Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.

Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1-3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss-Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.

Nicotinamide riboside kinases regulate skeletal muscle fiber-type specification and are rate-limiting for metabolic adaptations during regeneration.

Nicotinamide riboside kinases (NRKs) control the conversion of dietary Nicotinamide Riboside (NR) to NAD+, but little is known about their contribution to endogenous NAD+ turnover and muscle plasticity during skeletal muscle growth and remodeling. Using NRK1/2 double KO (NRKdKO) mice, we investigated the influence of NRKs on NAD+ metabolism and muscle homeostasis, and on the response to neurogenic muscle atrophy and regeneration following muscle injury. Muscles from NRKdKO animals have altered nicotinamide (NAM) salvage and a decrease in mitochondrial content. In single myonuclei RNAseq of skeletal muscle, NRK2 mRNA expression is restricted to type IIx muscle fibers, and perturbed NAD+ turnover and mitochondrial metabolism shifts the fiber type composition of NRKdKO muscle to fast glycolytic IIB fibers. NRKdKO does not influence muscle atrophy during denervation but alters muscle repair after myofiber injury. During regeneration, muscle stem cells (MuSCs) from NRKdKO animals hyper-proliferate but fail to differentiate. NRKdKO also alters the recovery of NAD+ during muscle regeneration as well as mitochondrial adaptations and extracellular matrix remodeling required for tissue repair. These metabolic perturbations result in a transient delay of muscle regeneration which normalizes during myofiber maturation at late stages of regeneration via over-compensation of anabolic IGF1-Akt signaling. Altogether, we demonstrate that NAD+ synthesis controls mitochondrial metabolism and fiber type composition via NRK1/2 and is rate-limiting for myogenic commitment and mitochondrial maturation during skeletal muscle repair.

Nicotinamide riboside kinase 1 protects against diet and age-induced pancreatic ß-cell failure.

OBJECTIVE: Disturbances in NAD+ metabolism have been described as a hallmark for multiple metabolic and age-related diseases, including type 2 diabetes. While alterations in pancreatic ß-cell function are critical determinants of whole-body glucose homeostasis, the role of NAD+ metabolism in the endocrine pancreas remains poorly explored. Here, we aimed to evaluate the role of nicotinamide riboside (NR) metabolism in maintaining NAD+ levels and pancreatic ß-cell function in pathophysiological conditions. METHODS: Whole body and pancreatic ß-cell-specific NRK1 knockout (KO) mice were metabolically phenotyped in situations of high-fat feeding and aging. We also analyzed pancreatic ß-cell function, ß-cell mass and gene expression. RESULTS: We first demonstrate that NRK1, the essential enzyme for the utilization of NR, is abundantly expressed in pancreatic ß-cells. While NR treatment did not alter glucose-stimulated insulin secretion in pancreatic islets from young healthy mice, NRK1 knockout mice displayed glucose intolerance and compromised ß-cells response to a glucose challenge upon high-fat feeding or aging. Interestingly, ß cell dysfunction stemmed from the functional failure of other organs, such as liver and kidney, and the associated changes in circulating peptides and hormones, as mice lacking NRK1 exclusively in ß-cells did not show altered glucose homeostasis. CONCLUSIONS: This work unveils a new physiological role for NR metabolism in the maintenance of glucose tolerance and pancreatic ß-cell function in high-fat feeding or aging conditions.

Nicotinamide Riboside and Dihydronicotinic Acid Riboside Synergistically Increase Intracellular NAD+ by Generating Dihydronicotinamide Riboside.

Through evolution, eukaryote organisms have developed the ability to use different molecules as independent precursors to generate nicotinamide adenine dinucleotide (NAD+), an essential molecule for life. However, whether these different precursors act in an additive or complementary manner is not truly well understood. Here, we have evaluated how combinations of different NAD+ precursors influence intracellular NAD+ levels. We identified dihydronicotinic acid riboside (NARH) as a new NAD+ precursor in hepatic cells. Second, we demonstrate how NARH, but not any other NAD+ precursor, can act synergistically with nicotinamide riboside (NR) to increase NAD+ levels in cultured cells and in mice. Finally, we demonstrate that the large increase in NAD+ prompted by the combination of these two precursors is due to their chemical interaction and conversion to dihydronicotinamide riboside (NRH). Altogether, this work demonstrates for the first time that NARH can act as a NAD+ precursor in mammalian cells and how different NAD+ precursors can interact and influence each other when co-administered.

