The backbone constitution drives passive permeability independent of side chains in depsipeptide and peptide macrocycles inspired by ent-verticilide.

The number of peptide-like scaffolds found in late-stage drug development is increasing, but a critical unanswered question in the field is whether substituents (side chains) or the backbone drive passive permeability. The backbone is scrutinized in this study. Five series of macrocyclic peptidic compounds were prepared, and their passive permeability was determined (PAMPA, Caco-2), to delineate structure-permeability relationships. Each series was based on the cell-permeable antiarrhythmic compound ent-verticilide, a cyclic oligomeric depsipeptide (COD) containing repeating ester/N-Me amide didepsipeptide monomers. One key finding is that native lipophilic ester functionality can impart a favorable level of permeability, but ester content alone is not the final determinant - the analog with highest P app was discovered by a single ester-to-N-H amide replacement. Furthermore, the relative composition of esters and N-Me amides in a series had more nuanced permeability behavior. Overall, a systematic approach to structure-permeability correlations suggests that a combinatorial-like investigation of functionality in peptidic or peptide-like compounds could better identify leads with optimal passive permeability, perhaps prior to modification of side chains.

The Association between "Knee Movement" Method and Traditional Radiograph Positioning Procedure with the Incidence of True Lateral Knee Radiograph Achieved.

Introduction: This study aimed to find the association between the Knee Movement or KM method versus the traditional lateral knee radiograph positioning procedure and the incidence of true lateral knee radiographs achieved. Materials and methods: A cross-sectional study of patients with knee problems that underwent lateral knee radiograph using the knee movement method (KM method), starting from March 2022 until August 2022. Fifty knee radiograph results using the KM method (KM group) were compared to retrospective data from fifty knee radiograph from the patients before March 2022 using the traditional method of lateral knee radiograph as the control (TM group). The data were analysed using the Chi-Square test to see if the KM method is associated with more true lateral knee radiograph results achieved compared to the traditional procedure. Results: Fifty patients in the KM method group had 80% (n=40) true lateral knee radiographs and 20% (n=10) untrue lateral knee radiographs, while in the Traditional Procedure group from the retrospective data of 50 patients had 44% (n=22) true lateral knee radiographs and 56% (n=28) untrue lateral knee radiographs (P<0.05). There is no significant association between the type of procedure applied with the types of error (P=0.432). Nevertheless, it helps us as it gives a gross picture that most of the errors are under-rotation of the knee, either from the KM method Group 90% (n=9) or the Traditional procedure Group 79% (n=22). Conclusion: The KM method was associated with achievement of a more true and accurate lateral knee radiograph. Additional studies with a larger sample should be done to evaluate the reliability of this method.

ent-Verticilide B1 Inhibits Type 2 Ryanodine Receptor Channels and is Antiarrhythmic in Casq2 -/- Mice.

Intracellular Ca2+ leak from cardiac ryanodine receptor (RyR2) is an established mechanism of sudden cardiac death (SCD), whereby dysregulated Ca2+ handling causes ventricular arrhythmias. We previously discovered the RyR2-selective inhibitor ent-(+)-verticilide (ent-1), a 24-membered cyclooligomeric depsipeptide that is the enantiomeric form of a natural product (nat-(-)-verticilide). Here, we examined its 18-membered ring-size oligomer (ent-verticilide B1; "ent-B1") in RyR2 single channel and [3H]ryanodine binding assays, and in Casq2 -/- cardiomyocytes and mice, a gene-targeted model of SCD. ent-B1 inhibited RyR2 single channels and RyR2-mediated spontaneous Ca2+ release in Casq2 -/- cardiomyocytes with sub-micromolar potency. ent-B1 was a partial RyR2 inhibitor, with maximal inhibitory efficacy of less than 50%. ent-B1 was stable in plasma, with a peak plasma concentration of 1460 ng/ml at 10 minutes and half-life of 45 minutes after intraperitoneal administration of 3 mg/kg in mice. In vivo, ent-B1 significantly reduced catecholamine-induced ventricular arrhythmias in Casq2 -/- mice in a dose-dependent manner. Hence, we have identified a novel chemical entity - ent-B1 - that preserves the mechanism of action of a hit compound and shows therapeutic efficacy. These findings strengthen RyR2 as an antiarrhythmic drug target and highlight the potential of investigating the mirror-image isomers of natural products to discover new therapeutics. SIGNIFICANCE STATEMENT: The cardiac ryanodine receptor (RyR2) is an untapped target in the stagnant field of antiarrhythmic drug development. We have confirmed RyR2 as an antiarrhythmic target in a mouse model of sudden cardiac death and shown the therapeutic efficacy of a second enantiomeric natural product.

