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OBJECTIVE: The objective of this study was to characterize the work-related asthma population seen by the New York State Occupational Health Clinic Network (OHCN) to determine which industries, occupations, and causal agents are associated with work-related asthma in New York State (NYS). METHODS: The OHCN patient database was analyzed to identify those patients with a diagnosis of work-related asthma and medical charts were then abstracted for data on demographics, clinical history, disease severity, industry, occupation, and putative agent. RESULTS: The OHCN patients with work-related asthma were most commonly employed in the service and manufacturing industries. Common occupations included teachers, farm operators/managers, and construction trades. The most frequently reported putative agents associated with work-related asthma were dust, indoor air, mold, and solvents. CONCLUSIONS: Our findings suggest the potential importance of prevention of workplace exposure in reducing adult asthma in NYS. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine the circumstances under which women receive blood lead tests in New York State and to characterize the sources of lead exposure among women of childbearing age with moderate blood lead levels. Telephone interviews were conducted with 135 women between the ages of 18 and 45, with blood lead levels from 10 through 25 micrograms/dl, were used to collect information on the reason for their blood lead test and possibel sources of lead exposure. It was found that the two most common reasons to be tested for blood lead were workplace screening (47%) and pregnancy (27%). Occupational exposure was the primary source of lead exposure in this population (46%). Another common source of lead exposure was home renovation (24%). A significant proportion (31%) of women with blood lead levels from 10 through 25 micrograms/dl had no known current source of lead exposure. Based on New York's sample, there are a significant number of women of reproductive age with potentially fetotoxic blood lead levels. [ABSTRACT FROM AUTHOR]

Abstract Background Inadequate fruit and vegetable consumption in childhood increases the risk of developing chronic disease. Despite this, a substantial proportion of children in developed nations, including Australia, do not consume sufficient quantities of fruits and vegetables. Parents are influential in the development of dietary habits of young children but often lack the necessary knowledge and skills to promote healthy eating in their children. The aim of this study is to assess the efficacy of a telephone-based intervention for parents to increase the fruit and vegetable consumption of their 3- to 5-year-old children. Methods/Design The study, conducted in the Hunter region of New South Wales, Australia, employs a cluster randomised controlled trial design. Two hundred parents from 15 randomly selected preschools will be randomised to receive the intervention, which consists of print resources and four weekly 30-minute telephone support calls delivered by trained telephone interviewers. The calls will assist parents to increase the availability and accessibility of fruit and vegetables in the home, create supportive family eating routines and role-model fruit and vegetable consumption. A further two hundred parents will be randomly allocated to the control group and will receive printed nutrition information only. The primary outcome of the trial will be the change in the child's consumption of fruit and vegetables as measured by the fruit and vegetable subscale of the Children's Dietary Questionnaire. Pre-intervention and post-intervention parent surveys will be administered over the telephone. Baseline surveys will occur one to two weeks prior to intervention delivery, with follow-up data collection calls occurring two, six, 12 and 18 months following baseline data collection. Discussion If effective, this telephone-based intervention may represent a promising public health strategy to increase fruit and vegetable consumption in childhood and reduce the risk of subsequent chronic disease. Trial registration Australian Clinical Trials Registry ACTRN12609000820202

Objective: Infectious myelopathy of any stage and etiology carries the potential for significant morbidity and mortality. This article details the clinical presentation, risk factors, and key diagnostic components of infectious myelopathies with the goal of improving the recognition of these disorders and guiding subsequent management., Latest Developments: Despite our era of advanced multimodal imaging and laboratory diagnostic technology, a causative organism often remains unidentified in suspected infectious and parainfectious myelopathy cases. To improve diagnostic capability, newer technologies such as metagenomics are being harnessed to develop diagnostic assays with a greater breadth of data from each specimen and improvements in infection identification. Conventional assays have been optimized for improved sensitivity and specificity., Essential Points: Prompt recognition and treatment of infectious myelopathy decreases morbidity and mortality. The key diagnostic tools include serologies, CSF analysis, and imaging; however clinical presentation, epidemiologic risk factors, and history of recent illness are all vital to making the proper diagnosis because current laboratory and imaging modalities are often inconclusive. The cornerstone of recommended treatment is targeted antimicrobials with appropriate immune modulation, surgical intervention, supportive care, and interdisciplinary involvement, all of which further improve outcomes for patients with infectious myelopathy., (Copyright © 2024 American Academy of Neurology.)

We describe the synthesis of trihydroxylated cyclohexane β-amino acids from (-)-shikimic acid, in their cis and trans configuration, and the incorporation of the trans isomer into a trans -2-aminocyclohexanecarboxylic acid peptide chain. Subsequently, the hydroxyl groups were partially or totally deprotected. The structural study of the new peptides by FTIR, CD, solution NMR and DFT calculations revealed that they all fold into a 14-helix secondary structure, similarly to the homooligomer of trans -2-aminocyclohexanecarboxylic acid. This means that the high degree of substitution of the cyclohexane ring of the new residue is compatible with the adoption of a stable helical secondary structure and opens opportunities for the design of more elaborate peptidic foldamers with oriented polar substituents at selected positions of the cycloalkane residues.

Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT 2B receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin's suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no 18 F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease., (© 2023. The Author(s).)

