Bismuth(III) triflate: an economical and environmentally friendly catalyst for the Nazarov reaction.

We describe the use of bismuth(III) triflate as an efficient and environmentally friendly catalyst for the Nazarov reaction of aryl vinyl ketones, leading to the synthesis of 3-aryl-2-ethoxycarbonyl-1-indanones and 3-aryl-1-indanones. By changing the temperature and reaction time, it was possible to modulate the reactivity, allowing the synthesis of two distinct product classes (3-aryl-2-ethoxycarbonyl-1-indanones and 3-aryl-1-indanones) in good to excellent yield. The reaction did not require additives and was insensitive to both air and moisture. Preliminary biological evaluation of some indanones showed a promising profile against some human cancer line cells.

One-pot organocatalyzed synthesis of tricyclic indolizines.

Indolizines and their saturated derivatives are important structural motifs present in several biologically active compounds of both natural and synthetic origin. We describe herein a one-pot approach for the synthesis of tricyclic indolizines catalyzed by a bicyclic imidazole-alcohol. The protocol is based on an aqueous Morita-Baylis-Hillman reaction between pyridine-2-carboxaldehydes and six- or seven-membered cyclic enones, followed by sequential intramolecular cyclization and dehydration. So, in a single operational step two new bonds (C-C and C-N) are formed in an organocatalyzed process that takes place in simple conditions (stirring in water at 60 °C for 12 h) and with great atom economy (water as the sole byproduct), affording the purified compounds in yields ranging from 19 to 70%. The facility of the cyclization strongly depends on the size of the cycloalkenone ring: while MBH adducts derived from six-, seven- or eight-membered cycloenones are readily transformed into the corresponding indolizines, cyclopentenone-derived MBH adducts do not cyclize. A competition experiment revealed that cycloheptenone-derived MBH adducts cyclize faster than cyclohexenone-derived adducts. Model DFT calculations have been performed to rationalize these reactivity trends.

Physical activity for obstructive sleep apnea after stroke? A pilot study assessing the contribution of body fluids.

PURPOSE: Obstructive sleep apnea (OSA) and physical inactivity are common after stroke. Physical inactivity can lead to/or exacerbate edema following stroke, and the resultant overnight fluid shift may increase the risk of OSA. We aimed to investigate the effect of physical activity on nocturnal rostral fluid shift, sleep pattern, and edematous state of hemiparetic patients. METHODS: Neck circumference (tape measured) and arms, legs, and trunk fluid volume (bioelectrical impedance spectrum analyzer) were measured before and after 2 polysomnography (PSG) examinations. In the lab, a whole night PSG was performed after the intervention. The intervention consisted of inactivity (lying down and sitting) or activity (standing, performing calf muscle contractions while standing, walking, and climbing stairs) between 13 and 21 h, after the randomization of the participants. With a 7-day interval, participants crossed over to the other group. RESULTS: From 126 eligible participants, 8 with hemiparetic post-first-ever ischemic stroke at the subacute phase were recruited (age: 53.2 ± 16.2; 6 women). Physical activity reduced AHI from 19 to 13 n°/h and wake after sleep onset from 76.5 to 60.3 min and increased fluid volume of paretic and non-paretic arms and trunk before sleep compared to inactivity. CONCLUSION: An acute bout of physical activity reduced OSA classification based on AHI (from moderate to mild) and sleep fragmentation. Our results provide preliminary evidence of a possible link between physical activity in patients after stroke as an intervention to counteract OSA severity and improve sleep.

Whole-genome analysis of monozygotic Brazilian twins discordant for type 1 narcolepsy: a case report.

