45, 46 Those markers were found to be down-regulated upon HO-1 induction, further indicating inhibition of proliferation. These results are in line with XL765 molecular weight our observation that HO-1 induction reduced early signs of dysplasia and indicate that HO-1 induction at early time points (e.g., during inflammation or fibrosis) might have consequences on subsequent progression to HCC. Preliminary results even indicate that early HO-1 induction might interfere with progression to HCC. HO-1 has been shown to be overexpressed in alcohol-induced HCC in patients.47 Moreover, HO-1 down-regulation via short interfering

RNA significantly decreased tumor growth, whereas it increased cellular damage and apoptosis.47 Therefore, in the liver, HO-1 overexpression seems to exert beneficial Sunitinib ic50 or detrimental effects, depending on pathological conditions (e.g., inflammation or solid tumor formation). However, tumor-promoting effects by early HO-1 induction are unlikely, because induced HO-1 protein is degraded within days after treatment, whereas anti-inflammatory effects of HO-1 induction seem to last for at least 8 weeks longer than treatment with CoPP. Therefore, follow-up experiments have to determine the consequences of early HO-1

induction on progression to HCC caused by chronic inflammation. The expert technical assistance by Elena Tassika, Christine Loscher, and Nicola Peters find more is gratefully acknowledged. Additional Supporting Information may be found in the online version of this article. “
“Background and Aim:  The Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG) is the standard questionnaire used in

Japan for the diagnosis of gastroesophageal reflux disease (GERD) and assessment of the response to treatment. We modified the FSSG in order to assess dyspepsia symptoms, and evaluated the modified questionnaire. Methods:  We modified the FSSG by adding two questions on interdigestive and postprandial epigastric pain. We then assessed the modified FSSG with 100 new untreated symptomatic patients presenting to hospital and in 200 subjects undergoing health checks. Endoscopic assessment of the esophagogastric junction was performed according to the modified Los Angeles classification with addition of Grade N (normal appearance) and Grade M (minimal change). Endoscopic images were assessed by five experienced endoscopists blinded to the questionnaire results. Results:  The 100 new patients included 16 with erosive GERD (>Grade A), 12 with peptic ulcer, and two with gastric cancer. Among the 70 patients with no evidence of organic disease, the modified FSSG diagnosed functional dyspepsia (FD) in 41 and non-erosive gastric disease (NERD) in 29. A significant difference was seen in the dyspepsia score between patients with FD and NERD.

The adenomatous polyp is regarded as a marker of a neoplasm-prone colon. The incidence of new adenomas in series of surveillance colonoscopies ranges from 16% to 41% depending on individuals risk status. The incidence of adenomas/ carcinomas in patients with CRC undergoing surveillance colonoscopy check details is unknown. We audited consecutive surveillance colonoscopies

done in patients with CRC at Tata Memorial Hospital over 2 years (2012–2013). We evaluated the yield of polyps /cancers. Methods: 373 consecutive patients with CRC who had completed treatment underwent an unsedated surveillance colonoscopy after standard bowel preparation. Patient demographics and colonoscopy findings were reviewed. Data was collected prospectively and analysed. Results: The mean age was 52 years (range 15–82 yrs). There were 247 (66%) males. The site of primary tumor was in the anorectum in 186 and colon in 187 (50% each). The bowel preparation was graded subjectively as good in 22 (6%), fair in 267 (72%) and poor in 40 (11%). 327 (88%) subjects underwent a complete colonoscopy. Common reasons for incomplete colonoscopy were stenotic tumor/ stricture in 15 (4%), poor bowel preparation in 10 (2.7%) and abdomen discomfort/pain or excessive looping in 19 (5%). 18 subjects (5%) had metachronous tumors with one subject having 3 tumors. 24 (6.4%) had polyps

