The lectin‐like domain of thrombomodulin is a drug candidate for both prophylaxis and treatment of liver ischemia and reperfusion injury in mice

Ischemia and reperfusion injury (IRI) can occur in any tissue or organ. With respect to liver transplantation, the liver grafts from donors by definition experience transient ischemia and subsequent blood reflow. IRI is a problem not only in organ transplantation but also in cases of thrombosis or circulatory disorders such as mesenteric ischemia, myocardial, or cerebral infarction. We have reported that recombinant human soluble thrombomodulin (rTM), which is currently used in Japan to treat disseminated intravascular coagulation (DIC), has a protective effect and suppresses liver IRI in mice. However, rTM may not be fully safe to use in humans because of its inherent anticoagulant activity. In the present study, we used a mouse liver IRI model to explore the possibility that the isolated lectin-like domain of rTM (rTMD1), which has no anticoagulant activity, could be effective as a therapeutic modality for IRI. Our results indicated that rTMD1 could suppress ischemia and reperfusion-induced liver damage in a dose-dependent manner without concern of associated hemorrhage. Surprisingly, rTMD1 suppressed the liver damage even after IR insult had occurred. Taken together, we conclude that rTMD1 may be a candidate drug for prevention of and therapy for human liver IRI without the possible risk of hemorrhage

Two Cases of High Tibial Osteotomy in Patients with Rheumatoid Arthritis Treated with Biologic Disease-modifying Anti-rheumatic Drugs

High tibial osteotomy (HTO) procedure is generally contraindicated in rheumatoid arthritis (RA) patients because synovial inflammation may exacerbate joint damage post-surgery. The natural course of joint destruction in RA changed dramatically with new treatment strategies and the introduction of biologic disease-modifying anti-rheumatic drugs (bDMARDs). We report the cases of two RA patients who underwent HTO and whose disease activities were well controlled by bDMARDs. Despite their short follow-up periods, they showed acceptable objective and subjective clinical results. We believe that the combination of bDMARDs and HTO can be indicated for selected RA patients before total knee arthroplasty

Biallelic mutations in <i>KDSR </i>disrupt ceramide synthesis and result in a spectrum of keratinization disorders associated with thrombocytopenia

Mutations in ceramide biosynthesis pathways have been implicated in a few Mendelian disorders of keratinization, although ceramides are known to have key roles in several biological processes in skin and other tissues. Using whole-exome sequencing in four probands with undiagnosed skin hyperkeratosis/ichthyosis, we identified compound heterozygosity for mutations in KDSR, encoding an enzyme in the de novo synthesis pathway of ceramides. Two individuals had hyperkeratosis confined to palms, soles, and anogenital skin, whereas the other two had more severe, generalized harlequin ichthyosis-like skin. Thrombocytopenia was present in all patients. The mutations in KDSR were associated with reduced ceramide levels in skin and impaired platelet function. KDSR enzymatic activity was variably reduced in all patients, resulting in defective acylceramide synthesis. Mutations in KDSR have recently been reported in inherited recessive forms of progressive symmetric erythrokeratoderma, but our study shows that biallelic mutations in KDSR are implicated in an extended spectrum of disorders of keratinization in which thrombocytopenia is also part of the phenotype. Mutations in KDSR cause defective ceramide biosynthesis, underscoring the importance of ceramide and sphingosine synthesis pathways in skin and platelet biology

Clinical impact of margin status on survival and recurrence pattern after curative-intent surgery for pancreatic cancer

Summary: Background/Objective: The definition of R0 resection for invasive pancreatic ductal carcinoma (IPDC) is important. However, there are different definitions among several countries in the world. Methods: From 2001 to 2015, 100 consecutive patients with IPDC who underwent pancreatic resection in our hospital were enrolled. We compared survival and recurrence patterns between the R0 group and R1 group based on the UICC (Union for International Cancer Control) classification (current-R0 vs. current-R1) and based on our revised classification, which defines R0 as a surgical margin of >1 mm (revised-R0 vs. revised-R1). Results: The 100 patients comprised 58 males and 42 females, and their median age was 70 [32–87]. There were 84 patients in the current-R0 group and 43 in the revised-R0 group. There was no difference in overall survival (OS) or recurrence-free survival (RFS) between the current-R0 group and current-R1 group. However, there was a tendency toward a higher OS rate in the revised-R0 than revised-R1 group (log-rank p = 0.065), and RFS was significantly better in the revised-R0 than revised-R1 group (log-rank p = 0.002). There was no significant difference in the recurrence patterns between the current-R0 and current-R1 groups. In contrast, the local recurrence rate was significantly lower in the revised-R0 than revised-R1 group (21% vs. 42%, respectively; p = 0.026). Conclusion: The revised classification of surgical resection may be more useful than the current UICC classification for prediction of prognosis and local recurrence of IPDC. Keywords: Pancreatic cancer, Pancreatic surgery, Prognostic factor, Surgical margin statu