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Biomedical subjects

G F Bottazzo

Publications and source records attributed to G F Bottazzo.

At least 19 recordsLinked to original sources
PubMed1992

No risk of diabetes after insulin-shock treatment.

Prophylactic insulin treatment is effective in preventing diabetes in animal models of insulin-dependent diabetes mellitus (IDDM) but the safety of such preventive treatment in prediabetic human subjects remains unclear; insulin is a potential autoantigen that could accelerate beta-cell decompensation and onset of IDDM. We have investigated whether insulin treatment of non-diabetic subjects increases the risk of subsequent development of diabetes in a retrospective study of Danish patients who received insulin-shock treatment for psychiatric disorders. Mean age of the 481 patients at insulin-shock treatment was 32.6 (range 12.9-69.6) years. The patients received 59 (6-200) injections of 78 (16-261) IU bovine/porcine insulin. Hospital records provided an average of 22.0 (0.6-51.2) years' observation. During the observation time, IDDM developed in only 1 patient; 1.3 cases would be expected from Danish incidence data (p = 0.75). Similarly, there was no significant difference between the observed number of cases of non-insulin-dependent diabetes mellitus (NIDDM) and the number expected from Danish prevalence data (12 vs 10.2; p = 0.45). We collected blood samples from 27 of the patients. All but 2 (who had previously diagnosed NIDDM) had normal fasting blood glucose and plasma insulin concentrations, none had islet-cell antibodies, and only 2 had detectable insulin antibodies. Thus, the risk of diabetes was not increased by the use of many insulin injections in these non-diabetic subjects. We conclude that clinical trials on prevention of IDDM by prophylactic insulin treatment can be regarded as safe.

Adolescent↗
PubMed1992

Loss of regular oscillatory insulin secretion in islet cell antibody positive non-diabetic subjects.

Basal insulin secretion was compared in nine islet-cell antibody positive, non-diabetic first-degree relatives of children with Type 1 (insulin-dependent) diabetes mellitus and nine normal control subjects matched for age, sex and weight. Acute insulin responses to a 25 g intravenous glucose tolerance test were similar in the two groups (243 (198-229) vs 329 (285-380) mU.l-1 x 10 min-1, mean (+/- SE), p = 0.25). Fasting plasma insulin was assayed in venous samples taken at one min intervals for 2 h. Time series analysis was used to demonstrate oscillatory patterns in plasma insulin. Autocorrelation showed that regular oscillatory activity was generally absent in the islet-cell antibody-positive group, whereas a regular 13 min cycle was shown in control subjects (p less than 0.0001). Fourier transformation did, however, show a 13 min spectral peak in the islet-cell antibody positive group, consistent with intermittent pulsatility. We conclude that overall oscillatory patterns of basal insulin secretion are altered in islet-cell antibody positive subjects even when the acute insulin response is within the normal range.

Activity Cycles↗
PubMed1992

Distinct cytoplasmic islet cell antibodies with different risks for type 1 (insulin-dependent) diabetes mellitus.

The cytoplasmic islet cell antibody patterns of sera from islet cell antibody positive non-diabetic and diabetic endocrine autoimmune patients, and newly-diagnosed Type 1 (insulin-dependent) diabetic patients were characterised using four layer immunofluorescence with monoclonal anti-proinsulin or anti-glucagon antibodies. Two distinct islet cell antibody types were identified. One gave a diffuse cytoplasmic staining in both Beta and Alpha cells ('whole' islet pattern), and was not affected by pre-incubation with rat brain homogenate. The other had a granular appearance with staining restricted predominantly to Beta cells ('selective' islet pattern) and was completely inhibited by pre-incubation with rat brain homogenate. Some sera appeared to have a 'mixed' islet pattern, in which glucagon-positive cells gave a weaker cytoplasmic staining than proinsulin-positive cells. The granular 'selective' pattern was found in sera from 19 (79%) of 24 non-diabetic endocrine autoimmune patients, in two (22%) endocrine autoimmune patients who developed Type 1 diabetes (p less than 0.0001 vs non-diabetic endocrine autoimmune patients), and in none of 19 newly-diagnosed diabetic patients. The 'whole' islet pattern was found only in sera from patients who had, or who subsequently progressed to, Type 1 diabetes. This study has identified a novel islet cell antibody specificity and demonstrates that in islet cell antibody positive endocrine autoimmune patients, only islet cell antibodies which stain both Beta and Alpha cells are associated with progression to Type 1 diabetes.

