Mucociliary clearance,airway inflammation and nasal symptoms in urban motorcyclists

OBJECTIVES:There is evidence that outdoor workers exposed to high levels of air pollution exhibit airway inflammation and increased airway symptoms. We hypothesized that these workers would experience increased airway symptoms and decreased nasal mucociliary clearance associated with their exposure to air pollution.METHODS:In total, 25 non-smoking commercial motorcyclists, aged 18-44 years, were included in this study. These drivers work 8-12 hours per day, 5 days per week, driving on urban streets. Nasal mucociliary clearance was measured by the saccharine transit test; airway acidification was measured by assessing the pH of exhaled breath condensate; and airway symptoms were measured by the Sino-nasal Outcome Test-20 questionnaire. To assess personal air pollution exposure, the subjects used a passive-diffusion nitrogen dioxide (NO₂) concentration-monitoring system during the 14 days before each assessment. The associations between NO₂ and the airway outcomes were analyzed using the Mann-Whitney test and the Chi-Square test. Clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01976039","term_id":"NCT01976039"}}NCT01976039.RESULTS:Compared with clearance in healthy adult males, mucociliary clearance was decreased in 32% of the motorcyclists. Additionally, 64% of the motorcyclists had airway acidification and 92% experienced airway symptoms. The median personal NO₂ exposure level was 75 mg/m³ for these subjects and a significant association was observed between NO₂ and impaired mucociliary clearance (p = 0.036).CONCLUSION:Non-smoking commercial motorcyclists exhibit increased airway symptoms and airway acidification as well as decreased nasal mucociliary clearance, all of which are significantly associated with the amount of exposure to air pollution.     

Synthesis of natural 1-O-alkylglycerols: a study on the chemoselective opening of the epoxide ring by onium quaternary salts (N and P) and ionic liquids

A chemoselective route for the synthesis of 1-O-alkylglycerols chimyl (1), batyl (2), and selachyl (3) is reported. These compounds can be naturally isolated from shark liver oil and the skin of animals such as stingrays and chimeras and exhibit potential anti-fouling activity. The synthetic approach developed in this work included two distinct methods of preparation. The first was based on solvent-free reactions catalyzed by onium quaternary salts (N and P) and ionic liquids; the second methodology was based on a series of one-pot reactions.

A chemoselective route for the synthesis of 1-O-alkylglycerols chimyl (1), batyl (2), and selachyl (3) is reported.     

Photocatalytic degradation of ibuprofen using titanium oxide: insights into the mechanism and preferential attack of radicals

The present work studied ibuprofen degradation using titanium dioxide as a photocatalyst. Mechanistic aspects were presented and the preferred attack sites by the OH˙ radical on the ibuprofen molecule were detailed, based on experimental and simple theoretical-computational results. Although some previous studies show mechanistic proposals, some aspects still need to be investigated, such as the participation of 4-isobutylacetophenone in the ibuprofen degradation and the preferred regions of attack by OH˙ radicals. The photodegradation was satisfactory using 0.03 g of TiO₂ and pH = 5.0, reaching 100% decontamination in 5 min. The zeta potential curve showed the regions of attraction and repulsion between TiO₂ and ibuprofen, depending on the pH range and charge of the species, influencing the amount of by-products formed. Different by-products have been identified by GC-MS, such as 4-isobutylacetophenone. Ibuprofen conversion to 4-isobutylacetophenone takes place through decarboxylation reaction followed by oxidation. The proposed mechanism indicates that the degradation of ibuprofen undergoes a series of elementary reactions in solution and on the surface. Three different radicals (OH˙, O₂⁻˙ and OOH˙) are produced in the reaction sequence and contribute strongly to the oxidation and mineralization of ibuprofen and by-products, but the hydroxyl radical has a greater oxidation capacity. The simple study using the DFT approach demonstrated that the OH˙ radical attacks preferentially in the region of the ibuprofen molecule with high electronic density, which is located close to the aromatic ring (C C bond). The presence of the OH˙ radical was confirmed through a model reaction using salicylic acid as a probe molecule.

