Etiology of sarcoidosis

The cause(s) of sarcoidosis is unknown. Sarcoidosis seems to result from exposure of a genetically susceptible subject to a specific environmental antigen(s). From biopsy samples of lymph nodes from patients with sarcoidosis, Propionibacterium acnes has been isolated in culture, and many genomes of P.acnes or P.granulosum have been detected by quantitative PCR. Antigen-specific mitogenic responses of peripheral blood mononuclear cells were induced in sarcoidosis patients but not in healthy controls, when recombinant proteins from a propionibacterial trigger factor were used as stimulators. Sarcoidosis may arise from a Th1 immune response to one or more antigens of propionibacteria in an individual with a hereditary or acquired abnormality of the immune system.     

Co-cultivation of pancreatic cancer cells with orthotopic tumor-derived fibroblasts: fibroblasts stimulate tumor cell invasion via HGF secretion whereas cancer cells exert a minor regulative effect on fibroblasts HGF production

The intensive stromal reaction is one of characteristics of pancreatic exocrine carcinoma. The mutual interaction between pancreatic cancer cells and orthotopic tumor-derived fibroblasts have not been clarified yet. In this study, we sought to elucidate the mechanism underlying the tumor-stromal interaction with an in vitro coculture experimental system. Considerable strong c-Met expression was detected in seven out ten lines of human pancreatic carcinoma cells, as determined by Western blotting. For hepatocyte growth factor (HGF)-production, however, none or only trace amounts of HGF could be detected in those ten cell lines. Of the two lots of tumor-derived fibroblasts obtained from two pancreatic cancer patients, the fibroblasts capable to produce HGF could initiate an apparent invasion-stimulating response in strong c-Met-expressed Suit-2 and Panc-1 cells but not in faint expressed Mia PaCa-2 and BxPC-3 cells. A specialized HGF antagonist, NK4 would effectively inhibit the fibroblast-mediated invasive growth, thus proving the key role of the paracrine-fashioned HGF/c-Met pathway in the tumor-stromal interaction. On the other hand, the regulative action of cancer cells on HGF expression of fibroblasts was also investigated using direct or indirect coculture systems. For the fibroblasts that originally did not produce HGF, cancer cells failed to show any HGF-inductive effect. For the HGF-producing fibroblasts, despite of somewhat upregulation or downregulation in fibroblast HGF expression, the feedback regulation by studied pancreatic cancer cells in both coculture modes were relatively limited. This in vitro study sketched out the interaction between cancerous and stromal compartments with an emphasis on HGF/c-Met signal pathway, thus possibly helping to unveil the more complicated mutual modulation in vivo between pancreatic cancer and host mesenchymal tissues.     

Radiation stimulates HGF receptor/c-Met expression that leads to amplifying cellular response to HGF stimulation via upregulated receptor tyrosine phosphorylation and MAP kinase activity in pancreatic cancer cells

Hepatocyte growth factor (HGF) is a stromal-derived cytokine that plays a crucial role in invasion and metastasis of tumor cells through the interaction with HGF receptor, c-Met, which is frequently overexpressed in pancreatic cancer. The present study was designed to investigate the change in HGF receptor and HGF-mediated signaling after irradiation in pancreatic cancer cells. Six cell lines from human pancreatic cancer were included in the study. Gamma-radiation was used for irradiation treatment. The changes in expression levels of c-Met were evaluated by immunoblot and confirmed morphologically by indirect immunofluorescence staining. Whether the resultant alteration in c-Met would cascade as biologically usable signals upon HGF ligation was traced by receptor tyrosine phosphorylation analysis and mitogen activated protein kinase (MAP kinase or MAPK) activity assay. The various biological responses to HGF (including cell proliferation, cell scattering, migration and invasion) were evaluated as well. We also used a 4-kringle antagonist of HGF, NK4, to block the HGF/c-Met signaling pathway. Both immunoblot and immunofluorescent analysis showed moderate increased expression of c-Met in 3 of 6 pancreatic cancer cell lines after irradiation. The actions seemed to be dose-responsible, which began at 3 hr and reached its peak value at 24 hr following irradiation. The radiation-increased expression of c-Met could transform into magnifying receptor tyrosine phosphorylation reaction and MAP kinase activity once the ligand was added, fairly corresponding with alteration in the receptor. Sequentially, the cellular responses to HGF, including scattering and invasion but not proliferation, were enhanced. Also, in the presence of HGF, the elevated receptor could help to recover the radiation-compromised cell migration. A recombinant HGF antagonist, NK4 could effectively block these aberrant effects activated by irradiation both in molecular and cellular levels, thus suggesting the deep involvement of the c-Met/HGF pathway in the enhanced malignant potential after irradiation. These results suggest that radiation may promote HGF-induced malignant biological behaviors of certain pancreatic cancer cells through the up-regulated HGF/c-Met signal pathway. Selectively targeted blockade of the HGF/c-Met pathway could help to abolish the enforced malignant behavior of tumor cells by irradiation and therefore may improve the efficacy of radiotherapy for pancreatic cancer.     