BACKGROUND: Narcolepsy type 1 (NT1) is a rare and chronic neurological disease characterized by sudden sleep attacks, overwhelming daytime drowsiness, and cataplexy. When associated with a sudden loss of muscle tone (cataplexy) narcolepsy is classified as type 1, while the absence of cataplexy indicates type 2. Genetic, degenerative, and immunological hypotheses to explain the pathophysiology of NT1 are still a matter of debate. To contribute to the understanding of NT1 genetic basis, here we describe, for the first time, a whole genome analysis of a monozygotic twin pair discordant for NT1. CASE PRESENTATION: We present the case of a pair of 17-year-old male, monozygotic twins discordant for NT1. The affected twin had Epworth Sleepiness Scale (ESS) of 20 (can range from 0 to 24), cataplexy, hypnagogic hallucinations, polysomnography without abnormalities, multiple sleep latency tests (MSLT) positive for narcolepsy, a mean sleep latency of 3 min, sleep-onset REM periods SOREMPs of 5, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of zero pg/mL (normal values are > 200 pg/mL). The other twin had no narcolepsy symptoms (ESS of 4), normal polysomnography, MSLT without abnormalities, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of 396,74 pg/mL. To describe the genetic background for the NT1 discordant manifestations in this case, we present the whole-genome analysis of this monozygotic twin pair. The whole-genome comparison revealed that both twins have identical NT1 pathogenic mutations in known genes, such as HLA-DQB1*06:02:01, HLA-DRB1*11:01:02/*15:03:01. The affected twin has the expected clinical manifestation while the unaffected twin has an unexpected phenotype. The unaffected twin has significantly more frameshift mutations as compared to the affected twin (108 versus 75) and mutations that affect stop codons (61 versus 5 in stop gain, 26 versus 2 in start lost). CONCLUSIONS: The differences observed in frameshift and stop codon mutations in the unaffected twin are consistent with loss-of-function effects and protective alleles, that are almost always associated with loss-of-function rare alleles. Also, overrepresentation analysis of genes containing variants with potential clinical relevance in the unaffected twin shows that most mutations are in genes related to immune regulation function, Golgi apparatus, MHC, and olfactory receptor. These observations support the hypothesis that NT1 has an immunological basis although protective mutations in non-HLA alleles might interfere with the expression of the NT1 phenotype and consequently, with the clinical manifestation of the disease.

Hierarchical Clustering and Target-Independent QSAR for Antileishmanial Oxazole and Oxadiazole Derivatives.

Leishmaniasis is a neglected tropical disease that kills more than 20,000 people each year. The chemotherapy available for the treatment of the disease is limited, and novel approaches to discover novel drugs are urgently needed. Herein, 2D- and 4D-quantitative structure-activity relationship (QSAR) models were developed for a series of oxazole and oxadiazole derivatives that are active against Leishmania infantum, the causative agent of visceral leishmaniasis. A clustering strategy based on structural similarity was applied with molecular fingerprints to divide the complete set of compounds into two groups. Hierarchical clustering was followed by the development of 2D- (R2 = 0.90, R2pred = 0.82) and 4D-QSAR models (R2 = 0.80, R2pred = 0.64), which showed improved statistical robustness and predictive ability.

Through space JFH spin-spin coupling constant transmission pathways in 2-(trifluoromethyl)thiophenol: formation of unusual stabilizing bifurcated CFHS and CFSH interactions.

Given its importance and the possibility of organic F to participate in hydrogen bonds (H-bonds), the understanding of its behavior as a H-bond acceptor with different donors is crucial. The interest in organofluorine compounds and the works related to the study of the participation of this atom in non-covalent interactions is constantly growing. Following recent studies in this subject, we evaluated the existence of two bifurcated intramolecular interactions, a bifurcated CFHS H-bond in the cis conformer of 2-trifluoromethylthiophenol and an unusual, bifurcated CFSH interaction in the trans conformer. The JFH spin-spin coupling constant (SSCC) was evaluated for 2-trifluoromethylthiophenol both experimentally by 1H and 19F NMR and theoretically using the natural bond orbitals (NBO), the quantum theory of atoms in molecules (QTAIM) and the non-covalent interactions (NCI) framework. Although both interactions are crucial for the stabilization of the conformer geometries, the observed positive JFH spin-spin coupling constant (SSCC) is mainly resultant from the trans conformer, which has a large calculated positive SSCC, and is transmitted through steric interactions involving the F lone pairs and the σSH bonding orbital.

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances.

Olefin double-bond functionalization has been established as an excellent strategy for the construction of elaborate molecules. In particular, the hydroalkylation of olefins represents a straightforward strategy for the synthesis of new C(sp3)-C(sp3) bonds, with concomitant formation of challenging quaternary carbon centers. In the last 20 years, numerous hydroalkylation methodologies have emerged that have explored the diverse reactivity patterns of the olefin double bond. This review presents examples of olefins acting as electrophilic partners when coordinated with electrophilic transition-metal complexes or, in more recent approaches, when used as precursors of nucleophilic radical species in metal hydride hydrogen atom transfer reactions. This unique reactivity, combined with the wide availability of olefins as starting materials and the success reported in the construction of all-carbon C(sp3) quaternary centers, makes hydroalkylation reactions an ideal platform for the synthesis of molecules with increased molecular complexity.

