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Gaucher disease is caused by mutations in human acid β-glucosidase or glucocerebrosidase (GCase), the enzyme responsible for hydrolysis of glucosyl ceramide in the lysosomes. Imino- and azasugars such as 1-deoxynojirimycin and isofagomine are strong inhibitors of the enzyme and are of interest in pharmacological chaperone therapy of the disease. Despite several crystal structures of the enzyme with the imino- and azasugars bound in the active site having been resolved, the actual acid-base chemistry of the binding is not known. In this study we show, using photoinduced electron transfer (PET), that 1-deoxynojirimycin and isofagomine derivatives are protonated by human acid β-glucosidase when bound, even if they are completely unprotonated outside the enzyme. While isofagomine derivative protonation to some degree was foreshadowed by earlier crystal structures, 1-deoxynojirimycin derivatives were not believed to act as basic amines in the enzyme.

The inherited thrombocytopenia syndromes are a group of disorders characterized primarily by quantitative defects in platelet number, though with a variety demonstrating qualitative defects and/or extrahematopoietic findings. Through collaborative international efforts applying next-generation sequencing approaches, the list of genetic syndromes that cause thrombocytopenia has expanded significantly in recent years, now with over 40 genes implicated. In this review, we focus on what is known about the genetic etiology of inherited thrombocytopenia syndromes and how the field has worked to validate new genetic discoveries. We highlight the important role for the clinician in identifying a germline genetic diagnosis and strategies for identifying novel causes through research-based endeavors.

Recent epidemiological studies suggest that the risk factors of breast density and obesity together increase breast cancer risk in premenopausal women, and these women have a worsened prognosis following breast cancer diagnosis. Although the underlying causes of increased risk associated with dense breasts and obesity have individually been explored, little is known about how these underlying risk factors interact together to enhance breast cancer risk. To model breast density, we used heterozygous Col1a1tmjae mice, that have a mutation that limits collagen degradation, leading to increased mammary collagen deposition. Heterozygous (het) mice or wild type (wt) litter mates were fed either a control diet (CD) or a high fat diet (HFD) to induce obesity. We quantified F4/80-positive macrophages within mammary glands using immunohistochemistry. We observed significantly increased numbers of macrophages in mammary glands of CD/het, HFD/wt and HFD/het mice compared to CD/wt mice. We observed significantly enhanced picrosirius red stained collagen surrounding mammary ducts from CD/het, HFD/wt, and HFD/het mice compared to those from CD/wt mice. Notably, HFD/het mice had significantly more collagen surrounding ducts than in mammary glands from CD/het mice. These results may suggest that obesity enhances collagen deposition and macrophage-driven inflammation within dense breast tissue in the mammary glands of non-tumor-bearing mice. Citation Format: Abbey E. Williams, Abbey E. Williams, Erica Hoffman, Julia Warren, Suzanne Ponik, Lisa M. Arendt. Collagen density and obesity promote mammary gland inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2574.

Adolescents with polycystic ovary syndrome (PCOS) have insulin resistance and higher rates of the metabolic syndrome.Our objective was to compare the effects of 6 months treatment with drospirenone/ethinyl estradiol (EE) (3 mg/30 μg) vs. rosiglitazone (4 mg) daily on the hormonal and cardiometabolic profiles of overweight/obese adolescents with PCOS.We conducted a randomized, double-blinded, parallel clinical trial in an academic hospital, with n = 46 patients.The primary outcome measure was insulin sensitivity, hepatic with [6,6-(2)H(2)]glucose and peripheral with a 3-h hyperinsulinemic-euglycemic clamp. Other outcome measures included plasma androgen profile and response to ACTH stimulation, glucose and insulin response to oral glucose tolerance test, insulin secretion with a 2-h hyperglycemic clamp, fasting lipid profile, inflammatory markers, intima media thickness, aortic pulse wave velocity, body composition by dual-energy x-ray absorptiometry, and abdominal adiposity by computed tomography scan.Drospirenone/EE resulted in greater reductions in androgenemia. Neither treatment led to change in weight or body mass index, but rosiglitazone led to a significant decrease in visceral adiposity. Compared with drospirenone/EE, treatment with rosiglitazone improved hepatic and peripheral insulin sensitivity and lowered fasting and stimulated insulin levels during the oral glucose tolerance test. Treatment with drospirenone/EE was associated with elevations in total cholesterol, high-sensitivity C-reactive protein and leptin concentrations, whereas treatment with rosiglitazone led to lower triglycerides and higher adiponectin concentrations. Neither treatment affected intima media thickness or pulse wave velocity.In overweight/obese adolescents with PCOS, 6 months treatment with rosiglitazone was superior to drospirenone/EE in improving the cardiometabolic risk profile, and effective but inferior in attenuating hyperandrogenemia. Additional studies are needed to test insulin sensitizers in the treatment of the reproductive and cardiometabolic aspects of PCOS.

