The Role of Reverse Cascade Screening in Children with Familial Hypercholesterolemia: A Literature Review and Analysis.

PURPOSE OF REVIEW: Familial Hypercholesterolemia (FH) is a common genetic disorder characterized by lifelong elevation of severely elevated plasma low-density lipoprotein cholesterol. Atherosclerotic cardiovascular disease (ASCVD) risk accelerates after age 20. Early diagnosis allows for treatment of children with FH and creates an opportunity to identify affected relatives through reverse cascade screening (RCS). Historically, cascade screening has had little impact on identifying individuals with FH. RECENT FINDINGS: Universal cholesterol screening (UCS) to identify youth with FH, beginning at 9-11 years-of-age, is currently recommended in the U.S. The European Atherosclerosis Society has called for UCS worldwide, emphasizing the need for educational programs to increase awareness amongst healthcare professions. Underdiagnoses and undertreatment of FH remain high. Improved rates of UCS and a systematic approach to RCS are needed. The absence of a coordinated RCS program limits the benefits of UCS. Further research is needed to identify barriers to cholesterol screening in youth.

Feeding tube use and complications in Prader-Willi syndrome: Data from the Global Prader-Willi Syndrome Registry.

Guidance on indications for, and types of, feeding tubes recommended in Prader-Willi syndrome (PWS) is needed. A Global PWS Registry survey was developed to investigate nasogastric (NG) and gastrostomy (G) tube use and associated complications. Of 346 participants, 242 (69.9%) had NG-tubes, 17 (4.9%) had G-tubes, and 87 (25.1%) had both NG- and G-tubes. Primary indication for placement was "feeding difficulties and/or poor weight gain" for both NG- (90.2%) and G-tubes (71.2%), while "aspiration/breathing difficulties" was the procedural indication for 6.4% of NG-tubes and 23.1% of G-tubes. NG-tubes were generally removed by age 6 months (NG Only: 82.9%; NG/G: 98.8%), while G-tubes were often removed by age 2 years (G Only: 85.7%; NG/G: 70.5%). The severe complication rate from G-tubes was 31.7% and from NG-tubes was 1.2%. Overall, caregivers indicated the presence of an NG- or G-tube had a positive effect on quality of life. Feeding difficulties in PWS are largely managed by NG-tube alone. The severe complication rate from G-tubes was about 25 times higher than from NG-tubes; yet, G-tube placement rates have generally increased. G-tube placement puts individuals with PWS at risk for anesthesia and surgery-related complications and should be considered judiciously by a multidisciplinary team.

Evaluation of Rhodanine Indolinones as AANAT Inhibitors.

Circadian rhythm (CR) dysregulation negatively impacts health and contributes to mental disorders. The role of melatonin, a hormone intricately linked to CR, is still a subject of active study. The enzyme arylalkylamine N-acetyltransferase (AANAT) is responsible for melatonin synthesis, and it is a potential target for disorders that involve abnormally high melatonin levels, such as seasonal affective disorder (SAD). Current AANAT inhibitors suffer from poor cell permeability, selectivity, and/or potency. To address the latter, we have employed an X-ray crystal-based model to guide the modification of a previously described AANAT inhibitor, containing a rhodanine-indolinone core. We made various structural modifications to the core structure, including testing the importance of a carboxylic acid group thought to bind in the CoA site, and we evaluated these changes using MD simulations in conjunction with enzymatic assay data. Additionally, we tested three AANAT inhibitors in a zebrafish locomotion model to determine their effects in vivo. Key discoveries were that potency could be modestly improved by replacing a 5-carbon alkyl chain with rings and that the central rhodanine ring could be replaced by other heterocycles and maintain potency.

Curcumin Stereoisomer, Cis-Trans Curcumin, as a Novel Ligand to A1 and A3 Adenosine Receptors.

