ß-Cell death is decreased in women with gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) affects approximately 7-17 % of all pregnancies and has been recognized as a significant risk factor to neonatal and maternal health. Postpartum, GDM significantly increases the likelihood of developing type 2 diabetes (T2D). While it is well established that insulin resistance and impaired ß-cell function contribute to GDM development, the role of active ß-cell loss remains unknown. Differentially methylated circulating free DNA (cfDNA) is a minimally invasive biomarker of ß-cell loss in type 1 diabetes mellitus. Here we use cfDNA to examine the levels of ß-cell death in women with GDM. METHODS: Second to third-trimester pregnant women with GDM were compared with women with normal pregnancy (PRG), women at postpartum (PP), and non-pregnant (NP) women. Fasting glucose levels, insulin, and C-peptide levels were measured. Serum samples were collected and cfDNA purified and bisulfite treated. Methylation-sensitive probes capable of differentiating between ß-cell-derived DNA (demethylated) and non-ß-cell-derived DNA (methylated) were used to measure the presence of ß-cell loss in the blood. RESULTS: GDM was associated with elevated fasting glucose levels (GDM = 185.9 ± 5.0 mg/dL) and reduced fasting insulin and c-peptide levels when compared with NP group. Interestingly, ß-cell derived insulin DNA levels were significantly lower in women with GDM when compared with PRG, NP, and PP groups (demethylation index: PRG = 7.74 × 10(-3) ± 3.09 × 10(-3), GDM = 1.01 × 10(-3) ± 5.86 × 10(-4), p < 0.04; NP = 4.53 × 10(-3) ± 1.62 × 10(-3), PP = 3.24 × 10(-3) ± 1.78 × 10(-3)). CONCLUSIONS: These results demonstrate that ß-cell death is reduced in women with GDM. This reduction is associated with impaired insulin production and hyperglycemia, suggesting that ß-cell death does not contribute to GDM during the 2nd and 3rd trimester of pregnancy.

A Minimally-invasive Blood-derived Biomarker of Oligodendrocyte Cell-loss in Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS). Minimally invasive biomarkers of MS are required for disease diagnosis and treatment. Differentially methylated circulating-free DNA (cfDNA) is a useful biomarker for disease diagnosis and prognosis, and may offer to be a viable approach for understanding MS. Here, methylation-specific primers and quantitative real-time PCR were used to study methylation patterns of the myelin oligodendrocyte glycoprotein (MOG) gene, which is expressed primarily in myelin-producing oligodendrocytes (ODCs). MOG-DNA was demethylated in O4(+) ODCs in mice and in DNA from human oligodendrocyte precursor cells (OPCs) when compared with other cell types. In the cuprizone-fed mouse model of demyelination, ODC derived demethylated MOG cfDNA was increased in serum and was associated with tissue-wide demyelination, demonstrating the utility of demethylated MOG cfDNA as a biomarker of ODC death. Collected sera from patients with active (symptomatic) relapsing-remitting MS (RRMS) demonstrated a higher signature of demethylated MOG cfDNA when compared with patients with inactive disease and healthy controls. Taken together, these results offer a minimally invasive approach to measuring ODC death in the blood of MS patients that may be used to monitor disease progression.

Circulating Differentially Methylated Amylin DNA as a Biomarker of ß-Cell Loss in Type 1 Diabetes.

In type 1 diabetes (T1D), ß-cell loss is silent during disease progression. Methylation-sensitive quantitative real-time PCR (qPCR) of ß-cell-derived DNA in the blood can serve as a biomarker of ß-cell death in T1D. Amylin is highly expressed by ß-cells in the islet. Here we examined whether demethylated circulating free amylin DNA (cfDNA) may serve as a biomarker of ß-cell death in T1D. ß cells showed unique methylation patterns within the amylin coding region that were not observed with other tissues. The design and use of methylation-specific primers yielded a strong signal for demethylated amylin in purified DNA from murine islets when compared with other tissues. Similarly, methylation-specific primers detected high levels of demethylated amylin DNA in human islets and enriched human ß-cells. In vivo testing of the primers revealed an increase in demethylated amylin cfDNA in sera of non-obese diabetic (NOD) mice during T1D progression and following the development of hyperglycemia. This increase in amylin cfDNA did not mirror the increase in insulin cfDNA, suggesting that amylin cfDNA may detect ß-cell loss in serum samples where insulin cfDNA is undetected. Finally, purified cfDNA from recent onset T1D patients yielded a high signal for demethylated amylin cfDNA when compared with matched healthy controls. These findings support the use of demethylated amylin cfDNA for detection of ß-cell-derived DNA. When utilized in conjunction with insulin, this latest assay provides a comprehensive multi-gene approach for the detection of ß-cell loss.

Clinical Practice Guidelines for Recall and Maintenance of Patients with Tooth-Borne and Implant-Borne Dental Restorations.

