Oral mite anaphylaxis caused by mite-contaminated okonomiyaki/ pancake-mix in Japan: 8 case reports and a review of 28 reported cases.

BACKGROUND: Anaphylaxis after the ingestion of foods contaminated with mites has recently been recognized. Case series and case reports thus far have shown that mite-contaminated wheat flour is the major cause of oral mite anaphylaxis. However, we have found 8 cases of oral mite anaphylaxis which were caused by mite-contaminated okonomiyaki-mix, a savory Japanese style pancake mix, in our hospital. METHODS: In addition to our 8 cases, the databases of MEDLINE and ICHUSHI were systematically searched for patients with oral mite anaphylaxis in Japan. RESULTS: Thirty-six patients including our 8 cases with oral mite anaphylaxis were identified. Thirty-four out of 36 cases (94%) ingested okonomiyaki or takoyaki, prepared at home using okonomiyaki-mix or takoyaki-mix which was previously opened and stored for months at ambient temperature. Microscopic examination of culprit mixes of 16 cases including our 1 case revealed contamination of mites such as Dermatophagoides farina (Der f) (5 cases), Tyrophagus putrescentiae (Tyr p) (4 cases), and Dermatophagoides pteronyssinus (Der p) (3 cases). The specific IgE to each mite is generally upregulated in these patients. Especially, the titers of specific IgE to Der p and Der f were more than class 2 in all cases. CONCLUSIONS: Mite-contaminated flavored flour is the major cause of oral mite anaphylaxis in Japan.

Markers for step-down of inhaled corticosteroid therapy in adult asthmatics.

BACKGROUND: Treatment guidelines recommend the use of inhaled corticosteroids (ICS) as first-line therapy for all stages of persistent asthma. However, it is unknown whether ICS dose reduction in adult asthmatics is compatible with maintaining asthma control. Moreover, there are no predictors of efficacy in maintaining asthma control upon ICS reduction. METHODS: We recruited 90 adult patients with moderate or severe asthma but no clinical symptoms of asthma for at least 6 months. All patients reduced their ICS doses by half but continued taking other asthma-related medications. As a primary outcome, we measured asthma exacerbations during the 12 months following ICS reduction. We also further monitored patients from the above study who had maintained total asthma control for 12 months after ICS reduction and who had continued on their reduced doses of ICS or had further reduced, or stopped, their ICS. RESULTS: Forty of ninety patients (44.4%) experienced exacerbations after ICS reduction (time to first exacerbation: 6.4 ± 3.6 months). Multivariate logistic regression modeling revealed a rank order of predictors of success in ICS reduction while retaining asthma control: acetylcholine (ACh) PC(20) (p < 0.01); length of time with no clinical symptoms before ICS reduction (p < 0.01); FeNO (p = 0.028); and forced expiratory volume in 1 s (FEV(1); % predicted) (p = 0.03). Finally thirty-nine of 50 patients maintained total asthma control for at least 2 years after the initial ICS reduction. CONCLUSIONS: In asthma patients with normalized AChPC(20) of 20mg/mL or 10mg/mL and no clinical symptoms for at least 12 or 24 months it may be possible to successfully reduce ICS without increasing exacerbations for long time.

[Survey of levels of asthma control among Japanese patients in general practice].

BACKGROUND: The purpose of this study was to investigate the levels of asthma control in Japanese adult patients in general practice. METHODS: 11490 Japanese patients with adult asthma who were treated by primary care physicians were enrolled. The treatment steps and levels of asthma control were determined according to the Japanese Asthma Prevention and Management Guideline 2009. In addition, patient satisfaction with asthma management was scored from 0 (dissatisfied) to 10 (fully satisfied). RESULTS: Inhaled corticosteroids were administered to 90.9% of patients. Of 11490 patients, the percentage of patients undergoing treatment steps 1, 2, 3, and 4 were 41.8%, 31.7%, 28.4%, and 22.1%, respectively. The average scores of satisfaction with asthma treatment in treatment steps 1, 2, 3, and 4 were 7.83, 7.68, 7.62 and 7.46, respectively. CONCLUSIONS: Although a large number of patients were treated with inhaled corticosteroids and the rate of satisfaction with asthma management was high in all treatment steps, asthma was poorly controlled in this study. This dissociation was considered to be due to low patient's own goals of asthma treatment.

