-1), interleukin-2 (IL-2), gamma-Interferon (gamma-IFN), and Tumor Necrosis Factor alpha (TNF-alpha) were detected in the supernatants of mixed lymphocyte cultures (MLC). The in vitro proliferative response was significantly reduced in the elderly subjects. The amount of IL-2 detected in the supernatant from cultures of cells from elderly donors was higher than for young controls, as were the production of cytokines predominantly secreted by the macrophage population (IL-1 and TNF-alpha). There was no difference in the production of gamma-IFN by cells of elderly and young subjects.
Adult↗
Cytokine production in scleroderma patients: effects of therapy with either iloprost or nifedipine.
OBJECTIVE: To compare the long-term effects of intermittent infusion of iloprost with those of oral nifedipine on the in vitro production of cytokines in patients with systemic sclerosis (SSc), and to evaluate their relationship with the effects of the two treatments on clinical parameters. METHODS: The production of cytokines by alloactivated circulating mononucleated cells was assessed before and after one year of treatment in a subset of 31 patients enrolled in a 12-month randomized clinical trial. Nineteen patients were treated with a 5-day (8 hr per day), 2.0 ng/kg per minute infusion followed by a 1-day infusion every 6 weeks; 12 patients were treated with an oral slow-release formulation of nifedipine, 20 mg twice daily. Quantitative determinations of interleukin-1 beta (IL1-beta) and interleukin-6 (IL6) in the culture supernatants were performed with a commercial ELISA; the levels of tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) were measured by specific radioimmunometric assays. RESULTS: The production of IL1-beta was significantly lower in the iloprost group than in the nifedipine group. Both the cutaneous fibrosis and the capillaroscopic patterns were better in patients treated with iloprost than in patients treated with nifedipine. There was a significant positive covariance between IL1-beta changes and the changes in both the skin score and the capillaroscopic score. CONCLUSION: There are several mechanisms by which iloprost could exert its clinical efficacy. Vasodilatation and inhibition of platelet aggregation are certainly important, but they are transient. We suggest that the long-lasting modulation of the cytokine network observed in the present study could be another potential mechanism responsible for the persistent efficacy of iloprost despite its intermittent administration.
Adult↗