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.

Salubrinal enhances eIF2α phosphorylation and improves fertility in a mouse model of Classic Galactosemia.

Loss of galactose-1 phosphate uridylyltransferase (GALT) activity in humans results in Classic Galactosemia, and the GalT-deficient (GalT-/-) mouse mimics the patient condition. GalT-/- ovaries display elevated endoplasmic reticulum (ER) stress marker, BiP, and downregulated canonical phosphatidylinositol 3-kinase (Pi3k)/protein kinase B (Akt) growth/pro-survival signaling. Numbers of primordial follicles are reduced in the mutants, recapitulating the accelerated ovarian aging seen in human patients. We previously found that oral administration of the compound Salubrinal (an eIF2α phosphatase inhibitor), resulted in reduction of ovarian BiP expression, rescued Pi3k/Akt signaling, and a doubling of primordial follicles in GalT-/- adults. Here, we further characterized galactosemic stress in GalT-/- mice versus wild-type (WT) controls, and examined whether Salubrinal treatment improved broader reproductive parameters. We assessed the expression levels of factors of the unfolded protein response (UPR), and found that BiP, phospho-Perk, and phospho-eIF2α were all elevated in GalT-/- ovaries. However, neither IKK activation (NFκB pathway) nor alternative Xbp1 splicing downstream of ER membrane protein Ire1α activation was induced, suggesting an Xbp1-independent UPR in galactosemic stress. Moreover, Salubrinal treatment significantly increased the number of ovulated eggs in mutant animals after gonadotrophic superovulation. Salubrinal treatment also normalized estrus cycle stage lengths and resulted in significantly larger litter sizes than vehicle-treated mutants. Overall, we show that Salubrinal protects against galactosemia-induced primordial follicle loss in a fashion that includes suppressing the de-phosphorylation of eIF2α, and that intervention in this way significantly improves and extends ovarian function, fertility, and fecundity.

De Novo Head and Neck Cancer After Liver Transplant With Antibody-Based Immunosuppression Induction.

BACKGROUND: Powerful antibody-based immunosuppression induction is now used routinely during organ transplantation and may place patients at even higher risk of post-transplant cancer. MATERIALS AND METHODS: Incidence of de novo head and neck cancer was extracted from the records of 1685 consecutive adult deceased donor liver transplant recipients with a minimum 1-year follow-up from 2001 to 2015. There were 121 patients positively identified as having developed de novo head and neck cancer post-liver transplant. Records of these patients were analyzed to determine demographics, history of cancer pre-liver transplant, de novo cancer type and location, treatment modalities, and alcohol and tobacco exposure. RESULTS: Of the 121 patients who developed cancer of the head and neck (7%), there were 103 cutaneous (6%) and 25 noncutaneous (1%). For noncutaneous cancers, factors associated with increased risk of cancer included alcohol abuse (P < .001), any smoking history (P = .05), and increasing exposure to tobacco (P < .01). Ten-year Cox regression patient survival demonstrates a survival disadvantage for patients who develop noncutaneous cancer (P  = .06) but a survival advantage for patients who develop cutaneous cancer (P < .01). CONCLUSIONS: The incidence and pattern of head and neck cancer in this population of liver transplant recipients was similar to those published previously, suggesting that induction immunosuppression does not increase risk of these types of cancers. Long-term survival was worse for patients with noncutaneous cancers, but better for those with cutaneous cancers, though the reason is unclear.

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.

Surgeons' follow-up practice after resection of colorectal cancer.

Consultant surgeons in two United Kingdom Health Regions were invited to complete a questionnaire on details of their personal management of patients with colon and rectal cancer, with particular emphasis on follow-up. Replies from 140 (94%) were analysed by the surgeon's subspecialty of colorectal and gastrointestinal surgery (group 1) and all others (group 2). There was a wide variation in the duration of followup, but no difference between the two groups. More group 1 surgeons carried out investigations as a routine after colonic (P < 0.01) and rectal (P < 0.01) resection. Colonoscopy was used more frequently by group 1 (P < 0.0001) and barium enema by group 2 surgeons (P < 0.05). Investigations to detect asymptomatic metastases were used as a routine by 33.3% of surgeons, in whom there was no concordance over the choice or combination of tests and no difference between the two groups of surgeons. There is no consensus among surgeons as to the ideal duration, intensity and method of follow-up after resection for colorectal cancer and little difference between the practice of colorectal and gastrointestinal surgeons and that of other specialists, except in the use of colonoscopy and barium enema. These results reflect the continuing lack of evidence on which to base the follow-up of patients after surgery for colorectal cancer.

Colorectal cancer pathology reporting: a regional audit.

