Development of 3D-QSAR and pharmacophoric models to design new anti-Trypanosoma cruzi agents based on 2-aryloxynaphthoquinone scaffold.

In this work we have collected a set of 30 trypanosomicidal naphthoquinones and developed pharmacophoric and 3D-QSAR models as tools for the design of new potential anti-Chagasic compounds. Firstly, qualitative information was obtained from SAR and pharmacophoric models identifying some fragments around the 2-aryloxynaphthoquinone scaffold important for the antiparasitic activity. Then, 3D-QSAR CoMFA and CoMSIA models were developed. The models showed adequate statistical parameters where the steric, electrostatic, and hydrophobic features explain the trypanosomicidal effect. Therefore, to validate our models, we carried out the design, synthesis, and biological evaluation on T. cruzi epimastigotes of five new compounds (33a-e). According to CoMFA model, three out of five compounds showed pIC50 values within one logarithmic unit of deviation. The two compounds that did not fit the predictions were those with high lipophilicity, which agreed with the SAR and pharmacophore models. Docking and molecular dynamic studies were performed on T. cruzi trypanothione reductase, in a proposed binding site for this type of naphthoquinone. Interestingly, 33a-e showed the same interaction pattern as a naphthoquinone inhibitor (2). Finally, predicted drug-likeness properties indicated that 33a-e have optimal oral bioavailability. Thus, this study provides new in silico models for obtaining novel trypanosomicidal compounds.

Topological properties of a bipartite lattice of domain wall states.

We propose a generalization of the Su-Schrieffer-Heeger (SSH) model of the bipartite lattice, consisting of a periodic array of domain walls. The low-energy description is governed by the superposition of localized states at each domain wall, forming an effective mono-atomic chain at a larger scale. When the domain walls are dimerized, topologically protected edge states can appear, just like in the original SSH model. These new edge states are formed exclusively by soliton-like states and therefore, the new topological states are qualitatively different from the regular SSH edge states. They posses a much longer localization length and are more resistant to on-site disorder, in marked contrast to the standard SSH case.

A combined CoMFA and CoMSIA 3D-QSAR study of benzamide type antibacterial inhibitors of the FtsZ protein in drug-resistant Staphylococcus aureus.

A major problem today is bacterial resistance to antibiotics and the small number of new therapeutic agents approved in recent years. The development of new antibiotics capable of acting on new targets is urgently required. The filamenting temperature-sensitive Z (FtsZ) bacterial protein is a key biomolecule for bacterial division and survival. This makes FtsZ an attractive new pharmacological target for the development of antibacterial agents. There have been several attempts to develop ligands able to inhibit FtsZ. Despite the large number of synthesized compounds that inhibit the FtsZ protein, there are no quantitative structure-activity relationships (QSAR) that allow for the rational design and synthesis of promising new molecules. We present the first 3D-QSAR study of a large and diverse set of molecules that are able to inhibit the FtsZ bacterial protein. We summarize a set of chemical changes that can be made in the steric, electrostatic, hydrophobic and donor/acceptor hydrogen-bonding properties of the pharmacophore, to generate new bioactive molecules against FtsZ. These results provide a rational guide for the design and synthesis of promising new antibacterial agents, supported by the strong statistical parameters obtained from CoMFA (r(2)(pred) = 0.974) and CoMSIA (r(2)(pred) = 0.980) analyses.

Hermansky Pudlak syndrome: an unusual form of procto-colitis

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder consisting of oculocutaneous albinism, platelet dysfunction and systemic complications associated with lipofuscin deposition in the reticuloendothelial system. HPS has been associated with a granulomatous enterocolitis with pathologic features suggestive of Crohn's disease. It remains uncertain if HPS represents a truly distinct form of granulomatous enterocolitis. We report a series of two patients with HPS treated in Puerto Rico, and the results from medical and surgical intervention for gastrointestinal disease. Our experience with HPS patients has shown the difficult management of perineal disease similar in the management of Crohn's. However, complications from the bleeding diathesis necessitate caution during surgery and potential anesthesia complications. Furthermore, avoidance of a perineal wound is preferred, and when possible, ileostomies have fewer complications than colostomies as they do not involve the small bowel.

