[Primary nasopharyngeal tuberculosis].

A 59-year-old female was complaining of sore throat, right otorrhea, and hearing impairment. There were no abnormal findings suggestive of pulmonary tuberculosis on her chest XP and CT. Nasopharyngoscopic examination detected a lesion coated with white mass on her nasopharynx, and a biopsy-specimen from this lesion revealed histopathological findings compatible with tuberculosis and the presence of acid-fast bacilli. PCR was positive for Mycobacterium tuberculosis complex. Therefore, we diagnosed the case as primary nasopharyngeal tuberculosis and treated her by 4-drug combination regimen with daily isoniazid, rifampicin, ethambutol and pyrazinamide. Later, low degree of resistance was noticed, isoniazid was replaced by levofloxacin. After the anti-tuberculosis chemotherapy, her symptoms almost completely diminished and the mass in her nasopharynx disappeared. As far as we can search, 23 Japanese cases of primary nasopharyngeal tuberculosis, including this case, have been reported in the literatures. We summarized the clinical features of these cases in Table. Nasopharyngeal tuberculosis is a rather rare disease. But, recently, due to the advances in diagnostic technology, the number of the case-reports has been increasing. Difficulties in detecting tubercle bacilli in nasopharyngeal lesion sometimes delayed definite diagnosis and treatment. If a patient complains the symptoms compatible with this disease, such as sore throat, pharyngeal pain and otorrhea, which are refractory to the general antibiotic therapy, we should be aware of the existence of this disease and repeat bacteriological and/or molecular examinations to prove tubercle bacilli to be able to start timely anti-tuberculosis chemotherapy.

Phenotypic change and accumulation of smooth muscle cells in strictures in Crohn's disease: relevance to local angiotensin II system.

BACKGROUND: Intestinal stricture lesions in Crohn's disease are characterized as submucosal fibromuscular accumulation. There has been a controversy about whether the fibrogenic cells in stricture lesions in Crohn's disease originate from a smooth muscle cell or a fibroblast lineage. In the present study, we aimed to elucidate: (1) the origin of the fibrogenic cells in stricture lesions; and (2) the roles of the local angiotensin II system, including mast cell chymase, in stricture formation. METHODS: Methanol-Carnoy's-fixed colonic tissues, obtained from the stricture sites of 18 patients with Crohn's disease, were analyzed by immunostaining for vimentin, smooth muscle actin (1A4 and CGA7), angiotensin II type-1 receptor, angiotensin II-converting enzyme, and mast cell tryptase and chymase. As controls, unaffected (normal) portions of 11 colonic tumor specimens were also investigated. RESULTS: Submucosal fibromuscular accumulation was seen in every stricture lesion. The majority of mesenchymal cells accumulated in the stricture lesions were moderately differentiated intestinal smooth muscle cells [vimentin(+), 1A4(+), and CGA7(+)]. Moreover, occasional intestinal smooth muscle cells in the muscular layers, adjacent to the site of the submucosal fibromuscular response, showed distinct positivity for vimentin, indicating phenotypic modulation toward an immature, or dedifferentiated state. These smooth muscle cells accumulated in the stricture lesions were positive for angiotensin II type-1 receptor. Abundant chymase-positive mast cells were distributed in these lesions. CONCLUSIONS: These results suggest that the proliferation and migration of moderately differentiated intestinal smooth muscle cells from the muscular layers are the major pathological mechanisms in stricture formation in Crohn's disease, and the angiotensin II system is involved in this process.

Small coronary calcium deposits and elevated plasma levels of oxidized low density lipoprotein are characteristic of acute myocardial infarction.

AIM: Predictions of the onset of acute myocardial infarction (AMI) in high risk individuals are of great clinical importance. Among various risk factors, elevated levels of oxidized low density lipoprotein (ox-LDL) in plasma have been shown to reflect unstable coronary plaques. Coronary calcification is a common finding in the elderly, however, its clinical implications as a risk factor for plaque rupture are controversial. This study was designed to investigate the clinical implications of plasma ox-LDL levels and coronary calcification detected by electron-beam computed tomography (EBCT), by comparing patients with AMI with those with stable angina pectoris (SAP). METHODS: We measured plasma ox-LDL levels in AMI (n=34) and SAP (n=49) patients. In addition, a coronary calcium score was quantified with the Agatston system. The total coronary calcium score (TCS) was defined as the sum of the scores for each lesion. RESULTS: TCS and total calcium area were significantly smaller in patients with AMI than in those with SAP. On the other hand, plasma ox-LDL levels were significantly higher in AMI patients than in SAP patients (p<0.0005). CONCLUSION: These results suggest that a combined assessment of coronary calcium and plasma ox-LDL levels may be useful for screening patients with unstable coronary plaques.

