BACKGROUND High mobility group box 1(HMGB1)has been studied as a molecule associated with severe outcomes in sepsis and thrombomodulin(TM)seems to decrease HMGB1 activity.AIM To investigate the role of the thrombomodu...BACKGROUND High mobility group box 1(HMGB1)has been studied as a molecule associated with severe outcomes in sepsis and thrombomodulin(TM)seems to decrease HMGB1 activity.AIM To investigate the role of the thrombomodulin/high mobility group box 1(T/H)ratio in patients with sepsis and their association with their clinic,testing the hypothesis that higher ratios are associated with better outcomes.METHODS Twenty patients diagnosed with sepsis or septic shock,according to the 2016 criteria sepsis and septic shock(Sepsis-3),were studied.Patients were followed until they left the intensive care unit or until they achieved 28 d of hospitalization(D28).The following clinical outcomes were observed:Sequential Organ Failure Assessment(SOFA)score;Need for mechanical pulmonary ventilation;Presence of septic shock;Occurrence of sepsis-induced coagulopathy;Need for renal replacement therapy(RRT);and Death.RESULTS The results showed that patients with SOFA scores greater than or equal to 12 points had higher serum levels of TM:76.41±29.21 pg/mL vs 37.41±22.55 pg/mL among those whose SOFA scores were less than 12 points,P=0.003.The T/H ratio was also higher in patients whose SOFA scores were greater than or equal to 12 points,P=0.001.The T/H ratio was,on average,three times higher in patients in need of RRT(0.38±0.14 vs 0.11±0.09),P<0.001.CONCLUSION Higher serum levels of TM and,therefore,higher T/H ratio in the first 24 h after the diagnosis of sepsis were associated with more severe disease and the need for renal replacement therapy,while those with better clinical outcomes and those who were discharged before D28 showed a tendency for lower T/H ratio values.展开更多
Fulminant hepatic failure(FHF) is a critical illness that can be comorbid to primary liver damage.FHF shows a high mortality rate,and patients with FHF require intensive therapy,including plasma apheresis.However,inte...Fulminant hepatic failure(FHF) is a critical illness that can be comorbid to primary liver damage.FHF shows a high mortality rate,and patients with FHF require intensive therapy,including plasma apheresis.However,intensive care at the present is not enough to restore the severe liver damage or promote hepatocellular reproduction,and a standard therapy for the treatment of FHF has not been established.An 86-year-old female with FHF was admitted to our hospital.Her manifestation demonstrated a clinical situation of systemic inflammatory response syndrome(SIRS) and disseminated intravascular coagulation.A diagnosis of fulminant hepatitis was made according to the definition given in the position paper of the American Association for the Study of Liver Diseases.Her serum hepatocyte growth factor(HGF) level had increased to 11.84 ng/m L.The HGF level indicated massive liver damage as seen in FHF.Recombinant thrombomodulin(r TM) was administered daily from the admission day for 1 wk at 380 U/kg.The patient's white blood cells and C-reactive protein responded to the r TM treatment within a few days.The HGF level and PT recovered to the normal range.The levels of proinflammatory cytokines(tumor necrosis factor-α and interleukin-1β) were suppressed by the administration of r TM.The patient's hepatic function(e.g.,PT and albumin) completely recovered without plasma exchange.r TM may modulate the over-response of SIRS with the improvement of proinflammatory cytokines.The underlying mechanism is thought to be the inhibitory effect of r TM on highmobility group box 1(HMBG1).The pathogenesis of HMBG1 protein in fulminant hepatic failure has beenalready known.A novel favorable effect of r TM for SIRS would be promising for FHF,and the wide application of r TM for SIRS should be considered.展开更多
