Post-sternotomy pain syndrome following cardiac surgery. case report

Over 2 million people undergo sternotomy worldwide for heart surgery each year, and many develop post-sternotomy pain syndrome (PSPS) which persists in the anterior thorax. In some patients, PSPS lasts for many years or suddenly reappears a long time after the sternotomy. The exact etiology of PSPS is unknown. This article presents a case report of a patient with a diagnosis of PSPS (after cardiac surgery 4 years prior) for whom an osteopathic approach was used, which successfully eliminated the pain. In a previous study, we demonstrated that this osteopathic procedure could reduce sternal pain associated with a recent surgical wound. Further efforts are needed to understand the reasons for PSPS. In light of new scientific data, these osteopathic techniques could contribute to a multidisciplinary approach to solve the proble

Synthesis of 2-Methyl-3-indolylacetic Derivatives as Anti-Inflammatory Agents That Inhibit Preferentially Cyclooxygenase 1 without Gastric Damage

Novel substituted 2-methyl-3-indolylacetic derivatives were synthesized and evaluated for their activity in vitro and in vivo on COX-1 and COX-2. Active compounds were screened to determine their gastrointestinal tolerability in vivo in the rat. Results showed that 3 and 4 preferentially inhibited COX-1 in vitro and in vivo. MD simulations indicated an induced fit for COX-1 but not for COX-2, probably because of a lower plasticity of the latter

Non-Natural Linker Configuration in 2,6-Dipeptidyl-Anthraquinones Enhances the Inhibition of TAR RNA Binding/Annealing Activities by HIV-1 NC and Tat Proteins

The HIV-1 nucleocapsid (NC) protein represents an excellent molecular target for the development of antiretrovirals by virtue of its well-characterized chaperone activities, which play pivotal roles in essential steps of the viral life cycle. Our ongoing search for candidates able to impair NC binding/annealing activities led to the identification of peptidylanthraquinones as a promising class of nucleic acid ligands. Seeking to elucidate the inhibition determinants and increase the potency of this class of compounds, we have now explored the effects of chirality in the linker connecting the planar nucleus to the basic side chains. We show here that the non-natural linker configuration imparted unexpected TAR RNA targeting properties to the 2,6-peptidyl-anthraquinones and significantly enhanced their potency. Even if the new compounds were able to interact directly with the NC protein, they manifested a consistently higher affinity for the TAR RNA substrate and their TARbinding properties mirrored their ability to interfere with NC-TAR interactions. Based on these findings, we propose that the viral Tat protein, sharing the same RNA substrate but acting in distinct phases of the viral life cycle, constitutes an additional druggable target for this class of peptidyl-anthraquinones. The inhibition of Tat-TAR interaction for the test compounds correlated again with their TAR-binding properties, while simultaneously failing to demonstrate any direct Tat-binding capabilities. These considerations highlighted the importance of TAR RNA in the elucidation of their inhibition mechanism, rather than direct protein inhibition. We have therefore identified anti-TAR compounds with dual in vitro inhibitory activity on different viral proteins, demonstrating that it is possible to develop multitarget compounds capable of interfering with processes mediated by the interactions of this essential RNA domain of HIV-1 genome with NC and Tat proteins

