Radiocontrast Medium-Induced Kounis Syndrome in a Dialysis Patient: A Case Report.

Kounis syndrome is defined as the concurrence of acute coronary syndrome and a condition related to mast cell activation, including anaphylaxis and anaphylactoid. A 58-year-old male hemodialysis patient underwent enhanced computed tomography (CT) using the radiocontrast medium, iopamidol for investigation of a kidney tumor. Two minutes after the administration of iopamidol, he developed respiratory symptoms and chest pain. Five minutes after that, disturbed consciousness and low blood pressure were observed. On the other hand, he did not demonstrate urticaria and swelling of the skin. A 12-lead electrocardiogram (ECG) and echocardiogram suggested the presence of cardiac ischemia. Therefore, he was diagnosed with Kounis syndrome caused by radiocontrast media. Eighteen minutes after this, he received an intramuscular injection of adrenaline (0.3 mg), and his vital signs stabilized and his ECG, echocardiogram, and symptoms improved. Without undergoing emergency coronary angiography (CAG), he was hospitalized and closely monitored. The next day, his symptoms had not worsened, and he underwent hemodialysis at his local hospital. The allergen radiocontrast media could be injurious and not sufficiently excreted if administrated for patients on weekly hemodialysis with radiocontrast medium-induced Kounis syndrome manifesting; hence, indication for emergency CAG in radiocontrast medium-induced Kounis syndrome should be cautiously evaluated by close observation.

One-pot ligation of multiple peptide segments via N-terminal thiazolidine deprotection chemistry.

Peptide ligation chemistries have revolutionized the synthesis of proteins with site-specific modifications or proteomimetics through assembly of multiple peptide segments. In order to prepare polypeptide chains consisting of 100-150 amino acid residues or larger generally assembled from three or more peptide segments, iterative purification process that decreases the product yield is usually demanded. Accordingly, methodologies for one-pot peptide ligation that omit the purification steps of intermediate peptide segments have been vigorously developed so far to improve the efficiency of chemical protein synthesis. In this chapter, we first outline the concept and recent advances of one-pot peptide ligation strategies. Then, the practical guideline for the preparation of peptide segments for one-pot peptide ligation is described with an emphasis on diketopiperazine thioester synthesis. Finally, we disclose the explicit protocols for one-pot four segment ligation via repetitive deprotection of N-terminal thiazolidine by a 2-aminobenzamide type aldehyde scavenger.

Characterizations of a neutralizing antibody broadly reactive to multiple gluten peptide:HLA-DQ2.5 complexes in the context of celiac disease.

In human celiac disease (CeD) HLA-DQ2.5 presents gluten peptides to antigen-specific CD4+ T cells, thereby instigating immune activation and enteropathy. Targeting HLA-DQ2.5 with neutralizing antibody for treating CeD may be plausible, yet using pan-HLA-DQ antibody risks affecting systemic immunity, while targeting selected gluten peptide:HLA-DQ2.5 complex (pHLA-DQ2.5) may be insufficient. Here we generate a TCR-like, neutralizing antibody (DONQ52) that broadly recognizes more than twenty-five distinct gluten pHLA-DQ2.5 through rabbit immunization with multi-epitope gluten pHLA-DQ2.5 and multidimensional optimization. Structural analyses show that the proline-rich and glutamine-rich motif of gluten epitopes critical for pathogenesis is flexibly recognized by multiple tyrosine residues present in the antibody paratope, implicating the mechanisms for the broad reactivity. In HLA-DQ2.5 transgenic mice, DONQ52 demonstrates favorable pharmacokinetics with high subcutaneous bioavailability, and blocks immunity to gluten while not affecting systemic immunity. Our results thus provide a rationale for clinical testing of DONQ52 in CeD.

A case of reexpansion pulmonary edema and acute pulmonary thromboembolism associated with diffuse large B-cell lymphoma treated with venovenous extracorporeal membrane oxygenation.

