Why anticoagulant studies on sepsis fail frequently --- start with SCARLET / 中华创伤杂志(英文版)

The Sepsis Coagulopathy Asahi Recombinant LE Thrombomodulin (SCARLET) trial has many defects, and thus cannot be the terminator of recombinant thrombomodulin (rTM). On the contrary, it provides sufficient evidence for further research. Based on analysis focusing on the failure of SCARLET and several previous anticoagulant studies, it is most important for new studies to grasp the following two points: (1) The enrolled cases should have sufficient disease severity and a clear standard for disseminated intravascular coagulation; (2) Heparin should not be used in combination with the investigated drugs. Multiple post-hoc analyses show that no combination of heparin will not increase the risk of thromboembolism. In fact, the combination of heparin can mask the true efficacy of the investigated drug. Due to the complexity of sepsis treatment and the limitations of clinical studies, the results of all treatment studies should be repeatedly verified, rather than be determined at one stroke. Some research conclusions contrary to disease physiology, pharmacology and clinical practice may be deceptive, and should be cautious rather than be simply accepted. On the other hand, the dissenting voices in the "consensus" scene are often well discussed by the authors and should be highly valued.

Clinical Impact of Recombinant Soluble Thrombomodulin for Disseminated Intravascular Coagulation Associated with Severe Acute Cholangitis

BACKGROUND/AIMS: Recently, recombinant human soluble thrombomodulin (rTM) has been developed as a new drug for disseminated intravascular coagulation (DIC). This study aims to evaluate the clinical benefit of rTM in patients with sepsis-induced DIC caused by acute cholangitis who underwent biliary drainage. METHODS: Patients were divided into two groups: the rTM therapy group and the non-rTM therapy group. The primary outcome was the DIC resolution rate at 7 days, and the secondary outcome was 28-day mortality rate. RESULTS: Thirty-five patients were treated by rTM, and 36 patients were treated without rTM for DIC. The rate of resolution of DIC at day 7 was significantly higher in the rTM group than in the non-rTM group (82.9% vs 55.6%, p=0.0012). Compared with the non-rTM group, the 28-day survival rate of the r-TM group was significantly higher (rTM vs non-rTM, 91.4% vs 69.4%, p=0.014). According to multivariate analysis, non-rTM (hazard ratio [HR], 2.681) and CRP (HR, 2.370) were factors related to decreased survival. CONCLUSIONS: rTM treatment may have a positive impact on improving DIC and survival rates in patients with severe acute cholangitis.

The involvement of endothelial mediators in leprosy

Leprosy is a chronic infectious disease that requires better understanding since it continues to be a significant health problem in many parts of the world. Leprosy reactions are acute inflammatory episodes regarded as the central etiology of nerve damage in the disease. The activation of endothelium is a relevant phenomenon to be investigated in leprosy reactions. The present study evaluated the expression of endothelial factors in skin lesions and serum samples of leprosy patients. Immunohistochemical analysis of skin samples and serum measurements of VCAM-1, VEGF, tissue factor and thrombomodulin were performed in 77 leprosy patients and 12 controls. We observed significant increase of VCAM-1 circulating levels in non-reactional leprosy (p = 0.0009). The immunostaining of VEGF and tissue factor was higher in endothelium of non-reactional leprosy (p = 0.02 for both) than healthy controls. Patients with type 1 reaction presented increased thrombomodulin serum levels, compared with non-reactional leprosy (p = 0.02). In type 2 reaction, no significant modifications were observed for the endothelial factors investigated. The anti-inflammatory and antimicrobial activities of the endotfhelial factors may play key-roles in the pathogenesis of leprosy and should be enrolled in studies focusing on alternative targets to improve the management of leprosy and its reactions.