Elevated plasma levels of oxidized low-density lipoprotein relate to the presence of angiographically detected complex and thrombotic coronary artery lesion morphology in patients with unstable angina.

BACKGROUND: Increased levels of oxidized low-density lipoprotein (ox-LDL) are related to plaque instability, so the aim of the present study was to investigate whether there is a relationship between angiographic coronary plaque morphology in patients with unstable angina pectoris (UAP) and the level of ox-LDL. METHODS AND RESULTS: Plasma ox-LDL levels were measured in 149 patients with UAP and in 88 control subjects, using a highly sensitive enzyme-linked immunosorbent assay method. Angiographic morphology of the culprit lesion was classified as either simple or complex based on the Ambrose classification. Plasma ox-LDL levels in patients with Braunwald class III were significantly higher than in patients with class I (p<0.0001) or in control subjects (p<0.0001). In each of the 3 Braunwald classes, plasma ox-LDL levels in patients with a complex lesion were significantly higher than in patients with a simple lesion. Multivariate logistic regression analysis revealed that ox-LDL level and Braunwald class III were independent factors associated with angiographically detected complex lesions. CONCLUSION: In each Braunwald class of UAP, elevated plasma levels of ox-LDL closely relate to the presence of angiographically detected complex and thrombotic lesion morphology.

Enhanced mast cell chymase expression in human idiopathic interstitial pneumonia.

Previous studies have shown that mast cell chymase induces and promotes fibrogenesis in injured tissues. We studied the roles of mast cell chymase in the fibritic processes of human idiopathic interstitial pneumonias. Frozen tissue sections from human lungs with usual interstitial pneumonia (n=7), nonspecific interstitial pneumonia (n=4) and normal lungs (n=10) were studied immunohistochemically. Monoclonal antibodies against mast cell chymase, tryptase, interleukin-4, and smooth muscle actin were used. Stained cells or areas were quantified by computer-aided morphometry. The numbers of both tryptase-positive mast cells and chymase-positive mast cells were significantly greater in lung tissues with idiopathic interstitial pneumonia than in normal lung tissues. The increase in the number of chymase-positive mast cells in the diseased lung tissues was closely related to an increase in interleukin-4-positive cells, and also to an accumulation of smooth muscle cells and myofibroblasts. Because smooth muscle cell and myofibroblast proliferation is a principal pathological change in idiopathic interstitial pneumonias, these observations suggest that mast cell chymase, possibly induced by interleukin-4-dependent phenotypic modulation, may be an important mediator in the inflammatory and fibrotic processes of idiopathic interstitial pneumonia in humans.

Enhanced expression of angiotensin II type 1 receptor in usual interstitial pneumonia.

BACKGROUND: Angiotensin II, a potent vasoconstrictor, has been considered to be involved in various fibrotic disorders including idiopathic interstitial pneumonias. To clarify whether this agent contributes to the development and progression of usual interstitial pneumonia, a major entity of idiopathic interstitial pneumonias, we immunohistochemically examined expression of its specific receptor, angiotensin II type 1 receptor, in human normal and diseased lung tissues. METHODS: Video-assisted thoracoscopic lung biopsy specimens obtained from patients with usual interstitial pneumonia (n=8) were sectioned and stained using single or double immunostaining techniques with specific antibodies against angiotensin II type 1 receptor and smooth muscle actin. Lung tissues of desquamative interstitial pneumonia (n=2) and normal lung tissues (n=6) were also examined for comparative analyses. RESULTS: Expression of angiotensin II type 1 receptor was limited in vascular and bronchial smooth muscle cells in normal lungs. In contrast, the receptor-positive mesenchymal cells, most of which were also positive for smooth muscle actin and arranged like a bundle, were markedly increased in association with dense collagen deposition in thickened alveolar walls of usual interstitial pneumonia. In desquamative interstitial pneumonia, the fibroproliferative change, including angiotensin II type 1 receptor-positive mesenchymal cell proliferation, was milder than that in usual interstitial pneumonia. CONCLUSIONS: These findings suggest that angiotensin II and its type 1 receptor play a profibrogenic role in idiopathic interstitial pneumonias, particularly in usual interstitial pneumonia. Furthermore, angiotensin II type 1 receptor-positive smooth muscle cells increased in diseased lung tissues may be contractile and may contribute to reduction of airspaces in usual interstitial pneumonia.

