Biomedical subjects

K P Peterson

Publications and source records attributed to K P Peterson.

11 recordsLinked to original sources

PubMed2000

Reactivation of type 1 diabetes in patients receiving human fetal pancreatic tissue transplants without immunosuppression.

BACKGROUND: Type 1 diabetes is a cell-mediated autoimmune disease. Successful transplantation of human fetal pancreatic tissue into type 1 diabetic patients must address both autoimmunity and allograft rejection. We investigated whether humoral and cellular responses to islet antigens could be demonstrated in the peripheral blood of type 1 diabetic subjects receiving human fetal pancreatic tissue transplants. METHODS: We investigated peripheral blood mononuclear cell (PBMC) responses, using cellular immunoblotting, and autoantibody responses to islet proteins, before transplant and at 3-month intervals after transplant, of nine long-term type 1 diabetes patients (mean disease duration of 21 years) receiving human fetal pancreatic tissue subcutaneously into the abdominal wall without immunosuppression. RESULTS: Before transplant, all nine subjects were islet cell autoantibody (ICA)-negative and seven out of nine subjects were glutamic acid decarboxylase autoantibody (GADAb)-positive. After transplant, all subjects became ICA(+) and the two patients who were GADAb(-) before transplant became GADAb(+) after transplant. Maximum PBMC reactivity to separated human fetal pancreatic proteins was observed in four patients 3 months after transplant, in one patient at 6 months, in two patients at 9 months, and in one patient at 12 months after transplant. One subject, who had PBMC reactivity to multiple islet proteins before transplant, continued to respond to multiple islet proteins throughout the study. CONCLUSIONS: We conclude that the development in the peripheral blood of ICA, GADAb, and PBMC reactivity to human fetal pancreatic proteins in the trans plant recipients is most consistent with reactivation of the type 1 diabetes disease process.

Adult↗

PubMed2000

Peripheral blood mononuclear cell responses from type 1 diabetic patients and subjects at-risk for type 1 diabetes to human fetal pancreatic tissue proteins.

BACKGROUND: Fetal pancreatic tissue has been suggested to be less immunogenic than adult islets. Thus, transplantation of human fetal pancreatic tissue as treatment for type 1 diabetes has been gaining interest. To investigate this question, we tested the peripheral blood mononuclear cell (PBMC) responses from different subject populations to human adult islet proteins (AIP) versus human fetal pancreatic proteins (FPP). METHODS: PBMC responses to FPP and AIP from normal controls (n=14), newly diagnosed type 1 diabetes patients (n=5), long-term type 1 diabetes patients (n=9), and subjects at-risk for development of type 1 diabetes (n=3) were studied. RESULTS: We observed that normal controls demonstrated PBMC reactivity to 0-3 molecular weight regions (mwr) for both the AIP (mean+/-SD, 0.8+/-1.1) and the FPP (0.6+/-0.7). In contrast, newly diagnosed type 1 diabetic patients (<1 year) demonstrated PBMC responses to 9-16 mwr for the AIP (12.8+/-2.5) and 0-14 mwr for the FPP (6.8+/-5.0). The PBMCs from long-term type 1 diabetes patients (> 3 years) were responsive to 2-11 mwr for AIP (6.0+/-2.8) and 0-11 mwr for FPP (4.9+/-4.0). Three nondiabetic ICA positive subjects at-risk for development of type 1 diabetes demonstrated positive PBMC reactivity to 9-18 mwr for the AIP (12.7+/-3.9) and 4-18 mwr for the FPP (10.0+/-5.9). CONCLUSIONS: We conclude that human fetal pancreatic proteins are not significantly less stimulatory than human adult islet proteins to PBMCs of subjects with or at risk for type 1 diabetes.

Adult↗

PubMed2000

Reactivation of type 1 diabetes in patients receiving human fetal pancreatic tissue transplants without immunosuppression.