The synthesis of a range of loline alkaloids is reported. The C(7) and C(7a) stereogenic centers for the targets were formed by the established conjugate addition of lithium ( S )- N -benzyl- N -(α-methylbenzyl)amide to tert -butyl 5-benzyloxypent-2-enoate, ensuing enolate oxidation to give an α-hydroxy-β-amino ester, and then formal exchange of the resultant amino and hydroxyl functionalities (via the intermediacy of the corresponding aziridinium ion) to give an α-amino-β-hydroxy ester. Subsequent transformation gave a 3-hydroxyprolinal derivative which was converted to the corresponding N - tert -butylsulfinylimine. Mannich-type reaction with the enolate derived from O -Boc protected methyl glycolate then formed the remaining C(1) and C(2) stereogenic centers for the targets. The 2,7-ether bridge was formed by a displacement reaction, completing construction of the loline alkaloid core. Facile manipulations then gave a range of loline alkaloids, including loline itself.

Purpose: We evaluated the potential associations between the consumption of ultra-processed food (UPF) and the incidence of obesity among Uruguayan and Brazilian preschoolers., Design and Methods: We conducted a longitudinal analysis using data from preschool children from Uruguay and Brazil. The "Health, child development and nutritional survey" (ENDIS) was conducted in Uruguay in 2013-2014 and 2015-2016. The Brazilian survey (Pelotas 2015 Birth Cohort) has measures from 2017 and 2019. The main outcome measure was obesity defined as body mass index (BMI) for age and sex ≥ +3 z-scores. The score of UPF consumption was the main exposure measured. Multilevel crude and adjusted Poisson regressions were performed to estimate risk ratios and the respective 95% Confidence Intervals (95% CI)., Results: The overall incidence of obesity in this group of young Latin-American children with a mean age of 48 months was 4.1%. We observed a relationship between UPF and obesity with statistical significance (RR: 1.10 (95% CI, 1.02-1.18). Adjustment for weight at birth, age, sex, breastfeeding, country, and time between waves resulted in a similar relationship but lack of statistical significance., Conclusions: Whilst in this study we did not find strong evidence of an association between the incidence of obesity and the intake at baseline and currently of UPF, results suggest that higher UPF consumption is more favorable than reduced consumption for the development of obesity., Practice Implications: The present study reinforces the importance of nutrition education and more effective public policies for promoting healthier food choices in early childhood., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The first asymmetric synthesis of microgrewiapine C, a piperidine alkaloid isolated from Microcos paniculata , is reported. This synthesis prompted correction of the 1 H and 13 C NMR data for the natural sample of the alkaloid, which was achieved by reanalysis of the original spectra. The corrected data for the natural product were found to be identical to those of the synthetic sample prepared herein, thus confirming the structural and relative configurational assignment of microgrewiapine C. Although comparison of specific rotation values indicates that the (1 R ,2 S ,3 S ,6 S ) absolute configuration should be assigned to the alkaloid, consideration of potential common biosynthetic origins of microgrewiapine C and congeners suggests that further phytochemical investigations are warranted.

The formation of O -acetyl microgrewiapine A is investigated. NMR data for the authentic sample derived from the natural product are corrected. Wholly synthetic samples, produced from reductive N -methylation of synthetic microcosamine A (to give synthetic microgrewiapine A) followed by O -acetylation, exhibit NMR data that are identical to those of the authentic sample. The previous report that this two-step transformation proceeds with epimerization at C-6 is thus shown to be in error: the purported sample of O -acetyl 6- epi -microgrewiapine A is structurally misassigned and is, in fact, O -acetyl microgrewiapine A. A plausible rationale for the structural misassignment is advanced.

Enantiorecognition between a racemic reagent and a racemic substrate can be a valuable process in organic synthesis. This review highlights representative examples of this phenomenon and the use of mutual kinetic resolution as a method for screening of kinetic and/or parallel kinetic resolutions.

5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[ d ]oxazole (ezutromid, 1 ) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to produce two regioisomeric 1,2-dihydronaphthalene-1,2-diols, DHD1 and DHD3, as the major metabolites after oral administration in humans and rodents. In many patients, plasma levels of the DHD metabolites were found to exceed those of ezutromid. Herein, we describe the structural elucidation of the main metabolites of ezutromid, the regio- and relative stereochemical assignments of DHD1 and DHD3, their de novo chemical synthesis, and their production in systems in vitro. We further elucidate the likely metabolic pathway and CYP isoforms responsible for DHD1 and DHD3 production and characterize their physicochemical, ADME, and pharmacological properties and their preliminary toxicological profiles.

Following on from ezutromid, the first-in-class benzoxazole utrophin modulator that progressed to Phase 2 clinical trials for the treatment of Duchenne muscular dystrophy, a new chemotype was designed to optimise its physicochemical and ADME profile. Herein we report the synthesis of SMT022357, a second generation utrophin modulator preclinical candidate, and an asymmetric synthesis of its constituent enantiomers. The pharmacological properties of both enantiomers were evaluated in vitro and in vivo . No significant difference in the activity or efficacy was observed between the two enantiomers; activity was found to be comparable to the racemic mixture., (© 2019 The Authors.)

