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R B Elliott

Publications and source records attributed to R B Elliott.

At least 37 records · Page 2Linked to original sources
PubMed1994

A universal model of antibody prediction (MAP) of type 1 diabetes in children.

The majority of children who develop Type 1 diabetes under the age of 10-years-old show islet cell antibodies at levels of 40 or more units. Those who have lower levels (10- < 40) usually have co-existent insulin autoantibodies. Of these children 85% have these criteria. When these criteria were applied to large groups of similarly aged children who were either first degree relatives of a type 1 diabetic or had no such family history, 3.8% and 0.38% respectively showed these criteria. The observed sensitivity of these characteristics in identifying children who develop diabetes in the subsequent 5 years is 79% for both groups. The calculated expected incidence of disease in the subsequent 10 years for these two groups is 2.15% and 0.215% respectively. This model of autoantibody prediction of diabetes in children thus applies equally well in terms of sensitivity and specificity to those with and without a family history of diabetes.

Autoantibodies↗
PubMed1994

Targeting of pancreatic islets of severe combined immunodeficient mice by passive transfer of allogeneic spleen cells from non-obese diabetic mice.

The precise role of immune cells in beta cell killing and their manner of invasion of pancreatic islets in insulin-dependent diabetes mellitus (IDDM) are unclear. We have attempted to target pancreatic islets of severe-combined immunodeficient (SCID) mice with spleen cells from diabetic and non-diabetic female non-obese diabetic (NOD) mice given i.p. or i.v. Pancreatic, liver and kidney sections of SCID mice were assessed histologically for the presence of donor cells. The presence of raised levels of serum Ig was also used as an index of engraftment of donor cells in the periphery of SCID mice. All six SCID mice which received i.v. spleen cells from normal Swiss mice died within 2 weeks from graft versus host disease (GVHD) whereas five out of nine mice survived for 30 days after i.p. injection. No deaths were recorded after i.v. or i.p. injection of spleen cells from NOD mice. Pancreatic islets of four out of six SCID recipients of diabetic and three out of five recipients of non-diabetic spleen cells following i.p. injection showed lymphocytic infiltrates in the peri-islet and perivascular regions. All SCID mice which received i.v. spleen cells from diabetic (six SCID recipients) and non-diabetic NOD mice (seven SCID recipients) showed peri-islet and perivascular infiltrates in their pancreas. Immunohistochemical analysis showed that the islet engrafted cells were of CD4 and CD8 phenotype. Donor cells were also observed in the exocrine pancreas of some recipients. A majority of mice showed various degrees of lymphocytic aggregates in the perivascular regions of the liver but not in the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Autoantibodies to glutamic acid decarboxylase and insulin in islet cell antibody positive presymptomatic type 1 diabetes mellitus: frequency and segregation by age and gender.

The frequency of antibodies to glutamic acid decarboxylase (GAD) and insulin (IAA) in presymptomatic Type 1 diabetes mellitus with a positive test for antibodies to islet cell antigen (ICA) was examined. Thirty-two persons positive for ICA (> 10 JDF units) were tested 2 to 48 months before their ascertained onset of Type 1 diabetes. ICA was quantitated by immunofluorescence as JDF units, anti-GAD by radioimmunoprecipitation and anti-insulin by radioimmunoassay. There was a positive test for anti-GAD in 25 (78%), and for IAA in 23 (72%), of the 32 prediabetic ICA-positive subjects. Stratification according to age at the onset of diabetes showed differing frequencies of anti-GAD and IAA in the prediabetic stage. Thus the positivity rate for anti-GAD for 18 subjects older than 10 years at onset of diabetes was 83%, and for 14 aged 10 or younger at onset was 71%; conversely, the rate for IAA for 18 subjects older than 10 at onset was 56% and for 14 aged 10 or less at time of onset was 93% (p = 0.01). The frequency of anti-GAD was higher in females (88%) than males (71%) whereas the frequency of IAA was higher in males (82%) than in females (60%). Since autoantibodies to GAD and insulin occur in presymptomatic Type 1 diabetes with differences in frequencies by age and gender, the stimuli to autoimmunity may operate differently at different ages, and may also be gender-related.

