Hemoglobin Alc: Structure, Biosynthesis and Clinical Significance In Diabetes Mellitus

Diabetes mellitus is a chronic metabolic disorder characterized by abnormally high blood glucose concentrations and a relative or absolute deficiency of insulin. Approximately 5 per cent of the American population are afflicted with this disease, which is a leading cause of morbidity and mortality in the United States today. Diabetes may result in the dysfunction of many different organ systems, yet the biochemical mechanism(s) underlying these dysfunctions is unknown. Even the importance of hyperglycemia in the development of the sequelae of diabetes is unsettled. One of the metabolic abnormalities known to characterize this disease is an increase in the peripheral blood concentration of hemoglobin Alc. This minor red cell component comprises 3-5 per cent of the total hemoglobin in non-diabetic humans but up to 15 per cent in diabetics. There is evidence to suggest that it is a glycosylated derivative of hemoglobin A. The aim·of these investigations has been to increase our understanding of the significance of increased hemoglobin Alc concentrations in diabetics. The studies described here in the diabetic mouse demonstrate increased hemoglobin Alc to be a marker for the diabetic phenotype regardless of the cause of diabetes. The increase in hemoglobin Alc concentration occurs 3-4 weeks after the onset of diabetes. Hemoglobin Alc is made as a post-synthetic modification of hemoglobin A at a constant slow rate throughout the life of the red cell. In diabetic humans, hemoglobin Alc concentration correlates with the severity of disease. Changes in the quality of diabetic control are followed, after a 3-4 week delay, by proportionate changes in hemoglobin Alc concentration. Hemoglobin Alc concentration reflects the mean blood glucose concentration for the 3-4 weeks prior to the measurement. Thus, infrequent hemoglobin Alc measurements would be sufficient to assess the quality of long-term diabetic control, a feature unique to this measurement. The periodic monitoring of hemoglobin Alc concentration should permit patients to achieve better diabetic control than is currently possible and should make it possible to determine whether hyperglycemia is important in the development of the sequelae of diabetes. The structure of hemoglobin Alc is identical to that of hemoglobin A, with the addition of l-deoxy fructose attached at the amino terminus of the B chains. The increased formation of hemoglobin Alc in diabetes is an example of the increased glycosylation of a protein (hemoglobin A) occurring in this disease process. The biosynthesis of hemoglobin Alc provides a conceptual framework that may explain the molecular basis for many of the sequelae of diabetes. Thus, the abnormal or excess glycosylation of other proteins may cause structural or functional changes in those proteins and thereby result in the diverse sequelae known to occur secondary to this disease

Regulation of Type 1 Iodothyronine Deiodinase in Health and Disease

The major physiologic function of type 1 iodothyronine deiodinase (D1) is to produce triiodothyronine (T3) for the plasma. D1 activity is regulated by numerous factors, perhaps the most important of which in human pathophysiology is T3. T3 induces D1 expression, contributing to the T3 excess commonly found in hyperthyroidism. Cytokines, nutritional status, sex steroids, and other factors also regulate D1 activity, although different organs often show different responses. Numerous homeostatic mechanisms can counterbalance isolated changes in D1 expression, such as the genetically decreased expression in C3H/He mice. Two relatively commonly used drugs, propylthiouracil and amiodarone, inhibit D1, which can have substantial effects on circulating thyroid hormone levels. Overall, many factors interact in complex ways to establish D1 levels, contributing to the circulating concentrations of thyroxine (T4) and T3.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63410/1/thy.2005.15.835.pd

A Locally Secreted Thyrotropin Variant May Regulate Thyroid Function in Thyroid Inflammatory Disorders

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78105/1/thy.2008.1564.pd

Identification of the Genomic Insertion Site of the Thyroid Peroxidase Promoter–Cre Recombinase Transgene Using a Novel, Efficient, Next-Generation DNA Sequencing Method