The bicarbonate/carbon dioxide pair increases hydrogen peroxide-mediated hyperoxidation of human peroxiredoxin 1.

2-Cys peroxiredoxins (Prxs) rapidly reduce H2O2, thereby acting as antioxidants and also as sensors and transmitters of H2O2 signals in cells. Interestingly, eukaryotic 2-Cys Prxs lose their peroxidase activity at high H2O2 levels. Under these conditions, H2O2 oxidizes the sulfenic acid derivative of the Prx peroxidatic Cys (CPSOH) to the sulfinate (CPSO2-) and sulfonated (CPSO3-) forms, redirecting the CPSOH intermediate from the catalytic cycle to the hyperoxidation/inactivation pathway. The susceptibility of 2-Cys Prxs to hyperoxidation varies greatly and depends on structural features that affect the lifetime of the CPSOH intermediate. Among the human Prxs, Prx1 has an intermediate susceptibility to H2O2 and was selected here to investigate the effect of a physiological concentration of HCO3-/CO2 (25 mm) on its hyperoxidation. Immunoblotting and kinetic and MS/MS experiments revealed that HCO3-/CO2 increases Prx1 hyperoxidation and inactivation both in the presence of excess H2O2 and during enzymatic (NADPH/thioredoxin reductase/thioredoxin) and chemical (DTT) turnover. We hypothesized that the stimulating effect of HCO3-/CO2 was due to HCO4-, a peroxide present in equilibrated solutions of H2O2 and HCO3-/CO2 Indeed, additional experiments and calculations uncovered that HCO4- oxidizes CPSOH to CPSO2- with a second-order rate constant 2 orders of magnitude higher than that of H2O2 ((1.5 ± 0.1) × 105 and (2.9 ± 0.2) × 103 m-1·s-1, respectively) and that HCO4- is 250 times more efficient than H2O2 at inactivating 1% Prx1 per turnover. The fact that the biologically ubiquitous HCO3-/CO2 pair stimulates Prx1 hyperoxidation and inactivation bears relevance to Prx1 functions beyond its antioxidant activity.

Catalyst-Free Conjugate Addition of Indolizines to In Situ-Generated Oxidized Morita-Baylis-Hillman Adducts.

Sequential one-pot 2-iodoxybenzoic acid (IBX) oxidation of Morita-Baylis-Hillman (MBH) adducts followed by catalyst-free indolizine conjugate addition was developed. The wide scopes of MBH adducts and indolizines were investigated, and densely functionalized adducts were obtained in yields of up to 94%. The conjugate addition step occurred in less than a minute at room temperature with total regioselectivity toward indolizine C3 carbon. Less nucleophilic C1 carbon was also alkylated when C3-substituted indolizines were employed as the substrate.

Origin of the Diastereoselectivity of the Heterogeneous Hydrogenation of a Substituted Indolizine.

In this work, the stereoselective heterogeneous hydrogenation of a tetrasubstituted indolizine was studied. Partial hydrogenation products were obtained in three steps from a substituted pyridine-2-carboxaldehyde prepared from commercial pyridoxine hydrochloride. The hydrogenation of the indolizine ring was shown to be diastereoselective, forming trans-6b and cis-9. Theoretical calculations (ab initio and DFT) were used to rationalize the unusual trans stereoselectivity for 6b, and a keto-enol tautomerism under kinetic control has been proposed as the source of diastereoselectivity.

Brønsted-acid-catalyzed selective Friedel-Crafts monoalkylation of isatins with indolizines in water.

The controlled mono-addition of indolizines to isatins under very mild conditions is described. The reaction occurs in water using diphenylphosphate as the catalyst, which is dramatically accelerated by surfactant addition. 3-Hydroxy-3-indolizinyl-2-oxindole scaffolds were synthesized in up to >99% yield. Notably, in organic solvents only bis-addition products were observed.

Chronic pain in narcolepsy type 1 and type 2 - an underestimated reality.