PEGylation is considered a safe mechanism to enhance the pharmacokinetics (PK) and pharmacodynamics (PD) of biotherapeutics. Previous studies using PEGylation as a PK enhancement tool have reported benign PEG-related vacuolation in multiple tissues. This paper establishes a threshold for PEG burden beyond which there are alterations in tissue architecture that could potentially lead to dysfunction. As part of the nonclinical safety assessment of Compound A, a 12 kDa protein conjugated to a 40 kDa branched PEG molecule, monkeys were dosed subcutaneously twice weekly for 3 months at protein doses resulting in weekly PEG doses of 8, 24, 120, or 160 mg/kg. Consistent with previous reports with PEGylated biomolecules, Compound A administration resulted in intracellular vacuoles attributed to the PEG moiety in macrophages in numerous tissues and epithelial cells in the choroid plexus and kidney. Vacuolation occurred at all doses with dose-dependent severity and no evidence of recovery up to 2 months after dosing cessation. The vacuolation was considered nonadverse at PEG doses ≤120 mg/kg/week. However, at 160 mg/kg/week PEG, the vacuolation in choroid plexus, pituitary gland, kidney, and choroid of the eye was considered adverse due to significant alterations of tissue architecture that raised concern for the possibility of compromised tissue function. To our knowledge, this is the first report of potentially adverse cellular consequences of PEG accumulation in tissues other than kidney. Furthermore, the lack of reversibility of vacuolation coupled with the lack of a biomarker for intracellular PEG accumulation highlights a potential risk that should be weighed against the benefits of PK/PD enhancement for long-term administration of PEGylated compounds at high doses., (Copyright © 2019. Published by Elsevier B.V.)

Objectives: Intraplaque angiogenesis and inflammation are key promoters of atherosclerosis and are mediated by the alpha-V beta-3 (α v β 3 ) integrin pathway. We investigated the applicability of the α v β 3 -integrin receptor-selective positron emission tomography (PET) radiotracer 18F-fluciclatide in assessing human aortic atherosclerosis., Methods: Vascular 18F-fluciclatide binding was evaluated using ex vivo analysis of carotid endarterectomy samples with autoradiography and immunohistochemistry, and in vivo kinetic modelling following radiotracer administration. Forty-six subjects with a spectrum of atherosclerotic disease categorised as stable (n=27) or unstable (n=19; recent myocardial infarction) underwent PET and CT imaging of the thorax after administration of 229 (IQR 217-237) MBq 18F-fluciclatide. Thoracic aortic 18F-fluciclatide uptake was quantified on fused PET-CT images and corrected for blood-pool activity using the maximum tissue-to-background ratio (TBR max ). Aortic atherosclerotic burden was quantified by CT wall thickness, plaque volume and calcium scoring., Results: 18F-Fluciclatide uptake co-localised with regions of increased α v β 3 integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide vascular uptake was confirmed in vivo using kinetic modelling, and on static imaging correlated with measures of aortic atherosclerotic burden: wall thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and aortic CT calcium score (r=0.37, p=0.01). Patients with recent myocardial infarction had greater aortic 18F-fluciclatide uptake than those with stable disease (TBR max 1.29 vs 1.21, p=0.02)., Conclusions: In vivo expression of α v β 3 integrin in human aortic atheroma is associated with plaque burden and is increased in patients with recent myocardial infarction. Quantification of α v β 3 integrin expression with 18F-fluciclatide PET has potential to assess plaque vulnerability and disease activity in atherosclerosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

A method to enable the synthesis of conduramines and their N -substituted derivatives (enantiopure or racemic form) in six steps (five steps for N -substituted derivatives) from cyclohexa-1,4-diene is reported. Key features of this reaction sequence include a preparation of benzene oxide that is amenable to multigram scale, and its efficient ring-opening upon treatment with a primary amine. Epoxidation of the resultant amino alcohols (40% aq HBF 4 then m -CPBA) is accompanied by hydrolytic ring-opening in situ to give the corresponding N -substituted conduramine derivatives directly. These may undergo subsequent N -deprotection to give the parent conduramines, as demonstrated by the preparation of enantiopure (-)-conduramine A1, (-)-conduramine A2, and (-)-conduramine E2 (the latter two for the first time). The selectivity of the epoxidation reaction is proposed to be the result of competitive ammonium-directed and hydroxyl-directed epoxidation processes, followed by either direct (S N 2-type) or conjugate (S N 2'-type) ring-openings of the intermediate epoxides.

The reported characterization data for the allocolchicinoid alkaloid suhailamine, isolated from Colchicum decaisnei and known to have an erroneous structure, have been reanalyzed. This analysis has led to the current proposal that suhailamine has the same structure as N -acetylcolchinol methyl ether (NCME), an assertion that is supported by comparison with previously reported data for NCME. Suhailamine is therefore a phantom natural product, while NCME represents a naturally occurring allocolchicinoid rather than a purely synthetic entity.

The overall goal of our research is to establish a preformed molecular guidance pathway to direct the growth of dopaminergic axons from embryonic ventral mesencephalon (VM), tissue placed within the substantia nigra (SN), into the striatum to reconstruct the nigrostriatal pathway in a hemi-Parkinson's disease rat model. Guidance pathways were prepared by injecting lentivirus encoding either GFP or a combination of glial-cell-line-derived neurotrophic factor (GDNF) with either GDNF family receptor α1 (GFRα1) or netrin1. In another cohort of animals, adeno-associated virus (AAV) encoding brain-derived neurotrophic factor (BDNF) was injected within the striatum after guidance pathway formation. GDNF combined with either GFRα1 or netrin significantly increased growth of dopaminergic axons out of transplants and along the pathway, resulting in a significant reduction in the number of amphetamine-induced rotations. Retrograde tract tracing showed that the dopaminergic axons innervating the striatum were from A9 neurons within the transplant. Increased dopaminergic innervation of the striatum and improved behavioral recovery were observed with the addition of BDNF. Preformed guidance pathways using a combination of GDNF and netrin1 can be used to reconstruct the nigrostriatal pathway and improve motor recovery.

