Alpha- and Beta-thalassemia: Rapid Evidence Review.

Thalassemia is a group of autosomal recessive hemoglobinopathies affecting the production of normal alpha- or beta-globin chains that comprise hemoglobin. Ineffective production of alpha- or beta-globin chains may result in ineffective erythropoiesis, premature red blood cell destruction, and anemia. Chronic, severe anemia in patients with thalassemia may result in bone marrow expansion and extramedullary hematopoiesis. Thalassemia should be suspected in patients with microcytic anemia and normal or elevated ferritin levels. Hemoglobin electrophoresis may reveal common characteristics of different thalassemia subtypes, but genetic testing is required to confirm the diagnosis. Thalassemia is generally asymptomatic in trait and carrier states. Alpha-thalassemia major results in hydrops fetalis and is often fatal at birth. Beta-thalassemia major requires lifelong transfusions starting in early childhood (often before two years of age). Alpha- and beta-thalassemia intermedia have variable presentations based on gene mutation or deletion, with mild forms requiring only monitoring but more severe forms leading to symptomatic anemia and requiring transfusion. Treatment of thalassemia includes transfusions, iron chelation therapy to correct iron overload (from hemolytic anemia, intestinal iron absorption, and repeated transfusions), hydroxyurea, hematopoietic stem cell transplantation, and luspatercept. Thalassemia complications arise from bone marrow expansion, extramedullary hematopoiesis, and iron deposition in peripheral tissues. These complications include morbidities affecting the skeletal system, endocrine organs, heart, and liver. Life expectancy of those with thalassemia has improved dramatically over the past 50 years with increased availability of blood transfusions and iron chelation therapy, and improved iron overload monitoring. Genetic counseling and screening in high-risk populations can assist in reducing the prevalence of thalassemia.

Health Literacy Initiatives and Lessons Learned with NGOs: Wisconsin Health Literacy.

This report discusses necessary steps to help ensure successful community-based health literacy interventions using adult learning principles. Two workshop topics are covered: one on the flu and the other on the safe and effective use of opioids. Successful implementation includes conducting a needs assessment, developing project content, identifying target audiences, building strong community partners, implementing the workshops, and evaluating outcomes. The report also features the importance of patient-centered prescription medication labels to improve patient understanding, safety, and adherence. Results from a case study suggest redesigned labels that are patient-centered are easier to understand and improve adherence.

Best Practices to Advance Health Literacy in a Wisconsin Adult Literacy Coalition.

Background: Wisconsin Literacy Incorporated is a statewide adult and family literacy coalition representing 75 community-based literacy organizations. This coalition focuses its work in four areas: (1) building capacity of its member agencies, (2) advocating for literacy, (3) preparing adults in worker readiness and career pathways, and (4) improving how health information is communicated through its division, Wisconsin Health Literacy (WHL). Brief Description of Activity: This article outlines how an adult basic education coalition successfully developed a statewide health literacy coalition that later transformed into a division of Wisconsin Literacy through a three-phase approach that included: (1) raising awareness and educating health care and literacy providers about health literacy, (2) implementing health literacy interventions through various grant funding, and (3) disseminating and sharing findings from such health literacy interventions to a broad audience. Implementation: Beginning its awareness work in 2003 with help from a physician champion, WHL implemented best practices within each of the three areas of approach. After being implemented, the initial volunteer-based health literacy coalition was transformed into a division of Wisconsin Literacy Incorporated. Results: The division now includes a full-time director, its own website, funding for community interventions, and a business plan for fee-for-service efforts with health care providers, public health agencies, and other stakeholders. Key relationships with Wisconsin health care organizations provided WHL venues to present about health literacy throughout the state and beyond. Wisconsin Literacy Incorporated helped secure a solid infrastructure by hosting two planning retreats and implementing both strategic and business plans for the newly formed division. Offering fee-for-service health literacy training to health care providers brought in new revenue to sustain the division and obtain buy-in from health care agencies on the importance of health literate organizations. Finally, participating in key partner coalitions and Communities of Practice allowed WHL to share experiences and best practices with a national audience. Lessons Learned: The importance of intentionally raising awareness in strategic health care settings across the state fostered many partnerships. Investing in a strategic planning retreat and a business plan guided the division's success. Delivering educational workshops in community-based literacy organizations and trusted settings where adults regularly go to learn was key to successful implementation. [HLRP: Health Literacy Research and Practice. 2019;3(Suppl.):S8-S14.]. Plain Language Summary: Wisconsin Literacy Incorporated is an adult basic education coalition that built a health literacy division over several years. Using best practices such as raising awareness, implementing pilot projects, and broadly sharing its experience, the Wisconsin Health Literacy division advanced the understanding and commitment to health literacy in and beyond Wisconsin.