Antagonizing S1P3 receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis

Bioactive lipids, derived from the metabolism of plasma membrane, are important mediators of cellular signaling in vertebrates. In recent years there has been a growing interest on sphingosine-1-phosphate (S1P) which is the final metabolite produced during the sequential degradation of plasma membrane glycosphingolipids and sphingomyelin. The S1P acts through five known subtypes of heptameric G-protein coupled receptors (GPCR), namely S1P1-S1P5 (S1PR). Recent evidence indicates that S1P signaling axis contributes to the development and maintenance of the fibrotic process [1]. Fibrosis is a pathological condition that can affect every organ, consequence of a persisting inflammatory and tissue remodeling condition. In different fibrotic models an extensive crosstalk between TGFβ and S1P signaling axis has been demonstrated. S1P3 plays a pivotal role in fibrosis development in different tissues such as skeletal muscle, liver, and kidney [2]. Thus, selective antagonists of the S1P3 receptor could be useful to deeply study its role in fibrosis as well as to develop new therapeutic entities to treat fibrotic diseases. Pepducins specifically target the intracellular loops, acting as allosteric modulators of GPCR activity. Using this approach, we have synthesized a pepducin based S1P3 antagonist namely KRX-725-II (Myristoyl-GRPYDAN-NH2) [3]. Here to improve the S1P1 vs S1P3 selectivity, we have synthesized several derivatives of KRX-725-II pointing our attention on the aromatic residue of the sequence, Tyr4, and with the aim to introduce molecular constraints. The new molecular entities have been evaluated for their selectivity profile by using mouse aortas. This screening allowed us to identify compounds V and VII (embodying respectively L- and D-Tic) as the most selective S1P3 antagonists. The selected compounds also displayed the ability to significantly reduce the profibrotic action of TGFβ1 in C2C12 myoblasts. To explain the higher selectivity observed for compounds V and VII, they were analyzed by Molecular Dynamics (MD) Simulations. The middle conformations of V and VII were compared by superimposing their GRP residues, which adopt a similar backbone orientation (see Figure). This revealed that the DAN residues with β-turn-like motif are located on opposite sides of the plane defined by the L- or D-Tic residue. This difference may explain, in structural terms, the selective S1P3 antagonism of V and VII in comparison to the unselective antagonist KRX-725-II, whose flexibility seems to be high enough for the adaptation to the binding regions of the individual receptor subtypes S1P1 and S1P3. Peptides V and VII possess, indeed, a highly constrained D- or L-Tic residue that hinder the pharmacophore from interacting properly with the binding pocket of the S1P1 receptor, therefore leading to S1P3 selectivity

Rebound effects of NCX3 pharmacological inhibition: A novel strategy to accelerate myelin formation in oligodendrocytes.

Abstract The Na+/Ca2+ exchanger NCX3 is an important regulator of sodium and calcium homeostasis in oligodendrocyte lineage. To date, no information is available on the effects resulting from prolonged exposure to NCX3 blockers and subsequent drug washout in oligodendroglia. Here, we investigated, by means of biochemical, morphological and functional analyses, the pharmacological effects of the NCX3 inhibitor, the 5–amino‐N‐butyl‐2–(4–ethoxyphenoxy)-benzamide hydrochloride (BED), on NCXs expression and activity, as well as intracellular [Na+]i and [Ca2+]i levels, during treatment and following drug washout both in human MO3.13 oligodendrocytes and rat primary oligodendrocyte precursor cells (OPCs). BED exposure antagonized NCX activity, induced OPCs proliferation and [Na+]i accumulation. By contrast, 2 days of BED washout after 4 days of treatment significantly upregulated low molecular weight NCX3 proteins, reversed NCX activity, and increased intracellular [Ca2+]i. This BED-free effect was accompanied by an upregulation of NCX3 expression in oligodendrocyte processes and accelerated expression of myelin markers in rat primary oligodendrocytes. Collectively, our findings show that the pharmacological inhibition of the NCX3 exchanger with BED blocker maybe followed by a rebound increase in NCX3 expression and reversal activity that accelerate myelin sheet formation in oligodendrocytes. In addition, they indicate that a particular attention should be paid to the use of NCX inhibitors for possible rebound effects, and suggest that further studies will be necessary to investigate whether selective pharmacological modulation of NCX3 exchanger may be exploited to benefit demyelination and remyelination in demyelinating diseases