PURPOSE: To provide guidelines for patient recall regimen, professional maintenance regimen, and at-home maintenance regimen for patients with tooth- and implant-borne removable and fixed restorations. METHODS: The American College of Prosthodontists (ACP) convened a scientific panel of experts appointed by the ACP, American Dental Association (ADA), Academy of General Dentistry (AGD), and American Dental Hygienists Association (ADHA) who critically evaluated and debated recently published findings from 2 systematic reviews on this topic. The major outcomes and consequences considered during formulation of the clinical practice guidelines (CPGs) were risk for failure of tooth- and implant-borne restorations. The panel conducted a round table discussion of the proposed guidelines, which were debated in detail. Feedback was used to supplement and refine the proposed guidelines, and consensus was attained. RESULTS: A set of CPGs was developed for tooth-borne restorations and implant-borne restorations. Each CPG comprised of 1) patient recall; 2) professional maintenance, and 3) at-home maintenance. For tooth-borne restorations, the professional maintenance and at-home maintenance CPGs were subdivided for removable and fixed restorations. For implant-borne restorations, the professional maintenance CPGs were subdivided for removable and fixed restorations and further divided into biological maintenance and mechanical maintenance for each type of restoration. The at-home maintenance CPGs were subdivided for removable and fixed restorations. CONCLUSION: The clinical practice guidelines presented in this document were initially developed using the 2 systematic reviews. Additional guidelines were developed using expert opinion and consensus, which included discussion of the best clinical practices, clinical feasibility and risk-benefit ratio to the patient. To the authors' knowledge, these are the first CPGs addressing patient recall regimen, professional maintenance regimen, and at-home maintenance regimen for patients with tooth-borne and implant-borne restorations. This document serves as a baseline with the expectation of future modifications when additional evidence becomes available.

Clinical practice guidelines for recall and maintenance of patients with tooth-borne and implant-borne dental restorations.

PURPOSE: To provide guidelines for patient recall regimen, professional maintenance regimen, and at-home maintenance regimen for patients with tooth-borne and implant-borne removable and fixed restorations. MATERIALS AND METHODS: The American College of Prosthodontists (ACP) convened a scientific panel of experts appointed by the ACP, American Dental Association (ADA), Academy of General Dentistry (AGD), and American Dental Hygienists Association (ADHA) who critically evaluated and debated recently published findings from two systematic reviews on this topic. The major outcomes and consequences considered during formulation of the clinical practice guidelines (CPGs) were risk for failure of tooth- and implant-borne restorations. The panel conducted a round table discussion of the proposed guidelines, which were debated in detail. Feedback was used to supplement and refine the proposed guidelines, and consensus was attained. RESULTS: A set of CPGs was developed for tooth-borne restorations and implant-borne restorations. Each CPG comprised (1) patient recall, (2) professional maintenance, and (3) at-home maintenance. For tooth-borne restorations, the professional maintenance and at-home maintenance CPGs were subdivided for removable and fixed restorations. For implant-borne restorations, the professional maintenance CPGs were subdivided for removable and fixed restorations and further divided into biological maintenance and mechanical maintenance for each type of restoration. The at-home maintenance CPGs were subdivided for removable and fixed restorations. CONCLUSIONS: The clinical practice guidelines presented in this document were initially developed using the two systematic reviews. Additional guidelines were developed using expert opinion and consensus, which included discussion of the best clinical practices, clinical feasibility, and risk-benefit ratio to the patient. To the authors' knowledge, these are the first CPGs addressing patient recall regimen, professional maintenance regimen, and at-home maintenance regimen for patients with tooth-borne and implant-borne restorations. This document serves as a baseline with the expectation of future modifications when additional evidence becomes available.

Clinical practice guidelines for recall and maintenance of patients with tooth-borne and implant-borne dental restorations.

The purpose of this article is to provide guidelines for patient recall regimen, professional maintenance regimen, and at-home maintenance regimen for patients with tooth-borne and implant-borne removable and fixed restorations. The American College of Prosthodontists (ACP) convened a scientific panel of experts appointed by the ACP, American Dental Association, Academy of General Dentistry, and American Dental Hygienists Association, who critically evaluated and debated recently published findings from 2 systematic reviews on this topic. The major outcomes and consequences considered during formulation of the clinical practice guidelines (CPGs) were risk for failure of tooth- and implant-borne restorations. The panel conducted a roundtable discussion of the proposed guidelines, which were debated in detail. Feedback was used to supplement and refine the proposed guidelines, and consensus was attained. A set of CPGs was developed for tooth-borne restorations and implant-borne restorations. Each CPG comprised (1) patient recall, (2) professional maintenance, and (3) at-home maintenance. For tooth-borne restorations, the professional maintenance and at-home maintenance CPGs were subdivided for removable and fixed restorations. For implant-borne restorations, the professional maintenance CPGs were subdivided for removable and fixed restorations and further divided into biological maintenance and mechanical maintenance for each type of restoration. The at-home maintenance CPGs were subdivided for removable and fixed restorations. The clinical practice guidelines presented in this document were initially developed using the 2 systematic reviews. Additional guidelines were developed using expert opinion and consensus, which included discussion of the best clinical practices, clinical feasibility, and risk-benefit ratio to the patient. To the authors' knowledge, these are the first CPGs addressing patient recall regimen, professional maintenance regimen, and at-home maintenance regimen for patients with tooth-borne and implant-borne restorations. This document serves as a baseline with the expectation of future modifications when additional evidence becomes available.

