Development of a dry powder insufflation device with application in in vitro cell-based assays in the context of respiratory delivery.

Research on pharmaceutical dry powders has been increasing worldwide, along with increased therapeutic strategies for an application through the pulmonary or the nasal routes. In vitro methodologies and tests that mimic the respiratory environment and the process of inhalation itself are, thus, essential. The literature frequently reports cell-based in vitro assays that involve testing the dry powders in suspension. This experimental setting is not adequate, as both the lung and the nasal cavity are devoid of abundant liquid. However, devices that permit powder insufflation over cells in culture are either scarce or technically complex and expensive, which is not feasible in early stages of research. In this context, this work proposes the development of a device that allows the delivery of dry powders onto cell surfaces, thus simulating inhalation more appropriately. Subsequently, a quartz crystal microbalance (QCM) was used to establish a technique enabling the determination of dry powder deposition profiles. Additionally, the determination of the viability of respiratory cells (A549) after the insufflation of a dry powder using the developed device was performed. In all, a prototype for dry powder insufflation was designed and developed, using 3D printing methods for its production. It allowed the homogenous dispersion of the insufflated powders over a petri dish and a QCM crystal, and a more detailed study on how dry powders disperse over the supports. The device, already protected by a patent, still requires further improvement, especially regarding the method for powder weighing and the efficiency of the insufflation process, which is being addressed. The impact of insufflation of air and of locust bean gum (LBG)-based microparticles revealed absence of cytotoxic effect, as cell viability roughly above 70 % was always determined.

Mycobacterium szulgai: A Rare Cause of Non-Tuberculous Mycobacteria Disseminated Infection.

Mycobacterium szulgai (MS) is a rare and slow-growing type of non-tuberculous mycobacteria (NTM), with a human isolation prevalence of less than 0.2% of all NTM cases. MS may cause pulmonary infection, extra-pulmonary localized disease involving the skin, lymph nodes, bone, synovial tissue or kidneys and disseminated infection, when two or more organs are affected. When disseminated infection is present, the patients usually have an underlying immunosuppressive condition. The authors report the case of a 25-year-old patient with systemic lupus erythematosus, presenting with recurrent fever, non-productive coughing, weight loss and asthenia, as well as two violaceous plaques with superficial ulceration in the gluteal region. MS was isolated from the bronchial lavage and skin biopsy cultures, confirming the rare disseminated form of MS infection. After 10 months of follow-up on isoniazid, rifampin, ethambutol and pyrazinamide, no signs of relapse were evident. To date, only 16 other cases of MS disseminated disease have been reported.

Toxic Epidermal Necrolysis-Like Lupus Erythematous Presentation Following SARS-CoV-2 Infection.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organs. Infectious agents have been implicated in the pathogenesis of SLE. The emergent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a pro-inflammatory cytokine storm and has been linked to autoimmune phenomena, which can lead to the onset of autoimmune diseases. We report the case of a 70-year-old patient who developed a toxic epidermal necrolysis (TEN)-like subacute cutaneous lupus (SCL) as a severe presentation of SLE, 1 month after SARS-CoV-2 infection. After excluding other causes of SLE, treatment was initiated with a successful outcome.

Spectrum of Imaging Findings at Chest Radiography, US, CT, and MRI in Multisystem Inflammatory Syndrome in Children Associated with COVID-19.

This case series examines the spectrum of imaging findings at chest radiography, US, CT, and MRI in 35 children admitted to a tertiary pediatric hospital in April and May 2020 with a post-coronavirus disease 2019 inflammatory condition known as multisystem inflammatory syndrome in children. The constellation of findings includes airway inflammation and rapid development of pulmonary edema on thoracic images, coronary artery aneurysms, and extensive right iliac fossa inflammatory changes on abdominal images. Awareness of this emerging condition and the expected multi-organ imaging findings will aid radiologists in the assessment of these complex cases.

Enterococcus gallinarum Causing Native Valve Endocarditis.

Endocarditis due to Enterococcus gallinarum is a rare condition, usually affecting older patients. The most frequent source of infection is the gastrointestinal or genitourinary tracts; it frequently involves the aortic valve and tends to produce heart failure. We present a case of Enterococcus gallinarum endocarditis developing on a normal native heart valve. Enterococcus gallinarum is intrinsically resistant to vancomycin. Antibiotic susceptibility patterns indicate that most isolates are penicillin and ampicillin-susceptible. LEARNING POINTS: Endocarditis due to Enterococcus gallinarum is rare.Enterococcus gallinarum is intrinsically resistant to vancomycin.Most isolates are penicillin and ampicillin-susceptible.