The SuperQuat (4-substituted 5,5-dimethyloxazolidine-2-one) family of chiral auxiliaries was first developed by us in the 1990s to address the shortcomings of the Evans (4-substituted oxazolidin-2-one) family of chiral auxiliaries. The incorporation of geminal dimethyl substitution at C(5) has two effects: (i) it induces a conformational bias on an adjacent, otherwise conformationally labile C(4)-substituent so that it projects towards the N-acyl fragment, thus offering superior diastereofacial selectivity in a range of transformations; and (ii) it hinders nucleophilic attack at the endocyclic carbonyl group, facilitating recovery and recyclability of the auxiliary, with enhanced cleavage properties. This review summarises the development and some of the most common uses of the SuperQuat family of chiral auxiliaries, particularly in the synthesis of natural products or other targets having bioloigcal interest. Where possible, comparisons with the performances of the corresponding Evans auxiliaries are presented.

The asymmetric syntheses of all members of the Hancock alkaloid family based upon a 2-substituted N-methyl-1,2,3,4-tetrahydroquinoline core are delineated. The conjugate addition of enantiopure lithium N-benzyl- N-(α-methyl- p-methoxybenzyl)amide to 5-( o-bromophenyl)- N-methoxy- N-methylpent-2-enamide is used to generate the requisite C-2 stereogenic center of the targets, while an intramolecular Buchwald-Hartwig coupling is used to form the 1,2,3,4-tetrahydroquinoline ring. Late-stage diversification completes construction of the C-2 side chains. Thus, (-)-cuspareine, (-)-galipinine, (-)-galipeine, and (-)-angustureine were prepared in overall yields of 30%, 28%, 15%, and 39%, respectively, in nine steps from commercially available 3-( o-bromophenyl)propanoic acid in all cases. Unambiguously corrected 1 H and 13 C NMR data for the originally isolated samples of (-)-cuspareine, (-)-galipinine, and (-)-angustureine are also reported, representing a valuable reference resource for these popular synthetic targets.

Epoxidations (40% aq HBF 4 then m-CPBA) of racemic cis-2-( N-benzylamino)cyclohex-3-en-1-ol and racemic cis-2-( N, N-dibenzylamino)cyclohex-3-en-1-ol proceed with very high levels of diastereoselectivity (>95:5 dr). The latter is in direct contrast to the epoxidation of the corresponding trans-diastereoisomer (which proceeds with essentially no selectivity), showing that the relative configuration of the substrate dramatically influences the diastereoselectivity in these instances. Meanwhile, epoxidations of enantiopure (1 R,2 S,α R)-2-[( N-α-methylbenzyl)amino]cyclohex-3-en-1-ol and (1 S,2 R,α R)-2-[( N-α-methylbenzyl)amino]cyclohex-3-en-1-ol [surrogates for the enantiomers of cis-2-( N-benzylamino)cyclohex-3-en-1-ol] proceed with complete diastereoselectivity (>95:5 dr) under the same conditions, showing that neither the presence of the α-methyl group nor the relative configuration of the α-methylbenzyl stereocenter have an effect upon the established level of diastereoslectivity in these cases. In contrast, epoxidations of enantiopure (1 R,2 S,α R)-2-[ N-benzyl- N-(α-methylbenzyl)amino]cyclohex-3-en-1-ol and (1 S,2 R,α R)-2-[ N-benzyl- N-(α-methylbenzyl)amino]cyclohex-3-en-1-ol [surrogates for the enantiomers of cis-2-( N, N-dibenzylamino)cyclohex-3-en-1-ol] proceed with lower diastereoselectivity (∼70:30 dr). Thus, the presence of the α-methyl group has a detrimental effect on the established level of diastereoselectivity in these cases (although again the relative configuration of the α-methylbenzyl stereocenter is unimportant). The diastereoselective epoxidation pathway is used to enable the asymmetric syntheses of six hitherto unknown, enantiopure dihydroconduramines (+)-C-2, (-)-C-2, (+)-D-2, (+)-E-2, (+)-F-2, and (-)-F-2 (>99% ee in each case).

Despite increasing awareness and significant progress in reducing lead exposure among workers, elevated blood lead levels (BLLs) continue to be an occupational health problem. Little is currently known about the extent of personal protective equipment (PPE) use among lead-exposed workers. We examined the patterns and predictors of consistent PPE use and workplace hygiene behaviors among workers with elevated BLLs using a survey of 1,459 workers with an occupational lead exposure in New York State (NYS). Routine availability of respirators was commonplace, however only approximately half of workers consistently wore PPE while working with lead. Regular access to showers was reported by 41% of workers, but less than a quarter took showers and subsequently changed into clean clothing before leaving work site. Significant predictors of consistent PPE use and good hygiene behaviors were identified. The findings highlight the need for further educational and policy interventions for lead-exposed employees. Increased employer efforts are also required to provide workplace structures and a culture that supports compliance. These include the provision of routine training and hazard communication, provision of appropriate PPE and hygiene facilities, and enforcing its use where necessary.