Background: It can be useful to know the transgene insertion site in transgenic mice for a variety of reasons, but determining the insertion site generally is a time consuming, expensive, and laborious task. Methods: A simple method is presented to determine transgene insertion sites that combines the enrichment of a sequencing library by polymerase chain reaction (PCR) for sequences containing the transgene, followed by next-generation sequencing of the enriched library. This method was applied to determine the site of integration of the thyroid peroxidase promoter?Cre recombinase mouse transgene that is commonly used to create thyroid-specific gene deletions. Results: The insertion site was found to be between bp 12,372,316 and 12,372,324 on mouse chromosome 9, with the nearest characterized genes being Cntn5 and Jrkl, ?1.5 and 0.9?Mbp from the transgene, respectively. One advantage of knowing a transgene insertion site is that it facilitates distinguishing hemizygous from homozygous transgenic mice. Although this can be accomplished by real-time quantitative PCR, the expected Ct difference is only one cycle, which is challenging to assess accurately. Therefore, the transgene insertion site information was used to develop a 3-primer qualitative PCR assay that readily distinguishes wild type, hemizygous, and homozygous TPO-Cre mice based upon size differences of the wild type and transgenic allele PCR products. Conclusions: Identification of the genomic insertion site of the thyroid peroxidase promoter?Cre mouse transgene should facilitate the use of these mice in studies of thyroid biology.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140267/1/thy.2015.0215.pd

Rare Clinical Entity: Metastatic malignant struma ovarii diagnosed during pregnancy – Lessons for management

Abstract Background Malignant struma ovarii is an ovarian teratoma containing at least 50% thyroid tissue which has the potential to metastasize and produce thyroid hormone. Given its rarity, management strategies are not well-established. We report a case of metastatic malignant struma ovarii discovered during pregnancy with lessons for evaluation and management. Case presentation A 30-year-old woman who was two months pregnant was discovered to have struma ovarii with over half of the struma comprised of papillary thyroid cancer. Following tumor resection, delivery, and thyroidectomy, she underwent evaluation with stimulated thyroglobulin testing and diagnostic staging sodium iodide-131 scan (I-131), which revealed the presence of skeletal metastases. Following administration of 320 mCi I-131, post-therapy scan also showed miliary pulmonary metastases with improved ability to localize the bony and pulmonary metastases with concurrent SPECT/CT imaging. A second dosimetry-guided I-131 therapy resulted in complete resolution of pulmonary metastases; however, small foci of residual bone disease persisted. Post-therapy scans demonstrated additional findings not shown on diagnostic I-131 scans obtained prior to both her initial and second I-131 therapy. Conclusions SPECT/CT provides accurate anatomic correlation and localization of metastatic foci and can serve as a baseline study to assess interval response to treatment. Post-therapy scans should always be obtained when I-131 treatment is administered, as additional findings may be revealed versus low dose I-131 activity diagnostic scans. This patient had a high metastatic burden that would not have been discovered in a timely fashion with the conservative approach advocated by others. Thyroidectomy followed by a diagnostic staging radioiodine scan and a stimulated thyroglobulin level should be considered in patients with malignant struma ovarii for guiding therapeutic I-131 administration as metastatic risk is difficult to predict based on histopathologic examination.https://deepblue.lib.umich.edu/bitstream/2027.42/144518/1/40842_2018_Article_64.pd

