Liquid Thyroxine Improves Outcomes in Hypothyroid Patients With Small Intestinal Bacterial Overgrowth and Irritable Bowel Syndrome.

OBJECTIVE: Malabsorption of levothyroxine (LT4) is often seen in patients with hypothyroidism and gastrointestinal (GI) conditions. Our study was designed to establish the prevalence of small intestinal bacterial overgrowth (SIBO) in patients with hypothyroidism and irritable bowel syndrome (IBS), and to demonstrate that liquid LT4 is more consistently absorbed vs tablet, leading to improvement in thyroid and GI symptoms. METHODS: This was a single-center, open label, prospective cohort study of liquid LT4 in 75 adult patients with hypothyroidism and IBS. Patients were transitioned from LT4 tablets to solution at equivalent dosing. Patients returned at 6 and 12 weeks for repeat thyroid levels and completion of validated questionnaires. A standard 2-hour SIBO breath test was administered at Week 6. Patients recorded daily stool appearance and frequency. RESULTS: Prevalence of SIBO was 65.3%. Liquid LT4 normalized thyroid stimulating hormone (TSH) in a higher percentage of patients vs tablet (77.55% vs 57.14%); significantly decreased TSH in subjects with SIBO; improved hypothyroid symptoms, IBS symptoms, stool appearance in all groups, and significantly altered bowel frequency among those with SIBO. CONCLUSION: Small intestinal bacterial overgrowth (SIBO) is common in patients with hypothyroidism and IBS. Among SIBO patients, LT4 tablets were inefficiently absorbed, leading to suboptimal thyroid control; however, transitioning from LT4 tablets to solution normalized TSH and improved hypothyroid symptoms. Liquid LT4 also significantly improved GI symptoms in all patients with hypothyroidism and IBS, regardless of SIBO status. Additionally, 1 in 5 patients had complete resolution of IBS symptoms after switching from LT4 tablets to solution, independent of changes in TSH.

Outcomes of Chronically Anticoagulated Patients Undergoing Split-Thickness Skin Grafting for Diabetic Foot Ulcers.

OBJECTIVE: Split-thickness skin grafting (STSG) is commonly used for wound closure in diabetic foot ulcers (DFUs). In many cases, patients with diabetes present on long-term anticoagulation therapy. The complications associated with anticoagulants can be discouraging to surgeons considering STSG. The goal of this study was to evaluate STSG outcomes in the setting of chronic anticoagulation across a large, multicenter database. METHODS: The authors queried the TriNetX Network, which provides access to electronic medical records for more than 75 million patients, to search for patients with a history of DFUs treated with STSG. They divided those found into two groups: long-term anticoagulant use prior to grafting and no long-term anticoagulant use. After matching, the researchers evaluated outcomes following STSG after 1 month and 5 years. RESULTS: The authors identified 722 patients on chronic anticoagulation with DFUs who were treated with STSG; 446 of these patients were matched to 446 patients with no prior anticoagulation. One month following STSG, the anticoagulated group showed no significant increase in death, graft failure, or regrafting. At 5 years, there was no significant increase in mortality, graft failure, regrafting, or lower extremity amputation rates. CONCLUSIONS: Chronic anticoagulation therapy does not lead to increased short- or long-term postoperative complications such as graft failure, regrafting, or increased amputation rates following STSG for wound closure. Negative outcomes following STSG for DFUs in chronically anticoagulated individuals are minimal, and grafting should be performed without hesitation.

Vismodegib for Preservation of Visual Function in Patients with Advanced Periocular Basal Cell Carcinoma: The VISORB Trial.

