Complete response to post-transplant lymphoproliferative disorder by surgical resection and rituximab after living-donor liver re-transplantation for recurrent primary sclerosing cholangitis

Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication of solid organ transplantation. We herein report a case of PTLD after living-donor liver re-transplantation (reLDLT) for recurrent primary sclerosing cholangitis (PSC), for which complete response was achieved by surgical resection and rituximab. A 47-year-old man, who had undergone living-donor liver transplantation (LDLT) twice at age of 43 and 45 years for end-stage liver disease firstly for PSC and secondary for recurrent PSC, suffered liver dysfunction due to an acute cellular rejection (ACR) 17 months after reLDLT. At reLDLT, a right liver lobe was donated from his spouse. Although steroid was effective for ACR, PTLD developed in the ileocecal area. The patient received rituximab for treatment of PTLD, and ileocecal resection for hemorrhage from ileocecal PTLD. The patient achieved complete response by rituximab and surgical resection for PTLD, but PSC recurred and hemophagocytic syndrome (HPS) developed with hyperbilirubinemia and elevated serum ferritin. The patient received steroid treatment for HPS, but thrombocytopenia and coagulopathy developed presumably due to thrombotic microangiopathy. Therefore, tacrolimus was switched to mycophenolate mofetil. Despite intensive treatment including plasmapheresis and platelet infusion, fungal infection of both lungs developed, and the patient died 22 months after reLDLT. Autopsy revealed complete response of PTLD, recurrence of PSC and persistance of HPS.     

Roles of ATP receptors in the regulation of various functions in spinal microglia

It is shown that glial cells have a pivotal influence on the formation of neuronal network in central nerve system. Moreover, spinal microglia has some important roles in the development and progression of various neurological disorders. Therefore, it is possible that modulation of microglial activity may be sufficient to alleviate those harmful responses. ATP is one of signaling molecules in the spinal cord, and involved in regulation of several microglial functions through the binding of P2X and P2Y receptors. Thus, I focused on the ATP-mediated regulation mechanisms for the two important proteins, which are p38 MAP kinase and excitatory amino acid transporters (EAATs), in cultured spinal microglia. Mounting evidence indicates that p38 in spinal microglia has crucial roles in some neurological diseases. Furthermore, it is recently suggested that microglial EAATs might participate in the homeostasis of glutamate in synapses. This review summarizes our finding regarding the involvement of P2Y receptors and β-adrenergic receptors in the regulation of p38 phosphorylation, and the mechanism of P2X7 receptor-mediated downregulation of EAATs function.     

Bone Marrow Mesenchymal Cells: How Do They Contribute to Tissue Repair and Are They Really Stem Cells?

Adult stem cells typically generate the cell types of the tissue in which they reside, and thus the range of their differentiation is considered limited. Bone marrow mesenchymal stem cells (MSCs) are different from other somatic stem cells in that they differentiate not only into the same mesodermal-lineage such as bone, cartilage, and adipocytes but also into other lineages of ectodermal and endodermal cells. Thus, MSCs are a unique type of adult stem cells. In addition, MSCs home to damaged sites, differentiate into cells specific to the tissue and contribute to tissue repair. Therefore, application of MSCs in the treatment of various diseases, including liver dysfunction, myocardial infarction, and central nervous system repair, has been initiated. Because MSCs are generally harvested as adherent cells from bone marrow aspirates, however, they comprise heterogeneous cell populations and their wide-ranging differentiation ability and repair functions are not yet clear. Recent evidence suggests that a very small subpopulation of cells that assume a repair function with the ability to differentiate into trilineage cells resides among human MSCs and effective utilization of such cells is expected to improve the repair effect of MSCs. This review summarizes recent advances in the clarification of MSC properties and discusses future perspectives.     

Hemobilia: another complication associated with anti-thrombotic therapy

It is generally accepted that anti-thrombotic therapy increases the risk of gastrointestinal bleeding, and concurrent therapy with a proton-pump inhibitor is the standard treatment for patients receiving aspirin. Therefore, much attention has been paid to the prevention of gastrointestinal bleeding in such patients; however, it should be noted that patients on anti-thrombotic therapy always carry a risk of hemorrhage from any organ, including the gastrointestinal tract. Here, we present a case with formation of a common bile duct stone caused by hemobilia associated with anti-thrombotic therapy. This case suggests that we need to be aware of the possibility of intrabiliary hemorrhage as well as gastrointestinal bleeding in patients receiving anti-thrombotic therapy. Patients with such complications show a variety of symptoms including liver abscess, cholangitis, pancreatitis, and duodenal bleeding.     

