Risk factors of thrombotic recurrence and major bleeding in patients with intermediate-risk for recurrence of venous thromboembolism

Journal of Thrombosis and Thrombolysis - Prolonged anticoagulation therapy is recommended for patients with intermediate-risk for recurrence of venous thromboembolism (VTE). The current study aimed...     

Hepatic follicular dendritic cell sarcoma favorably controlled by transcatheter arterial chemoembolization

A 78-year-old woman with multiple tumors in the liver and spleen was diagnosed with follicular dendritic cell (FDC) sarcoma based on the histological picture of splenectomized specimen and its expression of CD21 and CD 23. As a paraneoplastic immune disorder, Coombs' test was positive although hemolysis was not obvious. Since systemic chemotherapies were ineffective for residual liver tumors, transcatheter arterial chemoembolization (TACE) was performed with subsequent tumor reduction. Currently, the patient is alive 27 months after the diagnosis with residual hepatic tumors favorably controlled by repeated TACE. Our experience suggests that TACE is useful for the management of hepatic FDC sarcoma.     

Hepatic portal venous gas disappearing within 24 hours

Hepatic portal venous gas (HPVG) was detected by CT in a 64-year-old woman who suddenly complained of lower abdominal pain. However, the abdominal symptoms disappeared rapidly, and lower gastrointestinal endoscopy indicated only terminal ileitis. Conservative treatment alone was performed, and HPVG completely disappeared approximately 18 hours later. The use of CT proved to be useful for following the course of HPVG.     

Fourteen-membered ring macrolides inhibit vascular cell adhesion molecule 1 messenger RNA induction and leukocyte migration: role in preventing lung injury and fibrosis in bleomycin-challenged mice

BACKGROUND AND OBJECTIVE: Although the pathogenesis of interstitial pneumonia and pulmonary fibrosis are not well understood, it has been reported that inflammatory cells, especially neutrophils, and the injurious substances produced by them play important roles in the progression of interstitial pneumonia and subsequent fibrosis. Erythromycin and other 14-membered ring macrolides (14-MRMLs) have been reported to improve the survival of patients with diffuse panbronchiolitis by antineutrophil and several other anti-inflammatory mechanisms. The present study was undertaken to investigate the effects of 14-MRMLs on an experimental model of bleomycin-induced acute lung injury and subsequent fibrosis in mice. METHODS: Bleomycin was administered IV to ICR mice. At 28 days after bleomycin injection, fibrotic foci were histologically observed in left lung tissues, and hydroxyproline content in right lung tissues was chemically analyzed. The inhibitory effects of 14-MRMLs were assessed by overall comparison between control (normal saline solution [NS] alone), untreated (bleomycin alone), and treated (bleomycin plus 14-MRMLs) groups. For evaluation of early-phase inflammation, cell populations in BAL fluid and induction of messenger RNA (mRNA) of adhesion molecules (E-selectin, P-selectin, intercellular adhesion molecule 1 [ICAM-1], and vascular cell adhesion molecule 1 [VCAM-1]) in lung tissues were examined at 0 to 13 days after bleomycin treatment. These parameters were also compared with those for the control (NS alone), 14-MRML untreated (bleomycin alone), and 14-MRML pretreated (bleomycin plus 14-MRML pretreated) groups. RESULTS: Bleomycin-induced pulmonary fibrosis was inhibited by erythromycin and other 14-MRMLs on day 28 after bleomycin injection in ICR mice, especially those pretreated with 14-MRMLs. Hydroxyproline content in lung tissues was also decreased in the 14-MRML-pretreated groups. The number of neutrophils in BAL fluid significantly increased, with two peaks at 1 day and 9 days (from 6 to 11 days) after bleomycin administration. 14-MRMLs significantly inhibited both peaks of neutrophil infiltration into the airspace. Changes in mRNA expression of adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1) were associated with leukocyte migration into the airspace. 14-MRMLs clearly inhibited the induction of VCAM-1 mRNA, and tended to attenuate that of ICAM-1 mRNA, but inhibited the induction of neither E-selectin mRNA nor P-selectin mRNA. CONCLUSION: These findings indicate that attenuation of inflammatory cell migration into the airspace by 14-MRMLs, especially of neutrophils and macrophages, resulted in inhibition of lung injury and subsequent fibrosis. 14-MRMLs clearly attenuated the expression of VCAM-1 mRNA during the early phase of bleomycin-induced lung injury, and this might be one mechanism of inhibition of neutrophil and macrophage migration into the airspace by 14-MRMLs. This may be one mechanism of the anti-inflammatory and antifibrotic effects of 14-MRMLs. These findings suggest that prophylactic administration of 14-MRMLs may be clinically efficacious in preventing acute exacerbation of interstitial pneumonia and acute lung injury.     

