Comparable Ventilatory Inefficiency at Maximal and Submaximal Performance in COPD vs. CHF subjects: An Innovative Approach. / Ineficiência Ventilatória Comparável no Desempenho Máximo e Submáximo em Indivíduos com DPOC e ICC: Uma Abordagem Inovadora.

BACKGROUND: Currently, excess ventilation has been grounded under the relationship between minute-ventilation/carbon dioxide output ( V ˙ E - V ˙ CO 2 ). Alternatively, a new approach for ventilatory efficiency ( η E V ˙ ) has been published. OBJECTIVE: Our main hypothesis is that comparatively low levels of η E V ˙ between chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD) are attainable for a similar level of maximum and submaximal aerobic performance, conversely to long-established methods ( V ˙ E - V ˙ CO 2 slope and intercept). METHODS: Both groups performed lung function tests, echocardiography, and cardiopulmonary exercise testing. The significance level adopted in the statistical analysis was 5%. Thus, nineteen COPD and nineteen CHF-eligible subjects completed the study. With the aim of contrasting full values of V ˙ E - V ˙ CO 2 and η V ˙ E for the exercise period (100%), correlations were made with smaller fractions, such as 90% and 75% of the maximum values. RESULTS: The two groups attained matched characteristics for age (62±6 vs. 59±9 yrs, p>.05), sex (10/9 vs. 14/5, p>0.05), BMI (26±4 vs. 27±3 Kg m2, p>0.05), and peak V ˙ O 2 (72±19 vs. 74±20 %pred, p>0.05), respectively. The V ˙ E - V ˙ CO 2 slope and intercept were significantly different for COPD and CHF (27.2±1.4 vs. 33.1±5.7 and 5.3±1.9 vs. 1.7±3.6, p<0.05 for both), but η V ˙ E average values were similar between-groups (10.2±3.4 vs. 10.9±2.3%, p=0.462). The correlations between 100% of the exercise period with 90% and 75% of it were stronger for η V ˙ E (r>0.850 for both). CONCLUSION: The η V ˙ E is a valuable method for comparison between cardiopulmonary diseases, with so far distinct physiopathological mechanisms, including ventilatory constraints in COPD.

FUNDAMENTO: Atualmente, o excesso de ventilação tem sido fundamentado na relação entre ventilação-minuto/produção de dióxido de carbono ( V ˙ E − V ˙ CO 2 ). Alternativamente, uma nova abordagem para eficiência ventilatória ( η E V ˙ ) tem sido publicada. OBJETIVO: Nossa hipótese principal é que níveis comparativamente baixos de η E V ˙ entre insuficiência cardíaca crônica (ICC) e doença pulmonar obstrutiva crônica (DPOC) são atingíveis para um nível semelhante de desempenho aeróbico máximo e submáximo, inversamente aos métodos estabelecidos há muito tempo (inclinação V ˙ E − V ˙ CO 2 e intercepto). MÉTODOS: Ambos os grupos realizaram testes de função pulmonar, ecocardiografia e teste de exercício cardiopulmonar. O nível de significância adotada na análise estatística foi 5%. Assim, dezenove indivíduos elegíveis para DPOC e dezenove indivíduos elegíveis para ICC completaram o estudo. Com o objetivo de contrastar valores completos de V ˙ E − V ˙ CO 2 e η E V ˙ para o período de exercício (100%), correlações foram feitas com frações menores, como 90% e 75% dos valores máximos. RESULTADOS: Os dois grupos tiveram características correspondentes para a idade (62±6 vs 59±9 anos, p>.05), sexo (10/9 vs 14/5, p>0,05), IMC (26±4 vs 27±3 Kg m2, p>0,05), e pico V ˙ O 2 (72±19 vs 74±20 % pred, p>0,05), respectivamente. A inclinação V ˙ E − V ˙ CO 2 e intercepto foram significativamente diferentes para DPOC e ICC (207,2±1,4 vs 33,1±5,7 e 5,3±1,9 vs 1,7±3,6, p<0,05 para ambas), mas os valores médios da η E V ˙ foram semelhantes entre os grupos (10,2±3,4 vs 10,9±2,3%, p=0,462). As correlações entre 100% do período do exercício com 90% e 75% dele foram mais fortes para η E V ˙ (r>0,850 para ambos). CONCLUSÃO: A η E V ˙ é um método valioso para comparação entre doenças cardiopulmonares, com mecanismos fisiopatológicos até agora distintos, incluindo restrições ventilatórias na DPOC.