Adult↗
PubMed1992

Early T-cell defects in pre-type 1 diabetes.

Alterations of lymphocyte subsets have been recently reported in pre-type 1 diabetes but the relation with other immunological markers, in particular islet cell antibodies (ICA), is still unknown. In the present study, we have investigated prospectively changes of lymphocyte subsets in 86 first-degree relatives of patients affected by type 1 diabetes and correlated such modifications with ICA titres. Among individuals with persistent ICA, 8 had ICA titres of more than 20 JDF units, 14 had ICA titres between 5 and 20 JDF units and 64 had ICA titres between 0 and 5 JDF units. First-degree relatives with ICA titres of more than 20 JDF units had significantly decreased proportions of CD3 cells. This reduction was predominantly in the CD4 subset, giving rise to a decreased CD4/CD8 lymphocyte ratio. Those with ICA titres between 5 and 20 JDF units showed abnormalities in both CD3 and CD4 lymphocytes, but not in CD4/CD8 lymphocyte ratio. Further characterization of the CD4 cell subset was performed using three other monoclonal antibodies, CD45RO (UCHL1), CD45RA and CD29, phenotyping memory T-cells, the inducer cells of suppressor function and helper-inducer cells, respectively. The proportions of total CD45RO and CD45RA were not significantly different among first-degree relative with distinct ICA titres in a cross-sectional study, whereas a trend towards a reduced proportion of CD4/CD45RA cells was observed. The longitudinal study demonstrated that individuals potentially susceptible to the development of type 1 diabetes and who possess high titres of ICA have impairment of CD4/CD8 lymphocyte ratio, mainly due to a reduction in the CD4 subset.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1992

Autoimmunity--towards the year 2001.

The interactive roles of T cells, major histocompatibility complex (MHC) class I and II molecules and antigen-presenting cells in the generation of autoimmunity is the subject of much discussion. A recent symposium contributed to the debate by inviting experts in several fields of immunology to answer specific questions relating to the mechanisms that trigger autoimmunity.

Animals↗
PubMed1992

HLA and immunoglobulin polymorphisms in idiopathic dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is an idiopathic heart muscle disorder. The presence of circulating cardiac antibodies and the association with HLA-DR4 are consistent with autoimmune pathogenesis in a subset of patients. Sixty-eight DCM patients and 277 controls were typed for IgG heavy-chain constant region (Gm) and kappa light-chain (Km) allotypes. All patients and 210 of the 277 controls were HLA-DR typed. The Gm (1, 3, 17; 23; 5*, 21, 28) phenotype was overrepresented in DCM compared with controls (25% vs 13%, p = 0.0139, pc = NS, RR = 2.23). The frequency of this phenotype was higher in patients with younger age at onset, shorter symptom duration, and among those who were positive for cardiac as well as for non-organ-specific autoantibodies than in controls. A higher frequency of the Gm (1, +/- 2, 3, 17; +/- 23; 5*, 21, 28) heterozygous phenotypes was also found in DCM compared to controls (40.91% vs 26.89%; p = 0.02, pc = 0.04, RR = 1.88). The finding of Gm heterozygosity in DCM was associated with serum positivity for cardiac antibodies. A higher proportion of DCM patients were positive for both the Gm (1, 3, 17; 23; 5*, 21, 28) phenotype and HLA-DR4 compared to normals (3/68 vs 0/210; p = 0.04, RR = 22.50).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Isolation and biochemical characterization of the human sperm tail fibrous sheath.