[Clinical survey to understand real asthma life for patients-I].

BACKGROUND: Although several studies investigate the level of asthma control, real asthma life for patients, factors that influence on patients satisfaction, and reasons for irregular visit have not been studied in Japan. METHODS: One thousand and two hundreds patients with adult asthma were studied by internet-based questionnaire from March 25th to 31st in 2009. Satisfaction for asthma management was scored from 0 to 10 and then divided into three groups, such as high (10-8), middle (7-4), and low (3-0) groups. Major questions for these patients were precise explanations on diagnosis of asthma, goal of the treatment, and treatment with medications by the doctors. Furthermore, factors that might have influences on non-adherence and irregular visit by patients were investigated. RESULTS: Severity of the patients enrolled into this study was 34.8% in mild asthma, 19.2% in moderate asthma, and 7.8% in severe asthma. 81.6% of patients were treated with inhaled corticosteroids or combination of inhaled corticosteroid and long acting inhaled beta(2)-agonist. The average score for satisfaction of patients was 6.83 and satisfaction of patients was 43.2% in high, 48.9% in middle, and 7.9% in low group. Patients with low satisfaction group had not been precisely explained the diagnosis of asthma, goal of the treatment, and treatment with medications by the doctors. Less non-adherence and low number of irregular visits were observed in patients with high satisfaction group. CONCLUSION: Although this study was performed by internet-based questionnaire and might not reflect the real management of asthma in Japan, the lower the satisfaction, the less patients received explanations on the diagnosis of asthma, goal of the treatment, and treatment with medications by the doctors. Therefore, explanations for these factors may have great influences on non-adherence and irregular visits in patients with asthma.

Intermittent hypoxia reverses the diurnal glucose rhythm and causes pancreatic beta-cell replication in mice.

Obstructive sleep apnoea (OSA) and type 2 diabetes frequently co-exist and potentially interact haemodynamically and metabolically. However, the confounding effects of obesity have obscured the examination of any independent or interactive effects of the hypoxic stress of OSA and the hyperglycaemia of type 2 diabetes on haemodynamic and metabolic outcomes. We have developed a chronically catheterized, unhandled, lean murine model to examine the effects of intermittent hypoxic (IH) exposure and exogenous glucose infusion on the diurnal pattern of arterial blood pressure and blood glucose, as well as pancreatic beta-cell growth and function. Four experimental groups of adult male C57BL/J mice were exposed to 80 h of (1) either IH (nadir of inspired oxygen 5-6% at 60 cycles h(-1) for 12 h during light period) or intermittent air (IA; control) and (2) continuous infusion of either 50% dextrose or saline (control). IH exposure during saline infusion caused a sustained increase in arterial blood pressure of 10 mmHg (P < 0.0001), reversed the normal diurnal rhythm of blood glucose (P < 0.03), doubled corticosterone levels (P < 0.0001), and increased replication of pancreatic beta-cells from 1.5 +/- 0.3 to 4.0 +/- 0.8% bromodeoxyuridine (BrdU)-positive) beta-cells. The combined stimulus of IH exposure and glucose infusion attenuated the hypertension, exacerbated the reversed diurnal glucose rhythm, and produced the highest rates of apoptosis in beta-cells, without any additive effects on beta-cell replication. We conclude that, in contrast to the development of sustained hypertension, IH impaired glucose homeostasis only during periods of hypoxic exposure. IH acted as a stimulus to pancreatic beta-cell replication, but the presence of hyperglycaemia may increase the hypoxic susceptibility of beta-cells. This model will provide a basis for future mechanistic studies as well as assessing the metabolic impact of common comorbities in OSA, including obesity, insulin resistance and type 2 diabetes.

Activated protein C attenuates leukocyte elastase-induced lung injury in mice.