ent -Verticilide B1 inhibits type 2 ryanodine receptor channels and is antiarrhythmic in Casq2-/- mice.

Ca 2+ leak from cardiac ryanodine receptor (RyR2) is an established mechanism of sudden cardiac death (SCD), whereby dysregulated Ca 2+ handling causes ventricular arrhythmias. We previously discovered the RyR2-selective inhibitor ent- (+)-verticilide ( ent -1), a 24-membered cyclooligomeric depsipeptide that is the enantiomeric form of a natural product ( nat -(-)-verticilide). Here, we examined its 18-membered ring-size oligomer ( ent -verticilide B1; " ent -B1") in single RyR2 channel assays, [ 3 H]ryanodine binding assays, and in Casq2 -/- cardiomyocytes and mice, a gene-targeted model of SCD. ent -B1 inhibited RyR2 single-channels and [ 3 H]ryanodine binding with low micromolar potency, and RyR2-mediated spontaneous Ca 2+ release in Casq2-/- cardiomyocytes with sub-micromolar potency. ent -B1 was a partial RyR2 inhibitor, with maximal inhibitory efficacy of less than 50%. ent -B1 was stable in plasma, with a peak plasma concentration of 1460 ng/ml at 10 min and half-life of 45 min after intraperitoneal administration of 3 mg/kg in mice. Both 3 mg/kg and 30 mg/kg ent -B1 significantly reduced catecholamine-induced ventricular arrhythmia in Casq2-/- mice. Hence, we have identified a novel chemical entity - ent -B1 - that preserves the mechanism of action of a hit compound and shows therapeutic efficacy. These findings strengthen RyR2 as an antiarrhythmic drug target and highlight the potential of investigating the mirror-image isomers of natural products to discover new therapeutics. Significance statement: The cardiac ryanodine receptor (RyR2) is an untapped target in the stagnant field of antiarrhythmic drug development. We have confirmed RyR2 as an antiarrhythmic target in a mouse model of sudden cardiac death and shown the therapeutic efficacy of a second enantiomeric natural product.

In Vivo Pharmacokinetic and Pharmacodynamic Properties of the Antiarrhythmic Molecule ent-Verticilide.

The unnatural verticilide enantiomer (ent-verticilide) is a selective and potent inhibitor of cardiac ryanodine receptor (RyR2) calcium release channels and exhibits antiarrhythmic activity in a murine model of catecholaminergic polymorphic ventricular tachycardia (CPVT). To determine verticilide's pharmacokinetic and pharmacodynamic properties in vivo, we developed a bioassay to measure nat- and ent-verticilide in murine plasma and correlated plasma concentrations with antiarrhythmic efficacy in a mouse model of CPVT. nat-Verticilide rapidly degraded in plasma in vitro, showing >95% degradation within 5 minutes, whereas ent-verticilide showed <1% degradation over 6 hours. Plasma was collected from mice following intraperitoneal administration of ent-verticilide at two doses (3 mg/kg, 30 mg/kg). Peak C max and area under the plasma-concentration time curve (AUC) scaled proportionally to dose, and the half-life was 6.9 hours for the 3-mg/kg dose and 6.4 hours for the 30-mg/kg dose. Antiarrhythmic efficacy was examined using a catecholamine challenge protocol at time points ranging from 5 to 1440 minutes after intraperitoneal dosing. ent-Verticilide inhibited ventricular arrhythmias as early as 7 minutes after administration in a concentration-dependent manner, with an estimated potency (IC50) of 266 ng/ml (312 nM) and an estimated maximum inhibitory effect of 93.5%. Unlike the US Food and Drug Administration-approved pan-RyR blocker dantrolene, the RyR2-selective blocker ent-verticilide (30 mg/kg) did not reduce skeletal muscle strength in vivo. We conclude that ent-verticilide has favorable pharmacokinetic properties and reduces ventricular arrhythmias with an estimated potency in the nanomolar range, warranting further drug development. SIGNIFICANCE STATEMENT: ent-Verticilide has therapeutic potential to treat cardiac arrhythmias, but little is known about its pharmacological profile in vivo. The primary purpose of this study is to determine the systemic exposure and pharmacokinetics of ent-verticilide in mice and estimate its efficacy and potency in vivo. The current work suggests ent-verticilide has favorable pharmacokinetic properties and reduces ventricular arrhythmias with an estimated potency in the nanomolar range, warranting further drug development.

