Plasma antigen levels of thrombin-activatable fibrinolysis inhibitor did not differ in patients with or without disseminated intravascular coagulation

Thrombin-activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase that downregulates fibrinolysis and might play some roles in the pathogenesis of disseminated intravascular coagulation (DIC). We prospectively examined the plasma TAFI antigen levels in patients highly suspected to be suffering from DIC. Patients were subdivided into overt DIC and non-DIC groups according to a DIC scoring system. The Sepsis-related Organ Failure Assessment (SOFA) scores were concurrently calculated on patients with sepsis. Overall, there were 23 non-DIC patients and 20 patients with overt DIC. Their baseline characteristics were similar, but patients with overt DIC had much more aberrant coagulation tests and higher lactate dehydrogenase levels. However, there was no significant difference between overt DIC and non-DIC patients regarding their TAFI antigen levels [median/interquartile range (IQR) 74.41/13.98 and 75.29/15.16, respectively, p=0.543]. On regression analysis, TAFI antigen levels were not correlated with either C-reactive protein levels or various coagulation test results. In patients with sepsis (n=31), TAFI levels among three risk groups stratified by low (5), intermediate (6–10), and high (11) SOFA scores were not statistically disparate (median/IQR 65.24/15.14, 74.63/13.79, and 75.29/21.51, respectively, p=0.684), either. Our result indicated that plasma TAFI antigen levels did not vary significantly between patients with or without DIC. Further, they did not possess any correlation with the severity of organ injury in patients with sepsis. The role of TAFI antigen in the pathogenesis of DIC needs further elucidation by future studies.     

Cholelithiasis in Taiwan

The nature and occurrence of gallstones in Taiwan and their etiologic factors might not be the same as in Western countries and warranted a systematic investigation. Gallbladder biles and gallstones were obtained at surgery from 100 and 74 patients, respectively. Common duct bile and stones were either drained through an indwelling common duct T-tube or aspirated through a nasobiliary catheter in 108 patients. Gallstones were analyzed for bilirubin, cholesterol, bile acid, calcium, and residue, and biles for bile acid, cholesterol, phospholipid, bilirubin, and β-glucuronidase. There were four major kinds of gallstones in Taiwan: cholesterol/mixed stones, high-residue black formed pigment stones, low-residue brown formed pigment stones, and muddy pigment stones. The surgical incidence of all types of stones increased steadily during the past four decades. During the past 15 years the relative frequencies for mixed, formed pigment, and muddy pigment stones had been roughly 40, 40, and 20%, respectively, with a further increase in the mixed stones and a decrease in the muddy pigment stones in recent years. Improvement of nutritional status and living standards might contribute to such changes. Cholesterol content in the common duct and gallbladder biles was higher in the mixed stone group than in other groups. Bacterial β-glucuronidase activity was detected in 53% of patients with muddy pigment stones. Endogenous β-glucuronidase activity and concentration were also highest in this group, intermediate in the formed pigment and mixed stone group, and lowest in the control. We concluded that hypercholesterobilia was responsible for increasing incidence of mixed stones during the past two decades, while both bacterial and human β-glucuronidase might contribute to pigment cholelithiasis.     

Biliary tree in cystic fibrosis. Biliary tract abnormalities in cystic fibrosis demonstrated by endoscopic retrograde cholangiography

Two female adolescents with cystic fibrosis were investigated by endoscopic retrograde cholangiography for recurrent abdominal pain. The cholangiogram of 1 patient demonstrated multiple irregular filling defects throughout the biliary tree representing thickened bile and mucus as well as stones. The cholangiogram of the other case illustrated cystic dilatation of the intrahepatic bile ducts with intrahepatic cholelithiasis as well as extensive irregularities of the smaller proximal ductules secondary to recurrent cholangitis or focal biliary cirrhosis, or both. Endoscopic papillotomy resulted in drainage of tenacious bile and mucus and stones in both cases. Sustained clinical improvement did not follow papillotomy in either case, whereas radiologic improvement was demonstrated in 1 case.     

Treatment of high-risk acute myelogenous leukaemia by myeloablative chemoradiotherapy followed by co-infusion of T cell-depleted haematopoietic stem cells and culture-expanded marrow mesenchymal stem cells from a related donor with one fully mismatched human leucocyte antigen haplotype

A 20-year-old woman with high-risk acute myelogenous leukaemia was transplanted with granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood CD34+ haematopoietic stem cells and bone-marrow-derived mesenchymal stem cells (MSC) from her human leucocyte antigen haplotype-mismatched father after myeloablative conditioning therapy. The patient engrafted rapidly and had no acute or chronic graft-versus-host disease. Since transplantation, the patient has shown an enduring trilineage haematological complete response without any evidence of leukaemia relapse at 31 months. We suggest that MSC can be used effectively for genetically haploidentical haematopoietic stem cell transplantation for acute leukaemia.     

