PubMed Health⌕ Search

Biomedical subjects

R B Elliott

Publications and source records attributed to R B Elliott.

At least 19 recordsLinked to original sources
PubMed2003

A wheat-based, diabetes-promoting diet induces a Th1-type cytokine bias in the gut of NOD mice.

Dietary antigens are candidate environmental factors in the pathogenesis of type 1 diabetes. In the non-obese diabetic (NOD) mouse, an animal model of type 1 diabetes, cereal-based diets promote disease development, whereas the diets based on hydrolysed proteins or non-diabetogenic proteins are protective. The hypothesis that diabetogenic diets modulate the cytokine balance in the gut was tested. NOD mice were fed with NTP-2000 (mainly a wheat-based milk-free diet) or Prosobee (a semi-purified hypoallergenic diet based on soy protein isolate) or Prosobee plus casein (milk protein fraction). The mRNA levels of IFN-gamma, IL-10, TNF-alpha, TGF-beta, and inducible NO synthase in the small intestine and the Peyer's patches were determined by semi-quantitative RT-PCR. Mice fed on the cereal-based NTP-2000 diet expressed higher levels of the Th1-type and pro-inflammatory markers IFN-gamma, TNF-alpha, and inducible NO synthase mRNA compared to the Prosobee-fed animals. The expression of the counterregulatory cytokines IL-10 and TGF-beta was unaffected. This resulted in a significant bias of the intestinal cytokine balance towards T helper cell type 1 after feeding NTP-2000. The cytokine mRNA levels in the gut-associated Peyer's patches were not affected. Thus, modulation of gut immunoreactivity by diet may contribute to disease development in NOD mice.

Animal Feed↗
PubMed2002

A multi-centre, blinded international trial of the effect of A(1) and A(2) beta-casein variants on diabetes incidence in two rodent models of spontaneous Type I diabetes.

AIMS/HYPOTHESIS: The diabetes-inducing potential of cows' milk is still debated and there is no consensus on the diabetogenicity of individual milk proteins. A(1)-beta-casein has been associated with increased diabetes frequency in ecological studies and in NOD mice. Our aim was to ascertain whether A(1)-beta-casein was more diabetogenic than A(2) and to test the diabetogenicity of a milk-free diet in animals representing different forms of spontaneous Type I (insulin-dependent) diabetes mellitus. METHODS: Defined diets were coded and shipped to laboratories in New Zealand (NOD/NZ), Canada (BB) and the UK (NOD/Ba). Base diets were Pregestimil (PG) and ProSobee (PS). Purified fractions of whole casein (WC), A(1)or A(2)-beta-casein were added at 10%. A milk-free, wheat-predominant, NTP-2000 diet was the control. Animals were fed from weaning up to 150 or 250 days, and insulitis, diabetes frequency and expression of pancreatic cytokines were assessed. RESULTS: Diabetes incidence was highest in three locations in animals fed NTP-2000. PG and PS diets were protective except for NOD/Ba mice fed PG+WC where incidence was similar to NTP-2000. A(1) and A(2) diets were protective in both models, but A(1) beta-casein was slightly more diabetogenic in PS-fed BB rats. The New Zealand study was confounded by an infection. CONCLUSION/INTERPRETATION: A milk-free, wheat-predominant diet was highly diabetogenic in three widely separate locations in both animal models. A previous result that A(1) beta-casein was more diabetogenic than A(2) beta-casein in NOD mice was not confirmed; both beta-casein variants were protective in BB rats and NOD mice. Whole Casein promoted diabetes in NOD/Ba but protected BB showing that unique diabetes haplotypes react differently to dietary proteins. A(1)- was more diabetogenic than A(2)-beta-casein only in PS-fed BB rats. Neither the analysis of insulitis nor of pancreatic cytokine gene expression showed a difference between A(1) or A(2) beta-casein fed animals. Milk caseins are unlikely to be exclusive promoters of Type I diabetes, but could enhance the outcome of diabetes in some cases. Other diet components such as wheat could be more important promoters of Type I diabetes.

