Browsing by Author "Fisher, Marisa M."

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    Elevations in Circulating Methylated and Unmethylated Preproinsulin DNA in New-Onset Type 1 Diabetes
    (American Diabetes Association, 2015-11) Fisher, Marisa M.; Watkins, Renecia A.; Blum, Janice; Evans-Molina, Carmella; Chalasani, Naga; DiMeglio, Linda A.; Mather, Kieren J.; Tersey, Sarah A.; Mirmira, Raghavendra G.; Department of Pediatrics, School of Medicine
    Elevated ratios of circulating unmethylated to methylated preproinsulin (INS) DNA have been suggested to reflect β-cell death in type 1 diabetes (T1D). We tested the hypothesis that absolute levels (rather than ratios) of unmethylated and methylated INS DNA differ between subjects with new-onset T1D and control subjects and assessed longitudinal changes in these parameters. We used droplet digital PCR to measure levels of unmethylated and methylated INS DNA in serum from subjects at T1D onset and at 8 weeks and 1 year post-onset. Compared with control subjects, levels of both unmethylated and methylated INS DNA were elevated at T1D onset. At 8 weeks post-onset, methylated INS DNA remained elevated, but unmethylated INS DNA fell. At 1 year postonset, both unmethylated and methylated INS DNA returned to control levels. Subjects with obesity, type 2 diabetes, and autoimmune hepatitis exhibited lower levels of unmethylated and methylated INS compared with subjects with T1D at onset and no differences compared with control subjects. Our study shows that elevations in both unmethylated and methylated INS DNA occurs in new-onset T1D and that levels of these DNA species change during T1D evolution. Our work emphasizes the need to consider absolute levels of differentially methylated DNA species as potential biomarkers of disease.
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    Measurement of Differentially Methylated INS DNA Species in Human Serum Samples as a Biomarker of Islet β Cell Death
    (JoVE, 2016-12-21) Tersey, Sarah A.; Nelson, Jennifer B.; Fisher, Marisa M.; Mirmira, Raghavendra G.; Department of Pediatrics, IU School of Medicine
    The death of islet β cells is thought to underlie the pathogenesis of virtually all forms of diabetes and to precede the development of frank hyperglycemia, especially in type 1 diabetes. The development of sensitive and reliable biomarkers of β cell death may allow for early therapeutic intervention to prevent or delay the development of diabetes. Recently, several groups including our own have reported that cell-free, differentially methylated DNA encoding preproinsulin (INS) in the circulation is correlated to β cell death in pre-type 1 diabetes and new-onset type 1 diabetes. Here, we present a step-by-step protocol using digital PCR for the measurement of cell-free INS DNA that is differentially methylated at cytosine at position -69 bp (relative to the transcriptional start site). We demonstrate that the assay can distinguish between methylated and unmethylated cytosine at position -69 bp, is linear across several orders of magnitude, provides absolute quantitation of DNA copy numbers, and can be applied to samples of human serum from individuals with new-onset type 1 diabetes and disease-free controls. The protocol described here can be adapted to any DNA species for which detection of differentially methylated cytosines is desired, whether from circulation or from isolated cells and tissues, and can provide absolute quantitation of DNA fragments.
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    Resumption of Puberty in Girls and Boys Following Removal of the Histrelin Implant
    (Elsevier, 2014) Fisher, Marisa M.; Lemay, Deborah; Eugster, Erica A.; Pediatrics, School of Medicine
    Objectives: To determine time to menarche in girls and testicular volume increase in boys after removal of a histrelin implant, which causes profound hypothalamic-pituitary-gonadal axis suppression. Study design: Medical records of patients treated with a histrelin implant were reviewed. Seventy-one patients (56 girls) treated with the histrelin implant were identified, of these patients, 37 explanted girls (68% naïve) and 6 explanted boys (83% naïve) were included in the analysis. Time to menarche after explantation in girls and time to testicular volume increase after explantation in boys were determined. Additional variables investigated included indication for and duration of treatment, history of menarche (girls), previous therapy, and age at beginning and end of histrelin treatment. Results: Of the girls, 30 were treated for central precocious puberty (CPP), 26 had menarche at an average of 12.75 months after explantation. Of the 30, 7 were treated for other indications, of whom 6 had reached menarche. In girls with CPP, older age at explantation correlated with sooner menarche (P = .04). All boys achieved spontaneous testicular enlargement within 1 year of explantation. Conclusions: This study documented resumption of puberty after histrelin explantation in treatment naïve and non-naïve boys and girls with and without CPP. Menarche in girls with CPP occurs within a similar timeframe to that observed after other treatment approaches.
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    Successful treatment of neonatal severe hyperparathyroidism with cinacalcet in two patients
    (BioScientifica, 2015) Fisher, Marisa M.; Cabrera, Susanne M.; Imel, Erik A.; Department of Medicine, IU School of Medicine
    Neonatal severe hyperparathyroidism (NSHPT) is a rare disorder caused by inactivating calcium-sensing receptor (CASR) mutations that result in life-threatening hypercalcemia and metabolic bone disease. Until recently, therapy has been surgical parathyroidectomy. Three previous case reports have shown successful medical management of NSHPT with cinacalcet. Here we present the detailed description of two unrelated patients with NSHPT due to heterozygous R185Q CASR mutations. Patient 1 was diagnosed at 11 months of age and had developmental delays, dysphagia, bell-shaped chest, and periosteal bone reactions. Patient 2 was diagnosed at 1 month of age and had failure to thrive, osteopenia, and multiple rib fractures. Cinacalcet was initiated at 13 months of age in patient 1, and at 4 months of age in patient 2. We have successfully normalized their parathyroid hormone and alkaline phosphatase levels. Despite the continuance of mild hypercalcemia (11-12 mg/dl), both patients showed no hypercalcemic symptoms. Importantly, patient 1 had improved neurodevelopment and patient 2 never experienced any developmental delays after starting cinacalcet. Neither experienced fractures after starting cinacalcet. Both have been successfully managed long-term without any significant adverse events. These cases expand the current literature of cinacalcet use in NSHPT to five successful reported cases. We propose that cinacalcet may be considered as an option for treating the severe hypercalcemia and metabolic bone disease found in infants and children with inactivating CASR disorders. LEARNING POINTS: NSHPT due to mutations in the CASR gene occurs with hypercalcemia and metabolic bone disease, but not always with severe critical illness in infancy.NSHPT should be considered in the differential diagnosis for a newborn with a bell-shaped chest, osteopenia, and periosteal reactions.Neurodevelopmental consequences may occur in children with hypercalcemia and may improve during treatment.Calcimimetics can be used to successfully treat the pathophysiology of NSHPT directly to control serum calcium levels.
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    What is in our environment that effects puberty?
    (Elsevier, 2014) Fisher, Marisa M.; Eugster, Erica A.; Pediatrics, School of Medicine
    Recent studies indicate that the onset of puberty is occurring at increasingly younger ages. Many etiologies have been hypothesized to be involved, but environmental exposures are among the most worrisome. Multiple organizations have endorsed the need to study and provide clinical awareness regarding the effect of a child's environment on pubertal timing. This review article summarizes the current understanding of the major environmental influences on pubertal timing, focusing on factors for which the most scientific evidence exists. The research reviewed addresses intrinsic factors unique to each individual, naturally occurring endocrine disruptors and chemical endocrine disruptors. In each category, evidence was found for and against the involvement of specific environmental factors on pubertal timing. Ultimately, an individual's environment is likely comprised of many aspects that collectively contribute to the timing of puberty. The need for research aimed at elucidating the effects of numerous specific yet disparate forms of exposures is emphasized.