Adolescent↗
PubMed1994

Early environmental events as a cause of IDDM. Evidence and implications.

Insulin-dependent diabetes mellitus (IDDM) is caused by destruction of the insulin-secreting beta-cells of the islets of Langerhans. It is proposed that the disease is caused by nongenetic, probably environmental, factors operating in a genetically susceptible host to initiate a destructive immune process. These environmental factors may operate over a limited period in early childhood to induce the immune process that destroys the islet beta-cell. Thereafter, there is a long prodrome before the onset of clinical diabetes, during which clinical, immune, and metabolic changes can be detected. If these proposals are correct, epidemiological studies should focus on environmental events in early childhood that might induce, or accelerate, the disease process. Moreover, it should be possible to identify, from an early age, changes in the prediabetic period that persist to diagnosis and have predictive value. The variable age of presentation of IDDM may, therefore, reflect different rates of disease progression rather than different ages of exposure to the critical environmental events. Those patients in whom the disease process is slow could present with IDDM as adults, develop diabetes that does not require insulin treatment, or even fail to develop diabetes altogether. These proposed features, if confirmed, would have important implications for the prediction of IDDM and raise the possibility that modulation of the destructive immune process could prevent progression to clinical diabetes.

Adolescent↗
PubMed1993

The use of nicotinamide in the prevention of type 1 diabetes.

Nicotinamide can protect the NOD mouse from diabetes if given early enough and in sufficient dose. The effect partly wanes with time. There is reduced islet inflammation. Similar protective effects can be demonstrated in quasi-experimental interventions in humans--both diabetes related and unrelated deemed at risk of developing diabetes by reason of having islet cell antibodies. Nicotinamide protects isolated islets in vitro from the toxicity of a number of agents, but only in doses that produce significant PARP inhibition, and increased intracellular levels of NAD. It is unlikely that the protective effect demonstrated in humans is due to significant PARP inhibition, as the levels of nicotinamide achieved with the doses used are too low. Other effects of the vitamin are more likely, e.g., increase in NAD pool size by de novo synthesis, or inhibition of free radical generation. The drug appears to be safe in the doses employed in humans.

Animals↗
PubMed1993

Blood-brain glucose transfer in the mouse.

The intracarotid injection method has been utilized to examine blood-brain barrier (BBB) glucose transport in normal mice, and after a 2-day fast. In anesthetized mice, cerebral blood flow (CBF) rates were reduced from 0.86 ml.min-1 x gm-1 in control to 0.80 ml.min-1 x gm-1 in fasted animals (p > 0.05). Brain Uptake Indices were significantly (p < 0.05) higher in fasted (plasma glucose = 4.7 mM) than control (plasma glucose = 6.5 mM) mice, while plasma glucose was significantly lower. The maximal velocity (Vmax) for glucose transport was 1562 +/- 303 nmoles.min-1 x g-1, and the half-saturation constant (Km =) 6.67 +/- 1.46 mM in normally fed mice. In fasted mice the Vmax was 2053 +/- 393 nmoles.min-1 x g-1 (p > 0.05), and the half-saturation constant (Km =) 7.40 +/- 1.60 mM (not significant, P > 0.05). A rabbit polyclonal antiserum to a synthetic peptide encoding the 13 C-terminal amino acids of the human erythrocyte glucose transporter (GLUT-1) immunocytochemically confirmed that the mouse brain capillary endothelial glucose transporter is a GLUT-1 transporter, and immunoreactivity was similar in brain endothelia from fed and fasted animals. In conclusion, after a 2-day fast in the mouse, we saw significant reductions in forebrain weight (7%), and plasma glucose levels (27%). Increased brain glucose extraction (25%, p < 0.05), and a 22% increase in the unsaturated permeability-surface area product (p < 0.05) was also observed.