The isolation and biochemical characterization of the human sperm tail fibrous sheath (FS) is described for the first time. Initially, the solubilization properties of the FS were assessed immunocytochemically using GDA-J/F3 and RT97 monoclonal antibodies (MoAbs) and morphologically by electron microscopy. Following extensive investigations to optimize the conditions for the FS isolation, a simple method was developed which involved sequential extraction of the flageller components with Triton-dithiothreitol (DTT) and urea-DTT. The procedure was monitored by phase contrast microscopy and the purity of the FS preparations was confirmed by electron microscopy. SDS-PAGE of the isolated FS revealed seven major protein bands with mol. wt of 97, 76, 62, 55, 33, 28 and 25 kDa. In Western blotting, the reaction of RT97 MoAb with supernatants from the various extraction steps and the isolated FS indicated that its target antigen (AJ-p97) was an integral FS product and that disulphide bonding was probably involved in its stabilization. The reactivity of normal and aprotruded sperm tails with GDA-J/F3 and RT97 MoAbs was not affected by Triton while the GDA-J/F3 staining of the cytoplasmic matrix of other abnormal spermatids was abolished, thus suggesting variation in the biochemical properties of GDA-J/F3 in normal and abnormal germ cells. These and other data indicate that the FS could be a modified form of intermediate filament.

Antibodies, Monoclonal↗
PubMed1992

Abnormal urothelial HLA-DR expression in interstitial cystitis.

Interstitial cystitis is a chronic inflammatory disorder of the urinary bladder that predominantly afflicts middle-age women. The end stage of the disease is ulceration of the urothelium, the so-called Hunner's ulcer. The aetiology of interstitial cystitis remains obscure. We have studied bladder biopsies from 22 cases of interstitial cystitis and control groups consisting of six cases of bacterial cystitis and eight healthy women. Indirect immunofluorescence was performed on the biopsies using murine MoAbs to human HLA class I molecules, and class II molecules, HLA-DP, HLA-DQ and HLA-DR. In interstitial cystitis, bacterial cystitis and normal controls most cells expressed HLA class I products. In six cases of interstitial cystitis and one case of bacterial cystitis there was evidence of HLA class I hyperexpression. In normal bladder and bacterial cystitis HLA class II expression was restricted to submucosal dendritic cells, Langerhans cells macrophages, vascular endothelial cells and activated lymphocytes. All but two cases of interstitial cystitis showed surface expression of HLA-DR (but not HLA-DP or DQ). In all cases of interstitial cystitis there was an increase in the numbers of macrophages, activated lymphocytes and vascular endothelial cells expressing HLA class II molecules within the submucosa. These findings provide further evidence for the importance of inappropriate HLA molecule expression in a disease suspected of having an autoimmune pathogenesis and where cellular autoimmune mechanisms play a decisive role in the destruction of the target cells--the bladder urothelium.

Adult↗
PubMed1992

Adhesion molecule expression in Graves' thyroid glands; potential relevance of granule membrane protein (GMP-140) and intercellular adhesion molecule-1 (ICAM-1) in the homing and antigen presentation processes.

