Myocardial perfusion and fatty acid metabolism in patients with tako-tsubo-like left ventricular dysfunction

OBJECTIVES: We sought to assess myocardial perfusion and metabolism in patients with peculiar transient asynergy, which consisted of basal normokinesia and apical akinesia of the left ventricle (LV) at the same time. BACKGROUND: This asynergy has been widely called "tako-tsubo-like LV dysfunction" in Japan, but little is known about its pathophysiology. METHODS: We performed rest tallium-201 ((201)Tl) and iodine-123-beta-methyl-p-iodophenyl penta-decanoic acid ((123)I-BMIPP) dual-isotope myocardial single-photon emission computed tomography (SPECT) in 14 patients with tako-tsubo-like LV dysfunction. The LV was divided into 17 segments, and each segment was graded with scores between normal uptake (0) and defect (4). We also measured the Thrombolysis in Myocardial Infarction trial (TIMI) frame count in 28 patients and 20 control subjects. RESULTS: Early SPECT (5 +/- 3 days) revealed that the total defect score value with BMIPP was significantly higher than reduced uptake with (201)Tl (p < 0.01). Reduced uptake of BMIPP was observed in parallel with an apical akinetic region and usually involved uptake of (201)Tl. This discrepancy improved gradually during the follow-up period (29 +/- 6 days) (p = 0.36). Compared with control subjects, patients had a TIMI frame count that was significantly higher in all coronary arteries immediately after onset. This higher TIMI frame count decreased but was sustained even after resolution of tako-tsubo-like LV dysfunction. CONCLUSIONS: Our data suggest that myocardial fatty acid metabolism is more severely impaired than myocardial perfusion, in parallel with an apical akinetic region during the early phase, and that impaired multivessel coronary microcirculation is involved, at least in part, in tako-tsubo-like LV dysfunction.     

Application of real-time RT-PCR to quantifying gene expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human abdominal aortic aneurysm

BACKGROUND: The relative expression levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), key regulators in remodeling of extracellular matrix, are considered to play a pivotal role in the development of abdominal aortic aneurysm (AAA). However, few data exist regarding quantitative assessment of their expression in clinical settings. METHODS: In 22 patients with AAA who underwent graft replacement, tissue samples of the AAA and non-dilated aorta were obtained. Using a real-time RT-PCR method that enabled quantitative measurement of mRNA levels in small tissue samples, we determined gene expression levels of MMPs and TIMPs relative to that of glutaraldehyde 3-phosphate dehydrogenase in each sample. RESULTS: The expression levels of the MMP-1 and -3 genes were significantly augmented in AAA compared with non-dilated regions (4.48 +/- 2.01 versus 0.26 +/- 0.12, P < 0.01 and 1.89 +/- 1.00 versus 5.01 +/- 0.97, P < 0.05, respectively). Although genes for TIMP-1, -2 and -3 tended to be upregulated in AAA, relative expression levels of MMP-1 to TIMP-1, MMP-1 to TIMP-2, MMP-1 to TIMP-3, and MMP-3 to TIMP-2 were still higher in AAA than in non-dilated regions (1.12 +/- 0.63 versus 0.10 +/- 0.03, 4.13 +/- 1.12 versus 0.43 +/- 0.11, 1.61 +/- 0.59 versus 0.14 +/- 0.03, and 7.81 +/- 1.60 versus 2.56 +/- 0.76, respectively, P < 0.05). CONCLUSION: These results demonstrate that the present real-time RT-PCR method is reliable for the determination of mRNA levels in small samples of vascular tissue and that disproportional expression of both MMP-1 and MMP-3 relative to TIMPs relates pathologically to the evolution of AAA.     

Aberrant hepatic duct connected with the main pancreatic duct by anomalous pancreato-biliary ductal union: Case report

An aberrant hepatic duct directly connected to the main pancreatic duct with anomalous arrangement of the pancreato-biliary ductal system is reported here, the first report of such a case, to our knowledge. A 53-year-old woman was admitted to our hospital because of cholecystolithiasis with abdominal pain in the right upper quadrant. Endoscopic retrograde cholangiopancreatography (ERCP) showed that an aberrant hepatic duct, which independently drained the right posterior segment of the liver, connected to the main pancreatic duct at a high insertion site distal to the sphincter area of the major papilla. The common bile duct (containing stones), on the other hand, united with the main pancreatic duct in a normal fashion. Cholecystectomy and bile duct lithotomy were performed. The aberrant hepatic duct was separated from the main pancreatic duct just above the junction, and was anastomosed side-by-side to the common hepatic duct. The embryologic development of this lesion is not clear, but is discussed in this report.     

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.     

