Dys-regulated activation of a Src tyroine kinase Hck at the Golgi disturbs N-glycosylation of a cytokine receptor Fms.

HIV-1 Nef accelerates the progression to AIDS by binding with and activating a Src kinase Hck, but underlying molecular basis is not understood. We revealed that Nef disturbed N-glycosylation/trafficking of a cytokine receptor Fms in an Hck-dependent manner, a possible trigger to worsen uncontrolled immune system. Here, we provide direct evidence that dys-regulated activation of Hck pre-localized to the Golgi apparatus causes this Fms maturation arrest. A striking change in Hck induced by Nef other than activation was its skewed localization to the Golgi due to predominant Golgi-localization of Nef. Studies with different Nef alleles and their mutants showed a clear correlation among higher Nef-Hck affinity, stronger Hck activation, severe Golgi-localization of Hck and severe Fms maturation arrest. Studies with a newly discovered Nef-Hck binding blocker 2c more clearly showed that skewed Golgi-localization of active Hck was indeed the cause of Fms maturation arrest. 2c blocked Nef-induced skewed Golgi-localization of an active form of Hck (Hck-P2A) and Fms maturation arrest by Nef/Hck-P2A, but showed no inhibition on Hck-P2A kinase activity. Our finding establishes an intriguing link between the pathogenesis of Nef and a newly emerging concept that the Golgi-localized Src kinases regulate the Golgi function.

Tracheobronchial pulmonary disease associated with pyoderma gangrenosum.

We report a tracheobronchial pulmonary manifestation caused by pyoderma gangrenosum, a neutrophilic dermatosis of unknown etiology. A 54-year-old man presented with pulmonary infiltrates followed by multiple painful cutaneous pustules on the scrotum. Skin biopsy showed pronounced neutrophilic infiltration without microorganism or granuloma, consistent with pyoderma gangrenosum. Bronchoscopy revealed multiple scattered polypoid nodules with a yellowish irregular surface from the trachea to bilateral bronchi; the appearance closely mimicked that of a skin lesion. Endobronchial biopsy demonstrated inflamed granulation and necrosis with infiltration by numerous neutrophils without vasculitis or granulomas, interpreted as pyoderma gangrenosum of the bronchi. Although the etiology of pyoderma gangrenosum is poorly understood, this case suggests that a common pathogenesis may account for the simultaneous cutaneous and airway inflammation.

Bronchoscopic blood injection reducing lung volume in lymphangioleiomyomatosis.

Bronchoscopic lung-volume reduction for hyperinflated air-trapping disease is currently being investigated. A 41-year-old woman with pulmonary lymphangioleiomyomatosis presented with exertional dyspnea. A chest computed tomographic scan showed hyperinflation with diffuse cystic lesions throughout both lung fields. To reduce lung volume, transbronchial autologous blood was followed by thrombin solution, which was infused into cystic areas under fluoroscopic guidance. A post-treatment computed tomographic scan showed volume reduction corresponding to decreased total lung capacity by 240 mL on body plethysmography. Dyspnea was significantly improved. Bronchoscopic treatment by blood infusion is less invasive and appears clinically valuable, potentially providing therapeutic benefit in hyperinflated lung diseases such as lymphangioleiomyomatosis.

Efficacy of low-dose imatinib in chronic-phase chronic myelogenous leukemia patients.

Imatinib mesylate is very effective in the treatment of chronic myelogenous leukemia (CML) and 400 mg/day imatinib is considered the standard treatment dose for chronic-phase (CP) patients. However, despite its relative tolerability, some patients require a lower dosage or temporary cessation of treatment because of severe adverse events. It remains unclear whether reduced-dose imatinib is as effective as the standard dose in achieving and maintaining a major molecular response (MMolR), an important goal of imatinib therapy. In this study, Japanese patients with CML-CP, as classified by their Sokal scores, were treated with imatinib. MMolR was observed in all patients with low Sokal scores who were treated with 300 or 400 mg/day imatinib, suggesting that low scores predict favorable response to treatment even at lower dosages, which is preferable since it is associated with fewer adverse events. Low-dose therapy also achieved MMolR in patients with intermediate or high scores. However, loss of complete cytogenetic response (CCgR) or an increase in BCR-ABL transcripts was noted shortly after these patients achieved CCgR, suggesting that a CCgR short of MMolR still indicated a risk of loss of response in these risk categories. MMolR was maintained in these patients by timely increases in dosage. Achieving CCgR within 12 months and maintaining it without an increase in BCR-ABL transcripts might indicate that low-dose imatinib therapy can produce acceptable outcomes without excess toxicity.