M2‐like macrophage polarization in high lactic acid‐producing head and neck cancer

Reprogramming of glucose metabolism in tumor cells is referred to as the Warburg effect and results in increased lactic acid secretion into the tumor microenvironment. We have previously shown that lactic acid has important roles as a pro‐inflammatory and immunosuppressive mediator and promotes tumor progression. In this study, we examined the relationship between the lactic acid concentration and expression of LDHA and GLUT1, which are related to the Warburg effect, in human head and neck squamous cell carcinoma (HNSCC). Tumors expressing lower levels of LDHA and GLUT1 had a higher concentration of lactic acid than those with higher LDHA and GLUT1 expression. Lactic acid also suppressed the expression of LDHA and GLUT1 in vitro. We previously reported that lactic acid enhances expression of an M2 macrophage marker, ARG1, in murine macrophages. Therefore, we investigated the relationship between the lactic acid concentration and polarization of M2 macrophages in HNSCC by measuring the expression of M2 macrophage markers, CSF1R and CD163, normalized using a pan‐macrophage marker, CD68. Tumors with lower levels of CD68 showed a higher concentration of lactic acid, whereas those with higher levels of CSF1R showed a significantly higher concentration of lactic acid. A similar tendency was observed for CD163. These results suggest that tumor‐secreted lactic acid is linked to the reduction of macrophages in tumors and promotes induction of M2‐like macrophage polarization in human HNSCC.     

Factors contributing to blood-brain barrier disruption following intracarotid injection of nonionic iodinated contrast medium for cerebral angiography: experimental study in rabbits

Purpose This study was performed to investigate the role of injection methods and conditions under a fixed dose of radiographic contrast medium (CM) in respect to promoting blood–brain barrier (BBB) disruption. Materials and methods A total of 44 white rabbits (average body weight 2.7 ± 0.4 kg) were used, and their carotid injection was performed with nonionic CM. The variables assessed for the carotid injections included the following: iodine content (300 or 150 mg I/ml), liquid temperature (37° or 24°C), and the injection time duration (1 or 30 s). The rabbits were divided into five groups. To evaluate BBB disruption, pre- and post-contrast-enhanced magnetic resonance (MR) studies were performed. Results Abnormal enhancement of the brain parenchyma in MRI was noted in only one group, which consisted of high-iodine concentration CM injected at a low temperature over a short injection interval. Statistically significant increased values for the percentage of relative enhancement (RE%) were demonstrated (P < 0.05) in comparison with the saline-injected control group. Conclusion This result suggests variables that may need to be carefully considered to prevent BBB injury induced by nonionic CM for cerebral angiography, especially in the setting of a neurointerventional procedure.     

Ultrastructural differentiation in the distal ends of ameloblasts from the presecretory zone to the early secretory zone

Morphological differentiation of the distal ends of ameloblasts (AMs) from the late presecretory to early secretory zones of the rat upper incisor was studied by electron microscopy. Preameloblasts (PAs) showed a high columnar shape, with the nucleus located in the basal portion. The Golgi apparatus occupied the supranuclear region with type-1 vesicles, and microvilli were present at the distal cell membrane. Coarse-textured material was observed inside the type-1 vesicles and in the lateral intercellular spaces as well as along the distal cell membrane, whereas fine-textured material was found along the distal cell membrane. Near the region of initial enamel formation, large matrix islands were found in the lateral intercellular space. A thin electron-dense layer was observed on the dentin surface. This layer might have occurred as a result of diffusion after degradation of the coarse- or fine-textured material into a finer substance in the extracellular spaces. In the region of initial enamel formation, the distal cell membrane of AMs was flat, but shallow and narrow membrane invaginations were associated with the cell membrane close to the matrix islands. In the region of inner enamel formation, a cone-shaped Tomes' process was formed between large matrix islands which had developed in the intercellular spaces between the lateral portions of the distal ends of AMs. It was considered that the membrane invaginations which had existed at the distal end of PAs moved lower toward the distal terminal bar, thereafter becoming microvilli.     

The degree of microRNA-34b/c methylation in serum-circulating DNA is associated with malignant pleural mesothelioma

Objectives

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. microRNA-34b/c (miR-34b/c), which plays an important role in the pathogenesis of MPM, is frequently downregulated by DNA methylation in approximately 90% of MPM cases. In this study, we estimated the degree of miR-34b/c methylation in serum-circulating DNA using a digital methylation specific PCR assay (MSP).

Materials and methods

A real-time MSP assay was performed using the SYBR Green method. The melting temperature (Tm) of each PCR product was examined using a melting curve analysis. For a digital MSP assay, 40 wells were analyzed per sample. A total of 110 serum samples from 48 MPM cases, 21 benign asbestos pleurisy (BAP) cases, and 41 healthy volunteers (HVs) were examined.

Results

Positive range of Tm value for miR-34b/c methylation was defined as 77.71–78.79 °C which was the mean ± 3 standard deviations of 40 wells of a positive control. The number of miR-34b/c methylated wells was counted per sample according to this criterion. The number of miR-34b/c methylated wells in MPM cases was significantly higher than that in BAP cases (P = 0.03) or HVs (P < 0.001). Advanced MPM cases tended to have higher number of miR-34b/c methylated wells than early MPM cases. Receiver–operating characteristic (ROC) curve analysis revealed that three number of miR-34b/c methylated wells per sample was the best cut-off of positivity of MPM with a 67% of sensitivity and a 77% specificity for prediction. The area under the ROC curve was 0.77.

Conclusions

Our digital MSP assay can quantify miR-34b/c methylation in serum-circulating DNA. The degree of miR-34b/c methylation in serum-circulating DNA is associated with MPM, suggesting that this approach might be useful for the establishment of a new detection system for MPM.