Effect of Resveratrol on Preventing Steroid-induced Osteonecrosis in a Rabbit Model / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Prevention of osteonecrosis (ON) has seldom been addressed. The purpose of this study was to evaluate the effect of resveratrol on preventing steroid-induced ON in rabbits.</p><p><b>METHODS</b>Seventy-two rabbits were divided into four groups: (1) NEC (ON) group: thirty rabbits were treated with lipopolysaccharide (LPS) once, then with methylprednisolone (MPS) daily for 3 days; (2) PRE (prevention) group: thirty rabbits were given one dose of LPS, then MPS daily for 3 days, and resveratrol on day 0 and daily for 2 weeks; (3) RES (resveratrol) group: six rabbits were given resveratrol for 2 weeks but without LPS/MPS; (4) CON (control) group: six rabbits were given alcohol for 2 weeks but without LPS/MPS. Levels of plasma tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), thrombomodulin (TM), vascular endothelial growth factor (VEGF), maximum enhancement (ME) by magnetic resonance imaging, and ON incidence were evaluated.</p><p><b>RESULTS</b>The PRE group had a lower ON incidence than the NEC group, but with no significant differences at 2 weeks and 12 weeks. The RES and CON groups did not develop ON. TM and VEGF were significantly higher in the NEC group compared with the PRE group at weeks 1, 2, and 4 (TM: 1 week, P = 0.029; 2 weeks, P = 0.005; and 4 weeks, P = 0.047; VEGF: 1 week, P = 0.039; 2 weeks, P = 0.021; 4 weeks, P = 0.014), but the difference disappeared at 12 weeks. The levels of t-PA and PAI-1 were not significantly different between the NEC and PRE groups. The TM, t-PA, PAI-1, and VEGF concentrations in the RES and CON groups did not change over time. Compared to the baseline, ME in the NEC group decreased significantly (P = 0.025) at week 1, increased significantly (P = 0.021) at week 2, and was decreased at week 12. The variance was insignificant in the PRE group.</p><p><b>CONCLUSIONS</b>Resveratrol may improve blood supply to bone in a rabbit model of ON of the femoral head via anti-inflammatory effects to protect the vascular endothelium and reduce thrombosis.</p>

Risk Factors for Metachronous Gastric Neoplasms in Patients Who Underwent Endoscopic Resection of a Gastric Neoplasm

BACKGROUND/AIMS: To identify the risk factors for metachronous gastric neoplasms in patients who underwent an endoscopic resection of a gastric neoplasm. METHODS: We prospectively collected clinicopathologic data and measured the methylation levels of HAND1, THBD, APC, and MOS in the gastric mucosa by methylation-specific real-time polymerase chain reaction in patients who underwent endoscopic resection of gastric neoplasms. RESULTS: A total of 257 patients with gastric neoplasms (113 low-grade dysplasias, 25 high-grade dysplasias, and 119 early gastric cancers) were enrolled. Metachronous gastric neoplasm developed in 7.4% of patients during a mean follow-up of 52 months. The 5-year cumulative incidence of metachronous gastric neoplasm was 4.8%. Multivariate analysis showed that moderate/severe corpus intestinal metaplasia and family history of gastric cancer were independent risk factors for metachronous gastric neoplasm development; the hazard ratios were 4.12 (95% confidence interval [CI], 1.23 to 13.87; p=0.022) and 3.52 (95% CI, 1.09 to 11.40; p=0.036), respectively. The methylation level of MOS was significantly elevated in patients with metachronous gastric neoplasms compared age- and sex-matched patients without metachronous gastric neoplasms (p=0.020). CONCLUSIONS: In patients who underwent endoscopic resection of gastric neoplasms, moderate/severe corpus intestinal metaplasia and a family history of gastric cancer were independent risk factors for metachronous gastric neoplasm, and MOS was significantly hypermethylated in patients with metachronous gastric neoplasms.

Differential Immunohistochemical Profiles for Distinguishing Prostate Carcinoma and Urothelial Carcinoma

BACKGROUND: The pathologic distinction between high-grade prostate adenocarcinoma (PAC) involving the urinary bladder and high-grade urothelial carcinoma (UC) infiltrating the prostate can be difficult. However, making this distinction is clinically important because of the different treatment modalities for these two entities. METHODS: A total of 249 patient cases (PAC, 111 cases; UC, 138 cases) collected between June 1995 and July 2009 at Seoul St. Mary's Hospital were studied. An immunohistochemical evaluation of prostatic markers (prostate-specific antigen [PSA], prostate-specific membrane antigen [PSMA], prostate acid phosphatase [PAP], P501s, NKX3.1, and α-methylacyl coenzyme A racemase [AMACR]) and urothelial markers (CK34βE12, p63, thrombomodulin, S100P, and GATA binding protein 3 [GATA3]) was performed using tissue microarrays from each tumor. RESULTS: The sensitivities of prostatic markers in PAC were 100% for PSA, 83.8% for PSMA, 91.9% for PAP, 93.7% for P501s, 88.3% for NKX 3.1, and 66.7% for AMACR. However, the urothelial markers CK34βE12, p63, thrombomodulin, S100P, and GATA3 were also positive in 1.8%, 0%, 0%, 3.6%, and 0% of PAC, respectively. The sensitivities of urothelial markers in UC were 75.4% for CK34βE12, 73.9% for p63, 45.7% for thrombomodulin, 22.5% for S100P, and 84.8% for GATA3. Conversely, the prostatic markers PSA, PSMA, PAP, P501s, NKX3.1, and AMACR were also positive in 9.4%, 0.7%, 18.8%, 0.7%, 0%, and 8.7% of UCs, respectively. CONCLUSIONS: Prostatic and urothelial markers, including PSA, NKX3.1, p63, thrombomodulin, and GATA3 are very useful for differentiating PAC from UC. The optimal combination of prostatic and urothelial markers could improve the ability to differentiate PAC from UC pathologically.