Two synthetic routes have been developed for the asymmetric syntheses of (2 R,3 S)- and (2 S,3 S)-3-hydroxyproline. The key synthetic step in each of these strategies is the conversion of protected α,δ-dihydroxy-β-amino esters (either 2,3- anti- or 2,3- syn-configured) into β,δ-dihydroxy-α-amino esters (protected forms thereof), via the intermediacy of the corresponding aziridinium ions. The products of these stereospecific rearrangements were then cyclized and deprotected to afford (2 R,3 S)-3-hydroxyproline and (2 S,3 S)-3-hydroxyproline as single diastereoisomers (>99:1 dr) in >26% overall yield.

Current understanding of in vivo human brown adipose tissue (BAT) physiology is limited by a reliance on positron emission tomography (PET)/computed tomography (CT) scanning, which has measured exogenous glucose and fatty acid uptake but not quantified endogenous substrate utilization by BAT. Six lean, healthy men underwent 18 fluorodeoxyglucose-PET/CT scanning to localize BAT so microdialysis catheters could be inserted in supraclavicular BAT under CT guidance and in abdominal subcutaneous white adipose tissue (WAT). Arterial and dialysate samples were collected during warm (∼25°C) and cold exposure (∼17°C), and blood flow was measured by 133 xenon washout. During warm conditions, there was increased glucose uptake and lactate release and decreased glycerol release by BAT compared with WAT. Cold exposure increased blood flow, glycerol release, and glucose and glutamate uptake only by BAT. This novel use of microdialysis reveals that human BAT is metabolically active during warm conditions. BAT activation substantially increases local lipolysis but also utilization of other substrates such as glutamate., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

The asymmetric syntheses of a range of N- and O-protected 3-deoxy-3-aminosphingoid bases have been achieved using two complementary approaches. dl-Serine was converted to a racemic N,N-dibenzyl-protected γ-amino-α,β-unsaturated ester which was resolved using a parallel kinetic resolution (PKR) strategy upon reaction with a pseudoenantiomeric mixture of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide and lithium (S)-N-3,4-dimethoxybenzyl-N-(α-methylbenzyl)amide, giving the corresponding enantio- and diastereoisomerically pure β,γ-diamino esters. Alternatively, elaboration of l-serine gave the corresponding enantiopure N,N-dibenzyl-protected γ-amino-α,β-unsaturated ester, and doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide was found to proceed under the dominant stereocontrol of the lithium amide reagent in both cases, thus augmenting the accessible range of β,γ-diamino esters. Both of these protocols were expanded to include in situ oxidation of the enolate formed upon conjugate addition, giving access to the corresponding α-hydroxy-β,γ-diamino esters. Elaboration of these β,γ-diamino and α-hydroxy-β,γ-diamino esters gave the protected forms of the 3-deoxy-3-aminosphingoid base targets.

The 1 H and 13 C NMR data of synthetic samples of (S)-N(1)-methyl-2-[2'-(3″-hydroxy-4″-methoxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline, the originally proposed structure of the Hancock alkaloid (-)-galipeine, do not match those of the natural product. Herein, the preparation of the regioisomer (S)-N(1)-methyl-2-[2'-(3″-methoxy-4″-hydroxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline is reported, the 1 H and 13 C NMR data of which are in excellent agreement with those of (-)-galipeine. Comparison of specific rotation data enables assignment of the absolute (S)-configuration of the alkaloid, and together, these data engender the structural revision of (-)-galipeine to (S)-N(1)-methyl-2-[2'-(3″-methoxy-4″-hydroxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline.

The diastereoselectivities and rates of epoxidation (upon treatment with Cl 3 CCO 2 H then m-CPBA) of a range of cis- and trans-4-aminocycloalk-2-en-1-ol derivatives (containing five-, six-, and seven-membered rings) have been investigated. In all cases where the two potential directing groups can promote epoxidation on opposite faces of the ring scaffold, evidence of competitive epoxidation pathways, promoted by hydrogen-bonding to either the in situ formed ammonium moiety or the hydroxyl group, was observed. In contrast to the relative directing group abilities already established for the six-membered ring system (NHBn ≫ OH > NBn 2 ), an N,N-dibenzylammonium moiety appeared more proficient than a hydroxyl group at directing the stereochemical course of the epoxidation reaction in a five- or seven-membered system. In the former case, this was rationalized by the drive to minimize torsional strain in the transition state being coupled with assistance from hydrogen-bonding to the ammonium moiety. In the latter case, this was ascribed to the steric bulk of the ammonium moiety disfavoring conformations in which hydrogen-bonding to the hydroxyl group results in direction of the epoxidation to the syn face. In cases where the two potential directing groups can promote epoxidation on the same face of the ring scaffold, an enhancement of epoxidation diastereoselectivity was not observed, while introduction of a second, allylic heteroatom to the substrate results in diminishment of the rate of epoxidation in all cases. Presumably, reduction of the nucleophilicity of the olefin by the second, inductively electron-withdrawing heteroatom is the dominant factor, and any assistance to the epoxidation reaction by the potential to form hydrogen-bonds to two directing groups rather than one is clearly unable to overwhelm it.