The degradation of ibuprofen undergoes a series of elementary reactions, generating different radicals which attack preferentially in the region of the ibuprofen with high electron density.     

Isolated brachial artery aneurysm: a rare presentation of paediatric Behçet’s disease

Behçet’s disease is a rare disease characterised by recurrent oral ulcers, with systemic manifestations including genital ulcers, ocular disease, skin lesions, gastrointestinal disease, neurologic disease, vascular disease and arthritis. Most clinical manifestations of Behçet’s disease are believed to be due to vasculitis. The heterogeneous clinical spectrum is influenced by sex, ethnicity and country of residence. Vascular manifestation in the form of isolated large brachial artery aneurysm is rare in children. Treatment involves aneurysmorrhaphy to avoid rupture or ischaemic sequelae in addition to lifelong medical management to control vasculitis.     

Dacarbazine alone or associated with melanoma-bearing cancer pain model induces painful hypersensitivity by TRPA1 activation in mice

Antineoplastic therapy has been associated with pain syndrome development characterized by acute and chronic pain. The chemotherapeutic agent dacarbazine, used mainly to treat metastatic melanoma, is reported to cause painful symptoms, compromising patient quality of life. Evidence has proposed that transient receptor potential ankyrin 1 (TRPA1) plays a critical role in chemotherapy-induced pain syndrome. Here, we investigated whether dacarbazine causes painful hypersensitivity in naive or melanoma-bearing mice and the involvement of TRPA1 in these models. Mouse dorsal root ganglion (DRG) neurons and human TRPA1-transfected HEK293 (hTRPA1-HEK293) cells were used to evaluate the TRPA1-mediated calcium response evoked by dacarbazine. Mechanical and cold allodynia were evaluated after acute or repeated dacarbazine administration in naive mice or after inoculation of B16-F10 melanoma cells in C57BL/6 mice. TRPA1 involvement was investigated by using pharmacological and genetic tools (selective antagonist or antisense oligonucleotide treatment and Trpa1 knockout mice). Dacarbazine directly activated TRPA1 in hTRPA1-HEK293 cells and mouse DRG neurons and appears to sensitize TRPA1 indirectly by generating oxidative stress products. Moreover, dacarbazine caused mechanical and cold allodynia in naive but not Trpa1 knockout mice. Also, dacarbazine-induced nociception was reduced by the pharmacological TRPA1 blockade (antagonism), antioxidants, and by ablation of TRPA1 expression. TRPA1 pharmacological blockade also reduced dacarbazine-induced nociception in a tumor-associated pain model. Thus, dacarbazine causes nociception by TRPA1 activation, indicating that this receptor may represent a pharmacological target for treating chemotherapy-induced pain syndrome in cancer patients submitted to antineoplastic treatment with dacarbazine.     

Solvent-free synthesis of 3,5-isoxazoles via 1,3-dipolar cycloaddition of terminal alkynes and hydroxyimidoyl chlorides over Cu/Al2O3 surface under ball-milling conditions

Scalable, solvent-free synthesis of 3,5-isoxazoles under ball-milling conditions has been developed. The proposed methodology allows the synthesis of 3,5-isoxazoles in moderate to excellent yields from terminal alkynes and hydroxyimidoyl chlorides, using a recyclable Cu/Al₂O₃ nanocomposite catalyst. Furthermore, the proposed conditions are reproducible to a 1.0-gram scale without further milling time variations.

A practical and scalable mechanochemical 1,3-dipolar cycloaddition between hydroxyimidoyl chlorides and terminal alkynes catalyzed by Cu/Al₂O₃ allows a quick access to 3,5-isoxazole derivatives.