Hypercoagulable state in patients with multiple myeloma / 中国实验血液学杂志

<p><b>OBJECTIVE</b>This study was to detect the plasma thrombomodulin (TM), D-dimer and fibrinogen in patients with multiple myeloma (MM) and to analyze their relationship with morbid state, and also to investigate the relationship of the expression of coagulation factor with the ratio of myeloma cells.</p><p><b>METHODS</b>ELISA was used to detect the TM level in 45 cases of MM at different stages. The plasma level of D-dimer and fibrinogen was detected by STA automatic coagulation analyser.</p><p><b>RESULTS</b>The level of plasma TM in newly diagnosed patients was higer than that in normal control group and in platform stage group (P < 0.01; P < 0.05). There were significant differences between relapsed or refractory group and normal control group or those reached platform stage group (P < 0.05). Meanwhile, the level of plasma TM in the group of thalidomide combined with chemotherapy was higer than that in newly diagnosed patients (P < 0.05). The level of plasma D-dimer and fibrinogen of MM patients was higher than that in normal controls (P < 0.01;P < 0.05). The expression of D-Dimer in relapsed or refractory group reached the maximum. Also, the level of plasma D-Dimer in group of thalidomide combined chemotherapy was higer than in newly diagnosed patients (P < 0.05). The expression of coagulation factor did not correlate with the ratio of myeloma cells.</p><p><b>CONCLUSIONS</b>Level of plasma TM, D-Dimer and fibrinogen of MM patients is higher than that in control group. The level of plasma TM and D-Dimer can be elevated when thalidomide used, which indirectly suggested the tendency for thrombosis in MM patients.</p>

Cutaneous Metastasis of Transitional Cell Carcinoma of the Renal Pelvis, Clinically Mimicking an Abscess / 대한피부과학회지

Upper tract urothelial carcinoma (UTUC), which comprises tumors of the ureter and renal pelvis, is a rare genitourinary malignancy. Among these tumors, transitional cell carcinoma (TCC) of the renal pelvis is highly uncommon, and cutaneous metastasis of this tumor is very rare. Herein, we report a case of cutaneous metastasis of TCC of the renal pelvis, clinically mimicking an abscess. A 79-year-old woman was diagnosed with TCC of the left renal pelvis, and underwent wide nephrectomy and chemotherapy in August 2012. She presented with painful, solitary 3 cm sized erythematous dome-shaped mass on the right lower abdomen that had been present for two weeks. We took biopsies of the center and periphery of the mass. Histopathological findings were consistent with cutaneous metastasis of TCC. Immunohistochemical examination showed strongly positive cytokeratin 7 staining, and negative cytokeratin 20 and thrombomodulin staining.

Protective effect of recombinant TM-N and recombinant soluble RAGE in a mouse model of acute hepatic failure / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To evaluate the roles of N-terminal lectin-like domain of thrombomodulin (TM-N) and receptor for advanced glycation end products (RAGE) in acute hepatic failure using a mouse model system.</p><p><b>METHODS</b>Acute hepatic failure was induced in Kunming mice by intraperitoneal injection of D-galactosamine (D-Galn at 600 mg/kg) and lipopolysaccharide (LPS at 5 mug/kg) and mice were divided into groups for injection with saline, recombinant (r)TM-N protein, or recombinant soluble (rs)RAGE protein. Unmanipulated model mice served as the negative controls. Effects on liver expression of high mobility group box-1 (HMGB1) were detected by immunohistochemistry and real time RT-PCR. Effects on serum levels of tumor necrosis factor-alpha (TNFa) and interleukin-1 beta (IL)-1b were quantified by ELISA.</p><p><b>RESULTS</b>Treatment with rTM-N and rsRAGE both alleviated the acute liver damage induced by D-Galn/LPS exposure, and decreased the hepatic expression of HMGB1 as well as the serum levels of TNFa and IL-1b.</p><p><b>CONCLUSION</b>Intraperitoneal delivery of rTM-N and rsRAGE can alleviate acute liver damage by modulating the expression of necrosis- and inflammation-related factors.</p>