BACKGROUND: Basal cell carcinoma (BCC) is a common skin cancer often curable by excision; however, for patients with BCC around the eye, excision places visual organs and function at risk. In this article, we test the hypothesis that use of the hedgehog inhibitor vismodegib will improve vision-related outcomes in patients with orbital and extensive periocular BCC (opBCC). MATERIALS AND METHODS: In this open-label, nonrandomized phase IV trial, we enrolled patients with globe- and lacrimal drainage system-threatening opBCC. To assess visual function in the context of invasive periorbital and lacrimal disease, we used a novel Visual Assessment Weighted Score (VAWS) in addition to standard ophthalmic exams. Primary endpoint was VAWS with a score of 21/50 (or greater) considered successful, signifying globe preservation. Tumor response was evaluated using RECIST v1.1. Surgical specimens were examined histologically by dermatopathologists. RESULTS: In 34 patients with opBCC, mean VAWS was 44/50 at baseline, 46/50 at 3 months, and 47/50 at 12 months or postsurgery. In total, 100% of patients maintained successful VAWS outcome at study endpoint. Compared with baseline, 3% (95% confidence interval [CI], 0.1-15.3) experienced major score decline (5+ points), 14.7% (95% CI, 5 to 31.1) experienced a minor decline (2-4 points), and 79.4% experienced a stable or improved score (95% CI, 62.1-91.3). A total of 56% (19) of patients demonstrated complete tumor regression by physical examination, and 47% (16) had complete regression by MRI/CT. A total of 79.4% (27) of patients underwent surgery, of which 67% (18) had no histologic evidence of disease, 22% (6) had residual disease with clear margins, and 11% (3) had residual disease extending to margins. CONCLUSION: Vismodegib treatment, primary or neoadjuvant, preserves globe and visual function in patients with opBCC. Clinical trail identification number.NCT02436408. IMPLICATIONS FOR PRACTICE: Use of the antihedgehog inhibitor vismodegib resulted in preservation of end-organ function, specifically with regard to preservation of the eye and lacrimal apparatus when treating extensive periocular basal cell carcinoma. Vismodegib as a neoadjuvant also maximized clinical benefit while minimizing toxic side effects. This is the first prospective clinical trial to demonstrate efficacy of neoadjuvant antihedgehog therapy for locally advanced periocular basal cell carcinoma, and the first such trial to demonstrate end-organ preservation.

Giant tree frogs exemplify the promise of integrating multiple types of data in phylogeographic investigations.

Hugall et al. (2022) is one of the seminal publications from the single locus era of phylogeographic research. These authors were among the first to argue that genetic data are ideally suited to test hypotheses that are ultimately derived from other sources of information. While the testing of predictions from the fossil record has long been important to molecular systematics (e.g., Donoghue et al., 1989), phylogeographic investigations into the more recent evolutionary past lack a fossil record in most focal taxa. In lieu of fossils, which were not available for the small snails that served as the focal taxon, Hugall et al. (2002) applied the (then) new technique of environmental modelling to identify regions within the species range with habitat that was predicted to be stable throughout the Holocene. They then present data that suggests that these regions correspond to the areas with high genetic diversity. Apart from the inferences about snail evolutionary history, the core argument of Hugall et al. (2002) is that consilience (i.e., agreement between inferences drawn from different sources of data) is an important goal for phylogeographic investigation. Consilience in the inferences drawn from independent types of data has a multiplicative effect; when present the researcher is likely to have more confidence in their inference than would be possible to have in an inference from any one source of data. The manuscript by Jaynes et al. (2022) is a splendid illustration of this principle.

Low Yield of Clinically Significant Injury With Head-To-Pelvis Computed Tomography in Blunt Trauma Evaluation.

BACKGROUND: Many trauma centers have adopted routine head-to-pelvis computed tomography (CT) imaging for the evaluation of adults with blunt trauma. OBJECTIVE: We sought to determine the yields of detecting clinically significant injuries (CSIs) with CT in >1 anatomic region. METHODS: We conducted this observational cohort study of all trauma activation patients >14 years of age who received CT imaging during blunt trauma evaluation at a Level 1 trauma center from April to October 2014. Expert panels determined the clinical significance of head, neck, chest, abdomen, and pelvis injuries seen on CT. We calculated yields of CSI, defined as the number of patients with CSI divided by the total number of patients who underwent CT imaging. The 3 specified anatomic regions considered were head/neck, chest, and abdomen/pelvis. RESULTS: The median age of 1236 patients who had CT was 48 years; 69% were male; 51.2% were admitted; and hospital mortality was 4.4%. Yields of CSI with 95% confidence intervals (CIs) were: head/neck region injury 11.3% (9.6-13.3%); chest region injury only 7.9% (6.0-10.4%); abdomen/pelvis region injury only 5.1% (3.7-7.0%); both head/neck and chest CSI 2.8% (1.7-4.5%); both head/neck and abdomen/pelvis CSI 1.6% (0.9-2.9%); and both chest and abdomen/pelvis CSI 1.1% (0.5-2.4%). The yield of CSI in all 3 anatomic regions with head-to-pelvis CT was 0.6% (0.2-1.7%), and 76.7% (68.8-83.1%) of CSIs occurred in isolation. CONCLUSIONS: During multiple anatomic region CT imagng for adult blunt trauma evaluation, the yield for CSI in >1 region is low. In low-risk populations, selective CT imaging of anatomic regions (instead of reflexive head-to-pelvis CT imaging) may be more appropriate.

