2%). (Table 3) AZD8055 Advances in endoscopic technology and the widespread use of EGD and colonoscopy have increased the prevalence of the same-day bidirectional endoscopy procedure. However, because both of these procedures require gas insufflation for visualization, the necessary preparation for the first procedure

may significantly affect the context of the second procedure. Our results indicate that procedural sequence significantly affects the quality of EGD performance in same-day bidirectional endoscopy. Quality scores for retroflexion-related steps (P11-13), visualization of the angular fold (P10), and general assessment of the stomach and upper GI tract (P17 and P15, respectively) were superior when EGD was performed first (Group I) compared to performing colonoscopy first (Group II). These findings may have been due to gastric distension and altered bowel motility caused by insufflated gas during the first

colonoscopy procedure. Insufflated gas-induced bowel expansion and hyperactive movement may hinder the retroflexion steps of EGD (P11-13), as these require considerable luminal space. Such sequential limitations can manifest as decreased overall quality of assessment of EGD steps (P15 and P17). This was reflected in our results by the P-values calculated for differences between groups for each step (P11, P < 0.001; P12, P = 0.002; P13, P < 0.001; P15,

P = 0.047; Maraviroc P17, P = 0.008). However, despite mafosfamide these differences, the incidence of pathological findings did not differ in both groups because all scores in Group II were moderate at worst. Further, because EGD is technically simple to perform, colonoscopy followed by EGD remains an effective diagnostic method for evaluating the upper GI tract. Analysis of patient questionnaires revealed that the patients experienced greater subjective discomfort during EGD when subjected to the colonoscopy-EGD sequence compared to the EGD-colonoscopy sequence. This was likely because prior colonoscopy and subsequent bowel distension further exacerbates abdominal discomfort incurred during EGD. Endoscopic interventions such as biopsy and polypectomy may prolong the duration of colonoscopy and further intensify patient discomfort, and for this reason we re-analyzed 31 patients that did not require endoscopic interventions (16 patients in Group I and 15 patients in Group II). This sub-sample analysis showed no difference in colonoscopic variables, including insertion time, total time, and prolonged insertion ratio, but EGD continued to be perceived as more stressful by the colonoscopy-EGD sequence group (mean of discomfort scores: Group I vs Gorup II = 3.09 ± 2.28 [median, 2.50]: 5.53 ± 2.23 [median, 6.00]; P = 0.005).

7A). As described elsewhere,[15,

16, 25] ConA-driven hepatitis was accompanied by up-regulation of interferon-gamma (IFN-γ) and IL-17A RNA transcripts and protein (Supporting Fig. 7). Pretreatment of mice with IL-25 significantly reduced serum levels of both transaminases (Fig. 7A), attenuated histological damage (Fig. 7B), and decreased RNA and protein expression of IFN-γ and IL-17A (Supporting Fig. 7). Induction of liver damage by ConA was associated with infiltration of the liver by GR1+ and CD11b+ cells, and the presence of both these cell types was further increased in hepatitic mice treated with IL-25 (Fig. 7C). FCM analysis revealed that the percentage of GR1/CD11b+ double positive cells was higher in IL-25/ConA-treated mice, compared to mice treated with ConA alone (Fig. 7D). Despite ConA inducing massive damage of the

liver leading to the formation of large areas of necrosis, mice can survive more than Proteasome inhibitor 3 days. This allowed us to test the therapeutic effect of IL-25 by injecting mice 6 hours after ConA administration, a time that was sufficient to cause liver damage (as shown in Fig. 7A,B). Mice treated with ConA and receiving IL-25 showed significantly reduced levels of transaminases, minimal macroscopic lesions, and less necrotic areas (Fig. 7E,F), as compared to mice treated with ConA and receiving PBS. In a final set of studies, we analyzed IL-25 protein expression in paraffin-embedded PD0325901 supplier liver sections of patients with FH and controls by confocal IF. IL-25-positive cells were clearly evident in control livers, particularly in hepatocytes, Urocanase but staining was markedly reduced in liver sections from patients with FH (Fig. 8), thus confirming that acute hepatocyte damage is associated with decreased production of IL-25. IL-25 (also known as IL-17E), a

