Capnothorax During Laparoscopy in Trendelenburg Position: A Rare Case Study.

Pneumothorax is an infrequent complication of laparoscopic surgery. Most cases occur during upper abdominal surgery, since a head-down position (Trendelenburg) pushes the liver and peritoneum against the diaphragm, reducing gas release. When it is due to CO2 diffusion across congenital diaphragmatic defects, it usually resolves itself spontaneously after de-insufflation of the pneumoperitoneum. Increasing positive end-expiratory pressure to counteract intra-abdominal pressure is an effective measure when a pulmonary origin is excluded. We report a case of right-sided hypertensive capnothorax due to a diaphragmatic defect, during lower abdominal surgery, which was successfully managed without the need for chest drainage. This case highlights the importance of maintaining active vigilance and a high index of suspicion for pneumothorax during laparoscopic surgery.

O pneumotórax é uma complicação pouco frequente da cirurgia laparoscópica. A maioria dos casos ocorrem em cirurgias da região abdominal superior, uma vez que a posição de Trendelenburg por empurrar o fígado e o peritoneu contra o diafragma, reduz a perda de gás. Quando a causa é a difusão de CO2 através de um defeito diafragmático congénito, habitualmente resolve espontaneamente, após a desinsuflação do pneumoperitoneu. Quando se exclui uma causa parenquimatosa pulmonar o aumento de positive end-expiratory pressure para contrabalançar a pressão intra-abdominal é uma medida eficaz. O caso clínico que apresentamos refere-se a um caso de capnotórax hipertensivo que ocorreu devido à presença de um defeito diafragmático congénito, durante uma cirurgia abdominal inferior e que foi tratado com sucesso sem recorrer ao uso de dreno torácico. Este caso salienta a importância de manter uma vigilância ativa e alto indice de suspeição para o pneumotórax durante a cirurgia laparoscópica.

Solution structure of the soluble receptor for advanced glycation end products (sRAGE).

The receptor for advanced glycation end products (RAGE) is a multiligand cell surface receptor involved in various human diseases, as it binds to numerous molecules and proteins that modulate the activity of other proteins. Elucidating the three-dimensional structure of this receptor is therefore most important for understanding its function during activation and cellular signaling. The major alternative splice product of RAGE comprises its extracellular region that occurs as a soluble protein (sRAGE). Although the structures of sRAGE domains were available, their assembly into the functional full-length protein remained unknown. We observed that the protein has concentration-dependent oligomerization behavior, and this is also mediated by the presence of Ca(2+) ions. Moreover, using synchrotron small angle x-ray scattering, the solution structure of human sRAGE was determined in the monomeric and dimeric forms. The model for the monomer displays a J-like shape, whereas the dimer is formed through the association of the two N-terminal domains and has an elongated structure. These results provide insights into the assembly of the RAGE homodimer, which is essential for signal transduction, and the sRAGE:RAGE heterodimer that leads to blockage of the receptor signaling, paving the way for the design of therapeutic strategies for a large number of different pathologies.

Prenylated derivatives of baicalein and 3,7-dihydroxyflavone: synthesis and study of their effects on tumor cell lines growth, cell cycle and apoptosis.

Fourteen baicalein and 3,7-dihydroxyflavone derivatives were synthesized and evaluated for their inhibitory activity against the in vitro growth of three human tumor cell lines. The synthetic approaches were based on the reaction with prenyl or geranyl bromide in alkaline medium, followed by cyclization of the respective monoprenylated derivative. Dihydropyranoflavonoids were also obtained by one-pot synthesis, using Montmorillonite K10 clay as catalyst combined with microwave irradiation. In vitro screening of the compounds for cell growth inhibitory activity revealed that the presence of one geranyl group was associated with a remarkable increase in the inhibitory activity. Moreover, for the 3,7-dihydroxyflavone derivatives a marked increase in growth inhibitory effect was also observed for compounds with furan and pyran fused rings. The most active compounds were also studied regarding their effect on cell cycle profile and induction of apoptosis. Overall the results point to the relevant role of the prenylation of flavone scaffold in the growth inhibitory activity of cancer cells.

Iodination of salicylic acid improves its binding to transthyretin.

Transthyretin (TTR) is a plasma homotetrameric protein associated with senile systemic amyloidosis and familial amyloidotic polyneuropathy. In theses cases, TTR dissociation and misfolding induces the formation of amyloidogenic intermediates that assemble into toxic oligomeric species and lead to the formation of fibrils present in amyloid deposits. The four TTR monomers associate around a central hydrophobic channel where two thyroxine molecules can bind simultaneously. In each thyroxine binding site there are three pairs of symmetry related halogen binding pockets which can accommodate the four iodine substituents of thyroxine. A number of structurally diverse small molecules that bind to the TTR channel increasing the protein stability and thereafter inhibiting amyloid fibrillogenesis have been tested. In order to take advantage of the high propensity to interactions between iodine substituents and the TTR channel we have identified two iodinated derivatives of salicylic acid, 5-iodosalicylic acid and 3,5-diiodosalicylic acid, available commercially. We report in this paper the relative binding affinities of salicylic acid and the two iodinated derivatives and the crystal structure of TTR complexed with 3,5-diiodosalicylic acid, to elucidate the higher binding affinity of this compound towards TTR.

Merodrimanes and other constituents from Talaromyces thailandiasis.

