Myelin basic protein (MBP) is an auto-antigen able to induce intractable pain from innocuous mechanical stimulation (mechanical allodynia). The mechanisms provoking this algesic MBP activity remain obscure. Our present study demonstrates that membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) releases the algesic MBP peptides from the damaged myelin, which then reciprocally enhance the expression of MT1-MMP in nerve to sustain a state of allodynia. Specifically, MT1-MMP expression and activity in rat sciatic nerve gradually increased starting at day 3 after chronic constriction injury (CCI). Inhibition of the MT1-MMP activity by intraneural injection of the function-blocking human DX2400 monoclonal antibody at day 3 post-CCI reduced mechanical allodynia and neuropathological signs of Wallerian degeneration, including axon demyelination, degeneration, edema and formation of myelin ovoids. Consistent with its role in allodynia, the MT1-MMP proteolysis of MBP generated the MBP69-86-containing epitope sequences in vitro. In agreement, the DX2400 therapy reduced the release of the MBP69-86 epitope in CCI nerve. Finally, intraneural injection of the algesic MBP69-86 and control MBP2-18 peptides differentially induced MT1-MMP and MMP-2 expression in the nerve. With these data we offer a novel, self-sustaining mechanism of persistent allodynia via the positive feedback loop between MT1-MMP and the algesic MBP peptides. Accordingly, short-term inhibition of MT1-MMP activity presents a feasible pharmacological approach to intervene in this molecular circuit and the development of neuropathic pain.

Patients with end-stage liver disease show sarcopenia, and preoperative sarcopenia is independently associated with patient mortality after liver transplantation. However, few studies have examined the relationship between perioperative loss of core muscle and patient mortality in living donor liver transplantation (LDLT). This study was performed to investigate the association between a perioperative decrease in the psoas muscle index (PMI) and patient mortality after LDLT. Adult patients (age ≥ 18 years) undergoing LDLT between January 2009 and December 2016 were classified into low-loss (>25th quartile) versus high-loss (≤25th quartile) groups according to PMI change between the day before surgery and postoperative day (POD) 7. Patient survival was compared between the 2 groups, and factors affecting survival were analyzed. The median (interquartile range) level of PMI change from the day before surgery to POD 7 was -4.8% (-11.7%-1.2%). Although there was no preoperative difference in PMI between the low-loss and high-loss groups, patients with PMI change ≤-11.7% showed poorer survival than those with PMI change >-11.7% during the follow-up period. A PMI decrease ≤-11.7% between the day before surgery and POD 7 is an independent predictor of patient mortality after LDLT. In addition, intraoperative packed red blood cell transfusion, graft fat percentage, and reoperation and infection after surgery were significantly associated with patient mortality. In conclusion, a PMI decrease ≤-11.7% between the day before surgery and POD 7 is an independent predictor of patient mortality after LDLT. It is necessary to identify the factors responsible for the perioperative decrease in skeletal muscle mass and to ascertain if they are modifiable to improve patient survival after LDLT. Liver Transplantation 24 623-633 2018 AASLD.

BackgroundLiver graft regeneration is orchestrated by specific and sequential stimuli, including hepatocyte growth factors, cytokines, and catecholamines. We evaluated the association between preoperative serum cytokines and early liver graft regeneration in human living donor liver transplantation (LDLT).Patients and methodsWe retrospectively reviewed the data of adult patients who underwent LDLT from January 2010 to December 2014. Serum cytokines, including interleukin (IL)-2, 6, 10, 12, 17, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured in the recipients 1 day before surgery and on postoperative day (POD) 7. Liver graft volume was estimated using abdominal computed tomography images of the donors and recipients.ResultsIn total, 226 patients were analyzed in this study. Median preoperative levels of serum cytokines were as follows: IL-2, 0.1 (0.1–1.6) pg/mL; IL-6, 7.3 (0.1–30.2) pg/mL; IL-10, 0.5 (0.1–11.0) pg/mL; IL-12, 0.1 (0.1–0.1) pg/mL; IL-17, 2.0 (0.1–16.4) pg/mL; IFN-γ, 3.2 (0.1–16.0) pg/mL; and TNF-α, 9.8 (5.4–17.9) pg/mL. Higher preoperative serum levels of IL-6, IL-10, and TNF-α, dichotomized at the median, were associated with increased relative liver volumes by POD 7. Multivariate analysis revealed that higher levels of serum IL-6 and TNF-α were independently associated with increased graft volume during the first 1 week after LDLT, based on the lower levels of those cytokines.ConclusionsIL-6 and TNF-α were important mediators of the success of early graft regeneration in patients who underwent LDLT.

SummaryAdministration of vasopressors or inotropes during liver transplant surgery is almost universal, as this procedure is often accompanied by massive haemorrhage, acid-base imbalance, and cardiovascular instability. However, the actual agents that should be used and the choice between a vasopressor and an inotrope strategy are not clear from existing published evidence. In this prospective, randomised, controlled and single-blinded study, we compared the effects of a vasopressor strategy on intra-operative blood loss and acid-base status with those of an inotrope strategy during living donor liver transplantation. Seventy-six adult liver recipients with decompensated cirrhosis were randomly assigned to receive a continuous infusion of either phenylephrine at a dose of 0.3-0.4 lg.kg Patients undergoing liver transplantation for decompensated liver cirrhosis invariably demonstrate pathophysiological circulatory changes. Elevated intrahepatic vascular resistance induces dilatation of extrahepatic vessels, which is aggravated by overproduction and impaired hepatic metabolism of endogenous vasodilators such as nitric oxide [1]. Dilatation of extrahepatic vessels, including portosplanchnic vessels, redistributes body fluid from the central to the peripheral compartment, reducing effective blood flow to the major organs. Additionally, wide surgical dissection of porto-systemic collateral vessels and an inherent haemorrhagic