Acute airway obstruction due to benign multinodular goitre.

Benign multinodular goitre is a common illness. When accompanied by obstructive symptoms, such as dyspnoea, it carries an indication for surgery. Benign multinodular goitres rarely cause acute airway obstruction. We report the case of a 88-year-old woman who presented with acute shortness of breath and stridor. A chest CT revealed marked enlargement of the thyroid gland, with an extensive intrathoracic component. She was proposed for total thyroidectomy. Her intraoperative course was unremarkable, but the patient passed away in postoperative period from ventricular fibrillation. Recognition of these cases is important, as they constitute a preventable cause of mortality if timely diagnosed and treated.

Recurrent mesalazine-induced myopericarditis in a patient with ulcerative colitis.

Mesalazine is a common treatment for inflammatory bowel disease and can be rarely associated with myopericarditis. We report a case of a 19-year-old man recently diagnosed with ulcerative colitis and started on mesalazine, who presented with chest pain 2 weeks after beginning this therapy. Blood tests demonstrated elevated troponin I. ECG and echocardiographic changes were consistent with myopericarditis. When mesalazine was reintroduced 2 weeks after discharge, he suffered from myopericarditis again. On cessation of the drug, the cardiac symptoms resolved in combination with anti-inflammatory therapy. The onset of symptoms after mesalazine, and improvement of chest pain and cardiac biomarkers after discontinuing the drug, suggest that our patient suffered from a rare drug-hypersensitivity reaction to mesalazine.

Macrophagic myofasciitis: a challenging diagnosis.

A 25-year-old man admitted for generalised muscle pain with an insidious onset 3 years ago. He had exercise intolerance and decrease in muscle strength, requiring gait support. He was previously healthy, with no chronic medication or recent history of drugs or toxics. National vaccination plan actualised with hepatitis B and tetanus vaccines administered 10 and 2 years, respectively, before symptom onset. No analytical, imaging or electromyography changes were found. Muscle biopsy revealed an inflammatory infiltrate predominantly macrophagic with aluminium deposits suggestive of macrophagic myofasciitis (MMF). It is probably associated with vaccines previously administered. MMF lesion can be regarded as pathological only if detected at least 18 months after last aluminic immunisation, as our case illustrates.

The thermochemistry of cubane 50 years after its synthesis: a high-level theoretical study of cubane and its derivatives.

The gas-phase enthalpy of formation of cubane (603.4 ± 4 kJ mol(-1)) was calculated using an explicitly correlated composite method (W1-F12). The result obtained for cubane, together with the experimental value for the enthalpy of sublimation, 54.8 ± 2.0 kJ mol(-1), led to 548.6 ± 4.5 kJ mol(-1) for the solid-phase enthalpy of formation. This value is only 6.8 kJ mol(-1) higher than the 50-year-old original calorimetric result. The carbon-hydrogen bond dissociation enthalpy (C-H BDE) of cubane (438.4 ± 4 kJ mol(-1)), together with properties relevant for its experimental determination using gas-phase ion thermochemistry, namely the cubane gas-phase acidity (1704.6 ± 4 kJ mol(-1)), cubyl radical electron affinity (45.8 ± 4 kJ mol(-1)), cubane ionization energy (1435.1 ± 4 kJ mol(-1)), cubyl radical cation proton affinity (918.8 ± 4 kJ mol(-1)), cubane cation appearance energy (1099.6 ± 4 kJ mol(-1)), and cubyl ionization energy (661.2 ± 4 kJ mol(-1)), were also determined. These values were compared with those calculated for unstrained hydrocarbons (viz., methane, ethane, and isobutane). The strain energy of cubane (667.2 kJ mol(-1)) and cubyl radical (689.4 kJ mol(-1)) were independently estimated via quasihomodesmotic reactions. These values were related via a simple model to the C-H BDE in cubane. Taking into account the accuracy of the computational method, the comparison with high-precision experimental results, and the data consistency afforded by the relevant thermodynamic cycles, we claim an uncertainty better than ±4 kJ mol(-1) for the new enthalpy of formation values presented.