A 37-year-old man diagnosed with diffuse large B-cell lymphoma two weeks previously, visited our emergency department with sudden dyspnea. He had a severe respiratory failure with saturated percutaneous oxygen at 80% (room air). Chest radiography showed a large amount of left pleural effusion. After 1000 mL of the effusion was urgently drained, reexpansion pulmonary edema (RPE) occurred. Despite ventilator management, oxygenation did not improve and venovenous extracorporeal membrane oxygenation (VV-ECMO) was initiated in the intensive care unit. The next day, contrast-enhanced computed tomography showed a massive thrombus in the right pulmonary artery, at this point the presence of pulmonary thromboembolism (PTE) was revealed. Fortunately, the patient's condition gradually improved with anticoagulant therapy and VV-ECMO support. VV-ECMO was successfully discontinued on day 4, and chemotherapy was initiated on day 8. We speculated the following mechanism in this case: blood flow to the right lung significantly reduced due to acute massive PTE, and blood flow to the left lung correspondingly increased, which could have caused RPE in the left lung. Therefore, our observations suggest that drainage of pleural effusion when contralateral blood flow is impaired due to acute PTE may increase the risk of RPE. .

Involvement of Tumor Lymphatic System in Translocation of Intratumorally Injected Liposomes.

The tumor microenvironment is one of the key factors contributing to the efficiency of drug delivery to a tumor. It has been reported that lymphangiogenesis is induced in certain tumors. Because the lymphatic system functions as a drainage one, it is possible that tumor lymphatic vessels alter not only the tumor microenvironment, but also the distribution of drug nanocarriers accumulated in the tumor tissue. Herein, we aimed to elucidate the involvement of the tumor lymphatic system in the translocation of intratumoral liposomes to regional lymph nodes by using vascular endothelial growth factor (VEGF)-C-overexpressing B16F10 tumor-bearing mice (B16/VEGF-C). When the amount of polyethylene glycol (PEG)-modified liposomes in lymph nodes (cervical, brachial, axillary, and inguinal lymph nodes) was measured after the radiolabeled liposomes had been intratumorally injected into B16/VEGF-C-bearing mice or wild-type B16-bearing mice, the accumulation of liposomes in the axillary and inguinal lymph nodes was significantly higher on the tumor-implanted side of B16/VEGF-C-bearing mice than on that of the B16-bearing ones. On the other hand, the accumulation of liposomes in these lymph nodes on the control side (no implantation) of either type of tumor-bearing mice was very low; and no difference could be observed between the 2 sides. Furthermore, the intratumoral distribution of liposomes was observed to be located near the lymphatic vessels. These results indicate that the tumor lymphatic system contributed to the extrusion of a portion of PEG-modified liposomes from the tumor tissue, suggesting that tumor lymphangiogenesis would be one of the key factors to determine the intratumoral distribution of liposomes and their subsequent fate.

Suppression in mice of immunosurveillance against PEGylated liposomes by encapsulated doxorubicin.

PEGylated liposomes (PEG-lip) can escape from recognition by immune system and show a longer half-life in the blood than non-PEGylated liposomes. In this study, we investigated the influence of injected PEG-lip encapsulating doxorubicin (PEG-lip-DOX) on the biodistribution of subsequently injected PEG-lip in mice. PEG-lip-DOX, free doxorubicin or empty PEG-lip were initially injected into BALB/c mice via a tail vein, and 3days later [(3)H]-labeled PEG-lip ([(3)H] PEG-lip) were injected into these same mice. At 24h after the injection, the distribution of [(3)H] PEG-lip in the liver and spleen was significantly reduced in the PEG-lip-DOX group compared with that in the free doxorubicin or PEG-lip group. Consequently, the plasma concentration of [(3)H] PEG-lip was significantly elevated by the pretreatment with PEG-lip-DOX. Altered pharmacokinetics was observed at least until 72h after the injection of [(3)H] PEG-lip. The influence of the injected PEG-lip-DOX on the pharmacokinetics of the subsequently injected [(3)H] PEG-lip was clearly observed from 1 to 14days, and slightly observed on days 21 and 28, after the injection of the PEG-lip-DOX. Flow cytometric analysis showed that the number of liver Kupffer cells was significantly reduced after the treatment with PEG-lip-DOX. On the other hand, a similar alteration in the distribution of the subsequently injected [(3)H] PEG-lip was observed in immunodeficient mice such as BALB/c nu/nu and severe combined immunodeficiency (SCID) mice. These findings suggest that immune cells including liver Kupffer cells responsible for recognizing PEG-lip were selectively damaged by the encapsulated doxorubicin in PEG-lip injected initially, which damage led to prolongation of the half-life of subsequently injected [(3)H] PEG-lip in the blood.