Decreased Basophil Activation against House Dust Mite after Japanese Cedar Pollen Subcutaneous Immunotherapy: A Retrospective Study.

BACKGROUND: Allergen-specific immunotherapy (AIT), an established treatment for allergic diseases, prevents the development of other allergic manifestations. Although the mechanisms remain unclear, AIT has been shown to reduce basophil activation (BA) against nontarget allergens. OBJECTIVES: The aim of this study was to assess immunological changes in Dermatophagoides farinae (Der f) after Japanese cedar pollen (JCP)-based subcutaneous immunotherapy (SCIT) monotherapy. METHOD: The data of 16 patients (age: 6-37 years) with JCP-induced allergic rhinitis who were sensitive to Der f (serum Der f-specific immunoglobulin E [IgE] level >0.34 kUA/L) and received JCP-based SCIT for 5 years were reviewed retrospectively. BA by Der f and JCP extracts and serum-specific IgE and immunoglobulin G4 (IgG4) levels against these allergens were evaluated before and after completing 5 years of JCP-based SCIT monotherapy. RESULTS: The areas under the dose-response curves of BA by Der f and JCP extracts were significantly reduced (p = 0.02 and p = 0.002, respectively). JCP-specific IgE levels decreased and JCP-specific IgG4 levels increased significantly (p < 0.001 for both), whereas Der f-specific IgE and IgG4 levels did not change significantly. CONCLUSIONS: JCP-based SCIT monotherapy reduced Der f-specific BA. These findings suggest that JCP-based SCIT has the potential to modulate immune response toward nontarget allergens.

Elucidation of the mechanisms underlying tumor aggravation by the activation of stress-related neurons in the paraventricular nucleus of the hypothalamus.

A growing body of evidence suggests that excess stress could aggravate tumor progression. The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the adaptation to stress because the hypothalamic-pituitary-adrenal (HPA) axis can be activated by inducing the release of corticotropin-releasing hormone (CRH) from the PVN. In this study, we used pharmacogenetic techniques to investigate whether concomitant activation of CRHPVN neurons could directly contribute to tumor progression. Tumor growth was significantly promoted by repeated activation of CRHPVN neurons, which was followed by an increase in the plasma levels of corticosterone. Consistent with these results, chronic administration of glucocorticoids induced tumor progression. Under the concomitant activation of CRHPVN neurons, the number of cytotoxic CD8+ T cells in the tumor microenvironment was dramatically decreased, and the mRNA expression levels of hypoxia inducible factor 1 subunit α (HIF1α), glucocorticoid receptor (GR) and Tsc22d3 were upregulated in inhibitory lymphocytes, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Furthermore, the mRNA levels of various kinds of driver molecules related to tumor progression and tumor metastasis were prominently elevated in cancer cells by concomitant activation of CRHPVN neurons. These findings suggest that repeated activation of the PVN-CRHergic system may aggravate tumor growth through a central-peripheral-associated tumor immune system.

Association between Serum Inorganic Phosphorus Levels and Adverse Outcomes in Chronic Kidney Disease: The Fukushima CKD Cohort Study.

Objective Although an association between serum inorganic phosphorus levels and a poor prognosis has been noted in dialysis patients, these associations have been insufficiently reported in non-dialysis-dependent chronic kidney disease (NDD-CKD) patients. This study attempted to determine the association between serum inorganic phosphorus levels and adverse outcomes in Japanese NDD-CKD patients. Methods We investigated the relationships between serum inorganic phosphorus levels and adverse outcomes, such as kidney events, cardiovascular events, and all-cause death, in Japanese NDD-CKD patients using longitudinal data from the Fukushima CKD Cohort Study with a median follow-up period of 2.8 years. The study evaluated 822 patients with NDD-CKD enrolled between June 2012 and July 2014. A kidney event was defined as a combination of doubling of the baseline serum creatinine or end-stage renal disease. Cox regression was performed to analyze the relationships of the quartile of the serum inorganic phosphorus with kidney events, cardiovascular events, and all-cause death. Results The frequency of kidney events per 1,000 person-years exhibited a U-shaped distribution based on serum inorganic phosphorus levels, with these levels not significantly associated with an increased risk of cardiovascular events and all-cause death. A multivariable Cox regression analysis showed an increased risk of kidney events for the highest quartile of the serum inorganic phosphorus levels (≥3.7 mg/dL) versus the second quartile (2.9-3.2 mg/dL, hazard ratio, 3.30; 95% confidence interval, 1.50-7.28; p=0.003). There were no significant associations between the serum calcium levels and adverse outcomes. Conclusion Serum inorganic phosphorus levels were associated with an increased risk of CKD progression in Japanese NDD-CKD patients.