Expression of cyclooxygenase-2 in Hodgkin's lymphoma: its role in cell proliferation and angiogenesis.

Although many studies have revealed the association between cyclooxygenase-2 (COX-2) and carcinogenesis, the association between COX-2 and Hodgkin's lymphoma (HL) remains unknown. We examined the immunohistochemical expression of COX-2, p53, bcl-2, and Ki-67 in 33 patients with HL, and counted microvessels stained with CD34. Hodgkin and Reed - Sternberg (HRS) cells with COX-2 expression were scored as 0 = no staining; 1 = <25% of cells staining; 2 = 25-49%; 3 = 50-75%; and 4 = > or =75%. COX-2 expression was observed in 15 cases of classical HL. Nevertheless, neither accumulation of p53 nor bcl-2 expression was associated with COX-2 expression. The percentage of Ki-67 positive-HRS cells and microvessel density in COX-2 score groups 2-4 were significantly higher than those in score group 0, respectively. We show that COX-2 expression is associated with cell proliferation and angiogenesis in HL. These findings suggest that COX-2 may be a target for therapy in HL.

Endothelin-converting enzyme expression in the neointima after percutaneous coronary intervention.

Smooth muscle cells (SMCs) are the major cellular component of neointimal tissues after percutaneous coronary intervension (PCI). Endothelin-1 (ET-1) is a powerful vasoconstrictor and has a mitogenic effect on SMCs. Endothelin-converting enzyme (ECE) is a key enzyme in the process of ET-1 generation. However, the expression of ECE in association with post-PCI repair processes has not been reported. Thirteen coronary sites after PCI obtained at autopsy and 6 atherectomy specimens obtained from restenotic sites were investigated. Frozen sections were stained with antibodies against ECE, SMCs, macrophages, and endothelial cells. The immunoreactivity of ECE was quantified using computer-aided planimetry. At the early stage after PCI, most neointimal SMCs expressed ECE. The ECE-positive cell area was significantly (p<0.005) larger in the sites within 3 months after PCI than in the sites from 6 months onward. In atherectomy specimens, neointimal SMCs showed distinct ECE positivity. These findings suggest that ECE is upregulated in the neointima at early stages after PCI injury. ECE may be one of the mediators in the repair processes after PCI in humans.

Close association between activated platelets and neutrophils in the active phase of ulcerative colitis in humans.

BACKGROUND: Neutrophils are considered to play a causative role in inflammatory mucosal injury in ulcerative colitis (UC), and an association between platelets and neutrophils may contribute to the progression of the inflammatory processes. To test this hypothesis, we performed immunohistochemical and flow cytometric analyses on tissue and blood samples from patients with UC. MATERIALS AND METHODS: Colonic mucosal tissues of patients with active (n = 27) or inactive (n = 16) UC and normal controls (n = 11) were subjected to immunohistochemical staining for markers of activated platelets (glycoprotein IIb/IIIa and P-selectin) and neutrophils (neutrophil elastase, myeloperoxidase, and CD66b). The amounts of stained cells were evaluated by computer-aided morphometry. Peripheral blood samples from patients (n = 8) and healthy volunteers (n = 8) were subjected to comparative flow cytometric analysis of activated platelets. RESULTS: P-selectin-positive activated platelets were frequently aggregated in the inflamed mucosa, especially in ulcerative lesions, and were close to regions of dense neutrophil infiltration. An increase in the number of activated platelets in the colonic lesions was associated with an increase in infiltrating neutrophils and was related to the severity of the disease. The flow cytometric analysis indicated that circulating platelets of patients with UC were highly activated. CONCLUSIONS: The present study demonstrated that a close association between activated platelets and neutrophils is a prominent pathological change in both the affected colonic mucosa and peripheral blood of patients with active-phase UC. This suggests that platelet-neutrophil association may play an important role in the progression of inflammatory processes in UC.

