Central Nervous System Pathways Research Articles

Aerobic Exercise Preserves Olfaction Function in Individuals with Parkinson's Disease.

Introduction. Based on anecdotal reports of improved olfaction following aerobic exercise, the aim of this study was to evaluate the effects of an 8-week aerobic exercise program on olfaction function in individuals with Parkinson's disease (PD). Methods. Thirty-eight participants with idiopathic PD were randomized to either an aerobic exercise group (n = 23) or a nonexercise control group (n = 15). The aerobic exercise group completed a 60-minute cycling session three times per week for eight weeks while the nonexercise control group received no intervention. All participants completed the University of Pennsylvania Smell Identification Test (UPSIT) at baseline, end of treatment, and a four-week follow up. Results. Change in UPSIT scores between the exercise and nonexercise groups from baseline to EOT (p = 0.01) and from baseline to EOT+4 (p = 0.02) favored the aerobic exercise group. Individuals in the nonexercise group had worsening olfaction function over time, while the exercise group was spared from decline. Discussion. The difference in UPSIT scores suggested that aerobic exercise may be altering central nervous system pathways that regulate the physiologic or cognitive processes controlling olfaction in individuals with PD. While these results provide promising preliminary evidence that exercise may modify the disease process, further systematic evaluation is necessary.

Increased Autism Incidence: Is there a Single Cause?

The Quantitative Threshold Exposure (QTE) hypothesis proposes that Autism Spectrum Disorder (ASD) is triggered by the cumulative effects of high-level exposure to endogenous and environmental factors that act as antigens to impair normal immune system (IS) and associated central nervous system (CNS) functions during critical prenatal and early childhood developmental stages. The hypothesis predicts that the greater the number of risk factors and the quantitative amounts of each to which a child is exposed prenatally and in early postnatal life, the greater the likelihood the child will develop some form of ASD as a result of their effects on critically integrated IS and CNS pathways active during prenatal, neo-natal and early childhood brain maturation. These risk factors have been identified in extensive epidemiological studies to include genetic predisposition, maternal fetal exposure to infectious disease, inflammatory and autoimmune phenomena, as well as exposure to antigenic and proinflammatory environmental factors. The incidence rates of several potential risk factors for ASD correlates with observed increases in ASD incidence over the past several decades, including increased incidence of pediatric infectious disease, increased obesity/ diabetes type-2 in parents of child-bearing age and Increased use of tetrahydrocannabinol (THC) during childbearing years. This model may be useful even when the individual contributions of specific risk factors cannot be quantified, as it proposes that the combined quantitative level of exposure to risk factors for ASD rather than exposure to any one risk factor per se defines threshold occurrence rates. The model has important predictive value, as it suggests that, rather than attempting to identify a specific causative agent linked to ASD, the combined risk factor profile should be evaluated in population studies in order to specify more accurately the limits of pre- threshold exposure.

Angiotensin II-triggered kinase signaling cascade in the central nervous system.

Recent studies have projected the renin-angiotensin system as a central component of the physiological and pathological processes of assorted neurological disorders. Its primary effector hormone, angiotensin II (Ang II), not only mediates the physiological effects of vasoconstriction and blood pressure regulation in cardiovascular disease but is also implicated in a much wider range of neuronal activities and diseases, including Alzheimer's disease, neuronal injury, and cognitive disorders. Ang II produces different actions by acting on its two subtypes of receptors (AT1 and AT2); however, the well-known physiological actions of Ang II are mainly mediated through AT1 receptors. Moreover, recent studies also suggest the important functional role of AT2 receptor in the brain. Ang II acts on AT1 receptors and conducts its functions via MAP kinases (ERK1/2, JNK, and p38MAPK), glycogen synthase kinase, Rho/ROCK kinase, receptor tyrosine kinases (PDGF and EGFR), and nonreceptor tyrosine kinases (Src, Pyk2, and JAK/STAT). AT1R-mediated NADPH oxidase activation also leads to the generation of reactive oxygen species, widely implicated in neuroinflammation. These signaling cascades lead to glutamate excitotoxicity, apoptosis, cerebral infarction, astrocyte proliferation, nociception, neuroinflammation, and progression of other neurological disorders. The present review focuses on the Ang II-triggered signal transduction pathways in central nervous system.

