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N,N-Diformylmescaline, a novel analogue of mescaline, has recently been detected in Australia in two unrelated seizures. To confirm the identification, a three-step synthesis from 3,4,5-trimethoxyphenylacetic acid was devised. However, purification of the final product proved problematic with the compound prone to degradation in solution. Analysis of the compound by LC-MS indicated that the compound was unstable under acidic and basic conditions, breaking down to N-formylmescaline. Further degradation to mescaline was observed when the compound was dissolved in hydrochloric acid for an extended period of time suggesting that N,N-diformylmescaline may be a prodrug for mescaline. The GC-MS, NMR and FTIR data for the seized compound are presented along with details of the synthesis and studies of the compound's stability in solution., (© 2022 Commonwealth of Australia. Drug Testing and Analysis © 2022 John Wiley & Sons Ltd.)

Herein, we report the development of a novel route to tricyclic lactam products via a facile aza-[4 + 2] cycloaddition of catalytically generated acyliminium ions. Employing a Ca(NTf 2 ) 2 / n Bu 4 NPF 6 catalyst system in low loadings, a range of diverse fused ring systems can be synthesised in predominantly good yields.

A range of highly functionalized polycyclic fragments have been synthesized, employing a catalytic dehydrative cyclization. A range of nucleophiles are shown to be successful, with the reaction producing numerous high value motifs., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The regio and stereoselective hydrosilylation of a variety of homopropargylic alcohols and their derivatives is described. The reaction is tolerant to a variety of sterically and electronically varied substrates, affording only the E -vinyl silane as a sole regioisomer. The application of the resultant vinyl silanes towards the diastereoselective synthesis of tetrasubstituted oxetanes is demonstrated.

Cucurbitacins are dietary compounds that have been shown to elicit a range of anti-tumour, anti-inflammatory and anti-atherosclerotic activities. Originally identified as signal transducer and activator of transcription, STAT, inhibitors, a variety of mechanisms of action have since been described, including dysregulation of the actin cytoskeleton and disruption of integrin function. Integrin outside-in signalling and cytoskeletal rearrangements are critical for the propagation of stable thrombus formation and clot retraction following platelet adhesion at the site of vessel damage. The effects of cucurbitacins on platelet function and thrombus formation are unknown. We report for the first time anti-platelet and anti-thrombotic effects of cucurbitacins B, E and I in human platelets. Treatment of platelets with cucurbitacins resulted in attenuation of platelet aggregation, secretion and fibrinogen binding following stimulation by platelet agonists. Cucurbitacins were also found to potently inhibit other integrin- and cytoskeleton-mediated events, including adhesion, spreading and clot retraction. Further investigation of cytoskeletal dynamics found treatment with cucurbitacins altered cofilin phosphorylation, enhanced activation and increased F actin polymerisation and microtubule assembly. Disruption to cytoskeletal dynamics has been previously shown to impair integrin activation, platelet spreading and clot retraction. Anti-platelet properties of cucurbitacins were found to extend to a disruption of stable thrombus formation, with an increase in thrombi instability and de-aggregation under flow. Our research identifies novel, anti-platelet and anti-thrombotic actions of cucurbitacins that appear to be linked to dysregulation of cytoskeletal dynamics and integrin function., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

We describe, for the first time, a highly regioselective hydrosilylation of propargylic amines. The reaction utilizes a PtCl 2 /XantPhos catalyst system to deliver hydrosilanes across the alkyne to afford multifunctional allylic amines in high yields. The reaction is tolerant to a wide variety of functional groups and provides high value intermediates with two distinct functional handles. The synthetic applicability of the reaction has been shown through the synthesis of diverse ambiphilic aziridines.

Herein, we report a sustainable, modular, rapid and high-yielding transformation to afford densely functionalized 5-aminooxazoles and thiazoles. The reaction is tolerant to a wide range of functional groups and is typically complete in under 30 min. Furthermore, the described transformation is inherently green in relation to the catalyst and solvent choice as well as producing environmentally benign alcoholic by-products., (© 2021 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

The zinc-containing histone deacetylase enzyme HDAC7 is emerging as an important regulator of immunometabolism and cancer. Here, we exploit a cavity in HDAC7, filled by Tyr303 in HDAC1, to derive new inhibitors. Phenacetyl hydroxamates and 2-phenylbenzoyl hydroxamates bind to Zn 2+ and are 50-2700-fold more selective inhibitors of HDAC7 than HDAC1. Phenylbenzoyl hydroxamates are 30-70-fold more potent HDAC7 inhibitors than phenacetyl hydroxamates, which is attributed to the benzoyl aromatic group interacting with Phe679 and Phe738. Phthalimide capping groups, including a saccharin analogue, decrease rotational freedom and provide hydrogen bond acceptor carbonyl/sulfonamide oxygens that increase inhibitor potency, liver microsome stability, solubility, and cell activity. Despite being the most potent HDAC7 inhibitors to date, they are not selective among class IIa enzymes. These strategies may help to produce tools for interrogating HDAC7 biology related to its catalytic site.