Normal aging induces PD-1-enriched exhausted microglia and A1-like reactive astrocytes in the hypothalamus.

Hypothalamic aging is considered to be critical for systemic aging, and the accumulation of "exhausted glial cells" in the hypothalamus may contribute to brain dysfunction. In this study, we used normal aging mice and investigated aging-specific transcriptional identities of microglia and astrocytes in the hypothalamus. We confirmed that normal aging promoted anxiety, induced impairment of motor coordination and reduced physical strength of muscle in mice. To investigate the senescence of hypothalamic glial cells, we isolated CD11b-positive microglia and ACSA-2-positive astrocytes from the hypothalamus of aged mice using magnetic-activated cell sorting (MACS). The mRNA level of p16INK4A was dramatically increased in the hypothalamic microglia of aged mice compared to young mice. Furthermore, the expression of programmed cell death 1 (PD-1) as well as A1-like astrocyte mediators in the hypothalamic microglia was dramatically induced by aging, indicating that normal aging may produce PD-1-enriched "exhausted microglia" in the hypothalamus. Furthermore, neuroinflammatory A1-like reactive astrocytes with a p16INK4A-positive senescent state were predominantly detected in the hypothalamus of aged mice. Exhausted microglia were also detected in the prefrontal cortex of aged mice, whereas astrocytic neuroinflammation was milder than that observed in the hypothalamus, even with p16INK4A-positive senescence. These results suggest that the production of PD-1-enriched exhausted and senescent microglia and neuroinflammatory A1-like reactive astrocytes in the hypothalamus may partly contribute to aging-related emotional and physical dyscoordination.

Antifibrinolytic Drugs and Allogeneic Transfusion in Pediatric Multilevel Spine Surgery: A Propensity Score Matched Cohort Study.

STUDY DESIGN: Observational cohort study with propensity score matching. OBJECTIVE: Determine whether antifibrinolytic drug use is associated with decreased allogeneic blood transfusion in multilevel pediatric spine surgery. SUMMARY OF BACKGROUND DATA: Antifibrinolytic drugs are commonly used in adult multilevel spine surgery to reduce blood loss and allogeneic transfusion; however, only small studies have examined their efficacy in pediatric patients having multilevel spine surgery. METHODS: Pediatric patients who had posterior multilevel spine surgery between 2016 and 2017 were identified in the national surgery quality improvement program participant use file. Propensity score matching was used to reduce bias from confounding and the rate of intraoperative allogeneic transfusion was compared between patients who received antifibrinolytic drugs and those who did not. Secondary outcomes included intraoperative cell saver volume, postoperative allogeneic transfusion, massive intraoperative transfusion, and adverse events including venous thromboembolism and seizure. RESULTS: A total of 6904 patients underwent posterior multilevel spine surgery during the study period and 83% received antifibrinolytics. The matched cohort included 604 patients. Antifibrinolytic use had no association with reduced intraoperative allogeneic transfusion: odds ratio (OR) = 0.71 (99% confidence interval [CI] = 0.40-1.26, P = 0.12) or cell saver volume, median volume = 114 mL (0, 250 mL) in antifibrinolytic group versus 100 mL (0, 246 mL) in control group, P = 0.04. There was also no association with reduced postoperative allogeneic transfusion OR = 1.23 (99% CI = 0.54-2.81, P = 0.52) or massive transfusion OR = 1.0 (99% CI = 0.34-2.92, P = 1.0). No patient in the matched cohort had a venous thromboembolism or seizure. CONCLUSION: Antifibrinolytic drugs are commonly used in pediatric multilevel spine surgery in the United States, but no efficacy was demonstrated in our study. There were no venous thromboembolisms or seizures implying an excellent safety profile in pediatric patients. LEVEL OF EVIDENCE: 3.