Liver‐infiltrating CD56 positive T lymphocytes in hepatitis C virus infection

Abstract: Aim: Hepatitis C virus (HCV) is a major cause of post‐transfusional and sporadic hepatitis, and leads to chronic liver disease. It has been suggested that virus‐specific cytotoxic T lymphocytes are responsible for liver injuries that occur in HCV‐infected patients. However, the detailed characteristics of these lymphocytes have not yet been defined. We have previously reported that CD56⁺ T lymphocytes, as intermediates between natural killer cell and T lymphocytes, predominantly infiltrated the liver and were increased in patients with chronic hepatitis related to HCV (CH‐C). Material and Methods: We obtained peripheral blood and liver tissues from 32 patients diagnosed as having CH‐C, and 10 other liver disease patients (5 chronic hepatitis related to HBV, 5 alcoholics), and analyzed peripheral blood and liver‐infiltrating lymphocytes using flow cytometric and immunohistochemical techniques. Results: The CD56⁺ T lymphocyte ratio in the liver of patients with a high histology activity index (HAI) score for chronic hepatitis was higher than that of patients with a low HAI score and patients with other liver diseases. In addition, T lymphocytes from patients with chronic hepatitis with a high HAI score carried mostly γδ‐TCR. There was a correlation between the ratio of CH‐C and serum alanine aminotransferase, category I (periportal inflammation and necrosis), and IV (fibrosis) of the HAI scoring system. The ratio was highest in zone 1 of the hepatic lobules. Conclusion: The correlation between CD56⁺ T lymphocyte ratios and hepatocellular damage was examined. These findings suggest strongly that liver‐infiltrating CD56⁺ T lymphocytes play an important pathologic role in hepatocellular injury in CH‐C.     

Interleukin 15 activity in the rectal mucosa of inflammatory bowel disease

Background & Aims: Interleukin (IL)-15 has been found to share many immunoregulatory activities in lymphocytes with IL-2. The aim of this study was to investigate IL-15 activity in organ cultures, localization of IL-15 messenger RNA (mRNA), and proliferation of lamina propria mononuclear cells (LPMCs) in response to recombinant IL-15 using the mucosal tissues obtained from patients with inflammatory bowel disease (IBD). Methods: The contents of IL-15, tumor necrosis factor α, and IL-2 in the culture supernatant of the rectal mucosal tissues were determined by an enzyme-linked immunosorbent assay. Expression of IL-15 mRNA was analyzed by in situ hybridization, and proliferative response of LPMCs to recombinant IL-15 was determined by [³H]thymidine incorporation into DNA. Results: Significantly greater IL-15 activity was detected in active IBD, and this elevation was also observed in inactive ulcerative colitis. In contrast, greater tumor necrosis factor α activity was observed only in active IBD, and IL-2 was not detected in organ cultures. In situ hybridization showed IL-15 mRNA in macrophages and epithelial cells in active IBD specimens, and recombinant IL-15 induced a dose-dependent proliferative response in LPMCs. Conclusions: Mucosal IL-15 may be involved in the pathogenesis of IBD as one of the important mediators in activation of mucosal immune cells.GASTROENTEROLOGY 1998;114:1237-1243     

Inhibition of ciliary activity by phorbol esters in rabbit tracheal epithelial cells

To study the effect of protein kinase C activation on respiratory ciliary activity, we measured ciliary beat frequency (CBF) by a photoelectric technique in response to phorbol esters and cell-permeable diglyceride in cultured tracheal epithelial cells from rabbits. Phorbol 12-myristate 13-acetate (PMA) resulted in a concentration- and time-dependent inhibition of CBF (half maximum inhibitory concentration (IC₅₀)=3×10⁻¹⁰ M) with the maximal decrease being 21.0±1.4% (mean±SE,p<0.001) observed at 10⁻⁶ M. L-α-dioctanoylglycerol (DiC8), another known activator of protein kinase C, likewise reduced CBF in a dose-dependent fashion. In contrast, phorbol 12,13-didecanoate, a non-tumor-promoting phorbol ester that does not stimulate protein kinase C, produced no significant changes in CBF. The decrease in CBF induced by PMA was not affected by blockade of arachidonic acid metabolism with indomethacin and nordihydroguaiaretic acid, but was antagonized by pretreatment with H-7, a specific inhibitor of protein kinase C (p<0.01). Maximal ciliary inhibition with either PMA or DiC8 was not accompanied by a decrease in intracellular concentration of cyclic AMP. These results indicate that activation of protein kinase C has a significant depressive effect on ciliary activity, and hence the airway mucociliary transport function, presumably through a regulatory pathway that is not dependent on cyclic AMP or arachidonic acid metabolites.     

Establishment of a T-Cell Line from Lymphocytes Presumably Implicated in Posttransfusion Graft-versus-Host Disease

Posttransfusion graft-versus-host disease (PTGVHD) is known to develop in immunocompetent patients exhibiting clinical symptoms such as erythroderma, fever, liver dysfunction, diarrhea and pancytopenia. It is speculated that transfused blood donors' lymphocytes might recognize the recipients' HLAs as alloantigens. The thus stimulated lymphocytes might proliferate, expand and finally attack the host's immune system or tissues. However, details regarding these expanded donor cells such as: (1) whether they represent one clone or more, (2) the composition of lymphocyte subsets, and (3) the target HLA antigens of recipients, are not clear, since T-cell lines derived from PTGVHD patients have not yet been obtained. The aim of this study is to characterize T-cells responsible for PTGVHD and to identify their target molecules. For that purpose, we attempted to establish T-cell lines derived from a PTGVHD patient. We show that the established T-cell line, proven to be derived from donor lymphocytes, showed a CD4+ phenotype and had cytotoxic activities. Furthermore, we describe that the target of the cytotoxic T-cell line (CTL) is an HLA-DRBl*0405-related molecule of the patient.