On the origins of autism: The Quantitative Threshold Exposure hypothesis

The Quantitative Threshold Exposure (QTE) hypothesis is a multifactorial threshold model that accounts for the cumulative effects of risk factor exposure in both the causation of autism spectrum disorder (ASD) and its dramatic increase over the past 30years. The QTE hypothesis proposes that ASD is triggered by the cumulative effects of high-level exposure to endogenous and environmental factors that act as antigens to impair normal immune system (IS) and associated central nervous system (CNS) functions during critical developmental stages. The quantitative threshold parameters that comprise a cumulative risk for the development of ASD are identified by the assessment of documented epidemiological factors that, in sum, determine the likelihood that ASD will occur as a result of their effects on critically integrated IS and CNS pathways active during prenatal, neo-natal and early childhood brain maturation. The model proposes an explanation for the relationship between critical developmental stages of brain/immune system development in conjunction with the quantitative effects of genetic and environmental risk factors that may interface with these critical developmental windows. This model may be useful even when the individual contributions of specific risk factors cannot be quantified, as it proposes that the combined quantitative level of exposure to risk factors for ASD rather than exposure to any one risk factor per se defines threshold occurrence rates.

Assessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS): study protocol for a randomised controlled trial.

BackgroundWe have recently completed an evaluation of the safety and feasibility of intravenous delivery of autologous bone marrow in patients with progressive multiple sclerosis (MS). The possibility of repair was suggested by improvement in the neurophysiological secondary outcome measure seen in all participants. The current study will examine the efficacy of intravenous delivery of autologous marrow in progressive MS. Laboratory studies performed in parallel with the clinical trial will further investigate the biology of bone marrow-derived stem cell infusion in MS, including mechanisms underlying repair.Methods/designA prospective, randomised, double-blind, placebo-controlled, stepped wedge design will be employed at a single centre (Bristol, UK). Eighty patients with progressive MS will be recruited; 60 will have secondary progressive disease (SPMS) but a subset (n = 20) will have primary progressive disease (PPMS). Participants will be randomised to either early or late (1 year) intravenous infusion of autologous, unfractionated bone marrow. The placebo intervention is infusion of autologous blood. The primary outcome measure is global evoked potential derived from multimodal evoked potentials. Secondary outcome measures include adverse event reporting, clinical (EDSS and MSFC) and self-assessment (MSIS-29) rating scales, optical coherence tomography (OCT) as well as brain and spine MRI. Participants will be followed up for a further year following the final intervention. Outcomes will be analysed on an intention-to-treat basis.DiscussionAssessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS) is the first randomised, placebo-controlled trial of non-myeloablative autologous bone marrow-derived stem cell therapy in MS. It will determine whether bone marrow cell therapy can, as was suggested by the phase I safety study, improve conduction in multiple central nervous system pathways affected in progressive MS. Furthermore, laboratory studies performed in parallel with the clinical trial will inform our understanding of the cellular pharmacodynamics of bone marrow infusion in MS patients and the mechanisms underlying cell therapy.Trial RegistrationISRCTN27232902 Registration date 11/09/2012. NCT01815632 Registration date 19/03/2013

Filling in the Acupuncture Jigsaw Puzzle.