Impact of intraoperative high-volume autologous blood collection on allogeneic transfusion during and after cardiac surgery: a propensity score matched analysis.

BACKGROUND: Perioperative use of allogeneic blood products is associated with higher morbidity, mortality, and hospital costs after cardiac surgery. Blood conservation techniques such as acute normovolemic hemodilution (ANH) report variable success. We hypothesized that large-volume ANH with limited hemodilution would reduce allogeneic blood transfusion compared to the standard practice. STUDY DESIGN AND METHODS: Retrospective observational study of cardiac surgery patients at the University of Maryland Medical Center between January 2014 and September 2017. Using the institutional Society of Thoracic Surgeons database 91 autologous and 981 control patients who underwent coronary artery bypass grafting, aortic valve replacement, or both were identified. After propensity matching of 13 preoperative characteristics, 84 autologous and 84 control patients were evaluated. Our primary endpoint was avoidance of blood transfusion during index hospitalization, and secondary endpoints were postoperative bleeding and major adverse outcomes. RESULTS: The median harvest volumes in the ANH and control groups were 1100 mL and 400 mL, respectively. Of the ANH group, 25% received any transfusion versus 45.2% of the control group after propensity score matching (p < 0.006). When controlling for preoperative platelet count, the transfusion rate ratios for ANH were 0.58 (95% confidence interval, 0.39-0.88) for RBCs and 0.63 (0.44-0.89) for non-RBC components, which were both found to be statistically significant. There was no difference found in major adverse events. CONCLUSION: These results suggest that large-volume ANH is beneficial in reducing both RBC and non-RBC component usage in cardiac surgery. A further prospective validation is warranted.

Supplementation with branched-chain amino acids ameliorates hypoalbuminemia, prevents sarcopenia, and reduces fat accumulation in the skeletal muscles of patients with liver cirrhosis.

BACKGROUND: Liver cirrhosis induces marked metabolic disorders, protein-energy malnutrition, and sarcopenia. The objective of the study reported here was to investigate the effects of dietary branched-chain amino acids (BCAAs) on systemic glucose metabolism, skeletal muscle, and prognosis of patients with liver cirrhosis. METHODS: Japanese patients with liver cirrhosis (n = 21) were enrolled into a longitudinal study in which their diets were supplemented with BCAAs. We evaluated glucose metabolism and analyzed the skeletal muscle area index (SAI) and intramuscular adipose tissue content (IMAC) using computed tomography. RESULTS: After 48 weeks of supplementation with BCAAs, there were no changes in glucose metabolism and skeletal muscle findings. In patients with ameliorated hypoalbuminemia, IMAC was significantly decreased and SAI was preserved concomitant with decreasing 90- and 120-min post-challenge plasma glucose levels (P < 0.01 each). In patients without increased albumin levels, IMAC was significantly increased and the SAI was significantly decreased (P < 0.01 each). Liver-related event-free survival rates for 72 months were 63.6% in patients with decreased IMAC and 20.0% in patients with increased IMAC. CONCLUSIONS: Amelioration of hypoalbuminemia associated with BCAA supplementation correlated with decreased fat accumulation in skeletal muscle, maintenance of skeletal muscle mass, and improved glucose sensitivity, all factors which may contribute to improving the survival of patients with liver cirrhosis.

Prediction of Femoral Neck Strength in Patients with Diabetes Mellitus with Trabecular Bone Analysis and Tomosynthesis Images.