Development of Highly Selective Pyrimidine-Based Aldosterone Synthase (CYP11B2) Inhibitors.

Excess aldosterone production and signaling are primary contributors to numerous cardiovascular disorders including primary aldosteronism and resistant hypertension. Recently, inhibition of aldosterone synthesis via the enzyme aldosterone synthase (CYP11B2) has been pursued to ameliorate the negative effects of elevated aldosterone. Herein, we report the development of aldosterone synthase inhibitors using a pyrimidine-based metal binding group leading to the highly selective CYP11B2 inhibitor 22. Superior selectivity combined with robust pharmacokinetics afforded highly selective in vivo aldosterone suppression in a monkey model of adrenal steroidogenesis, demonstrating the potential for selective aldosterone lowering in humans with pyrimidine 22.

Identification of potent, nonabsorbable agonists of the calcium-sensing receptor for GI-specific administration.

Modulation of gastrointestinal nutrient sensing pathways provides a promising a new approach for the treatment of metabolic diseases including diabetes and obesity. The calcium-sensing receptor has been identified as a key receptor involved in mineral and amino acid nutrient sensing and thus is an attractive target for modulation in the intestine. Herein we describe the optimization of gastrointestinally restricted calcium-sensing receptor agonists starting from a 3-aminopyrrolidine-containing template leading to the identification of GI-restricted agonist 19 (GSK3004774).

Exploration of phenylpropanoic acids as agonists of the free fatty acid receptor 4 (FFA4): Identification of an orally efficacious FFA4 agonist.

The long chain free fatty acid receptor 4 (FFA4/GPR120) has recently been recognized as lipid sensor playing important roles in nutrient sensing and inflammation and thus holds potential as a therapeutic target for type 2 diabetes and metabolic syndrome. To explore the effects of stimulating this receptor in animal models of metabolic disease, we initiated work to identify agonists with appropriate pharmacokinetic properties to support progression into in vivo studies. Extensive SAR studies of a series of phenylpropanoic acids led to the identification of compound 29, a FFA4 agonist which lowers plasma glucose in two preclinical models of type 2 diabetes.

Identification of nonabsorbable inhibitors of the scavenger receptor-BI (SR-BI) for tissue-specific administration.

The identification of a low-permeability scavenger receptor BI (SR-BI) inhibitor starting from the ITX-5061 template is described. Structure-activity and structure-permeability relationships were assessed for analogs leading to the identification of compound 8 as a potent and nonabsorbable SR-BI inhibitor.

Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120).

The exploration of a diarylsulfonamide series of free fatty acid receptor 4 (FFA4/GPR120) agonists is described. This work led to the identification of selective FFA4 agonist 8 (GSK137647A) and selective FFA4 antagonist 39. The in vitro profile of compounds 8 and 39 is presented herein.

Lipid-mediated release of GLP-1 by mouse taste buds from circumvallate papillae: putative involvement of GPR120 and impact on taste sensitivity.

Glucagon-like peptide-1 (GLP-1) signaling modulates sweet-taste sensitivity in the mouse. Because circumvallate papillae (CVPs) express both GLP-1 and its receptor, a local regulation has been suggested. However, whether dietary lipids are involved in this regulation, as shown in the gut, is unknown. By using a combination of biochemical, immunohistochemical, and behavioral approaches, the present data i) confirm the role of GLP-1 signaling in the attraction for sucrose, ii) demonstrate that minute quantities of long-chain FAs (LCFAs) reinforce the attraction for sucrose in a GLP-1 receptor-dependent manner, iii) suggest an involvement of the LCFA receptor GPR120 expressed in taste buds in this system, and iv) support the existence of a regulation by GLP-1 of the lipid sensing mediated by lingual CD36. Therefore, oro-sensory detection of LCFAs may affect sweet and fatty taste responsiveness by controlling the secretion of lingual GLP-1. This regulatory loop, probably triggered by the LCFA-GPR120 interaction, might contribute to the high palatability of foods rich both in fat and sugar.

