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.

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.

Myocyte hypertrophy in the transplanted heart. A morphometric analysis.

In order to better define long-term changes in the transplanted heart with respect to the effects of cyclosporine and the ischemic time of the donor heart, endomyocardial biopsies were examined ultrastructurally from 20 cardiac transplant recipients three years posttransplantation. The biopsies were divided into four groups of five based on the donor heart ischemic time in "on-site" versus "distantly procured" hearts and on the immunosuppression protocol: group A: "on site" donor hearts and cyclosporine-based immunosuppression; group B: "on site" donor hearts with conventional immunosuppression (azathioprine-based immunosuppression without cyclosporine); group C: distantly procured donor hearts treated with cyclosporine; and group D: distantly procured donor hearts treated with conventional immunosuppression. All four groups showed a significant increase in the average width of myocytes when compared with normal myocardium, (group A, P less than 0.05; groups B, C, D, P less than 0.01). Also, there was a significant difference between the average widths of myocytes from on-site donor hearts and distantly procured donor hearts (P less than 0.04). There was no significant difference between the average myocyte widths of groups treated with cyclosporine and those with conventional immunosuppression. This study shows that despite the hypertension induced by cyclosporine, myocyte hypertrophy at 3 years posttransplantation does not appear to be significantly greater than in patients treated with conventional immunosuppression. Distantly procured donor hearts have more hypertrophy. Due to the increasing evidence that cardiac hypertrophy per se may predispose to serious ventricular arrhythmias, this study supports the use of on-site as opposed to distantly procured donor hearts.

A case of overlap syndrome of systemic sclerosis and dermatomyositis with right ventricular dysplasia.

We report a 39-year-old woman with overlap syndrome of systemic sclerosis and dermatomyositis who died of congestive heart failure. The pathologic findings of the heart included contraction band necrosis and myocardial fibrosis. Unique was the finding of remarkable replacement of the right ventricle with fatty tissue.

Nodular regenerative hyperplasia of the liver associated with primary pulmonary hypertension.

Nodular regenerative hyperplasia (NRH), a rare hyperplastic condition of the liver, is reported in two patients with primary pulmonary hypertension (PPH). The first patient was a 26-year-old man who died of PPH and showed multiple NRH without cirrhosis of the liver. The second patient was a 25-year-old man who had a PPH with pulmonary arterial thrombi and NRH of the liver. NRH has been described in association with immune disease, hematopoietic disorder, and diabetes mellitus, so that NRH with PPH is considered to be very rare. Histologic findings of the lungs show typically plexogenic pulmonary arteriopathy in both cases, and the livers of these patients are composed of multiple nodules that are histologically represented by slightly larger hepatocytes arranged in a cobblestone-like fashion, and are ultramicroscopically characterized by massive proliferation of mitochondria. The pathogenetic association of nodular regenerative hyperplasia with primary pulmonary hypertension will be discussed.

Congenital nemaline myopathy with dilated cardiomyopathy: an autopsy study.

A 3-year-old boy with congenital nemaline myopathy had generalized muscle weakness and hypotonia since birth. He developed cardiac symptoms at 2 years of age and died from congestive heart failure. At autopsy, the heart was markedly dilated, involving both ventricles. Rod bodies were recognized not only in skeletal muscles but in cardiac muscles on light and electron microscopy. Desmin and alpha-actinin, which constitute Z-line protein, were shown to localize in the rod structures in both skeletal and myocardial cells by immunohistochemistry. Seven cases of nemaline myopathy with cardiomyopathy have been reported in the literature. All of these patients were over 20 years of age, and the condition appeared mostly in the adult onset and the asymptomatic forms. This is the first infantile case of congenital nemaline myopathy which showed dilated cardiomyopathy with a fatal outcome.

Prophylactic treatment of cytomegalovirus infection with traditional herbs.

Hot water extracts of four traditional herbs, Geum japonicum, Syzygium aromaticum, Terminalia chebula and Rhus javanica, which have been shown to have anti-herpes simplex virus (HSV) activity in vivo, were examined for anti-cytomegalovirus (CMV) activity in vitro and in vivo in this study. They inhibited replication of human CMV and murine CMV (MCMV) in vitro. These anti-CMV activities in vivo were examined in an MCMV infection model using immunosuppressed mice. Mice were subcutaneously treated with various doses of cyclosporine, and immunosuppression and MCMV infection were monitored by suppression of antibody production and virus yield in the lung, respectively. Each herbal extract was orally administered to mice treated with 50 mg/kg of cyclosporine from a day before intraperitoneal infection, and the efficacy of herbs was evaluated by the reduction in the virus yield in the lung. Among them Geum japonicum, Syzygium aromaticum, and Terminalia chebula significantly suppressed MCMV yields in lungs of treated mice compared with water treatment. Efficacy of oral treatment with 750 mg/kg per day of Geum japonicum extract was similar to that of the intraperitoneal administration of 2 mg/kg per day of ganciclovir in increasing the body weight of infected mice and reducing the virus yield in the lungs. These herbs may be beneficial for the prophylaxis of CMV diseases in immunocompromised patients.