Western medical practitioners often express scepticism about the role and validity of acupuncture as a therapeutic technique, despite the fact that it has been a part of traditional Chinese medicine (TCM) practice for more than 2000 years. Their uncertainty reflects in part difficulties that have been experienced in providing convincing proof to support the wide-ranging claims made regarding the benefits of acupuncture that it can be applied for the treatment of a seemingly endless list of conditions, extending from infectious diseases, to cancers, to metabolic, psychiatric, and other illnesses (1). It also reflects apparent discrepancies between TCM theories about the supposed mechanisms of action of acupuncture and Western science, which has been unable to find histological or physiological evidence for concepts such as qi and the theory of meridians. Despite the scepticism, over time, compelling evidence has accumulated that acupuncture is indeed an effective treatment for at least a small number of conditions, including notably pain syndromes and nausea (2, 3). In addition, physiological studies, enhanced by the advent of reliable animal models, have suggested a range of possible pathways of action, even if uncertainty has persisted about the specificity of the effects seen with respect to particular acupuncture points and techniques. The pathways are nowthought to comprise a rangeofmechanismsat various sites of action, including peripheral (eg, axon reflexes, neuropeptides, local endorphins), spinal (eg, gate control, propriospinal inhibition, etc), supraspinal (eg, sympathetic nervous system and effects on the hypothalamicpitituary-adrenal [HPA] axis), and central (eg, paraventricular nuclear, locus ceruleus, periaqueductal gray, and cortical) (4–6). Among the clinical conditions, about which claims of benefit from acupuncture have been made but which have remained controversial, are anxiety and depressive states. It is well recognized that many sufferers of these conditions use complementary and alternative medicines (7) and that a number of studies have supported the possibility of beneficial effects. However, a systematic review in 2007 concluded that, despite the positive findings, methodological deficiencies limit the conclusions that can be drawn about the efficacy of acupuncture in the treatment of anxiety and depression, (8) and especially the ability to exclude placebo or “expectancy” effects (9). It is agreed that, as with the other conditions, there remains a need for improved methodologies, larger studies, better standardization of treatments, and more rigorous control processes. On the other hand, an expanding body of evidence has supported claims for a physiological basis for an effect of acupuncture on stress responses and anxiety. Functional magnetic resonance imaging studies in humans have demonstrated activation of specific central nervous system pathways known to be associated with pain perception and stress, including the limbic system and subcortical gray structures (10). Animal models focusing on a limited number of clearly defined acupuncture points, including, especially, the so-called stomach 36 (St36) (also known as Zusanli) point, have assisted with the standardization of experimental procedures and supported the generation of an array of commensurable data. Studies of St36, in both humans and animal models, have shown effects on the HPA system and other brain structures, mediated through changes in neuropeptide Y expression and a variety of other neurotransmitters, endogenous opioid-like substances, and second messenger pathways (11–14).

Repeat infusion of autologous bone marrow cells in multiple sclerosis: protocol for a phase I extension study (SIAMMS-II)

IntroductionThe ‘Study of Intravenous Autologous Marrow in Multiple Sclerosis (SIAMMS)’ trial was a safety and feasibility study which examined the effect of intravenous infusion of autologous bone marrow without myeloablative...

Effects of intermittent fasting on age-related changes on Na,K-ATPase activity and oxidative status induced by lipopolysaccharide in rat hippocampus

Chronic neuroinflammation is a common characteristic of neurodegenerative diseases, and lipopolysaccharide (LPS) signaling is linked to glutamate-nitric oxide-Na,K-ATPase isoforms pathway in central nervous system (CNS) and also causes neuroinflammation. Intermittent fasting (IF) induces adaptive responses in the brain that can suppress inflammation, but the age-related effect of IF on LPS modulatory influence on nitric oxide-Na,K-ATPase isoforms is unknown. This work compared the effects of LPS on the activity of α1,α2,3 Na,K-ATPase, nitric oxide synthase gene expression and/or activity, cyclic guanosine monophosphate, 3-nitrotyrosine–containing proteins, and levels of thiobarbituric acid–reactive substances in CNS of young and older rats submitted to the IF protocol for 30 days. LPS induced an age-related effect in neuronal nitric oxide synthase activity, cyclic guanosine monophosphate, and levels of thiobarbituric acid–reactive substances in rat hippocampus that was linked to changes in α2,3-Na,K-ATPase activity, 3-nitrotyrosine proteins, and inducible nitric oxide synthase gene expression. IF induced adaptative cellular stress-response signaling pathways reverting LPS effects in rat hippocampus of young and older rats. The results suggest that IF in both ages would reduce the risk for deficits on brain function and neurodegenerative disorders linked to inflammatory response in the CNS.

