Sacral neuromodulation might be effective to palliate low anterior resection syndrome after rectal cancer surgery, but robust evidence is not available.
To assess the impact of sacral neuromodulation ...on low anterior resection syndrome symptoms as measured by validated scores and bowel diaries.
Randomized, double-blind, 2-phased, controlled, multicenter crossover trial (NCT02517853).
Three tertiary hospitals.
Patients with major low anterior resection syndrome 12 months after transit reconstruction after rectal resection who had failed conservative treatment.
Patients underwent an advanced test phase by stimulation for 3 weeks and received the pulse generator implant if a 50% reduction in low anterior resection syndrome score was achieved. These patients entered the randomized phase in which the generator was left active or inactive for 4 weeks. After a 2-week washout, the sequence was changed. After the crossover, all generators were left activated.
The primary outcome was low anterior resection syndrome score reduction. Secondary outcomes included continence and bowel symptoms.
After testing, 35 of 46 patients (78%) had a 50% or greater reduction in low anterior resection syndrome score. During the crossover phase, all patients showed a reduction in scores and improved symptoms, with better performance if the generator was active. At 6- and 12-month follow-up, the mean reduction in low anterior resection syndrome score was -6.2 (95% CI -8.97 to -3.43; p < 0.001) and -6.97 (95% CI -9.74 to -4.2; p < 0.001), with St. Mark's continence score -7.57 (95% CI -9.19 to -5.95, p < 0.001) and -8.29 (95% CI -9.91 to -6.66; p < 0.001). Urgency, bowel emptiness sensation, and clustering episodes decreased in association with quality-of-life improvement at 6- and 12-month follow-up.
The decrease in low anterior resection syndrome score with neuromodulation was underestimated because of an unspecific measuring instrument. There was a possible carryover effect in sham stimulation sequence.
Neuromodulation provides symptoms and quality-of-life amelioration, supporting its use in low anterior resection syndrome. See Video Abstract .
ANTECEDENTES:La neuromodulación sacra podría ser eficaz para paliar el síndrome de resección anterior baja después de la cirugía de cáncer de recto, pero no hay pruebas sólidas disponibles.OBJETIVO:Evaluar el impacto de la neuromodulación sacra en los síntomas del síndrome de resección anterior baja, medido mediante puntuaciones validadas y diarios intestinales.DISEÑO:Ensayo cruzado multicéntrico, controlado, aleatorizado, doble ciego, de dos fases (NCT02517853).LUGARES:Tres hospitales terciarios.PACIENTES:Pacientes con puntuación de resección anterior baja importante, 12 meses después de la reconstrucción del tránsito después de la resección rectal en quienes había fracasado el tratamiento conservador.INTERVENCIONES:Los pacientes se sometieron a una fase de prueba avanzada mediante estimulación durante tres semanas y se les implantó el generador de impulsos si se lograba una reducción del 50% en la puntuación del síndrome de resección anterior baja, ingresando a la fase aleatorizada en la que el generador se dejaba activo o inactivo durante cuatro semanas. Después de observar por 2 semanas, se cambió la secuencia. Después del cruce, todos los generadores quedaron activados.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la reducción de la puntuación del síndrome de resección anterior baja. Los resultados secundarios incluyeron continencia y síntomas intestinales.RESULTADOS:Después de las pruebas, 35 de 46 pacientes (78%) tuvieron una reducción ≥50% en la puntuación del síndrome de resección anterior baja. Durante el cruce, todos los pacientes mostraron una reducción en las puntuaciones y una mejora de los síntomas, con un mejor rendimiento si el generador estaba activo. A los 6 y 12 meses de seguimiento, la reducción media en la puntuación del síndrome de resección anterior baja fue -6,2 (-8,97; -3,43; p < 0,001) y -6,97 (-9,74; -4,2; p < 0,001), con Puntuación de continencia de St. Mark's -7,57 (-9,19; -5,95, p < 0,001) y -8,29 (-9,91; -6,66; p < 0,001). La urgencia, la sensación de vacío intestinal y los episodios de agrupamiento disminuyeron en asociación con una mejora en la calidad de vida a los 6 y 12 meses de seguimiento.LIMITACIONES:La disminución en la puntuación del síndrome de resección anterior baja con neuromodulación se subestimó debido a un instrumento de medición no específico. Posible efecto de arrastre en la secuencia de estimulación simulada.CONCLUSIONES:La neuromodulación mejora los síntomas y la calidad de vida, lo que respalda su uso en el síndrome de resección anterior baja. (Traducción-Dr. Mauricio Santamaria ).