Background: Recombinant human soluble thrombomodulin (rhTM) was approved for the treatment of disseminated intravascular coagulation in Japan, and rhTM has anti-inflammatory effects. Disordered coagulation is a part o...Background: Recombinant human soluble thrombomodulin (rhTM) was approved for the treatment of disseminated intravascular coagulation in Japan, and rhTM has anti-inflammatory effects. Disordered coagulation is a part of the acute respiratory distress syndrome (ARDS) pathophysiology and thus we hypothesize that anticoagulant therapy may help. This preliminary study was to observe the safety of rhTM administration and the improvement on biomarker levels after the therapy for ARDS-patients. Objectives: Case series of ARDS-patients. Methods: Seventeen ARDS-patients that required ventilatory management were treated with rhTM and clinical and laboratory data were collected including platelets, thrombin-antithrombin complex (TAT), fibrinogen degradation products, oxygen saturation/the fraction of inspired oxygen (SpO2/FIO2), and high-mobility group-1 (HMG-1). The administration of rhTM was started during 6 days at a bolus dose of 0.06 mg/kg/day immediately after the diagnosis of ARDS. Results: Eleven of the 17 ARDS-patients were alive at 28 days after the beginning of the administration of rhTM. The serial pattern of the SpO2/FIO2 showed remarkable differences between the survivors and nonsurvivors from day 5 to day 7. The TAT in the survivors significantly decreased after treatment, and there were significantly lower levels in the TAT on day 7 in comparison to that of the nonsurvivors. The serial changes of HMG-1 showed increased levels in the nonsurvivors until day 5 after the administration of rhTM. Conclusions: Additional rhTM administration can safely improve the parameters in survival ARDS-patients, as demonstrated by significant improvements in the SpO2/FIO2, HMG-1 and TAT.展开更多
AIM To investigate the efficacy of thrombomodulin(TM)-α for treatment of disseminated intravascular coagulopathy(DIC) in the field of gastrointestinal surgery. METHODS Thirty-six peri-operative DIC patients in the fi...AIM To investigate the efficacy of thrombomodulin(TM)-α for treatment of disseminated intravascular coagulopathy(DIC) in the field of gastrointestinal surgery. METHODS Thirty-six peri-operative DIC patients in the field of gastrointestinal surgery who were treated with TM-α were retrospectively investigated. The relationships between patient demographics and the efficacy of TM-α were examined. Analysis of survival at 28 d was also performed on some parameters by means of the Kaplan-Meier method. Relationships between the ini-tiation of TM-α and patient demographics were also evaluated. RESULTS Abscess formation or bacteremia was the most frequent cause of DIC(33%), followed by digestive tract perforation(31%). Twenty-six patients developed DIC after surgery, frequently within 1 wk(81%). TM-α was most often administered within 1 d of the DIC diagnosis(72%) and was continued for more than 3 d(64%). Although bleeding tendency was observed in 7 patients(19%), a hemostatic procedure was not needed. DIC scores, systemic inflammatory response syndrome(SIRS) scores, quick-sequential organ failure assessment(qS OFA) scores, platelet counts, and prothrombin time ratios significantly improved after 1 wk(P < 0.05, for all). The overall survival rate at 28 d was 71%. The duration of TM-α administration(≥ 4, ≤ 6) and improvements in DIC-associated scores(DIC, SIRS and q SOFA) at 1 wk were significantly better prognostic factors for 28-d survival(P < 0.05, for all). TM-α was administered significantly earlier to patients with severe clinical symptoms, such as high qS OFA scores, sepsis, shock or high lactate values(P < 0.05, for all). CONCLUSION Early administration of TM-α and improvements in each parameter were essential for treatment of DIC. The diagnosis of patients with mild symptoms requires further study.展开更多
Objective:To explore the effect of plasma homocysteine(Hcy)levels on methylation and expression of thrombomodulin(TM)gene in patients with retinal vein occlusion(RVO).Methods:11 cases of patients who were diagnosed as...Objective:To explore the effect of plasma homocysteine(Hcy)levels on methylation and expression of thrombomodulin(TM)gene in patients with retinal vein occlusion(RVO).Methods:11 cases of patients who were diagnosed as RVO in Department of Ophthalmology in Baogang Hospital from January 2019 to December 2020 were included in this research.11 cases of healthy people who came to our physical examination center for physical examination during the same period were included into the control group.Fasting cubital venous blood was collected in the morning,plasma Hcy levels were measured by means of enzyme cycle assay,TM gene methylation was detected by methylation-specificity polymerase chain reaction(MSP),and the correlation between characteristic changes in plasma Hcy and TM gene methylation was analyzed in the research subjects.Results:Plasma Hcy expression levels were higher in the RVO group than those in the control group(p<.01).In the control group,the TM primer set region was basically unmethylated,while in the RVO group,the TM primer set region was partially methylated.Conclusions:Plasma Hcy affects the occurrence and development of RVO through methylation of TM encoding gene.展开更多