Purpose To determine trabecular bone analysis values by using tomosynthesis images in determining femoral neck strength in patients with diabetes mellitus and compare its parameters between vertebral compression fracture and nonfracture groups. Materials and Methods The institutional review board approved this study, and written informed consent was obtained from all patients. Forty-nine patients with diabetes mellitus were included. Within 1 week, patients underwent dual x-ray absorptiometry (DXA), tomosynthesis, and computed tomography (CT) covering the T10 vertebral body to the hip joints. The trabecular patterns of tomosynthesis images were extracted, and the total strut length, bone volume per tissue volume, and five textural features (homogeneity, entropy, correlation, contrast, and variance) were obtained as the indices of tomosynthesis images. Failure load of the femoral neck, which was determined with the CT-based finite-element method (FEM), was used as the reference standard for bone strength. A forward stepwise multiple regression analysis for evaluating the availability of the tomosynthesis image indices was performed. The bone mineral density (BMD) at DXA and tomosynthesis image indices were compared between the vertebral compression fracture (n = 16) and nonfracture groups (n = 33) according to Genant semiquantitative morphometry methods by using one-way analysis of variance. Results The combination of BMD with the bone volume per tissue volume at the principal tensile group and the correlation at the principal compressive group showed the highest correlation to the failure load at CT FEM, and the correlation (r2 = 0.83) was higher than that between the failure load and the BMD alone (r2 = 0.76; P < .001). The averages of the bone volume per tissue volume and entropy at the principal tensile group in the vertebral compression fracture group were lower than those in the nonfracture group (P = .017 and P = .029, respectively), but there was no difference in BMD. Conclusion Tomosynthesis-based trabecular bone analysis is technically feasible and, in combination with BMD measurements, can potentially be used to determine bone strength in patients with diabetes mellitus. © RSNA, 2016 Online supplemental material is available for this article.

Prognostic significance of pathological response to preoperative chemoradiotherapy in patients with locally advanced rectal cancer.

BACKGROUND: Preoperative chemoradiotherapy (CRT) is widely used in the treatment of locally advanced rectal cancer (LARC). Pathological response to CRT has been shown to be a potential prognostic predictor in rectal cancer patients. The aim of this study was to determine the prognostic significance of pathological response to preoperative CRT in LARC patients. METHODS: Thirty-two patients with LARC were retrospectively analyzed to determine the relationships of pathological response and clinicopathological characteristics to survival outcomes. Patients received CRT with tegafur/uracil and leucovorin. Radiotherapy was administered in fractions of 1.8 Gy/day and 5 days per week. The total dose of radiation delivered was 45 Gy. RESULTS: All patients underwent total mesorectal excision with lymph node dissections after CRT, and resected specimens were examined pathologically. Four patients showed pathological complete response, 14 showed good response, and 14 showed poor response. Pathological complete or good response was associated with longer survival (P = 0.041). Clinicopathological factors excluding gender were not correlated with outcome. No factor was associated with recurrence. CONCLUSION: Pathological response to preoperative CRT may be a useful prognostic predictor in patients with LARC.

Japanese cedar pollen-based subcutaneous immunotherapy decreases tomato fruit-specific basophil activation.

BACKGROUND: Some patients with Japanese cedar pollen (JCP)-induced allergic rhinitis develop pollen-food allergy syndrome (PFAS) as a reaction to tomato fruit. Pollen allergen-specific subcutaneous immunotherapy (SCIT) is reportedly beneficial for some associated food allergies; however, the reported changes in food allergen-specific immunoglobulin (Ig)E and IgG4 levels are inconsistent. Here, we investigated immunologic reactivity to tomato fruit after JCP-based SCIT. METHODS: Twenty-three children (aged 6-17 years) with JCP-induced allergic rhinitis and sensitized to tomato (serum tomato fruit-specific IgE level >0.34 UA/ml) received JCP-based SCIT. Basophil activation by tomato and JCP extracts and serum-specific IgE and IgG4 levels against these allergens were determined before and after 4 or 5 months of maintenance SCIT. Basophil activation was assessed by monitoring CD203c upregulation on flow cytometry. RESULTS: JCP-based SCIT significantly reduced the basophil activation caused by tomato fruit (p = 0.03) and JCP (p < 0.001) extracts. JCP-specific IgG4 levels markedly increased after SCIT (p < 0.001), whereas tomato fruit-specific IgG4 levels did not. After SCIT, no significant changes were observed in specific IgE levels for tomato fruit (p = 0.11) or JCP (p = 0.19). CONCLUSIONS: Tomato fruit-specific basophil activation decreases after JCP-based SCIT, suggesting that it is efficacious in relieving and preventing the symptoms of PFAS in patients with JCP-induced allergic rhinitis.