Puerto Rico experience with plugs in the treatment of anal fistulas

BACKGROUND: Anorectal fistula is a common problem that affects quality of life. Main objective of therapy has been to eradicate the fistula tract while preserving fecal continence. Latest good results for anal fistula treatment have been an anal fistula plug. This study was undertaken to determine if these results could be reproduced in Puerto Rico. METHOD: From January 2003 to January 2008, two experienced colorectal surgeons performed this new operation in 23 consecutive patients. A multivariable analysis was undertaken including age, sex, location of the fistula, previous surgeries, Seton placement before the insertion of the plug, continence pre and post operation, as well as close follow up. No patient with inflammatory bowel disease was included. RESULTS: We had a good result or healing of the fistula in 14 of 23 patients for a success rate of 60%. We had a subgroup of patients who did slightly better and had a healing rate of 66% compared to the 60% of the whole group. It appears to be a trend in favor of the Seton group but is not statically significant. We had 9 failures of 23 patients or 39%. Suppuration was noticed in three patients and all three had failures of the plug with recurrences. CONCLUSIONS: This new operation is another alternative to add to our armamentarium but we need to search for an operation that decreases the incidence of recurrences we had in our study while maintaining function of the sphincters.

[Enteral nutrition in severe ulcerative colitis. Digestive tolerance and nutritional efficiency]. / Nutrición enteral en crisis grave de colitis ulcerosa: efectividad nutricional y tolerancia digestiva.

BACKGROUNDS AND AIMS: Total parenteral nutrition (TPN) has been traditionally used as an adjunctive therapy in severe ulcerative colitis patients. We performed a prospective study to ascertain the safety, nutritional efficiency, tolerance and costs of total enteral nutrition in this situation. METHODS: After 48 hours of intensive medical treatment, severe ulcerative colitis patients initiated enteral feeding with a polymeric formula. The formula concentration and volume were increased daily. RESULTS: 17 patients (7 women, 10 men; age 36.8 +/- 12.8 years) with a mean clinical activity score of 15.6 +/- 1.5 were included. In 14 patients (82.4%) enteral nutrition was well tolerated, attaining in 11 of them more than 80% of the caloric requirements by day 4. In 3 cases we observed vomiting and bloating. Prealbumin levels improved significantly from 11.1 +/- 3.4 mg/dl to 22.7 +/- 6.8 mg/dl (p = 0.002) at the end of enteral nutrition (11.8 +/- 4.7 days). Albumin and other nutritional parameters did not change. CONCLUSIONS: Total enteral nutrition could be considered a safe and well tolerated nutritional support in these patients. Although albumin and other nutritional parameters did not change during the study period, the increase in prealbumin levels suggests a favourable anabolic effect of total enteral nutrition.

Exploring the genetic role of the HLA-DPB1 locus in Chileans with intrahepatic cholestasis of pregnancy.

BACKGROUND/AIMS: Intrahepatic cholestasis of pregnancy is a rare disease of unknown etiology, with a strikingly higher prevalence in Chile than in most other countries. Although several studies suggest that a genetic predisposition is involved in the pathogenesis, no genetic disease-marker has so far been identified. Using a recently developed HLA-genotyping technique, we performed an association study with a highly polymorphic HLA class II gene in patients with recurrent intrahepatic cholestasis of pregnancy and normal control patients. METHODS: Genomic DNA was extracted from 26 unrelated patients with recurrent ICP and 30 unrelated multiparous women without a personal or family history of this disease among a Chilean population. The polymorphic second exon of the HLA-DPB1 gene was amplified by the polymerase chain reaction and hybridized with 25 sequence-specific oligonucleotide probes to assign the HLA-DPB1 alleles on the basis of known sequence variations. RESULTS: Out of more than 50 HLA-DPB1 alleles presently known, 13 were represented in the analyzed groups. Patients with ICP had a higher frequency of the allele DPB*0402 when compared to controls (69% vs 43%). This difference failed to reach statistical significance (x2 = 2.81, corrected p > 0.5). No significant differences were observed between the frequencies of other detected HLA-DPB1 alleles in the analyzed groups. CONCLUSION: In this study, we observed a high frequency of the allele HLA-DPB1*0402 among Chilean patients with recurrent ICP, but no association of the disease with HLA-DPB1 alleles. Therefore, HLA-DPB1 alleles do not play a major role in determining susceptibility or resistance to intrahepatic cholestasis of pregnancy.