Neutrophil infiltration of culprit lesions in acute coronary syndromes.

BACKGROUND: Neutrophils in unstable atherosclerotic lesions have not received much consideration, despite accumulating evidence suggesting a link between systemic inflammation and acute coronary syndromes. METHODS AND RESULTS: Coronary artery segments were obtained at autopsy from 13 patients with acute myocardial infarction (AMI); 8 had a ruptured and 5 an eroded plaque. Patients (n=45) who had died of noncardiovascular diseases served as reference. Atherectomy specimens were obtained from 35 patients with stable angina pectoris (SAP) and from 32 patients with unstable angina pectoris (UAP). Antibodies against CD66b, elastase, myeloperoxidase, and CD11b identified neutrophils; CD10 identified neutral endopeptidase (NEP). CD66b-positive and NEP-positive neutrophils were counted and expressed as a number per square millimeter of tissue. All specimens with plaque rupture or erosion showed distinct neutrophil infiltration; the number did not differ between ruptured and eroded plaques. However, the number of NEP-positive neutrophils was significantly higher (P<0.0001) in ruptured plaques than in eroded plaques. UAP patients showed neutrophils in 14 of 32 culprit lesions; in SAP only 2 of 35 lesions contained neutrophils. The number of neutrophils and NEP-positive cells in patients with UAP was significantly higher (neutrophils, P<0.0005; NEP-positive cells, P<0.005) than in patients with SAP. CONCLUSIONS: The observations suggest that neutrophil infiltration is actively associated with acute coronary events. The high number of NEP-positive neutrophils in ruptured plaques, compared with eroded plaques, may reflect differences in the underlying pathophysiological mechanisms.

Telomere shortening in human coronary artery diseases.

BACKGROUND: Increased cell turnover in response to injury is considered to be important in the development of atherosclerotic plaques. Telomere shortening has been shown to be associated with cell turnover. We assessed the telomere length of human coronary endothelial cells to clarify whether there is a relationship between telomere shortening and coronary artery disease (CAD). METHODS AND RESULTS: Coronary endothelial cells were obtained from 11 patients with CAD who underwent autopsy and 22 patients without CAD who underwent autopsy by scraping off the luminal surface of coronary arteries. DNA extracted from the endothelial cells were blotted and hybridized with telomere-specific oligonucleotide ([TTAGGG]4). The hybridization signal intensity, which represented telomeric DNA content, was standardized with centromeric DNA content (T/C ratio) to estimate telomere length. The T/C ratios were significantly smaller (P<0.0001) in CAD patients than in age-matched non-CAD patients (CAD patients, 0.462+/-0.135; non-CAD patients, 1.002+/-0.212). In 6 individual CAD patients, the T/C ratio at the atherosclerotic lesion was significantly smaller (P<0.05) than that at the non-atherosclerotic portion. CONCLUSIONS: These findings suggest that focal replicative senescence and telomere shortening of endothelial cells may play a critical role in coronary atherogenesis and CAD.

Ultrasonographic diagnosis of degree of chronic type C liver disease.

BACKGROUND/AIMS: We propose a method, named US score, for semi-quantitative determination of the stage of chronic type C liver disease by ultrasonography. METHODOLOGY: The subjects were 454 patients with chronic type C liver disease. Of the patients with chronic hepatitis C, 208 underwent US-guided or laparoscopic liver biopsy. US score was the sum of the scores representing five morphological variables, to be evaluated semi-quantitatively, and change in US score with chronic liver disease progression was determined. RESULTS: The average US score was 2.5 +/- 0.4 for F0, 2.8 +/- 0.6 for F1, 3.0 +/- 0.6 for F2, 3.7 +/- 0.9 for F3 and 5.5 +/- 0.8 for F4. There was a significant correlation between US score and the degree of fibrosis of chronic hepatitis C as assessed by the new European classification (p<0.0001). The average US score was 5.6 +/- 0.9 for Child A, 6.6 +/- 1.1 for Child B, and 7.8 +/- 0.7 for Child C. There was a significant correlation between US score and the results of classification by Child-Turcotte criteria (p<0.0001). CONCLUSIONS: These results suggest that US score is a stable, convenient method of evaluating the degree of progression of chronic type C liver disease.