Reduced graphene oxide decorated with magnetite nanoparticles enhance biomethane enrichment.

The addition of magnetite nanoparticles (MNPs), reduced graphene oxide (rGO), and reduced graphene oxide decorated with magnetite nanoparticles (rGO-MNPs) was evaluated during biomethane enrichment process. rGO-MNPs presented the highest beneficial impact on the hydrogenotrophic assays with an improvement of 47 % in CH4 production. The improvement was linked to the increase of the electron shuttling capacity (ESC) by rGO-MNPs addition, which boosted the hydrogenotrophic activity of microorganisms, to the rGO and rGO-MNPs, which served as reservoirs of hydrogen, improving H⁠2 transport from the gas to the liquid phase, and to the iron ions released, which acted as a dietary supply for microorganisms. Raman and XRD confirmed a greater disorder and lower crystallinity of rGO-MNPs after the hydrogenotrophic assays, with a lower effect at a nanoparticle concentration of 50 mg/L. Moreover, FTIR analysis indicated that rGO-MNPs were oxidized during the hydrogenotrophic tests. This study highlights the advantages of adding rGO-MNPs as a magnetic nanocomposite. Furthermore, rGO-MNPs can be easily recovered, minimizing their release to the environment.

Cierre de la laparotomía electiva y urgente. Importancia de protocolizar la técnica / Elective and emergent laparotomy closure: The importance of protocolizing the technique

Introducción: La hernia incisional es una patología altamente prevalente cuya prevención incluye medidas como el correcto cierre de la pared abdominal. Métodos: Se llevó a cabo un estudio prospectivo en un centro de tercer nivel que incluyó a pacientes intervenidos de modo electivo y de urgencias tras la implementación de un protocolo de cierre de la laparotomía media. Se realizó una medida objetiva de la relación entre la sutura usada y la longitud de la laparotomía y se analizaron los resultados postoperatorios. Resultados: De los 127 pacientes incluidos, 34 (26,8%) recibieron un cierre técnicamente deficiente. La incidencia de hernia incisional fue del 20,5%. Se demostró una mejoría progresiva en la calidad del cierre. Conclusiones: El cierre de la pared abdominal es deficiente en cerca de una cuarta parte de las laparotomías realizadas en un centro de tercer nivel. La implementación de un protocolo de cierre mejora la calidad del mismo

Background: Incisional hernias are a frequent complication, and their prevention includes proper closure of the abdominal wall. Methods: A prospective study was conducted at a third-level hospital after the introduction of a midline laparotomy closure protocol. An objective measurement of the suture length to incision length ratio was made. and the postoperative results were analyzed. Results: 127 patients were included and 34 of them (26.8%) had received a technically deficient closure. Incisional hernia was described in 20.5% of cases. An improvement in the quality of the abdominal wall closure was demonstrated over time. Conclusion: The abdominal wall closure was deficient in nearly one- quarter of the laparotomies performed at a third-level medical center. A protocol improved the quality of the laparotomy closure

Elective and emergent laparotomy closure: The importance of protocolizing the technique. / Cierre de la laparotomía electiva y urgente. Importancia de protocolizar la técnica.

BACKGROUND: Incisional hernias are a frequent complication, and their prevention includes proper closure of the abdominal wall. METHODS: A prospective study was conducted at a third-level hospital after the introduction of a midline laparotomy closure protocol. An objective measurement of the suture length to incision length ratio was made. and the postoperative results were analyzed. RESULTS: 127 patients were included and 34 of them (26.8%) had received a technically deficient closure. Incisional hernia was described in 20.5% of cases. An improvement in the quality of the abdominal wall closure was demonstrated over time. CONCLUSION: The abdominal wall closure was deficient in nearly one- quarter of the laparotomies performed at a third-level medical center. A protocol improved the quality of the laparotomy closure.

