Autism spectrum disorder (ASD) is characterized by dysfunction in social interactions, stereotypical behaviours and high co-morbidity with intellectual disability. A variety of syndromic and non-syndromic neurodevelopmental disorders have been connected to alterations in metabotropic glutamate receptor (mGluR) signalling. These receptors contribute to synaptic plasticity, spine maturation and circuit development. Here, we investigate the physiological role of Gprasp2 , a gene linked to neurodevelopmental disabilities and involved in the postendocytic sorting of G-protein-coupled receptors. We show that Gprasp2 deletion leads to ASD-like behaviour in mice and alterations in synaptic communication. Manipulating the levels of Gprasp2 bidirectionally modulates the surface availability of mGluR 5 and produces alterations in dendritic complexity, spine density and synaptic maturation. Loss of Gprasp2 leads to enhanced hippocampal long-term depression, consistent with facilitated mGluR-dependent activation. These findings demonstrate a role for Gprasp2 in glutamatergic synapses and suggest a possible mechanism by which this gene is linked to neurodevelopmental diseases.

Lack of axon regeneration following spinal cord injury has been mainly ascribed to the inhibitory environment of the injury site, i.e., to chondroitin sulfate proteoglycans (CSPGs) and myelin-associated inhibitors (MAIs). Here, we used shiverer (shi) mice to assess axon regeneration following spinal cord injury in the presence of MAIs and CSPG but in the absence of compact myelin. Although in vitro shi neurons displayed a similar intrinsic neurite outgrowth to wild-type neurons, in vivo, shi fibers had increased regenerative capacity, suggesting that the wild-type spinal cord contains additional inhibitors besides MAIs and CSPG. Our data show that besides myelin protein, myelin lipids are highly inhibitory for neurite outgrowth and suggest that this inhibitory effect is released in the shi spinal cord given its decreased lipid content. Specifically, we identified cholesterol and sphingomyelin as novel myelin-associated inhibitors that operate through a Rho-dependent mechanism and have inhibitory activity in multiple neuron types. We further demonstrated the inhibitory action of myelin lipids in vivo, by showing that delivery of 2-hydroxypropyl-β-cyclodextrin, a drug that reduces the levels of lipids specifically in the injury site, leads to increased axon regeneration of wild-type (WT) dorsal column axons following spinal cord injury. In summary, our work shows that myelin lipids are important modulators of axon regeneration that should be considered together with protein MAIs as critical targets in strategies aiming at improving axonal growth following injury.

