A new heparin fragment decreases liver ischemia-reperfusion injury

<正>To the Editor:Ischemia-reperfusion injury following surgery and transplantation can lead to irreversible multiorgan failure.Intracellular calcium overload is associated to cellular death during ischemiareperfusion.A recently discovered heparin fragment (HF),trisulfated disaccharide (TD),that acts on sodium-calcium exchanger(NCX) decreasing intracellular Ca²⁺,showed effectiveness on protecting hepatocytes from ischemia-reperfusion injury [1],     

Imaging evaluation of suspected pulmonary embolism.

Venous thromboembolism (VTE) is a common disorder that is difficult to diagnose clinically but carries significant morbidity and mortality if untreated. Additionally, although demonstrated to be of benefit in cases of proven deep vein thrombosis (DVT) and pulmonary embolism (PE), anticoagulation therapy is not without risk. Because the clinical exam is known to be unreliable for the detection of both DVT and PE, many imaging modalities have been used in the diagnostic imaging algorithm for the detection of VTE, including chest radiography, ventilation/perfusion (V/Q) scintigraphy, pulmonary angiography, and recently, spiral computed tomography (CT) and magnetic resonance imaging (MRI). Chest radiographic findings in acute PE include focal oligemia, vascular enlargement, atelectasis, pleural effusions, and air space opacities representing pulmonary hemorrhage or infarction. The chest radiograph can occasionally be suggestive of PE but is more often nonspecifically abnormal. The main use of the chest radiograph in the evaluation of suspected PE is to exclude entities that may simulate PE and to assist in the interpretation of V/Q scintigraphy. Lower extremity venous compression ultrasonography (CU) is both sensitive and specific for the diagnosis of femoropopliteal DVT, and the value of negative CU results has been established in outcomes studies. However, the reliability of CU for the detection of isolated calf vein thrombosis is not well established, and the clinical significance of such thrombi is debatable. Additional methods such as color and spectral Doppler analysis are also useful in the diagnostic evaluation of DVT but are best considered as adjuncts to the conventional CU examination rather than as primary diagnostic modalities themselves. Compression ultrasonography and Doppler techniques are useful in the evaluation of suspected upper extremity DVT; spectral Doppler waveform analysis is particularly useful to assess for the patency of veins that cannot be directly visualized and compressed with conventional gray-scale sonography. V/Q scintigraphy has been the initial modality obtained in patients suspected of PE for a number of years. Although many studies have investigated the role of V/Q scintigraphy in the evaluation of VTE, the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study has provided the most useful information regarding the utility of V/Q scintigraphy in this setting. A high probability scan interpretation is sufficient justification to institute anticoagulation, and a normal perfusion scan effectively excludes the diagnosis of PE. A normal/near normal scan interpretation also carries a sufficiently low prevalence of angiographically proven PE to withhold anticoagulation. Although the prevalence of PE in the setting of low probability scan interpretations is low and several outcomes studies have demonstrated a benign course in untreated patients with low probability scan results, patients with inadequate cardiopulmonary reserve do not necessarily have good outcomes. Such patients deserve more aggressive evaluation. Patients with intermediate probability scan results have a 20% to 40% prevalence of angiographically proven PE and thus require further investigation. The radionuclide investigation of DVT includes such techniques as radionuclide venography and thrombus-avid scintigraphy. Although these methods have not been as thoroughly evaluated as CU, studies thus far have indicated encouraging results, and further investigations are warranted. Pulmonary angiography has been the gold standard for the diagnosis of PE for decades. Studies have indicated that angiography has probably been underutilized by referring physicians for the evaluation of suspected PE, likely because of the perception of significant morbidity and mortality associated with the procedure. (ABSTRACT TRUNCATED)     

Heparin inhibits bovine testicular hyaluronidase activity in myocardium of dogs with coronary artery occlusion

