Interleukin 12 is a primary cytokine responding to influenza virus infection in the respiratory tract of mice.

We have reported previously that an increase in interleukin 12 (IL-12) production in the lungs of mice infected with Influenza A virus or an intranasal (i.n.) administration of IL-12 to the infected mice alleviated pneumonia (Tsurita et al., J. Pharmacol. Exp. Therapeut. 298, 362-368, 2001). In this study, we found that in the bronchoalveolar lavage fluids (BALF) obtained from mice infected i.n. with Influenza A virus IL-12 was elevated on day 1 post infection (p.i.) and was followed by tumor necrosis factor alfa (TNF-alfa), IL-18, and interferons alfa, beta, and gama (IFN-alfa, -beta, and -gama) on day 2 p.i. Histochemical analyses of the infected lungs on day 1 p.i. showed the presence of IL-12 and IL-12 mRNA in mononuclear and macrophage-like cells and co-localization of macrophages with viral antigen, while other cytokines were absent. Thus, IL-12 was produced by macrophages infiltrating the infected epithelium as the first response cytokine and its production at the site of infection may direct an early immune defense to alleviate the severity of infection.

[Extrapleural pneumonectomy of malignant pleural mesothelioma].

We analyzed 7 patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy. Six men and a woman had a mean age of 65 years old. The postoperative mortality rate was 14% (1 death) and morbidity, 43% (3 cases). According to staging of International Mesothelioma Interest Group, 2 patients had stage I disease, 1 did stage II, 3 did stage III and 1 did stage IV. Local recurrences were found in 3 patients and metastasis in 2. In patients with local recurrences, 2 had irradiation with chemotherapy and 1, irradiation. In patients with recurrences of metastasis, 1 had chemotherapy and 1, supportive care. Seven patients with extrapleural pneumonectomy and 10 without surgery had median survivals of 16 months and 10 months, 1-year survival rates of 71% and 40% and 2-year survival rates of 57% and 0% respectively (p=0.071). Extrapleural pneumonectomy with adjuvant therapy could be effective treatment for malignant pleural mesothelioma.

Left-hand-assisted laparoscopic resection of hepatocellular carcinoma in an accessory liver.

We report a left-hand-assisted laparoscopic resection of hepatocellular carcinoma that developed in an accessory liver in a 47-year-old man. Preoperative assessment of the location of the tumor and the feeder vessels by combined selective angiography and computed tomography studies predicted the feasibility of laparoscopic procedures for complete removal of the tumor. In an attempt to avoid direct contact of the tumor capsule with rigid instruments during the operation, left-hand-assisted procedures were attempted. The encapsulated mass, 6 x 5 x 3 cm in size, was located on the posterior side of the left diaphragm, and a thin stalk between the tumor and the margin of the left lateral segment of the liver proper was recognized. Hand-assisted procedures ensured the complete mobilization of the lesion with an adequate margin, without any unexpected capsular tear. Left-hand-assisted laparoscopic procedures would be feasible for the easy and safe resection of localized hepatocellular carcinoma developing in an accessory liver.

Early augmentation of interleukin (IL)-12 level in the airway of mice administered orally with clarithromycin or intranasally with IL-12 results in alleviation of influenza infection.

The protective role of interleukin (IL)-12 against influenza infection was assessed by analyzing the efficacies of orally administered clarithromycin (CAM) as an immunomodulator and intranasal administration of recombinant IL-12 in intranasally influenza virus-infected mice. In infected mice, CAM at 20 mg/mouse/day significantly elevated the levels of IL-12 and interferon-gamma on days 2 and 3, respectively, after infection in the bronchoalveolar lavage fluid (BALF), but the levels in the sera were not affected. The levels of IL-4, -6, and -10 were not significantly affected in the sera and BALF. Corresponding with the local elevation of IL-12 level, CAM reduced virus yield and the number of infiltrated cells in the BALF, the severity of pneumonia, and mortality of the treated mice. The potential activity of CAM as an experimental immunomodulator was verified at a dose of 20 mg/mouse/day. Intranasal administration of the optimal dose (20 ng/mouse) of IL-12 on day 2 significantly reduced virus yield in the BALF after infection. The loss of body weight was significantly suppressed by IL-12 administration. The local elevation of IL-12 level at the optimal dose and timing in influenza infection was confirmed to be effective in alleviating the influenza infection in mice treated with the two different ways. Thus, the augmentation of IL-12 production or administration of supplementary IL-12 in the respiratory tract was essential in reducing virus yield in the early phase of influenza and may be crucial for recovery from influenza infection.