[Lithokelyphopedion]. / Litoquelifopédio.

Lithopedions are extremely rare conditions. Less than 300 cases were described worldwide. We report a case occurring in a woman of 77 years of age, admitted with dehydration, urinary tract infection and infected limb pressure ulcers. She had been recently admitted in a Surgery ward for incarcerated umbilical hernia. At the time the abdominal examination revealed a mass with about 10 cm in diameter, with petrous consistency, adherent to the deep plans around the umbilical regium and the hypogastrium. This finding was interpreted as a probable left renal tumor. The abdominal X-ray revealed voluminous calcified mass and the CT-scan showed to be a lithokelyphopedion with about fifty years, of a full term pregnancy.

Energetics of tert-butoxyl addition reaction to norbornadiene: a method for estimating the pi-bond strength of a carbon-carbon double bond.

The energetics of tert-butoxyl radical addition reaction to norbornadiene was investigated by time-resolved photoacoustic calorimetry (TR-PAC). The result, together with the C-O bond dissociation enthalpy (BDE) in the addition product, allowed us to calculate the pi-bond dissociation enthalpy in norbornadiene. Quantum chemistry (QC) methods were also used to obtain several enthalpies of reaction of the addition of oxygen-centered radicals to alkenes. The pi-bond dissociation enthalpies in these molecules were calculated by a procedure similar to that used in the case of norbornadiene and were compared with the pi-BDE values obtained by the method proposed by Benson. These two different approaches yield similar values for the pi-BDEs in alkenes, indicating that the addition method proposed in the present study is a valid way to derive that quantity. The influence of strain in the pi-BDEs of cyclic alkenes was investigated and allowed us to justify the difference between the pi-BDE in norbornene and norbornadiene. Finally, the thermochemistry of the addition and abstraction reactions involving these two molecules and tert-butoxyl radical was analyzed.

Energetic differences between the five- and six-membered ring hydrocarbons: strain energies in the parent and radical molecules.

The C-H bond dissociation enthalpies (BDEs) for the five- and six-membered ring alkanes, alkenes, and dienes were investigated and discussed in terms of conventional strain energies (SEs). New determinations are reported for cyclopentane and cyclohexane by time-resolved photoacoustic calorimetry and quantum chemistry methods. The C-H BDEs for the alkenes yielding the alkyl radicals cyclopenten-4-yl and cyclohexen-4-yl and the alpha-C-H BDE in cyclopentene were also calculated. The s-homodesmotic model was used to determine SEs for both the parent molecules and the radicals. When the appropriate s-homodesmotic model is chosen, the obtained SEs are in good agreement with the ones derived from group additivity schemes. The different BDEs in the title molecules are explained by the calculated SEs in the parent molecules and their radicals: (1) BDEs leading to alkyl radicals are ca. 10 kJ mol (-1) lower in cyclopentane and cyclopentene than in cyclohexane and cyclohexene, due to a smaller eclipsing strain in the five-membered radicals relative to the parent molecules (six-membered hydrocarbons and their radicals are essentially strain free). (2) C-H BDEs in cyclopentene and cyclohexene leading to the allyl radicals are similar because cyclopenten-3-yl has almost as much strain as its parent molecule, due to a synperiplanar configuration. (3) The C-H BDE in 1,3-cyclopentadiene is 27 kJ mol (-1) higher than in 1,4-cyclohexadiene due to the stabilizing effect of the conjugated double bond in 1,3-cyclopentadiene and not to a destabilization of the cyclopentadienyl radical. The chemical insight afforded by group additivity methods in choosing the correct model for SE estimation is highlighted.

C-H bond dissociation enthalpies in norbornane. An experimental and computational study.

Gas-phase C-H bond dissociation enthalpies (BDEs) in norbornane were determined by quantum chemistry calculations and the C2-H BDE was experimentally obtained for the first time by time-resolved photoacoustic calorimetry. CBS-Q and CBS-QB3 methods were used to derive the values DH degrees (C1-H) = 449 kJ mol-1, DH degrees (C7-H) = 439 kJ mol-1, and DH degrees (C2-H) = 413 kJ mol-1. The experimental result DH degrees (C2-H) = 414.6 +/- 5.4 kJ mol-1 is in excellent agreement with the theoretical value. The trend DH degrees (C1-H) > DH degrees (C7-H) > DH degrees (C2-H) is discussed.