Clinical effectiveness of hymenoptera venom immunotherapy

Treatment failure during venom immunotherapy (VIT) may be associated with a variety of risk factors. Our aim was to evaluate the association of baseline serum tryptase concentration (BTC) and of other parameters with the frequency of VIT failure during the maintenance phase. In this observational prospective multicenter study, we followed 357 patients with established honey bee or vespid venom allergy after the maintenance dose of VIT had been reached. In all patients, VIT effectiveness was either verified by sting challenge (n = 154) or patient self-reporting of the outcome of a field sting (n = 203). Data were collected on BTC, age, gender, preventive use of anti-allergic drugs (oral antihistamines and/or corticosteroids) right after a field sting, venom dose, antihypertensive medication, type of venom, side effects during VIT, severity of index sting reaction preceding VIT, and duration of VIT. Relative rates were calculated with generalized additive models. 22 patients (6.2%) developed generalized symptoms during sting challenge or after a field sting. A strong association between the frequency of VIT failure and BTC could be excluded. Due to wide confidence bands, however, weaker effects (odds ratios <3) of BTC were still possible, and were also suggested by a selective analysis of patients who had a sting challenge. The most important factor associated with VIT failure was a honey bee venom allergy. Preventive use of anti-allergic drugs may be associated with a higher protection rate. It is unlikely that an elevated BTC has a strong negative effect on the rate of treatment failures. The magnitude of the latter, however, may depend on the method of effectiveness assessment. Failure rate is higher in patients suffering from bee venom allergy

Heavy Metals Size Distribution in PM10 and Environmental-Sanitary Risk Analysis in Acerra (Italy)

The present research has been focused on the evaluation of seasonal changes in mass concentrations and compositions of heavy metals in Particular Matters (PM)10 collected from a typical urban-industrial site in Acerra, a city located in an area called "triangle of death". No significant (p < 0.05) seasonal variation was evidenced for the PM10 concentration, but in all the seasons (except for autumn) exceedances of daily concentrations (50 μg m−3) were observed. Airborne PM was analyzed for these heavy metals: Al, As, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Sb, V and Zn, which represented about 8% of the PM10 concentrations. None of the metals classified by IARC as carcinogenic in humans (group 1) exceeded on average the annual EU's and Italy's limit. For the mentioned heavy metals the enrichment factors (EnFs) were analyzed and highlighted high enrichment for Cd, Sb, Pb, As, Cu and Zn. Principal component analysis (PCA) for the heavy metals in PM10 identified oil combustion, vehicle and industrial emissions as major sources. To assess the health risk related to the inhalation to airborne PM10 metals, we applied the Cancer Risk (CR) and Target Hazard Quotient (THQ). The results showed that the CR was similar for a child and an adult, while the THQ proved to be higher for a child than for an adult. The low PM metals risk in the urban industrial site was in agreement with the ongoing lowering trend of metals in Italy and Europe

Design, Synthesis and Evaluation of Novel Molecular Hybrids between Antiglaucoma Drugs and H2S Donors

Glaucoma is a group of eye diseases consisting of optic nerve damage with corresponding loss of field vision and blindness. Hydrogen sulfide (H2S) is a gaseous neurotransmitter implicated in various pathophysiological processes. It is involved in the pathological mechanism of glaucomatous neuropathy and exerts promising effects in the treatment of this disease. In this work, we designed and synthetized new molecular hybrids between antiglaucoma drugs and H2S donors to combine the pharmacological effect of both moieties, providing a heightened therapy. Brinzolamide, betaxolol and brimonidine were linked to different H2S donors. The H2S-releasing properties of the new compounds were evaluated in a phosphate buffer solution by the amperometric approach, and evaluated in human primary corneal epithelial cells (HCEs) by spectrofluorometric measurements. Experimental data showed that compounds 1c, 1d and 3d were the hybrids with the best properties, characterized by a significant and long-lasting production of the gasotransmitter both in the aqueous solution (in the presence of L-cysteine) and in the intracellular environment. Because, to date, the donation of H2S by antiglaucoma H2S donor hybrids using non-immortalized corneal cells has never been reported, these results pave the way to further investigation of the potential efficacy of the newly synthesized compounds