To assess the potential role of adhesion molecules in the pathogenesis of Graves' disease, we examined the expression of several of these adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM-1) and granule membrane protein-140 (GMP-140), in sections of Graves' thyroid glands and control thyroids, using immunohistochemical techniques. Up-regulated expression of GMP-140 was frequently observed on endothelial cells (EC) of post-capilliary venules in all Graves' thyroids examined, compared with an occasional weak staining on EC control glands. Some capillary EC around thyroid follicles (perifollicular EC) were strongly positive for GMP-140 in the Graves' thyroids in contrast to a negative staining on the same structures in the control glands. In addition, there was a correlation between the reactivity and frequency of GMP-140 expression on EC and the severity of mononuclear cell (MNC) infiltration in the Graves' thyroids. The expression of ICAM-1 was up-regulated on perifollicular EC and EC of small venules in some thyroids of both Graves' and control groups. Conversely, no significant expression was observed on any type of EC for both endothelial-leucocyte adhesion molecule-1 (ELAM-1) and VCAM-1. However, dendritic-like cells, present within lymphocytic infiltrates, were positive for VCAM-1 in most of the Graves' thyroids examined, especially in those with a severe lymphocytic infiltration. Thyrocytes were constantly negative for the expression of all four adhesion molecules investigated. These data suggest that GMP-140, as well as ICAM-1, could play an important role in the initiation of MNC infiltration in Graves' disease. ELAM-1 and VCAM-1 appear not to be relevant for the migration of MNC from the blood vessels into the target gland, although VCAM-1 expression on dendritic-like cells might play an additively tissue-selective role in autoantigen presentation and subsequent elicitation of autoimmune phenomena.

Cell Adhesion Molecules↗
PubMed1992

Idiopathic dilated cardiomyopathy: lack of association between circulating organ-specific cardiac antibodies and HLA-DR antigens.

Organ-specific cardiac antibodies are serological markers of autoimmunity in dilated cardiomyopathy (DCM). HLA-DR4 and possibly DR5 are immunogenetic markers of susceptibility in DCM, but it is not known whether they are associated with autoantibody production. We studied the frequency of HLA-DR antigens and the presence of organ-specific cardiac antibodies in 80 DCM Caucasian patients from Northern Italy. HLA-DR typing was performed by serology; 289 healthy blood donors from the same region were tested as controls. HLA-DR frequencies in DCM were also compared with VIII International Workshop control data for Italy. Cardiac antibodies were detected by indirect immunofluorescence on human heart. Skeletal muscle was used to identify cross-reacting antibodies. The prevalence of cardiac antibodies in DCM was: organ-specific 34% and skeletal muscle cross-reactive 30%. The previously reported positive association between DCM and HLA-DR4 was confirmed using either the controls from the same region (21.25% vs 10.73% p = 0.02, relative risk = 2.30) or from all of Italy (21.25% vs 12.3%, p = 0.03). HLA-DR5 frequency was slightly but not significantly higher in DCM than in controls from the same region (46.25% vs 31.49% p = 0.02, relative risk of 1.87, p corrected = NS) or from all of Italy (46.25% vs 35.8% p = NS). HLA-DR3 frequency was lower in DCM than in controls from the same region (12.50% vs 29.41% p = 0.003, relative risk of 0.36, p corrected = 0.03). This negative association was not confirmed using the control data from the whole of Italy (12.50% vs 16.5% p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

HLA-DP polymorphism in Sudanese controls and patients with insulin-dependent diabetes mellitus.

Human leukocyte antigen (HLA) genes are candidates for susceptibility to insulin-dependent diabetes mellitus (IDDM). The association of IDDM with particular DR and DQ alleles has been reported in all populations studied, but its association with HLA-DP alleles has been controversial. To address this question we analyzed 19 DPB1 and 2 DPA1 alleles and their associations in well-characterized Sudanese (an admixture of Arab and Black) IDDM patients (n = 71) and ethnically matched controls (n = 86) using polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) typing. There were no significant differences between the patient and control groups in the DPB1 frequencies. DPB1*0201, *0401 and DPA1*01 were the most frequent alleles in both IDDM patients and control subjects. Significant positive and negative associations between DPB1 and DPA1 alleles were detected in both groups. A novel DPB1 allele included in DPB1*1701 was identified.

Alleles↗
PubMed1992

Distribution of HLA-DQA1, -DQB1 and DRB1 alleles in black IDDM patients and controls from Zimbabwe.