Effective Treatment of Methotrexate Induced Oral Mucositis With a Morphine Mouthwash Solution: A Case Report.

Introduction: Methotrexate (MTX) is a common medication used to treat rheumatoid arthritis (RA). MTX inhibits rapid cell turnover throughout the body which can lead to significant side effects. Patients who present with oral lesions may have suffered severe acute toxicity from MTX. Supportive pain treatment includes magic mouthwash solution and/or oral viscous lidocaine to manage pain and allow for healing. We report a case of MTX induced oral mucositis that did not respond to magic mouthwash but did improve with a morphine mouthwash solution. Case: A 67-year-old female with RA presented with worsening oral lesions over 2 weeks. She reported non-compliance with folic acid for 2 weeks while on MTX. Physical exam revealed ulcerating oral lesions on the mucous membranes consistent with mucositis. Pain treatment was initiated with magic mouthwash, but her pain was not well controlled after 24 hours, and still unable to swallow. An oral morphine mouthwash solution was initiated, and patient reported improved pain control over the next 48 hours. She was on the morphine mouthwash for 6 days during which improvement in the lesions was noted. Discussion: Pain management is imperative for oral mucositis. When traditional therapies do not provide adequate control, morphine mouthwash can be considered. It is a safer alternative to systemic opioids and topical opioids may influence cell proliferation and migration, which can positively impact healing of oral lesions. Conclusion: A morphine mouthwash solution can provide effective pain management for oral mucositis lesions in patients who do not respond adequately to magic mouthwash.

Patterns of antibiotic administration in patients with burn injuries: A TriNetX study.

BACKGROUND: In the advent of increasing antibiotic resistance, several studies sought to determine antibiotic prescription trends; however, no pattern has been firmly identified particularly for the burned population. We performed a query of burned patients in a large established database to understand differences in antibiotic use related to patient-specific factors. METHODS: Burned patients with systemic antibiotics given within 7 days of injury were identified on the TriNetX database. The patient population was stratified by age, 1-year time intervals of antibiotic prescription from 2004 to 2019, time of antibiotic prescription in 1-day intervals after injury, and % TBSA burned in 10% intervals ranging from < 10% to > 90%. Data were analyzed using χ2 with p < 0.05 considered significant. Pearson coefficients (r2) values were used to correlate differences in antibiotic prescription between age groups and to changes over time. RESULTS: Stratification by age revealed higher use of antibiotics in older burned patients compared to younger patients. Surprisingly, 87.6% of burn patients of those who received antibiotic therapy was on the day of injury. Penicillins and beta-lactam antimicrobials were used most often at a frequency of 64%. No statistically significant differences in rates of antibiotic therapy were observed in burned patients when stratified by %TBSA burned. CONCLUSIONS: The study elucidates current patterns of antibiotic use in burn care in the United States, allowing for improved understanding of both past and present patterns of antibiotic prescription.

zA map for sequence analysis of the Arabidopsis thaliana genome.