Pathophysiological role of oxidized low-density lipoprotein in plaque instability in coronary artery diseases.

Oxidized low-density lipoprotein (ox-LDL) is considered to play a key role in the genesis of inflammatory processes in atherosclerotic lesions. It has also been shown that LDL isolated from patients with diabetes mellitus (DM) has an enhanced susceptibility to oxidation. Recently, a sandwich ELISA method for measurement of plasma ox-LDL levels has been developed. To elucidate the role of ox-LDL in plaque instability in coronary artery disease, we measured the plasma ox-LDL levels in patients with acute myocardial infarction (AMI), unstable angina pectoris (UAP), and stable angina pectoris (SAP), and moreover assessed whether a relationship is present between plasma ox-LDL levels and DM. We also measured the plasma ox-LDL level in a patient who died of AMI, thus enabling us to study the presence of ox-LDL and CD 36, which is one of the ox-LDL receptors, in the culprit lesion. Plasma ox-LDL levels were measured in 210 patients (AMI: 70, UAP: 70, SAP: 70), and in 55 control subjects. Plasma ox-LDL levels in AMI patients were significantly higher than in UAP patients (P<.0001), SAP patients (P<.0001), or controls (P<.0001). In the UAP group, plasma ox-LDL levels in patients with DM were significantly higher than those without DM (P<.005). The autopsied patient who died of AMI revealed an increased plasma level of ox-LDL, and immunohistochemically, the culprit coronary lesion contained abundant macrophage-derived foam cells, showing distinct positivity for ox-LDL and CD 36. These results strongly suggest an important role for ox-LDL in the genesis of plaque instability in human coronary atherosclerotic lesions.

Effects of alanine in patients with advanced primary biliary cirrhosis: preliminary report.

When rats given D-galactosamine are then treated with the glucogenic amino acid alanine, their alanine aminotransferase (ALT) activity, total bilirubin level, and survival rate improve compared with when other amino acids are used. Here, we report a preliminary study of the clinical and pharmacological effects of alanine given to three patients with primary biliary cirrhosis (PBC). The patients were jaundiced and were in the end-stage of the disease. The treatment they had been receiving was continued while they were given 18 g of alanine per day for a planned 8 weeks. For all three patients, test results for total bilirubin, alkaline phosphatase, and ALT decreased by 25% or more from the base line at some time during treatment. The arterial ketone-body ratio increased. Two of the patients reported that their itching and fatigue lessened. Except for one patient given a second course, who reported nausea, adverse effects were not found. In end-stage PBC, alanine administration decreased the total bilirubin level and improved symptoms, so this compound may decrease jaundice in this disease. A long-term study of a larger group of patients is needed.

Meshwork pattern is an important risk factor for development of hepatocellular carcinoma in patients with HBV-related chronic hepatitis and cirrhosis.

We analyzed the importance of 'meshwork pattern', a sign representing severe irregularity on the intra-hepatic echogram, in hepatitis B virus (HBV)-related chronic hepatitis and cirrhosis, as a risk factor for development of hepatocellular carcinoma (HCC). Two hundred and thirty-one patients (143 men and 88 women) with HBV-related chronic hepatitis and cirrhosis who visited our hospital from January 1993 to December 1994 were enrolled in this study. Since enrollment, abdominal ultrasonography had in principle been performed every 3 months for cirrhotic patients and every 4-6 months for patients with chronic hepatitis for HCC screening. Cumulative HCC incidences in patient groups positive or negative for meshwork pattern were calculated by the Kaplan-Meier method. The incidence of HCC was significantly higher in the group positive for meshwork pattern (average incidence per year: 4.4%) than in the group negative for it (average incidence per year: 0.5%) (P<0.0001, Mantel-Cox test). On regression analysis with Cox's proportional hazards model, sex, alpha-fetoprotein and meshwork pattern were selected as independent risk factors for HCC. In conclusion, meshwork pattern appears to be an ultrasonographic sign useful for detecting a latent risk factor for HCC in patients with HBV-related chronic hepatitis and cirrhosis.

