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Biomedical subjects

P Pozzilli

Publications and source records attributed to P Pozzilli.

At least 235 records · Page 13Linked to original sources
PubMedDate not supplied

Bovine beta-casein antibodies in breast- and bottle-fed infants: their relevance in Type 1 diabetes.

BACKGROUND: Bovine beta-casein is a cow's milk protein that targets both humoral and cellular immune responses in patients with Type 1 diabetes and, to a lesser degree, also in normal subjects. In this study we aimed to determine whether the avoidance of cow's milk consumption early in life could prevent the development of antibody response to bovine beta-casein despite the mother being exposed on a daily basis to cow's milk consumption. MATERIALS AND METHODS: We measured the antibody response to bovine beta-casein using an ELISA method in 28 healthy infants under 4 months of age, of whom 16 were exclusively breast-fed and 12 were bottle-fed with cow's milk. In addition, beta-casein antibodies were measured in 37 prepubertal children with Type 1 diabetes and in 31 healthy children who were exposed to cow's milk or dairy products to see whether differences in antibody titers exist in this young age group. Antibodies binding to beta-casein were also evaluated by immunoblotting analysis. RESULTS: Elevated levels of beta-casein antibodies were found in bottle-fed infants compared to breast-fed infants (p<0.0001). Antibody levels to bovine beta-casein were also significantly higher in children with Type 1 diabetes compared to age-matched controls (p=0.03). By western blot analysis we confirmed specific binding to bovine beta-casein in bottle-fed infants, in children with Type 1 diabetes and in controls exposed to cow's milk, but not in infants who were exclusively breast-fed. CONCLUSIONS: The results of this study indicate that breastfeeding within the first 4 months of life prevents the generation of antibody response to bovine beta-casein despite the mothers' consumption of cow's milk during the breastfeeding period. These findings may have relevance for disease prevention.

Animals↗
PubMedDate not supplied

Oral insulin and the induction of tolerance in man: reality or fantasy?

Induction of tolerance to insulin, the only beta-cell-specific antigen in Type 1 diabetes, is under testing for prevention of Type 1 diabetes in the US multicentre trial DPT1. Recently a multicentre double-blind trial with oral insulin in patients with recent onset Type 1 diabetes, conducted by our group, has been completed and showed that oral insulin administration at the dose of 5 mg daily for one year starting at the time of disease onset had no effect on residual beta-cell function as assessed by C-peptide secretion. A similar trial using different doses was carried out at the same time and similarly showed no beneficial effect on the decline of beta-cell function during the first year after diagnosis. In this study oral insulin was administered at the daily doses of 2.5 and 7. 5 mg over a one-year period. Such results challenge the current view that induction of oral tolerance can be established when the immune process is already active.

Administration, Oral↗
PubMedDate not supplied

An introduction to new advances in diabetes.

Diabetes is a potentially devastating disease with a high morbidity and mortality. There is an excess risk of both microvascular and macrovascular complications with diabetes [1]. Recent studies have emphasised and illustrated how we might be able to limit these diabetic complications. The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) found that improved control of blood glucose reduced the risk of major diabetic eye disease by 25%, serious deterioration of vision by nearly 50%, and early kidney damage by 33%. Other studies including the UKPDS have demonstrated the importance of blood pressure control and reduced cholesterol in addition to the use of aspirin in limiting progression of macrovascular disease. Diabetes is no longer viewed as a disease of sugar alone; a more holistic approach is required if our patients are to benefit from the information we have acquired through these recent studies. Some of the most recent developments in the field are presented in this review.

Blood Glucose↗
PubMedDate not supplied

Reduced cumulative incidence of diabetes but not insulitis following administration of chimeric human IL-15-murine IgG2b in NOD mice.

BACKGROUND: It has been recently demonstrated that apoptosis is involved in beta-cell destruction in the NOD mouse model of diabetes. The aim of the present study was to investigate whether IL-15, a cytokine involved in the modulation of the apoptotic process, is capable of modifying the natural history of diabetes and/or insulitis in pre-diabetic NOD mice. The rationale for the use of IL-15-IgG2b recombinant cytokine is related to its long half-life (28 +/- 4 h). METHODS: At 10 weeks of age, 2 groups of 24 female mice were treated with single or multiple i.p. doses of IL-15-IgG2b respectively. As control, 2 groups of 24 age- and litter-matched female mice were injected intra-peritoneally with single or multiple doses of IgG2b immunoglobulin. RESULTS: Diabetes incidence at 33 weeks of age was lower in the group of mice treated with multiple doses than in the control group (p = 0.03). The cumulative incidence of diabetes at 33 weeks of age between single-dose treated mice and the control group was similar. No significant differences in the calculated index of insulitis were observed in all treated and control mice. CONCLUSIONS: We conclude that IL-15-IgG2b reduces the cumulative incidence of diabetes, without affecting the extent and severity of the insulitis process. Considering this and the well-defined anti-apoptotic effects of IL-15, we suggest that the reduction of diabetes incidence could be due to a down-regulation of beta-cell apoptosis.