BACKGROUND: Insulin-dependent (type 1) diabetes is a cell-mediated autoimmune disease. Successful transplantation of human fetal pancreatic tissue into type 1 diabetic patients must address both autoimmunity and allograft rejection. We investigated whether humoral and cellular responses to islet antigens could be demonstrated in the peripheral blood of type 1 diabetic subjects receiving human fetal pancreatic tissue transplants. METHODS: We investigated peripheral blood mononuclear cell (PBMC) responses, using cellular immunoblotting, and autoantibody responses to islet proteins, before transplantation and at 3-month intervals after transplantation. Our study population included nine long-term type 1 diabetes patients (mean disease duration of 21 years) receiving human fetal pancreatic tissue subcutaneously into the abdominal wall without immunosuppression. RESULTS: Before transplantation, all nine subjects tested negative for islet cell autoantibody (ICA), and seven of nine subjects tested positive for glutamic acid decarboxylase autoantibody (GADAb). After transplantation, all subjects became ICA(+), and the two patients who were GADAb(-) before transplantation, became GADAb(+) after transplantation. Maximum PBMC reactivity to separated human fetal pancreatic proteins was observed in four patients at 3 months, in one patient at 6 months, in two patients at 9 months, and in one patient at 12 months after transplantation. One subject, who had PBMC reactivity to multiple islet proteins before transplantation, continued to respond to multiple islet proteins throughout the study. CONCLUSIONS: We conclude that the development in the peripheral blood of ICA, GADAb, and PBMC reactivity to human fetal pancreatic proteins in the transplant recipients is most consistent with reactivation of the type 1 diabetes disease process.

Adult↗

PubMed1998

IFN-gamma-deficient mice develop severe granulomatous experimental autoimmune thyroiditis with eosinophil infiltration in thyroids.

To study the role of IFN-gamma in the development of granulomatous experimental autoimmune thyroiditis (EAT), DBA1 mice with a disrupted IFN-gamma gene were used for adoptive EAT induction. Effector cells from either IFN-gamma(+/+) or IFN-gamma(-/-) donor mice activated with mouse thyroglobulin and anti-IL-2R mAb induced severe granulomatous EAT. A predominant infiltration of the thyroid by eosinophils was observed in recipients of IFN-gamma(-/-) effector cells but not in recipients of IFN-gamma(+/+) cells. Compared with wild-type mice, thyroids of recipients of IFN-gamma(-/-) effector cells had decreased expression of mRNA for Th1 cytokines and inducible nitric oxide synthetase. Expression of Th2 cytokine mRNA was comparable to that of IFN-gamma(+/+) mice, and expression of eotaxin was increased in the thyroids of recipients of IFN-gamma(-/-) effector cells. Activation of cells from either IFN-gamma(+/+) or IFN-gamma(-/-) donors in the presence of IL-12 also induced severe granulomatous EAT. Eosinophil infiltration in recipients of IFN-gamma(-/-) cells was unaffected when effector cells were activated with IL-12, and thyroids expressed predominantly Th2 cytokines. The extent of fibrosis of recipient thyroids was generally greater when donor IFN-gamma(+/+) and IFN-gamma(-/-) cells were activated with IL-12. Compared with IFN-gamma(+/+) mice, IFN-gamma(-/-) mice produced lower levels of mouse thyroglobulin-specific autoantibodies after immunization with MTg and LPS. These results indicate that cells from both IFN-gamma(+/+) and IFN-gamma(-/-) donors can induce severe granulomatous EAT. However, damage of thyroid follicles by IFN-gamma(-/-) and that by IFN-gamma(+/+) cells appear to involve different mediators of inflammation.

Animals↗

PubMed1998

The prenatal detection of significant alcohol exposure with maternal blood markers.

OBJECTIVE: To examine the efficacy of a combination of 4 blood markers of alcohol use in detecting alcohol-abusing pregnant women. STUDY DESIGN: Two new markers of alcohol use, whole blood-associated acetaldehyde and carbohydrate-deficient transferrin, and 2 traditional markers of alcohol use, gamma-glutamyl transpeptidase and mean red blood cell volume, were measured in the blood of pregnant women. Each woman was interviewed about alcohol and drug use, medical and obstetric histories, and nutrition. Each infant was examined by a clinician who was blinded to exposure status. RESULTS: All of the women who reported drinking an average of 1 or more ounces of absolute alcohol per day had at least 1 positive blood marker. The infants of mothers with 2 or more positive markers had significantly smaller birth weights, lengths, and head circumferences than the infants with negative maternal screens. The presence of 2 or more positive markers was more predictive of infant outcome than any self-reporting measure. CONCLUSIONS: These markers, which detect more at-risk pregnant women than self-reporting methods, could lead to better efforts at detection and prevention of alcohol-induced fetal damage.