Ineficiência Ventilatória Comparável no Desempenho Máximo e Submáximo em Indivíduos com DPOC e ICC: Uma Abordagem Inovadora / Comparable Ventilatory Inefficiency at Maximal and Submaximal Performance in COPD vs. CHF subjects: An Innovative Approach

Resumo Fundamento: Atualmente, o excesso de ventilação tem sido fundamentado na relação entre ventilação-minuto/produção de dióxido de carbono ( V ˙ E − V ˙ CO 2). Alternativamente, uma nova abordagem para eficiência ventilatória ( η E V ˙) tem sido publicada. Objetivo: Nossa hipótese principal é que níveis comparativamente baixos de η E V ˙ entre insuficiência cardíaca crônica (ICC) e doença pulmonar obstrutiva crônica (DPOC) são atingíveis para um nível semelhante de desempenho aeróbico máximo e submáximo, inversamente aos métodos estabelecidos há muito tempo (inclinação V ˙ E − V ˙ CO 2 e intercepto). Métodos: Ambos os grupos realizaram testes de função pulmonar, ecocardiografia e teste de exercício cardiopulmonar. O nível de significância adotada na análise estatística foi 5%. Assim, dezenove indivíduos elegíveis para DPOC e dezenove indivíduos elegíveis para ICC completaram o estudo. Com o objetivo de contrastar valores completos de V ˙ E − V ˙ CO 2 e η E V ˙ para o período de exercício (100%), correlações foram feitas com frações menores, como 90% e 75% dos valores máximos. Resultados: Os dois grupos tiveram características correspondentes para a idade (62±6 vs 59±9 anos, p>.05), sexo (10/9 vs 14/5, p>0,05), IMC (26±4 vs 27±3 Kg m2, p>0,05), e pico V ˙ O 2 (72±19 vs 74±20 % pred, p>0,05), respectivamente. A inclinação V ˙ E − V ˙ CO 2 e intercepto foram significativamente diferentes para DPOC e ICC (207,2±1,4 vs 33,1±5,7 e 5,3±1,9 vs 1,7±3,6, p<0,05 para ambas), mas os valores médios da η E V ˙ foram semelhantes entre os grupos (10,2±3,4 vs 10,9±2,3%, p=0,462). As correlações entre 100% do período do exercício com 90% e 75% dele foram mais fortes para η E V ˙ (r>0,850 para ambos). Conclusão: A η E V ˙ é um método valioso para comparação entre doenças cardiopulmonares, com mecanismos fisiopatológicos até agora distintos, incluindo restrições ventilatórias na DPOC.

Abstract Background: Currently, excess ventilation has been grounded under the relationship between minute-ventilation/carbon dioxide output ( V ˙ E − V ˙ CO 2). Alternatively, a new approach for ventilatory efficiency ( η E V ˙) has been published. Objective: Our main hypothesis is that comparatively low levels of η E V ˙ between chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD) are attainable for a similar level of maximum and submaximal aerobic performance, conversely to long-established methods ( V ˙ E − V ˙ CO 2 slope and intercept). Methods: Both groups performed lung function tests, echocardiography, and cardiopulmonary exercise testing. The significance level adopted in the statistical analysis was 5%. Thus, nineteen COPD and nineteen CHF-eligible subjects completed the study. With the aim of contrasting full values of V ˙ E − V ˙ CO 2 and η V ˙ E for the exercise period (100%), correlations were made with smaller fractions, such as 90% and 75% of the maximum values. Results: The two groups attained matched characteristics for age (62±6 vs. 59±9 yrs, p>.05), sex (10/9 vs. 14/5, p>0.05), BMI (26±4 vs. 27±3 Kg m2, p>0.05), and peak V ˙ O 2 (72±19 vs. 74±20 %pred, p>0.05), respectively. The V ˙ E − V ˙ CO 2 slope and intercept were significantly different for COPD and CHF (27.2±1.4 vs. 33.1±5.7 and 5.3±1.9 vs. 1.7±3.6, p<0.05 for both), but η V ˙ E average values were similar between-groups (10.2±3.4 vs. 10.9±2.3%, p=0.462). The correlations between 100% of the exercise period with 90% and 75% of it were stronger for η V ˙ E (r>0.850 for both). Conclusion: The η V ˙ E is a valuable method for comparison between cardiopulmonary diseases, with so far distinct physiopathological mechanisms, including ventilatory constraints in COPD.

Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile.

Inappropriate expression of histone deacetylase (HDAC-6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signalling pathway are common aberrations observed in cancers. LASSBio-2208, has been previously described as a dual inhibitor in the nanomolar range of HDAC-6 and PI3Kα and is three times more potent in inhibiting HDAC-6. In this paper we described the cytotoxic and antiproliferative potency of LASSBio-2208 on different tumour cell lines, its possible synergism effect in association with PI3K and HDAC-6 inhibitors, and its drug metabolism and pharmacokinetics (DMPK) in vitro profile. Our studies have demonstrated that LASSBio-2208 has moderate cytotoxic potency on breast cancer cell line MCF-7 (IC50 = 23 µM), human leukaemia cell line CCRF-CEM (IC50 = 8.54 µM) and T lymphoblast cell line MOLT-4 (IC50 = 7.15 µM), with no cytotoxic effect on human peripheral blood mononuclear cells (hPBMC). In addition, it has a good antiproliferative effect on MCF-7 cells (IC50 = 5.44 µM), low absorption by parallel artificial membrane permeability-gastrointestinal tract (PAMPA-GIT) and low permeation by parallel artificial membrane permeability-blood-brain barrier (BBB) (PAMPA-BBB), exhibiting high metabolic stability in rat plasma. Moreover, LASSBio-2208 exhibited synergism when combined with getadolisib and tubastatin A, using the concentrations corresponding to their CC50 values on MOLT-4 and CCRF-CEM cells.

Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues.

Targeted antitumour therapy has revolutionized the treatment of several types of tumours. Among the validated targets, phosphatidylinositol-3 kinase (PI3K) deserves to be highlighted. Several PI3K inhibitors have been developed for the treatment of cancer, including gedatolisib (4). This inhibitor was elected as a prototype and molecular modifications were planned to design a new series of simplified gedatolisib analogues (5a-f). The analogues were synthesised, and the comparative cytotoxic activity profile was studied in phenotypic models employing solid and nonadherent tumour cell lines. Compound 5f (LASSBio-2252) stood out as the most promising of the series, showing good aqueous solubility (42.38 µM (pH = 7.4); 39.33 µM (pH = 5.8)), good partition coefficient (cLogP = 2.96), cytotoxic activity on human leukemia cell lines (CCRF-CEM, K562 and MOLT-4) and an excellent metabolic stability profile in rat liver microsomes (t1/2 = 462 min; Clapp = 0.058 mL/min/g). The ability of 5f to exert its cytotoxic effect through modulation of the PI3K pathway was demonstrated by flow cytometry analysis in a comparative manner to gedatolisib.

2-Arylpropionic Acid Pyrazolamides as Cannabinoid CB2 Receptor Inverse Agonists Endowed with Anti-Inflammatory Properties.