member of the IL-17 cytokine gene family, is made by several immune and nonimmune cell types and plays a critical role in expansion of Th2 cell responses and negative regulation of both Th1 and Th17 immunity.[8, 9, 13, 14] Deregulation of IL-25 production has been described in many inflammatory disorders and is supposed to contribute to the progression of the pathology.[8, 9, 13, 14] For example, high IL-25 sustains inflammation in airways of patients with asthma, whereas defective IL-25 synthesis helps perpetuate chronic inflammation in the gut of patients with inflammatory bowel disease.[9, 26] This later finding fits with the demonstration that IL-25 delivers negative signals to macrophages and DCs with the downstream effect of suppressing detrimental inflammatory responses in the gut.[9] The data in the present study expand on these data and indicate that IL-25 is produced in both human and mouse liver. Despite its ability to amplify Th2 cell programs, IL-25 does not polarize Th cell responses along the Th2 pathway.[8, 26] Therefore, it is not surprising that expression of IL-25 in the uninjured liver was associated with no induction of Th2 cytokines.

Since dolphins could remain in the study area for several hours resulting in temporal autocorrelation, an autoregressive correlation structure was used within the GEE, each cluster representing hours within a day of survey effort. The results of the GEE model showed that there was significant diel, tidal, and interannual variation in the presence of dolphins. Dolphins were most likely to be seen in the early morning and during the summer months. Dolphin presence generally peaked during low tide, but this varied among years. There was a significantly lower probability of dolphins selleck products being present in 2003 than

2004, but not between 2004 and the other years (1991, 1992, and 2002). GEE-model fitting packages are now readily available, making this a valuable, versatile tool for marine mammal biologists. “
“The behavioral and environmental context of animal calls provides insights into their functions. Narwhals are a highly vocal species and, like other social cetaceans, rely check details on acoustic signals to communicate. We characterize and categorize narwhal whistles and pulsed calls, as well as investigate variation

in these calls under different contexts (behavior, herd, and year) using recordings made during the month of August 2006–2008, in Koluktoo Bay (72°04′N, 80°32′W). We detected similarities among whistles but not pulsed calls that were produced under a similar behavioral context. Both whistles and pulsed calls recorded within the same herd were more similar than whistles and pulsed calls recorded within different herds. We did not find any type of whistle to be associated with a specific behavior although some acoustical features might be behavior specific. Both whistles and pulsed calls show properties that are consistent with the hypothesis that narwhals produce group-

or individual-specific CYTH4 calls. “
“Communicating animals must balance fitness benefits against the costs of signaling, such as increased predation risk. Cetaceans communicate mainly with sound and near-surface vocalizations can place signalers at risk from shallow-diving top-predators with acute hearing such as killer whales. Beaked whales are deep divers living in small cohesive groups with little social defense from predation. Little if anything is known about their acoustic communication. Here, eight Blainville’s beaked whales were studied with suction cup attached DTags to provide the first report on social communication as a function of diving behavior for any of the 21 ziphiid species. Tagged whales produced two previously unrecorded signals with apparent communicative functions: (1) fast series of ultrasonic frequency modulated clicks (rasps) were recorded from six individuals, and (2) harmonically rich short whistles with a mean fundamental frequency of 12 kHz were recorded from one whale at up to 900 m depth, the deepest whistles recorded from a marine mammal.

Control animals (n = 10) were injected with an equal volume of phosphate-buffered saline (PBS) or scramble-saRNA. Torin 1 mouse All animals received humane care according to the criteria outlined in the “Guide for the Care and Use of Laboratory Animals” prepared

by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 86-23 revised 1985). We assessed the effect of transfecting C/EBPα-saRNA on C/EBPα and albumin transcript levels. Both C/EBPα (Fig. 1A) and albumin transcripts (Fig. 1B) increased over 2-fold. Increasing the amounts of C/EBPα-saRNA (5, 10, and 20 nM) dose-dependently enhanced C/EBPα transcript levels (Fig. 1C). The maximum expression of albumin was achieved with 5 nM of C/EBPα-saRNA, with no further dose-dependent increase at higher saRNA levels (Fig. 1D). Analysis of the promoter regions of C/EBPα (Fig. 1E), the binding box of albumin (DBP) (Fig. 1F), and albumin (Fig. 1G) showed the presence of the core C/EBPα binding motifs (GCAAT), thus supporting targeting of both transcripts by C/EBPα-saRNA-induced up-regulation of C/EBPα. An EpiTect Methyl PCR assay also demonstrated

reduced methylation at the CpG-island of both C/EBPA VX-765 cell line and DBP promoters following transfection of C/EBPα-saRNA (Fig. 2A,B). To determine the biological relevance of increased albumin mRNA transcripts in C/EBPα-saRNA-transfected HepG2 cells, a human albumin specific ELISA was performed. Secreted albumin peptide was detected in the culture media of the transfected cells (Fig. 2C). To establish if enhanced albumin secretion in HepG2 cells by C/EBPα-saRNA also affected other hepatocyte-specific functions and maintenance of hepatocyte differentiation, we measured expression levels of the ornithine cycle enzyme ornithine transcarbamylase (OTC) and alpha-fetoprotein

