المؤلفون: Redondo, Maria J., Warnock, Megan V., Libman, Ingrid M., Bocchino, Laura E., Cuthbertson, David, Geyer, Susan, Pugliese, Alberto, Steck, Andrea K., Evans-Molina, Carmella, Becker, Dorothy, Sosenko, Jay M., Bacha, Fida, Type 1 Diabetes TrialNet Study Group

المصدر: Diabetes Care; Sep2021, Vol. 44 Issue 9, p2039-2044, 6p

مصطلحات موضوعية: INSULIN sensitivity, GENETIC variation, TYPE 1 diabetes, INSULIN, SECRETION, SINGLE nucleotide polymorphisms, PROTEINS, RESEARCH, RESEARCH methodology, GENETIC polymorphisms, MEDICAL cooperation, EVALUATION research, TYPE 2 diabetes, COMPARATIVE studies, RESEARCH funding, INSULIN resistance, C-peptide

مستخلص: Objective: We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D).Research Design and Methods: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (N = 1,061) (mean age 16.3 years) with TCF7L2 single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, P values < 0.0086 were considered statistically significant.Results: None, one, and two T2D-linked TCF7L2 alleles were present in 48.1%, 43.9%, and 8.0% of the participants, respectively. Insulin sensitivity (as reflected by 1/fasting insulin [1/IF]) decreased with increasing BMI z score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI z score. Oral disposition index was negatively correlated with age, BMI z score, and Hispanic ethnicity. None of the indices were associated with TCF7L2 SNPs. In multivariable analysis models with age, BMI z score, ethnicity, sex, and TCF7L2 alleles as independent variables, C-peptide index increased with age, while BMI z score was associated with higher insulin secretion (C-peptide index), lower insulin sensitivity (1/IF), and lower disposition index; there was no significant effect of TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with a normal OGTT (n = 743; 70%), the results were similar.Conclusions: In nondiabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI z score, age, sex, and ethnicity. [ABSTRACT FROM AUTHOR]

: Copyright of Diabetes Care is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Snowhite, Isaac, Pastori, Ricardo, Sosenko, Jay, Messinger Cayetano, Shari, Pugliese, Alberto

المصدر: Diabetes; Feb2021, Vol. 70 Issue 2, p638-651, 14p

مصطلحات موضوعية: TYPE 1 diabetes, SECRETION, INSULIN, MICRORNA, NUCLEOTIDE sequence, RESEARCH, RESEARCH methodology, MEDICAL cooperation, EVALUATION research, COMPARATIVE studies, C-peptide

مستخلص: Type 1 diabetes is an autoimmune disease resulting in severely impaired insulin secretion. We investigated whether circulating microRNAs (miRNAs) are associated with residual insulin secretion at diagnosis and predict the severity of its future decline. We studied 53 newly diagnosed subjects enrolled in placebo groups of TrialNet clinical trials. We measured serum levels of 2,083 miRNAs, using RNA sequencing technology, in fasting samples from the baseline visit (<100 days from diagnosis), during which residual insulin secretion was measured with a mixed meal tolerance test (MMTT). Area under the curve (AUC) C-peptide and peak C-peptide were stratified by quartiles of expression of 31 miRNAs. After adjustment for baseline C-peptide, age, BMI, and sex, baseline levels of miR-3187-3p, miR-4302, and the miRNA combination of miR-3187-3p/miR-103a-3p predicted differences in MMTT C-peptide AUC/peak levels at the 12-month visit; the combination miR-3187-3p/miR-4723-5p predicted proportions of subjects above/below the 200 pmol/L clinical trial eligibility threshold at the 12-month visit. Thus, miRNA assessment at baseline identifies associations with C-peptide and stratifies subjects for future severity of C-peptide loss after 1 year. We suggest that miRNAs may be useful in predicting future C-peptide decline for improved subject stratification in clinical trials. [ABSTRACT FROM AUTHOR]

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المؤلفون: Sosenko, Jay M., Skyler, Jay S., Herold, Kevan C., Schatz, Desmond A., Haller, Michael J., Pugliese, Alberto, Cleves, Mario, Geyer, Susan, Rafkin, Lisa E., Matheson, Della, Palmer, Jerry P., Type 1 Diabetes TrialNet Study Group