Leukocyte elastase (LE), a neutrophil serine protease, is known to cause alveolar wall destruction and alveolar hemorrhage in the lung, but recent evidence suggests that it may also produce a significant inflammatory response. The purpose of the current study was to (1) examine the relationship between LE-induced lung injury and specific markers of inflammation and cytokine/chemokine, and to (2) determine the potential of activated protein C (APC), a potent immunomodulator, to block the inflammatory response to LE. We treated the C57BL/6 mice with LE (10 U/kg, i.t.) and assessed the lung inflammation over 72 h. Total cells, total protein, and neutrophils were increased and peaked at 16 h in bronchial alveolar lavage fluid. Macrophages were also increased and peaked at 24 h. Administration of LE up-regulated the synthesis of proinflammatory cytokines, IL-1beta and IL-6, chemokines, keratinocyte-derived chemokine, and macrophage inflammatory protein 2 in bronchial alveolar lavage fluid, and their peaks were at 6 h. Furthermore, the mice were treated with APC at 0.2, 2.0, and 10 mg/kg (i.v.) after instillation of LE. Therapeutic treatment of APC at 2.0 and 10 mg/kg significantly attenuated the increases in all these parameters. Lung histology revealed that, in addition to inflammation, alveolar hemorrhage and alveolar wall destruction induced by LE were also attenuated by APC. Finally, the expression of tissue plasminogen activator and plasminogen activator inhibitor in whole lung of mice exposed to LE, detected by means of reverse-transcriptase-polymerase chain reaction, were not influenced by the treatment with APC. These data demonstrate that intratracheal administration of LE to mice causes a transient inflammatory response, and APC can play a protective role against LE-induced lung injury.

[Advocating the diagnostic criteria for early stage of asthma].

BACKGROUND: In asthmatic patients, first asthmatic symptoms are not often typical. In those cases, it takes long time before asthma diagnosis, and the severities are progressed in some patients. For early intervention, we tried to make the diagnostic criteria for asthma, which are useful to diagnose as early stage of asthma. METHODS: Three hundred and eighty eight of asthmatic patients, who were recorded first their symptoms in asthma, were enrolled. Their first symptoms and examinations were analyzed. RESULTS: In first asthmatic symptoms, 79% of patients had cough, 68% patients had wheezing, 49% patients had dyspnoea, and 15% of patients did not have typical asthmatic symptoms in the early stage. The percentages of abnormal in first examinations were 99% in airway hypersensitivity, 92% of low %V25, 82% of eosinophila in sputum and 77% of low %V50. Low FEV1% and reversible airway obstruction were not seen in a lot of patients. CONCLUSION: We advocate that the diagnostic criteria for early stage of asthma are the following three elements. First criterion is spasmodic cough, wheezing and dyspnoea. Second criterion is airway hypersensitivity, or over 3% of eosinophils in sputum, or under 70% of %V50, or under 50% of %V25, or effect of bronchodilator. Effect of bronchodilator will be required, when the symptom is cough only. Third criterion is the exclusion of other lung and heart diseases.

[Adrenal effect of inhaled corticosteroids in adult asthmatic patients].

Inhaled corticosteroids (ICS) are usually well tolerated with smaller systemic effects than intravenous steroids, however, when the dose is high the likelihood of steroid-related systemic side effects like hypothalamic pituitary adrenal (HPA) axis suppression and osteoporosis are reported. We reviewed HPA axis suppression related to different ICS characteristics by affinity to steroid receptor and their pharmacokinetics, and also reviewed by randomized, controlled clinical trials. Within the approved dosages for each ICS in Japan, HPA axis suppression is basically minimal and clinically negligible.

Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure.

BACKGROUND: C-reactive protein (CRP) and interleukin (IL)-6 are important risk factors for atherosclerosis and coronary heart disease. In the present study, we examined serum levels of CRP and IL-6, IL-6 production by monocytes, and the effect of nasal continuous positive airway pressure (nCPAP) in patients with obstructive sleep apnea syndrome (OSAS). METHODS AND RESULTS: After polysomnography, venous blood was collected at 5 AM from 30 patients with OSAS and 14 obese control subjects. Serum levels of CRP and IL-6 and spontaneous production of IL-6 by monocytes were investigated. In addition, the effects of 1 month of nCPAP were studied in patients with moderate to severe OSAS. Levels of CRP and IL-6 were significantly higher in patients with OSAS than in obese control subjects (CRP P<0.001, IL-6 P<0.05). IL-6 production by monocytes was also higher in patients with OSAS than in obese control subjects (P<0.01). In patients with OSAS, the primary factors influencing levels of CRP were severity of OSAS and body mass index and those influencing levels of IL-6 were body mass index and nocturnal hypoxia. nCPAP significantly decreased levels of both CRP (P<0.0001) and IL-6 (P<0.001) and spontaneous IL-6 production by monocytes (P<0.01). CONCLUSIONS: Levels of CRP and IL-6 and spontaneous production of IL-6 by monocytes are elevated in patients with OSAS but are decreased by nCPAP. Therefore, OSAS is associated with increased risks for cardiovascular morbidity and mortality, and nCPAP may be useful for decreasing these risks.