Antibody-dependent cell-mediated cytotoxicity against cells infected with the human immunodeficiency virus

Human immunodeficiency virus (HIV) elicits the production of virus-specific antibodies in infected individuals. We investigated the ability of serum from HIV-infected individuals to mediate antibody-dependent cellular cytotoxicity in an in vitro 51Cr release assay system. Fresh peripheral blood mononuclear cells from healthy donors seronegative for HIV were used as cellular effectors against HIV-infected and uninfected H9 target cells in the presence of serum from HIV-infected or uninfected donors. Serum from HIV-infected, but not uninfected, donors significantly augmented cytolysis of virus-infected targets (P less than .005). There was no augmented killing of uninfected H9 cells with sera from either group. Studies using serum from mice that had been immunized with synthetic peptides from the HIV envelope region suggested that this response is directed, at least in part, at several determinants of the transmembrane portion of the HIV envelope glycoprotein.     

Imatinib therapy prior to myeloablative allogeneic stem cell transplantation

It is unknown whether imatinib prior to myeloablative haematopoietic stem cell transplantation (HSCT) increases transplant-related toxicity. Among the side effects induced by imatinib, myelosuppression and liver injury might worsen HSCT outcomes. We retrospectively analysed engraftment, liver toxicity, acute graft-versus-host disease (aGVHD) incidence and 100-day mortality in 30 patients with BCR/ABL-positive leukaemias who received imatinib before HSCT and compared results of 48 age-matched controls who did not receive preceding imatinib. Both neutrophil and platelet engraftment occurred more rapidly among imatinib patients but the differences adjusted for Gratwohl scale were not statistically significant (P = 0.18 and 0.22, respectively). The adjusted hazards of having liver function tests (LFTs) >1.5 normal increased and the adjusted durations of elevated LFTs were not significantly different. The estimated adjusted difference in mean peak bilirubin values was also not significantly different (P = 0.48). However, the adjusted hazard of increased creatinine >1.5 normal was significantly higher in the imatinib group (HR = 4.09, P = 0.02). The adjusted odds of grades II-IV aGVHD were similar in both groups (OR = 0.86, P = 0.78), and while the adjusted odds of 100-day mortality were lower among imatinib patients, the difference was not significant (OR = 0.65, P = 0.60). These data do not provide any evidence that imatinib preceding HSCT increases acute transplant-related toxicities.     

Demonstration of cooperative contribution of MET- and EGFR-mediated STAT3 phosphorylation to liver regeneration by exogenous suppressor of cytokine signalings

BACKGROUND/AIMS: As conditional knockout mice for stat3 are impaired in liver regeneration after partial hepatectomy while those for gp130 have defects in early STAT3 phosphorylation but have normal DNA synthesis, late STAT3 phosphorylation induced independently of gp130 seems to be essential for liver regeneration. Since HGF and EGF can activate STAT3 via gp130-independent MET and EGFR, respectively, we assumed that these factors account for STAT3-dependent liver regeneration. Here, we investigated this hypothesis by introducing suppressor of cytokine signaling (SOCS)-1 and SOCS3, potent negative regulators of STAT3 signaling, selectively in hepatocytes. METHODS: We generated recombinant adenoviruses expressing socs1 and socs3. RESULTS: Hepatocytes infected with socs1-virus lacked STAT3 phosphorylation in response to IL-6 and HGF, while cells infected with socs3-virus lacked the response to all of IL-6, HGF and EGF, indicating that those SOCS proteins differently regulate EGFR signaling. Mice infected with socs3-virus exhibited severe and persistent impairment while those with socs1-virus showed only delayed regeneration, indicating requirement of both MET and EGFR signalings. CONCLUSIONS: These results clearly demonstrated that MET- and EGFR-mediated STAT3 signalings cooperatively contribute to liver regeneration and could provide new insights into tissue homeostasis.     

Kinetics and thermodynamics of T cell receptor- autoantigen interactions in murine experimental autoimmune encephalomyelitis

In the current study, cellular and molecular approaches have been used to analyze the biophysical nature of T cell receptor (TCR)-peptide MHC (pMHC) interactions for two autoreactive TCRs. These two TCRs recognize the N-terminal epitope of myelin basic protein (MBP1-11) bound to the MHC class II protein, I-A(u), and are associated with murine experimental autoimmune encephalomyelitis. Mice transgenic for the TCRs have been generated and characterized in other laboratories. These analyses indicate that the mice either develop encephalomyelitis spontaneously (172.10 TCR) or only if immunized with autoantigen in adjuvant (1934.4 TCR). Here, we show that the 172.10 TCR binds MBP1-11:I-A(u) with a 4-5-fold higher affinity than the 1934.4 TCR. Consistent with the higher affinity, 172.10 T hybridoma cells are significantly more responsive to autoantigen than 1934.4 cells. The interaction of the 172.10 TCR with cognate ligand is more entropically unfavorable than that of the 1934.4 TCR, indicating that the 172.10 TCR undergoes greater conformational rearrangements upon ligand binding. The studies therefore suggest a correlation between the strength and plasticity of a TCR-pMHC interaction and the frequency of spontaneous disease in the corresponding TCR transgenic mice. The comparative analysis of these two TCRs has implications for understanding autoreactive T cell recognition and activation.