Background
The aim of this study was to analyze factors contributing to prolonged postoperative ileus (POI) after elective bowel resection in patients with colorectal cancer.
Methods
This was a ...retrospective review of a prospectively maintained database of patients operated on for colorectal cancer during 2006–2009. Patients with abdominal procedures and bowel resection without anastomotic leakage were included. Prolonged POI was defined as no flatus by postoperative day (POD) 6, with or without intolerance to oral intake by POD 6. Variables studied included demographics, prior medical conditions, details of the surgical procedure, and hospital stay.
Results
A total of 773 patients met the inclusion criteria. POI occurred in 15.9%. The mean hospital stay was 11 days without POI and 20 days for POI patients (
P
< 0.001). Factors associated with POI in the univariate analysis were ASA III–IV (
P
< 0.005), male sex (
P
< 0.004), smoking (
P
< 0.015), chronic pulmonary disease (COPD) (
P
< 0.002), rectal cancer (
P
< 0.02), and ileostomy (
P
< 0.001). Multivariate logistic regression analysis showed male sex odds ratio (OR) 1.6, 95% confidence interval (CI) 1.04–3.5; COPD (OR 1.9, 95% CI 1.25–31.0), and ileostomy (OR 1.9; 95% CI 1.23–3.07) as risk factors for POI.
Conclusions
The risk of POI seems increased in patients with preoperative COPD and patients with an ileostomy, especially in men. Consideration of these factors could be important for the prevention and treatment of POI.
Molecular dynamics (MD) simulations are powerful tools to investigate the conformational dynamics of proteins that is often a critical element of their function. Identification of functionally ...relevant conformations is generally done clustering the large ensemble of structures that are generated. Recently, Self-Organising Maps (SOMs) were reported performing more accurately and providing more consistent results than traditional clustering algorithms in various data mining problems. We present a novel strategy to analyse and compare conformational ensembles of protein domains using a two-level approach that combines SOMs and hierarchical clustering.
The conformational dynamics of the α-spectrin SH3 protein domain and six single mutants were analysed by MD simulations. The Cα's Cartesian coordinates of conformations sampled in the essential space were used as input data vectors for SOM training, then complete linkage clustering was performed on the SOM prototype vectors. A specific protocol to optimize a SOM for structural ensembles was proposed: the optimal SOM was selected by means of a Taguchi experimental design plan applied to different data sets, and the optimal sampling rate of the MD trajectory was selected. The proposed two-level approach was applied to single trajectories of the SH3 domain independently as well as to groups of them at the same time. The results demonstrated the potential of this approach in the analysis of large ensembles of molecular structures: the possibility of producing a topological mapping of the conformational space in a simple 2D visualisation, as well as of effectively highlighting differences in the conformational dynamics directly related to biological functions.
The use of a two-level approach combining SOMs and hierarchical clustering for conformational analysis of structural ensembles of proteins was proposed. It can easily be extended to other study cases and to conformational ensembles from other sources.
Abstract Background To evaluate the probability of recurrence and the virulence of colonic diverticulitis correlated with immunocompromised status. Methods Nine hundred thirty-one patients admitted ...in a single tertiary referral university hospital over a 14-year period were included. Patients were divided into 2 groups: group 1, 166 immunosuppressed patients, and group 2, 765 nonimmunosuppressed patients. The variables studied were sex, age, American Society of Anesthesiologist status, reasons of immunosuppression (eg, chronic use of corticosteroids, transplant recipients, and diseases affecting the immune system), severity of the diverticulitis episode, recurrence, emergency and elective surgery, and morbidity and mortality rates. Results Two hundred thirteen patients underwent an emergency operation during the first hospitalization and 26 patients in further episodes. One hundred thirty-six patients developed 1 or more recurrent episodes of diverticulitis. The overall recurrence rate was similar in both groups. Patients in group 1 with a severe first episode presented significantly higher rates of recurrence and severity without needing more emergency surgery. Mortality after emergency surgery was 33.3% in group 1 and 15.9% in group 2 ( P = .004). Conclusions After successful medical treatment of acute diverticulitis, patients with immunosuppression need not be advised to have an elective sigmoidectomy.