Objective. To measure the circulating levels of thrombomodulin (TM) and plasminogen activator inhibitor type- I (PAI- I) in women with pregnancy induced hypertension (PIH). Methods. Blood samples were drawn from 97 pr...Objective. To measure the circulating levels of thrombomodulin (TM) and plasminogen activator inhibitor type- I (PAI- I) in women with pregnancy induced hypertension (PIH). Methods. Blood samples were drawn from 97 pregnant women in their third trimester, grouped as 25 mild PIH,26 moderate PIH,22 severe PIH and 24 normotensive healthy pregnant women for determining levels of TM by ELISA,PAI- I by colorimetric assay methods, and creatinine (Cr) in serum by biochemical method. Results. Circulating levels of TM, PAI- I and TM/Cr ratio increased with increasing severity of PIH. There were no significant differences between mild and normotensive pregnant women. The parameters were significantly changed in the moderate and severe PIH groups. Conclusion. TM and PAI- I may serve as meaningful clinical markers for the assessment of the endothelial damage in PIH, which is very important in evaluating and following the development of PIH.展开更多
Objective In order to investigate the pharmacological properties of Ginkgo biloba extract (GBE) on improving blood circulation, the regulating action of GBE and quercetin (a main flavonoid ingredient in GBE) on thromb...Objective In order to investigate the pharmacological properties of Ginkgo biloba extract (GBE) on improving blood circulation, the regulating action of GBE and quercetin (a main flavonoid ingredient in GBE) on thrombomodulin (TM) expression and tissue-type plasminogen activator (t-PA) secretion was studied. Methods Using flow cytometer and gel image system respectively, we evaluated the TM expression and the t-PA secretion by human umbilical vein endothelial cells (HUVECs) in vitro. Results The increase of TM expression on HUVECs surface was induced by GBE rather than quercetin in a dose- and time-dependent manner. Both GBE and quercetin increased the t-PA release significantly. Conclusion The effect of GBE on improving blood circulation may be partly attributed to its promoting TM expression and t-PA secretion by endothelial cells, and quercetin participated in the effect of GBE on t-PA secretion. However, the action of GBE on increasing TM expression needs further study.展开更多
To study the changes of thrombomodulin(TM) in both plasma and tissue extracts of cancer patients for evaluating its clinical significance. Methods: PlasmaTM levels were measured by enzyme-linked immunosorbent assay (E...To study the changes of thrombomodulin(TM) in both plasma and tissue extracts of cancer patients for evaluating its clinical significance. Methods: PlasmaTM levels were measured by enzyme-linked immunosorbent assay (ELISA) in both plasma of 188 cancer patients and 24 cancer tissue extractsincluding their adjacent non-cancer tissues. Results:The plasma TM levels both in cancer patients and in metastasis patients were significantly higher than that in controls [(33.4714.25)mg/L, (41.6816.96)mg/L, vs(20.40 7.22) mg/L,P<0.01]. The plasma TM levels incancer patients after operation decreased obviously thanthat before operation [(18.459.96)mg/L, vs (28.2911.74)mg/L, P<0.01], whereas, the plasma TM levels in patientswith recurrence and metastasis after operation increasedobviously [(34.5012.57)mg/L]. Among the types of cancer,the plasma TM levels in metastasis lung cancers, gastric cancers and pancreatic cancers were significantly higherthan that in non-metastasis respective cancers. Nosignificant differences were found between controls andnon-metastasis cancers including gastric cancers,pancreatic cancers, nasopharyngeal cancers, large intestine cancers and laryngeal cancers (P>0.05). The TM levels incancer tissue extracts were significantly lower than that intheir adjacent non-cancer tissue extracts [(647.71317.51)mg/L vs (1455.63772.22)mg/L, P<0.01]. On the contrary, the plasma TM levels in these cancers were significantly higher than that in controls. Conclusion: The rise of plasma TMlevels in cancer patients was associated with metastasis and diffusion of cancers. The TM levels can be served as ansensitive index for judging progression and metastasis展开更多