Among the most recent proposals regarding the mechanism of action of dipyrone, the modulation of cannabinoid receptors CB1 and CB2 appears to be a promising hypothesis. In this context, the present work describes a series of five novel pyrazolamides (7-11) designed as molecular hybrids of dipyrone metabolites and NSAIDs, such as ibuprofen and flurbiprofen. Target compounds were obtained in good overall yields (50-80%) by classical amide coupling between 4-aminoantipyrine and arylacetic or arylpropionic acids, followed in some cases by N-methylation of the amide group. The compounds presented good physicochemical properties in addition to stability to chemical (pH 2 and 7.4) and enzymatic (plasma esterases) hydrolysis and showed medium to high gastrointestinal and BBB permeabilities in the PAMPA assay. When subjected to functional testing on CB1- or CB2-transfected cells, compounds demonstrated an inverse agonist profile on CB2 receptors and the further characterization of compound LASSBio-2265 (11) revealed moderate binding affinity to CB2 receptor (Ki = 16 µM) with an EC50 = 0.36 µM (Emax = 63%). LASSBio-2265 (11) (at 1, 3, and 10 mg/kg p.o.) was investigated in the formalin test in mice and a remarkable analgesic activity in the late inflammatory phase was observed, suggesting it could be promising for the treatment of pain syndromes associated with chronic inflammatory diseases.

Discovery of Putative Dual Inhibitor of Tubulin and EGFR by Phenotypic Approach on LASSBio-1586 Homologs.

Combretastatin A-4 (CA-4, 1) is an antimicrotubule agent used as a prototype for the design of several synthetic analogues with anti-tubulin activity, such as LASSBio-1586 (2). A series of branched and unbranched homologs of the lead-compound 2, and vinyl, ethinyl and benzyl analogues, were designed and synthesized. A comparison between the cytotoxic effect of these homologs and 2 on different human tumor cell lines was performed from a cell viability study using MTT with 48 h and 72 h incubations. In general, the compounds were less potent than CA-4, showing CC50 values ranging from 0.030 µM to 7.53 µM (MTT at 72 h) and 0.096 µM to 8.768 µM (MTT at 48 h). The antimitotic effect of the target compounds was demonstrated by cell cycle analysis through flow cytometry, and the cellular mechanism of cytotoxicity was determined by immunofluorescence. While the benzyl homolog 10 (LASSBio-2070) was shown to be a microtubule stabilizer, the lead-compound 2 (LASSBio-1586) and the methylated homolog 3 (LASSBio-1735) had microtubule destabilizing behavior. Molecular docking studies were performed on tubulin protein to investigate their binding mode on colchicine and taxane domain. Surprisingly, the benzyl homolog 10 was able to modulate EGFR phosphorylate activity in a phenotypic model. These data suggest LASSBio-2070 (10) as a putative dual inhibitor of tubulin and EGFR. Its binding mode with EGFR was determined by molecular docking and may be useful in lead-optimization initiatives.

Design, synthesis, and biological evaluation of new thalidomide-donepezil hybrids as neuroprotective agents targeting cholinesterases and neuroinflammation.

A new series of eight multifunctional thalidomide-donepezil hybrids were synthesized based on the multi-target-directed ligand strategy and evaluated as potential neuroprotective, cholinesterase inhibitors and anti-neuroinflammatory agents against neurodegenerative diseases. A molecular hybridization approach was used for structural design by combining the N-benzylpiperidine pharmacophore of donepezil and the isoindoline-1,3-dione fragment from the thalidomide structure. The most promising compound, PQM-189 (3g), showed good AChE inhibitory activity with an IC50 value of 3.15 µM, which was predicted by docking studies as interacting with the enzyme in the same orientation observed in the AChE-donepezil complex and a similar profile of interaction. Additionally, compound 3g significantly decreased iNOS and IL-1ß levels by 43% and 39%, respectively, after 24 h of incubation with lipopolysaccharide. In vivo data confirmed the ability of 3g to prevent locomotor impairment and changes in feeding behavior elicited by lipopolysaccharide. Moreover, the PAMPA assay evidenced adequate blood-brain barrier and gastrointestinal tract permeabilities with an Fa value of 69.8%. Altogether, these biological data suggest that compound 3g can treat the inflammatory process and oxidative stress resulting from the overexpression of iNOS and therefore the increase in reactive nitrogen species, and regulate the release of pro-inflammatory cytokines such as IL-1ß. In this regard, compound PQM-189 (3g) was revealed to be a promising neuroprotective and anti-neuroinflammatory agent with an innovative thalidomide-donepezil-based hybrid molecular architecture.