The addition of oxygen or nitrogen-containing heterocycles in drug candidates has become a common feature of the recently approved drugs by the FDA.^1,2 In particular, isoxazoles are common molecular scaffolds employed in medicinal chemistry due to the non-covalent interactions such as hydrogen bonding (through the N) and π–π stacking (by the unsaturated 5-membered ring).^3–6 Within the isoxazole family, 3,5-isoxazoles (1) are regularly utilized as pharmacophores in medicinal chemistry.^2,5,6 Selected examples including muscimol (GABA_a agonist), isocarboxazib (antidepressant), isoxicam (anti-inflammatory), berzosertib (ATR kinase inhibitor), and sulfamethoxazole (antibiotic) are highlighted in Fig. 1.^7–10Open in a separate windowFig. 1Examples of isoxazoles with pharmacological activity.Various methodologies to synthesize 3,5-isoxazoles have been developed over the years.^7,9,11–13 Specifically, 1,3-dipolar cycloaddition between terminal alkynes (2) and nitrile oxides (4) formed in situ by deprotonation of hydroxyimidoyl chlorides (3) is a standard route to access 3,5-isoxazoles (1) (Fig. 2).^7,9,14 Recent reports have sought to mitigate the environmental impact of this reaction by performing 1,3-dipolar cycloaddition under solvent-free conditions, using green solvents such as water or ionic liquids, under metal-free conditions, or using mild oxidants.^14–28 However, these methodologies have a low atom economy, have a higher hazardous waste production, and are less energy efficient. Therefore, developing a greener methodology that enables rapid and efficient access to these scaffolds is highly desirable.Open in a separate windowFig. 21,3-Dipolar cycloaddition of terminal alkynes and nitrile oxides.Mechanochemistry has been recognized as an environmentally friendly technique as reactions can be performed under solvent-free conditions. Additionally, in some instances, work-up and purification are simplified or absent from procedures, and the process consumes less energy than other solution-based techniques.^29–33 The use of mechanochemical techniques to synthesize isoxazoles is limited. Sherin et al. reported a synthesis of 3,5-isoxazoles (7) by grinding in a mortar and pestle curcumin derivatives (5), hydroxylamine (6), and sub-stoichiometric amounts of acetic acid to form the 3,5-isoxazole (7) in short times and excellent yields (Fig. 3a).³⁴ Likewise, Xu et al. studied the synthesis of trisubstituted isoxazoles (10) via 1,3-dipolar cycloaddition of N-hydroxybenzimidoyl chlorides (8) and N-substituted β-enamino carbonyl (9) compounds by ball-milling (Fig. 3b) in high yields, short reaction times, in the absence of catalyst and liquid additives.³⁵ To our knowledge, mechanochemical synthesis of 3,5-isoxazoles (1) from terminal alkynes (2) and hydroxyimidoyl chloride (3) has not been reported (Fig. 3c). The proposed methodology employs a planetary ball-milling technique that provides a route to access in large scale, short reaction times, and high atom economy the corresponding 3,5-isoxazoles (1). Additionally, it utilizes synthetically accessible or commercially available motifs such as terminal alkynes (2) and hydroxyimidoyl chlorides (3) that are recurrent or easily installed in many substrates. Herein, we report a mechanochemical 1,3-dipolar cycloaddition using the planetary ball-mill to synthesize a wide range 3,5-isoxazoles from a broad library of alkynes and (E,Z)-N-hydroxy-4-nitrobenzimidoyl chloride (3a), ethyl (E,Z)-2-chloro-2-(hydroxyimino)acetate (3b), hydroxycarbonimidic dibromide (3c), or (E,Z)-N-hydroxy-4-methoxybenzimidoyl chloride (3d) in moderate to excellent yields, in short reaction time, and with less waste production than in solution based reactions (Fig. 3c).Open in a separate windowFig. 3Previously reported synthesis of isoxazoles.We began our investigation by performing an optimisation of the 1,3-dipolar cycloaddition reaction between alkyne 2a and hydroxyimidoyl chlorides 3a by milling the selected substrates in a stainless-steel (SS) jar in the planetary ball-mill to obtain 3,5-isoxazole 1a (36,37Optimization of reaction conditions^a

Angioplasty for primary treatment of aortic coarctation: immediate results in two adult patients

Two adult patients with severe aortic coarctation were treated by angioplasty performed percutaneously through the right femoral artery. A 20 mm balloon catheter was used, being inflated several times within the stenosis. The final angiographic result was excellent in both cases. The gradients were 38 and 46 mm Hg before and 5 and 3 mm Hg after angioplasty, respectively. The arterial pulses in the legs were normal after the procedure and no complication was observed.