A Systematic Review of Recall Regimen and Maintenance Regimen of Patients with Dental Restorations. Part 2: Implant-Borne Restorations.

PURPOSE: To evaluate the current scientific evidence on patient recall and maintenance of implant-supported restorations, to standardize patient care regimens and improve maintenance of oral health. An additional purpose was to examine areas of deficiency in the current scientific literature and provide recommendations for future studies. MATERIALS AND METHODS: An electronic search for articles in the English language literature from the past 10 years was performed independently by multiple investigators using a systematic search process. After application of predetermined inclusion and exclusion criteria, the final list of articles was reviewed to meet the objectives of this review. RESULTS: The initial electronic search resulted in 2816 titles. The systematic application of inclusion and exclusion criteria resulted in 14 articles that satisfied the study objectives. An additional 6 articles were added through a supplemental search process for a total of 20 studies. Of these, 11 were randomized controlled clinical trials, and 9 were observational studies. The majority of the studies (15 out of 20) were conducted in the past 5 years and most studies were conducted in Europe (15), followed by Asia (2), South America (1), the United States (1), and the Middle East (1). Results from the qualitative data on a combined 1088 patients indicated that outcome improvements in recall and maintenance regimen were related to (1) patient/treatment characteristic (type of prosthesis, type of prosthetic components, and type of restorative materials); (2) specific oral topical agents or oral hygiene aids (electric toothbrush, interdental brush, chlorhexidine, triclosan, water flossers) and (3) professional intervention (oral hygiene maintenance, and maintenance of the prosthesis). CONCLUSIONS: There is minimal evidence related to recall regimens in patients with implant-borne removable and fixed restorations; however, a considerable body of evidence indicates that patients with implant-borne removable and fixed restorations require lifelong professional recall regimens to provide biological and mechanical maintenance, customized for each patient. Current evidence also demonstrates that the use of specific oral topical agents and oral hygiene aids can improve professional and at-home maintenance of implant-borne restorations. There is evidence to demonstrate differences in mechanical and biological maintenance needs due to differences in prosthetic materials and designs. Deficiencies in existing evidence compel the forethought of creating clinical practice guidelines for recall and maintenance of patients with implant-borne dental restorations.

A Systematic Review of Recall Regimen and Maintenance Regimen of Patients with Dental Restorations. Part 1: Tooth-Borne Restorations.

PURPOSE: To evaluate the current scientific evidence on patient recall and maintenance of dental restorations on natural teeth, standardize patient care regimens, and improve maintenance of oral health. An additional purpose was to examine areas of deficiency in the current scientific literature and provide recommendations for future studies. MATERIALS AND METHODS: An electronic search for articles in the English language literature from the past 15 years was performed independently by multiple investigators using a systematic search process. After application of predetermined inclusion and exclusion criteria, the final list of articles was reviewed in depth to meet the objectives of this review. RESULTS: The initial electronic search resulted in 2161 titles. The systematic application of inclusion and exclusion criteria resulted in 12 articles that met the objectives of the study. An additional 4 articles were added through a supplemental search process for a total of 16 studies. Out of these, 9 were randomized controlled clinical trials and 7 were observational studies. The majority of the studies (14 out of 16) were conducted in the past 5 years, and most of the studies were conducted in Europe (10). Results from the qualitative data, on a combined 3569 patients, indicated that outcome improvements in recall and maintenance regimen were related to (1) patient/treatment characteristics (adherence to recall appointments, type of restoration and type of restorative material); (2) agent (chlorhexidine, fluoride, triclosan); and (3) professional interventions (repeated oral hygiene instruction, regular oral hygiene intervention). CONCLUSIONS: There is minimal evidence related to recall regimens in patients with removable and fixed tooth-borne restorations; however, there is considerable evidence indicating that patients with tooth-borne removable and fixed restorations require lifelong dental professional maintenance to provide repeated oral hygiene instruction and regular oral hygiene intervention customized to each patient's treatment. Current evidence also indicates that use of specific oral topical agents like chlorhexidine, fluoride, and triclosan can aid in reducing risk for gingival inflammation, dental caries, and candidiasis. Therefore, these agents may aid in improvement of professional and at-home maintenance of various tooth-borne dental restorations. Furthermore, due to the heterogeneity of patient populations, restorations, and treatment needs, the evidence compels forethought of creating clinical practice guidelines for recall and maintenance of patients with tooth-borne dental restorations.