Kruppel-like factor 2 might mediate the rapamycin-induced arterial thrombosis in vivo: implications for stent thrombosis in patients / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Stent thrombosis is one of severe complications after sirolimus-eluting stent implantation. Rapamycin (sirolimus) promotes arterial thrombosis in in vivo studies. However, the underlying molecular and transcriptional mechanisms of this adverse effect have not been thoroughly investigated. This study was designed to examine the effects of rapamycin on the expression of the gene, Kruppel-like factor 2 (KLF2), and its transcriptional targets in mice.</p><p><b>METHODS</b>Mice were randomly divided into four groups: the control group (intraperitoneal injection with 2.5% of dimethyl sulfoxide (DMSO) only), rapamycin group (intraperitoneal injection with 2 mg/kg of rapamycin only), Ad-LacZ + rapamycin group (carotid arterial incubation with Ad-LacZ plus intraperitoneal injection with 2 mg/kg of rapamycin 10 days later), and Ad-KLF2 + rapamycin group (carotid arterial incubation with Ad-KLF2 plus intraperitoneal injection with 2 mg/kg rapamycin 10 days later). The carotid arterial thrombosis formation was induced by FeCl3 and the time of arterial thrombosis was determined. Finally, the RNA and protein of carotid arteries were extracted for KLF2, tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1), endothelial nitric oxide synthase (eNOS), thrombomodulin (TM) mRNA and protein analysis.</p><p><b>RESULTS</b>Compared with controls, treatment with rapamycin inhibited KLF2, eNOS and TM mRNA and protein expression, and enhanced TF and PAI-1 mRNA and protein expression, and shortened time to thrombotic occlusion from (1282 ± 347) seconds to (715 ± 120) seconds (P < 0.01) in vivo. Overexpression of KLF2 strongly reversed rapamycin-induced effects on KLF2, eNOS, TM, TF and PAI-1 expression. KLF2 overexpression increased the time to thrombotic occlusion to control levels in vivo.</p><p><b>CONCLUSIONS</b>Rapamycin induced an inhibition of KLF2 expression and an imbalance of anti- and pro-thrombotic gene expression, which promoted arterial thrombosis in vivo. Overexpression of KLF2 increased KLF2 expression and reversed time to thrombosis in vivo.</p>

Changes in plasma thrombomodulin and D-dimer levels and their clinical significance in neonates with sepsis / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To observe changes in plasma thrombomodulin (TM) and D-dimer (DD) levels in neonates with sepsis, and to investigate their significance in evaluating the patients' condition and prognosis.</p><p><b>METHODS</b>Fifty-six neonates with sepsis were classified into extremely critical (n=13), critical (n=22) and non-critical groups (n=21) based on neonatal critical illness score (NCIS). Fasting venous blood samples were collected on admission and in the recovery phase. Plasma TM and D-dimer levels were measured using enzyme-linked immunosorbent assay and immune turbidimetry, respectively. Twenty-six healthy neonates were selected as the control group. Plasma TM and D-dimer levels were compared between groups, and the changes after treatment were determined.</p><p><b>RESULTS</b>Plasma TM levels in the extremely critical, critical and non-critical groups were 25.5±6.6, 17.3±4.7 and 13.3±2.8 µg/L respectively, significantly higher than in the control group (9.8±2.7 µg/L) (P<0.01). Plasma D-dimer levels in the extremely critical and critical groups were 744±262 and 436±147 µg/L respectively, also significantly higher than in the control group (205±61 µg/L) (P<0.01). The extremely critical group had significantly higher plasma TM and DD levels than the critical group (P<0.05), and the critical group had significantly higher plasma TM and DD levels than the non-critical group (P<0.05). All patients showed significant decreases in plasma TM and DD levels in the recovery phase after treatment (P<0.01). Plasma TM and DD levels were significantly negatively correlated with NCIS (r=-0.428, P<0.01; r=-0.363, P<0.01).</p><p><b>CONCLUSIONS</b>Determination of plasma TM and DD levels may be helpful in evaluating severity and prognosis in neonates with sepsis.</p>

Changes in plasma levels of thrombomodulin and D-dimer in children with different types of Mycoplasma pneumoniae pneumonia / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the changes in plasma levels of thrombomodulin (TM) and D-dimer (DD) in children with different types of Mycoplasma pneumoniae pneumonia (MPP), and their role in the pathogenesis of MPP in children.</p><p><b>METHODS</b>Fifty-two children with MMP were divided into lobar pneumonia (n=30) and interstitial pneumonia groups (n=22) and another 30 healthy children were selected as the control group. Plasma levels of TM and D-D were measured using enzyme-linked immunosorbent assay and latex-enhanced immunoturbidimetric assay, respectively.</p><p><b>RESULTS</b>The lobar pneumonia, interstitial pneumonia and control groups had median plasma TM levels of 23.83, 15.56 and 8.78 μg/L respectively, with significant differences between the three groups (P<0.01). The lobar pneumonia and interstitial pneumonia groups had significantly higher plasma TM levels than the control group (P<0.01), and the lobar pneumonia group had a significantly higher plasma TM level than the interstitial pneumonia group (P<0.05). Median plasma D-D levels in the lobar pneumonia and interstitial pneumonia groups were significantly higher than the reference value (P<0.01). The lobar pneumonia group had a significantly higher plasma D-D level than the interstitial pneumonia group (0.35 μg/mL vs 0.13 μg/mL; P<0.01), and the percentage of patients with elevated plasma D-D levels was significantly higher in the lobar pneumonia group than in the interstitial pneumonia group (87% vs 59%; P<0.05).</p><p><b>CONCLUSIONS</b>Children with MPP, especially those with lobar pneumonia, have increased plasma levels of TM and D-D. This suggests that damage to vascular endothelial cells and blood hypercoagulability may be involved in the pathogenesis of MPP.</p>

