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.

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.

[Analysis of endobronchial aspergillosis in patients without obvious systemic predisposing factors].

BACKGROUND: Endobronchial aspergillosis is still an insufficiently recognized concept. PATIENTS AND METHODS: Ten patients who did not have obvious predisposing factors and parenchymal fungal infection were analyzed. They were confirmed to have endobronchial Aspergillus by histology and culture, and were classified according to the presence of bronchiectasis, allergic reaction, and asthmatic symptom. RESULTS: Bronchiectasis was detected in all 10 patients, IgE elevation (>370 IU/ml) in 7, Aspergillus specific IgE-RAST in 8, eosinophilia in 7, and asthmatic symptom in 5. Cases were classified into allergic bronchopulmonary aspergillosis (ABPA) (5 cases), ABPA not fulfilling Rosenberg's criteria (2 cases), and endobronchial aspergilloma (3 cases). CONCLUSION: We proposed classifying endobronchial aspergillosis without obvious systemic predisposing factors into "ABPA", "ABPA without asthma", "ABPA-S (seropositive)", and "Endobronchial aspergilloma". A fifth subtype of endobronchial aspergillosis containing "saprophyte" is warranted.

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.

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.

M-CSF accelerates neointimal formation in the early phase after vascular injury in mice: the critical role of the SDF-1-CXCR4 system.

OBJECTIVE: Since the macrophage colony-stimulating factor (M-CSF) has been shown to stimulate differentiation and proliferation of monocyte/macrophage lineage and to be involved in the process of neointimal formation after vascular injury, we tested the effects of M-CSF on the recruitment of bone marrow-derived progenitor cells in neointimal formation after vascular injury in mice. METHODS AND RESULTS: Wire-mediated vascular injury was produced in the femoral artery of C57BL/6 mice. Recombinant human M-CSF [500 microg/(kg x day)] or saline (control) was administered for 10 consecutive days, starting 4 days before the injury. Treatment with M-CSF accelerated neointimal formation in the early phase after injury, and this neointimal lesion mainly consisted of bone marrow-derived cells. M-CSF treatment had no effect on the mobilization of endothelial progenitor cells (EPCs: CD34+/Flk-1+) and reendothelialization after injury. The stromal cell-derived factor-1 (SDF-1) was markedly expressed in the neointima and media after injury, whereas CXCR4+ cells were observed in the neointima. Further, a novel CXCR4 antagonist, AMD3100, significantly attenuated the M-CSF-induced neointimal formation. CONCLUSIONS: These findings suggest that M-CSF accelerated neointimal formation after vascular injury via the SDF-1-CXCR4 system, and the inhibition of this system has therapeutic potential for the treatment of cardiovascular diseases.

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.

Clinical features of opticospinal multiple sclerosis with anti-aquaporin 4 antibody.

BACKGROUND: We have followed 9 Japanese patients with opticospinal multiple sclerosis (OSMS), some of whom showed longitudinally extensive spinal cord lesions, deep sensory disturbances and resistance to treatment. We investigated the patients for anti-aquaporin 4 (AQP4) antibodies and related this to their neuroimaging, clinical and laboratory features. METHODS: We studied the clinical course, neurological findings, cerebrospinal fluid (CSF), and electrophysiological findings, and determined the presence of anti-AQP4 antibody and human leukocyte antigen DPB1 and DRB1 alleles. RESULTS: Five patients (56.6%) had anti-AQP4 antibody. Antibody-positive patients displayed female predominance, longitudinally extensive spinal cord lesions, higher frequency of exacerbations, severe disability, and higher cell counts and total protein content without IgG oligoclonal bands in the CSF. They also showed poor steroid responsiveness and poor therapeutic response to interferon beta(1b). CONCLUSIONS: The presence of anti-AQP4 antibodies correlates with clinical severity and poor prognosis in OSMS.

[Methicillin-resistant Staphylococcus aureus-induced pyomyositis that emerged during recovery from drug-induced pancytopenia].

Pyomyositis is a purulent infection of skeletal muscle characterized by fever, localized muscle pain and stiffness, swelling and tenderness. Hematological disorder is one of the predisposing conditions for the development of pyomyositis. A 54-year-old man developed methicillin-resistant Staphylococcus aureus pyomyositis during drug-induced pancytopenia. Debridement of the infection foci combined with antimicrobial agents proved effective even in the advanced stage of the disease. In patients with hematological disorders, pyomyositis should be considered when evaluating local myalgia and high fever because this disease can be very difficult to identify and can become rapidly progressive under a myelosuppressive condition.