[Case of metastatic germ cell tumor with testicular calcification detected by MD-CT].

Metastasis of testicular germ cell tumor should be included in the differential diagnosis when young male patient have multiple pulmonary metastases. However burned-out tumors cannot be easily detected on inspection and palpation of the testis. A 19 year-old man visited to our hospital complaining of anorexia, weight loss and dyspnea. Chest X-ray films showed multiple lung nodules. Physical examination revealed gynecomastia, and many cervical, axillary, and inguinal lymph nodes with a diameter of 1 cm were palpable. Physical examination of testis revealed no laterality. Multi-detector CT showed multiple lung nodules, a hepatic and a retroperitoneal large mass and a tiny calcification in the right testis. Histological findings of the lung obtained by percutaneous biopsy and the presence of a calcification in the testis led to a diagnosis of testicular choriocarcinoma showing burned-out tumor. However there was no previous report of burned-out tumor detected by CT, MD-CT including that of the testis was valuable at the first diagnostic stage when germ cell tumor was suspected.

Impact of AB0-blood group incompatibility on the outcome of recipients of bone marrow transplants from unrelated donors in the Japan Marrow Donor Program.

BACKGROUND: Although the AB0 blood group is one of two major antigen systems of relevance for transplantation in humans, there are still conflicting data concerning the influence of AB0 incompatibility on transplant outcome. This study investigated the effect of AB0 incompatibility in recipients of bone marrow transplants from unrelated donors. DESIGN AND METHODS: We retrospectively analyzed data from 5,549 patients who underwent bone marrow transplantation from unrelated donors in the Japan Marrow Donor Program. RESULTS: Overall survival rates in the group with major and minor mismatches were significantly lower than the rate in the AB0-identical group (AB0-identical 63.0%; major mismatch, 56.9%; minor mismatch, 57.1% at 1 year). Treatment-related mortality was higher in the major and minor mismatch groups, but there was no significant difference in the rate of relapse. Cox proportional hazards modeling showed that both major and minor AB0 incompatibility were significant risk factors for transplant-related mortality, independently of disease, patients' age, and HLA incompatibility. Delayed engraftment of neutrophils, platelets, and erythrocytes was observed in transplants with major incompatibility. There was a high incidence of grade 3 and 4 acute graft-versus-host disease in the groups with major and minor mismatches, which was caused by a high incidence of stage 2 to 4 liver graft-versus-host disease. Interestingly, the risk of grade 2 to 4 graft-versus-host disease in the major mismatch group was higher in patients with early engraftment of erythrocytes. Among the patients receiving reduced-intensity conditioning, the transplant-related mortality was also increased in AB0-incompatible transplants. CONCLUSIONS: Major and minor AB0 incompatibility have specific effects on transplant-related mortality and acute graft-versus-host disease in recipients of bone marrow transplants from unrelated donors.

[A case of radiographic stage 0 sarcoidosis with severe cough].

A 63-year-old woman complained of continuous dry cough and high fever for two months. Chest radiography showed no abnormality, but inspiratory fine crackles were audible. Interstitial lung disease was suspected and bronchoalveolar lavage was performed via a bronchoscope. Disseminated minute granular lesions with redness and hypervascularity from the upper trachea to bilateral lober bronchi were detected. Lesions were also present in the membranous portion of the left main bronchus. Histological results for bronchial biopsy and transbronchial lung biopsy showed non-caseous epithelioid cell granuloma. This, together with a high CD4/8 lymphocyte ratio (4.11) in bronchoalveolar lavage fluid and the gallium scintigraphic findings, confirmed the diagnosis of sarcoidosis. To the best of our knowledge there are no other reports of cases with a similar bronchoscopic appearance in which the chest roentgenologic classification was stage 0, despite severe respiratory symptoms. Nodular lesions are seen in some cases of endobronchial sarcoidosis, but in this case, these widespread granular lesions were a unique feature that prompted us to make this report.

[Solitary nodular sarcoidosis demonstrating reversed tuberculin skin reaction].