Herein we report our full investigation into the calcium catalyzed generation and trapping of N -acyliminium ions from readily available 3-hydroxyisoindolinones. We have successfully employed a range of traditional nucleophiles including carbon, nitrogen, and sulfur containing reactive partners. The reaction is tolerant to a wide range of functionalities and provides high value scaffolds in good to excellent yields.

A mild and facile Peterson olefination has been developed employing low catalyst loading of the Brønsted acid HNTf 2 . The reactions are typically performed at room temperature, with the reaction tolerant to a range of useful functionalities. Furthermore, we have extended this methodology to the synthesis of enynes.

A rapid and functionally tolerant calcium catalysed Hosomi-Sakurai reaction has been realised. Employing 1 mol% calcium, allylated isoindolinones can be synthesised in high yields and the reaction is shown to be tolerant to a range of medicinally relevant functional groups including heterocycles. The synthetic utility of the reaction has been shown, and a plausible reaction mechanism is provided.

A mild calcium catalysed Beckmann rearrangement has been realised, which forgoes the more traditional harsh reactions conditions associated with the transformation. The catalyst system is shown to be tolerant towards a wide variety of functional groups relevant to natural product synthesis and medicinal chemistry and the synthetic utility of the reaction has also been investigated. A preliminary mechanistic investigation was performed to understand the nature of the incoming nucleophile and a possible reaction pathway is described.

We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.

A rapid and stereodefined synthesis of MIDA-boryl vinylsilanes has been achieved through the hydrosilylation of an alkynylboronic ester. The E products which contain a silyl and boryl group can be selectively cross-coupled in a two-step bidirectional sequence to provide a rapid and high-yielding synthesis of complex styrenes.

The highly syn-selective hydrosilylation of allylic alcohols was developed which, following oxidation, provided 1,3 alcohols containing two contiguous stereocentres. Through judicious choice of silane the complementary anti-selective hydrosilylation was also developed. This protocol was applied to the synthesis of an all syn polyketide stereotriad.

A base mediated isomerisation-allylation protocol of 1,3-disubstituted propenols has been established. The use of diaryl and aryl-silyl substrates is reported alongside the use of substituted allyl bromides. Mechanistic experiments have also been conducted to elucidate the reaction pathway.

Objective: The purpose of this study was to evaluate use of the send-to-editor function of a radiology voice recognition dictation system and compare study volumes of radiologists who self-edit with those of radiologists who send reports to the editor. Use of voice recognition shortcuts was also evaluated., Materials and Methods: Voice recognition dictation systems were installed in a six-hospital system, including an 800-bed tertiary care center and five community hospitals, in 2002. This became the only means of radiologist dictation in July 2005. Report volumes, use of the send-to-editor function, and use of shortcuts were tracked from October 2005 through October 2008. A subspecialty private radiology group, ranging from 37 radiologists in July 2005 to 50 radiologists in October 2008, interpreted the imaging studies. Radiologists had no financial incentives to self-edit., Results: The percentage of radiologists using the send-to-editor function remained relatively constant at 46%, resulting in 21% of total reports sent to the editor. Radiologists who used the send-to-editor function dictated approximately 41% more reports than those who self-edited. The volume of reports generated by general radiologists reading large volumes of computed radiography cases and sending to the editor was greater than that of radiologists who self-edited (p < 0.05). There was no significant difference between radiologists who self-edited and those who sent to the editor with respect to number of shortcuts used., Conclusion: Radiologists reading large volumes of computed radiography cases and using the send-to-editor function generated significantly more reports than radiologists who did not, suggesting that the send-to-editor function may be useful for improving productivity among radiologists reading large volumes of computed radiography cases.