Use of Antithrombin and Thrombomodulin in the Management of Disseminated Intravascular Coagulation in Patients with Acute Cholangitis

BACKGROUND/AIMS: To evaluate the usefulness and safety of treating disseminated intravascular coagulation (DIC) complicating cholangitis primarily with antithrombin (AT) and thrombomodulin (rTM). METHODS: A DIC treatment algorithm was determined on the basis of plasma AT III levels at the time of DIC diagnosis and DIC score changes on treatment day 3. Laboratory data and DIC scores were assessed prospectively at 2-day intervals. RESULTS: DIC reversal rates >75% were attained on day 7. In the DIC reversal group, statistically significant differences from baseline were observed in interleukin-6 and C-reactive protein levels within 5 days. Patients with no DIC score improvements after treatment with AT alone experienced slow improvement on a subsequent combination therapy with rTM. Although a subgroup with biliary drainage showed greater improvement in DIC scores than did the nondrainage subgroup, the mean DIC score showed improvement even in the nondrainage subgroup alone. Gastric cancer bleeding that was treated conservatively occurred in one patient. As for day 28 outcomes, three patients died from concurrent malignancies. CONCLUSIONS: Although this algorithm was found to be useful and safe for DIC patients with cholangitis, it may be better to administer rTM and AT simultaneously from day 1 if the plasma AT III level is less than 70%.

Alteration of placental haemostatic mechanisms in idiopathicintrauterine growth restriction / Alteración de los mecanismos hemostáticos de la placenta en restricción de crecimiento intrauterino idiopático / Alteração dos mecanismos hemostáticos da placenta em restrição de crescimento intra-uterino idiopático

La restriccióndel crecimiento intrauterino es una complicación del embarazo con alta probabilidad de morbilidad y mortalidad perinatal, que pareceser causada por desarrollo anormal de la vasculatura placentaria. Los procesos hemostáticos son importantes para el desarrollo de laplacenta y el desequilibrio entre factores procoagulantes y anticoagulantes se ha asociado con restricción del crecimiento intrauterino.Objetivo. Evaluar el compromiso hemostático en la placenta de los embarazos complicados con restricción del crecimiento intrauterinoidiopática. Materiales y métodos. Se estudiaron cinco placentas de embarazos con restricción de crecimiento intrauterino idiopática y 19controles. Se realizó examen macroscópico e histológico, y análisis de la expresión de factor tisular y trombomodulina a nivel de ARNmpor PCR en tiempo real y proteínas por ELISA. Resultados. Se evidenció compromiso hemostático en las placentas de embarazos conrestricción de crecimiento intrauterino idiopática, siendo la trombosis de los vasos coriales el hallazgo histológico más importante. Seencontró aumento en la expresión de la proteína del factor tisular (p=0,0411) y en la razón de factor tisular/trombomodulina a nivel deARNm (p=0,0411) y proteína (p=0,0215). No hubo diferencias estadísticamente significativas entre los grupos en los niveles de ARNmde factor tisular o trombomodulina, ni de trombomodulina a nivel de proteína. Conclusión. Se presenta evidencia de alteración de losmecanismos hemostáticos de la placenta, incluyendo la expresión anormal de factor tisular y de la razón factor tisular/trombomodulina,en embarazos complicados con restricción del crecimiento intrauterino idiopática...

Intrauterine growth restriction is a complication of pregnancy with a high probability of perinatal morbidity and mortality. It appears tobe caused by abnormal development of placental vasculature. Haemostatic processes are important for the development of the placenta,and an imbalance between procoagulant and anticoagulant factors has been associated with risk of intrauterine growth restriction.Objective. To evaluate coagulation abnormalities in placenta of pregnancies complicated with idiopathic intrauterine growth restriction.Materials and methods. Five placentas from pregnancies with idiopathic intrauterine growth restriction were compared to 19 controls.We performed gross and histological examination of the placenta. Analysis was made of both mRNA expression by real-time PCRand protein by ELISA of tissue factor and thrombomodulin in placental tissue. Results. Results based on histological evaluation wereconsistent with an increased prothrombotic state in placentas from pregnancies with idiopathic intrauterine growth restriction, andthrombosis of chorionic vessels was the most important finding. The study showed an increased expression of tissue factor protein(p=0.0411) and an increase in the ratio of tissue factor/thrombomodulin mRNA (p=0.0411) and protein (p=0.0215) in placentas frompregnancies with idiopathic intrauterine growth restriction. There were no statistically significant differences neither between cases andcontrols in the mRNA levels of tissue factor or thrombomodulin nor at the protein level of thrombomodulin. Conclusion. Evidence ofalteration of local haemostatic mechanisms at the level of the placenta, including abnormal expression of tissue factor and tissue factor/thrombomodulin ratio, in pregnancies that occur with idiopathic intrauterine growth restriction is presented...