Expression of endothelin-converting enzyme, endothelin-1 and endothelin receptors at the site of percutaneous coronary intervention in humans.

OBJECTIVE: The repair process at the site of injury after percutaneous coronary intervention (PCI) is dominated by neointimal formation composed mainly of smooth muscle cells (SMC). Endothelin-1 (ET-1) is a powerful vasoconstrictor and SMC mitogen. Endothelin-converting enzyme (ECE) is the final key enzyme of endothelin processing. The effects of ET-1 are mediated by binding to endothelin type A (ETA) and endothelin type B (ETB) receptors. The ligand/receptor/ligand-producing system (ET system) could be involved in the pathogenesis of neointimal formation in humans. METHODS: Fifteen post-PCI sites obtained at autopsy and eight atherectomy specimens obtained from restenotic sites were investigated using immunohistochemical single and double staining techniques. Frozen sections were stained with antibodies against ECE, ET-1, ETA and ETB receptors, SMC, macrophages and endothelial cells. RESULTS: At the early stage, less than 3 months after PCI, neointimal SMC were positive for ECE, ET-1, ETA and ETB receptors. The expression of ECE, ET-1, ETA and ETB receptors in these neointimal SMC decreased markedly from 6 months onwards. The ECE, ET-1, ETA and ETB receptor-positive cell areas were significantly (P < 0.005) greater in the first 3 months after PCI compared with 6 months or more after PCI. Atherectomy specimens also showed similar positivity. CONCLUSIONS: These observations strongly suggest that the expression of ECE, ET-1, ETA and ETB receptors is enhanced in neointimal SMC at early stages after PCI injury in human coronary arteries. The increased expression of the ET system may contribute to SMC proliferation/migration and vasoconstriction in human post-PCI coronary lesions.

C-Type natriuretic peptide and natriuretic peptide receptors are expressed by smooth muscle cells in the neointima after percutaneous coronary intervention.

Understanding restenosis after percutaneous coronary intervention (PCI) remains a challenge. Neointimal proliferation is the main cause of restenosis. C-Type natriuretic peptide (CNP) plays a role in relaxation and growth inhibition of vascular smooth muscle cells (SMCs); the effects depend on the presence of specific natriuretic peptide receptors (NPRs) consisting of NPR-A, NPR-B, and NPR-C. To test the hypothesis that CNP and NPRs may be involved in restenosis, we immunohistochemically studied the expression of CNP and NPRs during the post-PCI healing process; 10 sites after PCI obtained at autopsy and 14 atherectomy specimens obtained from restenotic sites were investigated. Frozen sections were stained with antibodies against CNP, NPRs, SMCs, macrophages, and endothelial cells. Within 2 months after PCI, most neointimal SMCs expressed CNP and NPR-A. The expression of CNP and NPR-A in these neointimal SMCs decreased from 6 months onward. In contrast, NPR-C was strongly expressed in neointimal SMCs from 1 to 9 months after PCI. In atherectomy specimens, most neointimal SMCs showed weak positivity for CNP and NPR-A, but NPR-C was strongly expressed in the neointimal SMCs. These findings strongly suggest that a paracrine and autocrine system of CNP and NPRs may be important in controlling neointimal growth after PCI in humans.

[A case of effective readministration of itraconazole for recurrent allergic bronchopulmonary aspergillosis].

A 67-year-old woman suffered from productive cough but not from bronchial asthma. Her peripheral blood showed eosinophilia, a high serum level of total immunoglobulin E (IgE), and elevated specific IgE and positive precipitating antibody against Aspergillus fumigatus. Her chest radiograph and computed tomography revealed infiltrative shadows but not central bronchiectasis. Fibreoptic bronchoscopy detected some mucous plugs which grew Aspergillus fumigatus on culture. We therefore made a diagnosis of allergic bronchopulmonary aspergillosis (ABPA). We treated her using only itraconazole. Her respiratory symptoms, eosinophilia, serum IgE level, and pulmonary infiltration gradually improved, but withdrawal of itraconazole exacerbated her respiratory symptom and laboratory data. Administration of itraconazole again resulted in improvement of her symptoms and laboratory data. We report a case of ABPA without bronchial asthma or central bronchiectasis and refer to our diagnostic rationale. Furthermore, we discuss the decrease of allergens by the eradication of Aspergillus fumigatus in the airway with itraconazole to reduce the allergic reaction and improve the clinical symptoms.