Second nation-wide study of atherosclerosis in infants, children and young adults in Japan.

This paper reports the results of the second nation-wide cooperative study of atherosclerosis in young Japanese, aged from 1 month to 39 years, who were autopsied between 1991 and 1995. Atherosclerotic lesions in 1066 aortas and 974 coronary arteries were classified into fatty streaks, fibrous plaques and complicated lesions and quantificated with the point-counting method. The results of this study were compared with those of the former study, which was conducted 13 years earlier in almost the same fashion as this study. Atherosclerosis of aorta, which was determined by surface involvement (SI) of atherosclerotic lesions and atherosclerotic index (AI), increased with age in both sexes of the former and the present studies and their tendency for the progression of the extent of atherosclerotic lesions appeared to be similar. In the coronary arteries, the mean values of SI and AI in the males of the present study were greater significantly than those in the male of the former studies and in the female of the both studies in the third and fourth decades. This difference suggests that atherosclerotic lesions are increasing in young Japanese males. It also suggests that these subjects may be increasingly susceptible to atherosclerotic cardiovascular disease with increasing age.

Cerebral primitive neuroectodermal tumor in an adult male. A case report.

BACKGROUND: Primitive neuroectodermal tumors (PNETs) are very rare. Malignant tumors of the cerebrum in young individuals are composed predominantly of undifferentiated cells, with moderate differentiation along either neuronal or glial lines. To our knowledge, cerebral PNETs in adults are extraordinarily rare and have been reported in only 11 cases, with little cytologic documentation in the literature. The cytopathologic, immunohistochemical and ultrastructural features of cerebral PNET arising in an adult male are presented. CASE: A cystic tumor, on computed tomography and magnetic resonance imaging, arose from the left frontal lobe in a 39-year-old man and contained histopathologic features of PNET. Specimens obtained from surgery revealed the presence of an undifferentiated type of PNET with moderate neuronal and glial differentiation and mild characteristic findings of peripheral PNET. The cytologic and histologic specimens showed evidence of a scattered pattern of blastic and undifferentiated tumor cells and a neural arrangement with Homer-Wright-like rosettes. Immunohistochemically, the tumor cells were glial fibrillary acidic protein, neuron-specific enolase, synaptophysin and CD-99 positive and epithelial membrane antigen, S-100 protein and vimentin negative. Ultrastructurally, neither microtubular structures nor intermediate filaments, except neurosecretory granules, were found in the tumor cells. CONCLUSION: Both immunohistochemical and ultrastructural studies on cytologic and histologic slides were important for the diagnosis of PNET because of establishing not only undifferentiated tumor cells but also neural and glial differentiation.

Does topical cooling alleviate ischemia/reperfusion injury during inflow occlusion in hepatectomy? Results of an experimental and clinical study.

This study was undertaken to evaluate whether topical cooling can alleviate ischemia/reperfusion injury, after continuous inflow occlusion during hepatectomy. Using a canine model of 70% partial liver ischemia (60 min), alteration in the subcellular (cytoplasm, mitochondria, nucleus) elements calcium, sodium, potassium, and chloride, and liver functions following reperfusion were compared between control livers and livers subjected to topical cooling down to 23 degrees +/- 4.9 degrees C by seeding ice slush over the ischemic lobe. The elements were determined by X-ray microanalysis using liver biopsy specimens. A similar clinical study was undertaken examining ten patients with hepatocellular carcinoma and chronic liver disease who underwent right-sided segmentectomy under continuous right inflow occlusion, five of whom were given topical cooling and five of whom were not. In the experimental study, postreperfusion worsening of liver function tests was significantly suppressed in the cooling group, which was associated with the suppression of subcellular Ca, Na, and Cl increases and K decreases after reperfusion. In the clinical study, the occlusion time was significantly longer in the hypothermic patients than in the normothermic patients, but no significant differences in postoperative liver function or postischemic increases in Ca, Na, or Cl and decreases in K were observed. These experimental and clinical findings suggest that topical cooling alleviates ischemic insult and enhances safe prolonged inflow occlusion.

Recurrent incompetence of repaired floppy mitral valves and the severity of myxomatous degeneration.