Arabidopsis thaliana has emerged as a model system for studies of plant genetics and development, and its genome has been targeted for sequencing by an international consortium (the Arabidopsis Genome Initiative; http://genome-www. stanford.edu/Arabidopsis/agi.html). To support the genome-sequencing effort, we fingerprinted more than 20,000 BACs (ref. 2) from two high-quality publicly available libraries, generating an estimated 17-fold redundant coverage of the genome, and used the fingerprints to nucleate assembly of the data by computer. Subsequent manual revision of the assemblies resulted in the incorporation of 19,661 fingerprinted BACs into 169 ordered sets of overlapping clones ('contigs'), each containing at least 3 clones. These contigs are ideal for parallel selection of BACs for large-scale sequencing and have supported the generation of more than 5.8 Mb of finished genome sequence submitted to GenBank; analysis of the sequence has confirmed the integrity of contigs constructed using this fingerprint data. Placement of contigs onto chromosomes can now be performed, and is being pursued by groups involved in both sequencing and positional cloning studies. To our knowledge, these data provide the first example of whole-genome random BAC fingerprint analysis of a eucaryote, and have provided a model essential to efforts aimed at generating similar databases of fingerprint contigs to support sequencing of other complex genomes, including that of human.

Copper(I)-catalyzed cycloaddition of bismuth(III) acetylides with organic azides: synthesis of stable triazole anion equivalents.

Fully loaded: Readily accessible and shelf-stable 1-bismuth(III) acetylides react rapidly and regiospecifically with organic azides in the presence of a copper(I) catalyst. The reaction tolerates many functional groups and gives excellent yields of the previously unreported 5-bismuth triazolides. This uniquely reactive intermediate is functionalized under mild reaction conditions to give fully substituted 1,2,3-triazoles.

Case Report: Possible Serotonin Syndrome in a Patient Taking Kratom and Multiple Serotonergic Agents.

INTRODUCTION: Kratom, an unregulated herbal supplement, has emerged as self-treatment for anxiety/depression. Kratom exhibits inhibition at multiple cytochrome P450 isozymes involved in metabolism of prescription medications, including serotonergic agents. We report a case of possible serotonin syndrome induced by kratom use in combination with prescription psychotropic medications. CASE: A 63-year-old male presented with diaphoresis, flushing, aphasia, confusion, dysarthria, right facial droop, and oral temperature of 39.6oC (103.2oF), lactate 2.7 mmol/L, and creatine phosphokinase of 1507 IU/L. Initial differential diagnoses included acute ischemic stroke and bacterial meningitis. Despite partial treatment with alteplase and broad-spectrum antibiotics, symptoms persisted, and subsequent physical exam noted hyperreflexia, clonus, tremors, and temperature of 41.1oC (106oF). Home medications included a chronic regimen for anxiety/depression with bupropion, buspirone, desvenlafaxine, trazodone, and ziprasidone, in addition to kratom. Clinical suspicion for serotonin syndrome led to initiation of cyproheptadine, lorazepam, and cooling blankets. Aphasia, facial droop, and confusion improved after administration of cyproheptadine. Bupropion was restarted during hospitalization; remaining medications restarted at the discretion of the primary care provider. DISCUSSION: Risk of serotonin syndrome with multiple serotonergic agents is well-known. Kratom is metabolized by cytochrome P40 isozymes 3A4, 2C9, and 2D6, and exhibits inhibition at those enzymes, in addition to 1A2. Pharmacokinetic interactions of kratom with prescription serotonergic agents metabolized through these isozymes has the potential to increase systemic exposure of serotonin, potentially leading to serotonin syndrome. CONCLUSION: Because substances contained in kratom can inhibit metabolism of prescription serotonergic medications, clinicians must be aware of potential development of serotonin syndrome.

Increased Nerve Density Adversely Affects Outcome in Oral Cancer.

PURPOSE: Perineural invasion (PNI) in oral cavity squamous cell carcinoma (OSCC) is associated with poor survival. Because of the risk of recurrence, patients with PNI receive additional therapies after surgical resection. Mechanistic studies have shown that nerves in the tumor microenvironment promote aggressive tumor growth. Therefore, in this study, we evaluated whether nerve density (ND) influences tumor growth and patient survival. Moreover, we assessed the reliability of artificial intelligence (AI) in evaluating ND. EXPERIMENTAL DESIGN: To investigate whether increased ND in OSCC influences patient outcome, we performed survival analyses. Tissue sections of OSCC from 142 patients were stained with hematoxylin and eosin and IHC stains to detect nerves and tumor. ND within the tumor bulk and in the adjacent 2 mm was quantified; normalized ND (NND; bulk ND/adjacent ND) was calculated. The impact of ND on tumor growth was evaluated in chick chorioallantoic-dorsal root ganglia (CAM-DRG) and murine surgical denervation models. Cancer cells were grafted and tumor size quantified. Automated nerve detection, applying the Halo AI platform, was compared with manual assessment. RESULTS: Disease-specific survival decreased with higher intratumoral ND and NND in tongue SCC. Moreover, NND was associated with worst pattern-of-invasion and PNI. Increasing the number of DRG, in the CAM-DRG model, increased tumor size. Reduction of ND by denervation in a murine model decreased tumor growth. Automated and manual detection of nerves showed high concordance, with an F1 score of 0.977. CONCLUSIONS: High ND enhances tumor growth, and NND is an important prognostic factor that could influence treatment selection for aggressive OSCC. See related commentary by Hondermarck and Jiang, p. 2342.