A facile and user-friendly protocol has been developed for the selective synthesis of E-vinyl silanes derived from propargylic alcohols using a PtCl2/XPhos catalyst system. The reaction is generally high yielding and provides a single regioisomer at the β-position with E-alkene geometry. The reaction is extremely tolerant of functionality and has a wide scope of reactivity both in terms of alkynes and silanes used. The catalyst loading has been investigated and it is found that good reactivity is observed at extremely low catalyst loadings. This methodology has also been extended to a one-pot hydrosilylation Denmark-Hiyama coupling.

A one-pot isomerization-Claisen protocol has been developed for the synthesis of highly substituted allylsilanes. Monosilylated divinyl ethers can be isomerized using a cationic iridium(I) catalyst followed by a thermal Claisen rearrangement to provide the allylsilanes in excellent yields and diastereoselectivities.

A highly regioselective hydrosilylation of propargylic alcohols has been developed using an in situ prepared PtCl(2)/XPhos catalyst system. The reaction is tolerant of many functional groups and exhibits excellent regio and geometric selectivity.

Objectives: The aim of this study was to determine the impact of delay to angioplasty in patients with acute coronary syndromes (ACS)., Background: There is a paucity of data on the impact of delays to percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) undergoing an invasive management strategy., Methods: Patients undergoing PCI in the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial were stratified according to timing of PCI after clinical presentation for outcome analysis., Results: Percutaneous coronary intervention was performed in 7,749 patients (median age 63 years; 73% male) with NSTE-ACS at a median of 19.5 h after presentation (<8 h [n=2,197], 8 to 24 h [n=2,740], and >24 h [n=2,812]). Delay to PCI>24 h after clinical presentation was significantly associated with increased 30-day mortality, myocardial infarction (MI), and composite ischemia (death, MI, and unplanned revascularization). By multivariable analysis, delay to PCI of >24 h was a significant independent predictor of 30-day and 1-year mortality. The incremental risk of death attributable to PCI delay>24 h was greatest in those patients presenting with high-risk features., Conclusions: In this large-scale study, delaying revascularization with PCI>24 h in patients with NSTE-ACS was an independent predictor of early and late mortality and adverse ischemic outcomes. These findings suggest that urgent angiography and triage to revascularization should be a priority in NSTE-ACS patients., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: We sought to investigate the impact of multivessel coronary artery disease (CAD) on reperfusion success and prognosis following primary percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI). The influence of multivessel disease on myocardial reperfusion and subsequent survival after primary PCI has not been studied., Methods and Results: In the CADILLAC trial, primary PCI was performed in 2082 patients of any age with AMI within 12 h of symptom onset. Myocardial perfusion post-PCI assessed by ST-segment recovery and myocardial blush and clinical outcomes were stratified by the extent of CAD. Single-, double-, and triple-vessel disease were present in 1066 (51.2%), 692 (33.2%), and 324 (15.6%) patients, respectively. Patients with multivessel disease compared with those with single-vessel disease undergoing primary PCI were significantly more likely to have absent ST-segment recovery (13.3 vs. 7.4%, P = 0.01), though the rates of post-procedural TIMI-3 flow (89.7 vs. 88.9%, P = 0.66) and grade 2 or 3 myocardial blush (51.2 vs. 51.5%, P = 0.91) in the infarct vessel were comparable. By 1 year, the cumulative incidence of death for patients with single-, double-, and triple-vessel disease was 3.2, 4.4, and 7.8%, respectively (P = 0.003), and the composite rate of major adverse cardiac events (MACE) was 14.8, 19.5, and 23.6%, respectively (P = 0.0006). By multivariable analysis, the presence of triple-vessel disease was the strongest predictor of 1-year death [hazard ratio (HR) = 2.60, P = 0.009], death and re-infarction (HR = 1.88, P = 0.03), and MACE (HR = 1.80, P = 0.0009)., Conclusion: Patients with extensive CAD in vessels remote from the infarct-related artery have reduced reperfusion success and an adverse prognosis following primary PCI in AMI. Future studies regarding the optimal treatment of patients with multivessel disease and AMI are warranted.