Factors That Influence Radioactive Iodine Use for Thyroid Cancer

Background: There is variation in the use of radioactive iodine (RAI) as treatment for well-differentiated thyroid cancer. The factors involved in physician decision-making for RAI remain unknown. Methods: We surveyed physicians involved in postsurgical management of patients with thyroid cancer from 251 hospitals. Respondents were asked to rate the factors important in influencing whether a thyroid cancer patient receives RAI. Multivariable analyses controlling for physician age, gender, specialty, case volume, and whether they personally administer RAI, were performed to determine correlates of importance placed on patients' and physicians' worry about death from cancer and differences between low? versus higher?case-volume physicians. Results: The survey response rate was 63% (534/853). Extent of disease, adequacy of surgical resection, patients' willingness to receive RAI, and patients' age were the factors physicians were most likely to report as quite or very important in influencing recommendations for RAI to patients with thyroid cancer. Interestingly, both physicians' and patients' worry about death from thyroid cancer were also important in determining RAI use. Physicians with less thyroid cancer cases per year were more likely than higher-volume physicians to report patients' (p<0.001) and physicians' worry about death (p=0.016) as quite or very important in decision-making. Other factors more likely to be of greater importance in determining RAI use for physicians with lower thyroid cancer patient volume versus higher include the accepted standard at the affiliated hospital (p=0.020), beliefs about RAI expressed by colleagues comanaging patients (p=0.003), and patient distance from the nearest facility administering RAI (p=0.012). Conclusion: In addition to the extent of disease and adequacy of surgical resection, physicians place importance on physician and patient worry about death from thyroid cancer when deciding whether to treat a patient with RAI. The factors important to physician decision-making differ based on physician thyroid-cancer case-volume, with worry about death being more influential for low?case-volume physicians. As the mortality from thyroid cancer is low, the importance placed on death in decision making may be unwarranted.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140258/1/thy.2012.0380.pd

Causes of prehospital misinterpretations of ST elevation myocardial infarction

Objectives: To determine the causes of software misinterpretation of ST elevation myocardial infarction (STEMI) compared to clinically identified STEMI to identify opportunities to improve prehospital STEMI identification. Methods: We compared ECGs acquired from July 2011 through June 2012 using the LIFEPAK 15 on adult patients transported by the Los Angeles Fire Department. Cases included patients ≥18 years who received a prehospital ECG. Software interpretation of the ECG (STEMI or not) was compared with data in the regional EMS registry to classify the interpretation as true positive (TP), true negative (TN), false positive (FP), or false negative (FN). For cases where classification was not possible using registry data, 3 blinded cardiologists interpreted the ECG. Each discordance was subsequently reviewed to determine the likely cause of misclassification. The cardiologists independently reviewed a sample of these discordant ECGs and the causes of misclassification were updated in an iterative fashion. Results: Of 44,611 cases, 50% were male (median age 65; inter-quartile range 52–80). Cases were classified as 482 (1.1%) TP, 711 (1.6%) FP, 43371 (97.2%) TN, and 47 (0.11%) FN. Of the 711 classified as FP, 126 (18%) were considered appropriate for, though did not undergo, emergent coronary angiography, because the ECG showed definite (52 cases) or borderline (65 cases) ischemic ST elevation, a STEMI equivalent (5 cases) or ST-elevation due to vasospasm (4 cases). The sensitivity was 92.8% [95% CI 90.6, 94.7%] and the specificity 98.7% [95% CI 98.6, 98.8%]. The leading causes of FP were ECG artifact (20%), early repolarization (16%), probable pericarditis/myocarditis (13%), indeterminate (12%), left ventricular hypertrophy (8%), and right bundle branch block (5%). There were 18 additional reasons for FP interpretation (&lt;4% each). The leading causes of FN were borderline ST-segment elevations less than the algorithm threshold (40%) and tall T waves reducing the ST/T ratio below threshold (15%). There were 11 additional reasons for FN interpretation occurring ≤3 times each. Conclusion: The leading causes of FP automated interpretation of STEMI were ECG artifact and non-ischemic causes of ST-segment elevation. FN were rare and were related to ST-segment elevation or ST/T ratio that did not meet the software algorithm threshold

Welcome to the 83rd Annual Meeting of the American Thyroid Association

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140259/1/thy.2013.0486.pd

Protein-protein interactions involving erbA superfamily receptors: through the TRAPdoor

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29320/1/0000385.pd