Animals↗
PubMed1993

Distribution of pancreatic macrophages preceding and during early insulitis in young NOD mice.

Indirect evidence suggests there may be early influx of beta-cell-directed macrophages into the islets of NOD mice, and before the onset of T-cell insulitis. We have therefore examined immunohistochemically the pancreas of young female NOD mice with monoclonal antibody F4/80 for the presence of macrophages in intraislet, peri-islet, exocrine, and perivascular regions preceding insulitis (days 18 and 22) and during early insulitis (days 30 and 40) and compared their distribution in age-matched normal Swiss mouse pancreas. In the absence of insulitis (day 18 and day 22) and during very early insulitis (day 30) macrophage-positive cells had a predominantly exocrine and perivascular distribution with reduced numbers in the peri-islet area. Intraislet macrophages usually occurred singly and were sparse. At day 40, an enhanced influx of the immune cells was observed in intra- and peri-islet locations and in parallel with increased numbers in the exocrine areas. At this age, higher numbers of macrophages were observed within the islet, distributed among the T-cell infiltrate and also scattered among the endocrine cells. During the study period, the number of macrophages in the peri-, intraislet, and exocrine regions was significantly higher among NOD mice than in the Swiss mouse group (p = 0.003, p = 0.005, and p = 0.0009, respectively). In the absence of insulitis (days 18 and 22), although the number of positive cells tended to be higher in NOD mice, this difference reached statistical significance in the peri-islet area (p = 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

A comparison of two pancreatin microsphere preparations in cystic fibrosis.

OBJECTIVES: to compare the efficacy and tolerance of Creon and Pancrease in children and young adults with cystic fibrosis. METHODS: a double blind, crossover study of two pH sensitive microsphere preparations of pancreatin (Creon, Pancrease), given in equivalent lipase dosage to 27 children with cystic fibrosis, was conducted. RESULTS: at similar lipase activity no significant difference was found in the following: coefficient of fat absorption (CFA), coefficient of nitrogen absorption (CNA), weight gain, mean adequate daily intake for energy, and subjective symptoms. Three children who had a CFA less than 70% while receiving Pancrease all improved on Creon. No children had a CFA less than 70% while receiving Creon. A significant reduction in the number of capsules required daily to achieve similar control was possible when changing from Pancrease (mean 25/day) to Creon (mean 15/day). Seventy percent of patients preferred Creon and this was likely to be related to a perceived reduction in abdominal pain and stool frequency, and need for less capsules per day. CONCLUSION: Creon and Pancrease are equally effective at doses providing equal lipase activity, however, the reduced number of capsules, fewer symptoms, and possible improvement of more severe steatorrhoea result in an increased patient preference for Creon.

Adolescent↗
PubMed1992

An immunocytochemical study of endocrine cell development in the early fetal guinea pig pancreas.

The presence of insulin, glucagon, pancreatic polypeptide, and somatostatin containing cells and their ontogenic changes were investigated immunocytochemically in the early fetal pancreas of the guinea pig (Days 25-40). In the earliest tissues examined (Day 25 and Day 30) brightly staining glucagon cells were the most predominant endocrine cell population, followed by slightly fewer and weaker staining pancreatic polypeptide cells. Insulin and somatostatin immunoreactive cells were less numerous. At Day 25 all endocrine cells were located within the pancreatic tubules where some glucagon cells also coexpressed insulin. Similar dual immunoreactivity was present at Day 30. At Day 25 some of the pancreatic polypeptide cells also showed coexpression of somatostatin which persisted until Days 35-40. At these later stages insulin and somatostatin cells were increasingly frequent. Glucagon and pancreatic polypeptide cells were also conspicuous. The four endocrine cell types were found either in the pancreatic tubules or in the developing islets where they began to acquire an adult-like topographic distribution. These studies in the fetal guinea pig show that the four islet hormonal cells cytodifferentiate from an early stage. A small proportion of endocrine cells coexpress either insulin and glucagon or pancreatic polypeptide and somatostatin.