Peripheral blood mononuclear cells are possible extrahepatic replication sites for hepatitis C virus.

BACKGROUND/AIMS: Hepatitis C virus is a major causative agent of chronic liver disease and hepatocellular carcinoma and is considered to be a hepatotropic virus. It remains controversial whether hepatitis C virus exists in peripheral blood mononuclear cells and replicates there. In order to resolve this issue, we performed nested RT-PCR (reverse transcription polymerase chain reaction) and RT-PCR in situ hybridization in peripheral blood mononuclear cells of patients with chronic hepatitis C. METHODOLOGY: We collected peripheral blood mononuclear cells from patients with chronic hepatitis C, extracted total RNA from the samples, and performed nested RT-PCR to detect hepatitis C virus RNA in the peripheral blood mononuclear cells lysates. We also fixed peripheral blood mononuclear cells of the patients in 4% paraformaldehyde and performed RT-PCR in situ hybridization with a digoxigenin-labeled RNA probe to detect hepatitis C virus RNA in the cells. RESULTS: Using these methods, we detected both positive- and negative-stranded hepatitis C virus RNA in peripheral blood mononuclear cells of hepatitis C patients. To determine in which cell population of peripheral blood mononuclear cells hepatitis C virus is present, we performed PCR in situ hybridization after incubation with fluorescent latex microbeads which could be phagocytozed by monocytes. We obtained positive signals of the replicative hepatitis C virus genome not only in lymphocytes but also in monocytes. CONCLUSIONS: RT-PCR in situ hybridization with a nonradioactive probe was found to be useful for in situ detection of hepatitis C virus RNA. Our findings suggest that peripheral blood mononuclear cells may be extrahepatic replication sites for hepatitis C virus.

An autopsy case of POEMS syndrome with a high level of IL-6 and VEGF in the serum and ascitic fluid.

A 45-year-old woman was hospitalized because of systemic edema and peripheral nerve impairment. The patient had complications of organomegaly, endocrinopathy, and monoclonal gammmopathy, and was diagnosed with POEMS syndrome based on these characteristic signs and symptoms. Interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) levels in the serum and ascitic fluid were high. Many of the patient's symptoms were ameliorated, and IL-6 and VEGF levels in the serum and ascitic fluid decreased slightly during chemotherapy, but she died of respiratory failure. Autopsy revealed severe systemic edema and macroscopic hemorrhage in many organs, but VEGF and IL-6 producing cells were not found.

Sporadic intra-abdominal desmoid with acute abdomen.

We report a 72-year-old man with sporadic intra-abdominal desmoid tumor manifesting as acute abdomen. CT scan revealed an air-containing tumor 7 cm in diameter; three weeks later, the tumor had shrunk to 4 cm on antibiotics. At surgery, a tumor arising from the transverse colon mesentery and infiltrating the jejunum was resected. No recurrence occurred over a 1-year follow-up.

Alterations to hepatic microcirculation in thioacetamide-induced cirrhotic livers of rats.

In liver cirrhosis, increased resistance of intrahepatic microvasculature contribute to the development of portal hypertension. This study aimed to reveal the alterations to hemodynamics in microvasculature of thioacetamide-induced fibrotic and cirrhotic rat livers, using in vivo microscopy. In fibrotic livers, although intrahepatic blood flow remained unaltered, area percentage of sinusoids was significantly decreased. In cirrhotic livers, intrahepatic blood flow was significantly increased concurrently with decrease in area percentage of sinusoids. The flow velocity and volume flow were significantly increased in terminal portal venules (TPVs) without changes in vascular diameters, whereas all these parameters were not altered in terminal hepatic venules (THVs). Intrahepatic shunts which emerged from TPVs and ran toward THVs, and anastomoses between neighboring THVs were formed in cirrhotic livers. These data indicate that the first occurring alteration of microcirculation in liver cirrhosis is decrease in sinusoidal beds.