We have used the XI Histocompatibility Workshop sequence-specific oligonucleotide probes to determine the DRB1, DQA1 and DQB1 genotypes by dot-blot hybridization of polymerase chain reaction (pcr)-amplified material from a homogenous black population in Zimbabwe. The DR4 subtype DRB1*0405, the DR3 subtype DRB1*0301, DQB1*0201 and DQB1*0302 and DQA1*0301 and DQA1*0501 were significantly increased in the IDDM group compared to the controls, whereas DRB1*11, DQB1*0602 and DQA1*0102 were significantly decreased. Taken together, the data show that susceptibility and resistance to IDDM are associated both with particular haplotypes and DQA1-DQB1 heterodimers without one or other being overriding.

Adult↗
PubMed1992

The treatment of Peyronie's disease with tamoxifen.

This is a preliminary study of the treatment of 36 patients with Peyronie's disease who received tamoxifen 20 mg twice daily for 3 months. An improvement occurred in 16 of 20 patients with penile pain, in 11 of 31 patients with an erectile deformity and 12 of 35 patients had a plaque shrinkage of at least 1 cm. Some improvement occurred in 6 of the 8 patients with a histologically confirmed inflammatory infiltrate of the plaque but not in any of the 4 patients without an infiltrate. The inflammatory infiltrate was found in patients in whom the duration of the disease was less than 4 months.

Adult↗
PubMed1992

Stimulation of human B cells specific for Candida albicans for monoclonal antibody production.

The stimulation and immortalisation of human peripheral blood B lymphocytes specific for Candida albicans antigen were investigated. An in vitro immunisation system was employed which involved pretreatment of mononuclear cells with L-leucyl L-leucine methyl ester which removes the suppressive effects of CD8+ T cells, NK cells and monocytes. The remaining cells, CD4+ T cells, B cells and dendritic cells, were cultured with antigen and a mixture of cytokines. A mixture of IL-2, -4 and -6 was found to be optimal for antibody production as determined by an Elispot assay. Transformation of the activated B cells by Epstein Barr virus was found to be optimal after 2 days and lines secreting anti-Candida antibodies were established. These lines could form the basis for specific monoclonal antibody production by generating hybridomas, or by a newly described technique whereby cDNA encoding antibody Fab regions is transferred into phage display libraries. The overall strategy might be generally applicable for the generation of human monoclonal antibodies to infectious agents.

Antibodies, Monoclonal↗
PubMed1992

Similar prevalence of enteroviral genome within the myocardium from patients with idiopathic dilated cardiomyopathy and controls by the polymerase chain reaction.

OBJECTIVE: To assess the prevalence and significance of enteroviral genome within myocardial biopsy specimens taken from patients with idiopathic dilated cardiomyopathy and from controls. DESIGN: Prospective evaluation of myocardial tissue for the presence of an enteroviral genome by the polymerase chain reaction. SETTING: A tertiary referral centre for patients with idiopathic dilated cardiomyopathy. PATIENTS: Tissue for the study came from 50 consecutive patients with dilated cardiomyopathy, 41 with other forms of heart disease and 34 from coroners' necropsy cases. RESULTS: Enteroviral genome was detected in 6/50 (12%) patients with dilated cardiomyopathy and 13/75 (17%) of the controls (not significant). No differences were seen between dilated cardiomyopathy patients with or without myocardial enteroviral genome in respect of age; duration of symptoms; proportion of patients with a premorbid acute viral illness, excess alcohol consumption, or hypertension; New York Heart Association functional class; measures of left ventricular function; or endomyocardial histology. Within the control group enteroviral genome was detected in 3/15 (20%) patients with ischaemic heart disease, 2/19 (10.5%) with valvar heart disease, 1/5 (20%) with specific heart muscle disease, 0/2 (0%) with congenital heart disease, and 7/34 (20.6%) cases of sudden death. During 2-52 month follow up (mean 22) 15/44 (34%) patients without myocardial enteroviral genome and 2/6 (33%) with myocardial enteroviral genome died suddenly or required orthotopic heart transplantation for progressive heart failure. CONCLUSIONS: These findings do not support the hypothesis that persistent enteroviral infection is of pathogenic or prognostic importance in dilated cardiomyopathy but they are consistent with enterovirus being a common environmental pathogen.