The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates the biological and toxic effects of a wide variety of structurally diverse chemicals, including the toxic ...environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). While significant interspecies differences in AHR ligand binding specificity, selectivity, and response have been observed, the structural determinants responsible for those differences have not been determined, and homology models of the AHR ligand-binding domain (LBD) are available for only a few species. Here we describe the development and comparative analysis of homology models of the LBD of 16 AHRs from 12 mammalian and nonmammalian species and identify the specific residues contained within their ligand binding cavities. The ligand-binding cavity of the fish AHR exhibits differences from those of mammalian and avian AHRs, suggesting a slightly different TCDD binding mode. Comparison of the internal cavity in the LBD model of zebrafish (zf) AHR2, which binds TCDD with high affinity, to that of zfAHR1a, which does not bind TCDD, revealed that the latter has a dramatically shortened binding cavity due to the side chains of three residues (Tyr296, Thr386, and His388) that reduce the amount of internal space available to TCDD. Mutagenesis of two of these residues in zfAHR1a to those present in zfAHR2 (Y296H and T386A) restored the ability of zfAHR1a to bind TCDD and to exhibit TCDD-dependent binding to DNA. These results demonstrate the importance of these two amino acids and highlight the predictive potential of comparative analysis of homology models from diverse species. The availability of these AHR LBD homology models will facilitate in-depth comparative studies of AHR ligand binding and ligand-dependent AHR activation and provide a novel avenue for examining species-specific differences in AHR responsiveness.
The biological function of proteins is strictly related to their molecular flexibility and dynamics: enzymatic activity, protein-protein interactions, ligand binding and allosteric regulation are ...important mechanisms involving protein motions. Computational approaches, such as Molecular Dynamics (MD) simulations, are now routinely used to study the intrinsic dynamics of target proteins as well as to complement molecular docking approaches. These methods have also successfully supported the process of rational design and discovery of new drugs. Identification of functionally relevant conformations is a key step in these studies. This is generally done by cluster analysis of the ensemble of structures in the MD trajectory. Recently Artificial Neural Network (ANN) approaches, in particular methods based on Self-Organising Maps (SOMs), have been reported performing more accurately and providing more consistent results than traditional clustering algorithms in various data-mining problems. In the specific case of conformational analysis, SOMs have been successfully used to compare multiple ensembles of protein conformations demonstrating a potential in efficiently detecting the dynamic signatures central to biological function. Moreover, examples of the use of SOMs to address problems relevant to other stages of the drug-design process, including clustering of docking poses, have been reported. In this contribution we review recent applications of ANN algorithms in analysing conformational and structural ensembles and we discuss their potential in computer-based approaches for medicinal chemistry.
We have developed a virtual screening procedure to identify potential ligands to the aryl hydrocarbon receptor (AhR) among a set of industrial chemicals. AhR is a key target for dioxin-like ...compounds, which is related to these compounds’ potential to induce cancer and a wide range of endocrine and immune system-related effects. The virtual screening procedure included an initial filtration aiming at identifying chemicals with structural similarities to 66 known AhR binders, followed by 3 enrichment methods run in parallel. These include two ligand-based methods (structural fingerprints and nearest neighbor analysis) and one structure-based method using an AhR homology model. A set of 6445 commonly used industrial chemicals was processed, and each step identified unique potential ligands. Seven compounds were identified by all three enrichment methods, and these compounds included known activators and suppressors of AhR. Only approximately 0.7% (41 compounds) of the studied industrial compounds was identified as potential AhR ligands and among these, 28 compounds have to our knowledge not been tested for AhR-mediated effects or have been screened with low purity. We suggest assessment of AhR-related activities of these compounds and in particular 2-chlorotrityl chloride, 3-
p
-hydroxyanilino-carbazole, and 3-(2-chloro-4-nitrophenyl)-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one.
Purpose Hartmann's procedure (HP) still remains the most frequently performed procedure for diffuse peritonitis due to perforated diverticulitis. The aims of this study were to assess the feasibility ...and safety of resection with primary anastomosis (RPA) in patients with purulent or fecal diverticular peritonitis and review morbidity and mortality after single stage procedure and Hartmann in our experience. Methods From January 1995 through December 2008, patients operated for generalized diverticular peritonitis were studied. Patients were classified into two main groups: RPA and HP. Results A total of 87 patients underwent emergency surgery for diverticulitis complicated with purulent or diffuse fecal peritonitis. Sixty (69%) had undergone HP while RPA was performed in 27 patients (31%). At the multivariate analysis, RPA was associated with less post-operative complications (P < 0.05). Three out of the 27 patients with RPA (11.1%) developed a clinical anastomotic leakage and needed re-operation. Conclusions RPA can be safely performed without adding morbidity and mortality in cases of diffuse diverticular peritonitis. HP should be reserved only for hemodynamically unstable or high-risk patients. Specialization in colorectal surgery improves mortality and raises the percentage of one-stage procedures.
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