Fatal complication of Legionella pneumophila pneumonia in a tocilizumab-treated rheumatoid arthritis patient.

We herein report a fatal case of Legionella pneumophila pneumonia in a tocilizumab-treated rheumatoid arthritis patient who was in a state of shock on admission but remained afebrile even during severe pneumonia. Legionella antigen was detected in the urine and neutrophil CD64 expression was highly elevated. Despite undergoing intensive treatment, the patient developed sepsis and died 12 days after admission. An autopsy indicated that while the Legionella infection had almost been controlled, a subarachnoid hemorrhage was the ultimate cause of death.

Elevated production of tumor necrosis factor-alpha by monocytes in patients with obstructive sleep apnea syndrome.

STUDY OBJECTIVES: Tumor necrosis factor (TNF)-alpha is involved in the pathogenesis of atherosclerosis. In the present study, we examined TNF-alpha production by monocytes, serum levels of TNF-alpha, and the effects of nasal continuous positive airway pressure (nCPAP) in patients with obstructive sleep apnea syndrome (OSAS). DESIGN: Prospective observational study. SETTING: University hospital. SUBJECTS: Twenty-four patients with OSAS, 15 obese control subjects, and 12 healthy subjects. MEASUREMENTS AND RESULTS: After polysomnography, venous blood was collected at 5 am. Spontaneous production of TNF-alpha by monocytes for 24 h and serum levels of TNF-alpha were investigated. In addition, patients with moderate-to-severe OSAS were treated with nCPAP for 1 month, and spontaneous production of TNF-alpha by monocytes and serum levels of TNF-alpha were also measured. Spontaneous production of TNF-alpha by monocytes was significantly higher in patients with moderate-to-severe OSAS than in patients with mild OSAS (p < 0.0001), obese control subjects (p < 0.0001), or healthy subjects (p < 0.0001). Serum levels of TNF-alpha were also significantly higher in patients with moderate-to-severe OSAS than in patients with mild OSAS (p < 0.03), obese control subjects (p < 0.0005), or healthy subjects (p < 0.0001). Duration of hypoxia during total sleep time was independently associated with spontaneous production of TNF-alpha by monocytes in patients with OSAS and healthy and obese control subjects. nCPAP significantly decreased spontaneous production of TNF-alpha by monocytes (p < 0.03) and serum levels of TNF-alpha (p < 0.05) in patients with moderate-to-severe OSAS. CONCLUSIONS: Spontaneous production of TNF-alpha by monocytes and serum levels of TNF-alpha are elevated in patients with moderate-to-severe OSAS but are decreased by nCPAP.

Reduction of eosinophilic inflammation in the airways of patients with asthma using montelukast.

OBJECTIVE: Leukotrienes (LTs) are involved in airway eosinophilic inflammation in patients with asthma. We examined the effects of a cysteinyl LT 1-receptor antagonist, montelukast, on sputum eosinophil levels, and the correlation between sputum eosinophils and bronchodilatation in patients with asthma. DESIGN: Double-blind, randomized, crossover study. SETTING: University hospital and private hospital. PATIENTS: Twenty-nine patients with mild-to-moderate asthma. INTERVENTIONS: Montelukast, 10 mg, and placebo tablet, once daily, each for 4 weeks. MEASUREMENTS: Sputum eosinophils analyzed using hypertonic saline solution-induced sputum and airway hyperresponsiveness to histamine were evaluated before and after treatment. In addition, morning and evening peak expiratory flow (PEF), asthma symptoms, and peripheral blood eosinophil levels were assessed. RESULTS: The percentage of eosinophils in sputum decreased from 24.6 +/- 12.3% at baseline to 15.1 +/- 11.8% after montelukast treatment, for a change of - 9.5 +/- 12.7% (n = 20). During placebo administration, the percentage of eosinophils fell from 21.3 +/- 12.1% to 21.0 +/- 11.5%, resulting in a decrease of - 0.3 +/- 10.8% (n = 20). There was a statistically significant difference in the change in sputum eosinophil levels between these two periods (p < 0.005). The number of peripheral blood eosinophils also significantly decreased after montelukast treatment (314.1 +/- 237.6/mL) compared with placebo (413.1 +/- 232.1/mL; p < 0.005, n = 21). Although morning and evening PEF values were significantly improved from baseline after montelukast treatment (p < 0.01, n = 20), asthma symptoms and airway responsiveness to histamine were not significantly altered. Furthermore, there was no significant correlation between the decrease in sputum eosinophils and the increase in PEF. CONCLUSION: These results suggest that montelukast has anti-inflammatory effects on the airway in patients with asthma, and that its bronchodilatory effect is not solely dependent on a decrease in airway eosinophilia.