[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.

[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.

[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.

[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.

[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.

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.

[Case of opticospinal multiple sclerosis showing phenotype change to conventional type induced by interferon beta-1b].

A 57-year-old woman who had severe opticospinal multiple sclerosis (OSMS) was admitted to our hospital. She had presented with visual loss and gait disturbance at the age of 48, and had since experienced more than 10 relapses and been hospitalized 9 times. Interferon beta-lb treatment (8,000,000 units on alternate days) had been started at her last admission. Prior to the present admission, she had developed left visual loss and gait difficulty after headache lasting a few days. Cerebrospinal fluid showed elevation of cell count (322/mm3), protein (130 mg/dl), and myelin basic protein (462 pg/ml; normal, <102 pg/ml). On examination, she exhibited decreased left visual acuity, paraplegia, ataxia of the right upper extremity, and sensory disturbance, particularly in the lower extremities. Bowel and bladder disturbances were also evident Laboratory testing showed lymphocytopenia (420/microl), compared to a white cell count of 1700/microl just before initiation of interferon beta-lb1therapy. MRI revealed a new lesion in the cerebellum in addition to small T2-hyperintense lesions in the white matter of the brain;these had been noted previously. Interferon beta-1b therapy was ceased and she was treated using methylprednisolone pulse therapy. After the abnormal findings resolved, however, interferon beta-lb1therapy was restarted. Three months after, she exhibited right hemiparesis without facial palsy concurrent with lymphocytopenia. MRI showed T2-hyperintense lesions in the periventricular white matter, left cerebral peduncle, bilateral middle cerebellar peduncles, and right cerebellar hemisphere. We reduced the doses of interferon beta-lb1immediately. Thereafter, she did not have relapse for 29 months, but her EDSS (expanded disability status scale) has not recovered. Although interferon beta-lb1has been recognized as an effective drug for decreasing the relapse rate and severity of both secondary progressive MS and relapsing-remitting MS, the present case showed the possibility of interferon beta-1b being associated with phenotype change from OSMS to conventional MS (CMS).

[Two cases of idiopathic carotid-cavernous fistula with headache and ophthalmoplegia].

We report two cases of idiopathic carotid-cavernous fistula (CCF) with primary symptoms of headache and diplopia. A 47-year-old woman presented with throbbing headache in her right frontal region followed by right trochlear nerve palsy. Brain magnetic resonance imaging (MRI) was normal but magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) revealed abnormal signals around the right cavernous sinus. CCF was diagnosed by conventional angiography. The symptoms improved naturally but after about 1 year she suddenly exhibited conjunctival congestion. A 41-year-old man complained of fluctuating headache with sudden left abducens nerve palsy. MRI and MRA were normal but CTA showed abnormal signals around the left cavernous sinus. A final diagnosis of CCF was made by conventional angiography and he was transferred to another hospital for stereotactic radiosurgery. Diagnosis of CCF tends to be delayed in cases presenting with only headache and external ophthalmoplegia. However, CCF with cortical vein drainage can lead to cerebral hemorrhage and early correct diagnosis is needed. Our cases showed a dilated superior ophthalmic vein in enhanced CT and an abnormal signal around the cavernous sinus in CTA. Therefore, CTA may be useful as a relatively non-invasive method that can provide diagnostic clues for CCF.

[Resected pulmonary sarcoidosis after corticosteroid treatment still showing pathological granulomatous inflammation].

It is not well understood what kind of histologic resolution is obtained with corticosteroid medication in sarcoidosis, or how we are able to judge cure in that disease. We examined the cases of sarcoidosis who were under steroid medication and received lobectomy and lymphadenectomy for combined lung cancer. Steroid treatment had been introduced for the relief of visual disturbance, not for the pulmonary lesion. Administration of corticosteroid improves clinical, laboratory, bronchoalveolar lavage and radiological findings, but it is difficult to make histological granulomatous inflammation completely disappear. Improvement of radiological and clinical problems in sarcoidosis is not the same as complete cure in patients with steroid-treated sarcoidosis.

[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.