Effect of Japanese cedar specific immunotherapy on allergen-specific T(H)2 cells in peripheral blood.

BACKGROUND: The involvement of a shift from TH2 to TH1 responses in peripheral blood in pollen subcutaneous immunotherapy (SCIT) has been contentious, partly because of difficulties analyzing antigen-specific TH cells. OBJECTIVES: To use recent technical advances to establish a more direct and simple method to analyze antigen-specific TH cells and to clarify the involvement of a TH2/TH1 shift in peripheral blood in pollen specific immunotherapy. METHODS: After short-term (6-hour) antigen stimulation, antigen-specific TH cells in peripheral blood of Japanese children and young adults with Japanese cedar pollinosis undergoing SCIT were analyzed by multicolor flow cytometry for the presence of the activation marker CD154 and intracellular cytokines. RESULTS: Twenty-eight patients between 5 and 22 years of age were enrolled in the study; 22 had started SCIT after enrolling in the study (SCIT group), and the remaining 6 were planning to start SCIT in the next off-season (control group). The number of Japanese cedar-specific interleukin (IL) 5-, IL-4-, interferon γ-, IL-17A-, IL-10-, and tumor necrosis factor α-producing TH cells without antigen-driven cell proliferation was determined. The seasonal increase in the number of Japanese cedar-specific IL-5- and IL-4-producing TH cells seen in the control group was suppressed in the SCIT group (P < .005 and <.001, respectively). CONCLUSION: We report a powerful method for the analysis of antigen-specific TH cells in peripheral blood. This method will contribute to our understanding of immune mechanisms of immunotherapy and help us develop more sophisticated allergen specific immunotherapy.

Anti-factor IXa Aptamer reduces propagation of thrombin generation in plasma anticoagulated with warfarin.

BACKGROUND: Warfarin is routinely used in the prevention and treatment of prothrombotic events. During initiation of warfarin therapy levels of factor (F) VII and protein C decrease rapidly but prothrombin, FIX and FX decline much slower. Therefore, propagation of thrombin generation (TG) remains unaffected much longer, increasing the risk of inadequate anticoagulation. Recently, a novel agent, anti-IXa aptamer, RB006, has been developed. Therefore, we have evaluated the in vitro effects of this agent in warfarin plasma. METHODS: The investigation consisted of two parts. First, a computer simulated time course of TG with warfarin alone and in combination with FIXa inhibition was evaluated and, second, normal volunteer, protein C deficient, FVII deficient and commercial warfarin plasmas (INR 2.1 and 3.1) were spiked with increasing concentrations of aptamer (0-24 microg/ml) and its anticoagulant effects were evaluated using prothrombin time (PT), activated partial thromboplastin time (aPTT) and TG with tissue factor and Actin as activators. Direct effects of aptamer on protein C were also evaluated. RESULTS: Simulation of coagulation during warfarin induction showed that TG can be significantly delayed and decreased by inhibiting FIXa (i.e., with anti-FIXa aptamer). The anti-FIXa aptamer inhibited TG in all tested plasmas, but was most efficacious in warfarin and FVII deficient plasma. The aptamer itself did not inhibit protein C and had no effect on PT, but concentration-dependently increased aPTT. CONCLUSION: The anti-FIXa aptamer potentiates the inhibitory effects of warfarin on TG, and may fill the need as an adjuvant agent during initiation of warfarin therapy.

Prothrombin complex concentrate versus recombinant factor VIIa for reversal of hemodilutional coagulopathy in a porcine trauma model.