(AFP). C/EBPα-saRNA caused an increase in OTC levels (Fig. 2D), suggesting an improved ability of urea production. The expression level of AFP decreased (Fig. 2E), indicative of the negative regulation typically observed with normal hepatocytes.[26] In addition to the observed gene changes described, we also observed that C/EBPα-saRNA caused a marked down-regulation of HepG2 cell proliferation (Fig. 2F). This observation confirms the known antiproliferative Reverse transcriptase effects of C/EBPα.[14, 27] The stability of C/EBPα-saRNA was initially tested in circulating serum by performing a nuclease activity assay using blood samples from C/EBPα-saRNA-treated rats. We observed a significant reduction in the stability of C/EBPα-saRNA duplex by 48 hours (Fig. 3A,B). We thus injected cirrhotic rats over a period of 1 week with repeat doses of C/EBPα-saRNA-dendrimer. Measurement of circulating albumin showed a significant increase of over 30% after three doses of C/EBPα-saRNA-dendrimer injection when compared to PBS control or scramble-saRNA-dendrimer control groups (Fig. 3C).

7%) either withdrew from the study at week 12 or

were nonresponders, and treatment was stopped as defined in the protocol Fulvestrant datasheet (Fig. 1). Patient demographics were generally similar across the treatment groups (Table 1). A baseline viral load >800,000 IU/mL was more common in slow responders than patients with cEVR. In total, eight patients in group A and 17 patients in group B failed to complete the study (Fig. 1). All eight patients in group A discontinued treatment between weeks 24 and 48. Of the 17 slow responders in group B who failed to complete treatment, 11 discontinued treatment between weeks 24 and 48, and six discontinued treatment between weeks 49 and 72. Reasons for discontinuation in group B were adverse events (n = 6 [4 prior to week 48 and 2 after week 48]), lost to follow-up (n = 1 [prior to week 48]), did not wish to continue (n = 6 [4 prior to week 48 and 2 after week 48]), noncompliance (n = 2 [1 prior to week 48 and 1 after week 48]), and other reasons (n = 2 [1 prior to week 48 and 1 after week 48]). In total, 721 of 1,427 (50.5%) patients who received treatment per protocol attained an SVR. Among

patients with cEVR, 27.5% had undetectable HCV RNA at week 4 of treatment (rapid virologic response), and 71.4% had undetectable HCV RNA at week 8. In the intent-to-treat analysis, SVR rates were similar in groups A and B (43% versus 48%; P = 0.6445) and higher in group C (80%; P < 0.0001 versus group A) (Fig. 2). End-of-treatment response was 83%, 70%, selleck screening library and 89% in groups A, Cyclin-dependent kinase 3 B, and C, respectively. Relapse rates were 47% for group A and 33% for group B; however, the difference was not statistically

significant (P = 0.1699). Relapse rates were significantly lower for group C compared with group A (10% versus 47%; P < 0.0001). Among adherent patients (those who received ≥80% of the planned dose of each drug for ≥80% of the assigned treatment duration), SVR rates were 44% for group A and 57% for group B (P = 0.20); SVR rates in the per-protocol population were 44% and 49%, respectively (P = 0.63). Similarly, SVR rates in the completers population were 46% and 57% (P = 0.28), and relapse rates were 47.1% and 28.9% in the 48- and 72-week treatment arms, respectively. Slow responders <40 years old were significantly more likely to attain an SVR compared with those >60 years old (odds ratio 3.991; 95% CI 1.043-15.277; P = 0.017). Other variables including weight, treatment arm (group A versus group B), and week 12 HCV RNA levels (<50 versus >5,000 IU/mL or 50-5,000 versus >5,000 IU/mL) did not achieve any statistical significance. There was a trend toward a significant association between week 8 viral load (<2-log versus ≥2-log drop from baseline), 72 weeks of treatment, and SVR among slow responders (odds ratio 2.504; 95% CI 0.948-6.613; P = 0.064). The negative predictive value for a <2-log decline at week 8 was 81% among patients treated for 48 weeks and 62% among those treated for 72 weeks (Fig.