Energetics of the allyl group.

Aiming to improve our understanding of the stability of radicals containing the allylic moiety, carbon-hydrogen bond dissociation enthalpies (BDEs) in propene, isobutene, 1-butene, (E)-2-butene, 3-metylbut-1-ene, (E)-2-pentene, (E)-1,3-pentadiene, 1,4-pentadiene, cyclohexene, 1,3-cyclohexadiene, and 1,4-cyclohexadiene have been determined by quantum chemistry calculations. The BDEs in cyclohexene, 1,3-cyclohexadiene, and 1,4-cyclohexadiene have also been obtained by time-resolved photoacoustic calorimetry. The theoretical study involved a DFT method as well as ab initio complete basis-set approaches, including the composite CBS-Q and CBS-QB3 procedures, and basis-set extrapolated coupled-cluster calculations (CCSD(T)). By taking the C(sp3)-H BDE in propene as a reference, we have concluded that one methyl group bonded to C3 in propene (i.e., 1-butene) leads to a decrease of 12 kJ mol(-1) and that a second methyl group bonded to C3 (3-methylbut-1-ene) further decreases the BDE by 8 kJ mol(-1). When the methyl group is bonded to C2 in propene (isobutene), an increase of 7 kJ mol(-1) is observed. Finally, a methyl group bonded to C1 in propene (2-butene) has essentially no effect (-1 kJ mol(-1)). While this trend can be rationalized in terms of stabilization of the corresponding radical (through hyperconjugation and pi-delocalization), the BDE values observed for the dienes can only be understood by considering the thermodynamic stabilities of the parent compounds.

Enthalpy of formation of the cyclopentadienyl radical: photoacoustic calorimetry and ab initio studies.

The gas-phase C-H bond dissociation enthalpy (BDE) in 1,3-cyclopentadiene has been determined by time-resolved photoacoustic calorimetry (TR-PAC) as 358 +/- 7 kJ mol(-1). Theoretical results from ab initio complete basis-set approaches, including the composite CBS-Q and CBS-QB3 procedures, and basis-set extrapolated coupled-cluster calculations (CCSD(T)) are reported. The CCSD(T) prediction for the C-H BDE of 1,3-cyclopentadiene (353.3 kJ mol(-1)) is in good agreement with the TR-PAC result. On the basis of the experimental and the theoretical values obtained, we recommend 355 +/- 8 kJ mol(-1) for the C-H BDE of 1,3-cyclopentadiene and 271 +/- 8 kJ mol(-1) for the enthalpy of formation of cyclopentadienyl radical.

Antioxidant activity of a catechol derived from abietic acid.

The demand for novel effective antioxidant-based drugs has led to the synthesis and evaluation of the antioxidant potential in several molecules derived from natural compounds. In this work the in vitro antioxidant activity of an abietic acid-derived catechol (methyl 11,12-dihydroxyabietate-8,11,13-trien-18-oate, MDTO) was evaluated. This substance, possessing important biological properties, is similar to carnosic acid, a natural antioxidant from rosemary or sage leaves. Aiming to understand the antioxidant activity of MDTO, the energetics of its O-H bond, using time-resolved photoacoustic calorimetry (TR-PAC), was investigated. On energetic grounds it is predicted that MDTO is a good free radical scavenger, although its activity is lower than that of quercetin, a very effective antioxidant, which was used for comparison. In agreement with these predictions, the DPPH(*) and ABTS(*+) radical scavenging activities are lower than those of quercetin. In addition, MDTO also reacts with HOCl, a powerful proinflammatory oxidant produced by activated neutrophils, and protects liposomes against iron-ascorbate-induced oxidation. The discussion of these results foresees potential applications of MDTO as an antioxidant.

[Acute myelogenous leukemia presenting as diabetes insipidus]. / Diabetes insípida como forma de apresentação de leucemia mielóide aguda.

Central diabetes insipidus, is a syndrome characterized by the excretion of abnormally elevated volumes of diluted urine, due to the diminution of reabsorption of water in the collecting ducts, induced by the diminution of production of antidiuretic hormone. The involvement of the central nervous system in the leukaemia is frequent, but the association leukaemia/diabetes insipidus is rare. We describe a clinical case of a 40 years old female, whose first manifestation of leukaemia was diabetes insipidus; we discuss the difficulties of diagnosis, the particularities of the case and its evolution.