Urotherapy for Tear Production With Painless Urination

We report a rare case of a 4-year-old girl with involuntary watering of eyes and facial redness during painless voiding since early infancy. Here, we describe her response to urotherapy with improvement of involuntary tearing during micturition, which although neither life threatening nor debilitating, may be quite bothersome for children and their parents, leading to anxiety, emotional burden, or embarrassment. We hypothesize that the lacrimal glands and the bladder and bowel have common central nervous system pathways and that bladder retraining and bowel management might be a potential treatment for this rare condition.

Synthesis and biological activity of small peptides as NOP and opioid receptors' ligands: view on current developments.

The heptadecapeptide nociceptin, also called orphanin FQ (N/OFQ), is the endogenous agonist of the N/OFQ peptide receptor (NOP receptor) and is involved in several central nervous system pathways, such as nociception, reward, tolerance, and feeding. The discovery of small molecule ligands for NOP is being actively pursued for several therapeutic applications. This review presents overview of the several recently reported NOP ligands (agonists and antagonists), with an emphasis of the structural features that may be important for modulating the intrinsic activity of these ligands. In addition, a brief account on the characterization of newly synthesized ligands of NOP receptor with aminophosphonate moiety and β-tryptophan analogues will be presented.

Cyclodextrin-complexed Ocimum basilicum leaves essential oil increases Fos protein expression in the central nervous system and produce an antihyperalgesic effect in animal models for fibromyalgia.

O. basilicum leaves produce essential oils (LEO) rich in monoterpenes. The short half-life and water insolubility are limitations for LEO medical uses. β-Cyclodextrin (β-CD) has been employed to improve the pharmacological properties of LEO. We assessed the antihyperalgesic profile of LEO, isolated or complexed in β-CD (LEO/β-CD), on an animal model for fibromyalgia. Behavioral tests: mice were treated every day with either LEO/β-CD (25, 50 or 100 mg/kg, p.o.), LEO (25 mg/kg, p.o.), tramadol (TRM 4 mg/kg, i.p.) or vehicle (saline), and 60 min after treatment behavioral parameters were assessed. Therefore, mice were evaluated for mechanical hyperalgesia (von Frey), motor coordination (Rota-rod) and muscle strength (Grip Strength Metter) in a mice fibromyalgia model. After 27 days, we evaluated the central nervous system (CNS) pathways involved in the effect induced by experimental drugs through immunofluorescence protocol to Fos protein. The differential scanning analysis (DSC), thermogravimetry/derivate thermogravimetry (TG/DTG) and infrared absorption spectroscopy (FTIR) curves indicated that the products prepared were able to incorporate the LEO efficiently. Oral treatment with LEO or LEO-βCD, at all doses tested, produced a significant reduction of mechanical hyperalgesia and we were able to significantly increase Fos protein expression. Together, our results provide evidence that LEO, isolated or complexed with β-CD, produces analgesic effects on chronic non-inflammatory pain as fibromyalgia.

Perturbed glucose metabolism: insights into multiple sclerosis pathogenesis.

Multiple sclerosis (MS) is a complex debilitating disease of the central nervous system (CNS) perceived to result from the autoimmune effect of T cells in damaging myelin sheath. However, the exact pathogenesis of the disease remains elusive. Initial studies describing the possibility of defective pyruvate metabolism in MS were performed in 1950s. The group observed elevated blood pyruvate level in both fasting and postprandial times in MS patients with relapse. Similarly, other investigators also reported increased fasting pyruvate level in this disease. These reports hint to a possible abnormality of pyruvate metabolism in MS patients. In addition, increase in levels of Krebs cycle acids like alpha-ketoglutarate in fasting and citrate after glucose intake in MS patients further strengthened the connection of disturbed pyruvate metabolism with MS progression. These studies led the investigators to explore the role of disturbed glucose metabolism in pathophysiological brain function. Under normal circumstances, complex molecules are metabolized into simpler molecules through their respective pathways. Differential expression of genes encoding enzymes of the glucose metabolic pathway in CNS may result in neurological deficits. In this review article, we discuss the studies related to disturbed carbohydrate metabolism in MS and other neurodegenerative diseases. These observations open new perspectives for the understanding of metabolic dynamics in MS yet many puzzling aspects and critical questions need to be addressed. Much more research is required to fully unravel the disease mechanism, and a proper understanding of the disease could eventually lead to new treatments.