of which 4 (1.1%) had multiple polyps. 13 polyps (3.5%) were tubular adenomas, 11 (2.9%) were tubulovillous adenomas and 3 (0.8%) were hyperplastic polyps. RAD001 supplier 1 subject each had a non hodgkins lymphoma and a serrated adenoma. Conclusion: Of the subjects undergoing surveillance colonoscopy, 18 (5%) had a metachronous cancer in the colon and 24 (6.4%) had a polyp. 1 subject was diagnosed

to have a second tumor (lymphoma). 12% patients could not have a complete colonoscopy. Key Word(s): 1. colorectal cancer; 2. surveillance; 3. colonoscopy; 4. yield Presenting Author: LING FEI WU Additional Authors: WEI DENG, MENG QI XIANG, LI XUAN LIU, XIAO TAO ZHOU, PEI RUI CHEN, LING FEI WU Corresponding Author: LING FEI WU Affiliations: Second Affiliated Hospital, Shantou University Med, Second Affiliated Hospital, Shantou University Med, Second Affiliated Hospital, Shantou University Med, Second Affiliated Hospital, Shantou University Med, Second Affiliated Hospital, Shantou University Med, Second Affiliated Hospital, Amobarbital Shantou University Med Objective: The aim of the present study was to confirm whether long non-coding RNA MEG3 is downregulated, determine its possible mechanism of action and elucidate the role of MEG3 in human HCC. Methods: Differences in the expression of MEG3 and in the methylation status of the MEG3 promoter were analyzed in HCC tissues and HepG2 cell line using RT-PCR and methylation-specific PCR (MSP), respectively. CCK-8 assay and colony formation assays were used to assess the effect of MEG3 on cell proliferation; Flow cytometric analysis was used to evaluate the cell apoptosis. PcDNA 3.

70 A 67Ga radionuclide

scan may show uptake in the right lower quadrant, although there may also be activity in the gastrointestinal tract, the liver, and the spleen. However, both tumor and inflammatory cells can bind gallium.71,72 The use of indium-labelled white cells will avoid this problem and will not be affected by neutropenia. Arteriography Protein Tyrosine Kinase inhibitor may show increased cecal vascularity with mucosal staining and dilatation of branches of the superior mesenteric artery. Also, there may be arteriovenous shunting as suggested by dilated, early-filling veins.73 Embolization of bleeding sites can be done although there is always a risk of transmural necrosis and perforation.35,73 Colonoscopy is not usually performed due to the severe leukopenia, thrombocytopenia, and fragile bowel wall but may reveal nodularity, ulceration, and hemorrhage.50 Macroscopically, the affected bowel is edematous, hemorrhagic, and thickened, with diffuse ischemic colitis in 69% of cases, a finding associated with increased mortality.36 The management of NE is controversial as it is based on only small case studies.36 Initially, patients should receive bowel rest, fluids, antibiotics, and, if needed, recombinant granulocyte colony stimulating factor. Non-operative treatment, found to be effective in many cases, is associated

with a 67% recurrence rate in one study from 1989.54 Surgery is indicated for persistent GI bleeding, perforation, uncontrolled sepsis, and an intra-abdominal process normally requiring surgery. Localized peritoneal CH5424802 in vitro signs do not constitute an adequate reason for intervention.35 For necrosis or perforation, a right hemicolectomy is advised.39 A cecostomy and drainage may be adequate in some cases.74 In cases where surgery is done on an emergency basis with an unprepared bowel or with perforation or gross peritonitis, a two-stage procedure rather than a primary anastomosis is advisable.75 It is controversial as to whether to resect a bowel that is thickened and edematous without perforation or necrosis.53 Complications developed

in 4.6% of patients with leukemia, most commonly abscess formation, such as hepatic abscess probably from seeding from the portal circulation;35 intussusception;29 postinflammatory find more colonic stricture;76 and obstruction.28 Acute abdominal conditions can be seen in both acute and chronic leukemias (5.3% and 2.6%, respectively).31 In acute leukemia, these episodes usually occur during periods of chemotherapy and are related to the primary disease, such as neutropenic colitis or splenic rupture. Acute cholecystitis may be managed with antibiotics delaying surgery until recovery of hematopoiesis.48 Rarely, myeloid leukemia cells infiltrate the gallbladder resulting in cholecystitis.27 Fatal acute abdominal catastrophes may occur with ischemic bowel.77 In chronic leukemia, abdominal conditions tend to develop randomly during the course of disease and are similar to those seen in an elderly population.