Combined Use of Dendritic Cells Enhances Specific Antileukemia Immunity by Leukemia Cell-Derived Heat Shock Protein 70 in a Mouse Model with Minimal Residual Leukemia Cells

We have reported that immunotherapy using leukemia cell-derived heat shock proteins (HSPs) is effective against minimal residual disease (MRD) after syngeneic stem cell transplantation (SCT) in mice. However, leukemia patients after SCT are usually immunocompromised and immunologically tolerant to leukemia cells. We investigated whether the use of dendritic cells (DCs) in combination with HSP70 enhances cytotoxicity against B-cell leukemia cell line A20 in mice after syngeneic SCT. All unimmunized mice died of leukemia early after A20 cell inoculation, whereas mice immunized with HSP70 or HSP70-pulsed DCs survived significantly longer. Although only 60% of the HSP70-immunized mice survived, all mice immunized with HSP70-pulsed DCs survived without MRD. In addition, the cytotoxicities against A20 cells for splenocytes from mice immunized with HSP70-pulsed DCs were significantly higher than those of HSP70-immunized mice, and the cytotoxicities against A20 cells were significantly blocked by anti-CD8 antibody and by major histocompatibility complex class I antibody, but not by anti-CD4 antibody. Moreover, abnormalities were detected in neither the biochemical data nor the histopathologic findings. These findings indicate that the combined use of DCs and leukemia cell-derived HSP70 enhances the antileukemia effect by inducing the specific cytotoxicities of CD8+ cytotoxic T-cells, thereby eradicating MRD effectively and safely, even in an immunocompromised state after syngeneic SCT. This approach may thus be useful for further application of HSP in leukemia patients after autologous SCT.     

Role of medial amygdala in controlling hemodynamics via GABA(A) receptor in anesthetized rats.

Experiments were conducted to determine whether the medial amygdala could control hemodynamics through the GABA receptor in anesthetized rats. Bicuculline (10-100pmol), a GABA(A) antagonist, injected into the anterior basomedial amygdala (medial amygdala) produced dose-related increases in blood pressure (BP) and heart rate (HR). Following microinjection of a 100pmol dose, plasma norepinephrine and epinephrine also rose significantly. In a group that had undergone bilateral adrenalectomy, the same dose of bicuculline into the same region of the amygdala caused similar increases in BP and HR to those produced in normal rats. Pretreatment with an intraperitoneal injection of hexamethonium prevented these responses. When bicuculline was given intravenously (100pmol) it failed to effect these cardiovascular changes. Bicuculline-induced hypertension and tachycardia were inhibited by microinjection of muscimol, a GABA agonist, into the anterior basomedial amygdala. The results thus demonstrate that the influence of bicuculline on BP and HR is through action on the anterior basomedial amygdala and direct sympathetic outflow to heart and vascular smooth muscle. There is tonic GABAergic inhibition of sympathetic outflow in the medial amygdala that plays a part in regulating hemodynamics in the limbic system.     