A restrição do crescimentointra-uterino é uma complicação da gravidez com alta probabilidade de morbidade e mortalidade perinatal, que parece ser causada pelodesenvolvimento anormal da vasculatura placentária. Os processos hemostáticos são importantes para o desenvolvimento da placenta,e o desequilíbrio entre fatores pró-coagulantes e anticoagulantes têm sido associadas com a restrição de crescimento intra-uterino.Objetivo. Avaliar o compromisso hemostático na placenta com gestações complicadas com restrição de crescimento intra-uterinoidiopático. Materiais e métodos. Foram estudadas cinco placentas de gestações com restrição de crescimento intra-uterino idiopáticoe 19 controles. Foi realizada uma análise macroscópica e histológica e análise da expressão do factor tecidual e trombomodulina emARNm por PCR em tempo real e de proteína pelo método de ELISA. Resultados. Foi evidente o compromisso hemostático nas placentasde gestações com restrição de crescimento intra-uterino idiopático; a trombose dos vasos coriônicos é o descobrimento histológico maisimportante. Aumentaram a expressão de proteína do fator tecidual (p= 0,0411) e a proporção do fator tecidual/ trombomodulina aonível de ARNm (p= 0,0411) e de proteína (p= 0,0215). Não houve diferenças estatisticamente significativas entre os grupos nos níveisde ARNm do fator tecidual ou trombomodulina, nem de trombomodulina ao nível de proteína. Conclusão. Se apresenta evidência dealteração dos mecanismos hemostáticos da placenta, incluindo a expressão anormal de fator tecidual e da proporção do fator tecidual/trombomodulina, em gestações complicadas com restrição de crescimento intra-uterino idiopático...

Correlation between serum osteoprotegerin and atherosclerotic vascular disorders in rheumatoid arthritis patients

The aim of the present study was to investigate the association of serum osteoprotegerin [OPG] level with the presence of angiographically documented asymptomatic coronary artery disease [CAD] in patients with rheumatoid arthritis [RA] and to evaluate its relationship with plasma thrombomodulin [TM], as a marker of endothelial dysfunction and with carotid artery intima media thickness [IMT], as a marker of atherosclerosis. The study included 20 rheumatoid patients without CAD [negative results on exercise ECG stress test] and other 20 rheumatoid patients with CAD [positive results on exercise ECG stress test and confirmed by coronary angiography]. In addition, 20 age and sex matched normal control subjects were studied. Serum OPG and plasma TM levels were measured and carotid artery IMT was determined. The study revealed that serum OPG levels were significantly higher in rheumatoid patients with and without CAD than in controls [P < 0.001,P < 0.01; respectively] and were positively correlated with age, duration of disease, Disease active score 28[DAS28], Erythrocyte sedimentation rate [ESR], C-reactive protein [CRP] and carotid IMT in rheumatoid patients with and without CAD. Serum OPG level was correlated significantly with plasma TM only in rheumatoid patients with CAD [P < 0.001]. Osteoprotegerin is a clinically important molecule independently associated with the presence of coronary artery disease and may be a good indicator of atherosclerotic vascular damage and macroangiopathy in asymptomatic rheumatoid patients. Hence, measurement of serum OPG merits further investigation as a simple test for improving early diagnosis of asymptomatic CAD in rheumatoid patients

Proinflammatory cytokines and thrombomodulin in patients with peptic ulcer disease and gastric cancer, infected with Helicobacter pylori.

Backgrounds: Helicobacter pylori infect more than half of the global population. It is suggested to be related with gastritis, peptic ulcer disease (PUD), and gastric cancer. Aims: The aim of this present study was to evaluate proinflammatory cytokines including interleukin 1, 6, 8, 10, and thrombomodulin in H. pylori-infected patients with PUD and gastric cancer. Patients: This cross-sectional study was conducted in Taleghani Hospital on 111 patients with H. pylori infection. Materials and Methods: Patients were divided into three groups of PUD, cancer, and control (normal on endoscopy), according to the results of endoscopy. The serum levels of interleukins 1, 6, 8, and 10 and thrombomodulin was determined using enzyme-linked immunosorbent assay (ELISA) technique. H. pylori infection was diagnosed by histological examination of the endoscopic biopsy. Results: One hundred eleven patients were included in the study; 30 as PUD group, 30 as gastric cancer group, and 51 as controls. There was no significant difference between the means of IL-1 and IL-10 levels among the three groups (P = 0.744 and 0.383, respectively). IL-6, IL-8, and thrombomodulin levels were found to be statically different among the three groups (P < 0.05). The level of IL-6, IL-8, and thrombomodulin in cancer group was significantly higher than PUD and control groups (P < 0.05). Conclusion: There is a significant association between H. pylori infection and serum IL-6, IL-8, and thrombomodulin but such relation is not present between H. pylori and IL-1 and IL-10. Immunity response (IL-6, IL-8 and thrombomodulin) is more severe in cancer patient than PUD.