A Mechanistic Clinical Trial Using (R)- Versus (S)-Propafenone to Test RyR2 (Ryanodine Receptor) Inhibition for the Prevention of Atrial Fibrillation Induction.

BACKGROUND: Experimental data suggest ryanodine receptor-mediated intracellular calcium leak is a mechanism for atrial fibrillation (AF), but evidence in humans is still needed. Propafenone is composed of two enantiomers that are equally potent sodium-channel blockers; however, (R)-propafenone is an ryanodine receptor inhibitor whereas (S)-propafenone is not. This study tested the hypothesis that ryanodine receptor inhibition with (R)-propafenone prevents induction of AF compared to (S)-propafenone or placebo in patients referred for AF ablation. METHODS: Participants were randomized 4:4:1 to a one-time intravenous dose of (R)-propafenone, (S)-propafenone, or placebo. The study drug was given at the start of the procedure and an AF induction protocol using rapid atrial pacing was performed before ablation. The primary endpoint was 30 s of AF or atrial flutter. RESULTS: A total of 193 participants were enrolled and 165 (85%) completed the study protocol (median age: 63 years, 58% male, 95% paroxysmal AF). Sustained AF and/or atrial flutter was induced in 60 participants (84.5%) receiving (R)-propafenone, 60 (80.0%) receiving (S)-propafenone group, and 12 (63.2%) receiving placebo. Atrial flutter occurred significantly more often in the (R)-propafenone (N=23, 32.4%) and (S)-propafenone (N=26, 34.7%) groups compared to placebo (N=1, 5.3%, P=0.029). There was no significant difference between (R)-propafenone and (S)-propafenone for the primary outcome of AF and/or atrial flutter induction in univariable (P=0.522) or multivariable analysis (P=0.199, adjusted for age and serum drug level). CONCLUSIONS: There is no difference in AF inducibility between (R)-propafenone and (S)-propafenone at clinically relevant concentrations. These results are confounded by a high rate of inducible atrial flutter due to sodium-channel blockade. REGISTRATION: https://clinicaltrials.gov; Unique Identifier: NCT02710669.

Prospective Observational Study of Clinical Outcomes After Intravenous Magnesium for Moderate and Severe Acute Asthma Exacerbations in Children.