AIMS: To audit the information content of pathology reports of colorectal cancer specimens in one National Health Service region. METHODS: All reports of colorectal cancer resection specimens from the 17 NHS histopathology laboratories in Wales during 1993 were evaluated against: (a) standards previously agreed as desirable by pathologists in Wales; and (b) standards considered to be the minimum required for informed patient management. RESULTS: 1242 reports were audited. There was notable variation in the performance of different laboratories and in the completeness of reporting of individual items of information. While many items were generally well reported, only 51.5% (640/ 1242) of rectal cancer reports contained a statement on the completeness of excision at the circumferential resection margin and only 30% (373/1242) of all reports stated the number of involved lymph nodes. All of the previously agreed items were contained in only 11.3% (140/1242) of reports on colonic tumours and 4.0% (40/1242) of reports on rectal tumours. Seventy eight per cent (969/1242) of colonic carcinoma reports and 46.6% (579/ 1242) of rectal carcinoma reports met the minimum standards. CONCLUSIONS: The informational content of many routine pathology reports on colorectal cancer resection specimens is inadequate for quality patient management, for ensuring a clinically effective cancer service through audit, and for cancer registration. Template proforma reporting using nationally agreed standards is recommended as a remedy for this, along with improved education, review of laboratory practices in the light of current knowledge, and further motivation of pathologists through their involvement in multidisciplinary cancer management teams.

Population-based audit of colorectal cancer management in two UK health regions. Colorectal Cancer Working Group, Royal College of Surgeons of England Clinical Epidemiology and Audit Unit.

BACKGROUND: To obtain information on the contemporary management of colorectal cancer in the UK to assist in the development of management guidelines, an independent, 1-year population audit was carried out in Trent Region and Wales. METHODS: Data were collected on all patients admitted to hospital with a new diagnosis of colorectal cancer in a 1-year period. RESULTS: Of 3520 patients, 3221 (91.5 per cent) had surgery. Emergency/urgent operations were carried out as the first procedure in 552 (17.1 per cent). Resection of the primary disease was achieved in 2859 (81.2 per cent) and this was deemed curative in 2070 (58.8 per cent). Twenty-one per cent of all patients had metastatic disease at presentation. Overall, 30-day operative mortality was 7.6 per cent (21.7 per cent for emergency/urgent and 5.5 per cent for scheduled/elective procedures). Anastomotic dehiscence occurred in 105 patients (4.9 per cent); this was 3.9 per cent after colonic resections and 7.9 per cent after anterior rectal resections. Elective rectal excision resulted in a permanent stoma in 486 of 1054 patients (46 per cent). CONCLUSION: This initial report from a comprehensive, independent audit of colorectal cancer management shows improvement in some aspects of treatment as evidenced by improved anastomotic dehiscence and stoma rates when compared with previous studies. However, there has been little improvement in the proportion of patients presenting with advanced disease, and curative resection rates remain low.

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.

Association of primary biliary cirrhosis with the allele HLA-DPB1*0301 in a German population.

The major histocompatibility complex class II alleles at the HLA-DPB1 locus were investigated in 32 German Caucasoid patients with primary biliary cirrhosis (PBC) and compared with those from 47 normal control patients using molecular genotyping techniques. The second exon of the HLA-DPB1 gene was amplified by polymerase chain reaction (PCR) and hybridized with 25 sequence-specific oligonucleotides (SSOs) to assign the HLA-DPB1 alleles on the basis of known sequence variations, according to the protocols of the Eleventh International Histocompatibility Workshop. A strong association of PBC was found with the allele HLA-DPB1*0301. The allele HLA DPB1*0301 was present in 50% (16 of 32) of the patients with PBC compared with 13% (6 of 47) of normal controls (P corrected < .015), whereas the other HLA-DPB1 alleles showed no significant differences in both groups. The relative risk (RR) estimate for the allele HLA-DPB1*0301 was 6.8 (95% confidence limits: 2.27 to 20.57). In summary, this study clearly demonstrates an association of PBC with the HLA-DPB1*0301 allele in German Caucasoids and may add new data to the immunogenetic background of PBC, suggesting a contribution of the HLA-DPB1 gene to the genetic susceptibility of the disease.

Ciliary responsiveness in allergic and nonallergic airways.

Allergic asthma is associated with airway (smooth muscle) hyperresponsiveness to several chemical mediators of anaphylaxis; however, it is not known whether this is accompanied by mucociliary hyperresponsiveness. The purpose of this study was therefore to determine if airway ciliary activity, a component function of mucociliary clearance, exhibits exaggerated responses to prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), and leukotriene D4 (LTD4) in allergic sheep when compared with nonallergic sheep, and the effects of LTD4 are direct or involve the generation of cyclooxygenase products of arachidonate metabolism. Ciliary beat frequency (CBF) was measured in a perfusion chamber with a microscopic technique using tracheal epithelial cells obtained from brushing of "allergic" (positive cutaneous reaction and previous bronchospastic response to inhaled specific antigen) and "nonallergic" (negative cutaneous reaction, no previous inhalation challenge with antigen) sheep. Mean base-line CBF was not different among the groups; PGE1, PGE2, and LTD4 induced dose-dependent increases in CBF, and these increases were not different in allergic and nonallergic sheep. At the highest agonist concentration the mean increase in CBF from base line varied between 13 and 16% (P less than 0.05). The ciliostimulatory effect of LTD4 was significantly blunted by both the sulfidopeptide leukotriene antagonist FPL-55712 and the cyclooxygenase inhibitor indomethacin. These results suggest that allergic sheep fail to exhibit ciliary hyperresponsiveness to selected chemical mediators of anaphylaxis and the ciliostimulatory effect of LTD4 depends on the activation of cyclooxygenase and possibly the generation of prostaglandins.