2290 Background: Intra-operative autologous red blood cell (RBC) salvaging (SRBC) reduces requirements for allogeneic RBC transfusion during surgery, and should be considered in surgeries with anticipated blood losses over 1 L. However, the auto-transfusion of large volumes of SRBC can lead to dilutional coagulopathy, due to the loss of clotting factors and platelets during cell processing, worsening the outcome of surgery. Orthotopic liver transplantation (OLT) has historically been associated with major blood loss and massive blood transfusion due to the aggressiveness of surgery, the anhepatic phase and the pre-existing underlying disease. While transfusion requirements have been greatly reduced over the past decade, large volumes correlate with worsened prognosis and can also lead to dilutional coagulopathy. Most published series on cell salvaging focus on orthopedic, cardiac or oncologic patients, and data on its use in liver transplantation remains insufficient and contradictory, with the suggestion that salvage is associated with a higher degree of dilutional coagulopathy than allogeneic transfusion. Methods: We performed a retrospective analysis of a 5-year series of OLT patients undergoing surgery (including for fulminant liver failure) in our Centre, comparing the number of units of Red Cell Concentrate (RCC) transfused during each procedure and the volume of autologous SRBC obtained intra-operatively and reinfused before the conclusion of surgery, with the number of units of fresh frozen plasma (Plasma) and Platelet Concentrate (PC) consumed, as a clinical marker of the depth of coagulopathy, both through univariate and multivariate analysis. Results: A total of 218 OLTs were analyzed; an average of 13.6±17.5 units (U) of RCC, 7.4±12.4 U of Plasma and 5.0±7.9 U of PC were used. In one third of patients (30.7%) no allogeneic RCC was transfused, and in a further third (34.4%) less than 5 U were consumed, resulting in a median of 2 U of RCC per patient. A mean of 1003.4±1061.3 mL of SRBC were reinfused in the 70 patients (32.1%) who underwent salvage. There was no correlation between the number of RCC units and the volume of SRCB infused (−0.04, p=NS), and the mean volume of SRBC was not different between patients who were transfused with RCC (315.3±845.4) and those who were not (337.7±527.0, p=NS); on the other hand, patients who underwent cell salvage used significantly less units of RCC (3.3±6.1) than those who did not (9.4±14.1, p<0.001). We found a strong correlation between the number of Plasma and PC units administered (0.73, p<0.001), and between the number of RCC and Plasma (0.91, p<0.001) and PC units (0.68, p<0.001) used; patients who were transfused with at least 1 U of RCC consumed significantly more Plasma (18.7±18.7 U) and PC (7.1±8.6 U) than patients who did not receive any allo-RCC (1.9±4.0, p<0.001 and 0.3±1.8, p<0.001, respectively). Likewise, there was a significant correlation between the volume of SRBC and the number of Plasma (0.63, p<0.001) and PC units used (0.31, p=0.009); however, patients who underwent cell salvage used significantly less Plasma (7.4±11.7 U) and PC (2.8±6.1 U) than patients who did not (16.1±19.1, p<0,001 and 6.1±8.4, p=0.002, respectively), and patients who received only autologous SRBC were transfused with significantly less Plasma (2.0±4.4 U) and PC (0.0±0.0 U) than patients who received only allogeneic RCC units (20.6±19.8, p<0.001 and 7.6±8.9, p<0.001, respectively). Discussion: The choice to use SRBC was introduced a priori, as reflected in the absence of correlation between the volume of RCC and SRBC used. However, the use of salvaging resulted in a significantly lower need for allogeneic RCC. The volume of allo or auto-RBC needed during surgery correlated with the severity of coagulopathy, and the number of Plasma and PC units administered to revert it were strongly correlated, as expected. However, the choice to use SRBC was associated with a decrease in the volume of Plasma and PC needed, when compared to surgeries without salvaging. Likewise, the exclusive use of SRBC resulted in a significantly lower use of Plasma and PC during surgery than the exclusive use of allo-RCC. Conclusion: In our series, intraoperative salvaging not only reduced the consumption of RCC, but was also associated with a lower severity of surgical coagulopathy, as evaluated clinically through the number of units of Plasma and PC needed to stabilize the patient. Disclosures: No relevant conflicts of interest to declare.

The current study supports a relevant role for p15, p16, and DAPK hypermethylation in the genesis of the plasma cell neoplasm. DAPK hypermethylation also might be an important step in the progression from MGUS to MM.

No abstract

Dendritic cells (DCs) are a heterogeneous population of antigen-presenting cells derived from hematopoietic progenitors that bridge the transition between the innate and adaptive immune responses, while maintaining self-tolerance and Th1/Th2 homeostasis, by priming other cells in either an immunogenic or tolerogenic direction. Through their role in both innate and adaptive immunity, DCs play a major part in transplant engraftment and rejection and in graft-versus-host disease (GvHD). Preferentially tolerogenic or immunogenic DC subtypes offer targets for immunotherapy, to optimize transplant success rates and prolong disease-free and overall survival. Cord blood DCs are immature and preferentially tolerogenic, due to maternal-fetal tolerance, leading to better graft acceptance and immune reconstitution and explaining the lower incidence and severity of GvHD in CB transplantation, despite donor-host mismatching. Manipulation of DC maturation and cell loading with tumor-antigens can direct antitumor immunity and target minimal residual disease, as demonstrated for acute myeloid leukemia, optimizing the graft-versus-leukemia effect.