Pre-clinical evaluation of LASSBio-1491: From in vitro pharmacokinetic study to in vivo leishmanicidal activity.

Leishmaniasis is a public health issue. It is among the top five parasitic illnesses worldwide and is one of the most neglected diseases. The current treatment disease includes limitations of toxicity, variable efficacy, high costs and inconvenient doses and treatment schedules. LASSBio-1736 was described as antileishmanial drug-candidate to cutaneous leishmaniasis, displaying plasma stability and with no preliminary signals of hepatic or renal toxicity. In this paper, we described the in vitro pharmacokinetic study of LASSBio-1491 (a less lipophilic isostere of LASSBio-1736) and it is in vitro and in vivo leishmanicidal activities. Our results demonstrated that LASSBio-1491 has high permeability, satisfactory aqueous solubility, long plasma and microsomal half-lives and low in vitro systemic clearance, suggesting a pharmacokinetic profile suitable for its use in a single daily dose. The antileishmanial effect of LASSBio-1491 was confirmed in vitro and in vivo. It exhibited no cytotoxic effect to mammalian cells and displayed good in -vivo effect against BALB/c mice infected with Leishmania major LV39 substrain, being 3 times more efficient than glucantime.

A new ventilatory efficiency index and accuracy for early lung diffusion impairment in non-COPD smokers.

In smokers without manifest airway obstruction, early emphysema and endothelial dysfunction has been related to minute-ventilation/carbon dioxide output ratio (V'E/V'CO2). Thus, smokers with reduced lung carbon monoxide diffusion capacity (DLco) have a heightened V'E/V'CO2 ratio. We hypothesized that ventilatory inefficiency could contribute to the suspicion of impaired diffusive capacity in the absence of significant airway obstruction. Thus, 15 smokers with impaired DLco were compared to 15 smokers with normal DLco. Accuracy through sensibility and specificity for V'E/V'CO2 slope and nadir was compared with a new index for ventilatory efficiency (ηV'E,%), to uncover early diffusive changes in smokers without COPD.

ß-lactam antibiotics: An overview from a medicinal chemistry perspective.

ß-Lactam antibiotics are one of the most relevant drug classes of antibacterial agents worldwide. The discovery and the market of first ß-lactam antibiotic (Penicillin G) is a symbolic landmark of modern chemotherapy. Since then, several other ß-lactam antibiotics have been introduced in the therapy, revolutionizing the treatment of bacterial infections. Their antibacterial efficacy has been kept in check by the emergence of bacterial resistance. Among the resistance mechanisms, the expression of ß-lactamase enzymes is one of the most studied and prevalent. The combined use of beta-lactamase inhibitors with broad spectrum activity ß-lactam antibiotics has been an effective strategy to circumvent the resistance issue. This review discusses, with a focus on structural aspects, the different classes of beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, monobactams and penems) in light of their stability, sensitivity to ß-lactamases, mechanism of action and spectrum of antimicrobial activity. ß-Lactamase inhibitors (structurally correlated and non-correlated to the ß-lactam system) and their proposed inhibition mechanisms are also discussed.

The terpenic diamine GIB24 inhibits the growth of Trypanosoma cruzi epimastigotes and intracellular amastigotes, with proteomic analysis of drug-resistant epimastigotes.

The effect of N-geranyl-ethane-1,2-diamine dihydochloride (GIB24), a synthetic diamine, was assayed against different developmental forms of the parasitic protozoan Trypanosoma cruzi (strain Dm28c). The compound was effective against culture epimastigote forms (IC50/24h = 5.64 µM; SI = 16.4) and intracellular amastigotes (IC50/24h = 12.89 µM; SI = 7.18), as detected by the MTT methodology and by cell counting, respectively. Incubation of epimastigotes for 6h with 6 µM GIB24 (IC50/24h value) resulted in significant dissipation of the mitochondrial membrane potential, prior to permeabilization of the plasma membrane. Rounded epimastigotes with cell size reduction were observed by scanning electron microscopy. These morpho-physiological changes induced by GIB24 suggest an incidental death process. Treatment of infected Vero cells did not prevent the intracellular amastigotes from completing the intracellular cycle. However, there was a decrease in the number of released parasites, increasing the ratio amastigotes/trypomastigotes. Proteomic analysis of 15 µM GIB24 resistant epimastigotes indicated that the compound acts mainly on mitochondrial components involved in the Krebs cycle and in maintaining the oxidative homeostasis of the parasites. Our data suggest that GIB24 is active against the main morphological forms of T. cruzi.

Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies.

Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability.

Combinação de processos com membranas para remoção de sulfato da água do mar para injeção em reservatórios de petróleo / Combination of membrane processes for desulfation of seawater used for injection in oilfields

RESUMO Água do mar é comumente utilizada como fluido de injeção em plataformas offshore na recuperação secundária do petróleo. Porém, a presença de sulfato causa diversos inconvenientes, como a formação de precipitados, que podem se depositar em diversas partes da plataforma de produção. Atualmente, a dessulfatação é realizada em unidades removedoras de sulfato (URS) por processo de nanofiltração (NF), cujas amostras precisam ser pré-tratadas, usualmente em filtros cartuchos. Os sólidos suspensos e os microrganismos que não foram retidos pelo sistema de filtração podem depositar sobre a superfície das membranas de NF, diminuindo a produtividade do sistema e reduzindo o tempo de vida das membranas. O processo de microfiltração (MF) pode ser utilizado como pré-tratamento alternativo e possibilitaria a remoção desses elementos. Neste estudo, foi desenvolvido um processo combinado de MF e NF para a dessulfatação da água do mar, visando a sua injeção em reservatórios de petróleo. Módulos de permeação contendo membranas de poli(imida) no formato de fibras ocas foram utilizados na construção de um sistema piloto de MF integrado a um sistema piloto de NF similar aos já atualmente utilizados nas plataformas. O desempenho dos sistemas foi avaliado por meio do acompanhamento da permeabilidade de ambos durante a filtração da água do mar. Parâmetros como grau de recuperação de água, frequência e eficiência de procedimentos de retrolavagem e limpeza química também foram estudados. Os resultados demonstraram que o pré-tratamento da água do mar por MF é uma alternativa eficaz para a dessulfatação por NF.

ABSTRACT Seawater is commonly used in offshore platforms as an injection fluid in secondary oil recovery. However, the sulfate found in seawater has been the cause of many inconveniences, such as the formation of precipitates, which can settle in various parts of the production platform. Nowadays, nanofiltration (NF) is used in sulfate removal units for seawater desulfation, where cartridge filters are commonly used for seawater pretreatment. Suspended solids and microorganisms that have not been retained by the filtration system may deposit on the surface of NF membranes, decreasing system productivity and reducing membrane life. The microfiltration (MF) process can be used as an alternative pretreatment and would allow the removal of these elements. In this study, a combined process of MF and NF for seawater desulfation was developed for injection into oil reservoirs. Permeation modules containing hollow fiber shaped poly (imide) membranes were used in the construction of an MF pilot system, integrated with an NF pilot system similar to those already used on platforms. The performance of the systems was evaluated by monitoring the permeability of both during seawater filtration. Parameters such as degree of water recovery, frequency, and efficiency of backwash procedures and chemical cleaning were also studied. The results showed that MF seawater pretreatment is an effective alternative for NF desulfation.

Cardiopulmonary and Muscular Interactions: Potential Implications for Exercise (In)tolerance in Symptomatic Smokers Without Chronic Obstructive Pulmonary Disease.