The asymmetric syntheses of all eight tetraponerine alkaloids (T1-T8) were achieved using the diastereoselective conjugate additions of lithium amide reagents in the key stereodefining steps. Conjugate addition of either lithium (R)-N-allyl-N-(α-methylbenzyl)amide or lithium (R)-N-(but-3-en-1-yl)-N-(α-methylbenzyl)amide to tert-butyl sorbate was followed by ring-closing metathesis of the resultant N-alkenyl β-amino esters, reduction to the corresponding aldehydes, and reaction with tert-butyl (triphenylphosphoranylidene)acetate. Subsequent conjugate addition of the requisite antipode of lithium N-benzyl-N-(α-methylbenzyl)amide to the resultant α,β-unsaturated esters gave a range of diamines for elaboration to T1-T8 via a sequence involving reduction of the ester moiety to give the corresponding aldehyde, olefination, tandem hydrogenation/hydrogenolysis, and cyclization upon reaction with 4-bromobutanal to give the tricyclic skeleton.

(-)-Pseudodistomin E has been prepared for the first time, allowing its structure and absolute configuration to be confirmed. The established conjugate addition of lithium (S)-N-allyl-N-(α-methyl-p-methoxybenzyl)amide to methyl (E,E)-hepta-2,5-dienoate generated the C(2)-stereocenter, and iodolactonisation of a derivative generated the remaining two stereogenic centers. Ensuing iodide displacement was achieved using a tethering strategy, to introduce the nitrogen atom to C(5). Decarboxylative coupling of a carboxylic acid with a dialkylzinc reagent completed construction of the tridecadienyl chain.

The discovery of brown adipose tissue (BAT) in adult humans presents a new therapeutic target for metabolic disease; however, little is known about the regulation of human BAT. Chronic glucocorticoid excess causes obesity in humans, and glucocorticoids suppress BAT activation in rodents. We tested whether glucocorticoids regulate BAT activity in humans. In vivo, the glucocorticoid prednisolone acutely increased (18)fluorodeoxyglucose uptake by BAT (measured using PET/CT) in lean healthy men during mild cold exposure (16°C-17°C). In addition, prednisolone increased supraclavicular skin temperature (measured using infrared thermography) and energy expenditure during cold, but not warm, exposure in lean subjects. In vitro, glucocorticoids increased isoprenaline-stimulated respiration and UCP-1 in human primary brown adipocytes, but substantially decreased isoprenaline-stimulated respiration and UCP-1 in primary murine brown and beige adipocytes. The highly species-specific regulation of BAT function by glucocorticoids may have important implications for the translation of novel treatments to activate BAT to improve metabolic health., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Efficient de novo asymmetric syntheses of (+)-preussin B, the C(2)-epimer of (-)-preussin B, and 3-deoxy-(+)-preussin B have been developed, using the diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 4-phenylbut-2-enoate and diastereoselective reductive cyclizations of γ-amino ketones as the key steps to set the stereochemistry. Conjugate addition followed by enolate protonation generated the corresponding β-amino ester. Homologation using the ester functionality as a synthetic handle gave the corresponding γ-amino ketone. Hydrogenolytic N-debenzylation was accompanied by diastereoselective reductive cyclization in situ; reductive N-methylation then gave 3-deoxy-(+)-preussin B as the major diastereoisomeric product. Meanwhile, the same conjugate addition but followed by enolate oxidation with (+)-camphorsulfonyloxaziridine gave the corresponding anti-α-hydroxy-β-amino ester. α-Epimerization by oxidation and diastereoselective reduction then gave access to the corresponding syn-α-hydroxy-β-amino ester. Homologation of both of these diastereoisomeric α-hydroxy-β-amino esters gave the corresponding β-hydroxy-γ-amino ketones. N-Debenzylation and concomitant diastereoselective reductive cyclization, followed by reductive N-methylation, provided the C(2)-epimer of (-)-preussin B and (+)-preussin B as the major diastereoisomeric products, respectively. The overall yields (from phenylacetaldehyde) were 19% for 3-deoxy-(+)-preussin B over seven steps, 8% for the C(2)-epimer of (-)-preussin B over nine steps, and 7% for (+)-preussin B over eleven steps.