Cigarette smoking is a well-known risk factor for cardiovascular disease. Smoking can cause vascular endothelial dysfunction and consequently trigger haemostatic activation and thrombosis. However, the mechanism of ho...Cigarette smoking is a well-known risk factor for cardiovascular disease. Smoking can cause vascular endothelial dysfunction and consequently trigger haemostatic activation and thrombosis. However, the mechanism of how smoking promotes thrombosis is not fully understood. Thrombosis is associated with the imbalance of the coagulant system due to endothelial dysfunction. As a vital anticoagulation cofactor, thrombomodulin (TM) located on the endothelial cell surface is able to regulate intravascular coagulation by binding to thrombin, and the binding results in thrombosis inhibition. This work focused on the effects of cigarette smoke extract (CSE) on TM-thrombin binding by atomic force microscopy (AFM) based single-molecule force spectroscopy. The results from both in vitro and live-cell experiments indicated that CSE could notably reduce the binding probability of TM and thrombin. This study provided a new approach and new evidence for studying the mechanism of thrombosis triggered by cigarette smoking.展开更多
文摘BACKGROUND High mobility group box 1(HMGB1)has been studied as a molecule associated with severe outcomes in sepsis and thrombomodulin(TM)seems to decrease HMGB1 activity.AIM To investigate the role of the thrombomodulin/high mobility group box 1(T/H)ratio in patients with sepsis and their association with their clinic,testing the hypothesis that higher ratios are associated with better outcomes.METHODS Twenty patients diagnosed with sepsis or septic shock,according to the 2016 criteria sepsis and septic shock(Sepsis-3),were studied.Patients were followed until they left the intensive care unit or until they achieved 28 d of hospitalization(D28).The following clinical outcomes were observed:Sequential Organ Failure Assessment(SOFA)score;Need for mechanical pulmonary ventilation;Presence of septic shock;Occurrence of sepsis-induced coagulopathy;Need for renal replacement therapy(RRT);and Death.RESULTS The results showed that patients with SOFA scores greater than or equal to 12 points had higher serum levels of TM:76.41±29.21 pg/mL vs 37.41±22.55 pg/mL among those whose SOFA scores were less than 12 points,P=0.003.The T/H ratio was also higher in patients whose SOFA scores were greater than or equal to 12 points,P=0.001.The T/H ratio was,on average,three times higher in patients in need of RRT(0.38±0.14 vs 0.11±0.09),P<0.001.CONCLUSION Higher serum levels of TM and,therefore,higher T/H ratio in the first 24 h after the diagnosis of sepsis were associated with more severe disease and the need for renal replacement therapy,while those with better clinical outcomes and those who were discharged before D28 showed a tendency for lower T/H ratio values.
文摘Fulminant hepatic failure(FHF) is a critical illness that can be comorbid to primary liver damage.FHF shows a high mortality rate,and patients with FHF require intensive therapy,including plasma apheresis.However,intensive care at the present is not enough to restore the severe liver damage or promote hepatocellular reproduction,and a standard therapy for the treatment of FHF has not been established.An 86-year-old female with FHF was admitted to our hospital.Her manifestation demonstrated a clinical situation of systemic inflammatory response syndrome(SIRS) and disseminated intravascular coagulation.A diagnosis of fulminant hepatitis was made according to the definition given in the position paper of the American Association for the Study of Liver Diseases.Her serum hepatocyte growth factor(HGF) level had increased to 11.84 ng/m L.The HGF level indicated massive liver damage as seen in FHF.Recombinant thrombomodulin(r TM) was administered daily from the admission day for 1 wk at 380 U/kg.The patient's white blood cells and C-reactive protein responded to the r TM treatment within a few days.The HGF level and PT recovered to the normal range.The levels of proinflammatory cytokines(tumor necrosis factor-α and interleukin-1β) were suppressed by the administration of r TM.The patient's hepatic function(e.g.,PT and albumin) completely recovered without plasma exchange.r TM may modulate the over-response of SIRS with the improvement of proinflammatory cytokines.The underlying mechanism is thought to be the inhibitory effect of r TM on highmobility group box 1(HMBG1).The pathogenesis of HMBG1 protein in fulminant hepatic failure has beenalready known.A novel favorable effect of r TM for SIRS would be promising for FHF,and the wide application of r TM for SIRS should be considered.