Clinical Practice Guidelines for Recall and Maintenance of Patients with Tooth-Borne and Implant-Borne Dental Restorations.

PURPOSE: To provide guidelines for patient recall regimen, professional maintenance regimen, and at-home maintenance regimen for patients with tooth-borne and implant-borne removable and fixed restorations. MATERIALS AND METHODS: The American College of Prosthodontists (ACP) convened a scientific panel of experts appointed by the ACP, American Dental Association (ADA), Academy of General Dentistry (AGD), and American Dental Hygienists Association (ADHA) who critically evaluated and debated recently published findings from two systematic reviews on this topic. The major outcomes and consequences considered during formulation of the clinical practice guidelines (CPGs) were risk for failure of tooth- and implant-borne restorations. The panel conducted a round table discussion of the proposed guidelines, which were debated in detail. Feedback was used to supplement and refine the proposed guidelines, and consensus was attained. RESULTS: A set of CPGs was developed for tooth-borne restorations and implant-borne restorations. Each CPG comprised (1) patient recall, (2) professional maintenance, and (3) at-home maintenance. For tooth-borne restorations, the professional maintenance and at-home maintenance CPGs were subdivided for removable and fixed restorations. For implant-borne restorations, the professional maintenance CPGs were subdivided for removable and fixed restorations and further divided into biological maintenance and mechanical maintenance for each type of restoration. The at-home maintenance CPGs were subdivided for removable and fixed restorations. CONCLUSIONS: The clinical practice guidelines presented in this document were initially developed using the two systematic reviews. Additional guidelines were developed using expert opinion and consensus, which included discussion of the best clinical practices, clinical feasibility, and risk-benefit ratio to the patient. To the authors' knowledge, these are the first CPGs addressing patient recall regimen, professional maintenance regimen, and at-home maintenance regimen for patients with tooth-borne and implant-borne restorations. This document serves as a baseline with the expectation of future modifications when additional evidence becomes available.

Islet Endothelial Cells Induce Glycosylation and Increase Cell-surface Expression of Integrin ß1 in ß Cells.

The co-culturing of insulinoma and islet-derived endothelial cell (iEC) lines results in the spontaneous formation of free-floating pseudoislets (PIs). We previously showed that iEC-induced PIs display improved insulin expression and secretion in response to glucose stimulation. This improvement was associated with a de novo deposition of extracellular matrix (ECM) proteins by iECs in and around the PIs. Here, iEC-induced PIs were used to study the expression and posttranslational modification of the ECM receptor integrin ß1. A wide array of integrin ß subunits was detected in ßTC3 and NIT-1 insulinomas as well as in primary islets, with integrin ß1 mRNA and protein detected in all three cell types. Interestingly, the formation of iEC-induced PIs altered the glycosylation patterns of integrin ß1, resulting in a higher molecular weight form of the receptor. This form was found in native pancreas but was completely absent in monolayer ß-cells. Fluorescence-activated cell sorting analysis of monolayers and PIs revealed a higher expression of integrin ß1 in PIs. Antibody-mediated blocking of integrin ß1 led to alterations in ß-cell morphology, reduced insulin gene expression, and enhanced glucose secretion under baseline conditions. These results suggest that iEC-induced PI formation may alter integrin ß1 expression and posttranslational modification by enhancing glycosylation, thereby providing a more physiological culture system for studying integrin-ECM interactions in ß cells.

Remyelination in multiple sclerosis: cellular mechanisms and novel therapeutic approaches.

The myelin sheath that coats axons allows rapid propagation of electrical impulses across the nervous system. Oligodendrocytes (ODs) are myelin-producing cells of the central nervous system (CNS) responsible for wrapping the axons of neurons. Multiple sclerosis (MS) is a demyelinating disease of the CNS identifiable by white and gray matter lesions. These lesions consist of axons that have lost their myelin through an autoimmune response to myelin and ODs. Current treatments for MS target the autoimmune aspect of the disease. However, these immunomodulators do not directly enhance the process of remyelination. The ability to remyelinate lesions can be enhanced by neural progenitor cells that can differentiate into ODs and replace lost myelin, although successful remyelination is complex and dependent on multiple factors. The restoration of lost myelin might protect the axon from degeneration and restore optimal conduction of impulses in MS patients, requiring further research on proremyelinating therapies. The combination of immunomodulators and remyelinating enhancers might be the best course of treatment for many MS patients. This Review discusses demyelination in MS, the mechanisms of remyelination, and current therapies designed to promote remyelination in MS patients.