Analysis of residual disease in periocular basal cell carcinoma following hedgehog pathway inhibition: Follow up to the VISORB trial.

Basal cell carcinoma (BCC) is a common skin cancer caused by deregulated hedgehog signaling. BCC is often curable surgically; however, for orbital and periocular BCCs (opBCC), surgical excision may put visual function at risk. Our recent clinical trial highlighted the utility of vismodegib for preserving visual organs in opBCC patients: 67% of patients displayed a complete response histologically. However, further analysis of excision samples uncovered keratin positive, hedgehog active (Gli1 positive), proliferative micro-tumors. Sequencing of pre-treatment tumors revealed resistance conferring mutations present at low frequency. In addition, one patient with a low-frequency SMO W535L mutation recurred two years post study despite no clinical evidence of residual disease. Sequencing of this recurrent tumor revealed an enrichment for the SMO W535L mutation, revealing that vismodegib treatment enriched for resistant cells undetectable by traditional histology. In the age of targeted therapies, linking molecular genetic analysis to prospective clinical trials may be necessary to provide mechanistic understanding of clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02436408.

Evaluation of student-perceived growth in entrustable professional activities after involvement in a transitions-of-care process within an adult medicine advanced pharmacy practice experience.

BACKGROUND AND PURPOSE: Involvement of pharmacists and trainees in care transitions reduces medication-related problems. Participation in the transitions-of-care (TOC) process may impact self-perceived growth of autonomy within selected entrustable professional activities (EPAs). EDUCATIONAL ACTIVITY AND SETTING: A student-driven TOC documentation process was implemented within an inpatient family medicine advanced pharmacy practice experience. During the month-long rotation, students rounded with an interdisciplinary care team. Responsibilities included ensuring accurate medication reconciliation at care transitions throughout hospitalization and prior to discharge as well as medication optimization during hospitalization. Another responsibility was completing a medication-specific TOC note in the clinic-based electronic health record at discharge for patients receiving primary care from the associated clinic. The note was available to the outpatient interdisciplinary care team during the hospital follow-up appointment. Student-perceived growth in autonomy within selected EPAs was determined through an online anonymous survey. FINDINGS: Ninety percent (n = 18) of eligible students completed the survey. For specific EPA statements (collecting information, establishing patient-centered goals and establishing a care plan, implementing a care plan, collaborating as an interdisciplinary team member, and ensuring immunization), student-perceived autonomy increased after involvement in this student-driven TOC process. During the study period, 215 notes were generated by student pharmacists and included interventions/recommendations within the following themes: evidence-based changes in therapy, patient counseling, and medication access. SUMMARY: The importance of pharmacist and pharmacy trainee involvement in the TOC process has been well-documented. Involving students in student-driven TOC documentation processes serves to facilitate student-perceived growth in autonomy within selected EPAs.

Student Performance on Graded Versus Ungraded Readiness Assurance Tests in a Team-Based Learning Elective.