Caffeine inhibits paresthesia induced by herpes simplex virus through action on primary sensory neurons in rats.

Herpetic infection causes paresthesia, including hypoalgesia, in humans and hypoalgesia in rats. This study was conducted to examine the effect of caffeine, which inhibits replication of herpes simplex virus type-1 (HSV) and affects several neuronal functions, on HSV-induced paresthesia in rats. HSV-induced hypoalgesia was suppressed by repeated treatment of unilateral hindpaw with 10% caffeine gel regardless of when the treatment was started. Repeated treatment with acyclovir, an anti-HSV agent, suppressed HSV-induced hypoalgesia only when started before inoculation; acyclovir did not produce therapeutic effects on the HSV-induced sensory abnormality. Many dorsal root ganglion neurons were positive for HSV antigen following HSV inoculation of the hindpaw. Repeated treatment with caffeine and acyclovir markedly decreased HSV antigen-positive neurons in the dorsal root ganglia when started before, but not 2 or 4 days after, infection. These results suggest that topical caffeine inhibited HSV-induced paresthesia through direct action on sensory neurons, and that not only antiviral activity but also direct alteration of neural functions are involved in the caffeine sensory actions.

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.

Histologic modification by cryopreservation in rat aortic allografts.

Histologic changes after the cryopreserved rat aortic transplantation were studied, and the influences of the cryopreservation and of the allografting on the histology were examined. Four groups of Brown Norway (RT1n) and Lewis rats (RT1(1)) were used (n = 4 at each examined period in each group): the cryopreservation-allograft group (from Brown Norway to Lewis with cryopreservation), the cryopreservation-isograft group (from Lewis to Lewis with cryopreservation), the fresh allograft group (from Brown Norway to Lewis without cryopreservation), and the fresh isograft group (from Lewis to Lewis without cryopreservation). The graft was harvested from a descending thoracic aorta of a donor rat, implanted to an infrarenal abdominal aorta of a recipient rat, and extracted at 10 days, 1, 3, 6, and 12 months after the operation. The intimal thickening, cellular loss in the media, and cellular infiltration in the adventitia were observed, which were the same phenomena seen in chronic rejection of human organ allografts. Although the degree of intimal thickening and cellular loss in the media were higher in the cryopreserved groups than in the fresh groups, the cryopreservation procedure suppressed cellular infiltration in the adventitia after allotransplantation. The immunologic attack against the graft might be diminished by cryopreservation.

Topical cooling-assisted hepatic segmentectomy for cirrhotic liver with hepatocellular carcinoma.

BACKGROUND: A safe limit for normothermic consecutive portal triad occlusion in hepatectomy for the cirrhotic liver was believed to be around 30 minutes. Possibly, the occlusion time can be prolonged by cooling the ischemic liver in vivo. We describe the technique of segmentectomy assisted by topical cooling and its usefulness in prolonging the hepatic inflow occlusion time for cirrhotic livers without causing further ischemic injury. STUDY DESIGN: Fifty patients with hepatocellular carcinoma and chronic hepatic disease who underwent right-sided segmentectomy under hemihepatic inflow occlusion were divided into two groups: normothermic (n = 27), and hypothermic with hemihepatic topical cooling using ice slush (n = 23). Segmentectomies were carried out in the same way in both groups, guided by initial enbloc ligation of the corresponding portal pedicles. RESULTS: The mean right hepatic inflow occlusion time was significantly longer in the hypothermic group than in the normothermic group (53 +/- 22 minutes compared with 17 +/- 9.3 minutes). Despite the significant difference in occlusion time, no differences were found in the recovery of hepatic functions and the incidence of postoperative complications between the groups. Intraoperative blood loss was significantly less in the hypothermic group. CONCLUSIONS: The hepatic right-sided partial inflow occlusion time can safely be prolonged to 60 to 90 minutes in the presence of cirrhosis without causing another injury from ischemia and intermittent reperfusion.

Thrombus formation by the application of thrombin to the outer surface of mouse mesenteric vein: comparison with the application of ADP.

Mesenteries of mice under anesthesia were stretched over an inverted microscope. A micropipette filled with solution containing various concentrations of ADP or thrombin was brought into contact with the outside of a mesenteric vein by micromanipulation, and then poured over the outer surface of the vein. Morphological characteristics of the thrombi and the time needed for thrombus formation were examined. Application of either thrombin or ADP to the adventitia of mesenteric veins caused thrombus formation. Although thrombi by application of ADP seemed to be anchored by direct adhesion of platelets to the exposed subendothelium, thrombi by application of thrombin seemed to be anchored by deposited fibrin.