Thymus irrigation and morphology in hybrid Dalland and Penarlan pigs

O objetivo desta pesquisa foi contribuir com dados relativos à morfologia e à irrigação do timo de fetos de suínos, resultantes do cruzamento entre as raças Dalland e Penarlan. Para tanto, foram utilizados 40 fetos de suínos (16 machos e 24 fêmeas), após óbito natural; eles foram doados pela Granja Beira-Rio, do município de Andradas (MG). O sistema vascular arterial dos animais foi preenchido com solução aquosa corada de látex (diluição a 50%), via aorta torácica, em seguida, houve fixação em formoldeído estabilizado (diluição a 10%), para posterior dissecação das artérias endereçadas aos lobos tímicos. As observações permitiram relatar que o timo foi irrigado por ramos diretos e indiretos das artérias cervicais superficiais direita e esquerda, carótidas comuns direita e esquerda, torácicas externas direita e esquerda e torácicas internas direita e esquerda. As principais artérias supridoras dos lobos tímicos cervicais foram as artérias cervicais superficiais, enquanto que o lobo torácico recebeu um maior número de ramos das artérias torácicas internas direita e esquerda. Após as análises estatísticas, foi possível concluir que não existe correlação entre o tamanho do timo e os ramos das artérias que o irrigam.This research aimed to contribute with data related to the morphology and irrigation of the thymus of swine fetuses, resulting from the mating between Dalland and Penarlan breeds. For this, 40 swine fetuses (16 males and 24 females) were used, after natural death; they were donated by Granja Beira-Rio, from the town of Andradas (MG). The arterial vascular system of animals was filled in with an aqueous solution of colored latex (50% dilution), via thoracic aorta, then, there was fixation in stabilized formaldehyde (10% dilution), for later dissection of arteries directed towards the thymic lobes. The observations allowed us to report that thymus was irrigated by the direct and indirect branches of the right and left superficial cervical arteries, right and left common carotid arteries, right and left external thoracic arteries, and right and left internal thoracic arteries. The main arteries supplying the thymic cervical lobes were the superficial cervical arteries, while the thoracic lobe received a major number of branches from the right and left internal thoracic arteries. After the statistical analyses, it was possible to conclude that there is no correlation between the thymus size and the branches of arteries irrigating it

Quantification of 3α-hydroxytibolone in human plasma by high performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS): Application in a bioequivalence study in healthy postmenopausal volunteers

Abstract A sensitive, specific and fast method to quantify 3α-hydroxytibolone in human plasma using deuterated 3α-hydroxytibolone (d5) as internal standard is described. The analyte and the internal standard were extracted from plasma (900 μL) by liquid-liquid extraction using ethyl ether/hexane (50/50, v/v) and ammonium hydroxide (50%). The extracts were analyzed by high performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry without derivatization. Chromatography was performed isocratically on a Gemini-NX™ C18 5 μm (150 × 4.6 mm i. d.) column. The method had a chromatographic run time of 3.75 min and a linear calibration curve over the range 1–100 ng/mL. The limit of quantification validated was 1 ng/mL. This method was used to assess the bioequivalence between two different tibolone oral formulations: Livolon (1.25 mg tablet) provided by Biolab Sanus Farmaceutica (Brazil), as the test formulation, and Libiam™ (1.25 mg tablet) produced by Libbs Farmaceutica (Brazil), as the reference formulation. A single 3.75 mg dose of each formulation was administered to 46 postmenopausal female healthy volunteers. The study was conducted in an open, randomized, two-period crossover balanced design with a 2 week washout interval between the doses. The 90% confidence interval for Cmax, AUC(0-last) and AUC(0-inf) individual test/reference ratios were 97.48–111.51, 95.35–103.20 and 96.42–103.86, respectively. It is concluded that Livolon (1.25 mg tablet) is bioequivalent to Libiam™ (1.25 mg tablet), with regards to both rate and extent of absorption