Drug development strategies for the treatment of obesity: how to ensure efficacy, safety, and sustainable weight loss.

The prevalence of obesity has increased worldwide, and approximately 25%–35% of the adult population is obese in some countries. The excess of body fat is associated with adverse health consequences. Considering the limited efficacy of diet and exercise in the current obese population and the use of bariatric surgery only for morbid obesity, it appears that drug therapy is the only available method to address the problem on a large scale. Currently, pharmacological obesity treatment options are limited. However, new antiobesity drugs acting through central nervous system pathways or the peripheral adiposity signals and gastrointestinal tract are under clinical development. One of the most promising approaches is the use of peptides that influence the peripheral satiety signals and brain–gut axis such as GLP-1 analogs. However, considering that any antiobesity drug may affect one or several of the systems that control food intake and energy expenditure, it is unlikely that a single pharmacological agent will be effective as a striking obesity treatment. Thus, future strategies to treat obesity will need to be directed at sustainable weight loss to ensure maximal safety. This strategy will probably require the coadministration of medications that act through different mechanisms.

Loss of NEIL1 causes defects in olfactory function in mice

Oxidative DNA damage accumulation has been implicated in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The base excision repair pathway is a primary responder to oxidative DNA damage. Effects of loss of base excision repair on normal brain function is a relatively nascent area of research that needs further exploration for better understanding of related brain diseases. Recently, we found that loss of a versatile DNA glycosylase endonuclease 8-like 1 (NEIL1) causes deficits in spatial memory retention using the Morris water maze test. Furthermore, we found that there is a significant loss of NEIL1 enzyme levels and its activity in postmortem Alzheimer's disease brains. Based on the Allen Brain Atlas in situ hybridization data, the expression levels of Neil1 messenger RNA are higher in the olfactory bulb compared with other areas of the brain. Olfaction in mice is a central brain function that involves many central nervous system pathways. Here, we studied the effect of complete loss of Neil1 gene on olfactory function. We explored olfactory function in mice with 3 different behavioral tests namely, olfactory sensitivity, performance, and buried food tests. Neil1−/− mice performed poorly compared with wild-type mice in all 3 tests. Our data indicate that loss of Neil1 causes olfactory function deficits supporting our previous findings and that normal brain function requires robust DNA repair.

Inflammasomes in neuroinflammation and changes in brain function: a focused review

Recent literature has pointed to the existence of inflammasome-mediated inflammatory pathways in central nervous system (CNS) disorders and associated changes in behavior. Neuroinflammation, which is an innate immune response in the CNS against harmful and irritable stimuli such as pathogens and metabolic toxic waste, as well as to chronic mild stress, is mediated by protein complexes known as inflammasomes. Inflammasomes activate pro-inflammatory caspases 1 and 5, which then cleave the precursor forms of pro-inflammatory cytokines IL-1β, IL-18, and IL-33 into their active forms. These pro-inflammatory cytokines have been shown to promote a variety of innate immune processes associated with infection, inflammation, and autoimmunity, and thereby play an instrumental role in the instigation of neuroinflammation during old age and subsequent occurrence of neurodegenerative diseases, cognitive impairment, and dementia. In particular, NLRP inflammasomes may also have a role in the etiologies of depression, Alzheimer's disease (AD) and in metabolic disorders, such as Type II diabetes, obesity and cardiovascular diseases that have been shown to be co-morbid with psychiatric illnesses. It has been reported that while these inflammasomes may be activated through TNF-α dependent pathways, other cytokines, like IFN-γ, may assist in inhibiting their activation and thus delay disease progression. Furthermore, some other cytokines, including IL-6, may not have a direct role in inflammasome-mediated diseases. An array of recent research suggests that NLRP inflammasomes targeted therapies could be used for alleviating neuroinflammation and for treatment of associated psychiatric illnesses, although this still remains a challenge and necessitates further extensive research. This review examines the complex inflammatory signaling pathways involved in the activation of NLRP inflammasomes and the role they play in promoting neuroinflammation and subsequent behavioral changes.