Smoking and physical inactivity are important preventable causes of disability and early death worldwide. Reduced exercise tolerance has been described in smokers, even in those who do not fulfill the extant physiological criteria for chronic obstructive pulmonary disease (COPD) and are not particularly sedentary. In this context, it is widely accepted that exercise capacity depends on complex cardio-pulmonary interactions which support oxygen (O2) delivery to muscle mitochondria. Although peripheral muscular factors, O2 transport disturbances (including the effects of increased carboxyhemoglobin) and autonomic nervous system unbalance have been emphasized, other derangements have been more recently described, including early microscopic emphysema, pulmonary microvascular disease, ventilatory and gas exchange inefficiency, and left ventricular diastolic dysfunction. Using an integrative physiological approach, the present review summarizes the recent advances in knowledge on the effects of smoking on the lung-heart-muscle axis under the stress of exercise. Special attention is given to the mechanisms connecting physiological abnormalities such as early cardio-pulmonary derangements, inadequate oxygen delivery and utilization, and generalized bioenergetic disturbances at the muscular level with the negative sensations (sense of heightened muscle effort and breathlessness) that may decrease the tolerance of smokers to physical exercise. A deeper understanding of the systemic effects of smoking in subjects who did not (yet) show evidences of COPD and ischemic heart disease - two devastating smoking related diseases - might prove instrumental to fight their ever-growing burden.

Synthesis of new lophine-carbohydrate hybrids as cholinesterase inhibitors: cytotoxicity evaluation and molecular modeling.

In this study, we synthesized nine novel hybrids derived from d-xylose, d-ribose, and d-galactose sugars connected by a methylene chain with lophine. The compounds were synthesized by a four-component reaction to afford the substituted imidazole moiety, followed by the displacement reaction between sugar derivatives with an appropriate N-alkylamino-lophine. All the compounds were found to be the potent and selective inhibitors of BuChE activity in mouse serum, with compound 9a (a d-galactose derivative) being the most potent inhibitor (IC50 = 0.17 µM). According to the molecular modeling results, all the compounds indicated that the lophine moiety existed at the bottom of the BuChE cavity and formed a T-stacking interaction with Trp231, a residue accessible exclusively in the BuChE cavity. Noteworthily, only one compound exhibited activity against AChE (8b; IC50 = 2.75 µM). Moreover, the in silico ADME predictions indicated that all the hybrids formulated in this study were drug-likely, orally available, and able to reach the CNS. Further, in vitro studies demonstrated that the two most potent compounds against BuChE (8b and 9a) had no cytotoxic effects in the Vero (kidney), HepG2 (hepatic), and C6 (astroglial) cell lines.

Shoulder injuries in soccer goalkeepers: review and development of a FIFA 11+ shoulder injury prevention program.

In the last years, shoulder injuries have represented an increasing health problem in soccer players. The goalkeepers are more exposed to shoulder disorders than other field players. Injury prevention exercises for upper limbs were cited in few studies involving throwing athletes, but we know that goalkeepers need a specific program. The purpose of this study is to describe the development of an adapted Fédération Internationale de Football Association (FIFA) 11+ program, namely the FIFA 11+ shoulder, which targets the prevention of shoulder injuries in soccer goalkeepers. The FIFA 11+ shoulder program is structured into three parts: general warming-up exercises, exercises to improve strength and balance of the shoulder, elbow, wrist, and finger muscles, and advanced exercises for core stability and muscle control. The exercises were selected based on recommendations from studies demonstrating high electromyographic activity.

Análise do SICK Scapula em jogadores de handebol com e sem dor no ombro durante o arremesso / Analysis of the sick scapula in handball players with and without shoulder pain during throwing / Análisis del sick scapula en jugadores de handbol con y sin dolor en el hombro durante el lanzamiento