المصدر: Diabetes; Aug2020, Vol. 69 Issue 8, p1827-1832, 6p

مصطلحات موضوعية: TYPE 1 diabetes, INSULIN, GLUCOSE tolerance tests, PLACEBOS, DIABETES, INSULIN therapy, THERAPEUTIC use of monoclonal antibodies, BLOOD sugar, C-peptide, COMPARATIVE studies, RESEARCH methodology, MEDICAL cooperation, PHARMACOKINETICS, RESEARCH, EVALUATION research, RANDOMIZED controlled trials

مستخلص: We assessed whether oral insulin slowed metabolic decline after 1 year of treatment in individuals at high risk for type 1 diabetes. Two oral insulin trials that did not show efficacy overall and had type 1 diabetes as the primary end point were analyzed: the Diabetes Prevention Trial-Type 1 (DPT-1) and the TrialNet oral insulin trials. Oral glucose tolerance tests at baseline and after 1 year of treatment were analyzed. Among those at high risk (with a Diabetes Prevention Trial-Type 1 Risk Score [DPTRS] ≥6.75), the area under the curve (AUC) C-peptide increased significantly from baseline to 1 year in each oral insulin group, whereas the AUC glucose increased significantly in each placebo group. At 1 year, the AUC C-peptide/AUC glucose (AUC Ratio) was significantly higher in the oral insulin group than in the placebo group in each trial (P < 0.05; P = 0.057 when adjusted for age in the TrialNet trial) and in both trials combined (P < 0.01 with or without adjustment for age). For a DPTRS <6.75, oral insulin groups did not differ from placebo groups in the AUC Ratio. The findings suggest that 1 year of treatment with oral insulin slows metabolic deterioration in individuals at high risk for type 1 diabetes. Moreover, the findings further suggest that metabolic end points can be useful adjuncts to the diagnostic end point in assessments of preventive treatments for the disorder. [ABSTRACT FROM AUTHOR]

: Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Cabello-Kindelan, Cecilia, Mackey, Shane, Sands, Alexander, Rodriguez, Jennifer, Vazquez, Claudia, Pugliese, Alberto, Bayer, Allison L.

المصدر: Diabetes; Feb2020, Vol. 69 Issue 2, p215-227, 13p, 1 Chart, 6 Graphs

مصطلحات موضوعية: SUPPRESSOR cells, IMMUNOREGULATION, TYPE 1 diabetes, ISLANDS of Langerhans, T cells, IMMUNOLOGICAL tolerance, RESEARCH, SKIN grafting, ANIMAL experimentation, RESEARCH methodology, IMMUNE system, CELL physiology, EVALUATION research, MEDICAL cooperation, COMPARATIVE studies, IMMUNITY, RESEARCH funding, MICE

مستخلص: Optimal immune-based therapies for type 1 diabetes (T1D) should restore self-tolerance without inducing chronic immunosuppression. CD4+Foxp3+ regulatory T cells (Tregs) are a key cell population capable of facilitating durable immune tolerance. However, clinical trials with expanded Tregs in T1D and solid-organ transplant recipients are limited by poor Treg engraftment without host manipulation. We showed that Treg engraftment and therapeutic benefit in nonautoimmune models required ablative host conditioning. Here, we evaluated Treg engraftment and therapeutic efficacy in the nonobese diabetic (NOD) mouse model of autoimmune diabetes using nonablative, combinatorial regimens involving the anti-CD3 (αCD3), cyclophosphamide (CyP), and IAC (IL-2/JES6-1) antibody complex. We demonstrate that αCD3 alone induced substantial T-cell depletion, impacting both conventional T cells (Tconv) and Tregs, subsequently followed by more rapid rebound of Tregs Despite robust depletion of host Tconv and host Tregs, donor Tregs failed to engraft even with interleukin-2 (IL-2) support. A single dose of CyP after αCD3 depleted rebounding host Tregs and resulted in a 43-fold increase in donor Treg engraftment, yet polyclonal donor Tregs failed to reverse diabetes. However, infusion of autoantigen-specific Tregs after αCD3 alone resulted in robust Treg engraftment within the islets and induced remission in all mice. This novel combinatorial therapy promotes engraftment of autoantigen-specific donor Tregs and controls islet autoimmunity without long-term immunosuppression. [ABSTRACT FROM AUTHOR]