文摘Background: Recombinant human soluble thrombomodulin (rhTM) was approved for the treatment of disseminated intravascular coagulation in Japan, and rhTM has anti-inflammatory effects. Disordered coagulation is a part of the acute respiratory distress syndrome (ARDS) pathophysiology and thus we hypothesize that anticoagulant therapy may help. This preliminary study was to observe the safety of rhTM administration and the improvement on biomarker levels after the therapy for ARDS-patients. Objectives: Case series of ARDS-patients. Methods: Seventeen ARDS-patients that required ventilatory management were treated with rhTM and clinical and laboratory data were collected including platelets, thrombin-antithrombin complex (TAT), fibrinogen degradation products, oxygen saturation/the fraction of inspired oxygen (SpO2/FIO2), and high-mobility group-1 (HMG-1). The administration of rhTM was started during 6 days at a bolus dose of 0.06 mg/kg/day immediately after the diagnosis of ARDS. Results: Eleven of the 17 ARDS-patients were alive at 28 days after the beginning of the administration of rhTM. The serial pattern of the SpO2/FIO2 showed remarkable differences between the survivors and nonsurvivors from day 5 to day 7. The TAT in the survivors significantly decreased after treatment, and there were significantly lower levels in the TAT on day 7 in comparison to that of the nonsurvivors. The serial changes of HMG-1 showed increased levels in the nonsurvivors until day 5 after the administration of rhTM. Conclusions: Additional rhTM administration can safely improve the parameters in survival ARDS-patients, as demonstrated by significant improvements in the SpO2/FIO2, HMG-1 and TAT.
文摘AIM To investigate the efficacy of thrombomodulin(TM)-α for treatment of disseminated intravascular coagulopathy(DIC) in the field of gastrointestinal surgery. METHODS Thirty-six peri-operative DIC patients in the field of gastrointestinal surgery who were treated with TM-α were retrospectively investigated. The relationships between patient demographics and the efficacy of TM-α were examined. Analysis of survival at 28 d was also performed on some parameters by means of the Kaplan-Meier method. Relationships between the ini-tiation of TM-α and patient demographics were also evaluated. RESULTS Abscess formation or bacteremia was the most frequent cause of DIC(33%), followed by digestive tract perforation(31%). Twenty-six patients developed DIC after surgery, frequently within 1 wk(81%). TM-α was most often administered within 1 d of the DIC diagnosis(72%) and was continued for more than 3 d(64%). Although bleeding tendency was observed in 7 patients(19%), a hemostatic procedure was not needed. DIC scores, systemic inflammatory response syndrome(SIRS) scores, quick-sequential organ failure assessment(qS OFA) scores, platelet counts, and prothrombin time ratios significantly improved after 1 wk(P < 0.05, for all). The overall survival rate at 28 d was 71%. The duration of TM-α administration(≥ 4, ≤ 6) and improvements in DIC-associated scores(DIC, SIRS and q SOFA) at 1 wk were significantly better prognostic factors for 28-d survival(P < 0.05, for all). TM-α was administered significantly earlier to patients with severe clinical symptoms, such as high qS OFA scores, sepsis, shock or high lactate values(P < 0.05, for all). CONCLUSION Early administration of TM-α and improvements in each parameter were essential for treatment of DIC. The diagnosis of patients with mild symptoms requires further study.
基金financially supported by the Baotou Science and Technology Bureau Fund Subject(2020Z1009-6).
文摘Objective:To explore the effect of plasma homocysteine(Hcy)levels on methylation and expression of thrombomodulin(TM)gene in patients with retinal vein occlusion(RVO).Methods:11 cases of patients who were diagnosed as RVO in Department of Ophthalmology in Baogang Hospital from January 2019 to December 2020 were included in this research.11 cases of healthy people who came to our physical examination center for physical examination during the same period were included into the control group.Fasting cubital venous blood was collected in the morning,plasma Hcy levels were measured by means of enzyme cycle assay,TM gene methylation was detected by methylation-specificity polymerase chain reaction(MSP),and the correlation between characteristic changes in plasma Hcy and TM gene methylation was analyzed in the research subjects.Results:Plasma Hcy expression levels were higher in the RVO group than those in the control group(p<.01).In the control group,the TM primer set region was basically unmethylated,while in the RVO group,the TM primer set region was partially methylated.Conclusions:Plasma Hcy affects the occurrence and development of RVO through methylation of TM encoding gene.