Factors associated with low anterior resection syndrome after surgical treatment of rectal cancer.

AIM: To assess factors independently associated with low anterior resection syndrome (LARS) following resection or rectal cancer. METHOD: Cross-sectional study carried out in two acute-care teaching hospitals in Barcelona, Spain. Patients who had undergone sphincter preserving low anterior resection with curative intent, with total or partial mesorectal excision (with and without protective ileostomy) between January 2001 and December 2009 completed a self-administered questionnaire to assess bowel dysfunction after rectal cancer surgery. Predictors of LARS were assessed by univariate and multivariate analyses. RESULTS: The questionnaire was sent to 329 patients (response rate 57.7%). Six cases of incomplete questionnaires were excluded. The study population included 184 patients (66.8% men) with a mean age of 63 years. There were 44 (23.9%) patients with no LARS, 36 (19.6%) with minor LARS and 104 (56.2%) with major LARS. In the univariate analysis, total mesorectal excision (P = 0.0008), protective ileostomy (P = 0.002), preoperative and postoperative radiotherapy (P = 0.0000), postoperative chemotherapy (P = 0.0046) and age (P = 0.035) were significantly associated with major LARS, whereas in the multivariate analysis, total mesorectal excision (odds ratio [OR] 2.18, 95% confidence interval [CI] 1.02-4.65), preoperative radiotherapy (OR 4.33, 95% CI 2.03-9.27) and postoperative radiotherapy (OR 9.52, 95% CI 1.74-52.24) were independent risk factors for major LARS. CONCLUSIONS: In this study, the risk of having major LARS increases with total mesorectal excision and both neoadjuvant and adjuvant radiotherapy. This article is protected by copyright. All rights reserved.

Preventing Parastomal Hernia Using a Modified Sugarbaker Technique With Composite Mesh During Laparoscopic Abdominoperineal Resection: A Randomized Controlled Trial.

OBJECTIVE: The aim of this study was to assess the reduction in the incidence of parastomal hernia (PH) after placement of prophylactic synthetic mesh using a modified Sugarbaker technique when a permanent end-colostomy is needed. SUMMARY OF BACKGROUND DATA: Prevention of PH formation is crucial given the high prevalence of PH and difficulties in the surgical repair of PH. METHODS: A randomized, prospective, double-blind, and controlled trial. Rectal cancer patients undergoing laparoscopic abdominoperineal resection with permanent colostomy were randomized (1 : 1) to the mesh and nonmesh arms. In the mesh group, a large-pore lightweight composite mesh was placed in the intraperitoneal/onlay fashion using a modified Sugarbaker technique. PH was detected by computed tomography (CT) after a minimum follow-up of 12 months. Analysis was per-protocol. RESULTS: The mesh group included 24 patients and the control group 28. Preoperative data, surgical time, and postoperative morbidity were similar. The median follow-up was 26 months. After CT examination, 6 of 24 PHs (25%) were observed in the mesh group compared with 18 of 28 (64.3%) in the nonmesh group (odds ratio 0.39, 95% confidence interval 0.18-0.82; P = 0.005). The Kaplan-Meier curves showed significant differences in favor of the mesh group (long-rank = 4.21, P = 0.04). The number needed to treat was 2.5, which confirmed the effectiveness of the intervention. CONCLUSIONS: Placement of a prosthetic mesh by the laparoscopic approach following the modified Sugarbaker technique is safe and effective in the prevention of PH, reducing significantly the incidence of PH.

Low anterior resection syndrome: a survey of the members of the American Society of Colon and Rectal Surgeons (ASCRS), the Spanish Association of Surgeons (AEC), and the Spanish Society of Coloproctology (AECP).