Adolescent↗
PubMed1992

Identification of alpha- and beta-cardiac myosin heavy chain isoforms as major autoantigens in dilated cardiomyopathy.

BACKGROUND: Immunization with cardiac myosin induces experimental autoimmune heart disease in genetically predisposed mice. These mice produce heart-specific autoantibodies, some of which are directed against the cardiac myosin isoform. METHODS AND RESULTS: We have reported the presence of circulating heart-specific autoantibodies in 26% of patients with idiopathic dilated cardiomyopathy (DCM) using indirect immunofluorescence. To identify the autoantigen(s) recognized by heart-specific autoantibodies in human disease, we tested, by Western blotting, sera from 26 DCM patients, 14 of whom were cardiac antibody-positive and 12 antibody-negative, as well as sera from 12 patients with cardiac failure from ischemic or valvular heart disease and from 13 normal subjects who were cardiac antibody-negative. Crude myofibrillar proteins and myosin preparations extracted from human atrial or ventricular specimens were used as antigens. Sodium dodecyl sulfate polyacrylamide gel electrophoresis was performed. The proteins were electrophoretically transferred to nitrocellulose sheets. The paper strips were incubated in sera from patients or controls at 1:100 dilution; the reaction was revealed with a peroxidase-labeled second antibody against human immunoglobulin. Twelve of the 14 DCM sera (86%) containing heart-specific antibodies reacted with both the alpha- (atrial specific) and beta- (ventricular and slow skeletal) myosin heavy chain isoforms; none of the 13 normal sera (p = 0.0001) and one of the 24 heart failure-negative control sera (4%, p = 0.0001) contained antibodies against myosin heavy chain. CONCLUSIONS: These findings indicate that alpha- and beta-cardiac myosin heavy chain isoforms as in the murine model of autoimmune heart disease are major autoantigens in patients with idiopathic DCM.

Adult↗
PubMed1992

Tumor necrosis factor beta gene polymorphisms in Graves' disease.

The physical mapping of tumor necrosis factor alpha (TNF alpha) and lymphotoxin (TNF beta) genes to the short arm of chromosome 6 in man between the loci for histocompatibility leucocyte antigens (HLA)-B and the complement system focused attention to this genetic region that controls immune responses in many ways. It also holds susceptibility genes for a variety of autoimmune disorders that are linked to specific alleles of loci in the HLA D subregion. We have recently identified a TNF restriction fragment length polymorphism with the enzyme NcoI (K. Badenhoop, G. Schwarz, J. Trowsdale, et al. Diabetologia. 1989;32:445-8). The less frequent fragment of 5.5 kilobase (kb) is in strong linkage disequilibrium with the HLA haplotype A1B8DR3. Since Graves' disease is linked to A1B8DR3, we analyzed TNF gene polymorphisms in a large group of Graves' disease patients and normal controls derived from four Centers. We show here a significant association of TNF beta polymorphisms with Graves' disease. The patients have less homozygotes for the 10.5 kb band (60 of 174, 34%) and more heterozygotes 10.5/5.5 kb (96 of 174, 55%), than 173 controls (49% homozygotes 10.5 kb and 42% heterozygotes; chi 2 = 7.45, P less than 0.03). When DR3+ patients and controls were analyzed separately, heterozygotes were still significantly increased in DR3+ Graves' disease patients (54 of 77, 70%) compared to DR3+ controls (21 of 45, 47%; chi 2 = 6.6, P less than 0.04). Furthermore, TNF fragment heterozygotes were found predominantly in patients, who had TSH-receptor antibodies (29/45, 64%, P less than 0.007), implying that these patients might represent an immunogenetic subset of the disease. Although TNF beta polymorphisms are linked to A1B8DR3, these results suggest that they represent an additional susceptibility marker in Graves' disease.

Autoantibodies↗