Disseminated infection due to Scedosporium apiospermum in a patient with acute myelogenous leukemia

A 62-year-old man diagnosed with acute myelogenous leukemia which had developed from myelodysplastic syndrome received cytarabine and idarubicine as an induction therapy. The patient developed pneumonia and bacterial sepsis during profound neutropenia. Fever and sepsis improved by using many anti-bacterials and anti-fungals but he became febrile again and complained of severe lumbar pain. 67Ga scintigram showed abnormal uptake in the lumbar vertebra and left sternoclavicular joint, suggesting a diagnosis of discitis and osteomyelitis in the lumbar vertebra and sternoclavicular arthritis. We biopsied the site several times but culture of the biopsy specimen could not isolate any pathogens, and high fever persisted for about 10 months despite administration of various anti-bacterials and anti-fungals. Finally we inserted a catheter into the abscess at the iliopsoas muscle and Scedosporium apiospermum was isolated in the bloody pus obtained from the catheter. Itraconazole and amphotericin B were restarted, and the high fever and lumbar pain improved rapidly. The findings of S. apiospermum infection in this patient emphasizes the importance of being aware of this pathogen in patients with hematologic malignancy during the neutropenic phase.     

Attenuation of microcirculatory disturbance after liver ischemia by newly synthesized inflammatory cytokine suppressor,FR167653

BACKGROUND/AIMS: Inflammatory cytokines, such as interleukin-1 beta and tumor necrosis factor-alpha, which activate neutrophils, contribute to hepatic warm ischemia-reperfusion injury. However, the role of the cytokines in hepatic microcirculation immediately after reperfusion is still unclear. This study was carried out to investigate whether FR167653, a dual inhibitor of interleukin-1 beta and tumor necrosis factor-alpha, attenuates hepatic microcirculatory disturbance at the initial phase of reperfusion following liver ischemia. METHODOLOGY: Adult mongrel dogs were subjected to 90 minutes of liver ischemia by a Pringle's maneuver under portosystemic bypass. The animals were divided into two groups: a control group (n = 10), subjected to hepatic warm ischemia only, and a FR167653 administered group (n = 5), which received 1 mg/kg/h FR167653 for 4 hours since 30 minutes before the ischemia to 2 hours after the reperfusion continuously. Seven days animal survival, hepatic tissue blood flow, liver function test, hepatic venous blood concentration of endothelin-1 and plasminogen activator inhibitor-1, liver tissue biochemistry, and histopathology were analyzed. RESULTS: The treatment with FR167653 attenuated microcirculatory disturbance, lessened liver injury, enhanced adenine nucleotides resynthesis, and improved animal survival after liver ischemia. In addition, FR167653 significantly inhibited release of both endothelin-1 and plasminogen activator inhibitor-1 from the liver cells. CONCLUSIONS: These results suggest that the inflammatory cytokines induce microcirculatory disturbance in the initial phase of reperfusion following liver ischemia.     