Narcolepsy is a rare sleep disorder classified in types 1 and 2. The co-morbidities of narcolepsy type 1, with hypocretin-1 deficiency, are established. Hypocretin-1 in the central and peripheral nervous systems regulates nociception and pain. However, the patients with narcolepsy type 2 have similar excessive daytime sleepiness and co-morbidities without elucidation. The objective of the study was to determine the frequency and the characteristic of chronic pain according to the type of narcolepsy. We also investigated the effect of the interaction between the nutritional status and the type of narcolepsy. It was a cross-sectional study using self-administered questionnaires. Patients with narcolepsy (33 type 1 and 33 type 2), from Universidade Federal de São Paulo, Brazil, matched by age and gender to 33 control subjects were included. Both types of narcolepsy presented a high frequency of chronic pain (84.84% type 1 versus 75.75% type 2), with indistinct pain characteristics between them. The odds ratio was 20.8 in type 1 and 11.6 in type 2, compared with controls. Obese individuals with narcolepsy type 1 and type 2 did not present a significant difference in pain intensity, compared with obese controls. Patients with narcolepsy type 1 and type 2 were associated with a high frequency of chronic pain. Chronic pain emerged as a co-morbidity never reported before in type 2. Depression possibly influences pain perception in these patients. Obesity might play a role in pain intensity in narcolepsy. The treatment of narcolepsy should take account of chronic pain, depression and obesity management.

Palladium-Mediated Oxidative Annulation of δ-Indolyl-α,ß-Unsaturated Compounds toward the Synthesis of Cyclopenta[ b]indoles and Heterogeneous Hydrogenation To Access Fused Indolines.

The cyclopenta[ b]indole moiety represents a key skeletal unit in several natural and synthetic compounds that exhibit diverse biological properties. We described herein a two-step sequence for synthesizing cyclopenta[ b]indoles with great structural diversity in overall yields up to 37%. The key step was a palladium-catalyzed oxidative annulation of 3-alkylindoles (Fujiwara-Moritani reaction). The obtained cyclopenta[ b]indoles were used as substrates in heterogeneous hydrogenation reactions to afford new fused indolines in moderate yields. An acid-catalyzed intramolecular cyclization of three such indolines gave tetracyclic lactams in 89, 90, and 61% yields.

Sleep Disorders in Hereditary Ataxias.

PURPOSE OF REVIEW: In this review, we aim to describe the main sleep disorders observed in patients with different forms of hereditary ataxias and discuss the main pathophysiological mechanisms. RECENT FINDINGS: Several pathological studies have demonstrated that the degenerative process in patients with hereditary ataxias may involve not only the cerebellum, but also other areas of the nervous system, and explain noncerebellar symptoms, such as sleep disorders. Hereditary ataxias are neurodegenerative disorders with heterogeneous genetic and clinical presentation. This group of diseases usually affects other areas of the nervous system, besides the cerebellum, and noncerebellar signs and symptoms may occur, such as sleep disorders. The main sleep disorders related to hereditary ataxias include REM sleep behavior disorder, insomnia, excessive daytime sleepiness, obstructive and central sleep apnea, periodic leg movement in sleep, and restless legs syndrome.

Intramolecular H-Bond Is Formed in 2-Fluorophenol and 2-Fluorothiophenol, but It May Not Be the Main Pathway of the JFH Coupling Constant Transmission.

The intramolecular CF···HX (X = O or S) H-bond and JFH spin-spin coupling constants (SSCCs) in 2-fluorophenol and 2-fluorothiophenol were investigated experimentally by 1H and 19F NMR and theoretically in the framework of the natural bond orbital analysis. In contrast with recent findings from the literature, the results obtained in this work showed that an intramolecular H-bond is formed in the cis conformers and that it has an electrostatic origin. Such an intramolecular electrostatic H-bond is the interaction that rules the conformational preferences on these compounds. Moreover, the natural J-coupling analysis indicated that the JHF SSCC in 2-fluorophenol has its origin on LP(F)/σOH steric interactions and should be labeled as 4TSJHF. On the other hand, the analogue SSCC for 2-fluorothiophenol has its origin on the intramolecular H-bond LP(F) → σSH* hyperconjugative interaction and should be described as a 1hJFH SSCC.

Vinyl-1,2,4-oxadiazoles Behave as Nucleophilic Partners in Morita-Baylis-Hillman Reactions.