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المؤلفون: Redondo, Maria J., Geyer, Susan, Steck, Andrea K., Sharp, Seth, Wentworth, John M., Weedon, Michael N., Antinozzi, Peter, Sosenko, Jay, Atkinson, Mark, Pugliese, Alberto, Oram, Richard A., Type 1 Diabetes TrialNet Study Group

المصدر: Diabetes Care; Sep2018, Vol. 41 Issue 9, p1887-1894, 8p

مصطلحات موضوعية: DIABETES complications, AUTOANTIBODIES, COMPARATIVE studies, DISEASE susceptibility, GENETIC polymorphisms, IMMUNITY, ISLANDS of Langerhans, TYPE 1 diabetes, RESEARCH methodology, MEDICAL cooperation, PROGNOSIS, RESEARCH, HLA-B27 antigen, EVALUATION research, DISEASE progression, GENOTYPES, DISEASE complications, DIAGNOSIS

مستخلص: Objective: We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals.Research Design and Methods: We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients' relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2-51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial-Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables.Results: Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06-1.6; P = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS >0.295, 95% CI 1.47-3.51; P = 0.0002).Conclusions: The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives. [ABSTRACT FROM AUTHOR]

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المؤلفون: Redondo, Maria J., Geyer, Susan, Steck, Andrea K., Sosenko, Jay, Anderson, Mark, Antinozzi, Peter, Michels, Aaron, Wentworth, John, Ping Xu, Pugliese, Alberto, Xu, Ping, Type 1 Diabetes TrialNet Study Group

المصدر: Diabetes Care; Feb2018, Vol. 41 Issue 2, p311-317, 7p

مصطلحات موضوعية: PHENOTYPES, TYPE 1 diabetes, TRANSCRIPTION factors, SINGLE nucleotide polymorphisms, DIAGNOSIS of diabetes, ALLELES, COMPARATIVE studies, DISEASE susceptibility, GENETIC polymorphisms, GENETICS, LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, PROTEINS, RESEARCH, EVALUATION research

مستخلص: Objective: The phenotypic diversity of type 1 diabetes suggests heterogeneous etiopathogenesis. We investigated the relationship of type 2 diabetes-associated transcription factor 7 like 2 (TCF7L2) single nucleotide polymorphisms (SNPs) with immunologic and metabolic characteristics at type 1 diabetes diagnosis.Research Design and Methods: We studied TrialNet participants with newly diagnosed autoimmune type 1 diabetes with available TCF7L2 rs4506565 and rs7901695 SNP data (n = 810; median age 13.6 years; range 3.3-58.6). We modeled the influence of carrying a TCF7L2 variant (i.e., having 1 or 2 minor alleles) on the number of islet autoantibodies and oral glucose tolerance test (OGTT)-stimulated C-peptide and glucose measures at diabetes diagnosis. All analyses were adjusted for known confounders.Results: The rs4506565 variant was a significant independent factor of expressing a single autoantibody, instead of multiple autoantibodies, at diagnosis (odds ratio [OR] 1.66 [95% CI 1.07, 2.57], P = 0.024). Interaction analysis demonstrated that this association was only significant in participants ≥12 years old (n = 504; OR 2.12 [1.29, 3.47], P = 0.003) but not younger ones (n = 306, P = 0.73). The rs4506565 variant was independently associated with higher C-peptide area under the curve (AUC) (P = 0.008) and lower mean glucose AUC (P = 0.0127). The results were similar for the rs7901695 SNP.Conclusions: In this cohort of individuals with new-onset type 1 diabetes, type 2 diabetes-linked TCF7L2 variants were associated with single autoantibody (among those ≥12 years old), higher C-peptide AUC, and lower glucose AUC levels during an OGTT. Thus, carriers of the TCF7L2 variant had a milder immunologic and metabolic phenotype at type 1 diabetes diagnosis, which could be partly driven by type 2 diabetes-like pathogenic mechanisms. [ABSTRACT FROM AUTHOR]

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المؤلفون: Jinquan Cai, ZhixianWu, Xiumin Xu, Lianming Liao, Jin Chen, Lianghu Huang, WeizhenWu, Fang Luo, Chenguang Wu, Pugliese, Alberto, Pileggi, Antonello, Ricordi, Camillo, Jianming Tan, Cai, Jinquan, Wu, Zhixian, Xu, Xiumin, Liao, Lianming, Chen, Jin, Huang, Lianghu, Wu, Weizhen