Animals↗
PubMedDate not supplied

Genetic prediction of type 1 diabetes in a population with low frequency of HLA risk genotypes and low incidence of the disease (the DIABFIN study).

BACKGROUND: To develop a sensitive, specific screening strategy for predicting genetic risk for type 1 diabetes mellitus (T1DM) in the low-incidence continental Italian population, and to define with this tool, a cohort of high-to-moderate risk infants for an immunological follow-up study aimed at identifying environmental risk factors for T1DM. METHODS: 4855 newborns in three regions of continental Italy were screened for T1DM HLA-DRB1-DQB1 risk genotypes using a reverse line blot typing method. Risk classification was based on odds ratios (OR) found in a preliminary case-control study (356 T1DM patients, 412 controls). Screening efficiency was optimized by allele subtyping. RESULTS: Screening for well-known T1DM susceptibility genotypes [DRB1*03/*04-DQB1*0302; DRB1*03/*03; DRB1*04/*04-DQB1*0302; DRB1*04-DQB1*0302/X where X is not equal to DRB1*03, DRB1*04-DQB1*0302, DQB1*0602 or DQB1*0603] was associated with <60% sensitivity due to their low frequencies in the general Italian population. Inclusion of an additional genotype from which protective DRB1 and DQB1 alleles had been excluded [DRB1*03/X degrees where DQB1 is not equal to *0301, *0503, *0602, or *0603 and X degrees not equal DRB1*03, DRB1*04-DQB1*0302 or DRB1*07] increased screening sensitivity to 75% (specificity: 85%). Among 4855 newborns, we have found the high-risk genotype [DRB1*03/*04-DQB1*0302; estimated absolute risk (AR) 1/23] to be present in only 0.9%. The moderate-risk genotypes were found in 13.8% of newborns (estimated AR 1/177). CONCLUSIONS: Risk classification must be tailored to the characteristics of the individual population, in particular, the allelic frequencies in the background population and T1DM prevalence. We have developed a screening strategy with good levels of sensitivity that should prove effective for use throughout the Italian peninsula.

Adult↗
PubMedDate not supplied

The natural history of insulin content in the pancreas of female and male non-obese diabetic mouse: implications for trials of diabetes prevention in humans.

BACKGROUND: The non-obese diabetic (NOD) mouse is a well-established animal model used to study the pathogenesis of type 1 diabetes. The NOD mouse spontaneously develops an autoimmune form of the disease between 12 and 18 weeks of age, characterized by an infiltration of the endocrine pancreas by autoreactive mononuclear cells. In our colony, all animals showed signs of insulitis, but only approximately 60% of females and 15% of males developed diabetes. The aim of this study was to determine the natural history of insulin content in the pancreas of female and male NOD/Ba mice during their life span. METHODS: Pancreata were collected at two-week intervals, from 4 weeks of age to 30 weeks of age. Four animals at each age as well as 18 diabetic female NOD mice were studied. Pancreata were homogenized, supernatants collected and insulin measured by radioimmunoassay. RESULTS: Female and male non-diabetic NOD mice showed significantly higher levels of insulin in the pancreata in comparison to the diabetic female animals. Pancreata from female (n = 56) animals showed more insulin content than male pancreata (n = 56), suggesting beta-cell hyperactivity as a result of the ongoing beta-cell destruction. However this difference was only significant at an early age (4-12 weeks of age) (p < 0.04). Insulin content in diabetic female NOD pancreas declines with time, and was very low at the age of 25 to 34 weeks. This decline was not observed in male pancreata despite the presence of lymphocytic infiltration. CONCLUSION: We conclude that a reduction in pancreatic insulin content occurs slowly in the natural history of the disease and that such reduction only becomes apparent after diagnosis of hyperglycaemia. Occurrence of extensive lymphocytic infiltration in non-diabetic male mice is not accompanied by a reduction of insulin content in the pancreas. These findings have implications for designing studies in humans which aims to protect residual beta-cell function.

Animals↗
PubMedDate not supplied

Residual insulin secretion at diagnosis of type 1 diabetes is independently associated with both, age of onset and HLA genotype.