Aims: ST-segment recovery (SigmaSTR) and myocardial blush (MB) evaluate different elements of microcirculatory integrity after reperfusion therapy in acute myocardial infarction (AMI). We sought to determine whether the combination of SigmaSTR and MB after primary percutaneous coronary intervention (PCI) in AMI has greater prognostic utility than either measure alone., Methods and Results: The 30 days and 1 year clinical outcomes of 456 patients were assessed as a function of SigmaSTR and MB after primary PCI from the CADILLAC trial. SigmaSTR and MB were concordant (> or =70% SigmaSTR and MB grade 2/3 or <70% SigmaSTR and MB grade 0/1) in 60.1% of patients and discordant in 39.9% of patients. The greatest survival was observed among patients with complete SigmaSTR (> or =70%) and MB grade 2/3 in whom the cumulative rates of death at 30 days and 1 year were 0.6 and 1.2%, respectively. Poorest survival was observed among patients with incomplete SigmaSTR (<70%) and reduced MB (grade 0/1), in whom 30 days and 1 year rates of death were 8.3 and 10.1%, respectively. Intermediate outcomes were present in patients with discordant MB and SigmaSTR. By multivariable analysis, however, SigmaSTR was an independent correlate of survival at 30 days and 1 year (P=0.05 and 0.01, respectively), whereas MB was no longer predictive (P=0.38 and 0.72, respectively)., Conclusion: SigmaSTR and MB are not infrequently discordant after primary PCI. By univariate analysis, both measures of reperfusion success strongly correlate with survival and assessment of both yields incremental prognostic information beyond either measure alone. By multivariable analysis, however, SigmaSTR is the stronger prognostic variable.

Objective: This study was done to assess and compare the prognostic significance of multiple methods for measuring ST-segment elevation resolution (STR) following primary percutaneous coronary intervention (PCI)., Background: Resolution of ST-segment elevation (STE) is a powerful predictor of both infarct-related artery patency and mortality in acute myocardial infarction (AMI). Recent thrombolytic studies have suggested that simple measures of STR may be as powerful as more complex algorithms. The optimal method of assessing STR following primary PCI has not been studied., Methods: We analyzed 700 patients with technically adequate baseline and post-PCI electrocardiograms from the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial. Five methods were used to assess STR: 1) summed %STR across multiple leads (SigmaSTR); 2) %STR in the single lead with maximum baseline STE (MaxSTR); 3) absolute maximum STE before the procedure; 4) absolute maximum STE after intervention (MaxSTPost); and 5) a categorical variable based upon MaxSTPost (High Risk)., Results: At 30 days, SigmaSTR, MaxSTR, and MaxSTPost all correlated strongly with mortality (p = 0.004, p = 0.005, and p < 0.0001, respectively) and the combined end point of mortality or reinfarction (p = 0.001, p = 0.001, and p < 0.0001). At one year, SigmaSTR and MaxSTPost correlated with mortality (p = 0.04, p = 0.0001), reinfarction (p = 0.02, p = 0.0015), and the combined end point (p = 0.02, p < 0.0001). By multivariate analysis, only the simpler measures of MaxSTPost and High Risk categorization independently predicted all outcomes at both time points., Conclusions: The STR following primary PCI in AMI correlates strongly with mortality and reinfarction, independent of target vessel patency. The simple measure of the maximal residual degree of STE after primary PCI is a strong independent predictor of both survival and freedom from reinfarction at 30 days and 1 year.

The laboratory rat, Rattus novegicus, is a major model system for physiological and pathophysiological studies, and since 1966 more than 422,000 publications describe biological studies on the rat (NCBI/Medline). The rat is becoming an increasingly important genetic model for the study of specific diseases, as well as retaining its role as a major preclinical model system for pharmaceutical development. The initial genetic linkage map of the rat contained 432 genetic markers (Jacob et al. 1995) out of 1171 developed due to the relatively low polymorphism rate of the mapping cross used (SHR x BN) when compared to the interspecific crosses in the mouse. While the rat genome project continues to localize additional markers on the linkage map, and as of 11/97 more than 3,200 loci have been mapped. Current map construction is using two different crosses (SHRSP x BN and FHH x ACI) rather than the initial mapping cross. Consequently there is a need to provide integration among the different maps. We set out to develop an integrated map, as well as increase the number of markers on the rat genetic map. The crosses available for this analysis included the original mapping cross SHR x BN reciprocal F2 intercross (448 markers), a GH x BN intercross (205 markers), a SS/Mcw x BN intercross (235 markers), and a FHH/Eur x ACI/Hsd intercross (276 markers), which is also one of the new mapping crosses. Forty-six animals from each cross were genotyped with markers polymorphic for that cross. The maps appear to cover the vast majority of the rat genome. The availability of these additional markers should facilitate more complete whole genome scans in a greater number of strains and provide additional markers in specific genomic regions of interest.