The purpose of this study was to clarify whether or not severe myxomatous degeneration impairs the stability of a repaired mitral valve after valve-conservative surgery. A total of 21 patients who underwent successful valve-conservative surgery for pure isolated mitral incompetence were classified into two groups, one comprising those with stable mitral valve function and the other comprising those who developed recurrent incompetence within 1 year after surgery. The histological severity of myxomatous degeneration of the mitral leaflet was compared between the two groups, based upon microscopic observation and quantification of the myxomatous area in the fragment that had been surgically excised from the floppy mitral leaflet during valve-conservative surgery. The degree of myxomatous degeneration of the surgically excised fragment was significantly higher in the "recurrent" group than in the "stable" group (P = 0.02). As a microscopically confirmed severely degenerative myxomatous mitral valve may develop recurrent incompetence after valve-conservative surgery within a relatively short period, careful and regular follow-up is required.

Transmural necrosis of the esophagus secondary to acute aortic dissection.

A case of transmural ischemic necrosis of the esophagus secondary to aortic dissection is presented. A 66-year-old woman with acute type A aortic dissection underwent total arch replacement with a technique of deep hypothermic arrest and retrograde cerebral perfusion. Postoperatively she had hematemesis, and endoscopic examination revealed circumferential mucosal necrosis and desquamation of the lower esophagus. She died of multiple organ failure on postoperative day 74. Autopsy demonstrated transmural necrosis of the esophagus secondary to ischemia. Ischemia of the esophagus secondary to aortic dissection is extremely rare.

Cardiac transplantation under new legislation for organ transplantation in Japan: report of two cases.

During the past 2 years since new legislation for organ transplantation from brain-dead donors came into effect in Japan, 3 cardiac transplants have been carried out, 2 of which were performed at the National Cardiovascular Center (NCVC). The recipient cases were 46- and 25-year-old male patients who suffered from end-stage dilated cardiomyopathy and had been listed for cardiac transplantation in the Japan Organ Transplantation Network as status I candidates. The first patient was supported by the use of a paracorporeal air-driven left ventricular assist device of the NCVC type, and had a moderate degree of renal and hepatic dysfunction at the time of transplantation. Donor hearts were transported from distant hospitals (Tokyo and Miyagi prefecture) and the transportation time was 1 h 33 min and 2h 4 min, respectively. The operation was performed by the standard technique (Lower-Shumway) in the first patient and by the bicaval anastomosis technique in the second patient. Reperfusion of the transplanted heart was performed retrogradely through the coronary sinus utilizing leukocyte-depleted blood with a gradual increase in temperature. Total ischemic time was 3 h 34 min and 3 h 35 min, respectively. Weaning from the cardiopulmonary bypass was easy and uneventful in each patient. Immunosuppressive therapy was conducted with OKT-3 induction in the first patient because of the coexisting renal dysfunction and with a triple immunosuppressive regimen for both patients. Routine endomyocardial biopsy showed acute rejection of less than grade Ib, and the patients were discharged on the 65th and 46th postoperative day, respectively. At present, both patients are in the NYHA class I state and are ready to return to work. The uneventful recovery seen in these patients shows the advances made in transplant medicine, including the progress and improvement of immunosuppressive therapy, surgical techniques, myocardial protection, and detection and treatment of infection. Further efforts are required to fully establish the cardiac transplantation program in Japan.

Long-term gene expression in the anterior horn motor neurons after intramuscular inoculation of a live herpes simplex virus vector.

To clarify the feasibility of the herpes simplex virus (HSV) vector in expressing the foreign gene in the motor neuron, we inoculated a live attenuated HSV expressing beta-galactosidase (beta-gal) activity under a latency-associated transcript promoter in the right gastrocnemius muscle of rats. Expression of beta-gal activity was observed 5 days after inoculation in the bilateral anterior horn cells of the spinal cord that innervates the inoculation muscle. However, the spread of beta-gal activity was not observed in the inoculation muscle. Without significant pathological changes, the spread of beta-gal-expressing neurons was observed in the lumbosacral spinal cord until 14 days after inoculation with staining concentrated in the anterior horn cells. Ninety percent of the anterior horn motor neurons expressed beta-gal activity with expression continuing to at least 182 days after inoculation. Thus beta-gal activity was expressed in the bilateral anterior horn cells at the lumbosacral spinal cord that innervates the inoculated muscle for a long time, possibly a life-long period. This indicates that this recombinant HSV vector system to motor neurons may further improve the understanding and treatment of neurological diseases in motor neurons of the spinal cord.

Differences in left ventricular response between rheumatic and myxomatous mitral valve disease following mitral valve replacement.