[5] However, any significant reduction of MRC activity can induce

ROS overproduction, thus triggering oxidative stress.5,7,17 Thirteen MRC polypeptides are encoded by mitochondrial DNA (mtDNA), a small circular DNA present in several copies within the matrix (Fig. 1),12,17 and sensitive to oxidative damage.5,19 The oxidative attack of mtDNA can generate 8-hydroxydeoxyguanosine, point mutations, and deletions. In addition to ROS, reactive nitrogen species (RNS) and lipid peroxidation products are able to damage mtDNA.20,21 Irreparable damages to mtDNA can induce its Navitoclax manufacturer degradation by nucleases, thus leading to mtDNA depletion.19,22 Mitochondria also contain nuclear-encoded proteins required for mtDNA maintenance including mitochondrial transcription factor A (Tfam) involved in mtDNA transcription and mtDNA repair enzymes. Importantly, expression of Tfam and several MRC polypeptides is controlled by nuclear respiratory factors 1 and 2 (NRF1 and 2). Moreover, PGC1α interacts in the nucleus with NRF1, NRF2, and PPARα in order to coordinate the expression of nuclear genes governing mitochondrial function and biogenesis.16,23 Insulin resistance (IR) in muscle and WAT plays a central role in the pathogenesis of fatty liver (Fig. 2).8,24

In particular, IR in WAT favors TAG lipolysis, thus leading to uncontrolled NEFA release into the circulation.9,25 Because NEFA uptake by the hepatocytes is concentration-dependent, IR greatly increases the amount of NEFAs entering the liver.26 FAs are also click here synthesized more actively in liver during IR (Fig. Pyruvate dehydrogenase lipoamide kinase isozyme 1 2), since hyperinsulinemia overactivates SREBP1c.5,26 Excess of fat in liver can in turn cause IR in this organ.5,27 Intriguingly, IR in liver only affects some, but not all, insulin-sensitive metabolic pathways.28,29 For instance, whereas

gluconeogenesis is less inhibited by insulin, DNL is overactivated by hyperinsulinemia.5,29 However, the mechanisms responsible for mixed hepatic insulin sensitivity and resistance are not fully understood, although different hypotheses have been put forward.29-34 Hyperglycemia contributes to fatty liver during type 2 diabetes, in particular by overactivating ChREBP.5,35 Furthermore, high glucose levels promote ROS overproduction within hepatocytes, thus favoring oxidative stress and mitochondrial dysfunction.5,36 Type 2 diabetes can also be associated with high glucagonemia, which contributes to hyperglycemia and ketoacidosis.37 High glucagonemia could also impair hepatic function,38 possibly by increasing the expression of cytochrome P450 2E1 (CYP2E1).39 At least three major events are involved in the progression of fatty liver to NASH, including overproduction of ROS and RNS, lipotoxicity, and increased release of proinflammatory and profibrogenic cytokines.