BACKGROUND: Low anterior resection syndrome (LARS) is frequent following sphincter-sparing procedures for rectal cancer. OBJECTIVE: This study aims to assess surgeons' awareness of LARS. DESIGN: This was a survey study. SETTINGS: Members of the American Society of Colon and Rectal Surgeons (ASCRS), the Spanish Association of Surgeons (AEC), and the Spanish Society of Coloproctology (AECP). PARTICIPANTS: Three hundred thirty-four surgeons from the ASCRS and 150 from the Spanish Societies completed a 23-item electronic questionnaire. MAIN OUTCOME MEASURES: Surgeons' opinions regarding different aspects of LARS. RESULTS: The proportion of rectal cancer patients undergoing sphincter-sparing operations ranged between 71 and 90 %. Low anterior resection with end-to-end anastomosis was the most frequently cited procedure after mesorectal excision. More than 80 % of participants were recognized to be moderately or extremely aware of the condition, but regarding the method used to assess LARS, the majority relied on clinical manifestations. Around 35 % of surgeons considered that severe LARS developed in less than 40 % of patients. The most important factor related to defecatory function impairment in the surgeons' opinion was the distance from the anal margin to anastomosis. Other factors thought to be involved were anastomotic leakage, preoperative radiation therapy, age, and postoperative radiotherapy, with similar percentages in the two groups of surgeons. Lifestyle changes and dietary measures associated with or without drug treatment was the modality of choice. The experience with transanal irrigation or sacral nerve stimulation was limited. It was considered that <30 % of patients chronically suffer from severe LARS with significant quality of life impairment. LIMITATIONS: The limitations of this study are the international mix and expert status of the specialists. CONCLUSIONS: The probability of patients suffering from LARS was underestimated despite reporting good knowledge of the syndrome. Validated methods for the assessment of LARS were rarely used. Deficient awareness regarding risk factors for LARS was documented. Knowledge of therapeutic options was also limited.

Producción de órganos bioartificiales / Artificial organs production

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Laparoscopy-assisted versus open colectomy for treatment of colon cancer in the elderly: morbidity and mortality outcomes in 545 patients.

BACKGROUND: Advanced age is a risk factor of major abdominal surgery due to diminished functional reserve and increased comorbidity. Laparoscopy-assisted colectomy is a well-established procedure in colon cancer surgery. The aim of this study was to compare early outcome of elective laparoscopy surgery and open colectomy in colon cancer patients according to age. METHODS: A total of 545 patients with colonic adenocarcinoma underwent elective surgery between 2005 and 2009. There were 277 patients in the laparoscopic group and 268 in the open. Patient characteristics in both groups were homogeneous and further stratified into three subgroups by age: <75, between 75-84, and ≥ 85 years. Main outcome measures were early morbidity, mortality, and hospital stay. RESULTS: Open surgery group showed a higher overall morbidity rate (37.3 vs. 21.6%, P = 0.001), medical complications (16.4 vs. 10.5%, P = 0.033), surgical complications (23.5 vs. 15.5%, P = 0.034), and mortality (6.7 vs. 3.2%, P = 0.034). The overall morbidity rate difference between open and laparoscopy approach disappeared in the oldest group (≥ 85 years old). Surgical site infections rate was inferior for patients <75 years old in laparoscopy group compared with open. Mortality was also significantly inferior in laparoscopy group in younger patients (<75 years, 0 vs. 3%, P = 0.038). Mean hospital stay was shorter for patients in <75 and 75-84 groups with laparoscopic approach (7.8 vs. 11.4 days and 10 vs. 14.3, respectively, P = 0.001) as compared with those who underwent open surgery, but these differences disappeared in patients aged ≥ 85 years. CONCLUSION: Laparoscopy-assisted colectomy in patients underwent elective surgical resections for colon cancer showed advantages in rate of early complications in patients younger than 85 years of age and was found to be as safe and well tolerated as open surgery in patients over 85 years of age.

Ultralow anterior resection with mechanical anastomosis in the treatment of distal third rectal cancer.