BACKGROUND: There is limited knowledge regarding whether intravenous magnesium (IV-Mg) improves outcomes in children with acute asthma exacerbations. OBJECTIVE: To examine whether IV-Mg improves outcomes in children with moderate and severe exacerbations. METHODS: We performed a secondary analysis using data from a prospective observational cohort of children aged 5 to 17 years with moderate and severe exacerbations. Standardized treatment included systemic corticosteroid and inhaled albuterol, with consideration of IV-Mg (75 mg/kg) for patients with insufficient response after 20 minutes. Propensity score (PS) models were used to examine associations of IV-Mg treatment with change in the validated Acute Asthma Intensity Research Score, hospitalization rate, and time to spacing of inhaled albuterol of 4 hours or more among hospitalized participants. RESULTS: Among 301 children, median (interquartile range) age was 8.1 (6.4-10.2) years, 170 were Black (57%), 201 were male (67%), and 84 received IV-Mg (28%). In a PS covariate-adjusted multivariable linear regression model, IV-Mg treatment was associated with a 2-hour increase in the Acute Asthma Intensity Research Score (ß-coefficient = 0.98; 95% confidence interval [CI], 0.20-1.77), indicating increased exacerbation severity. Three additional PS-based models yielded similar results. Participants receiving IV-Mg had 5.8-fold (95% CI, 2.8-11.9) and 6.8-fold (95% CI, 3.6-12.9) greater odds of hospitalization in PS-based multivariable regression models. Among hospitalized participants, there was no difference in time to albuterol of every 4 hours or more in a PS covariate-adjusted Cox proportional hazards model (hazard ratio = 1.2; 95% CI, 0.8-1.8). CONCLUSIONS: Among children with moderate and severe exacerbations, IV-Mg is associated with increased exacerbation severity, increased risk for hospitalization, and no acceleration in exacerbation resolution among hospitalized participants.

Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CLpro).

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.

2-Hydroxybenzylamine (2-HOBA) to prevent early recurrence of atrial fibrillation after catheter ablation: protocol for a randomized controlled trial including detection of AF using a wearable device.

BACKGROUND: Although catheter ablation is an effective therapy for atrial fibrillation (AF), the most common cardiac arrhythmia encountered in clinical practice, AF ablation generates inflammation and oxidative stress in the early postoperative period predisposing to recurrence of AF. Isolevuglandins (IsoLGs) are reactive lipid mediators of oxidative stress injury that rapidly react with endogenous biomolecules to compromise their function. 2-Hydroxybenzylamine (2-HOBA), a potent small molecule scavenger of IsoLGs, sequesters the reactive species as inert adducts. This mechanism, coupled with reported safety in humans, supports the investigation of 2-HOBA as a novel therapeutic to reduce AF caused by oxidative stress, such as that which occurs after catheter ablation. Accordingly, we seek to test the hypothesis that treatment with 2-HOBA will decrease early recurrence of AF and other atrial arrhythmias following AF ablation by decreasing IsoLG adducts with native biomolecules. METHODS: The proposed trial will randomly assign 162 participants undergoing cryo- or radiofrequency catheter ablation for AF to 2-HOBA (N = 81) or placebo (N = 81). Individuals will begin the study drug 3 days prior to ablation and continue for 28 days. Participants will be given a wearable smartwatch capable of detecting and recording atrial arrhythmias. They will be instructed to record ECGs daily with additional ECGs if they experience symptoms of AF or when alerted by the smartwatch AF detection alarm. The primary clinical endpoint will be an episode of AF, atrial tachycardia, or atrial flutter lasting 30 s or more within 28 days post-AF ablation. Secondary measures will be the change in IsoLG adduct levels from blood samples collected immediately pre-ablation and post-ablation and reduction in AF burden as calculated from the smartwatch. DISCUSSION: The proposed trial will test the hypothesis that 2-HOBA reduces post-ablation atrial arrhythmias through sequestration of reactive IsoLG species. The results of this study may improve the understanding of the role of IsoLGs and oxidative stress in AF pathogenesis and provide evidence to advance 2-HOBA and related compounds as a new therapeutic strategy to treat AF. TRIAL REGISTRATION: ClinicalTrials.gov NCT04433091 . Registered on June 3, 2020.

Pilot Study of Peak Plasma Concentration After High-Dose Oral Montelukast in Children With Acute Asthma Exacerbations.