BACKGROUND: We investigated whether residual insulin secretion and metabolic derangement at diagnosis of type 1 diabetes (T1DM) are influenced by human leukocyte antigens (HLA) class II genes. METHODS: Eight hundred and seventy-one T1DM consecutive Caucasian patients were typed for HLA class II genes. In 300 of these patients, glycated haemoglobin, insulin requirement, baseline C-peptide and body mass index (BMI) Z-score were measured at clinical diagnosis. The effect of the HLA genotypes on the quantitative variables was investigated using multiple linear regression. The beta coefficient regression of the age at onset and HLA genotypes were standardized to compare their specific importance for C-peptide levels. RESULTS: The HLA genotypes were divided in high-, moderate- and low-risk categories. The frequency of high-risk genotype, DRB1*03-DQB1*0201/DRB1*04-DQB1*0302, decreased with increasing age of onset (p < 0.0001, chi(2) linear trend). The presence of the high-risk genotype was independently associated with lower C-peptide levels at diagnosis (p = 0.002). In the regression analysis of C-peptide levels, the standardized beta coefficient for age of onset and high risk compared to low-risk genotypes showed similar results (0.27 and 0.24 respectively). There was a positive association between age of onset and C-peptide (p < 0.0001) and a negative association between age of onset and insulin requirement (p < 0.0001). CONCLUSIONS: The degree of beta-cell destruction at diagnosis of T1DM is independently associated with both, age of onset and HLA genotypes, the two variables exert a similar quantitative effect on residual beta-cell function at diagnosis.

Adolescent↗
PubMedDate not supplied

Antibody-dependent and natural killer cytotoxicity in type 1 diabetes.

The antibody-dependent cell-mediated cytotoxicity and the spontaneous cell-mediated cytotoxicity against Chang liver cells in relation to the levels of circulating K-cells (low affinity E-rosetting cells) were investigated in 23 newly diagnosed insulin-dependent (Type 1) diabetics, and in 17 unaffected islet cell antibody-positive subjects. Antibody-dependent cell-mediated cytotoxicity was significantly increased in those newly diagnosed diabetics with K-cells levels greater than 2 SD above the mean of normal controls (p less than 0.02). A similar but not significant trend was also found in islet cell antibody-positive subjects with raised K-cells. Spontaneous cell-mediated cytotoxicity was not different in any of the groups. These results lend further support to the concept that antibody-dependent lymphocyte cytotoxicity is enhanced in type 1 diabetes at diagnosis.

Adolescent↗
PubMedDate not supplied

The importance of measuring Fc+ (killer) cells in insulin-dependent (type 1) diabetes.

The measurement of Fc+ (killer or K) cells in insulin dependent (Type 1) diabetes may be of considerable value in monitoring activity of immune disturbance. K cells were investigated in Type 1 diabetics, their relatives and normal controls employing two methods based upon different principles. A close positive linear correlation was observed between the two methods in all subjects. Type 1 diabetic patients showed an increased level of K-cells with both techniques. In addition there was a good correlation between raised levels of K-cells and the occurrence of organ specific autoantibodies.

Adolescent↗
PubMedDate not supplied

Cell-mediated immunity and immune complexes in the pathogenesis of type 1 (insulin-dependent) diabetes.

Evidence for a role of the immune system in the pathogenesis of insulin-dependent (Type 1) diabetes is now plentiful. In the light of the lymphocytic infiltration in the islets of Langerhans, different autoaggressive mechanisms have been suggested in the initiation of B-cell damage. Lymphocytes characterized by cytotoxic properties (K cells) and having receptors for the Fc of IgG are increased in newly diagnosed Type 1 diabetics. Circulating immune complexes are also raised in these patients at the time of clinical diagnosis and there is evidence that K cells bind immune complexes which can modulate the activity of these cells. Here we propose a possible interrelationship between K or Fc gamma receptor+ T lymphocytes and immune complexes which could have a 'key' role in the mechanism of activation of cell-mediated immunity towards B-cells.

Antigen-Antibody Complex↗
PubMedDate not supplied

Inhibition of killer cell cytotoxicity induced by carbimazole in vitro.

The in vitro effect mediated by carbimazole (CBZ), a classical anti-thyroid agent on the antibody dependent cellular cytotoxicity (ADCC), low affinity E-rosetting cells (E-RFC) and high affinity E-RFC was investigated using lymphocytes from 11 normal subjects. CBZ at the doses of 250 and 500 mumol/l significantly reduced ADCC in all subjects studied. Low affinity E-RFC--mainly cells possessing receptors for the Fc portion of IgG and expressing cytotoxic properties in the ADCC system--were also significantly reduced following incubation with the same CBZ doses. These results suggest that CBZ, in addition to the known inhibitory effect on thyroid hormone synthesis, may be useful by depressing lymphocyte cytotoxicity in the treatment of autoimmune thyroid disease.