Introduction: Pipotiazine palmitate depot injection (Piportil) was withdrawn from the UK marketplace in 2015. Few studies exist on the clinical impact of such market withdrawal. Purpose: We aimed to identify a cohort of patients switching from pipotiazine following this withdrawal and explore factors associated with effectiveness of the medication switched to and subsequent acute service use. Methods: A naturalistic retrospective cohort study was conducted in Sussex, United Kingdom. Those discontinuing pipotiazine solely due to market withdrawal were identified from electronic patient database and manual searching. Multivariate logistic regression analyses and survival analyses were performed to explore associations between available baseline variables and dichotomous all-cause discontinuation of the next prescribed medication and admission to acute mental health services over the subsequent year. Results: Of 205 patients identified as receiving pipotiazine in October 2014, 137 switched from this due to market withdrawal. Over the subsequent year, 31.5% discontinued the medication to which they were switched and 19% required acute care. Drug class switched to (typical depot vs atypical long acting injection (LAI) vs atypical oral) had no significant association with discontinuation. Switch to atypical LAI was significantly associated with acute care in comparison to typical depot. Those with a schizophrenia diagnosis were significantly less likely to discontinue switched medication or to receive acute care in comparison to those with schizoaffective disorder. Women were significantly more likely to discontinue switched medication than men. Of those requiring acute care, only 38% had required this in the previous 2 years. Conclusions: Antipsychotic market withdrawal has demonstrable negative clinical implications and requires careful clinical management. Increased acute care rates in those receiving an atypical LAI versus a typical depot following pipotiazine suggests lower effectiveness or possible withdrawal effects. No significant difference between depots, LAIs and oral medications on discontinuation supports the importance of a collaborative, fully informed approach when deciding next treatment options.

F AMILIAL amyloidotic polyneuropathy (FAP) ATTRMet 30 is the result of an inherited disorder of transthyretin metabolism. Both amyloid transthyretin and normal transthyretin are produced in the liver and the transplantation is a successful therapy for this disease and is performed in spite of the completely normal liver function of these patients.1 A high incidence of hyperfibrinolysis was reported during liver transplantation but these studies were performed in patients with previous liver insufficiency and the relative role of preoperative factors (liver disease, coagulation disorders, increased fibrinolytic activity) and intraoperative factors (surgical trauma, hypotension, and graft reperfusion) is not clearly established.2,3 As far as we know, the incidence and the severity of hyperfibrinolysis during liver transplantation in patients without preoperative liver insufficiency has not yet been studied. The aim of this study was to evaluate the incidence of hyperfibrinolysis during liver transplantation in FAP and to correlate these findings with several perioperative factors. PATIENTSGroup I included 75 FAP ATTR Met 30 recipients of first liver transplants during a 6-year period, 41 male and 34 female, with age of 35.1 Ϯ 7.2 years, body mass index (BMI) of 20.7 Ϯ 4.1 kg/m 2 , disease duration (since the first symptom) of 4.4 Ϯ 2.4 years and neurologic score of 32.7 Ϯ 11.3 in the scale of Macedo et al. 4 Every patient in this group received prophylactic antifibrinolytic therapy. For a control, 102 patients with liver diseases transplanted during the same period were used as follows: 21 patients that did not receive prophylactic antifibrinolytic therapy were considered as group IIA; 81 patients that received high-dose aprotinin during all the surgical procedure were considered as group IIB. Not different concerning sex, both group IIA (43.2 Ϯ 13.8 years, P Ͻ .01) and group IIB (43.2 Ϯ 12.5 years, P Ͻ .001) were older than group I. Group I patients had normal liver tests: AST, 26.0 Ϯ 12.2 U/L; ALT, 25.3 Ϯ 15.7 U/L; total bilirubin 0.8 Ϯ 0.4 mg/dL; direct bilirubin 0.1 Ϯ 0.1 mg/dL. The same was not observed in the other groups: AST was 124 Ϯ 228 U/L in group IIA (P ϭ ns) and 191 Ϯ 467 U/L in group IIB (P Ͻ .01); ALT, 100 Ϯ 156 U/L in group IIA (P ϭ ns) and 169 Ϯ 419 U/L in group IIB (P Ͻ .01); total bilirubin 5.3 Ϯ 9.9 mg/dL in group IIA (P ϭ ns) and 10.1 Ϯ 12.5 mg/dL in group IIB (P Ͻ .001); direct bilirubin 3.0 Ϯ 6.5 mg/dL in group IIA (P ϭ ns) and 5.1 Ϯ 7.7 mg/dL in group IIB (P Ͻ .001). The values of P account comparisons with group I. METHODAnesthesia, monitoring, circulatory, and coagulation goals and treatments were the same in the three groups. Thrombelastograms (TEG) were retrospectively evaluated in a blind fashion by two independent observers. As standardized, one intraoperative value of a60/ma (whole blood clot lysis index) less than 0.8 was considered a signal of hyperfibrinolysis. Before the evaluation of any TEG of this study, we decided to consider one intraoperative value of F (whole blood clot l...