Chronic Idiopathic Nausea

Chronic nausea is a prevalent but poorly described symptom in adolescents. It often co-occurs with other functional gastrointestinal disorders (FGIDs) but may also present in isolation. A multitude of triggers and complex neural pathways underlie the sensation of nausea. These include gastrointestinal and blood-borne insults, dysmotility, vestibular or central nervous system pathways, an aberrant autonomic nervous system, and psychosocial factors. Although clinical algorithms are lacking, diagnosis is typically made on the basis of a thorough clinical history and without extensive testing. Treatment is mainly empiric and may be directed at comorbid symptoms such as migraine, delayed gastric emptying, orthostatic intolerance, and visceral hypersensitivity. Chronic idiopathic nausea is an increasingly prevalent symptom that needs careful clinical assessment and individualized treatment plans.

Altered cardiovascular reactivity to mental stress in patients with multiple sclerosis

Cold pressure test (CPT) and mental stress test (MST) are distinct tests usually leading to blood pressure (BP) and heart rate (HR) increase. Their patterns in multiple sclerosis (MS) are still unknown. This study assessed cardiovascular reactivity to MST and CPT in patients with MS and controls. MST was performed with Stroop test card. CPT was performed with cold stimulus. The BP and HR were digitally recorded at rest and test phases. The delta (Δ) and the variance of BP and HR were compared between patients and controls. Patients with MS had lower Δ of diastolic BP and HR induced by MST than controls. There were no differences between patients and controls with CPT. The reduced autonomic reactivity to MST but not with CPT suggests that specific central nervous system pathways involved in MST may be responsible for autonomic findings in MS.

Central nervous system circuits modified in heart failure: pathophysiology and therapeutic implications

The pathophysiology of heart failure (HF) is characterized by an abnormal activation of neurohumoral systems, including the sympathetic nervous and the renin-angiotensin-aldosterone systems, which have long-term deleterious effects on the disease progression. Perpetuation of this neurohumoral activation is partially dependent of central nervous system (CNS) pathways, mainly involving the paraventricular nucleus of the hypothalamus and some regions of the brainstem. Modifications in these integrative CNS circuits result in the attenuation of sympathoinhibitory and exacerbation of sympathoexcitatory pathways. In addition to the regulation of sympathetic outflow, these central pathways coordinate a complex network of agents with an established pathophysiological relevance in HF such as angiotensin, aldosterone, and proinflammatory cytokines. Central pathways could be potential targets in HF therapy since the current mainstay of HF pharmacotherapy aims primarily at antagonizing the peripheral mechanisms. Thus, in the present review, we describe the role of CNS pathways in HF pathophysiology and as potential novel therapeutic targets.

Noninvasive Quantification of Metabotropic Glutamate Receptor Type 1 with [11C]ITDM: a Small-Animal PET Study

Because of its role in multiple central nervous system (CNS) pathways, metabotropic glutamate receptor type 1 (mGluR1) is a crucial target in the development of pharmaceuticals for CNS disorders. N-[4-[6-(isopropylamino)-pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[(11)C]-methylbenzamide ([(11)C]ITDM) was recently developed as a positron emission tomography (PET) ligand for mGluR1. To devise a method for measurement of the binding potential (BPND) of [(11)C]ITDM to mGluR1, reference tissue methods aimed at replacing measurement of the arterial input function are desirable. In this study, we evaluated a noninvasive quantification method of mGluR1 with [(11)C]ITDM, demonstrating its accuracy using Huntington disease model R6/2 mice. The BPND measurements based on the Logan reference (Logan Ref) method have closely approximated that based on the arterial input method. We performed PET analysis with Logan Ref to assess its accuracy in quantifying the decline of mGluR1 expression in R6/2 mice. Significant decreases in BPND values in R6/2 mice were detected in cerebellum, thalamus, striatum, and cingulate cortex. We compared autoradiographs of R6/2 mouse brain sections with immunohistochemical images, and found a close correlation between changes in radioactive signal intensity and degree of mGluR1 expression. In conclusion, [(11)C]ITDM-PET is a promising tool for in vivo quantification of mGluR1 expression.