INTRODUÇÃO: A discinesia escapular é definida como uma alteração da posição escapular, tanto dinâmica quanto estática, resultante de desequilíbrios da musculatura periescapular secundários à fadiga, trauma ou lesão neurológica. O SICK Scapula avalia e caracteriza as alterações escapulares estaticamente, variando de 0 a 20 pontos (0 = melhor possível). No exame, a escápula é avaliada em três aspectos: dor objetiva, dor subjetiva e mau posicionamento escapular. OBJETIVO: Comparar o SICK Scapula entre jogadores de handebol sintomáticos e assintomáticos. MÉTODOS: A amostra foi composta por 57 atletas de handebol divididos em dois grupos, de acordo com a presença de dor no ombro: grupo assintomático (GA) (N = 27) e grupo sintomático (GS) (N = 30). O SICK Scapula foi avaliado entre os atletas, tanto em relação à sua pontuação final como às subescalas. O GS apresentou maior pontuação no SICK Scapula em relação ao GA (8 ± 2,3 vs 2,7 ± 1,8; p<0,001). RESULTADOS: Nas subescalas, os GA e GS também apresentaram diferenças significantes quanto à dor subjetiva (0 vs. 1,73 ± 0,83; p < 0,001), dor objetiva (0,41 ± 0,64 vs. 2,5 ±0,86; p < 0,001) e mau posicionamento escapular (2,3 ± 1,9 vs. 3,7 ± 1,5; p = 0,002). CONCLUSÃO: Os atletas de handebol com dor relacionada ao arremesso apresentam maior pontuação com relação à dor e às alterações de posicionamento escapular, segundo avaliação pelo SICK Scapula, em comparação com os que não apresentam sintomatologia. .

INTRODUCTION: The scapular dyskinesia is defined as a change in scapular position, both dynamic and static, resulting from periscapular imbalances secondary to muscle fatigue, trauma or neurological injury. The SICK Scapula statically evaluates and characterizes the scapular changes, ranging from 0 to 20 (0 = best). This exam addressed three aspects: objective pain, subjective pain and scapular malposition. OBJECTIVE: To compare the SICK Scapula in symptomatic and asymptomatic handball players. METHODS: The sample consisted of 57 handball athletes divided into two groups according to the presence of shoulder pain: asymptomatic group (AG) (N = 27) and symptomatic group (SG) (N = 30). The SICK Scapula score has been reported among athletes, both in relation to the total score and its subscales. The GS had a significantly higher score than the GA (8±2.3 vs. 2.7±1.8; p<0.001). RESULTS: In the subscales, GA and SG also showed significant differences in subjective pain (0 vs. 1.73±0.83, p<0.001), objective pain (0.41±0.64 vs. 2.5±0.86, p<0.001) and scapular malposition (2.3±1.9 vs. 3.7±1.5, p=0.002). CONCLUSION: The handball athletes with throwing-related pain have a higher score with respect to pain and changes of scapular positioning, as assessed by SICK Scapula, compared with those who did not have symptoms. .

INTRODUCCIÓN: La discinesia escapular es definida como una alteración de la posición escapular, tanto dinámica como estática, resultante de desequilibrios de la musculatura periescapular secundarios a la fatiga, trauma o lesión neurológica. El SICK Scapula evalúa y caracteriza las alteraciones escapulares estáticamente, variando de 0 a 20 puntos (0 = mejor posible). En el examen, la escápula es evaluada en tres aspectos: dolor objetivo, dolor subjetivo y mal posicionamiento escapular. OBJETIVO: Comparar el SICK Scapula entre jugadores de handbol sintomáticos y asintomáticos. MÉTODOS: La muestra fue compuesta por 57 atletas de handbol divididos en dos grupos, de acuerdo con la presencia de dolor en el hombro: grupo asintomático (GA) (N = 27) y grupo sintomático (GS) (N = 30). El SICK Scapula fue evaluado entre los atletas, tanto en relación a su puntuación final como a las subescalas. GS presentó mayor puntuación en el SICK Scapula en relación al GA (8 ± 2,3 vs 2,7 ± 1,8; p<0,001). RESULTADOS: En las subescalas, los GA y GS también presentaron diferencias significativas sobre el Dolor Subjetivo (0 vs. 1,73 ± 0,83; p < 0,001), Dolor Objetivo (0,41 ± 0,64 vs. 2,5 ±0,86; p < 0,001) y mal posicionamiento escapular (2,3 ± 1,9 vs. 3,7 ± 1,5; p = 0,002). CONCLUSIÓN: Los atletas de handbol con dolor relacionado al lanzamiento presentan mayor puntuación con relación al dolor y a las alteraciones de posicionamiento escapular, según evaluación por el SICK Scapula, en comparación con los que no presentan sintomatología. .