Mild hemophilia A diagnosed at the onset of acute epidural hematoma after lumbar epidural block

The patient was a 36-year-old man who had been aware of a mild bleeding tendency since childhood, but did not show any history of severe bleeding. After lumbar epidural block was performed for pain caused by lumbar disc herniation, the patient developed paraplegia due to an acute epidural hematoma, and rectovesical disorder. He was admitted to our hospital, and wide fenestration and hematoma evacuation were performed. Because of persistent bleeding, reoperation was performed to achieve hemostasis. Although factor VIII antigen was 138%, its activity was decreased to 18% of normal. A diagnosis of cross-reacting material positive mild hemophilia A was made. Postoperative injection of a factor VIII preparation resulted in complete hemostasis. The activated partial thromboplastin time was within normal range. A thrombin generation test showed reduced endogenous thrombin potential, peak thrombin levels, and prolonged time-to-peak levels. The thrombin generation test, which allows comprehensive assessment of the coagulation profile, was useful for diagnosis and treatment of this case.     

Effectiveness of propagermanium treatment in multiple myeloma patients

Interferon (IFN) is one of several drugs effective in treating multiple myeloma (MM), and propagermanium is an IFN inducer. We report on 10 MM patients who were treated with propagermanium at doses from 10 to 40 mg. Two patients achieved complete remission (CR), two patients achieved partial remission (PR), and the condition of four patients was stable (stable disease, SD). After discontinuation of propagermanium, the status of MM progressed in two patients who were in SD and in two patients who had achieved PR. The administration of propagermanium was restarted in one patient resulting in a decrease in her paraprotein.     

From the Cover: PNAS Plus: Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema

Alveolar fluid clearance driven by active epithelial Na⁺ and secondary Cl⁻ absorption counteracts edema formation in the intact lung. Recently, we showed that impairment of alveolar fluid clearance because of inhibition of epithelial Na⁺ channels (ENaCs) promotes cardiogenic lung edema. Concomitantly, we observed a reversal of alveolar fluid clearance, suggesting that reversed transepithelial ion transport may promote lung edema by driving active alveolar fluid secretion. We, therefore, hypothesized that alveolar ion and fluid secretion may constitute a pathomechanism in lung edema and aimed to identify underlying molecular pathways. In isolated perfused lungs, alveolar fluid clearance and secretion were determined by a double-indicator dilution technique. Transepithelial Cl⁻ secretion and alveolar Cl⁻ influx were quantified by radionuclide tracing and alveolar Cl⁻ imaging, respectively. Elevated hydrostatic pressure induced ouabain-sensitive alveolar fluid secretion that coincided with transepithelial Cl⁻ secretion and alveolar Cl⁻ influx. Inhibition of either cystic fibrosis transmembrane conductance regulator (CFTR) or Na⁺-K⁺-Cl⁻ cotransporters (NKCC) blocked alveolar fluid secretion, and lungs of CFTR^−/− mice were protected from hydrostatic edema. Inhibition of ENaC by amiloride reproduced alveolar fluid and Cl⁻ secretion that were again CFTR-, NKCC-, and Na⁺-K⁺-ATPase–dependent. Our findings show a reversal of transepithelial Cl⁻ and fluid flux from absorptive to secretory mode at hydrostatic stress. Alveolar Cl⁻ and fluid secretion are triggered by ENaC inhibition and mediated by NKCC and CFTR. Our results characterize an innovative mechanism of cardiogenic edema formation and identify NKCC1 as a unique therapeutic target in cardiogenic lung edema.Traditionally, the formation of cardiogenic pulmonary edema has been attributed to passive fluid filtration across an intact alveolocapillary barrier along an increased hydrostatic pressure gradient. However, recent studies show that cardiogenic edema is critically regulated by active signaling processes. Activation of mechanosensitive endothelial ion channels increases lung vascular permeability (1), whereas alveolar epithelial cells lose their physiological ability to clear the distal airspaces from excess fluid by their capacity to actively transport ions across the epithelial barrier (2–4).In the intact lung, the predominant force driving alveolar fluid clearance is an active transepithelial Na⁺ transport from the alveolar into the interstitial space. A major portion of the apical Na⁺ entry is mediated by the amiloride-inhibitable epithelial Na⁺ channel (ENaC), with basolateral Na⁺ extrusion through the Na⁺-K⁺-ATPase (5). Cl⁻ and water are considered to follow paracellularly for electroneutrality and osmotic balance. In cardiogenic lung edema, the physiological protection against alveolar flooding provided by an intact alveolar fluid clearance is largely attenuated (3, 4). Previously, we have outlined the signaling events at the alveolocapillary barrier that underlie this inhibition of alveolar fluid clearance by showing that hydrostatic stress increases endothelial NO production in lung capillaries (6), which in turn, blocks alveolar Na⁺ and liquid absorption by a cGMP-dependent inhibition of epithelial ENaC (2).Unexpectedly, however, we observed that increased hydrostatic pressure not only blocks alveolar fluid clearance but reverses transepithelial fluid transport, resulting in effective alveolar fluid secretion that accounts for up to 70% of the total alveolar fluid influx at elevated hydrostatic pressure (2). This effect is not explicable by impaired alveolar fluid clearance and/or passive fluid leakage, and thus, it points to a previously unrecognized and potentially therapeutically exploitable pathomechanism in cardiogenic lung edema, namely alveolar fluid secretion driven by active transepithelial ion transport.Here, we aimed to analyze alveolar fluid secretion and its underlying cellular mechanisms in cardiogenic lung edema. We considered the Cl⁻ channel cystic fibrosis transmembrane conductance regulator (CFTR) as a putative key ion channel in this scenario, because it permits bidirectional permeation of anions under physiologically relevant conditions (7). Hence, the direction of Cl⁻ flux by CFTR may reverse depending on actual electrochemical gradients, thus turning an absorptive into a secretory epithelium or vice versa. This notion is supported by reports describing CFTR as both an absorptive and secretory channel in the regulation of alveolar fluid homeostasis (8, 9). By a combination of indicator dilution, imaging, and radioactive tracer techniques for the measurement of alveolar ion and fluid fluxes in the isolated lung, we show a critical role for CFTR-mediated Cl⁻ secretion in cardiogenic lung edema and identify the Na⁺-K⁺-2Cl⁻ cotransporter 1 (NKCC1) as a therapeutic target in this pathology.     