Comparison of quality of life after pylorus-preserving pancreatoduodenectomy and Whipple resection

BACKGROUND/AIMS: There have been many supportive data that the postoperative changes in nutritional status are more favorable after pylorus-preserving pancreatoduodenectomy than after Whipple resection; however, few reports are available on the postoperative changes in subjective quality of life after pancreatoduodenectomy. The aim of this study was to compare the postoperative change in quality of life after pylorus-preserving pancreatoduodenectomy and Whipple resection. METHODOLOGY: A total of 36 patients (31 with pylorus-preserving pancreatoduodenectomy and five with Whipple resection) were studied regarding quality of life before and at short term (within two months) and at long term (six months to one year) after surgery, using a questionnaire. The questionnaire consisted of 13 physical and 10 psychosocial items. The medical records were also reviewed to evaluate their objective nutritional status. Postoperative changes in quality of life and nutritional status were compared between the pylorus-preserving pancreatoduodenectomy and Whipple groups. RESULTS: Overall and physical quality of life scores dropped at short term and then recovered at long term in the pylorus-preserving pancreatoduodenectomy group, but showed a persistently low value even at long term in the Whipple group. The change in physical quality of life showed almost parallel changes with the nutritional status in both groups. However, the scores of psychosocial quality of life, which reflected the patient's mental status, remained low even at long term in both pylorus-preserving pancreatoduodenectomy and Whipple groups. CONCLUSIONS: Quality of life is more favorable after pylorus-preserving pancreatoduodenectomy than after Whipple resection, but long-standing mental health care is necessary in patients with pyloruspreserving pancreatoduodenectomy and Whipple resection.     

Annuloaortic Repair in the Treatment of Aortic Regurgitation and Aortic Root Pathology

We developed a new technique of aortic root repair which may be able to eliminate the potential problem of leaflet damage, resulting from the direct contact of the aortic leaflets with synthetic vascular grafts during systole. This report describes our technique of annuloaortic repair and the operative results. Between February 1995 and October 1998, 13 patients underwent annuloaortic repair. The patients included 8 males and 5 females (mean age 50 years). Four patients had grade IV/IV aortic regurgitation (AR), 5 had III/IV AR, 2 had II/IV AR, and 1 had no AR preoperatively. Regarding the preoperative functional status, 1 patient was classified as New York Heart Association class IV, 5 were class III, 6 class II, and 1 class I. Concomitant cardiovascular procedures were performed in 12 cases. Aortic valvuloplasty or annuloplasty was performed in 7 patients. Both operative and short-term postoperative results with pre- and postoperative echocardiographic findings were studied retrospectively. The mean total cardiopulmonary bypass time was 212 min. The mean aortic cross-clamp time was 130 min. Circulatory arrest was induced in 5 patients. Postoperatively, 7 patients had no AR. Three patients had grade I/IV AR and 3 had grade II/IV AR. Perioperative changes in aortic annulus, mid-sinus portion, and sinotubular junction diameters were determined echocardiographically in 5 patients. The preoperative diameters were 2.7 +/- 0.4, 5.4 +/- 0.5, and 4.7 +/- 1.0 cm, respectively. The postoperative diameters were 2.3 +/- 0.5, 4.2 +/- 0.5, and 3.5 +/- 0.5cm, respectively. Ten patients were class I and 2 were class II. This technique of annuloaortic repair with or without aortic valvuloplasty is applicable to a certain subset of patients with aortic root disease and AR. Both the indications for this procedure and the long-term results should be confirmed.     

Adult pigment type (Peiffer) of sudanophilic leukodystrophy

Summary Two autopsy cases of siblings with the adult pigment (Peiffer) type of sudanophilic leukodystrophy (SLD), which demonstrated the full-blown stage (case 1) and early stage (case 2) of demyelination, were examined. Numerous brown pigments deposited in demyelinated cerebral areas were characterized histochemically and ultrastructurally as lipofuscin and ceroid. Under the electron microscope formation of blebs due to myelin splitting associated with deposition of multilamellar myeloid bodies within them was a prominent feature in the demyelinated cerebral areas of case 2 as compared with case 1. However, various features of myelin degradation such as thinning, partial or complete circumferential myelin loss, and deposition of electron-dense material on the interperiodic lines were found in both cases. Blebs occurred in all layers of myelin, and axons were compressed by these blebs or the hydropically swollen inner lips of oligodendroglias. Oligodendroglias were relatively well preserved in the demyelinated and nondemyelinated areas in case 2, although the cytoplasm was hydropic. Many spheroids were present in demyelinated areas and were irregularly distributed in both cases. The peripheral nerves in case 1 presented essentially the same changes as those in the brain, although those in case 2 were not affected. Morphometrically, the results showed that hypomyelination was not the mechanism for this pigment type of SLD. One possible cause may be an accelerated ageing of the metabolic process of myelin turnover.