Antibody-Dependent Cell Cytotoxicity↗
PubMedDate not supplied

Why do so few diabetic patients attend dialysis centers in central Italy?

We report the prevalence of end-stage diabetic nephropathy treated by hemodialysis in the Lazio region, which includes the City of Rome, with a total population of over 5 million people. The percentage of diabetic patients among those attending the dialysis centers was 5% (n = 59), which is below the figures reported for both Northern Europe or Southern Italy (Sicily). A higher number (40%) of patients were affected by non-insulin treated diabetes. This figure is similar to that reported in Southern Italy, but highly discordant from the Northern European data where the large majority of diabetics on hemodialysis are affected by insulin-treated diabetes. Genetic differences and the type of diet may account for the difference in prevalence of end-stage nephropathy between Northern and Southern Caucasians affected by diabetes.

Adult↗
PubMedDate not supplied

Nicotinamide increases C-peptide secretion in patients with recent onset type 1 diabetes.

Nicotinamide, a poly-(ADP-ribose) synthetase inhibitor, has been shown in animal models to induce islet B-cell regeneration. An open controlled trial was therefore carried out for 1 year in 36 patients with recent onset (less than 4 weeks symptoms) Type 1 diabetes. Twenty-three patients were treated with nicotinamide (200 mg daily) in addition to insulin, and 13 control patients were treated with insulin alone. Metabolic and immunological variables at entry were similar in the two groups. A significant increase of stimulated plasma C-peptide levels compared to diagnosis was observed only in the nicotinamide treated group (1.4 +/- 0.3 (+/- SE) micrograms l-1 at diagnosis vs 2.4 +/- 0.4 at 6 months, p less than 0.04; and 3.0 +/- 0.5 at 1 year, p less than 0.01). Patients receiving nicotinamide had lower glycosylated haemoglobin levels at 6 months and 1 year compared to the control group (p less than 0.04 and p less than 0.03, respectively) although insulin dose was lower. Small doses of nicotinamide may be successful in improving metabolic control in recent onset Type 1 diabetes, probably by increasing residual islet B-cell function.

Adolescent↗
PubMedDate not supplied

Randomized trial comparing nicotinamide and nicotinamide plus cyclosporin in recent onset insulin-dependent diabetes (IMDIAB 1). The IMDIAB Study Group.

A 1-year open randomized controlled multicentre trial was carried out on 90 patients with recent onset (< 4 weeks) insulin-dependent diabetes (IDDM) to compare the effect of nicotinamide (NCT) with the combination NCT and low dose cyclosporin (CyA) on clinical remission and optimization of metabolic control during the first year from diagnosis. Three groups of patients were randomly assigned to receive for 12 months either NCT 25 mg kg-1 day-1 (n = 30) or NCT 25 mg kg-1 day-1 + CyA 5 mg kg-1 day-1 (n = 30), the latter adjusted to maintain 12 whole blood trough levels of 83 nmol l-1; a third group of patients (n = 30) receiving insulin only acted as a control group for spontaneous remission and metabolic control. Clinical remission (i.e. suspension of insulin therapy with normal metabolic parameters for more than 2 weeks according to the International Diabetes Immunotherapy Group) was achieved at 3 months in 6/30 NCT treated patients and in 1/30 NCT + CyA treated patient (p = 0.05); no remission was observed in control patients. At 6 months the number of patients achieving remission in each group was 4/29, 3/27, and 1/29, respectively (p = NS). One year after diagnosis 4/27 NCT treated, 2/25 NCT+CyA treated but 0/28 of the control patients were in remission (NCT vs control p = 0.05). Clinical remission lasted longer (7 +/- 3 SD months) in NCT treated patients than in NCT+CyA treated or control patients (p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMedDate not supplied

Imaging of leukocytic infiltration in human cerebral infarcts.

The circulating white blood cells of patients with brain infarction were labelled in vitro with Indium-111 tropolonate; the cells were reinjected to study the inflammatory process by gamma camera imaging. Eight patients with acute cerebral ischemic infarct were studied during the first two weeks after the onset of neurological symptoms. In seven cases a well defined area of increased radioactivity was revealed in the infarcted hemisphere indicating active migration and tracking of labelled leukocytes in cerebral infarct. This method allows monitoring of the cellular inflammatory response in human cerebral infarcts and adds another imaging technique.

Acute Disease↗