Animals↗
PubMed1999

Genetic determination of islet cell autoimmunity in monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1 diabetes: prospective twin study.

OBJECTIVE: To test the hypothesis that non-diabetic dizygotic and monozygotic twin siblings of patients with type 1 diabetes have a similar high prevalence of islet cell autoantibodies, thus suggesting that islet cell autoimmunity is mainly environmentally determined. DESIGN: Prospective twin study. SETTING: Two specialist centres for diabetes in the United States. PARTICIPANTS: Non-diabetic monozygotic twin (n=53), dizygotic twin (n=30), and non-twin (n=149) siblings of patients with type 1 diabetes; 101 controls. MAIN OUTCOME MEASURES: Analysis of progression to diabetes and expression of anti-islet autoantibodies. RESULTS: Monozygotic twin siblings had a higher risk of progression to diabetes (12/53) than dizygotic twin siblings (0/30; P<0.005). At the last follow up 22 (41.5%) monozygotic twin siblings expressed autoantibodies compared with 6 (20%) dizygotic twin siblings (P<0.05), 16 (10.7%) non-twin siblings (P<0.0001), and 6 (5.9%) controls (P<0.0001). Monozygotic twin siblings expressed multiple (>/=2) antibodies more often than dizygotic twin siblings (10/38 v 1/23; P<0.05). By life table analysis the probability of developing positive autoantibodies was higher among the monozygotic twin siblings bearing the diabetes associated HLA DQ8/DQ2 genotype than in those without this genotype (64.2% (95% confidence interval 32.5% to 96%) v 23.5% (7% to 40%) at 10 years of discordance; P<0.05). CONCLUSION: Monozygotic and dizygotic twins differ in progression to diabetes and expression of islet cell autoantibodies. Dizygotic twin siblings are similar to non-twin siblings. These two observations suggest that genetic factors play an important part in determination of islet cell autoimmunity, thus rejecting the hypothesis. In addition, there is a high penetrance of islet cell autoimmunity in DQ8/DQ2 monozygotic twin siblings.

Adolescent↗
PubMed1999

Type I (insulin-dependent) diabetes mellitus and cow milk: casein variant consumption.

Previously published Type I (insulin-dependent) diabetes mellitus incidence in 0 to 14-year-old children from 10 countries or areas was compared with the national annual cow milk protein consumption. Countries which were selected for study had appropriate milk protein polymorphism studies, herd breed composition information and low dairy imports from other countries. Total protein consumption did not correlate with diabetes incidence (r = +0.402), but consumption of the beta-casein A1 variant did (r = +0.726). Even more pronounced was the relation between beta-casein (A1+B) consumption and diabetes (r = +0.982). These latter two cow caseins yield a bioactive peptide beta-casomorphin-7 after in vitro digestion with intestinal enzymes whereas the common A2 variant or the corresponding human or goat caseins do not. beta-casomorphin-7 has opioid properties including immunosuppression, which could account for the specificity of the relation between the consumption of some but not all beta-casein variants and diabetes incidence.

Adolescent↗
PubMed1999

The gut cytokine balance as a target of lead toxicity.

The impact of exposure to lead on gut cytokine gene expression and oral tolerance was analyzed. Oral tolerization with ovalbumin (OVA) increased levels of IL-10 and TGF-beta in gut tissue while IFN-gamma mRNA levels remained unchanged in both autoimmune diabetes prone NOD and normal C57BL/6 mice. This shift towards Th2/Th3 type cytokine gene expression was completely abolished by concomitant treatment with PbCl2 (6 x 0.5 mg/kg) in NOD mice while the cytokine balance in C57BL/6 mice was unaffected. Suppression of Th2/Th3 type cytokine expression was associated with a dampened oral tolerance response to OVA as determined by T cell proliferation assays. We conclude that in autoimmunity prone NOD mice environmental toxicants may disturb immune homeostasis by targeting the gut immune system.