Correlation between blood levels of adhesion molecules ICAM-1 and VCAM-1 and thrombomodulin with coronary artery disease

The results of studies on coronary artery disease risk factors have demonstrated that some adhesion molecules could be risk factors for coronary artery disease. ICAM-1 and VACM-1 are the most important adhesion molecules. On the other hand, thrombomodulin is an anti-inflammatory factor and can reduce the risk for coronary artery disease. In this study, as well as evaluating these factors, we also studies the effect of the interaction between these factors on coronary artery disease. One hundred twenty-three patients between the ages of 45 and 70 years old who were admitted for coronary angiography in the cardiovascular center and met the inclusion criteria for the research, were selected in the first half of 2008. After recording their personal information and medical history in the questionnaires, blood samples were collected and after routine examination, the blood levels of these factors were measured. WE then entered the acquired results of the blood examination and the angiography in the patients' charts and analyzed the results using statistical methods. The angiography results in patient showed that 18 [14.7%] had normal coronary arteries, 5 [4%] had minimal coronary artery disease, 40 [32.5%] had single-vessel disease, 25 [20.3%] had two-vessel disease, and 35 [28.5%] had three-vessel disease. In laboratory tests, the mean soluble ICAM-1 level in patients with normal coronary arteries was 236 ngr/mL; however, in patients with coronary artery disease, the mean level was 274 ngr/mL. The average amount of VCAM-1 in patients with normal coronary arteries was 697 ngr/mL, whereas patients with coronary artery disase had an average of 108 ngr/mL. Thrombomodulin in the normal coronary artery group was 42 ngr/mL, but in patients with coronary artery disease the average level was 30 ngr/mL. The results in this research showed that increased levels of soluble ICAM-1 and also decreased levels of soluble thrombomodulin increased the risk and intensity of coronary artery disease, with statistical significance. The increase in soluble VCMA-1 also increased the risk of coronary artery disease; this was, however, not statistically significant. The important point is that increased levels of soluble ICAM-1 is a risk factor when the level of thrombomodulin is normal or below normal. When the levels of thrombomodulin and ICAM-1 have both increased, the increased risk and intensity of coronary disease is not statistically important

Effects of Danshensu on maternal syndrome in phosphatidylserine/phosphatidylcholine microvesicle induced-mouse model: is it a candidate for preeclampsia remedy? / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Up to date, there is few satisfactory pharmacotherapy, except for aspirin and heparin, to stop the preeclampsia progression. Although the mechanism of preeclampsia is poorly understood, it has been proven to be associated with coagulation activation. Researches on prophylactic and therapeutic application of anticoagulants may benefit the clinical aspects of preeclampsia individuals. This study aimed to evaluate the effects of Danshensu on maternal syndrome in phosphatidylserine/phosphatidylcholine (PS/PC) microvesicle induced-mouse model.</p><p><b>METHODS</b>Sixty-six preeclampsia-like pregnant mice, induced by PS/PC microvesicle administration, were randomly divided into six groups. From days 5.5 to 16.5 of pregnancy, each group was respectively treated as follows: a) mice in group C (n = 12, control group) were injected with 100 microl of filtered phosphate-buffered saline into the tail vein every day; b) group PE (n = 15, preeclampsia model group) were injected in the same way with 100 microl of filtered PS/PC vesicle suspension; c) group H (n = 9, group treated with heparin) were injected with 1 unit heparin together with PS/PC vesicle suspension; d) group A (n = 10, group treated with aspirin) were injected with 20 microg/g aspirin-DL lysine as well; e) group LD (n = 10, group treated with low-dose Danshensu) were injected with 10 microg/g Danshensu; and f) group HD (n = 10, group treated with high-dose Danshensu) were injected with 30 microg/g Danshensu. Systolic blood pressure, total urinary protein levels, blood tests for some hemostatic function parameters (mean platelet counts, plasma antithrombin III activity (AT-III), D-D dimmer levels, and thrombin time), fibrin deposition by phosphotungstic acid hematoxylin staining, and thrombomodulin expression by immunohistochemistry staining in placentas were examined as indices for maternal syndrome.</p><p><b>RESULTS</b>Heparin showed significant effects on maternal syndrome of preeclampsia such as hypertension and proteinuria, and different doses of Danshensu also presented the certain effects. High-dose Danshensu and aspirin all demonstrated better effects than low-dose Danshensu on decreasing blood pressure to normal level, while high-dose Danshensu demonstrated better effects than aspirin and low-dose Danshensu on decreasing proteinuria to normal level. As to Danshensu's effects on hemostatic function, high- and low-dose Danshensu's marked effects on increasing the plasma AT-III activity were the same as that of aspirin and inferior to that of heparin. High-dose Danshensu's better effect on elevating the platelet counts was superior to low-dose Danshensu and aspirin. Low-dose Danshensu's obvious effect on decreasing D-D levels was close to heparin and superior to high-dose Danshensu and aspirin. High- and low-dose Danshensu's significant effects on reduced thrombin time level are same to heparin. Different anticoagulants all played improvement roles in placental fibrin depositions, but heparin and high-dose Danshensu's roles on lowering thrombomodulin expression in placentas were superior to low-dose Danshensu and aspirin. However, anticoagulant function of high-dose Danshensu was still inferior to heparin. We found long-term use of heparin and aspirin, in spite of low-dose administration, could raise the risk of bleeding such as placental abruption and intestinal hemorrhage. But no any side effect was observed in mice treated with different doses of Danshensu in our study.</p><p><b>CONCLUSIONS</b>Danshensu has proven to be effective and safe in ameliorating the prognosis of maternal syndrome in a preeclampsia mouse model. We suggest long-term provision of low-dose Danshensu in pregnancy, leading to an improvement of preeclampsia syndrome with considerable maternal safety.</p>