Nevertheless, there have been new trends in organ transplantation, two of which were selleck kinase inhibitor driven mainly by the liver. A major gap in immunology (Theme III) when I stopped surgical practice was the inability to explain why organ transplantation had been possible. Because

organ recipients were not infused with donor leukocytes, it became dogma by the early 1960s that the donor leukocyte chimerism associated with acquired tolerance in experimental models was not a factor in organ engraftment. The dogma was not challenged until we discovered small numbers of multilineage donor leukocytes (microchimerism) in the blood or tissues of all studied long-surviving liver, kidney, and other organ recipients.63, 64,143 These findings in 1992-1993, and an array of supporting experimental studies in congenic rat144-150 and mouse models,151-154 mandated a change in the previously perceived landscape of transplantation immunology. It was proposed63, 64,155,156 that organ transplantation was the equivalent of a bone marrow transplantation. The key step leading to rejection, or alternatively alloengraftment, after both kinds of transplantation was hematogenous migration of leukocytes (including stem cells157-159) to the recipient’s lymphoid Metformin purchase organs (Fig. 9). Otherwise, the presence of the allograft would not be recognized: i.e., the “immune ignorance”160,161 first described in a transplant

model by Clyde Barker and Rupert Billingham 42 years ago. The seminal mechanism of alloengraftment was exhaustion-deletion of the T cell response162,163 induced at the host lymphoid sites by the invading cells (Fig. 9). Because the migrant donor leukocytes are immune-competent, successful alloengraftment involved a double immune reaction in which immune responses of coexisting donor and recipient cells, each to

the other, were Florfenicol reciprocally exhausted and deleted under a protective umbrella of immunosuppression (Fig. 10). Our interpretation of the microchimerism was at first highly controversial164,165 because it was incompatible with multiple theories and hypotheses that made up much of the base of transplant immunology. Resistance to the new concept was eroded when Rolf Zinkernagel in Zurich independently proposed an explanation of acquired tolerance to pathogens that was essentially the same as that of our allotolerance paradigm. In the 1970s, Zinkernagel and Doherty had demonstrated that the major histocompatibility complex-restricted cytolytic T cell response induced by noncytopathic microorganisms was the same as that induced by allografts. These studies were done in highly controlled experimental models of infection with the lymphocytic choriomeningitis virus and other intracellular parasites.166 Their subsequent investigations of tolerance were done with the same models and described in four landmark articles between 1993 and 1997.

6% were CD11c+. PHHs shipped in plates were incubated with InVitroGRO HI medium (Celsis)

for 4 hours at 37°C (5% CO2), followed by polyinosinic/polycytidylic acid (polyI:C) transfection or HCV infection, as described below. PHHs shipped in suspension were centrifuged at 50×g for 5 minutes, incubated in InVitroGRO CP medium (Celsis) in 12- (7 × 105/well) or 24-well (3.5 × 105/well) plates overnight, and transfected with 5 μg of polyI:C (InvivoGen, San Diego, CA) and 6.4 μL of Lipofectamine 2000 in Opti-MEM medium (Invitrogen), or infected with HCV (Japanese fulminant hepatitis type I [JFH-1] strain)22 at a multiplicity of infection (MOI) of 0.4-2.7. After 3-6 hours, culture medium was replaced with InVitroGRO HI including Torpedo antibiotic mix (Celsis). In some experiments, PHHs were incubated 30 minutes before HCV infection buy Lenvatinib with neutralizing antibodies (Abs) against type I IFNs (10 μg/mL each of anti-IFN-α [clone MMHA-2; PBL Interferon Source, Piscataway, NJ] and polyclonal anti-IFN-β [R&D Systems, Minneapolis, MN]) or type III IFNs (10 μg/mL each of polyclonal anti-IL-29, polyclonal anti-IL-28A, and anti-IL-29/IL-28B [clone 247801;, DAPT research buy R&D Systems]). Total RNA was isolated

from snap-frozen, mechanically homogenized liver biopsies or from PHH using the RNeasy Mini Kit (Qiagen, Valencia, CA) with on-column DNase digestion. A complementary DNA (cDNA) equivalent to 20-80 ng of total RNA, generated with the MonsterScript 1st-Strand cDNA Synthesis Kit (EPICENTRE Biotechnologies, Madison, WI), was used to determine IFN-induced protein with tetratricopeptide repeats 1 (IFIT1), myxovirus resistance 1 (MX1), chemokine (C-X-C motif) ligand (CXCL)10, CXCL11, IFN-α2, IFN-β, IL-29, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and proteasome subunit, beta type, 4 (PSMB4) Ribonucleotide reductase messenger RNA (mRNA) levels with predesigned human TaqMan Gene Expression Assays (Applied Biosystems, Foster City, CA). Because IL28A and IL28B