المصدر: Diabetes Care; Jan2016, Vol. 39 Issue 1, p149-157, 9p, 1 Diagram, 2 Charts, 1 Graph

مصطلحات موضوعية: UMBILICAL cord, MESENCHYMAL stem cells, STROMAL cells, BONE marrow, TYPE 1 diabetes, RANDOMIZED controlled trials, C-peptide, GLUCOSE tolerance tests, INSULIN therapy, STEM cell transplantation, TREATMENT of diabetes, AUTOGRAFTS, BONE marrow transplantation, COMPARATIVE studies, INSULIN, RESEARCH methodology, MEDICAL cooperation, QUALITY of life, RESEARCH, PILOT projects, EVALUATION research

مستخلص: Objective: To determine the safety and effects on insulin secretion of umbilical cord (UC) mesenchymal stromal cells (MSCs) plus autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation (SCT) without immunotherapy in established type 1 diabetes (T1D).Research Design and Methods: Between January 2009 and December 2010, 42 patients with T1D were randomized (n = 21/group) to either SCT (1.1 × 10(6)/kg UC-MSC, 106.8 × 10(6)/kg aBM-MNC through supraselective pancreatic artery cannulation) or standard care (control). Patients were followed for 1 year at 3-month intervals. The primary end point was C-peptide area under the curve (AUC(C-Pep)) during an oral glucose tolerance test at 1 year. Additional end points were safety and tolerability of the procedure, metabolic control, and quality of life.Results: The treatment was well tolerated. At 1 year, metabolic measures improved in treated patients: AUCC-Pep increased 105.7% (6.6 ± 6.1 to 13.6 ± 8.1 pmol/mL/180 min, P = 0.00012) in 20 of 21 responders, whereas it decreased 7.7% in control subjects (8.4 ± 6.8 to 7.7 ± 4.5 pmol/mL/180 min, P = 0.013 vs. SCT); insulin area under the curve increased 49.3% (1,477.8 ± 1,012.8 to 2,205.5 ± 1,194.0 mmol/mL/180 min, P = 0.01), whereas it decreased 5.7% in control subjects (1,517.7 ± 630.2 to 1,431.7 ± 441.6 mmol/mL/180 min, P = 0.027 vs. SCT). HbA1c decreased 12.6% (8.6 ± 0.81% [70.0 ± 7.1 mmol/mol] to 7.5 ± 1.0% [58.0 ± 8.6 mmol/mol], P < 0.01) in the treated group, whereas it increased 1.2% in the control group (8.7 ± 0.9% [72.0 ± 7.5 mmol/mol] to 8.8 ± 0.9% [73 ± 7.5 mmol/mol], P < 0.01 vs. SCT). Fasting glycemia decreased 24.4% (200.0 ± 51.1 to 151.2 ± 22.1 mg/dL, P < 0.002) and 4.3% in control subjects (192.4 ± 35.3 to 184.2 ± 34.3 mg/dL, P < 0.042). Daily insulin requirements decreased 29.2% in only the treated group (0.9 ± 0.2 to 0.6 ± 0.2 IU/day/kg, P = 0.001), with no change found in control subjects (0.9 ± 0.2 to 0.9 ± 0.2 IU/day/kg, P < 0.01 vs. SCT).Conclusions: Transplantation of UC-MSC and aBM-MNC was safe and associated with moderate improvement of metabolic measures in patients with established T1D. [ABSTRACT FROM AUTHOR]

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المؤلفون: Badillo, Freddy Gonzalez, Tegou, Flavia Zisi, Abreu, Maria M, Masina, Riccardo, Sha, Divya, Najjar, Mejdi, Wright, Shane, Bayer, Allison L, Korpos, Éva, Pugliese, Alberto, Molano, R Damaris, Tomei, Alice A, Gonzalez Badillo, Freddy E, Zisi Tegou, Flavia, Wright, Shane H

المصدر: Diabetes; Aug2019, Vol. 68 Issue 8, pN.PAG-N.PAG, 1p

مصطلحات موضوعية: ANIMAL experimentation, COMPARATIVE studies, CONNECTIVE tissue cells, CYTOKINES, TYPE 1 diabetes, ISLANDS of Langerhans, RESEARCH methodology, MEDICAL cooperation, MICE, PANCREAS, RESEARCH, EVALUATION research