Cardiac hypertrophy is a common but not inevitable complication of hypertension. Variation in heart size in hypertensives may reflect independent genetic susceptibility to cardiac hypertrophy. Using an experimental genetic model, we determined the location of quantitative trait loci responsible for cardiac hypertrophy and/or hypertension. We studied 182 F2 male animals derived from a cross of the spontaneously hypertensive rat and normotensive Donryu rats. Direct mean arterial pressure (MAP) and left ventricular (LV) mass were measured at 20 weeks of age, and DNA was obtained for linkage analysis. The estimated heritability of MAP was 62% and for LV mass expressed per unit of body weight (relative LV mass) was 76%. We used 185 polymorphic markers, with an average intermarker distance of 12.3 centimorgans for a genome-wide scan in a representative subgroup of 46 animals to identify preliminary quantitative trait loci, which were then mapped in all 182 male F2 rats. Two loci showed logarithm of the odds scores of > 4.0. One on chromosome 2, Lvm-1, was linked to relative LV mass but showed no evidence of linkage to MAP. Another locus on chromosome 1, Map-1, was linked to MAP. In the same region, a locus Lvm-2 was linked with relative LV mass. These data indicate the existence of a genetic locus on chromosome 2 of the spontaneously hypertensive rat that affects relative LV mass independently of blood pressure.

The ultimate informativeness of the zebrafish mutations described in this issue will rest in part on the ability to clone these genes. However, the genetic infrastructure required for the positional cloning in zebrafish is still in its infancy. Here we report a reference cross panel of DNA, consisting of 520 F2 progeny (1040 meioses) that has been anchored to a zebrafish genetic linkage map by 102 simple sequence length polymorphisms. This reference cross DNA provides: (1) a panel of DNA from the cross that was used to construct the genetic linkage map, upon which polymorphic gene(s) and genetic markers can be mapped; (2) a fine order mapping tool, with a maximum resolution of 0.1 cM; and (3) a foundation for the development of a physical map (an ordered array of clones each containing a known portion of the genome). This reference cross DNA will serve as a resource enabling investigators to relate genes or genetic markers directly to a single genetic linkage map and avoid the problem of integrating different maps with different genetic markers, as must be currently done when using randomly amplified polymorphic DNA markers, or as has occurred with human genetic linkage maps.

We report the CT and sonographic findings of transient acute tubular disease in a newborn infant, who was dehydrated at birth. The initial CT scan demonstrated focal areas of increased attenuation within the central portions of both kidneys, and sonography showed echogenic medullary pyramids. After adequate hydration, a follow-up examination demonstrated complete spontaneous resolution.

A 89-year-old, nursing home female presented with a two-week history of drooling and a hard palpable mass in the region of the larynx. Initial fiberoptic laryngoscopy revealed a hard pinkish-white mass which was felt to represent a tumor. Computed tomography demonstrated swallowed, impacted, complete, mandibular denture. Radiologists should be aware of this problem, particularly in the elderly demented patient.

Significant differences in the rate of reduction of two spin labels, 5-doxylstearic acid and TEMPOL, in the undifferentiated and differentiated NB-15 mouse neuroblastoma cells were demonstrated by using electron paramagnetic resonance (EPR) spectroscopy. The half-time (T1/2) values for decay of the EPR signal of 5-doxylstearic acid in the undifferentiated and differentiated neuroblastoma cells were 70 min and 290 min, respectively. The T1/2 values of TEMPOL in the undifferentiated and differentiated cells were 18 min and 34 min, respectively. The cellular reductant was characterized as non-protein-bound sulfhydryl groups. A corresponding difference in the cellular non-protein-bound sulfhydryl content, 19.30 nmol/mg protein for the undifferentiated cells and 6.78 nmol/mg protein for the differentiated cells, was observed. Comparison of the reduction rates of TEMPOL, 5-doxylstearic acid and 16-doxylstearic acid in the undifferentiated NB-15 cells suggested that the permeation of non-protein-bound sulfhydryl compounds from the cytosol to membrane may be responsible for the reduction of the lipid-soluble stearic acid spin labels.

A 69-year-old man with a left atrial myxoma underwent a gated cardiac blood pool radionuclide study that failed to visualize the cardiac tumor on either the planar images or on the composite cineangiograms from the anterior and 45 degrees LAO projections. A nongated cardiac SPECT examination, however, easily demonstrated the atrial myxoma in its characteristic location, adjacent to the interatrial septum. SPECT dramatically improved the image contrast; provided views in transaxial, coronal, and sagittal planes; and allowed direct comparison with computed tomography. Gated cardiac SPECT may be expected to provide a more accurate analysis of the complex motion and attachment site of these intracardiac tumors, as well as a more accurate tumor volume analysis.