Administration, Oral↗
PubMed1997

Double-label immunofluorescence study of glutamic acid decarboxylase in the fetal and adult ovine pancreas by light and confocal microscopy: evidence for predominant beta-cell coexpression.

Glutamic acid decarboxylase (GAD) is present in the central nervous system and in several nonneuronal tissues including the pancreatic islets. There are two isoforms with molecular weights of 65 kDa (GAD65) and 67 kDa (GAD67). The cellular specificity of the two molecular forms of GAD and their levels within the mammalian islets may be species-dependent, being coexpressed in both beta and in non-beta cells. We have examined the ovine pancreas, from the adult and fetal stages of late gestation, for the expression of GAD65 within the islet cells by double-label immunofluorescence light and confocal microscopy. In the adult tissue, GAD65 was colocalized in a majority of the beta cells (> 95%), with only a few glucagon and somatostatin cells (< 5%) showing immunolocalization. During the fetal stages GAD65 also showed a similar predominant beta-cell coexpression. The enzyme was also detected in a few fetal glucagon (< 5%) but not somatostatin cells. In the degenerating large fetal islets, GAD65 was also observed in the majority of the residual beta cells. These results demonstrate that in the ovine pancreas GAD65 is expressed during fetal development and is predominantly beta-cell-restricted. This pattern of expression is maintained during adult life. However, the physiological role of pancreatic GAD and/or its biosynthetic product, gamma-aminobutyric acid, in islet function in the sheep and in other ruminants remains unclear.

Aging↗
PubMed1995

A combined casein-free-nicotinamide diet prevents diabetes in the NOD mouse with minimum insulitis.

We have previously shown that diabetes in the NOD mouse can be prevented if mice are placed from weaning on an infant formula diet in which the protein source is replaced with casein hydrolysate (Pregestimil) or soy protein (Prosobee), or if 1% nicotinamide is given in the drinking water. Nicotinamide somewhat suppresses insulitis but the hydrolysed casein formula does not. In this study, Prosobee was given concurrently with oral nicotinamide from weaning and their effects on the development of insulitis and diabetes measured. These effects were also assessed in mice given Prosobee alone from conception (day -20) or from weaning. Unlike the earlier experiments, a marked suppression of insulitis was observed when the diets and nicotinamide were given concurrently (mean insulitis scores +95% confidence intervals (back transformed): day 40 = 0.4% [0.03, 1.17] vs. 12.5% [2.52, 28.40] and at day 90 = 8.8% [3.65, 15.68] vs. 48.1% [33.89, 62.49], P = 0.0001). A similar suppression was observed on day 90 with Pregestimil combined with nicotinamide 7.3% [3.88, 11.70] vs. 43.8% [32.59, 55.35] (P = 0.0001). Qualitatively, introduction of Prosobee from conception appeared to elicit a greater degree of suppression of insulitis than when introduced from day 21. Insulitis lesions were examined immunohistochemically for CD4, CD8 and MAC-1 cells. The proportion of these cells was not different for any regime despite the great differences in total number of inflammatory cells in and around the islets of mice fed the combined diet. All the three dietary treatments (Prosobee from day -20, Prosobee from day 21, Prosobee+nicotinamide from day 21) resulted in substantial protection from diabetes in mice followed until 250 days. We conclude that the complete prevention of diabetes in the NOD mouse fed a casein-free diet together with nicotinamide is accompanied by marked inhibition of insulitis, which is not seen when either dietary agent is introduced alone. The somewhat greater suppression of insulitis in mice given the soy diet from conception compared to those fed from day 21 may indicate that even maternal diet during gestation may influence diabetes outcome in the offspring.

Animals↗
PubMed1995

A method to position replacement dies accurately on a fixed partial denture master working cast.