We describe that vinyl-oxadiazoles function as a new and efficient nucleophilic partner for the Morita-Baylis-Hillman (MBH) reaction. The reaction between 5-vinyl-3-aryl-1,2,4-oxadiazoles and aromatic and aliphatic aldehydes, catalyzed by DABCO in the absence of solvent, showed high efficiency to afford a new class of heterocyclic MBH adducts with potential biological activity on yields up to 99% and short reaction times. These synthetically attractive adducts bear a heterocyclic scaffold of large pharmaceutical and commercial interest associated with a plethora of biological effects and technological applications. We also demonstrate their synthetic usefulness by a photoinduced addition reaction to a polyfunctionalized amino alcohol.

Withdrawing and Withholding Life Support in Patients With Cancer in an ICU Setting: A 5-Year Experience at a European Cancer Center.

OBJECTIVE: This was an observational retrospective study aimed to examine the frequency and associated factors of withdrawing or withholding life support (WWLS) in the intensive care unit (ICU) of a comprehensive cancer center. METHODS: Medical records of adult patients with cancer admitted to the ICU between January 2010 and December 2014 were reviewed. Patients who died during that period were classified into 2 groups: full life support and withdrawing and withholding life support. The relative impact of demographic and clinical factors was assessed using logistic regression. RESULTS: A total of 247 patients died in our unit (mortality rate of 16.3%). Their median age was 62 (interquartile range [IQR] 51-73) years, there were 142 (57.5%) male patients, and they had predominantly solid malignancies (62.3%). The median Simplified Acute Physiology Score II and Acute Physiology and Chronic Health Evaluation scores were 67 (IQR 54-80) and 29 (IQR 23-55), respectively. Ninety-six (38.9%) patients died after WWLS with no statistically significant differences in decisions to limit therapy during the study period. Patients with advanced age, solid malignancies, nonneutropenic, and longer duration of mechanical ventilation were more likely to die after WWLS. In multivariate analysis, presenting with neutropenia was independently associated with a lower likelihood of dying after WWLS (odds ratio: 0.34, 95% confidence interval: 0.15-0.80). CONCLUSION: Limitation of therapy has been a common practice in oncologic ICUs over recent years. Neutropenia is an independent predictor of limitation of therapy.

Narcolepsy, Precocious Puberty and Obesity in the Pediatric Population: a Literature Review.

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, sleep paralysis and hypnagogic and hypnopompic hallucinations. The onset of the symptoms usually occurs in childhood, and previous studies have reported an association between narcolepsy and other endocrine diseases in the pediatric population, such as obesity and precocious puberty. The incidence of overweight or obesity ranges from 25% to 74% in patients with narcolepsy type I, while precocious puberty is present in 17% of children with narcolepsy with cataplexy. However, the mechanisms involved in the association of narcolepsy with obesity and precocious puberty have not been fully elucidated yet. In this review, we aimed to discuss narcolepsy in pediatric populations, highlighting the diagnostic difficulties and the complexity of the possible mechanisms that can relate narcolepsy to precocious puberty and obesity. We also emphasized the fact that endocrine diseases must be taken into consideration in children diagnosed with narcolepsy.

Catalytic Asymmetric Conjugate Addition of Indolizines to α,ß-Unsaturated Ketones.

A catalytic enantioselective conjugate addition of indolizines to enones is described. The chiral phosphoric acid (S)-TRIP activates α,ß-unsaturated ketones, thereby promoting an enantioface-differentiating attack by indolizines. Using this reaction, several alkylated indolizines were synthesized in good yields and with enantiomeric ratios of up to 98:2.

Polysomnography findings in spinocerebellar ataxia type 6.

Spinocerebellar ataxia type 6 (SCA6) is usually described as a pure ataxia syndrome. However, SCA6 patients may have sleep complaints. In this paper, sleep disorders were investigated in patients with SCA6. Twelve SCA6 patients and 12 subjects matched by gender, age and body mass index (control group) underwent polysomnography and clinical investigation for sleep disorders. SCA6 had a higher frequency of snoring (P = 0.01), a higher index of awakening due to respiratory events (P = 0.003) and central apnea events during sleep (P = 0.024), a longer sleep Stage N1 (P = 0.02) and a lower sleep Stage N3 (P = 0.05) in SCA6 patients than in control subjects. SCA6 patients had a reduction in slow wave sleep and a higher frequency of snoring and respiratory disorders during sleep when compared to the control group.