[Japanese cedar pollinosis is a risk factor for bronchial asthma in Japanese adult asthmatics].

It is well known that allergic rhinitis and asthma often coexist in the same patients. Here, we investigated the influence of Japanese cedar pollinosis on the exacerbation of asthma investigated by questionnaire, daily asthma diary, and peak expiratory flow (PEF) monitoring. Furthermore, airway responsiveness to histamine before pollen season was also investigated in some patients. 333 adult patients with asthma were enrolled into the study and 116 patients (34.8%) were suffering from Japanese cedar pollinosis diagnosed by the presence of nasal allergic symptoms during pollen season and high titer of Japanese cedar-specific IgE antibody. Exacerbation of asthma symptoms, including wheezing, dyspnea, cough, and sputum, was detected in 41 of 116 patients (35.3%) during pollen season. Decrease in morning PEF more than 10% compared with the baseline values before pollen season was observed in 13 of 41 patients (11.2% of total asthmatic patients who complicated with Japanese cedar pollinosis). No significant differences in airway responsiveness to histamine and the titer of Japanese cedar-specific IgE antibodies before pollen season were observed between the patients whose asthma exacerbated and the patients whose asthma was not exacerbated. These results suggest that Japanese cedar pollinosis is one of risk factors for asthma in Japanese adult patients with asthma.

Asthma in patients with Japanese cedar pollinosis.

Japanese cedar pollen is the most common causative allergen for seasonal allergic rhinitis (AR) in Japan. More commonly known as Japanese cedar pollinosis, it occurs in spring causing the typical symptoms of seasonal AR, such as sneezing, rhinorrhea, nasal obstruction, nasal itching, and itching of the eyes. Previous reports indicate that the prevalence of Japanese cedar pollinosis among Japanese was 26.5%. According to a more recent questionnaire-based survey, the prevalence of Japanese cedar pollinosis in patients with adult asthma might be up to 30% to 50%, suggesting higher rates than that previously reported. Moreover, 30% to 60% of adult asthmatic patients with concomitant pollinosis have exacerbations of their asthma symptoms during the Japanese cedar pollen season. These findings suggest that concomitant Japanese cedar pollinosis may be an aggravating factor in patients with asthma. As with other pollens, such as grass and birch, Japanese cedar pollen was shown to be a trigger factor for worsening asthma. In clinical practice, a number of Japanese patients with asthma are monosensitized to Japanese cedar pollen but not to other antigens. Further studies are needed to elucidate the mechanisms of Japanese cedar pollen in inducing and in exacerbating asthma. The presence of concomitant AR is often associated with the difficulty in asthma control. However, there has been a controversy whether treating concomitant AR by intranasal corticosteroid would produce better asthma-related outcomes in patients with asthma and AR. The effect of treating concomitant cedar pollinosis by intranasal corticosteroids on asthma control in patients with asthma and cedar pollinosis also remains unknown. Certain systemic treatments, such as leukotriene receptor antagonist and anti-IgE monoclonal antibody, are supposed to reduce the symptoms of both asthma and AR in patients with asthma and concomitant AR. In conclusion, Japanese cedar pollinosis is often associated with exacerbations of asthma. Further investigations are expected to elucidate the precise impact and mechanisms of Japanese cedar pollinosis in asthma.

Silent brain infarction and platelet activation in obstructive sleep apnea.