Impressions are often remade because of insufficient detail in one of many preparations. These impressions may be salvaged with a replacement die procedure. Some transfer or replacement die procedures fail to position the dies accurately; other procedures involve many steps in the fabrication of copings. This article describes a method that quickly and accurately positions a replacement die in a fixed partial denture master working cast.

Acrylic Resins↗
PubMed1995

Immunohistochemical analyses of pancreatic macrophages and CD4 and CD8 T cell subsets prior to and following diabetes in the NOD mouse.

CD4 and CD8 T cells and macrophages have been implicated as cellular mediators of beta cell destruction in insulin-dependent diabetes mellitus (IDDM). The ratios of the two T cell subsets were, therefore, quantified in nonobese diabetic (NOD) mouse islets prior to IDDM, at the onset of the disease, and following onset by immunohistochemistry. The number of periislet-, intraislet-, and exocrine-located macrophages were also determined during these stages. At all time points studied (day 90, day 250, at diabetes onset, 4-6 weeks after diabetes), CD4 cells were 2.5 times higher than CD8 cells except at day 250, on which the CD4:CD8 ratio was 3.8. At days 90 and 250, islets were heavily infiltrated with both the T cell subsets associated with lower numbers of macrophages. At onset of the disease and after insulin treatment, although the CD4:CD8 ratios were similar, the absolute numbers of the two subsets were reduced-considerably. At these stages a majority of the islets was atrophied, some were still surrounded by T cells and macrophages and were enriched with glucagon cells. CD4 and CD8 cells were also observed in the exocrine region at the two stages. Macrophages located in the periislet areas were significantly higher in number than in the intraislet positions in all study groups (p = 0.001). They also showed a gradual decline from day 90 to clinical diabetes. Periislet-located macrophages were significantly higher at day 90 than after onset and in control Swiss mice (p < 0.05). The numbers of macrophages in the exocrine areas were similar in all groups of NOD mice. In control Swiss mice they were significantly lower in the periislet, intraislet, and exocrine regions.

Animals↗
PubMed1995

Low dose streptozotocin causes diabetes in severe combined immunodeficient (SCID) mice without immune cell infiltration of the pancreatic islets.

Streptozotocin (stz) given in low doses (40 mg/kg body weight) on 5 consecutive days to susceptible strains of mice causes diabetes. Previous studies have shown that the induction of diabetes is associated with inflammatory infiltrates within the pancreatic islets. However, it is unclear whether stz causes limited beta cell destruction followed by insulitis or whether the diabetogen promotes immune cell influx into the pancreatic islets, followed by immune-mediated beta-cell destruction. It is also unclear whether stz given in sub-diabetogenic doses is capable of causing diabetes independent of cell-mediated processes. Here we have examined these possibilities in CB.17 Scid mice which lack functional T and B cells but have immunocompetent macrophages and NK cells. Low dose stz given to Scid mice caused diabetes in approximately 50% of mice of both sexes by 21 days (14/24 males; 10/18 females). Sections of pancreas were examined immunohistochemically for the presence of MAC-1 positive cells (macrophages and natural killer cells) in the exocrine, peri- and intra-islet regions at different time points following the administration of stz. There were no statistically significant differences in the number of immunoreactive cells in the three locations between tissues obtained from stz-injected mice (3, 7, 14 and 21 days after stz injection and at onset of diabetes) and buffer-injected Scid mice. Although diabetic Scid mice showed a reduced number of insulin immunoreactive cells and peri- and intra-islet distributed glucagon cells, no insulitis was seen histochemically. In parallel studies, normal Swiss male mice given stz at a similar dose developed diabetes (10/10) associated with insulitis which consisted predominantly of CD4, CD8 and MAC-1 cells. Balb/c mice given stz similarly, also developed diabetes (5/8) without showing insulitis, although a moderate increase in the number of macrophages were observed within several islets. These studies demonstrate that stz administered in multiple low doses to Scid mice can cause beta cell destruction and diabetes in the absence of immune cell infiltrate within the pancreatic islets.

Animals↗
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↗