Adenosine receptors (ARs) are being explored to generate non-opioid pain therapeutics. Vanilloid compounds, curcumin, capsaicin, and vanillin possess antinociceptive properties through their interactions with the transient receptor potential channel family. However, their binding with adenosine receptors has not been well studied. The hypothesis in this study was that a vanilloid compound, cis-trans curcumin (CTCUR), binds to each of the two Gi-linked AR subtypes (A1AR and A3AR). CTCUR was synthesized from curcumin (CUR) using the cavitand-mediated photoisomerization technique. The cell lines transfected with the specific receptor (A1AR or A3AR) were treated with CTCUR or CUR and the binding was analyzed using competitive assays, confocal microscopy, and docking. The binding assays and molecular docking indicated that CTCUR had Ki values of 306 nM (A1AR) and 400 nM (A3AR). These values suggest that CTCUR is selective for Gi-linked ARs (A1AR or A3AR) over Gs-linked ARs (A2AAR or A2BAR), based on our previous published research. In addition, the docking showed that CTCUR binds to the toggle switch domain of ARs. Curcumin (CUR) did not exhibit binding at any of these receptors. In summary, CTCUR and other modifications of CUR can be developed as novel therapeutic ligands for the Gi-linked ARs (A1AR and A3AR) involved with pain and cancer.

Novel curcumin analog (cis-trans curcumin) as ligand to adenosine receptors A2A and A2B: potential for therapeutics.

All four of the adenosine receptor (AR) subtypes mediate pain and have been targeted by pharmacologists to generate new therapeutics for chronic pain. The vanilloid phytochemicals, which include curcumin, capsaicin, and gingerol, have been shown to alleviate pain. However, there is little to no literature on the interaction of vanilloid phytochemicals with ARs. In this study, photochemical methods were used to generate a novel isomer of curcumin (cis-trans curcumin or CTCUR), and the interactions of both curcumin and CTCUR with the two Gs-linked AR subtypes were studied. Competitive binding assays, docking analysis, and confocal fluorescence microscopy were performed to measure binding affinity; cell survival assays were used to measure toxicity; and cAMP assays were performed to measure receptor activation. Competitive binding results indicated that CTCUR binds to both AR A2A and AR A2B with Ki values of 5 µM and 7 µM, respectively, which is consistent with our docking results. Fluorescence microscopy data also shows binding for A2B and A2A. Cell survival results show that CTCUR and CUR are nontoxic at the tested concentrations in these cell lines. Overall, our results suggest that vanilloid phytochemicals may be slightly modified to increase interaction with Gs-ARs, and thereby can be further explored to provide a novel class of non-opioid antinociceptives.

Type 1 diabetes mellitus, familial hypercholesterolemia, and elevated lipoprotein (a).

Risk factor screening of all youth, including those with high-risk medical conditions such as diabetes mellitus, is important to reduce premature morbidity and mortality attributable to atherosclerotic cardiovascular disease. In those found to have significant hypercholesterolemia and/or elevated levels of lipoprotein (a), reverse cascade screening (child to parent) is recommended. This case demonstrates the benefits of targeted lipid testing. Early detection may provide additional motivation for families to adopt healthier lifestyles and reduce future atherosclerotic cardiovascular disease events in the child, siblings, and parents.

Severe hypercholesterolemia in a 2-year-old.

Routine and selective cholesterol screening of children is an effective tool to help identify those with familial hypercholesterolemia. In children found to have elevated levels of cholesterol, secondary causes should be excluded, including hypothyroidism. Thyroid hormone has multiple effects on the regulation of lipid synthesis, absorption, and metabolism. In this case report, we described a 2-year-old with a history of congenital hypothyroidism who was found to have severe hypercholesterolemia. A detailed medical history and appropriate screening tests are important in determining the underlying cause of elevated low-density lipoprotein cholesterol to help inform clinical decision-making.

Reverse Cascade Screening for Familial Hypercholesterolemia.

PROBLEM: Cardiovascular disease (CVD) is the leading cause of death in the U.S. and in most Western countries. Early identification and treatment of individuals with elevated levels of atherogenic cholesterol, a major contributor to CVD, have been shown to be effective and safe in reducing premature morbidity and mortality, especially in familial hypercholesterolemia (FH). Cholesterol screening of youth also provides a unique means of identifying affected family members through reverse cascade screening (RCS). ELIGIBILITY CRITERIA: A PubMed review of all relevant articles from 2000 to 2016 was conducted of familial hypercholesterolemia and cholesterol screening of youth. RESULTS: We provide an overview of cholesterol screening, outline the role of the pediatric nurse in the lipid clinic, and discuss effectiveness and potential barriers, including cost and confidentiality considerations of RCS. CONCLUSIONS: Early identification and effective intervention of youth with FH, including adoption of a heart-healthy lifestyle, has the potential of 1) markedly reducing or eliminating atherosclerotic cardiovascular disease and related events in future generations and 2) provides a unique means of identifying affected family members. IMPLICATIONS: Pediatric nurses play a vital role in the education and care coordination of children diagnosed with FH and screening of relatives. Identification of a child with FH with effective screening of relatives combines the benefits of universal and cascade screening, and has the potential of detecting all living cases of FH. While potentially providing significant benefit to those at risk for premature CVD, a RCS program needs to carefully consider ethical, psychological, and financial implications as well.