Immunohistochemical expression of multidrug resistance proteins as a predictor of poor response to chemotherapy and prognosis in patients with nodal diffuse large B-cell lymphoma.

BACKGROUND/AIMS: The aim of this study was to determine whether expression of P-glycoprotein (P-gp), multidrug-resistance-related protein 1 (MRP1), and lung resistance protein (LRP) was related to the response to induction chemotherapy and prognosis in untreated diffuse large B-cell lymphoma (DLBCL). METHODS: We assessed immunohistochemical expression of P-gp, MRP1 and LRP, using formalin-fixed and paraffin-embedded specimens of lymph node in 41 patients with DLBCL. Association between expression of these three proteins and their impact on clinical outcome and prognosis was statistically evaluated. RESULTS: P-gp was positive in 37% of subjects, MRP1 in 63%, and LRP in 68%. The complete remission rates achieved in the group expressing these multidrug resistance (MDR) proteins was significantly lower than in the group not expressing them (20 versus 58%; p = 0.025 in P-gp, 23 versus 80%; p < 0.001 in MRP1 and 32 versus 69%, p = 0.043 in LRP, respectively). Furthermore, the patients expressing LRP had a shorter overall survival rate than those that did not (median of 26 months versus median not reached; p = 0.013). CONCLUSIONS: These findings suggest that the three MDR proteins are important predictive factors for the clinical outcome and prognosis in patients with DLBCL.

Expression of angiotensin II type 1 receptor in human cirrhotic livers: Its relation to fibrosis and portal hypertension.

Angiotensin II (ANG-II) and its receptor (AT1) have been potential targets of therapy for liver cirrhosis. However, AT1 expression in human cirrhotic livers has not been clarified. We studied AT1 and ANG-II generating enzymes in human autopsy (20 cirrhotics and 20 normal controls) and biopsy (10 cirrhotics) livers. AT1 immunoreactivity in tissue sections was quantified by computer-aided morphometry. AT1 protein and mRNA levels were assessed by Western blotting and real-time polymerase chain reaction. Concerning ANG-II generating system, angiotensin-converting enzyme (ACE) and mast cell chymase were examined. AT1 expression was seen not only in vascular smooth muscle cells, but also in activated stellate cells/myofibroblasts and liver parenchymal cells. AT1-positive vessels and myofibroblasts were significantly increased in fibrous septa of cirrhosis, although overall hepatic AT1 expression was reduced in the cirrhotic livers compared with the controls. Augmentation of AT1-positive vessels was related to severity of portal hypertension. Expressions of ACE and chymase were enhanced in the cirrhotic livers. These results suggest that hepatic AT1 expression is shifted to and concentrated in vessels and myofibroblasts in cirrhotic settings, and increased ANG-II generation by ACE and chymase contributes to portal hypertension and liver fibrosis via binding to AT1 expressed on vessels and myofibroblasts.

[Carbamazepine-induced pneumonitis definitively diagnosed by accidental readministration].

An 82-year-old man had been treated by carbamazepine for convulsions. A month later he felt febrile and malaise. Laboratory data revealed liver dysfunction, hypoxemia, and chest radiograph and computed tomography (CT) of the thorax showed ground glass opacity in both lungs and mediastinal lymphadenopathy. Analysis of bronchoalveolar lavage fluid revealed pulmonary lymphocytosis. Drug-induced lymphocyte stimulation test (DLST) for carbamazepine using peripheral blood lymphocytes was negative. We gave him a possible diagnosis of carbamazepine-induced liver damage and pneumonitis. After stopping carbamazepine, we initiated corticosteroid therapy and he recovered well. One year later he again suffered from convulsions and was treated with carbamazepine in another hospital. A week later he became febrile and suffered appetite loss, and came to our hospital. His chest radiograph and CT again showed ground glass opacity and pleural effusion in both lungs. Along with the laboratory data we established a definitive diagnosis of carbamazepine-induced pneumonitis. We discuss the mechanism of carbamazepine-induced pneumonitis in which the DLST results were negative and the challenge test was positive.