RATIONALE: Silent brain infarction (SBI) and increased levels of soluble CD40 ligand (sCD40L) and soluble P-selectin (sP-selectin) are associated with an increased risk of cerebrovascular disease. OBJECTIVES: The aim of this study was to evaluate whether SBI and serum levels of sCD40L and sP-selectin are increased in patients with obstructive sleep apnea (OSA). METHODS: SBI was studied by brain magnetic resonance images in 50 male patients with OSA and 15 obese male control subjects who were free of comorbidities. In addition, the effects of 3 months of treatment with nasal continuous positive airway pressure (nCPAP) on serum parameters were studied in 24 patients with moderate to severe OSA. MEASUREMENTS AND MAIN RESULTS: The percentage of SBI in patients with moderate to severe OSA (25.0%) was higher than that of obese control subjects (6.7%) or patients with mild OSA (7.7%). Serum levels of sCD40L and sP-selectin were significantly higher in patients with moderate to severe OSA than in obese control subjects (p < 0.05) or patients with mild OSA (p < 0.05). In addition, nCPAP significantly decreased serum levels of sCD40L (p < 0.03) and sP-selectin (p < 0.01) in patients with moderate to severe OSA. CONCLUSIONS: These results suggest that serum levels of sCD40L and sP-selectin are elevated and SBI is more common in patients with moderate to severe OSA, leading to elevated cerebrovascular morbidity. Moreover, nCPAP may be useful for decreasing risk in patients with moderate to severe OSA.

Increased carotid intima-media thickness and serum inflammatory markers in obstructive sleep apnea.

Increased carotid intima-media thickness (IMT) and increased serum levels of inflammatory markers, such as C-reactive protein (CRP), interleukin (IL)-6, and IL-18, are associated with an increased risk of cardiovascular and cerebrovascular diseases. The aim of this study was to evaluate whether carotid IMT, a useful marker for early atherosclerosis, is associated with these inflammatory markers in patients with obstructive sleep apnea (OSA). Carotid IMT was investigated with ultrasonography in 36 patients with OSA and 16 obese control subjects. Serum levels of CRP, IL-6, and IL-18 were measured at 5:00 A.M. Carotid IMT (p < 0.001) and serum levels of CRP (p < 0.003), IL-6 (p < 0.005), and IL-18 (p < 0.03) of patients with OSA were significantly higher than those of obese control subjects. Carotid IMT was significantly correlated with serum levels of CRP (r = 0.61, p = 0.0001), IL-6 (r = 0.41, p = 0.01), and IL-18 (r = 0.45, p = 0.005), duration of OSA-related hypoxia (r = 0.60, p = 0.0001), and severity of OSA (r = 0.50, p = 0.002). In addition, the primary factor influencing carotid IMT was duration of hypoxia during total sleep time (p = 0.036). These results suggest that OSA-related hypoxia and systemic inflammation might be associated with the progression of atherosclerosis and thus might increase the risks of cardiovascular and cerebrovascular morbidity in patients with OSA.

Effect of fluvastatin on apoptosis in human CD4+ T cells.

Statins are lipid-lowering agents with pleiotropic effects. We investigated the apoptotic effects of fluvastatin on peripheral CD4+ T cells from healthy subjects. Fluvastatin induced apoptosis in resting CD4+ T cells but not in CD4+ T cells strongly activated with a high concentration of PMA plus ionomycin (PMA/I) analyzed with annexin V and propidium iodide staining. However, CD4+ T cells activated with a low concentration of PMA/I or with anti-CD3 antibodies were apoptotic after treatment with fluvastatin. Activities of caspases-8, -9, and -3 were increased in resting CD4+ T cells treated with fluvastatin (10 microM). In strongly activated CD4+ T cells, fluvastatin inhibited the activation of caspase-8 induced by PMA/I and increased caspase-9 activity. The caspase-3 activity did not differ between untreated and fluvastatin-treated strongly activated CD4+ T cells. Treatment with fluvastatin (10 microM) enhanced cytochrome c release and increased the Bax/Bcl-2 ratio in both resting and strongly activated CD4+ T cells. Although the in vitro concentration of fluvastatin used in this study is higher than in vivo, other factors may sensitize apoptotic cell death of CD4+ T cells in vivo. In conclusion, fluvastatin induces apoptosis in resting T cells but not in strongly activated T cells, a difference that might be due to the interaction between caspase-8 and caspase-9.