Celiac disease (CD) is a gastrointestinal disorder caused by sensitivity to the gliadin fraction of gluten proteins found in wheat, barley, and rye. In genetically prone individuals, exposure to gluten initiates an inflammatory response in the lining of the small bowel and development of circulating antibodies to tissue transglutaminase (TGA), to the endomysium, and/or to gliadin. Patients with classical or clinically overt CD usually complain of abdominal pain, bloating, and diarrhea. If untreated, the inflammation leads to chronic malabsorption of macronutrients as well as folate, fat-soluble vitamins, and iron. Complications may include growth failure, osteoporosis, hepatocellular dysfunction, anovulation, infertility and habitual miscarriage, neurologic dysfunction, and an increased risk of small bowel lymphoma (1-8). Currently, the only treatment is strict gluten restriction. The prevalence of CD in children with type 1 diabetes (1.7–10%) (1, 9-11) exceeds greatly than that in the general population (0.5-0.8%) (12-14). Interestingly, most patients with diabetes have a ‘subclinical’ form of the illness; they are seropositive to celiac antigens and may have pathological changes of the small bowel villi but lack the abdominal symptoms seen in classical CD. Serologic screening of children with diabetes for CD is controversial because no studies have demonstrated metabolic complications in asymptomatic, seropositive subjects or beneficial effects of dietary intervention. We hypothesized that seropositivity to celiac antigens is associated with decreased parameters of weight, height, and bone mineralization in asymptomatic children with type 1 diabetes. To that end, we compared baseline weight, height, and bone mineralization and serum insulin-like growth factor (IGF)-I, IGF-binding protein 3 (IGFBP-3), 25 hydroxy vitamin D (25 OHD), and parathyroid hormone (PTH) in seropositive children with diabetes with baseline values in seronegative diabetic controls. We analyzed parameters of weight gain and growth and bone mineralization in a subset of seropositive subjects who underwent small bowel biopsy to assess correlations with severity of villous pathology. Finally, we assessed the changes in growth and bone mineralization in four asymptomatic subjects who maintained for 1 yr or more a strict gluten-free diet.

Because in obese youth, pulse wave velocity (PWV), an early cardiovascular disease marker, is elevated, we tested if obese girls with polycystic ovary syndrome (OB-PCOS) have higher PWV and carotid intima-media thickness (cIMT) compared with obese girls without PCOS (OB-non-PCOS) and normal-weight girls without PCOS (NW-non-PCOS) and whether PWV and cIMT correlate with inflammatory and circulating endothelial function biomarkers.Cross-sectional study of PWV and cIMT in 91 OB-PCOS, 30 obese controls (OB-non-PCOS), and 19 normal-weight controls (NW-non-PCOS). Body composition, blood pressure, fasting glucose, insulin, lipid concentrations, and endothelial function biomarkers were measured. OB-non-PCOS and OB-PCOS underwent 2-hour oral glucose tolerance testing.PWV was higher in OB-PCOS (664 ± 24 cm/s) and OB-non-PCOS (624 ± 37 cm/s) compared with NW-non-PCOS (468 ± 13 cm/s, P.001), with no differences in cIMT. Systolic blood pressure, low-density lipoprotein, and non-high-density lipoprotein cholesterol were higher, and high-density lipoprotein cholesterol and indices of insulin sensitivity were lower in OB-PCOS and OB-non-PCOS compared with NW-non-PCOS. Vascular cell adhesion molecule-1 and high-sensitivity C-reactive protein were higher in OB-PCOS compared with NW-non-PCOS. PWV correlated with adiposity (rs = .46), insulin sensitivity index (homeostatic model assessment-insulin resistance rs = .31), systolic blood pressure (rs = .24; P ≤ .003 for all), and free testosterone (rs = .24; P = .03). In multiple regression analysis with PWV as the dependent variable and age, race, body mass index, PCOS, and dysglycemia as independent variables, only body mass index was an independent contributor to the model (r(2) = 0.068, P = .003).In adolescent girls, obesity and not PCOS appears to be associated with heightened cardiovascular disease risk. Increased PWV, vascular cell adhesion molecule-1, and high-sensitivity C-reactive protein may be the earliest subclinical atherosclerosis biomarkers in OB-PCOS.

Polycystic ovary syndrome (PCOS) is a common, heterogeneous disorder comprised of hyperandrogenism and anovulation. Although insulin action and secretion are neither necessary nor sufficient for the definition of PCOS, they are both disordered in this setting. Numerous studies have described hyperinsulinism and insulin resistance in both adults and adolescents. Those findings led to more experiments designed to further define the mechanism on a tissue, cellular, and even molecular level. In a time of obesity epidemic, the metabolic consequences of PCOS cannot be overlooked. The importance of complications and associations such as type 2 diabetes, metabolic syndrome, sleep apnea, fatty liver disease (FLD), and early cardiovascular dysfunction underscores the need for appropriate treatment.

Polycystic ovary syndrome (PCOS) is increasingly being recognized in adolescent girls seeking treatment for signs and symptoms of hyperandrogenism. It is difficult to diagnose PCOS in adolescents, therefore a high index of suspicion is necessary. Timely screening and treatment are crucial because another important component of the syndrome is insulin resistance/hyperinsulinemia increasing the risk for type 2 diabetes, dyslipidemia, and cardiovascular sequelae. Diagnosis of PCOS in adolescents should include a thorough family history, exclusion of other causes of hyperandrogenism, and appropriate laboratory evaluation. The scarcity of controlled clinical trials makes treatment controversial. Therapeutic options include lifestyle intervention, oral contraceptive pills, and insulin sensitizers. Long-term follow-up is needed to determine the effectiveness of these approaches in changing the natural history of the reproductive and metabolic outcomes without causing undue harm.