Phenoxyacetic acids as PPARδ partial agonists: synthesis, optimization, and in vivo efficacy.

A series of phenoxyacetic acids as subtype selective and potent hPPARδ partial agonists is described. Many analogues were readily accessible via a single solution-phase synthetic route which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of two potent exemplars which were further evaluated in vivo. Details of the SAR, optimization, and in vivo efficacy of this series are presented herein.

Anthranilimide based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes. Part 3: X-ray crystallographic characterization, core and urea optimization and in vivo efficacy.

Key binding interactions of the anthranilimide based glycogen phosphorylase a (GPa) inhibitor 2 from X-ray crystallography studies are described. This series of compounds bind to the AMP site of GP. Using the binding information the core and the phenyl urea moieties were optimized. This work culminated in the identification of compounds with single nanomolar potency as well as in vivo efficacy in a diabetic model.

Anthranilimide-based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes: 1. Identification of 1-amino-1-cycloalkyl carboxylic acid headgroups.

Optimization of the amino acid residue within a series of anthranilimide-based glycogen phosphorylase inhibitors is described. These studies culminated in the identification of anthranilimides 16 and 22 which displayed potent in vitro inhibition of GPa in addition to reduced inhibition of CYP2C9 and excellent pharmacokinetic properties.

Anthranilimide-based glycogen phosphorylase inhibitors for the treatment of Type 2 diabetes: 2. Optimization of serine and threonine ether amino acid residues.

Optimization of the amino acid residue of a series of anthranilimide-based glycogen phosphorylase inhibitors is described leading to the identification of serine and threonine ether analogs. t-Butylthreonine analog 20 displayed potent in vitro inhibition of GPa, low potential for P450 inhibition, and excellent pharmacokinetic properties.

Tandem Intramolecular Benzyne-Furan Cycloadditions. Total Synthesis of Vineomycinone B(2) Methyl Ester.

We have exploited tandem intramolecular benzyne-furan cycloadditions employing three different benzyne precursors to generate substituted bisoxabenzonorbornadienes in a single operation. The regiochemical outcomes in these Diels-Alder reactions were effectively controlled by using disposable silicon tethers to link the reacting benzynes and furan moieties. Two different methods for converting the intermediate bisoxabenzonorbornadienes to substituted anthrarufins were developed. The first tactic entails the initial cleavage of the silicon tethers followed by regioselective ring opening of the oxabicycloheptadienes and oxidation of the central ring giving the target anthrarufin, whereas the second features the regioselective ring opening of the oxabicycloheptadienes followed by protiodesilylation and oxidation. When the starting furans bear carbohydrate substitutents, this new methodology enables the rapid assembly of the glycosyl-substituted aromatic cores of complex C-aryl glycoside antibiotics from simple starting materials. The utility of this novel approach to anthrarufins and C-aryl glycosides is exemplified in a triply convergent synthesis of vineomycinone B(2) methyl ester.

C-Aryl glycosides via tandem intramolecular benzyne-furan cycloadditions. Total synthesis of vineomycinone B2 methyl ester.

A triply convergent total synthesis of vineomycinone B2 methyl ester has been achieved by an approach with a longest linear sequence of 16 steps. The synthesis features the use of silicon tethers as disposable linkers to control the regiochemistry in two tandem Diels-Alder reactions of substituted benzynes and glycosyl furans to provide rapid access to the fully intact anthrarufin core of vineomycinone B2 methyl ester.

Glycogen phosphorylase inhibitors.