Bovine testicular hyaluronidase (BTH) reduces experimental myocardial infarct size and ameliorates electrocardiographic signs of ischemia. This study was done to determine if heparin, an in vitro inhibitor of hyaluronidase activity, blocks the action of BTH in the myocardium of dogs after coronary artery occlusion. BTH was administered intravenously as 5,000 NF units/kg at 0.5 and 2.5 hours after coronary occlusion. Heparin was administered intravenously as a 150-unit/kg loading dose, followed by 10 units/kg per hour i.v., beginning 15 minutes before coronary occlusion. The area of myocardial ischemia at risk was assessed by a radiolabeled microsphere technique; the area that developed necrosis was assessed by a histochemical technique. In vivo activity of BTH was assessed by a colorimetric analysis of the BTH substrate, i.e., hyaluronic acid (HA), extracted from myocardial tissue. For biochemical analysis of HA, the heart was divided into anterior myocardium, which included ischemic tissue and posterior nonischemic myocardium. The myocardial HA content of dogs treated with BTH plus heparin (anterior, 3.44 +/- 0.40 micrograms HA/mg protein; posterior, 3.69 +/- 0.33 micrograms HA/mg protein) was not significantly different from control (anterior, 3.61 +/- 0.29 micrograms HA/mg protein; posterior, 3.55 +/- 0.23 micrograms HA/mg protein). In contrast, BTH lowered myocardial HA content (anterior, 2.16 +/- 0.21 micrograms HA/mg protein; posterior, 2.08 +/- 0.14 micrograms HA/mg protein) compared with either BTH plus heparin or control groups in both anterior myocardium (p = 0.006) and posterior myocardium (p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Primary tumor cells of myeloma patients induce interleukin-6 secretion in long-term bone marrow cultures

Long-term bone marrow cultures (LTBMC) from patients with multiple myeloma (MM) and normal donors were analyzed for immunophenotype and cytokine production. Both LTBMC adherent cells from myeloma and normal donor origin expressed CD10, CD13, the adhesion molecules CD44, CD54, vascular cell adhesion molecule 1, very late antigen 2 (VLA-2), and VLA- 5, and were positive for extracellular matrix components fibronectin, laminin, and collagen types 3 and 4. LTBMC from myeloma patients and normal donors spontaneously secreted interleukin-6 (IL-6). However, levels of IL-6 correlated with the stage of disease; highest levels of IL-6 were found in LTBMC from patients with active myeloma. To identify the origin of IL-6 production, LTBMC from MM patients and normal donors were cocultured with BM-derived myeloma cells and cells from myeloma cell lines. IL-6 was induced by plasma cell lines that adhered to LTBMC such as ARH-77 and RPMI-8226, but not by nonadhering cell lines U266 and FRAVEL. Myeloma cells strongly stimulated IL-6 secretion in cocultures with LTBMC adherent cells from normal donors and myeloma patients. When direct cellular contact between LTBMC and plasma cells was prevented by tissue-culture inserts, no IL-6 production was induced. This implies that intimate cell-cell contact is a prerequisite for IL-6 induction. Binding of purified myeloma cells to LTBMC adherent cells was partly inhibited by monoclonal antibodies against adhesion molecules VLA-4, CD44, and lymphocyte function-associated antigen 1 (LFA-1) present on the plasma cell. Antibodies against VLA-4, CD29, and LFA-1 also inhibited the induced IL-6 secretion in plasma cell-LTBMC cocultures. In situ hybridization studies performed before and after coculture with plasma cells indicated that LTBMC adherent cells produce the IL-6. These results suggest that the high levels of IL-6 found in LTBMC of MM patients with active disease are a reflection of their previous contact with tumor cells in vivo. These results provide a new perspective on tumor growth in MM and emphasize the importance of plasma cell-LTBMC interaction in the pathophysiology of MM.     

Purging of acute myeloid leukemic cells by ether lipids and hyperthermia

Ether lipids (EL) and hyperthermia have been shown to possess a relatively selective cytotoxicity to leukemic cells. In this study, the combined effects of EL (ET-18-OCH3, ET-16-NHCOCH3, or BM 41.440) and hyperthermia on the growth of hematopoietic progenitors, myeloid leukemic cell lines, and leukemic cells obtained from patients with acute myeloid leukemia (AML) were examined to determine if this combination resulted in a greater selective killing of leukemic cells than that achieved by either EL or heat alone. When the cells were treated simultaneously with EL (50 micrograms/mL) and hyperthermia (42 degrees C) for one hour, the killing of leukemic cell line cells was enhanced considerably. Among the three EL, however, the combination of ET-18-OCH3 and heat seemed to be the most cytotoxic to leukemic cell line cells with no effect on the growth of hematopoietic progenitors. An increase in the duration of treatment with ET-18-OCH3 to four hours with heat added during the last hour resulted in a further reduction of leukemic cell line cells while sparing 50% of hematopoietic progenitors after cryopreservation. The combined treatment with ET-18-OCH3 and heat also inhibited the growth of leukemic progenitors obtained from AML patients by 97% to 100%. These data indicate that the combined treatment with EL and hyperthermia might offer an efficient means to eliminate myeloid leukemic cells in vitro.