Dyslipidemia, weight gain, and decreased growth velocity in a 14-year-old male.

A 14-year-old male was referred for dyslipidemia. His findings were consistent with metabolic syndrome. Although he lacked the typical physical appearance, his accelerated weight gain combined with a decreased linear growth velocity suggested Cushing syndrome. He was subsequently found to have adrenocorticotropic hormone-independent Cushing syndrome secondary to primary pigmented nodular adrenal disease without Carney Complex. After bilateral adrenalectomy, his lipid profile returned to normal. In this article, we discuss the role of glucocorticoids on lipid and lipoprotein metabolism.

Provider variability in the initial diagnosis and treatment of congenital hypothyroidism.

BACKGROUND: Early diagnosis and expeditious treatment of newborns with congenital hypothyroidism (CH) is necessary to avoid mental retardation. METHODS: A survey of 44 practitioners in the southern US was conducted to better understand common practices regarding neonatal CH and the findings were compared with current guidelines in the US and Europe. RESULTS: Responses indicated some consensus that 10-15 µg of thyroid hormone/kg/day was the appropriate dosage. However, despite guidelines advocating their use, practitioners reported that they did not commonly use imaging or laboratory tests, though experienced providers apparently used them more often. CONCLUSIONS: Together, these results show moderate adherence to published guidelines for treating and diagnosing CH. Further research is needed to determine why providers deviate from these guidelines and to generalize these results to other populations.

The Prevalence of Dyslipidemia and Other Cardiovascular Risk Factors in Youth with Diabetes.

BACKGROUND: Individuals diagnosed with diabetes mellitus have an increased risk of cardiovascular disease, often leading to premature morbidity and mortality. As the number of youth developing T1D and T2D continues to grow, early onset predisposes patients to a longer burden of disease and earlier onset of cardiovascular complications. Early identification and effective management and treatment of risk factors can lead to decreased cardiovascular events and improved quality of life. OBJECTIVE: In this study, we describe the prevalence of CVD risk factors in children with diabetes. RESULTS: 274 subjects were included in this study, all > 1 year since the time of diagnosis. 134 participants were male (49%). Mean age was 13.7 years (males); 12.8 years (females). subjects averaged 4 diabetes-related visits per year. At the time of their most recent clinic visit, 33% of subjects had a HbA1c < 8%, and 29% had a HbA1c > 10%. Greater than 50% of subjects were overweight or obese. A significant number of subjects were found to have dyslipidemia, and elevated blood pressure was common. DISCUSSION: CVD risk factors are common in children with diabetes mellitus. Good glycemic control, early identification, and effective life-long management of all CVD risk factors may help decrease the high rate of premature morbidity and mortality in diabetes.

Universal cholesterol screening of children in community-based ambulatory pediatric clinics.

BACKGROUND: Early identification and treatment of individuals with elevated levels of atherogenic cholesterol have been shown to be effective and safe in reducing morbidity and mortality, especially in familial hypercholesterolemia. To better inform providers and identify children and adolescents at risk of premature cardiovascular disease, in November 2011, the National Heart, Lung, and Blood Institute (NHLBI) published guidelines recommending cholesterol screening of all children aged between 9 to 11 and 17 to 21 years regardless of the child's general health or the presence or the absence of cardiovascular disease risk factors. OBJECTIVE: To compare the number of 9- to 11-year-old children screened for hypercholesterolemia in 5 community-based ambulatory pediatric clinics before and after publication of the NHLBI's guidelines. METHODS: Practice demographics, screening frequency, and test results for each clinic were collected before and after publication of the NHLBI's recommendation. Provider education was provided between measures. RESULTS: Of all eligible 9- to 11-year-old children, 489 (17.1%) were screened before and 686 (20.1%) after the NHLBI's guidelines and provider education. CONCLUSIONS: Baseline rates of lipid screening for the 5 community-based ambulatory pediatric clinics were higher than those previously reported and increased significantly after publication of the NHLBI's recommendations and provider education. However, overall screening rates remained low. Given the high prevalence of premature cardiovascular disease associated with atherogenic cholesterol, especially familial hypercholesterolemia, additional strategies are needed to improve screening rates.