Expression of the hepatic endothelin system in human cirrhotic livers.

It is considered that endothelin-1 participates in the development of liver cirrhosis and it has been recognized that every component of the endothelin system is upregulated in cirrhotic livers. However, the expression pattern of this system, including interaction between its components, is not fully understood in human livers. In this study, the expression pattern of the endothelin system was examined. Immunohistochemical analysis for endothelin-1, endothelin receptors and endothelin-converting enzyme was performed in 16 cirrhotic and 17 normal human liver tissues. Peptides, proteins, and RNAs extracted from the livers were also investigated using quantitative assays for the components of the hepatic endothelin system. Hepatic endothelin-1 levels were significantly higher in cirrhotic livers (0.084 +/- 0.052 pg/mg wet liver) than in normal livers (0.041 +/- 0.032 pg/mg; p < 0.01), and were closely related to the severity of liver fibrosis and portal hypertension. Immunoreactivity for endothelin-1, endothelin receptors, and endothelin-converting enzyme was detected mainly in fibrous areas and in the hepatic vasculature, and was enhanced in cirrhosis. Although there was a negative correlation between the expression of receptor mRNA and the hepatic endothelin-1 level, the amounts of the mRNAs were greater in cirrhotic livers than in normal livers. However, expression of endothelin-converting enzyme in cirrhotic livers was increased at the protein level but was relatively reduced at the mRNA level. These findings suggest that the hepatic endothelin system is activated in human cirrhotic livers in association with worsening of the disease, but that the regulation of the components of this system in this disorder is complex.

Alterations of endothelin-converting enzyme expression in early and advanced stages of human coronary atherosclerosis.

Endothelin-1 is a potent vasoconstrictor and exhibits a mitogenic activity on vascular smooth muscle cells (SMCs). Endothelin-converting enzyme (ECE) is the final key enzyme of endothelin-1 processing. We studied the immunolocalization of ECE in human coronary atherosclerotic lesions with different disease stages. Frozen sections of normal coronary arteries with diffuse intimal thickening (n=13) and those of coronary arteries with early (n=10) or advanced atherosclerotic plaques (n=13) were studied. Monoclonal antibodies used were directed against SMCs, macrophages, endothelial cells, and ECE. For the identification of cell types that express ECE, double immunostaining analysis was also used. In normal coronary arteries, ECE immunoreactivity was observed in luminal endothelial cells and medial SMCs. Early atherosclerotic plaques, which consisted predominantly of SMCs, showed enhanced ECE expression in luminal endothelial cells and intimal SMCs. In advanced atherosclerotic plaques, distinct ECE expression was found in accumulated macrophages and in endothelial cells of intraplaque microvessels, while luminal endothelial cells showed relatively weak immunoreactivity for ECE. In conclusion, the present study demonstrates that the major cell types expressing ECE within the plaques are different between early and advanced stages of human coronary atherosclerosis. Enhanced ECE expression and possible endothelin-1 generation may contribute to SMC proliferation and vasoconstriction in early atherosclerotic stages, and may promote plaque destabilization in advanced atherosclerotic stages.

[Two cases of prostate cancer found primarily from lung metastatic lesions].

We report two cases of prostate cancer found primarily from a metastatic lesion appearing in a chest radiograph. Patient 1 was admitted to our hospital because his chest radiograph and chest CT showed pleural effusion on the left. Thoracocentesis and pleural biopsy were unremarkable, so he was observed as both an outpatient and an inpatient. His general condition worsened, and after the third admission, he died. His autopsy revealed prostate cancer and positive immunohistochemical reactions for PSA and PSAP in both lungs, and prostate specimens demonstrated that prostate cancer had metastasized to the lung. Patient 2 was referred for evaluation of a bilateral multiple nodular shadow in a chest radiograph, and prostate cancer was discovered. Immunohistochemical reactions for PSA and PSAP were positive in both specimens of TBLB and prostate biopsy, confirming that the multiple lung tumors were metastases from prostate cancer.