A 29-year-old woman was admitted because of chest radiograph abnormality. She had no respiratory complaints. Chest CT demonstrated an ill-defined nodule of 20mm with the "sarcoid galaxy sign" in the right upper lobe. Transbronchial biopsy (TBB) specimens from right S2 revealed non-caseating epithelioid cell granuloma. Initial clinical findings suggested mycobacterial infection. However, while waiting for the results of mycobacterial cultures in bronchial washing fluid, the tuberculin skin reaction was found to be negative, and enlargement of nodule, mediastinal lymphadenopathy and elevated soluble IL-2R were observed. Cultures for mycobacterium were negative and repeat TBB specimens revealed granulomatous inflammation. We diagnosed with sarcoidosis based on these findings. Solitary nodular sarcoidosis is rare with only 17 cases having been reported. These cases were diagnosed with difficulty because of non-specific clinical findings and of the 17, 16 cases (94%) were diagnosed by surgical procedures. We observed the clinico-radiological course of solitary nodules and the change in tuberculin reaction. Although a negative tuberculin skin reaction was commonly recognized in sarcoidosis patients, we confirmed that initial positive tuberculin reaction changed to negative according to disease progress. To the best of our knowledge, this is the first case report in adults.

Influenza virus reactivation after remission with oseltamivir treatment in a patient undergoing nonmyeloablative bone marrow transplantation.

Influenza virus infection is an important cause of mortality after hematopoietic stem cell transplantation (HSCT). Although early diagnosis followed by standard therapy with oseltamivir is thought to prevent influenza complications in myeloablative bone marrow transplant recipients, the optimal duration of therapy in these patients has not yet been determined. We describe a case of influenza virus reactivation, after remission had been achieved with standard oseltamivir therapy, in a patient undergoing nonmyeloablative bone marrow transplantation (NMBMT). A rapid diagnostic test (RDT) for influenza virus detection was performed with the ESPLINE Influenza A&B-N kit, which is a rapid, readily available, and widely used approach enabling highly specific and sensitive detection, as well as monitoring, of influenza A and B viruses. However, our case shows that a very low viral load that is undetectable by this RDT can reactivate influenza during the early phase of NMBMT. Our case suggests that oseltamivir administration for influenza infection should be continued, at least until successful engraftment, to prevent virus reactivation. The patient must be frequently and carefully monitored even after the resolution of symptoms and the clearance of viruses from respiratory secretions. The decision to cease oseltamivir therapy safely can be assisted by negative results on reverse transcription polymerase chain reaction (RTPCR) analysis.

Serum surfactant protein-A, but not surfactant protein-D or KL-6, can predict preclinical lung damage induced by smoking.

Serum surfactant protein (SP)-A offers a useful clinical marker for interstitial lung disease (ILD). However, SP-A is occasionally elevated in non-ILD pulmonary patients. The present study was conducted to investigate factors that affect serum SP- A levels in respiratory medicine. Serum SP-A, serum SP-D, serum Klebs von den Lungen (KL)-6 and pulmonary function tests were evaluated in 929 patients (current smokers, n=255; ex-smokers, n=242; never-smokers, n=432) without ILD or pulmonary alveolar proteinosis. Serum SP-A was significantly higher in current smokers than in never- or ex-smokers (p<0.01 and p<0.05, respectively). Serum SP- A was significantly higher in chronic obstructive pulmonary disease (COPD) and pulmonary thromboembolism than in other diseases (p<0.01). Serum SP-A correlated positively with amount of smoking (p<0.01) and negatively with forced expiratory volume in 1 s/forced vital capacity (p<0.05). Serum SP-D and KL-6 were unaffected by smoking. Smoking should be taken into account when evaluating serum SP-A levels, and different baseline levels of serum SP-A should be established for smokers and non-smokers. Serum SP-A may also represent a useful marker for predicting COPD in the preclinical stage.

[A case of idiopathic bronchial artery aneurysm connecting to the pulmonary artery].