share 98% of their nucleotide sequence, their mRNA levels were quantitated with shared forward primer 5′-TGAGGCAGCTGCAGGTGA-3′, reverse primer 5′-CTCCAGAACCTTCAGCGTCAG-3′, and probe 5′-FAM-TGGCTTTGGAGGCTGA-MGB-3′ designed with Primer Express (Applied Biosystems). The specific mRNA amount was quantitated using comparative cycle threshold values and 1-107 copies/well standard curves, and normalized to mean GAPDH and PSMB4 mRNA levels. Relative mRNA levels represent fold-increase over pre-infection or pre-transfection samples. For HCV RNA quantitation, we used TaqMan EZ RTPCR Core Reagents (Applied Biosystems) and forward primer 5′-CGGGAGAGCCATAGTGG-3′, reverse primer 5′AGTACCACAAGGCCTTTCG-3′, and probe 5′-FAM-CTGCGGAACCGGTGAGTACAC -TAMRA-3′ (Sigma-Aldrich). RT-PCR conditions are 2 minutes at 50°C, 30 minutes at 60°C, 5 minutes at 95°C, followed by 50 cycles at 95°C for 20 seconds and at 60°C for 1 minute. HCV RNA levels were normalized to microgram of total input RNA.

These portosystemic shunts can be categorized into intrahepatic and extrahepatic types. Common extrahepatic shunts involve gastroesophageal, gastrorenal, splenorenal and paraumbilical vessels. Under most circumstances, the presence of hepatic encephalopathy is a relative contraindication to

the insertion of a transjugular intrahepatic portosystemic shunt (TIPS). However, in the patient described below, TIPS permitted closure of an unusual shunt that was followed by improvement in encephalopathy. In 2011, a woman, aged 47, was admitted to our hospital with episodes EPZ 6438 of drowsiness attributed to hepatic encephalopathy. She was known to have hepatitis B with advanced cirrhosis (Child-Pugh class C). In 2006, she was treated medically for a major gastrointestinal bleed attributed to esophageal varices but there were no subsequent episodes of bleeding. Medical treatment for hepatic encephalopathy had included dietary protein restriction, lactulose, branched-chain amino acids and a course of rifaximin. On examination, she had several spider nevi and peripheral edema. An abdominal ultrasound study and a contrast-enhanced computed tomography scan showed that the portal

selleck kinase inhibitor vein was relatively narrow. However, the splenic vein, inferior mesenteric vein, left renal vein and left gonadal vein were markedly dilated. Subsequently, a catheter was passed into the left renal vein through the inferior vena cava. The injection of contrast revealed dilatation of the left renal vein and left gonadal vein and a varicose shunt between the left gonadal vein and the left inferior mesenteric

vein. A transjugular intrahepatic portosystemic shunt was then placed within the liver to reduce the portal pressure. Direct portography at the time of insertion of the stent (Figure 1 ) shows the stent (black arrowhead), the splenic vein (white arrowhead), the inferior mesenteric aminophylline vein (solid arrow) and the varicosity (dotted arrow) linking the inferior mesenteric vein to the left gonadal vein. The shunt was successfully embolized using coils (Figure 2). The patient has now been followed for 4 months without a recurrence of encephalopathy and without dietary or drug therapy. Patency of the portosystemic shunt was confirmed by an ultrasound study. “
“Induced pluripotent stem cell-derived human hepatocyte-like cells (iHeps) could provide a powerful tool for studying the mechanisms underlying human liver development and disease, testing the efficacy and safety of pharmaceuticals across different patients (i.e. personalized medicine), and enabling cell-based therapies in the clinic. However, current in vitro protocols that rely upon growth factors and extracellular matrices (ECM) alone yield iHeps with low levels of liver functions relative to adult primary human hepatocytes (PHHs).