Objective. Team-based learning is widely used in pharmacy education. In this context, students need to be incentivized to do preclass preparation, thus ensuring they are ready for team-based learning, via graded readiness assurance tests (RATs). The purpose of this study was to determine the effect of graded versus ungraded RATs on examination performance in an ambulatory care elective course for third-year student pharmacists.Methods. For the course offered in spring 2020 and 2021, a standard team-based learning framework was employed. In 2020 the RATs were graded and contributed to the overall course grade (graded RAT cohort), but in 2021 RAT grades did not contribute to the course grade (ungraded RAT cohort). For the ungraded RAT cohort, at the end of the course students completed an online anonymous survey regarding class preparation and perceived team accountability.Results. No significant difference was found between the graded RAT (n=47) and ungraded RAT cohorts (n=36) in the overall mean percentage score on individual RATs (76% vs 74%) and individual examinations (82% vs 80%). Most students (69%-91%) in the ungraded RAT cohort reported completing preclass preparation assignments. In the postcourse survey, 94% of students agreed or strongly agreed that RATs contributed to team members' learning, and 86% agreed or strongly agreed that they were proud of their ability to assist in the team's learning.Conclusion. Ungraded RATs did not significantly impact students' examination performance in an elective course. Removing the grading of this test, whereby grading promotes the performance approach to learning, may have shifted the students' motivation to the mastery approach in the context of preclass preparation. This challenges a widely held belief that grades are necessary incentives for preclass preparation within team-based learning.

Synthesis and biological evaluation of 2',4'- and 3',4'-bridged nucleoside analogues.

Most nucleosides in solution typically exist in equilibrium between two major sugar pucker forms, N-type and S-type, but bridged nucleosides can be locked into one of these conformations depending on their specific structure. While many groups have researched these bridged nucleosides for the purpose of determining their binding affinity for antisense applications, we opted to look into the potential for biological activity within these conformationally-locked structures. A small library of 2',4'- and 3',4'-bridged nucleoside analogues was synthesized, including a novel 3',4'-carbocyclic bridged system. The synthesized compounds were tested for antibacterial, antitumor, and antiviral activities, leading to the identification of nucleosides possessing such biological activities. To the best of our knowledge, these biologically active compounds represent the first example of 2',4'-bridged nucleosides to demonstrate such properties. The most potent compound, nucleoside 33, exhibited significant antiviral activity against pseudoviruses SF162 (IC(50)=7.0 µM) and HxB2 (IC(50)=2.4 µM). These findings render bridged nucleosides as credible leads for drug discovery in the anti-HIV area of research.

Preoperative mental health status is a significant predictor of postoperative outcomes in adolescents treated with hip preservation surgery.

PURPOSE: This study was designed to evaluate predictive factors that influence pain, mental health symptoms and postoperative outcomes at six-months post-hip preservation surgery (HPS) in adolescent surgical candidates. METHODS: In total, 58 HPS candidates (39 female, 19 male; mean age 15.53 years (10 to 19)) were evaluated. Diagnoses included: acetabular dysplasia (34); idiopathic femoroacetabular impingement (15); Perthes disease (six); avascular necrosis (six); and slipped capital femoral epiphysis (six). All patients underwent periacetabular osteotomy (36), surgical hip dislocation (17) or arthroscopy (five). Patients completed the following: Numerical Pain Rating Scale (NPRS); Child Health Questionnaire-87 (CHQ-87); Pediatric Symptom Checklist-Youth (PSC-Y), preoperatively and six months postoperatively. A single psychologist assessed patients in clinics and one to two additional appointments. RESULTS: In all, 78% of patients reported one to three years of pain prior to HPS (modified Harris hip score). All pain scores (NPRS) significantly decreased at six months postoperatively. Preoperative mental health scores (CHQ-87) significantly predicted postoperative pain scores (F(1, 57) = 4.07; p < 0.048; R2 = 0.068). Mental health symptoms (PSC-Y) decreased significantly (p < 0.001). Patients who were seen by a psychologist two or more times reported better six-month postoperative outcomes than those seen once: usual pain (NPRS; p = 0.012); patient-reported physical function (CHQ-87; p = 0.029); and mental health (PSC-Y; p = 0.019). HPS patients seen ≥ 60 days prior to surgery showed marked improvements at six months compared with patients seen < 60 days prior to surgery. CONCLUSION: HPS candidates evaluated preoperatively by psychology, as part of an integrated treatment approach, demonstrated statistically significant improvements in pain, health-related quality of life and mental health symptoms. Two+ visits, more than 60 days prior to surgery appears to be impactful. Preoperative pain and mental health symptoms were predictive of postoperative pain.Level of Evidence: II.