Case. A 54-year old woman was found to have an abnormal shadow in a regular checkup chest X-ray film. We suspected a bronchial artery aneurysm based on a contrast-enhanced chest CT. Aortography, bronchial arteriography and pulmonary arteriography showed a bronchial artery aneurysm, 2 cm in diameter, connecting the right bronchial artery, inferior phrenic artery, and pulmonary artery. Bronchoscopy revealed dilatation and hypervascularity of moniliform submucosal vessels below the right truncus intermedius. She underwent bronchial artery embolization several times, but new feeding vessels developed each time. We considered this case required surgical resection. Bronchoscopy after aneurysmectomy revealed decrease of moniliform submucosal vessels. Histological examination revealed a three-layer structure leading to both the pulmonary and bronchial arteries. Conclusion. We diagnosed idiopathic bronchial artery aneurysm connecting to a pulmonary artery.

Tracheo-broncho-bronchiolar lesions in Sjögren's syndrome.

A 53-year-old woman reported having a persistent cough and bloody sputum. She did not smoke but had received a diagnosis of Sjögren's syndrome. Chest CT revealed middle lobe syndrome, bronchiectasis and diffuse centrilobular nodular lesions. Bronchoscopy displayed multiple whitish polypoid lesions protruding from the cartilage rings and tracheobronchopathia osteochondroplastica was histologically confirmed by the presence of bony tissue in the tracheo-bronchial wall. Video-assisted thoracoscopic biopsy demonstrated lymphocyte aggregation causing follicular broncho-bronchiolitis. Erythromycin therapy resulted in improvement of the follicular bronchiolitis but not the tracheobronchopathia osteochondroplastica.

Histiocytic sarcoma of the spleen: case report of asymptomatic onset of thrombocytopenia and complex imaging features.

Histiocytic sarcoma of the spleen, in which the malignant cells display morphologic and immunophenotypic features similar to those of mature tissue histiocytes, is a rare but potentially lethal condition that can remain asymptomatic or only mildly symptomatic for a long period of time. We studied a case of histiocytic sarcoma of the spleen in an 82-year-old woman with prolonged chronic thrombocytopenia that was non-responsive to steroid therapy. Ultrasonography, computed tomography, and magnetic resonance imaging showed a characteristically enlarged spleen and liver. Palliative irradiation therapy was clinically effective; however, disease progression proved lethal. Autopsy revealed the proliferation of tumor cells within the splenic sinus and the liver sinusoids, which displayed extreme hemophagocytosis and strong expression of the histiocytic markers CD68 (KP1 and PG-M1) and CD163. The postmortem diagnosis showed histiocytic sarcoma of the spleen with liver infiltration. This and previous reports indicate that early detection (facilitated by imaging and clinical features) and management may improve patient prognosis and survival. Histiocytic sarcoma of the spleen should be considered as a differential diagnosis in therapeutically unresponsive patients with chronic thrombocytopenia.

Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor.

Nef is a multifunctional pathogenetic protein of HIV-1, the interaction of which with Hck, a Src tyrosine kinase highly expressed in macrophages, has been shown to be responsible for the development of AIDS. However, how the Nef-Hck interaction leads to the functional aberration of macrophages is poorly understood. We recently showed that Nef markedly inhibited the activity of macrophage colony-stimulating factor (M-CSF), a primary cytokine for macrophages. Here, we show that the inhibitory effect of Nef is due to the Hck-dependent down-regulation of the cell surface expression of M-CSF receptor Fms. In the presence of Hck, Nef induced the accumulation of an immature under-N-glycosylated Fms at the Golgi, thereby down-regulating Fms. The activation of Hck by the direct interaction with Nef was indispensable for the down-regulation. Unexpectedly, the accumulation of the active Hck at the Golgi where Nef prelocalized was likely to be another critical determinant of the function of Nef, because the expression of the constitutive-active forms of Hck alone did not fully down-regulate Fms. These results suggest that Nef perturbs the intracellular maturation and the trafficking of nascent Fms, through a unique mechanism that required both the activation of Hck and the aberrant spatial regulation of the active Hck.

[Bird-related chronic hypersensitivity pneuminitis demonstrating the fluctuation of disease activity accompanied with environmental changes].

We report a case of bird-related chronic hypersensitivity pneuminitis exhibiting the fluctuation of serum markers for interstitial lung disease along with the changes in life environment. A 65-year-old man had had an abnormal chest radiograph for 2 years and had complained of a non-productive cough. He had had 30 parakeets 20 years previously and had used feather products for 15 years. In autumn and early winter wild birds had visited persimmons trees in the neighboring garden. Antibodies to bird-related antigens in the broncho-alveolar lavage fluids and sera were positive and the thoracoscopic lung biopsy specimens histologically revealed airway-centered fibrosis. We then determined he was having bird-related chronic hypersensitivity pneumonitis. After avoidance of feather products, all of serum SP-A, SP-D and KL-6 decreased. But three markers elevated and radiographic findings worsened accompanied with the increase of visiting wild birds in next autumn. After pruning persimmon trees and starting corticosteroid with cyclosporine, disease activity gradually improved.