Objectives: Inflammation is critical in the pathogenesis of abdominal aortic aneurysm (AAA) disease. Combined (18)F-fludeoxyglucose ((18)F-FDG) positron emission tomography with computed tomography (PET-CT) and ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) are non-invasive methods of assessing tissue inflammation. The aim of this study was to compare these techniques in patients with AAA., Materials and Methods: Fifteen patients with asymptomatic AAA with diameter 46 ± 7 mm underwent PET-CT with (18)F-FDG, and T2*-weighted MRI before and 24 hours after administration of USPIO. The PET-CT and MRI data were then co-registered. Standardised uptake values (SUVs) were calculated to measure (18)F-FDG activity, and USPIO uptake was determined using the change in R2*. Comparisons between the techniques were made using a quadrant analysis and a voxel-by-voxel evaluation., Results: When all areas of the aneurysm were evaluated, there was a modest correlation between the SUV on PET-CT and the change in R2* on USPIO-enhanced MRI (n = 70,345 voxels; r = .30; p < .0001). Although regions of increased (18)F-FDG and USPIO uptake co-localised on occasion, this was infrequent (kappa statistic 0.074; 95% CI 0.026-0.122). (18)F-FDG activity was commonly focused in the shoulder region whereas USPIO uptake was more apparent in the main body of the aneurysm. Maximum SUV was lower in patients with mural USPIO uptake., Conclusions: Both (18)F-FDG PET-CT and USPIO-MRI uptake identify vascular inflammation associated with AAA. Although they demonstrate a modest correlation, there are distinct differences in the pattern and distribution of uptake, suggesting a differential detection of macrophage glycolytic and phagocytic activity respectively., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Benzonatate was FDA-approved in 1958 as an antitussive. Its mechanism of action is thought to be anesthesia of vagal sensory nerve fibers that mediate cough. Vagal sensory neurons highly express the Nav1.7 subtype of voltage-gated sodium channels, and inhibition of this channel inhibits the cough reflex. Local anesthetics inhibit voltage-gated sodium channels, but there are no reports of whether benzonatate affects these channels. Our hypothesis is that benzonatate inhibits Nav1.7 voltage-gated sodium channels. We used whole cell voltage clamp recording to test the effects of benzonatate on voltage-gated sodium (Na(+)) currents in two murine cell lines, catecholamine A differentiated (CAD) cells, which express primarily Nav1.7, and N1E-115, which express primarily Nav1.3. We found that, like local anesthetics, benzonatate strongly and reversibly inhibits voltage-gated Na(+) channels. Benzonatate causes both tonic and phasic inhibition. It has greater effects on channel inactivation than on activation, and its potency is much greater at depolarized potentials, indicating inactivated-state-specific effects. Na(+) currents in CAD cells and N1E-115 cells are similarly affected, indicating that benzonatate is not Na(+) channel subtype-specific. Benzonatate is a mixture of polyethoxy esters of 4-(butylamino) benzoic acid having varying degrees of hydrophobicity. We found that Na(+) currents are inhibited most potently by a benzonatate fraction containing the 9-ethoxy component. Detectable effects of benzonatate occur at concentrations as low as 0.3 μM, which has been reported in humans. We conclude that benzonatate has local anesthetic-like effects on voltage-gated sodium channels, including Nav1.7, which is a possible mechanism for cough suppression by the drug., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Preclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we investigated whether this phenomenon occurs in humans., Methods and Results: Overall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan. Radiotracer uptake was measured in aortic atheroma and nonvascular tissue (paraspinal muscle). In 1003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (≤30 days) and late (>30 days) recurrent coronary events. Compared with patients with stable angina, patients with MI had higher aortic 18F-fluorodeoxyglucose uptake (tissue-to-background ratio 2.15±0.30 versus 1.84±0.18, P<0.0001) and plasma C-reactive protein concentrations (6.50 [2.00 to 12.75] versus 2.00 [0.50 to 4.00] mg/dL, P=0.0005) despite having similar aortic (P=0.12) and less coronary (P=0.006) atherosclerotic burden and similar paraspinal muscular 18F-fluorodeoxyglucose uptake (P=0.52). Patients with ST-segment elevation MI had larger infarcts (peak plasma troponin 32 300 [10 200 to >50 000] versus 3800 [1000 to 9200] ng/L, P<0.0001) and greater aortic 18F-fluorodeoxyglucose uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non-ST-segment elevation MI. Peak plasma troponin concentrations correlated with aortic 18F-fluorodeoxyglucose uptake (r=0.43, P=0.01) and, on multivariate analysis, independently predicted early (tertile 3 versus tertile 1: relative risk 4.40 [95% CI 1.90 to 10.19], P=0.001), but not late, recurrent MI., Conclusions: The presence and extent of MI is associated with increased aortic atherosclerotic inflammation and early recurrent MI. This finding supports the hypothesis that acute MI exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: MI begets MI., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01749254., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Diastereoselective syntheses of dihydroconduramines (±)-B-1, (±)-E-1, and (±)-F-1 have been achieved from N-protected 4-aminocyclohex-2-en-1-ols via two complementary procedures for epoxidation as the key step. Treatment of either trans- or cis-4-N-benzylaminocyclohex-2-en-1-ol with Cl3CCO2H and then m-chloroperoxybenzoic acid (m-CPBA) resulted in initial formation of the corresponding ammonium species, followed by epoxidation on the face syn to the ammonium moiety exclusively; chemoselective N-benzylation then provided either (1RS,2SR,3RS,4RS)- or (1RS,2RS,3SR,4SR)-2,3-epoxy-4-N,N-dibenzylaminocyclohexan-1-ol, respectively. Treatment of either trans- or cis-4-N,N-dibenzylaminocyclohex-2-en-1-ol with m-CPBA resulted in initial formation of the corresponding N-oxide, followed by epoxidation on the face syn to the hydroxyl group exclusively; reduction then provided either (1RS,2RS,3SR,4RS)- or an alternative route to (1RS,2RS,3SR,4SR)-2,3-epoxy-4-N,N-dibenzylaminocyclohexan-1-ol, respectively. In all cases, S(N)2-type ring opening of these epoxides upon treatment with aqueous H2SO4 proceeded by nucleophilic attack with inversion at C(2) preferentially, distal to the in situ formed ammonium moiety. Hydrogenolytic N-deprotection then gave the corresponding dihydroconduramines (±)-B-1, (±)-E-1, and (±)-F-1.

A range of substituted anti-β-fluorophenylalanines was produced from the corresponding enantiopure α-hydroxy-β-amino esters using a stereospecific XtalFluor-E promoted rearrangement procedure as the key step. The requisite substrates are readily produced via aminohydroxylation of an α,β-unsaturated ester using our lithium amide conjugate addition methodology and, following rearrangement, deprotection of the resultant enantiopure β-fluoro-α-amino esters gives the corresponding enantiopure anti-β-fluorophenylalanines in good yield and high diastereoisomeric purity.