Tumors of the lower third of the rectum are a challenge for the surgeon. Among the various techniques of surgical treatment of these lesions, radical surgery and ultra low anterior anastomosis is one of the therapeutic options. This technique is a defy both in the evaluation of the potential patient as in the surgical technique. Such evaluation and treatment processes must be audited in order to keep proper quality indices both in the oncological as in their functional results. This is only possible when both the multidisciplinary and surgical teams have an adequate and ongoing specialized training and a satisfactory volume of patients treated. Details of this technique, its indications and results are reported in this paper.

Resección anterior ultrabaja con anastomosis mecánica en el tratamiento del cáncer de recto del tercio inferior / Ultralow anterior resection with mechanical anastomosis in the treatment of distal third rectal cancer

Los tumores del tercio inferior de recto son un reto para el cirujano. Entre las diferentes técnicas de tratamiento quirúrgico de estas lesiones se encuentra la cirugía radical y la anastomosis anterior ultrabaja, en la que solamente se conservan los últimos 2 cm hasta la unión anorrectal. Esta técnica constituye un desafío, tanto en la valoración del paciente candidato a esta como en el mismo gesto quirúrgico. Dichos procesos de evaluación y de ejecución deben mantener en las auditorías unos índices de calidad correctos en los resultados oncológicos y funcionales. Esto solo es posible cuando tanto el equipo multidisciplinar como el quirúrgico tienen una formación especializada adecuada y continua y un adecuado volumen de pacientes tratados. En este artículo se exponen los detalles de esta técnica, sus indicaciones y resultados

Tumors of the lower third of the rectum are a challenge for the surgeon. Among the various techniques of surgical treatment of these lesions, radical surgery and ultra low anterior anastomosis is one of the therapeutic options. This technique is a defy both in the evaluation of the potential patient as in the surgical technique. Such evaluation and treatment processes must be audited in order to keep proper quality indices both in the oncological as in their functional results. This is only possible when both the multidisciplinary and surgical teams have an adequate and ongoing specialized training and a satisfactory volume of patients treated. Details of this technique, its indications and results are reported in this paper

Yeast, beef and pork extracts counteract Clostridium difficile toxin A enterotoxicity.

Clostridium difficile is responsible for a large proportion of nosocomial cases of antibiotic-associated diarrhoea and pseudomembranous colitis. The present study provides evidence that yeast, beef and pork extracts, ingredients commonly used to grow bacteria, can counteract C. difficile toxin A enterotoxicity in vitro and in vivo. In model intestinal epithelial cells the individual extracts could prevent the toxin A-induced decrease in epithelial barrier function and partially prevented actin disaggregation and cell rounding. Mice with ad libitum access to individual extracts for 1 week had almost complete reduction in toxin A-induced fluid secretion in intestinal loops. Concomitantly, the toxin A-induced expression of the essential proinflammatory mediator Cox-2 was normalized. Moreover this protective effect was also seen when mice received only two doses of extract by intragastric gavage within 1 week. These results show that yeast, beef and pork extracts have the potential to counteract the intestinal pathogenesis triggered by C. difficile toxin A.

Pre-operative chemoradiotherapy with UFT and Leucovorin in patients with advanced rectal cancer: a phase II study.

PURPOSE: The aim this study was to determine the pathologic complete response (pCR) rate defined as tumor regression grade 1 (TRG1) and toxicity profile of the combination of high-dose pre-operative radiotherapy and simultaneous UFT/leucovorin (LV) in patients with locally advanced rectal cancer. MATERIALS/METHODS: Eligibility included biopsy proven rectal adenocarcinoma; T3-T4 N0-N2; performance status < 2 (ECOG) and adequate blood, hepatic and renal function. Treatment consisted of radiotherapy 54 Gy at 1.8 Gy/day and UFT 300 mg/m(2)/day and LV 60 mg/day, given simultaneously daily for 6 weeks. Surgery was performed within 4-6 weeks period after chemoradiotherapy. Patients who did not achieve TGR1 were to receive 4 cycles of adjuvant UFT/LV on days 1-28, every 5 weeks. RESULTS: Sixty-eight patients were included. All but one received full dose of radiation and 62 had the total planned pre-operative UFT/LV dose. Grade 3 toxicities were diarrhea 7% and proctitis 3%. Complete resection was achieved in 62 patients (91%). Tumor regression grade 1 (TRG1) was seen in 11 patients (16%). Forty-eight patients received adjuvant UFT/LV. Grade 3 toxicity during adjuvant UFT/LV included diarrhea 12%, asthenia 4%, neutropenia 2%, and hand-foot syndrome 2%. The 3-year disease-free survival was 71%. CONCLUSIONS: Simultaneous high-dose pre-operative localized radiation therapy concurrent with UFT/LV is feasible and has a low toxicity profile. This schedule is highly effective and merits further investigation.