Animals↗
PubMed1992

First phase insulin release in the non-obese diabetic mouse: correlation with insulitis, beta cell number and autoantibodies.

The ontogenic variation of beta cell function and its relationship with the degree of islet damage and levels of autoantibodies have been studied in the non-obese diabetic (NOD) mouse model. We conducted in vivo first phase insulin release (FPIR) in response to intravenous glucose and studied its correlation with the degree of insulitis, islet cell antibody (ICA) and insulin autoantibody (IAA) levels in female NOD mice cross-sectionally at days 40 (n = 19), 90 (n = 21), 150-160 (n = 21) and day 250 (n = 20). The mean +/- SEM FPIR values showed an age-related decline from day 40 (46.2 +/- 5.3 microU/ml) to day 150-160 (17.8 +/- 2.5 microU/ml) and then doubled at day 250 (34.5 +/- 5 microU/ml), while the mean +/- SEM insulitis scores increased progressively until day 150-160 (61.7 +/- 6.1%) and then declined slightly at day 250 to 50.2 +/- 6.2%. In female NOD mice with spontaneous diabetes (n = 4) and streptozotocin-induced diabetic Swiss mice (n = 5) FPIR was either absent or greatly attenuated. A statistically significant inverse correlation between FPIR and insulitis was found among NOD mice at days 90 (P = 0.02; r = -0.52) and 150-160 (P = 0.03; r = -0.48). However, no statistically significant correlation was observed at days 40 and 250. Morphometric techniques applied to day 150-160 pancreatic sections showed a statistically significant negative correlation between insulitis and beta cell number per unit area of islet tissue (P = 0.0001; r = - 0.75). At this age some islet beta cells showed different intensities of staining by immunofluorescence.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

An immunopotentiator of beta-1,6;1,3 D-glucan prevents diabetes and insulitis in BB rats.

The preventive effect of an immunopotentiator, beta-1,6;1,3 D-glucan, on the development of diabetes and insulitis was studied in BB rats. The intravenous administration of 1 mg kg-1 week-1 of beta-1,6;1,3 D-glucan from the age of 4 weeks decreased the cumulative incidence of diabetes from 43.3% (13/30) to 6.7% (2/30) (P less than 0.005) and also the incidence of insulitis from 82.4% (14/17) to 26.3% (5/19) at the age of 20 weeks (P less than 0.002). Eight of nine rats were free from diabetes for 5 weeks after stopping beta-1,6;1,3 D-glucan at the age of 20 weeks. The total numbers of leukocytes in the peripheral blood and spleen of the rats were increased by beta-1,6;1,3 D-glucan treatment (P less than 0.05), whereas their T lymphocytes subsets were not changed. These data indicate that immunopotentiators could modulate the autoimmune mechanisms directed to pancreatic islets and inhibit the development of diabetes in BB rats.

Adjuvants, Immunologic↗
PubMed1991

Newborn screening for cystic fibrosis: a historical perspective.

The historical development of blood immunoreactive trypsin as a screening procedure performed on neonatal dried blood is described. Our experience of false positive, and false positive results using the original procedure has led to some useful modifications which reduce these errors to an acceptable level. A satisfactory national screening programme has been in place in New Zealand for 10 years.

Cystic Fibrosis↗
PubMed1991

Prevention or delay of type 1 (insulin-dependent) diabetes mellitus in children using nicotinamide.

A controlled trial of oral nicotinamide to prevent the onset of diabetes mellitus in high risk children was conducted in two centres. The selection criteria were age less than 16 years, islet cell antibody greater than or equal to 80 IUs, and first phase insulin release less than 5th percentile. All of eight untreated control subjects have developed diabetes, whereas only 1 of 14 treated children has diabetes to date. This data suggests that nicotinamide has an effect in preventing Type 1 (insulin-dependent) diabetes and that randomized controlled studies are now indicated.