Retinoic Acid Potentiates Orbital Tissues for Inflammation Through NF-κB and MCP-1.

Purpose: The orbit displays unique vulnerability to inflammatory conditions. The most prevalent of these conditions, thyroid eye disease (TED), occurs in up to 50% of patients with Graves' disease (GD). Whereas the pathology of both TED and GD is driven by autoantibodies, it is unclear why symptoms manifest specifically in the orbit. Methods: We performed retinoic acid treatment on both normal and TED patient-derived orbital fibroblasts (OFs) followed by mRNA and protein isolation, quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay, RNA sequencing, and Western blot analyses. Results: Both normal and TED patient-derived OFs display robust induction of monocyte chemoattractant protein 1 (MCP-1) upon retinoid treatment; TED OFs secrete significantly more MCP-1 than normal OFs. In addition, pretreatment of OFs with thiophenecarboxamide (TPCA-1) inhibits retinoid-induced MCP-1 induction, suggesting an NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)-dependent mechanism. We also found that treatment with cholecalciferol (vitamin D3) mitigates MCP-1 induction, likely because of competition between retinoic acid receptors (RARs) and vitamin D receptors (VDR) for their common binding partner retinoid nuclear receptors (RXRs). Conclusions: Retinoids that naturally accumulate in orbital adipose tissue can act on orbital fibroblasts to induce the expression of inflammation-associated genes. These data suggest a potential role for retinoids in sensitizing the orbit to inflammation.

Twist3 is required for dedifferentiation during extraocular muscle regeneration in adult zebrafish.

Severely damaged adult zebrafish extraocular muscles (EOMs) regenerate through dedifferentiation of residual myocytes involving a muscle-to-mesenchyme transition. Members of the Twist family of basic helix-loop-helix transcription factors (TFs) are key regulators of the epithelial-mesenchymal transition (EMT) and are also involved in craniofacial development in humans and animal models. During zebrafish embryogenesis, twist family members (twist1a, twist1b, twist2, and twist3) function to regulate craniofacial skeletal development. Because of their roles as master regulators of stem cell biology, we hypothesized that twist TFs regulate adult EOM repair and regeneration. In this study, utilizing an adult zebrafish EOM regeneration model, we demonstrate that inhibiting twist3 function using translation-blocking morpholino oligonucleotides (MOs) impairs muscle regeneration by reducing myocyte dedifferentiation and proliferation in the regenerating muscle. This supports our hypothesis that twist TFs are involved in the early steps of dedifferentiation and highlights the importance of twist3 during EOM regeneration.

Total synthesis of platensimycin and related natural products.

Platensimycin is the flagship member of a new and growing class of antibiotics with promising antibacterial properties against drug-resistant bacteria. The total syntheses of platensimycin and its congeners, platensimycins B(1) and B(3), platensic acid, methyl platensinoate, platensimide A, homoplatensimide A, and homoplatensimide A methyl ester, are described. The convergent strategy developed toward these target molecules involved construction of their cage-like core followed by attachment of the various side chains through amide bond formation. In addition to a racemic synthesis, two asymmetric routes to the core structure are described: one exploiting a rhodium-catalyzed asymmetric cycloisomerization, and another employing a hypervalent iodine-mediated de-aromatizing cyclization of an enantiopure substrate. The final two bonds of the core structure were forged through a samarium diiodide-mediated ketyl radical cyclization and an acid-catalyzed etherification. The rhodium-catalyzed asymmetric reaction involving a terminal acetylene was developed as a general method for the asymmetric cycloisomerization of terminal enynes.

Samarium diiodide mediated reactions in total synthesis.

Introduced by Henri Kagan more than three decades ago, samarium diiodide (SmI(2)) has found increasing application in chemical synthesis. This single-electron reducing agent has been particularly useful in C-C bond formations, including those found in total synthesis endeavors. This Review highlights selected applications of SmI(2) in total synthesis, with special emphasis on novel transformations and mechanistic considerations. The examples discussed are both illustrative of the power of this reagent in the construction of complex molecules and inspirational for the design of synthetic strategies toward such targets, both natural and designed.