A set of other variants was also reported GDC-0068 solubility dmso as being associated with response, and in patients of European ancestry they were not statistically distinguishable from rs12979860. The C allele at rs12979860 was positively associated

with SVR. In patients of European ancestry, ≈80% of patients with the C/C genotype cleared the virus, whereas only ≈30% with the T/T genotype did so. The C/C genotype was also more common in European Americans (39%) than African Americans (16%). The difference in allele frequency between these population groups explains approximately half of the difference in response rates between patients of African American versus European ancestry. The association between the rs12979860 SNP and SVR appears to be clinically relevant. Thompson et al.8 reanalyzed the patient population DNA Damage inhibitor from Ge et al.3 on an intent-to-treat basis, meaning that patients were included regardless of adherence. Ethnicity was determined by patient self-reporting. Although including all subjects regardless of adherence does not result in the most powered study design for discovering gene variants influencing therapeutic efficacy, it provides a more accurate picture of the relevance of genotypic information in the clinic, where adherence is variable. Among patients of European ancestry (n = 1,171), SVR was attained by 27% with the T/T genotype, 33% with the C/T genotype, and 69% with the C/C genotype. Among African American patients

(n = 300), SVR was attained by 13% with the T/T genotype, 15% with the C/T genotype, and 48% with the C/C genotype. The presence of only one C allele conferred little benefit in treatment response, as was true in the analyses performed by Ge et al.3 and in the studies of spontaneous clearance reported by Thomas et al.6 African American patients with the C/C genotype had a significantly higher rate of SVR than European Americans who were non-C/C, indicating that genetic background is more important Proteasome inhibitor than ethnicity.

However, response rates were lower for African Americans in each genotype category. In a logistic regression analysis of pretreatmeant (baseline) factors, IL28B status (C/C versus non-C/C) was the strongest predictor of SVR (odds ratio [OR] 5.2; 95% confidence interval [CI] 4.1-6.7). When on-treatment parameters were considered, rapid virological response (RVR, HCV RNA negativity at week 4) was the strongest predictor of SVR, but only a minority of patients (14% of Caucasians) had rapid response. In patients that did have RVR, IL28B remained strongly predictive of SVR, even at 4 weeks after treatment initiation. To identify host genes associated with response to PEG-IFN and RBV, Tanaka et al.4 conducted a genome-wide association study in treatment-adherent Japanese patients with HCV genotype 1 infection. Among the 154 patients, 82 had virological nonresponse (defined as <2 log10 IU/mL reduction in serum HCV RNA at week 12 of treatment), and 72 had a virological response.

Furthermore, from a neuroscience perspective, rehabilitation

is a challenge, as the neurobiological processes underlying rehabilitation-related recovery have not been fully revealed. A key challenge in neurorehabilitation is to establish optimal training protocols for the given patient. The Rehabilitation Gaming System (RGS) is a virtual reality (VR)-based paradigm for the rehabilitation of motor deficits following brain damage such as stroke (Cameirão et al., 2010). Specifically, subjects engaged in the RGS observe colored balls in a outdoor environment that appear to fly from the far distant horizon towards them. The subject’s task is to grasp the balls with the arms of an animated body, that is an avatar, TGF-beta inhibitor which are steered by a calibrated motion capture system. The subject controls the arms of the avatar in the VR world, with the goal of intercepting the course of the flying balls. The speed, distribution check details and size of the balls can be adjusted to match the individual capacity of the subject in a flexible performance-adjusted manner, providing for individualised training. Thus, the RGS relies on visuomotor processing that includes action observation, object-oriented