Acute asthma exacerbations are primarily due to airway inflammation and remain one of the most frequent reasons for childhood hospitalizations. Although systemic corticosteroids remain the mainstay of therapy because of their anti-inflammatory properties, not all inflammatory pathways are responsive to systemic corticosteroids, necessitating hospital admission for further management. Cysteinyl leukotrienes (LTs) are proinflammatory mediators that play an important role in systemic corticosteroids non-responsiveness. Montelukast is a potent LT-receptor antagonist, and an intravenous preparation caused rapid, sustained improvement of acute asthma exacerbations in adults. We hypothesized that a 30-mg dose of oral montelukast achieves peak plasma concentrations (Cmax ), comparable to the intravenous preparation (1700 ng/mL) and would be well tolerated in 15 children aged 5 to 12 years with acute asthma exacerbations. After administration of montelukast chewable tablets, blood samples were collected at 0, 15, 30, 45, 60, 120, 180, and 240 minutes. Plasma was separated and frozen at -80°C until analysis for montelukast concentration using liquid chromatography- tandem mass spectrometry. Median time to Cmax (tmax ) was 3.0 hours. Six participants (40%) achieved Cmax of 1700 ng/mL or higher. However, there was high interindividual variability in peak plasma concentration (median Cmax of 1378 ng/mL; range, 16-4895 ng/mL). No participant had side effects or adverse events. Plasma concentrations from this pilot study support the design of a weight-based dose-finding study aimed at selecting an optimal dose for future clinical trials to assess the efficacy of high-dose oral montelukast in children with moderate to severe asthma exacerbations.

Safety, tolerability, and pharmacokinetics of repeated oral doses of 2-hydroxybenzylamine acetate in healthy volunteers: a double-blind, randomized, placebo-controlled clinical trial.

BACKGROUND: 2-Hydroxybenzylamine (2-HOBA) is a selective dicarbonyl electrophile scavenger being developed as a nutritional supplement to help protect against the development of conditions associated with dicarbonyl electrophile formation, such as the cognitive decline observed with Mild Cognitive Impairment or Alzheimer's disease. METHODS: This study evaluated the safety, tolerability, and pharmacokinetics of repeated oral doses of 2-HOBA acetate (500 or 750 mg) administered to healthy volunteers every eight hours for two weeks. The effects of 2-HOBA on cyclooxygenase function and cerebrospinal fluid penetrance of 2-HOBA were also investigated. RESULTS: Repeated oral administration of 2-HOBA was found to be safe and well-tolerated up to 750 mg TID for 15 days. 2-HOBA was absorbed within 2 h of administration, had a half-life of 2.10-3.27 h, and an accumulation ratio of 1.38-1.52. 2-HOBA did not interfere with cyclooxygenase function and was found to be present in cerebrospinal fluid 90 min after dosing. CONCLUSIONS: Repeated oral administration of 2-HOBA was found to be safe and well-tolerated. These results support continued development of 2-HOBA as a nutritional supplement. TRIAL REGISTRATION: Studies are registered at ClinicalTrials.gov (NCT03555682 Registered 13 June 2018, NCT03554096 Registered 12 June 18).

4-Hydroxy-pyran-2-one and 3-hydroxy-N-methyl-2-oxindole derivatives of Salinispora arenicola from Brazilian marine sediments.

Three new 3-hydroxy-N-methyl-2-oxindole (1 and 2) and 4-hydroxy-pyran-2-one (3) derivatives, along with the known 3-hydroxy-N-methyl-2-oxindole (4) and 6-methoxy-N-methylisatin (5) were isolated from a marine Salinispora arenicola strain from sediments of the St. Peter and St. Paul Archipelago, Brazil. The structures of the new compounds were elucidated by a combination of spectroscopic (1D and 2D NMR and HR-ESIMS) data, including single-crystal X-ray diffraction analysis for 2 and 3. Compounds 1 to 5 were assayed for their antimicrobial properties, but only 4 and 5 were active against Enterococcus faecalis with MIC value of 15.6 µg/mL.

Antibacterial Salinaphthoquinones from a Strain of the Bacterium Salinispora arenicola Recovered from the Marine Sediments of St. Peter and St. Paul Archipelago, Brazil.

Salinaphthoquinones A-E (1-5) were isolated from a marine Salininispora arenicola strain, recovered from sediments of the St. Peter and St. Paul Archipelago, Brazil. The structures of the compounds were elucidated using a combination of spectroscopic (NMR, IR, HRESIMS) data, including single-crystal X-ray diffraction analysis. A plausible biosynthetic pathway for 1-5 is proposed. Compounds 1 to 4 displayed moderate activity against Staphylococcus aureus and Enterococcus faecalis with MIC values of 125 to 16 µg/mL.