OBJECTIVE: We studied whether differences exist between hearts having rheumatic mitral valves and those having myxomatous mitral valves, in functional, geometrical, and mass changes in the left ventricle after mitral valve replacement. METHODS: Patients who underwent mitral valve replacement without preservation of annular-papillary continuity for pure mitral incompetence were classified into rheumatic and myxomatous based on valvular histopathology. Echographic data measured before surgery was compared to that about 3 weeks after surgery. RESULTS: In the rheumatic group, ejection fraction decreased from 57.5 +/- 10.8 to 47.7 +/- 12.0, indexed left ventricular internal dimension in systole (mm/m2) from 24.7 +/- 6.8 to 20.7 +/- 6.2 (P = 0.0001), and left ventricular mass index (g/m2) from 205 +/- 55 to 138 +/- 54 (P = 0.0002). In the myxomatous group, ejection fraction decreased from 60.4 +/- 11.6 to 39.7 +/- 14.5 (P = 0.0001), indexed left ventricular internal dimension in systole from 24.2 +/- 5.6 to 23.1 +/- 5.5, and left ventricular mass index from 195 +/- 83 to 111 +/- 72 (P = 0.0004). Mean wall thickness index and relative wall thickness showed significant differences between the two groups postoperatively but no significant difference preoperatively. CONCLUSION: Hearts dilated due to chronic mitral incompetence respond differently after valvular replacement with total chordal excision depending on whether a rheumatic or myxomatous mitral valve is involved.

Histologic comparison of coronary and iliac atherectomy tissue from cases of in-stent restenosis.

Pathologically, restenotic lesions after stenting were investigated by use of atherectomized tissues of seven coronary and seven iliac arteries. The mean interval of the stent deployment to restenosis was 9.1 months for the coronary artery and 33.7 months for the iliac artery, indicating a 3.7-fold longer interval for the latter. This study does not include cases of acute thrombotic occlusion. The atherectomized tissue from restenotic coronary arteries showed abundant neointima with alpha-actin-positive and ultrastructually synthetic-type smooth muscle cells in a rich myxomatous extracellular matrix. In the iliac arteries, the predominant component of restenosis consisted of organized thrombi. The neointima of the iliac arteries was mature, and only a small amount of spindle cells were observed in the hyalinized matrix. The tissue that developed restenosis after stenting was different in the coronary and iliac arteries included in this series. This study on the atherectomized tissue suggests that even in the chronic stage, a major cause of in-stent restenosis among the larger caliber vessels such as the iliac artery is not neointima but stent thrombosis.

Sutured wound in myxomatous mitral valve one month after repair surgery: report of two cases.

There have been no reports concerning wound healing at the site of the suture line in myxomatous leaflets. We microscopically studied the sutured wounds in two myxomatous posterior mitral leaflets which underwent quadrangular resection of the frail middle segment followed by primary suture. The sutured wounds had a thick scar which was abundant in collagen fibers about 1 month after the repair surgery. This suggests that severe myxomatous degeneration itself would not be a cause of wound dehiscence, and that a sutured wound could be a cause of rigidity and deformity of leaflets.

Dynamics of portal and peripheral endothelin-1 in hepatic resection and its implication.

BACKGROUND: The liver and portal circulation contribute to production and clearance of endothelin-1 (ET-1). This study was undertaken to investigate what variables relate to the dynamics of ET-1 in hepatic resection and its clinical implication. PATIENTS AND METHODS: On 20 patients with (n = 8) or without (n = 12) chronic liver disease who underwent hepatic resection, peripheral arterial and portal venous ET-1 were serially measured to determine a correlation with pre-, intra-, and postoperative variables. RESULTS: The preoperative factors with which the portal ET-1 showed a positive correlation were the indocyanine green retention rate at 15 min (ICG R15) and portal venous pressure. The ET-1 clearance, as calculated from the difference between the portal and the peripheral ET-1 concentrations, was also correlated with the ICG R15. The peripheral ET-1 elevated significantly in the patients with increasing intraoperative blood loss or hepatic inflow occlusion. An increase in the portal ET-1 was correlated with an elevation of portal venous pressure after hepatectomy. Postoperative increase in serum bilirubin was closely correlated with the peripheral ET-1 at closure. CONCLUSION: The peripheral and portal ET-1 are correlated with not only preoperative hepatic reserve and portal venous pressure but also invasiveness of hepatectomy and postoperative course.

Cytopathological observations in a 27-year-old female patient with endometrioid adenocarcinoma arising in the lower uterine segment of the uterus.