文摘Objective. To measure the circulating levels of thrombomodulin (TM) and plasminogen activator inhibitor type- I (PAI- I) in women with pregnancy induced hypertension (PIH). Methods. Blood samples were drawn from 97 pregnant women in their third trimester, grouped as 25 mild PIH,26 moderate PIH,22 severe PIH and 24 normotensive healthy pregnant women for determining levels of TM by ELISA,PAI- I by colorimetric assay methods, and creatinine (Cr) in serum by biochemical method. Results. Circulating levels of TM, PAI- I and TM/Cr ratio increased with increasing severity of PIH. There were no significant differences between mild and normotensive pregnant women. The parameters were significantly changed in the moderate and severe PIH groups. Conclusion. TM and PAI- I may serve as meaningful clinical markers for the assessment of the endothelial damage in PIH, which is very important in evaluating and following the development of PIH.
文摘Objective In order to investigate the pharmacological properties of Ginkgo biloba extract (GBE) on improving blood circulation, the regulating action of GBE and quercetin (a main flavonoid ingredient in GBE) on thrombomodulin (TM) expression and tissue-type plasminogen activator (t-PA) secretion was studied. Methods Using flow cytometer and gel image system respectively, we evaluated the TM expression and the t-PA secretion by human umbilical vein endothelial cells (HUVECs) in vitro. Results The increase of TM expression on HUVECs surface was induced by GBE rather than quercetin in a dose- and time-dependent manner. Both GBE and quercetin increased the t-PA release significantly. Conclusion The effect of GBE on improving blood circulation may be partly attributed to its promoting TM expression and t-PA secretion by endothelial cells, and quercetin participated in the effect of GBE on t-PA secretion. However, the action of GBE on increasing TM expression needs further study.
文摘To study the changes of thrombomodulin(TM) in both plasma and tissue extracts of cancer patients for evaluating its clinical significance. Methods: PlasmaTM levels were measured by enzyme-linked immunosorbent assay (ELISA) in both plasma of 188 cancer patients and 24 cancer tissue extractsincluding their adjacent non-cancer tissues. Results:The plasma TM levels both in cancer patients and in metastasis patients were significantly higher than that in controls [(33.4714.25)mg/L, (41.6816.96)mg/L, vs(20.40 7.22) mg/L,P<0.01]. The plasma TM levels incancer patients after operation decreased obviously thanthat before operation [(18.459.96)mg/L, vs (28.2911.74)mg/L, P<0.01], whereas, the plasma TM levels in patientswith recurrence and metastasis after operation increasedobviously [(34.5012.57)mg/L]. Among the types of cancer,the plasma TM levels in metastasis lung cancers, gastric cancers and pancreatic cancers were significantly higherthan that in non-metastasis respective cancers. Nosignificant differences were found between controls andnon-metastasis cancers including gastric cancers,pancreatic cancers, nasopharyngeal cancers, large intestine cancers and laryngeal cancers (P>0.05). The TM levels incancer tissue extracts were significantly lower than that intheir adjacent non-cancer tissue extracts [(647.71317.51)mg/L vs (1455.63772.22)mg/L, P<0.01]. On the contrary, the plasma TM levels in these cancers were significantly higher than that in controls. Conclusion: The rise of plasma TMlevels in cancer patients was associated with metastasis and diffusion of cancers. The TM levels can be served as ansensitive index for judging progression and metastasis
基金supported by the National Basic Research Program of China(Grant No.2011CB911001)National Natural Science Foundation of China(Grant Nos.21127901 and 21121063)Chinese Academy of Sciences
文摘Cigarette smoking is a well-known risk factor for cardiovascular disease. Smoking can cause vascular endothelial dysfunction and consequently trigger haemostatic activation and thrombosis. However, the mechanism of how smoking promotes thrombosis is not fully understood. Thrombosis is associated with the imbalance of the coagulant system due to endothelial dysfunction. As a vital anticoagulation cofactor, thrombomodulin (TM) located on the endothelial cell surface is able to regulate intravascular coagulation by binding to thrombin, and the binding results in thrombosis inhibition. This work focused on the effects of cigarette smoke extract (CSE) on TM-thrombin binding by atomic force microscopy (AFM) based single-molecule force spectroscopy. The results from both in vitro and live-cell experiments indicated that CSE could notably reduce the binding probability of TM and thrombin. This study provided a new approach and new evidence for studying the mechanism of thrombosis triggered by cigarette smoking.