Urothelial (Transitional Cell) Carcinoma Arising in Mature Cystic Teratoma: A Case Report

Mature cystic teratoma (MCT) is one of the most common benign ovarian tumors, but 1-2% of MCTs are transformed to a malignant neoplasm. Urothelial carcinoma (UC) or transitional cell carcinoma is the most common cancer in the urinary tract. However, UC is a very rare component of transformed malignancy of MCT. Here we report a case of UC arising in an MCT in a 52-year-old woman. Grossly, the ovary was partly cystic and partly solid. Microscopically, the cyst revealed the classic features of MCT and the solid area was papillary UC. By immunohistochemistry using cytokeratins and thrombomodulin, the UC showed a similar expression to that of UC arising in the urinary tract, rather than resembling a primary transitional cell carcinoma of the ovary. When UC is found in a component of MCT, the origin of the carcinoma should be evaluated and urinary tract examinations are required to rule out metastasis.

Serum thrombomodulin level in children with beta thalassaemia major

In recent years, it is suspected that vascular endothelial cells may have some role in vascular complications noted in thalassemic patients. Activated or injured endothelial cells release their protein constituents mainly thrombomodulin into the circulation. Thrombomodulin is considered the most important indicator of vascular endothelial injury. To study serum thrombomodulin level in children with B-thalassaemia major and its relation to the duration of disease and extent of iron overload. The present study was carried out on 35 patients with fl-thalassaemia major. They were divided according to the age into two groups. Group I: included 15 young children aged less than 10 years. Their mean disease duration was 5.5 years. Group II: included 20 older children and adolescents aged from 10 to 20 years. Their mean disease duration was 15.6 years. Ten apparently healthy children of matching age and sex served as control group. Estimation of serum levels of Thrombomodulin [TM] by ELISA. Echocardiography, two-dimensional, M-mode, and Doppler studies. Cardiomegaly was found in 7 [35%] patients of group II. Pulmonary hypertension was encountered only in 4 [20%] patients of group II. Thromboembolic manifestations [femoral deep vein thrombosis] were found in only 1 [5%] thalassaemic patient in group II. The serum TM level was significantly higher in both groups, in comparison with controls [F=10.36, p<0.001]. No significant difference was found between both thalassaemic groups [t=0.421, p=0.673]. Moreover, no significant difference was found between TM levels in splenectomized and non-splenectomized cases [t=0.62, p=0.541]. TM levels of both thalassemic groups showed no significant correlation with serum ferritin level [r=-0.02, p=0.914]. A significantly higher mean value of right ventricular wall thickness was encountered in group II thalassaemic patient as compared to group I [t=2, 57, P=0.019]. In conclusion, increased serum TM level in our polytransfused thalassaemic patients reflects a state of endothelial cell activation and/or injury in these patients. The statistically significant negative correlation between serum TM level and pulmonary acceleration time [r=-0.45, p=0.047], may point to the possible role of pulmonary vascular endothelium injury as a contributory factor in the pathogenesis of pulmonary hypertension in our thalassaemic patients