BACKGROUND: Fluid resuscitation after traumatic injury may necessitate coagulation factor replacement to prevent bleeding complications of dilutional coagulopathy. Recombinant activated factor VII (rFVIIa) is being widely investigated as a hemostatic agent in trauma. Multicomponent therapy with prothrombin complex concentrate (PCC) containing coagulation factors II, VII, IX, and X might offer potential advantages. METHODS: Anesthetized mildly hypothermic normotensive pigs were hemodiluted by substituting 65% to 70% of total blood volume in phases with hydroxyethyl starch and red cells. Thereafter, animals received 12.5 mL . kg isotonic saline placebo, 35 IU . kg PCC, or 180 microg x kg rFVIIa. Immediately afterward, a standardized spleen injury was inflicted, and prothrombin time (PT) and hemostasis were assessed. Thrombin generation was also determined. RESULTS: Hemodilution depleted levels of factors II, VII, IX, and X markedly, prolonged PT and decreased thrombin formation. PCC and rFVIIa both fully normalized the hemodilution-induced lengthening of PT. In PCC recipients, peak thrombin generation was greater by a median of 60.7 nM (confidence interval 56.4-64.9 nM) compared with the rFVIIa group (p = 0.008). After spleen trauma, time to hemostasis was shortened to a median of 35 minutes in animals treated with PCC versus 94 minutes with rFVIIa (p = 0.016). CONCLUSIONS: In a pilot study involving an in vivo large-animal model of spleen trauma, PCC accelerated hemostasis and augmented thrombin generation compared with rFVIIa. Further investigations are warranted on PCC as a hemostatic agent in trauma.

[A case of hyperammonemia with encephalopathy related to FOLFIRI chemotherapy for advanced colon cancer].

A 50-year-old man undergoing operations for sigmoid colon cancer, small intestine invasion, and liver metastasis was given adjuvant chemotherapy postoperatively. During the course, lung, brain and bone metastasis were found, FOLFIRI therapy was started. Fifth FOLFIRI therapy was performed, but on the night of the next day, he was transported on an emergency basis to our hospital because of a coma. Laboratory examination revealed hyperammonemia, so aminoleban was started for its treatment. After 3 days in the hospital, consciousness and serum ammonia were improved. Cases of hyperammonemia caused by 5-FU have been reported in the literature, and this case was diagnosed with the same. Hyperammonemia should be taken into account as a differential diagnosis in the disturbance of consciousness in chemotherapy.

Prophylactic therapy for patients with reproductive failure who were positive for anti-phospholipid antibodies.

PROBLEM: To elucidate the efficacy of the treatment using a Japanese-modified Chinese herbal medicine, Sairei-to, and low-dose aspirin with or without a corticosteroid hormone for the patients with adverse pregnancy histories positive for anti-phospholipid antibodies. METHOD OF STUDY: Fifteen cases positive for anti-phospholipid antibodies, who had experienced preterm delivery in which an extremely low birthweight infant (<1000 g) was born as a result of intrauterine growth restriction with or without severe preeclampsia, were treated with the medication according to the current protocol. Four cases with the same condition, who were treated with only low-dose aspirin, or without medication, were chosen as a control population. The pregnancy outcome was compared between the two groups. RESULTS: The rate of patients in whom the next pregnancy continued until the 36th week of gestation or later was significantly higher in treated patients (80.0%) compared with the control population (0%). CONCLUSIONS: In this series, we obtained case report data that Sairei-to may provide some benefit for patients with reproductive disorders positive for anti-phospholipid antibodies; however, randomized controlled trial evidence is needed before current treatment can be recommended.

In vivo platelet redistribution and acute transient thrombocytopenia after eptifibatide injection in baboons.