Giant cell arteritis involving the cerebral artery.

We describe a 59-year-old Japanese man with rare complications of giant cell arteritis. He presented with aortic insufficiency due to dilatation of the aortic root. Nine years after the occurrence of aortic insufficiency, he suffered from a cerebral infarction due to occlusion of the left middle and anterior cerebral arteries, showing giant cell arteritis.

Giant cell pneumonia caused by varicella zoster virus in a neonate.

A premature male neonate, born at the 25th gestational week, developed pneumonia six days after delivery and died. Postmortem examination of the lungs revealed giant cell pneumonia with intranuclear inclusion bodies; varicella zoster infection was confirmed by immunoperoxidase stain using monoclonal antibody to varicella zoster virus and electron microscopic examination. In previously reported necropsy cases of numerous giant-cell formation in the lung is not mentioned. Therefore, the unusual features prompting this report include the absence of skin lesions in this mother and infant and the presence of giant cell pneumonia, not previously reported in varicella zoster infection.

Histological change in cryopreserved rat aortic allograft.

In this study, we established an experimental cryopreserved aortic allograft model in rats and examined the long-term histological changes in the allograft. The thoracic aorta of Brown Norway rats (RT1n) was cryopreserved with 10% dimethylsulfoxide using a programmable freezer, and was allo-transplanted to the infrarenal abdominal aorta of Lewis rats (RT1l). Neither immunosuppressants nor anticoagulants were administered postoperatively. As a control, isografting was also performed between Lewis donor and recipient rats. In the allograft groups, cellular infiltration in the adventitia was massive at the acute phase after the operation and decreased gradually. Intimal thickening was predominantly observed from the early stage, followed by advancing thickening. In the media, decrease in cell number was detected after 1 month, and chondrocyte-like-cells were observed around which calcification was noted. Endothelial cells were observed in only one-third of the recipient investigated at 10 days and in over 80% of those at 12 months. In the isograft groups, a low grade of intimal thickening was detected over the experimental period. No decrease in cell number in the media was detected, and the degree of cellular infiltration in the adventitia was mild. After allotransplantation of the cryopreserved rat aorta, intimal thickening, medial necrosis and cellular infiltration in the adventitia, all the manifestations of rejection, occurred. Thus, as the cryopreserved tissue induces an immunological response, it is important to match the blood type and/or histocompatibility in clinical use.

Pulmonary thromboembolic hypertension in systemic lupus erythematosus with lupus anticoagulant: histopathological analysis of localization and distribution of thromboemboli in pulmonary vasculature.

We report a systemic lupus erythematosus patient with lupus anticoagulant accompanied by pulmonary thromboembolic hypertension possibly due to large vegetation of the tricuspid valve of the heart. Histopathological analysis of localization and distribution of thromboemboli in pulmonary vasculature revealed that the organized thromboembolic occlusion of multiple blood vessels (99 out of 222 arteries), might be responsible for the pulmonary hypertension both in quality and quantity. The contribution of lupus anticoagulant to the pathogenesis of Libman-Sacks endocarditis in systemic lupus erythematosus, and its possible relationship to pulmonary thromboembolic hypertension are discussed.

A huge coronary aneurysm resulting from a coronary artery-to-left ventricle fistula.

A huge coronary aneurysm resulting from a coronary artery-to-left ventricle fistula is a rare condition. A 57-year-old male had severe recurrent angina attacks. The cause of angina pectoris was a right coronary artery-to-left ventricle fistula with a huge coronary aneurysm. The histological examination of surgically excised specimens revealed that two vertical smooth muscle layers of media of the aneurysm might be associated with dysplasia. Mucoid degeneration was also shown in the intima and around the vasa-vasorum. Abnormal hemodynamics related to the fistula might have induced these vessel wall changes resulting in the huge coronary aneurysm.

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.

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.

Persistent infection with human polyomavirus revealed by urinary cytology in a patient with heart transplantation. A case report.

BACKGROUND: Management after heart transplantation must deal with the twin risks of rejection and infection. Early infection with viral infection, particularly cytomegalovirus (CMV), is becoming more prevalent two to three months after transplantation. To our knowledge, there has been no previous report of human polyomavirus (HPOV) infection after heart transplantation. CASE: A 20-year-old male with a history of Kawasaki disease and who had suffered from severe congestive heart failure after a coronary artery bypass graft, underwent heart transplantation. Urinary cytology demonstrated HPOV infection, the diagnosis of which was established by the immunoperoxidase technique, in situ hybridization and electron microscopy. CONCLUSION: The definitive diagnosis of HPOV infection after a heart transplant can be made on urinary cytology.