The determination of the malignancy of an endometrioid adenocarcinoma arising in the lower uterine segment (LUS) is difficult because of the high degree of differentiation of adenocarcinoma. The cytopathological and immunohistochemical features of endometrioid adenocarcinoma arising in the LUS of a young adult female are presented. The preoperative cytopathological examination of a 27-yr-old female could not enable an accurate diagnosis of malignancy. Hysterectomy specimens revealed the presence of an endometrioid-type adenocarcinoma with minimal atypia and myometrial invasion, which was located in the LUS. This tumor was consistent with a histological diagnosis of endometrioid minimal-deviation adenocarcinoma (MDA). Immunohistochemically, the tumor's glands were p53-, proliferating cell nuclear antigen-, and carcinoembryonic antigen-positive, and estrogen receptor-, progesterone receptor-,and vimentin-negative. The cytological and surgical specimens showed a remarkable association of squamous metaplasia. Although cytopathological difficulties in determining malignancy of MDA endometrioid adenocarcinoma arising in the LUS are well-known, the following features worth noting include: 1) squamous metaplasia on cytological and histological slides; 2) epithelial cells incorporating polymorphic nuclear neutrophils on cytological slides; and 3) positive immunohistochemistry of p53 protein. Diagn. Cytopathol. 1999;21:117-121.

Late in-stent restenosis of the abdominal aorta in a patient with Takayasu's arteritis and related pathology.

This report describes an in-stent restenosis of the infrarenal aorta in a patient with Takayasu's arteritis in a nonactive state. A 10-mm-diameter Wallstent had been deployed 42 months previously. The stented restenosed segment was replaced by a surgical graft. Histopathological examination of the excised aortic segment showed a thin layer of fibrocellular neointima and massive organized and calcified thrombus. To our knowledge, this is the first histopathological report of a late in-stent restenosis of the abdominal aorta in Takayasu's arteritis.

Coronary atherosclerosis and interventions: pathological sequences and restenosis.

The primary cause of cardiac morbidity and mortality in developed countries is ischemic (coronary) heart disease. The incidence of this disease is virtually all due to atherosclerosis, and ischemic heart disease is also the most prevalent disease in the industrialized world, causing over 40% of all deaths in the United States and Western Europe. In Japan, the incidence of ischemic heart disease due to coronary atherosclerosis is gradually increasing as well. Compared with the classical nomenclature of atherosclerosis; that is, fatty streak, fibrous plaque and complicated lesions, the term Stary's classification has been universally accepted because it reflects the more recently acquired knowledge about the morphological and biochemical details of the processes in coronary atherosclerosis, which have been obtained by new strategies such as angioscopy, intravascular ultrasound and molecular biological methods. The term Stary's classification has been applied for the coronary atherosclerosis of patients with acute coronary syndrome at the National Cardiovascular Center, for the analysis of predisposing atherosclerosis of these patients. The recent findings regarding acute coronary syndrome resulting from a rupture of coronary atherosclerotic plaques indicate that this syndrome is probably the most important mechanism underlying the sudden onset. It has been found that the risk of plaque rupture may depend more on plaque composition than on plaque size. Plaques rich in soft extracellular lipids and macrophages are possibly more vulnerable to plaque rupture. Two of the goals of the present review are to clarify how plaque disruption occurs and to elucidate the relationship between plaque disruption and coronary risk factors in elderly Japanese patients with acute coronary syndrome. Coronary stents have been shown to be efficacious in the treatment of acute and threatened closure complicating percutaneous transluminal coronary angioplasty (PTCA) and have produced encouraging initial results in the prevention of restenosis. In the autopsy study of restenosis after PTCA, it was observed that dense caps of collagen fibers in the adventitia in the vicinity of the disrupted internal elastic laminae were present in all of the remodeling lesions. It is suggested that remodeling, which resulted in adventitial scarring, is one of the major causative factors of restenosis after PTCA. The long-term success of stenting, however, remains limited by the occurrence of late in-stent restenosis, with an incidence of 20-42% depending on the stent design and the patient population studied. Another aim of the present review is to describe the pathological mechanism of restenosis after PTCA and/or stent replacement and, consequently, the vascular remodeling that occurs around adventitial tissue after PTCA and intimal hyperplasia that is chronically irritated by a foreign body granulomatous reaction after stenting. Finally, the results of the investigation of the effect of a tissue factor pathway inhibitor on the prevention of interventional restenosis is described.