Multimedia article. Laparoscopic-assisted rectosigmoidectomy with ileal loop interposition. Surgical treatment of chagasic megacolon.

BACKGROUND: Chagas disease is a frequent cause of acquired megacolon in several countries of Latin America. Several procedures have been described to treat this condition. Recently a report of 147 patients treated with an open rectosigmoidectomy with an ileal loop interposition showed a low rate of complications (8.5 percent) and recurrence (3.1 percent).1 TECHNIQUE: We present the video of a 42-year-old Latin American man who had a diagnosis of chagasic megacolon and was treated with the technique described by Netinho et al. 1 but with the use of laparoscopy. The patient was placed in a supine modified lithotomy position in Allen stirrups; the monitor was placed near the left leg of the patient, and both the surgeon and the assistant stood at the right side of the patient. Four trocars were used. Exploratory laparoscopy was performed. The proximal third of the rectum, sigmoid, and left colon were fully mobilized. Vascular pedicles were sectioned. The rectum was divided by using a linear laparoscopic cutter. A Pfannensteil incision was made and the colon was proximally divided. An ileal loop was interposed isoperistaltically between the descending colon and the rectum. Both the ileoileal and the ileocolic anastomoses were handsewn, and the distal ileorectal anastomoses were performed with a circular stapler under laparoscopic control. The patient is without symptoms or recurrence one year after the surgery. CONCLUSIONS: Laparoscopic approach allows the easy and correct dissection of the lateral attachments and offers the advantages of a more cosmetic and less painful procedure. Laparoscopic rectosigmoidectomy with ileal loop interposition is a technique that can be performed by laparoscopy with good results and should be an option in the treatment of chagasic megacolon.

Chicory increases acetate turnover, but not propionate and butyrate peripheral turnovers in rats.

Chicory roots are rich in inulin that is degraded into SCFA in the caecum and colon. Whole-body SCFA metabolism was investigated in rats during food deprivation and postprandial states. After 22 h of food deprivation, sixteen rats received an IV injection of radioactive 14C-labelled SCFA. The volume of distribution and the fractional clearance rate of SCFA were 0.25-0.27 litres/kg and 5.4-5.9 %/min, respectively. The half-life in the first extracellular rapidly decaying compartment was between 0.9 and 1.4 min. After 22 h of food deprivation, another seventeen rats received a primed continuous IV infusion of 13C-labelled SCFA for 2 h. Isotope enrichment (13C) of SCFA was determined in peripheral arterial blood by MS. Peripheral acetate, propionate and butyrate turnover rates were 29, 4 and 0.3 micromol/kg per min respectively. Following 4 weeks of treatment with chicory root or control diets, eighteen fed rats received a primed continuous IV infusion of 13C-labelled SCFA for 2 h. Intestinal degradation of dietary chicory lowered caecal pH, enhanced caecal and colonic weights, caecal SCFA concentrations and breath H2. The diet with chicory supplementation enhanced peripheral acetate turnover by 25 % (P = 0.017) concomitant with an increase in plasma acetate concentration. There were no changes in propionate or butyrate turnovers. In conclusion, by setting up a multi-tracer approach to simultaneously assess the turnovers of acetate, propionate and butyrate it was demonstrated that a chronic chicory-rich diet significantly increases peripheral acetate turnover but not that of propionate or butyrate in rats.