Type 2 diabetes is a complex metabolic disease with hyperglycemia as its recognizable hallmark. Hepatic glucose output is elevated in Type 2 diabetic patients, and evidence suggests drugs which lower hepatic glucose production are effective antihyperglycemic agents. Glycogenolysis, which is the release of monomeric glucose from its polymeric storage form called glycogen, is a key contributor to hepatic glucose output. Glycogen phosphorylase is the enzyme that catalyzes this process. This review covers advances in the design of small molecule inhibitors of this enzyme, their biological activity, and their potential as effective antihyperglycemic agents for the treatment of Type 2 diabetes.

Type 2 intramolecular N-acylnitroso Diels-Alder reaction: scope and application to the synthesis of medium ring lactams.

Heteroatom variants of the type 2 intramolecular Diels-Alder reaction provide an efficient method for the preparation of bridged bicyclic heterocycles. The type 2 variant of the intramolecular N-acylnitroso Diels-Alder reaction is an effective method for the synthesis of bridged bicyclic oxazinolactams. Structural studies of the cycloadducts have allowed for quantification of the deformations of the bridgehead functionalities and provided a strategy for the stereoselective synthesis of substituted seven- and eight-membered ring lactams. Diastereoselective cycloadditions followed by cleavage of the oxazine ring afford azepin-2-ones or azocin-2-ones.

Hemodynamic changes occurring during the progressive enlargement of abdominal aortic aneurysms.

The purpose of this study is to characterize the evolution of the hemodynamic forces acting on the arterial walls at progressive stages of enlargement of abdominal aortic aneurysms (AAA). The specific aims are twofold: first, to determine the magnitude of the "wall shear stresses" (WSS) and their spatial and temporal gradients at various stages of enlargement, and second, to identify the critical size at which the formation of regions of stasis and/or the transition to a turbulent state occur inside the AAA. A parametric in vitro study of the pulsatile blood flow was conducted in rigid models of AAA by systematically varying the hemodynamic conditions and the size of the aneurysm. The instantaneous flow characteristics inside the AAA models were measured along the cardiac cycle, using tomographic digital particle image velocimetry (TDPIV). The TDPIV measurements showed that even for the case of large dilatation ratios (internal diameter >4.5 mm), the flow inside the AAA remained fully attached to the walls during systole, but massively detached during diastole. A critical aneurysm aspect ratio (length-to-diameter ratio) was found, for which a transition to a turbulent state occurred. The formation of internal shear layers (internal jet) and slowly recirculating regions (stasis) generated large spatial gradients of WSS and regions of low and oscillating WSS. The formation of regions of flow stasis was observed even at very early stages in the aneurysm enlargement. These spatial and temporal variations in the hemodynamic forces, the formation of regions of stasis, and the transition to turbulence are postulated to play an important role in the etiology of the disease by activating endoluminar thrombus formation, lipid deposition, and certain inflammatory mechanisms.

Carotid arteries: contrast-enhanced US angiography--preliminary clinical experience.

B-mode ultrasonographic (US) angiography enhanced with a microbubble-based US contrast agent (FS069) was evaluated in human subjects with carotid artery disease. Results at contrast material-enhanced US angiography and duplex US were compared with those at conventional angiography. Both US angiography and duplex US accurately depicted stenoses of 70% or more compared with those depicted at conventional angiography. The percentage diameter stenosis of the internal carotid artery measured at US angiography strongly correlated with that measured at conventional angiography (r = 0.988). The percentage area stenosis measured at US angiography strongly correlated with ex vivo measurements of the resected carotid plaque at magnetic resonance imaging (r = 0.979). US angiography depicted unsuspected wall irregularities, ulceration, and dissection.

Regioselective synthesis of unsymmetrical C-aryl glycosides using silicon tethers as disposable linkers.

Silicon tethers were employed to control the regiochemistry of Diels-Alder reactions between substituted benzynes and glycosyl furans as a key step in the syntheses of unsymmetrical representatives of three major groups of C-aryl glycosides. The cycloaddition precursors were readily prepared by O-alkylation of substituted phenols with various sugar-substituted furylsilane derivatives. Selective deprotonation on the benzene ring of these ethers led to a benzyne that underwent an intramolecular Diels-Alder reaction to give bridged cycloadducts. Fluoride-induced removal of the silicon tether and acid-catalyzed ring opening of the oxabicycloheptadiene subunit yielded the desired C-aryl glycosides as single isomers.