The most common translocation t(11;18) is associated with antibiotic resistance and patients with this translocation may

require chemotherapy or radiation. DLBCL is treated with multi-agent chemotherapy and shows an approximately 60% 5-year survival. “
“A man, aged 76, was recovering selleck screening library after surgery for a perforated rectosigmoid cancer. His past history included a cholecystectomy for gallstones, 17 years previously. A computed tomography scan of the abdomen showed a small enhancing nodule in the mid-bile duct. Liver function tests were normal but the serum carbohydrate antigen, 19.9 (CA19.9) level was elevated at 302 U/mL (reference <37 U/mL). A magnetic resonance cholangiogram showed eccentric wall thickening of the mid-bile duct (arrow) consistent with a bile duct neoplasm (Figure 1). At surgery, he had a hard mass, 1 cm in diameter, in the mid-bile duct and had a segmental resection with a Roux-en-Y hepaticojejunostomy. Histological

examination revealed hyperplastic and disorganised nerve fibers surrounded by fibrous connective tissue (H&E x200, Figure 2). Immunohistochemical stains were positive for S100 (inset Figure 2). The diagnosis Crenolanib ic50 was that of a post-operative (traumatic) neuroma of the bile duct. A neuroma or traumatic neuroma is an exuberant but non-neoplastic proliferation of a nerve that occurs after Anacetrapib injury or surgery. After biliary surgery, neuromas can occur in the cystic duct stump but neuromas involving the bile duct are rare. Macroscopically, they are small white-gray nodules that develop at the proximal end of the injured or transected nerve. Histologically, there is a haphazard proliferation of nerve tissue that includes axons, Schwann cells and fibroblasts surrounded by a fibrous capsule. Cystic duct neuromas may be a cause of biliary-type pain after cholecystectomy

and, historically, one surgical option was shortening of the cystic duct stump. The results of this procedure remains unclear. More recently, an interesting case report described three patients with pain after cholecystectomy whose symptoms were aggravated by pushing on cystic duct clips with a needle guided by endoscopic ultrasound. Symptoms improved after an injection of local anesthetic and steroid into the region and 2 of 3 patients had resection of the cystic duct stump (Am J Gastroenterol, 2005; 100: 491). Whether neuromas of the bile duct cause pain remains unclear but these nodules can result in extra-hepatic obstruction. In the latter setting, the differential diagnosis can include post-operative strictures, retained stones, benign tumors and bile duct cancer. A pre-operative diagnosis of bile duct neuroma is likely to be difficult and most patients have been treated by surgery, usually with an hepaticojejunostomy.

06). At 5 years, the recurrence rate in both groups was similar (12% versus 14%; P = 0.94). Table 2 shows the results of univariate analysis for prognostic factors of recurrence in each group separately (LDLT and DDLT). The predictive factors of recurrence were similar in both groups, and were related to a more aggressive tumor (i.e., number of nodules, diameter of largest nodule, preoperative AFP levels, presence of satellite nodules and vascular invasion by the tumor) and to selecting patients beyond established and validated selection criteria (Milan and UCSF). The numbers of recurrences were small in both groups (LDLT, n = 4; DDLT, n = 27), hence a separate multivariate

analysis could not be performed. However, because the pattern of recurrence Stem Cells inhibitor in both groups was similar, multivariate analysis was performed combining the 2 groups (all 31 patients who had recurrence after LT). On multivariate analysis, among the preoperative variables, transplantation patients with tumors beyond UCSF criteria (P = 0.007) emerged as an independent predictive factor for recurrence (Table 3). Edmonson grade III-IV (P = 0.04) and presence of microscopic vascular invasion (P = 0.009) on the specimen were the other independent poor predictive factors for recurrence. We tested only UCSF criteria in multivariate analysis and not Milan criteria, number, or diameter of nodules