[A case of HTLV-1 associated bronchiolo-alveolar disorder showing progressive air trapping].

A 65-year-old woman whose parents were from Okinawa Prefecture, had productive cough and bilateral diffuse nodular lesions on chest X-ray. She had been shown a human T-cell lymphotropic virus type-1 (HTLV-1) carrier. Video-assisted thoracoscopic lung biopsy showed marked peribronchiolar infiltration of lymphocytes and stenosis of bronchioles. HTLV-1 associated bronchiolo-alveolar disorder (HABA) was diagnosed. The symptoms, hypoxemia and chest X-ray findings improved with oral erythromycin. However, expiratory chest CT showing mosaic perfusion, pulmonary function test demonstrating increased thoracic gas volume, and ventilation scintigraphy resulting in decreased clearance during 8 years, all of those findings indicated progression of air trapping. Abnormalities on chest CT partially improved, but bronchiolar lesions have deteriorated. Expiratory chest CT, body phlethysmography and ventilation scintigraphy were recommended to clarify the course of HABA.

Reversal of streptozotocin-induced hyperglycemia by continuous supply of betacellulin in mice.

Previous studies have shown the efficacy of betacellulin (BTC) to promote beta-cell regeneration. Because of its short half-life, however, the effect of BTC may have been underestimated. This study was conducted to assess the effect of continuous administration of BTC on beta-cell regeneration. Adenovirus vectors encoding proBTC (Ad-proBTC) and mature BTC (Ad-mBTC) were prepared, and the efficacy of secretion of BTC was compared in AML12 hepatocytes. When AML12 cells were infected with Ad-proBTC or Ad-mBTC, cells infected with Ad-mBTC secreted considerably larger amount of BTC. We then infused Ad-mBTC into the mouse tail vein. Expression of BTC was detected in the liver for at least 21 days, and serum BTC was maintained at approximately 1 ng/ml for 7 days. When Ad-mBTC was infused immediately after administration of STZ (170 mg/kg), elevation of the plasma glucose induced by STZ was markedly inhibited, and the plasma glucose concentration remained at less than 200 mg/dl for 21 days. The insulin content and the beta-cell mass were significantly increased in Ad-mBTC-infused mice. These results indicate that continuous administration of BTC is quite effective in promoting regeneration of beta-cells.

[A case of allergic bronchopulmonary aspergillosis localized in one bronchial segment].

A 64-year-old woman was admitted with a chest radiograph abnormality. She had no compliant and the results of her physical examination were normal. A chest radiograph showed a 25-mm area of patchy opacity in the left upper lung field. Chest CT demonstrated a finger-like opacity along the left B3a and c that was highly suggestive of mucoid impaction of the bronchi. Bronchofiberscopy revealed mucous plugs in left B3, in which the filariform fungul hyphae were detected by Grocott stain. Rosenberg's clinical criteria have been cited frequently for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA). On the one hand his criteria have historical significance, but at the same time various problems have been pointed out. Although the patient was not given a diagnosis of ABPA based on Rosenberg's criteria, she was given it based on the presence of type I immunologic response, mucoid plugs, hyphae of Aspergillus, central bronchiectasis. She had localized opacity only along a segmental bronchus. Our report may provide valuable information on the course of ABPA.

IgG4-positive pulmonary disease.

We report herein high-resolution computed tomography findings from a patient with IgG4-related pulmonary disease for the first time. The 61-year-old male patient complained of low-grade fever, dry mouth, and night sweats. He was diagnosed as having autoimmune pancreatitis, Sjögren syndrome, and elevated serum IgG4. High-resolution computed tomography of the lungs showed dense alveolar consolidation and air bronchograms in bilateral perihilar regions. IgG4-positive lymphoplasmacytes were detected in pulmonary lesions by immunostaining of biopsy samples. IgG4-related pulmonary disease can be associated with various radiologic findings.