Course of serological tests in treated subjects with chronic Trypanosoma cruzi infection: A systematic review and meta-analysis of individual participant data.

OBJECTIVE: To determine the course of serological tests in subjects with chronic Trypanosoma cruzi infection treated with anti-trypanosomal drugs. METHODS: A systematic review and meta-analysis was conducted using individual participant data. Survival analysis and the Cox proportional hazards regression model with random effects to adjust for covariates were applied. The protocol was registered in the PROSPERO database (http://www.crd.york.ac.uk/PROSPERO; CRD42012002162). RESULTS: A total of 27 studies (1296 subjects) conducted in eight countries were included. The risk of bias was low for all domains in 17 studies (63.0%). Nine hundred and thirteen subjects were assessed (149 seroreversion events, 83.7% censored data) for enzyme-linked immunosorbent assay (ELISA), 670 subjects (134 events, 80.0% censored) for indirect immunofluorescence assay (IIF), and 548 subjects (99 events, 82.0% censored) for indirect hemagglutination assay (IHA). A higher probability of seroreversion was observed within a shorter time span in subjects aged 1-19 years compared to adults. The chance of seroreversion also varied according to the country where the infection might have been acquired. For instance, the pooled adjusted hazard ratio between children/adolescents and adults for the IIF test was 1.54 (95% confidence interval 0.64-3.71) for certain countries of South America (Argentina, Bolivia, Chile, and Paraguay) and 9.37 (95% confidence interval 3.44-25.50) for Brazil. CONCLUSIONS: The disappearance of anti-T. cruzi antibodies was demonstrated along the course of follow-up. An interaction between age at treatment and country setting was found.

Allylic oxidation of steroidal olefins by vanadyl acetylacetonate and tert-butyl hydroperoxide.

Readily available vanadyl acetylacetonate was found to oxidize the allylic sites of Δ(5) steroidal alcohols without protection of hydroxyl groups. Cholesterol, dehydroepiandrosterone, cholesterol benzoate, cholesterol acetate, pregnenolone, and 5-pregnen-3,20-diene were oxidized to 7-keto products using vanadyl acetylacetonate in one pot reactions at room temperature in the presence of oxygen and water.

Effect of genetic variation in P2Y12 on TRAP-stimulated platelet response in healthy subjects.

In platelets, thrombin receptor signaling depends upon the release of adenosine diphosphate and subsequent activation at purinergic subtype Y (P2Y) receptors. The purpose of this study is to evaluate the influence of specific P2Y12 polymorphisms on platelet reactivity in healthy subjects mediated by thrombin receptor activating peptide (TRAP). We recruited a total of 29 healthy volunteers who had been previously genotyped for two polymorphisms of the P2Y12 receptor: the H2 haplotype (rs2046934) and 34C>T (rs6785930). Flow cytometry and the VerifyNow assay were used to assess platelet activation and aggregation stimulated by TRAP in the presence and absence of specific receptor antagonists for the P2Y1, P2Y12, and thromboxane A2 receptors. We identified a significant recessive effect of the P2Y12-receptor H2 haplotype on TRAP-induced flow cytometry. Specifically, H2/H2 carriers (n = 5) demonstrated a significant reduction in both glycoprotein IIb/IIIa receptor activation (p < 0.001) and CD62P expression (p = 0.035). While the VerifyNow assay did not reveal any effect of haplotype on TRAP-mediated platelet aggregation (p = 0.72), the H2/H2 subjects demonstrated greater platelet inhibition in the presence of cangrelor, a specific receptor antagonist for the P2Y12 receptor (p = 0.023). No consistent effects of the separate 34C>T genotype (rs6785930) were demonstrated under the conditions evaluated. The findings of this study suggest a potential association between P2Y12-receptor H2/H2 carriers and reduced platelet function mediated by TRAP in healthy volunteers.

Temperature-induced coexistence of a conducting bilayer and the bulk-terminated surface of the topological insulator Bi2Te3.