Fast recovery after radical cystectomy. A multidisciplinary challenge.

Radical cystectomy nowadays is the treatment of choice for muscle-invasive bladder cancer. Despite many efforts, the overall, cancer-specific survival and complication rate of patients after this procedure has not changed in the last few decades. In the recent years many fast recovery protocols or “fast track” programs have been designed to become the basis of perioperative management after colorectal surgery, vascular, thoracic, and even more recently radical cystectomy [1, 2]. These programs attempt to modify the physiological and psychological responses to major surgery, contributing to the reduction of post- surgical complications and hospital stay, and to the improvement of the cardiopulmonary and bowel function after surgery; this is translated into a faster recovery for patients [3, 4]. Nowadays, there are only a few studies based on the use of fast recovery protocols in urological surgery, this is why the authors of the paper “Alvimopan: A cost-effective tool to decrease cystectomy length of stay” [5] should be congratulated on presenting their experience concerning this topic. Arumainayagam et al. in 2007 implemented a fast recovery protocol which led to a significant reduction in hospital stay and an equivalent reduction in morbidity for patients undergoing radical cystectomy compared with traditional clinical guidelines [1]. The usage of a minimally invasive approach is included in the 22 items of the ERAS society recommendations [4]. Minimally invasive pelvic surgery has been shown to decrease the inflammatory response when compared to the open approach. Recently, laparoscopic and robotic radical cystectomy has been increasingly performed in the treatment of bladder cancer and merits special consideration. While open radical cystectomy and pelvic lymph node dissection remain the gold standard in treating non-metastatic muscle invasive bladder cancer, this major surgery is still associated with high morbidity close to 70% in some cases. Numerous centers have reported in the last years their experience with laparoscopic or robotic approach [6]. Unfortunately, most of these studies reported retrospective data or prospective comparative data. Despite these limitations, laparoscopic and robot-assisted radical cystectomy seem to be associated with overall lower perioperative complications, and shorter hospital stay with equivalent short term oncological safety. Future high quality, high volume controlled studies should help in reaching definitive conclusions. Intestinal complications are one of the most common problems after radical cystectomy. The etiology of ileus is multifactorial with a combination of central and peripheral nervous system, hormonal influences, neurotransmitter and local inflammatory pathways. Surgical stress, bowel manipulation, opioids and intraoperative fluids can break the standard homeostasis in the gastrointestinal tract and produce postoperative ileus and impaired function of gastrointestinal absorption; so the prevention and management of this complication should be with a multidisciplinary team (Nutrition, Anesthesiology and Urologist). Factors that help to reduce this are epidural anesthesia, minimally invasive surgery, fine tissue manipulation, avoidance of fluid overload, and early oral feeding. In addition, the routine use of nasogastric tube decompression should be avoided after surgery because of the higher incidence of fever, atelectasis and pneumonia in patients who carry it, and if any nasogastric tube is used during surgery it should be removed before extubation. Since 2012 our department has been exercising the application of an “early recovery protocol after surgery” program for patients undergoing laparoscopic radical cystectomy and urinary diversion with the collaboration of the Anesthesiology and Reanimation Department, and the Nutrition Unit of our hospital. We hope to have positive results in the years to come. The usage of fast recovery programs as the presented in this article using the Alvimopan shows that this is a feasible multidisciplinary challenge and is useful in the recovery of patients undergoing radical cystectomy, demonstrated by a shorter hospital stay without the increasing risk of postoperative complications. Future multicenter collaborations evaluating prospective cohorts of urological patients following identical standardized care pathways should be performed.