مستخلص: Tumors induce tolerance toward their antigens by producing the chemokine CCL21, leading to the formation of tertiary lymphoid organs (TLOs). Ins2-CCL21 transgenic, nonobese diabetic (NOD) mice express CCL21 in pancreatic β-cells and do not develop autoimmune diabetes. We investigated by which mechanisms CCL21 expression prevented diabetes. Ins2-CCL21 mice develop TLOs by 4 weeks of age, consisting of naive CD4+ T cells compartmentalized within networks of CD45-gp38+CD31- fibroblastic reticular cell (FRC)-like cells. Importantly, 12-week-old Ins2-CCL21 TLOs contained FRC-like cells with higher contractility, regulatory, and anti-inflammatory properties and enhanced expression of β-cell autoantigens compared with nontransgenic NOD TLOs found in inflamed islets. Consistently, transgenic mice harbored fewer autoreactive T cells and a higher proportion of regulatory T cells in the islets. Using adoptive transfer and islet transplantation models, we demonstrate that TLO formation in Ins2-CCL21 transgenic islets is critical for the regulation of autoimmunity, and although the effect is systemic, the induction is mediated locally likely by lymphocyte trafficking through TLOs. Overall, our findings suggest that CCL21 promotes TLOs that differ from inflammatory TLOs found in type 1 diabetic islets in that they resemble lymph nodes, contain FRC-like cells expressing β-cell autoantigens, and are able to induce systemic and antigen-specific tolerance leading to diabetes prevention. [ABSTRACT FROM AUTHOR]

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المؤلفون: Redondo, Maria J, Steck, Andrea K, Sosenko, Jay, Anderson, Mark, Antinozzi, Peter, Michels, Aaron, Wentworth, John M, Atkinson, Mark A, Pugliese, Alberto, Geyer, Susan, Type 1 Diabetes TrialNet Study Group

المصدر: Diabetes Care; Oct2018, Vol. 41 Issue 10, pN.PAG-N.PAG, 1p

مصطلحات موضوعية: OBESITY complications, AUTOANTIBODIES, COMPARATIVE studies, DISEASE susceptibility, GENES, GENETIC polymorphisms, IMMUNITY, TYPE 1 diabetes, LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, OBESITY, PROTEINS, RESEARCH, EVALUATION research, DISEASE progression, DISEASE complications

مستخلص: Objective: The type 2 diabetes-associated alleles at the TCF7L2 locus mark a type 1 diabetes phenotype characterized by single islet autoantibody positivity as well as lower glucose and higher C-peptide measures. Here, we studied whether the TCF7L2 locus influences progression of islet autoimmunity, from single to multiple (≥2) autoantibody positivity, in relatives of patients with type 1 diabetes.Research Design and Methods: We evaluated 244 participants in the Type 1 Diabetes TrialNet Pathway to Prevention study with confirmed single autoantibody positivity at screening and Immunochip single nucleotide polymorphism data (47.5% male; median age 12.8 years, range 1.2-45.9; 90.2% white). We analyzed risk allele frequency at TCF7L2 rs4506565 (in linkage disequilibrium with rs7903146). Altogether, 62.6% participants carried ≥1 risk allele. Univariate and multivariable Cox proportional hazards models and Kaplan-Meier statistical methods were used.Results: During follow-up (median 5.2 years, range 0.2-12.6), 62% of the single autoantibody-positive participants developed multiple autoantibody positivity. In the overall cohort, the TCF7L2 locus did not significantly predict progression to multiple autoantibody positivity. However, among single GAD65 autoantibody-positive participants (n = 158), those who carried ≥1 risk allele had a lower rate of progression to multiple autoantibody positivity (hazard ratio [HR] 0.65, P = 0.033) than those who did not, after adjustment for HLA risk haplotypes and age. Among subjects who were either IA-2 or insulin autoantibody positive only, carrying ≥1 TCF7L2 risk allele was not a significant factor overall, but in overweight or obese participants, it increased the risk of progression to multiple autoantibody positivity (HR 3.02, P = 0.016) even with adjustment for age.Conclusions: The type 2 diabetes-associated TCF7L2 locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight. [ABSTRACT FROM AUTHOR]

: Copyright of Diabetes Care is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)