Topological insulators such as Bi2Se3 and Bi2Te3 have extremely promising transport properties, due to their unique electronic behavior: they are insulators in the bulk and conducting at the surface. Recently, the coexistence of two types of surface conducting channels has been observed for Bi2Se3, one being Dirac electrons from the topological state and the other electrons from a conventional two-dimensional gas. As an explanation for this effect, a possible structural modification of the surface of these materials has been hypothesized. Using scanning tunneling microscopy we have directly observed the coexistence of a conducting bilayer and the bare surface of bulk-terminated Bi2Te3. X-ray crystal truncation rod scattering was used to directly show the stabilization of this epitaxial bilayer which is primarily composed of bismuth. Using this information, we have performed density functional theory calculations to determine the electronic properties of the possible surface terminations. They can be used to understand recent angular resolved photoemission data which have revealed this dual surface electronic behavior.

Elevation of plasma milrinone concentrations in stage D heart failure associated with renal dysfunction.

PURPOSE: To determine steady state milrinone concentrations in patients with stage D heart failure (HF) with and without renal dysfunction METHODS: We retrospectively identified patients with stage D HF at a single medical center on continuous milrinonein fusion at the time of plasma collection for entry into a research registry database. Milrinone was prescribed and titrated to improve hemodynamic and clinical status by a cardiologist. Plasma samples were obtained at steady state milrinone concentrations. Patients were stratified by creatinine clearance (CrCl) into 4 groups: group 1 (CrCl >60 mL/min), group 2 (CrCl 60-30 mL/min), group 3 (CrCl <30 mL/min), and group 4 (intermittent hemodialysis). Retrospective chart review was performed to quantify the post milrinone hemodynamic changes by cardiac catheterization and electrophysiologic changes by implantable cardiac defibrillator (ICD) interrogation. RESULTS: A total of 29 patients were identified: group 1 (n=14), group 2 (n=10), group 3(n=3), and group 4 (n = 2). The mean infusion rate (0.391+0.08 mg/kg/min) did not differ between groups (P=0.14). The mean milrinone concentration was 451+243 ng/mL in group 1, 591+293 ng/mL in group 2, 1575+962 ng/mL in group 3, and 6252+4409 ng/mL in group 4 (P<0.05 compared to groups 1). There was no difference in post milrinone hemodynamic improvements between the groups (P=0.41). The ICD interrogation revealed limited comparisons, but 6 of the 8 post milrinone ventricular tachycardia episodes requiring defibrillation occurred in group 4 patients. CONCLUSION: Patients with stage D HF having severe renal dysfunction have elevated milrinone concentrations. Future studies of milrinone concentrations are warranted to investigate the potential risk of life-threatening arrhythmias and potential dosing regimens in renal dysfunction.

Genome-wide association studies of pit-and-fissure- and smooth-surface caries in permanent dentition.

While genetics clearly influences dental caries risk, few caries genes have been discovered and validated. Recent studies have suggested differential genetic factors for primary dentition caries and permanent dentition caries, as well as for pit-and-fissure- (PF) and smooth- (SM) surface caries. We performed separate GWAS for caries in permanent-dentition PF surfaces (1,017 participants, adjusted for age, sex, and the presence of Streptococcus mutans) and SM surfaces (1,004 participants, adjusted for age, education group, and the presence of Streptococcus mutans) in self-reported whites (ages 14 to 56 yrs). Caries scores were derived based on visual assessment of each surface of each tooth; more than 1.2 million SNPs were either successfully genotyped or imputed and were tested for association. Two homologous genes were suggestively associated: BCOR (Xp11.4) in PF-surface caries (p value = 1.8E-7), and BCORL1 (Xq26.1) in SM-surface caries (p value = 1.0E-5). BCOR mutations cause oculofaciocardiodental syndrome, a Mendelian disease involving multiple dental anomalies. Associations of other plausible cariogenesis genes were also observed for PF-surface caries (e.g., INHBA, p value = 6.5E-6) and for SM-surface caries (e.g., CXCR1 and CXCR2, p value = 1.9E-6). This study supports the notion that genes differentially affect cariogenesis across the surfaces of the permanent dentition, and nominates several novel genes for investigation.