(all of which were significant on univariate analysis) to obviate colinearity. UCSF criteria essentially include the Milan criteria. Similarly, patients with macroscopic vascular Midostaurin invasion are already included in the larger group of patients with microscopic vascular invasion. The OS in the two groups (LDLT versus DDLT) after listing (intention-to-treat) and after transplantation (only for those patients with HCC confirmed on the explanted liver) were similar (P = 0.68 and P = 0.36, respectively) (Figs. 2A,B). On multivariate analysis, blood transfusion and microscopic vascular invasion emerged as independent poor prognostic factors for OS

on an intention-to-treat basis (data not shown). There was a trend toward isometheptene worse survival outcomes in those patients beyond Milan or UCSF criteria who underwent LDLT compared with those who underwent DDLT (P = 0.06 in both cases) (Figs. 3 and 4). There was no difference in the site of recurrence between the two groups (P = 0.77). In the LDLT group, of the four recurrences, two patients had extrahepatic recurrences (one in the lungs and one in the bony skeleton), one patient had an intrahepatic recurrence, and one patient had a recurrence in the liver, lungs, and suprarenal glands. In the DDLT group, of the 14 recurrences, six patients had an extrahepatic recurrence (four pulmonary, one in the bony skeleton, and one in the adrenal glands), six patients had intrahepatic recurrence, and two patients had both intrahepatic and extrahepatic recurrence.

, 2008) Further, in a test of the effect of eggshell colour on paternal provisioning, English & Montgomerie (2011) found that male American robins Turdus migratorius provisioned young nestlings (3 days old)

from vivid blue eggs more than those from pale eggs, but this difference did not hold for older (6 or 9 days old) nestlings. Moreover, in the great reed warbler Acrocephalus arundinaceus, Honza et al. (2011) report no association between the blue-green chroma of egg shells and measures of female quality, and also that males did not adjust their investment (in parasite defence) in relation to egg shell chroma. In Kilner’s (2006) review of bird egg colouration, she www.selleckchem.com/products/AZD2281(Olaparib).html reported that blue eggs were unusual among cavity nesters, and more often found in some (not all) species that build exposed nests. Kilner (2006) highlighted that if blue eggs are

cryptic in exposed nests this adaptation has only been selectively advantageous in some species. Wegrzyn et al. https://www.selleckchem.com/products/rgfp966.html (2011) argued that in cavity-nesting European starlings Sturnus vulgaris the ultraviolet and blue-green eggshell colour does not reflect female condition, but instead suggest that more intensely blue-green egg colouration makes eggs more easily visible in dark cavities. This is an intriguing hypothesis, but clearly, more empirical evidence is needed. Also, studies should be aware of the age of the eggs measured to avoid any confounding effects of fading (Moreno, Lobato & Morales, 2011). A for classic example of blue colour change as a signal is the diet-dependent

foot colouration of the blue-footed booby Sula nebouxii. Velando, Beamonte-Barrientos & Torres (2006) showed that the intensity of the blue of a male’s feet is a strong indication of his current condition, with the foot colour of nutrient-deprived males fading in less than two days. They also showed that maternal investment reduced when the feet of a male were experimentally dulled using cosmetics (Velando et al. 2006). These results indicate that females adjust their behaviour according to the foot colour of their mate and thus that females receive information on a male’s recent foraging success by assessing foot colour. Even though, foot colour fades, it is likely to be a good indicator of recent foraging success and in older birds, an indication of their levels of oxidative stress (Torres & Velando, 2007). Individual quality may be signalled by blue in inveretebrates. The evidence is sparse, but two examples that involve colour change have emerged. In the damselfly, Calopteryx maculata males with abdomens that are more blue than green are in better condition (Fitzstephens & Getty, 2000). Males that are better foragers increase their girth and in so doing the lamellae (microscopic ridges) in the epicuticle responsible for their blue-green colour are pushed closer together.

Despite the widespread use of PTA, to our knowledge there are no large studies that have investigated for factors predicting recurrence of Selleck PFT�� HCC post PTA. Our primary aim therefore was to evaluate factors predicting the recurrence of HCC post PTA. Methods: Multi-centre retrospective study of patients treated with PTA (Radiofrequency