The c¢ chain of human fibrin(ogen) has received much attention of late because of its apparent regulatory roles, both with regard to the binding of factor (F)XIII by fibrinogen [1,2] and the binding of thrombin by fibrin [3,4]. The c¢ chain is mostly a longer version of the c chain, the result of alternative splicing [5,6], or in this case non-splicing. The result in humans is a c chain 20 residues longer than the more usual spliced form. The extension is markedly anionic, in part because of two sulfated tyrosines [7] that have been implicated in binding to thrombin.Interestingly, mouse fibrin does not bind thrombin with the same avidity as human fibrin, an observation attributed to its shorter c¢ extension. In a recent genetic engineering study, the mouse c¢ sequence was replaced by the human version, after which tight thrombin binding was observed [8]. The experiment raises the question, are humans (or primates) unique in their ability to regulate coagulation by tight binding of c¢ to thrombin? In an effort to answer this question, we conducted a bioinformatics survey in which we examined the genomes of 16 vertebrates in search of putative c¢ sequences. The sine qua non for having two versions of the c chain is an intron near the 3¢ terminus of the coding region. It has long been known that the lamprey c-chain gene lacks the intron [9], as does the puffer fish [10].Publicly accessible data bases were searched for lamprey, puffer fish, zebra fish, frog, chicken, platypus, opossum, dog, cat, mouse, rat, ox, horse, macaque, chimpanzee and human genes. These databases can be accessed through various portals, including http://www.ncbi.nlm.gov, http://genome.wustl.edu/, http://genome.ucsc.edu/cgi-bin/hgGateway/ and http://www. sanger.ac.uk/. Various kinds of BLAST searches [11] were conducted, TBLASTN in particular being used to search translated amino acid sequences against raw DNA data. The highly conserved region composed of c-chain residues 380-410, which is present in both c and c¢ chains, was mostly used as the probe, high scoring hits being examined for introns in the region and, when found, downstream DNA sequences scrutinized for splicing candidates.We confirmed that the intron allowing alternative splicing leading to two forms of fibrinogen c chains does not occur in any fish or frog. It exists in the green lizard gene, but the most probable candidate sequence for a spliced form was a solitary isoleucine residue; direct experiment will be needed to determine whether splicing really occurs. Of more interest, the unspliced form of the lizard gene has an RGD sequence at the same position as occurs in frog and lamprey (Fig. 1A,C).The chicken gene also has the intron, but an almost immediate terminator codon leads to an unspliced form shorter than the spliced alternative (Fig. 1). Suspiciously, an RGD sequence occurs three residues after the terminator codon, followed by another terminator that coincides with lizard and frog (Fig. 1C).The situation in the platypus (a monotreme) is similar. There is an intron at...

We studied topographic distribution of tau and amyloid-β in a patient with variant Alzheimer's disease with spastic paraparesis (VarAD) by comparing AD patients. The proband developed progressive memory impairment, dysarthria, and spastic paraparesis at age 23. Heterozygous missense mutation (L166P) was found in exon 6 of presenilin-1 gene. The proband showed prominently increased amyloid binding in striatum and cerebellum and asymmetrical tau binding in the primary sensorimotor cortex contralateral to the side more affected by spasticity. We suspect that upper motor neuron dysfunctions may be attributed to excessive abnormal tau accumulation rather than amyloid-β in the primary motor cortex.

Background Early extubation after liver transplantation is safe and accelerates patient recovery. Patients with end-stage liver disease undergo sarcopenic changes, and sarcopenia is associated with postoperative morbidity and mortality. We investigated the impact of core muscle mass on the feasibility of immediate extubation in the operating room (OR) after living donor liver transplantation (LDLT). Methods A total of 295 male adult LDLT patients were retrospectively reviewed between January 2011 and December 2017. In total, 40 patients were excluded due to emergency surgery or severe encephalopathy. A total of 255 male LDLT patients were analyzed in this study. According to the OR extubation criteria, the study population was classified into immediate and conventional extubation groups (39.6 vs. 60.4%). Psoas muscle area was estimated using abdominal computed tomography and normalized by height squared (psoas muscle index [PMI]). Results There were no significant differences in OR extubation rates among the five attending transplant anesthesiologists. The preoperative PMI correlated with respiratory performance. The preoperative PMI was higher in the immediate extubation group than in the conventional extubation group. Potentially significant perioperative factors in the univariate analysis were entered into a multivariate analysis, in which preoperative PMI and intraoperative factors (i.e., continuous renal replacement therapy, significant post-reperfusion syndrome, and fresh frozen plasma transfusion) were associated with OR extubation. The duration of ventilator support and length of intensive care unit stay were shorter in the immediate extubation group than in the conventional extubation group, and the incidence of pneumonia and early allograft dysfunction were also lower in the immediate extubation group. Conclusions Our study could improve the accuracy of predictions concerning immediate post-transplant extubation in the OR by introducing preoperative PMI into predictive models for patients who underwent elective LDLT. Electronic supplementary material The online version of this article (10.1186/s12871-019-0781-z) contains supplementary material, which is available to authorized users.

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