Acetaldehyde↗

PubMed1998

Prevalence of ethanol consumption may be higher in women than men in a university health service population as determined by a biochemical marker: whole blood-associated acetaldehyde above the 99th percentile for teetotalers.

To estimate ethanol consumption by university students attending a student health facility, a biochemical marker of alcohol intake [whole blood associated acetaldehyde (WBAA)] was quantified by fluorimetric HPLC. Over a two year period we studied blood samples, coded by date and sex, from 645 females and 332 males, and compared the results to previously established reference ranges for teetotalers by sex. Men had higher absolute values for WBAA than women (9.9 versus 9.5 microM in the present study). However, significantly greater numbers of women (74%) than men (44%) had WBAA levels above the 99th percentile for teetotalers. Variations occurred during the academic year, with significant elevations occurring in the late fall and winter months. Testing of WBAA levels in a student health service may be important especially for women to facilitate counseling on the dangers of alcohol abuse.

Acetaldehyde↗

PubMed1998

Dapsone at onset of diabetes lowers glycated hemoglobin and delays death in NOD mice.

Dapsone (4,4'-diaminodiphenyl sulfone) is a compound that has a large clinical experience due to its antimicrobial effects against mycobacterium leprae, the causative agent of leprosy. It is increasingly used in a number of clinical situations where inflammation may play an ancillary role. An inhibitory effect of the drug or lack thereof in the cumulative incidence or propagation of diabetes mellitus in the NOD mouse has mechanistic as well as therapeutic implications. We previously showed that dapsone administered continuously as a percentage of food to NOD mice inhibits the cumulative incidence of diabetes in a dose dependent fashion. In the present experiment, female NOD litter mates were randomized to receive dapsone (0.001% w/w as a percentage of food) at onset of diabetes. There were no differences in weight, blood glucose, or glycated hemoglobin at 10 weeks of age among the animals that were ultimately to receive dapsone (n = 10), mouse chow alone (n = 9), or those who did not develop diabetes (n = 3). The mean time to onset of diabetes, mean blood glucose at onset, and mean glycated hemoglobin at onset did not differ between animals who did or did not receive dapsone. Animals receiving dapsone had significantly (p < or = 0.03) lower glycated hemoglobin at weeks 2, 3, and 4 following the onset of diabetes and lived significantly longer following diagnosis of diabetes (7 vs. 4 weeks, p < 0.05). In conclusion, dapsone modulates the progression of autoimmune diabetes in the NOD mouse even when administered after the initiation of hyperglycemia.

Age of Onset↗

PubMed1998

Silica sol-gel encapsulation of pancreatic islets.

We developed a biocomposite material containing silica ceramic. The sol-gel technology in which ceramic materials are polymerized from liquid solutions at room temperature and physiologic pH can be used to produce ceramics that have a determined pore size and that contain living organisms or cells. Capsules were stable to extreme acid and base conditions as well as to trypsin in vitro for 6 months. We used insulin-secreting murine islet cells as the first mammalian material for encapsulation. Two approaches to generating successful encapsulation of islets were used: drop-tower sphere generation and emulsion. Sphere diameters of less than 1 mm were associated with positive insulin secretory capacity as documented by a static batch incubation technique. Average pore sizes were 161 A for drop-tower spheres and 105 A for emulsion spheres. Capsules allowed the passage of insulin and cytokines but not the passage of antibody. Implantation of encapsulated islets did not result in fibrosis of the capsule in vivo, and retrieval of capsules after 1 month in vivo documented continued insulin secretory capacity. Further in vivo experiments documented increased survival of transplant recipients despite failure to achieve normoglycemia in all but a few cases. Silica sol-gel encapsulation provides a potentially useful alternative for encapsulation of cells for transplantation or drug delivery, and further work is warranted to develop this potentially useful approach for the treatment of diabetes mellitus.

Animals↗

PubMed1998

What is hemoglobin A1c? An analysis of glycated hemoglobins by electrospray ionization mass spectrometry.