Ablation [RFA] and Microwave Ablation [MWA]) between Jan 2006 – Dec 2012. Subjects included were consecutive patients who had PTA with curative intent. Subjects who had other loco-regional therapies prior to PTA or with evidence of macrovascular invasion were excluded. Primary end point was the identification of factors predicting overall intrahepatic PLX4032 chemical structure recurrence (IHR) using uni and multivariate analysis. A total 13 host, tumour and procedure related variables were analysed. IHR included both recurrence due to local tumour progression [LTP] and intrahepatic distant recurrence [IDR]. Secondary endpoints were rate of IHR (both LTP and IDR), recurrence free survival and the adverse event rate ( < 30 days from the procedure requiring hospitalization). Results: Ninety-three subjects [mean age ( ± SD): 62.7 ( ± 10.1) years, 77.4% males] were included in the study. 91.2% had cirrhosis and HCV (29%), HBV (18.3%) accounted for majority of the liver

disease. 11.8% had more than one nodule this website and the overall mean ( ± SD) tumour diameter was 26.1 (13.3) mm. 73.1% had RFA and the mean ( ± SD) follow-up duration was 421.3 ( ± 396.9) days. Overall IHR rate was 55.9% during the follow-up period with LTP in 33.3%, IDR in 29% and 6.5% had both. Overall median ( ± SE) recurrence free survival was 422 ( ± 48) days. Poorly differentiated HCC was the only independent predictor of overall IHR [HR (95% CI): 6.1 (1.9–19.2), p = 0.002], LTP [9.8 (2.3–41.3, p = 0.002]

and IDR [5.3 (1.2–22.9), p = 0.03]. There was a trend towards early IHR in patients having MWA compared to RFA [median ( ± SE) days: 399 ( ± 32) v 554 ( ± 111) days, p = 0.06). This was more evident in single tumours less than 30 mm where the recurrence was significantly earlier in those having MWA [median ( ± SE) days: 399 ( ± 37) v 568 ( ± 120) days, p = 0.02]. Overall, 11.8% had an adverse event and this was higher in the MWA group compared to RFA but, not significant (25% v 9.7%, p = 0.14). There were no procedure related deaths in this cohort. Conclusion: Poorly differentiated HCC is an important, independent predictor of overall IHR, LTP and IDR post PTA. Trends towards earlier recurrence in patients having MWA, together with a higher adverse event rates in the MWA group raise concerns about the efficacy and safety of this technique relative to RFA in real world settings and require further study.

g. C2-CH1, C2-CH2, C2-CH3). The constructs will then be used for tolerance induction both in vivo and in vitro in haemophilia A (FVIII Neratinib knockout) mice, which will be challenged with FVIII in our standard protocol. This will help determine which regions of the IgG scaffold are indispensable for immune tolerance, which will then be incorporated into minimized fusion proteins. These experiments will also test the hypothesis that the Tregitopes are important in the tolerogenicity

of IgG fusions. Recently, biodegradable nanoparticles have been developed both as vaccine vehicles, and as a novel approach for tolerance [64, 65]. In collaboration with Selecta Biosciences, we have tested nanoparticle delivery of an immune modulator with FVIII. The rationale for this approach was that the drug would be released in the local milieu of the lymphoid tissue and potentially only affect the APCs and specific responding lymphocytes, thus avoiding systemic immunosuppression by the drug. The results of one such study Palbociclib mouse (Zhang et al., in preparation) are summarized in Fig. 2. Both formulations of nanoparticles given with FVIII led to long-term suppression of inhibitor responses. Moreover, antibody responses to unrelated antigens were normal, a result which validates the

specificity of this effect. Suppression by intravenous immunoglobulin (IVIG,Group 4) occurred early on but was short-lived. Tregs have been proposed to treat undesirable immune responses [66-68]. Expanded so-called natural Tregs, originating in the thymus, have

the potential to be useful but are generally not antigen-specific and could potentially cause global immunosuppression. Activated specific Tregs generated in response to an antigen are more desirable, but obtaining large numbers of these cells from patient samples is technically challenging. To overcome these disadvantages, we elected to create antigen-specific Tregs by transduction of T-cell receptor (TCR) variable regions into expanded human Foxp3+ Tregs. The TCRs came from well-characterized T-cell clones that recognized defined FVIII epitopes [69, 70]. Using retroviral transduction of such an engineered TCR from a patient with Galactosylceramidase haemophilia into expanded human natural Tregs, we recently created epitope-specific Tregs. These are able to suppress the proliferation and cytokine production of FVIII-specific effector cells, thus validating their potential utility to treat inhibitor antibody formation in haemophilia. A model for clinical translation is shown in Fig. 3. Inhibitor formation is the major adverse event that pre-empts successful treatment of bleeding disorders. Efforts to prevent and/or reverse these antibody responses have emerged during the last decade based on increased knowledge of the immune response to FVIII and novel tolerogenic approaches.