The syn- and anti-diastereoisomeric forms of the reported structures of the marine alkaloids nakinadines D-F have been synthesized, for the first time in all cases, via an approach involving asymmetric Mannich-type (imino-aldol) reactions of methyl phenylacetate with N-tert-butylsulfinyl imines as the key steps to control the stereochemistry. Comparison of the (1)H and (13)C NMR spectroscopic data reported for the natural materials with those acquired for these synthetic samples confirms the initially assigned relative (RS,SR)-configurations of these three alkaloids. In the absence of specific rotation (or other diagnostic) data for the natural materials, it is not possible to unambiguously assign their absolute configurations, although given the absolute (2S)-configurations assigned to nakinadines B and C, and the absolute (2S,3R)-configuration previously established for nakinadine A, the data herein uphold our proposal that nakinadines D-F share the absolute (2S,3R)-configuration.

Concise asymmetric syntheses of (-)-lupinine, (+)-isoretronecanol, (+)-5-epi-tashiromine and (R,R)-1-(hydroxymethyl)octahydroindolizine (the azabicyclic core within stellettamides A-C) have been achieved in 8 steps or fewer from commercially available starting materials. The key steps in these syntheses involved the preparation of enantiopure β-amino esters, upon conjugate addition of lithium (R)-N-(p-methoxybenzyl)-N-(α-methyl-p-methoxybenzyl)amide to either ζ-chloro or ζ-hydroxy substituted tert-butyl (E)-hept-2-enoate, or ε-chloro or ε-hydroxy substituted tert-butyl (E)-hex-2-enoate. Activation of the ω-substituent as a leaving group led to SN2-type ring-closure, which occurred with concomitant N-debenzylation via an E1-type deprotection step, to give the corresponding pyrrolidine or piperidine in good yield. Subsequent alkylation of these enantiopure azacycles, followed by a second ring-closure/concomitant N-debenzylation step formed the pyrrolizidine, indolizidine or quinolizidine motif, and reduction with LiAlH4 gave the target compounds in diastereoisomerically and enantiomerically pure form.

A range of enantiopure polyhydroxylated piperidines, including (2R,3S,4R)-dihydroxypipecolic acid, (-)-3-epi-fagomine, (2S,3S,4R)-dihydroxyhomopipecolic acid, (2S,3R,4R)-dihydroxyhomopipecolic acid, and two trihydroxy-substituted homopipecolic acids, have been prepared using diastereoselective olefinic oxidations of a range of enantiopure tetrahydropyridines as the key step. The requisite substrates were readily prepared from tert-butyl sorbate using our diastereoselective hydroamination or aminohydroxylation protocols followed by ring-closing metathesis. After diastereoselective olefinic oxidation of the resultant enantiopure tetrahydropyridines and deprotection, enantiopure polyhydroxylated piperidines were isolated as single diastereoisomers (>99:1 dr) in good overall yield.

The asymmetric synthesis of (-)-lupinine was achieved in 8 steps, 15% overall yield and >99 : 1 dr from commercially available starting materials. The strategy used for the construction of the quinolizidine scaffold involved reaction of an enantiopure tertiary dibenzylamine via two sequential ring-closures which both occurred with concomitant N-debenzylation.

Purpose of Review: The field of anterior skull-base surgery has undergone rapid advancement in the last 10-15 years. As a result, tumors of the anterior skull base that were once considered inoperable are now routinely resected with reliable results and decreasing morbidity. The purpose of this review is to highlight the most up-to-date opinions and advancements within the field, and to evaluate the recent advances in the surgical management of anterior skull-base tumors., Recent Findings: In the last year, the body of literature in anterior skull-base surgery has been expanded with new anatomic insights, surgical techniques, and data on patient outcomes and quality of life. Much of this literature is focused on minimally invasive, endoscopic techniques, which have expanded greatly in the last decade., Summary: This article summarizes the most current opinion in the field of anterior skull-base surgery. Recent literature regarding new anatomic insights, surgical techniques (resection and reconstruction), and outcomes data are outlined.

Current therapies for Parkinson's disease (PD) offer symptomatic relief but do not provide a cure or slow the disease process. Treatments that could halt progression of the disease or help restore function to damaged neurons would be of substantial benefit. Calcitriol, the active metabolite of vitamin D, has been shown to have significant effects on the brain. These effects include upregulating trophic factor levels, and reducing the severity of some central nervous system lesions. While previous studies have shown that calcitriol can be neuroprotective in 6-hydroxydopamine (6-OHDA) rodent models of PD, the present experiments were designed to examine the ability of calcitriol to promote restoration of extracellular dopamine (DA) levels and tissue content of DA in animals previously lesioned with 6-OHDA. Male Fischer-344 rats were given a single injection of 12 µg 6-OHDA into the right striatum. Four weeks later the animals were administered vehicle or calcitriol (0.3 or 1.0 µg/kg, s.c.) once a day for eight consecutive days. Three weeks after the calcitriol treatments in vivo microdialysis experiments were conducted to measure potassium and amphetamine evoked overflow of DA from both the left and right striata. In control animals treated with 6-OHDA and vehicle there were significant reductions in both potassium and amphetamine evoked overflow of DA on the lesioned side of the brain compared to the contralateral side. In animals treated with 6-OHDA followed by calcitriol there was significantly greater potassium and amphetamine evoked overflow of DA from the lesioned striatum compared to that from the control animals. The calcitriol treatments also led to increases in postmortem tissue levels of DA in the striatum and substantia nigra. These results suggest that calcitriol may help promote recovery of dopaminergic functioning in injured nigrostriatal neurons.