Hemoglobin A1c (HbA1c) is a stable minor Hb variant formed in vivo by posttranslational modification by glucose, originally identified by using cation exchange chromatography, and containing primarily glycated N-terminal beta-chains. However, the structure(s) of the quantified species has not been elucidated, and the available methods lack a reference standard. We used electrospray ionization mass spectrometry to determine the extent of glycation of samples separated by boronate affinity and/or cation exchange chromatography. Analyses of clinical samples were consistent with the curvilinear relationship of patient glucose and HbA1c. As glycation increased, the ratio of beta-chain to alpha-chain glycation increased, and the number of glycation sites on the beta-chain increased, although these were relatively minor components. We found several glycated species that cochromatographed with HbA1c on cation exchange, including species with both glycated alpha- and beta-chains, nonglycated alpha- and glycated beta-chains, and multiply glycated beta-chains. The combined use of affinity and cation exchange chromatography with structural confirmation by electrospray ionization mass spectrometry was found to be useful in producing samples of sufficient purity for the standardization of glycohemoglobin clinical assays.

Blood Glucose↗

PubMed1997

Alcohol metabolism in Asian-American men with genetic polymorphisms of aldehyde dehydrogenase.

BACKGROUND: About half of certain Asians have a deficiency of the low-Km aldehyde dehydrogenase (ALDH2) isoenzyme. This deficiency results from inheritance of a mutant ALDH2*2 allele. OBJECTIVE: To determine whether Asian Americans with ALDH2*2 alleles differ from Asian Americans without this mutation in terms of blood levels of alcohol and acetaldehyde after ingestion of a moderate amount of alcohol. DESIGN: Double-blind, crossover study. SETTING: Private research institute. PARTICIPANTS: 35 healthy Asian-American men. Three men who became ill after alcohol ingestion and one who had outlying data were excluded. INTERVENTION: Alcoholic beverage, containing 0.56 g of alcohol per kg of body weight, or placebo beverage, containing 3 mL of alcohol, given orally on separate occasions. MEASUREMENTS: Blood levels of alcohol and acetaldehyde measured before and several times after ingestion of the alcoholic or placebo beverage. RESULTS: Participants with ALDH2*2 alleles had significantly higher blood acetaldehyde levels after ingesting alcoholic and placebo beverages than did participants with ALDH2*1 alleles, despite similar blood alcohol concentrations. CONCLUSIONS: Blood acetaldehyde levels rather than blood alcohol concentration may mediate enhanced alcohol sensitivity among Asians with ALDH2*2 alleles.

Acetaldehyde↗

PubMed1997

Dapsone decreases the cumulative incidence of diabetes in non-obese diabetic female mice.

Dapsone (4,4'-diaminodiphenyl sulfone) has a large clinical experience due to its antimicrobial effects against Mycobacterium leprae, the causative agent of leprosy, and is used clinically where inflammation mediated by neutrophils is perceived to play a role. We administered dapsone in two concentrations (0.001% and 0.0001% w/w of diet) to 30 female non-obese diabetic (NOD) mice to explore the effect of dapsone on the development of IDDM following either a 1-week pulse or 20 weeks of continuous oral dapsone administration. Those mice receiving either the high or low doses of dapsone in the continuous group had a significantly reduced cumulative percentage of onset of IDDM. One of the seven mice given 0.0001% dapsone became diabetic (age 25 weeks), while none of the eight high dose (0.001%) mice developed the disease. Histological examination of pancreatic sections revealed islet infiltration in all groups of animals. The pulse and continuous experiments showed no statistically significant difference in the frequency or severity of lymphocytic infiltration. Dapsone administration did not inhibit growth, and growth rates were greater in those animals receiving the higher dapsone dose compared with the lower dose comparable to controls. We studied whether dapsone influenced murine lymphocyte function in addition to the published effects of the drug on neutrophils. At doses approximating those achieved in vivo (0.4 and 2 micrograms/ml), dapsone was found to inhibit murine splenocyte IL-2 and IL-4 secretion in response to concanavalin A. In view of the wide clinical experience with dapsone, randomized trials of the drug in new onset diabetes may be warranted.

Animals↗