BACKGROUND: The occurrence of thrombocytopenia has been reported during clinical eptifibatide (Integrilin) therapy, but the exact mechanism is not yet established to explain the varied duration and severity of thrombocytopenia associated with glycoprotein (GP) IIb/IIIa inhibitors. We assessed the redistribution of platelets in juvenile baboons during acute transient thrombocytopenia that was observed after eptifibatide injection. METHODS: Eptifibatide was administered intravenously to eight baboons by infusion at 20 microg/kg/min or a bolus injection of 10 mg. Platelet distribution was measured with a gamma scintillation camera using 111In-labeled autologous platelets. Platelet function and GP IIb/IIIa receptor inhibition were evaluated using the Plateletworks system. The effects of pretreatment with abciximab (0.4 mg/kg) or human immunoglobulin concentrate (0.75 g/kg) were also investigated. RESULTS: Eptifibatide, administered as an infusion or a bolus, caused transient thrombocytopenia with uptake of platelets predominantly by the liver. The recovery of platelet aggregation was associated with the re-entry of platelets from the liver into the systemic circulation. Pretreatment with either abciximab (0.4 mg/kg) or human intravenous immunoglobulin (IVIG, 0.75 g/kg) attenuated eptifibatide-induced thrombocytopenia and the hepatic uptake of radiolabeled platelets. CONCLUSION: Acute thrombocytopenia after eptifibatide injection was caused by the transient redistribution of platelets to the liver. Attenuation of the decrease in platelet count and hepatic sequestration by abciximab and IVIG suggests that thrombocytopenia may have been caused by ligand-induced binding site antigen induction and recognition by the reticuloendothelial system.

Evaluation of a novel kallikrein inhibitor on hemostatic activation in vitro.

BACKGROUND: DX-88 is a potent kallikrein inhibitor that is being studied for the treatment of hereditary angioedema (HAE) and represents a potential alternative to aprotinin in cardiac surgical patients. The current study was designed to evaluate in vitro effects of DX-88 on coagulation in comparison with aprotinin. METHODS: Blood samples were obtained from consented 12 healthy volunteers. DX-88 or aprotinin was added to blood at 200 and 800 kallikrein inhibitory units (KIU) per milliliter for aprotinin, and at 1.1, 2.2, or 8.8 microg/ml for DX-88. Thromboelastography (TEG) was performed using celite, kaolin, or tissue factor (TF) activation. Kaolin-based activated clotting times (ACTs) were measured at different heparin levels. The whole blood prothrombin time (PT)/PTT values were also measured. The endogenous thrombin generation was assessed with a fluorogenic assay using platelet-poor plasma (PPP). RESULTS: With celite and kaolin activation of TEG, the reaction time was prolonged with DX-88 and aprotinin. With tissue factor activation, TEG parameters were not affected. DX-88 caused dose-dependent kaolin-ACT prolongation that was augmented by increasing doses of heparin. DX-88 or aprotinin had no significant effects on the PT values, but PTT values were dose-dependently prolonged. Both agents delayed the onset of thrombin generation when PTT reagent was used as a trigger, whereas no change was observed when tissue factor was used. CONCLUSION: We found that DX-88 delayed contact activator induced coagulation without affecting tissue factor mediated coagulation. For evaluation of coagulation during DX-88 therapy, the use of PT or tissue factor-activated TEG may be preferable.

Effect of sairei-to combined with aspirin and prednisolone on four recurrent reproductive failure women who are positive for anti-phospholipid antibodies.

We treated four pregnancy cases positive for antiphospholipid antibodies (APLs) who had experienced recurrent second trimester fetal or neonatal losses using a Japanese modified Chinese herbal medicine, Sairei-to, low dose aspirin and adrenocorticosteroid hormone. The clinical courses of their new pregnancies in conjunction with the dynamic changes in their APL titers are described in this paper, and the possible efficacy of this treatment is discussed. The concept that autoimmune abnormalities, especially positive APLs, are generative factors for a range of reproductive failures, such as recurrent abortions, intrauterine growth retardation, intrauterine fetal death and preeclampsia, is now attracting a great deal of attention in the fields of reproductive immunology and perinatal medicine (Yasuda et al., 1995). The main mechanisms in the generation of reproductive failures are considered to be direct damage to chorionic villi by APLs during the period of placentation (Rote et al., 1998), as well as the formation of thrombi intervillous spaces (Arakawa et al., 1999). Considering these mechanisms of the reproductive failure generation by APLs, the application of immune suppressive therapy in combination with anti-coagulation therapy should be reconsidered as a treatment option. In this context, we treated four pregnancy cases positive for APLs who had experienced recurrent second trimester fetal or neonatal losses using a Japanese modified Chinese herbal medicine, Sairei-to, low dose aspirin and an adrenocorticosteroid hormone.