action planning, and feedback of the successful action. In this context, so-called mirror neurons, which are primarily found in the inferior frontal gyrus (IFG) and anterior inferior parietal lobule (IPL), have come into the focus of research. As they have been shown to be active not only when a goal-directed action is performed but also when such actions are passively observed or imagined (Grezès & Decety, 2001; Rizzolatti & Craighero, 2004; Iacoboni & Dapretto, 2006), the mirror neuron system might represent the key neural

substrate for relearning or resuming impaired motor functions following focal brain damage such as occurs in stroke (Buccino et al., 2006; Garrison et al., 2010; Sale & Franceschini, 2012). Accordingly, it can be hypothesised that acting in the RGS exploits the notion of mirror mechanisms (Rizzolatti Alectinib clinical trial et al., 2009), combined with a number of considerations on perception, learning, action and motivation stemming from theoretical neuroscience (Verschure et al., 2003; Verschure, 2012). The central assumption behind the RGS is that, in order to drive the learning mechanisms underlying rehabilitation, the sensory aspects of sensorimotor contingencies must be enhanced (Cameirão et al., 2010; Verschure, 2011). Indeed, initial studies in acute and chronic stroke patients who were treated with RGS have shown significant improvements in functional capacities of the paretic arm as assessed by standard clinical scales, including the Motorcity Index, the Fugl–Meyer Assessment Test, the Chedoke Arm and Hand Activity Inventory, and the Barthel Index, as detailed by Cameirão et al. (2011, 2012).

Furthermore, from a neuroscience perspective, rehabilitation

is a challenge, as the neurobiological processes underlying rehabilitation-related recovery have not been fully revealed. A key challenge in neurorehabilitation is to establish optimal training protocols for the given patient. The Rehabilitation Gaming System (RGS) is a virtual reality (VR)-based paradigm for the rehabilitation of motor deficits following brain damage such as stroke (Cameirão et al., 2010). Specifically, subjects engaged in the RGS observe colored balls in a outdoor environment that appear to fly from the far distant horizon towards them. The subject’s task is to grasp the balls with the arms of an animated body, that is an avatar, Navitoclax which are steered by a calibrated motion capture system. The subject controls the arms of the avatar in the VR world, with the goal of intercepting the course of the flying balls. The speed, distribution Hydroxychloroquine ic50 and size of the balls can be adjusted to match the individual capacity of the subject in a flexible performance-adjusted manner, providing for individualised training. Thus, the RGS relies on visuomotor processing that includes action observation, object-oriented

action planning, and feedback of the successful action. In this context, so-called mirror neurons, which are primarily found in the inferior frontal gyrus (IFG) and anterior inferior parietal lobule (IPL), have come into the focus of research. As they have been shown to be active not only when a goal-directed action is performed but also when such actions are passively observed or imagined (Grezès & Decety, 2001; Rizzolatti & Craighero, 2004; Iacoboni & Dapretto, 2006), the mirror neuron system might represent the key neural

substrate for relearning or resuming impaired motor functions following focal brain damage such as occurs in stroke (Buccino et al., 2006; Garrison et al., 2010; Sale & Franceschini, 2012). Accordingly, it can be hypothesised that acting in the RGS exploits the notion of mirror mechanisms (Rizzolatti Metformin concentration et al., 2009), combined with a number of considerations on perception, learning, action and motivation stemming from theoretical neuroscience (Verschure et al., 2003; Verschure, 2012). The central assumption behind the RGS is that, in order to drive the learning mechanisms underlying rehabilitation, the sensory aspects of sensorimotor contingencies must be enhanced (Cameirão et al., 2010; Verschure, 2011). Indeed, initial studies in acute and chronic stroke patients who were treated with RGS have shown significant improvements in functional capacities of the paretic arm as assessed by standard clinical scales, including the Motorcity Index, the Fugl–Meyer Assessment Test, the Chedoke Arm and Hand Activity Inventory, and the Barthel Index, as detailed by Cameirão et al. (2011, 2012).