Chemical study of a previously undescribed fungus, Talaromyces thailandiasis, furnished the two new merodrimanes thailandolides A (1) and B (2), an O-methylated derivative (3) of the aromatic fragment incorporated in thailandolide B, and three known closely related 1(3H)-isobenzofuran derivatives, penisimplicissin (4a), vermistatin (4b), and hydroxydihydrovermistatin (4c). Structures were established by spectroscopic measurements and confirmed by X-ray analyses of compounds 1 and 4b. The unusual peptide analogue N-benzoylphenylalanyl-N-benzoylphenyl alaninate (5) isolated earlier from a higher plant was also found.

Towards a structural understanding of the fibrillization pathway in Machado-Joseph's disease: trapping early oligomers of non-expanded ataxin-3.

Machado-Joseph's disease is caused by a CAG trinucleotide repeat expansion that is translated into an abnormally long polyglutamine tract in the protein ataxin-3. Except for the polyglutamine region, proteins associated with polyglutamine diseases are unrelated, and for all of these diseases aggregates containing these proteins are the major components of the nuclear proteinaceous deposits found in the brain. Aggregates of the expanded proteins display amyloid-like morphological and biophysical properties. Human ataxin-3 containing a non-pathological number of glutamine residues (14Q), as well as its Caenorhabditis elegans (1Q) orthologue, showed a high tendency towards self-interaction and aggregation, under near-physiological conditions. In order to understand the discrete steps in the assembly process leading to ataxin-3 oligomerization, we have separated chromatographically high molecular mass oligomers as well as medium mass multimers of non-expanded ataxin-3. We show that: (a) oligomerization occurs independently of the poly(Q)-repeat and it is accompanied by an increase in beta-structure; and (b) the first intermediate in the oligomerization pathway is a Josephin domain-mediated dimer of ataxin-3. Furthermore, non-expanded ataxin-3 oligomers are recognized by a specific antibody that targets a conformational epitope present in soluble cytotoxic species found in the fibrillization pathway of expanded polyglutamine proteins and other amyloid-forming proteins. Imaging of the oligomeric forms of the non-pathological protein using electron microscopy reveals globular particles, as well as short chains of such particles that likely mimic the initial stages in the fibrillogenesis pathway occurring in the polyglutamine-expanded protein. Thus, they constitute potential targets for therapeutic approaches in Machado-Joseph's disease, as well as valuable diagnostic markers in disease settings.

Human transthyretin in complex with iododiflunisal: structural features associated with a potent amyloid inhibitor.

Ex vivo and in vitro studies have revealed the remarkable amyloid inhibitory potency and specificity of iododiflunisal in relation to transthyretin [Almeida, Macedo, Cardoso, Alves, Valencia, Arsequell, Planas and Saraiva (2004) Biochem. J. 381, 351-356], a protein implicated in familial amyloidotic polyneuropathy. In the present paper, the crystal structure of transthyretin complexed with this diflunisal derivative is reported, which enables a detailed analysis of the protein-ligand interactions. Iododiflunisal binds very deep in the hormone-binding channel. The iodine substituent is tightly anchored into a pocket of the binding site and the fluorine atoms provide extra hydrophobic contacts with the protein. The carboxylate substituent is involved in an electrostatic interaction with the N(zeta) of a lysine residue. Moreover, ligand-induced conformational alterations in the side chain of some residues result in the formation of new intersubunit hydrogen bonds. All these new interactions, induced by iododiflunisal, increase the stability of the tetramer impairing the formation of amyloid fibrils. The crystal structure of this complex opens perspectives for the design of more specific and effective drugs for familial amyloidotic polyneuropathy patients.

Bioactive friedolanostanes and 11(10-->8)-abeolanostanes from the bark of Garcinia speciosa.

A new friedolanostane, 7, and three triterpenes, 8, 9a, and 10, possessing the new 11(10-->8)-abeolanostane carbon skeleton were isolated from the bark of Garcinia speciosa. Structures were elucidated by spectroscopic and spectrometric studies and the structure of 8 by X-ray crystallographic analysis, thus forcing structure revision of a triterpene from the same source previously assumed to be a friedolanostane. These and several friedo- and lanostanes earlier isolated from the same source were evaluated for cytotoxicity against three human cell lines. Most were moderately active, with three friedolanostanes effective in inducing apoptosis in the MCF-7 cell line.

Lanostanes and friedolanostanes from the bark of Garcinia speciosa.

The CHCl(3) extract of the bark of Garcinia speciosa contained four 17,14-friedolanostanes and five lanostanes as well as friedelin and common plant constituents. The friedolanostanes were the previously known methyl ester of (24E)-3 alpha,23 alpha-dihydroxy-17,14-friedolanostan-8,14,24-trien-26-oic acid and the methyl esters of three hitherto unknown acids, 3 alpha-hydroxy-16 alpha,23 alpha-epoxy-17,14-friedolanostan-8,14,24-trien-26-oic acid, 3 alpha,23 alpha-dihydroxy-8 alpha,9 alpha-epoxy-17,14-friedolanostan-15-oxo-24-en-26-oic acid and 3 alpha,23 alpha-dihydroxy-17,14-friedolanostan-15-oxo-8(14),24-dien-26-oic acid. New lanostanes were 3 beta,9 alpha-dihydroxylanost-24-en-26-al and the methyl ester of 3 beta-hydroxy-23-oxo-9,16-lanostadien-26-oic acid. Structures were established by analysis of spectroscopic data. In the case of the lanostanes the previously unassigned C-25 stereochemistry was shown to be 25R by X-ray analysis of 3 beta-hydroxy-23-oxo-9,16-lanostadien-26-oic acid. In the case of the friedolanostanes the configuration at C-23 was established as 23R, identical with the absolute configuration at C-23 of mariesiic acids A and B.