Autoantibodies↗
PubMed1990

A sensitive and reproducible method for the assay of human islet cell antibodies.

The islet cell antibody test is increasingly used to predict insulin-dependent diabetes before it is clinically apparent. Four international workshops on the test have shown wide variations in reproducibility, sensitivity and specificity. This illustrates the need for a more clearly defined method. We report a technique which offers both increased sensitivity and reproducibility. Using this method 94% of newly diagnosed diabetic children have ICA levels greater than or equal to 10 international units, whereas only 1.5% of normal children are positive at his level, and 7% of first degree relatives (aged less than 20 years) of IDDM patients.

Adolescent↗
PubMed1990

Longitudinal study of islet cell antibodies and insulin autoantibodies and development of diabetes in non-obese diabetic (NOD) mice.

We have previously shown the presence of circulating islet cell cytoplasmic antibodies (ICA) and insulin autoantibodies (IAA) in the NOD mouse before onset of insulin-dependent diabetes mellitus (IDDM). Here we have determined the levels of the two autoantibodies in 28 female NOD mice longitudinally from approximately day 40 to day 250, to examine their ontogeny, association and predictive value for diabetes. All animals (11 diabetic, 17 non-diabetic) showed varying levels of ICA at some stage, while IAA activity was found in 21 out of 28 mice. Expression of both the markers was seen in more than half of the animals by day 60, with higher levels and rates occurring subsequently in both diabetic and non-diabetic groups. The expression of ICA did not always correlate with that of IAA. There was no apparent difference in the ontogeny of ICA and IAA between the two groups. During the study period the number of animals with ICA was similar in the two groups, while the number of those with IAA was higher in the diabetic animals. In this group declining and rising levels of ICA were seen just before clinical diabetes with frequent peaks of IAA. In the same animals, eight out of 11 mice showed co-expression of high levels of both markers either intermittently or persistently prior to onset, whereas only one non-diabetic animal showed this. We conclude that the ontogeny and serum level of ICA or IAA alone could not be used to predict the clinical onset of diabetes in these animals. However, co-expression of high levels of both markers prior to onset may suggest a strong predisposition to clinical diabetes. This may have relevance to attempts to predict the onset of IDDM in humans who have one or both of these immunological markers.

Animals↗
PubMed1990

Early nicotinamide treatment in the NOD mouse: effects on diabetes and insulitis suppression and autoantibody levels.

Nicotinamide, a vitamin B group substance, has previously been shown to prevent diabetes and suppress insulitis in the NOD mouse. In order to further understand its mode of action, we have administered the vitamin orally to female NOD mice from weaning and have examined its effect cross-sectionally (days 40, 106 and 250) on the severity of insulitis, changes in T cell subpopulations, levels of islet cell antibodies (ICA) and insulin autoantibodies (IAA) and diabetes development. At day 40, the incidence and severity of insulitis were much lower in the nicotinamide group (n = 22) than in the control mice (n = 21; 23.8% versus 57.1%, 2.9 +/- 1.4% versus 9.6 +/- 2.6%, respectively). At day 106, the incidence of insulitis increased to 82% in the nicotinamide group (n = 11) and remained similar at day 250 (n = 14). At these two age groups all control mice developed insulitis. The insulitis score increased to about 20% at day 106 in the nicotinamide mice and remained the same at day 250. In the control animals, this score increased from 9.6 +/- 2.6% at day 40 to about 33% and 60% at days 106 and 250, respectively. Diabetes was not detected in the 14 animals maintained on nicotinamide while 4/14 control mice developed the disease with severe insulitis. Most of the immune cells infiltrating the islets were T cells, with higher numbers of L3T4 than Lyt2 cells. At days 40 and 106, the L3T4:Lyt2 cell ratios remained unchanged in both the nicotinamide and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