Fundamental and intensive care of acute pancreatitis

Patients who have been diagnosed as having acute pancreatitis should be, on principle, hospitalized. Crucial fundamental management is required soon after a diagnosis of acute pancreatitis has been made and includes monitoring of the conscious state, the respiratory and cardiovascular system, the urinary output, adequate fluid replacement and pain control. Along with such management, etiologic diagnosis and severity assessment should be conducted. Patients with a diagnosis of severe acute pancreatitis should be transferred to a medical facility where intensive respiratory and cardiovascular management as well as interventional treatment, blood purification therapy and nutritional support are available. The disease condition in acute pancreatitis changes every moment and even symptoms that are mild at the time of diagnosis may become severe later. Therefore, severity assessment should be conducted repeatedly at least within 48 h following diagnosis. An adequate dose of fluid replacement is essential to stabilize cardiovascular dynamics and the dose should be adjusted while assessing circulatory dynamics constantly. A large dose of fluid replacement is usually required in patients with severe acute pancreatitis. Prophylactic antibiotic administration is recommended to prevent infectious complications in patients with severe acute pancreatitis. Although the efficacy of intravenous administration of protease inhibitors is still a matter of controversy, there is a consensus in Japan that a large dose of a synthetic protease inhibitor should be given to patients with severe acute pancreatitis in order to prevent organ failure and other complications. Enteral feeding is superior to parenteral nutrition when it comes to the nutritional support of patients with severe acute pancreatitis. The JPN Guidelines recommend, as optional continuous regional arterial infusion and blood purification therapy.