Tryptophan 650 of human granulocyte colony-stimulating factor (G-CSF) receptor, implicated in the activation of JAK2, is also required for G- CSF-mediated activation of signaling complexes of the p21ras route

Granulocyte colony-stimulating factor (G-CSF) induces rapid phosphorylation of JAK kinases as well as activation of the p21ras route through interaction with its specific receptor (G-CSF-R). The cytoplasmic membrane-proximal region of G-CSF-R (amino acids 631 to 684) is necessary for proliferation induction and activation of JAK2. In contrast, activation of Shc and Syp, signaling molecules implicated in the p21ras signaling route, depends on the phosphorylation of tyrosine residues located in the membrane-distal region (amino acids 685 to 813) of G-CSF-R. We investigated whether G-CSF-induced activation of signaling complexes of the p21ras route depends on the function of the membrane-proximal cytoplasmic region of G-CSF-R. A G- CSF-R mutant was constructed in which tryptophan 650 was replaced by arginine and expressed in BAF3 cells (BAF/W650R). In contrast to BAF3 cell transfectants expressing wild-type G-CSF-R, BAF/W650-R cells did not proliferate and did not show activation of JAK2, STAT1, or STAT3 in response to G-CSF. Immunoprecipitations with anti-Shc and anti-Grb2 antisera showed that mutant W650R also failed to activate Syp and Shc. These data indicate that the membrane-proximal cytoplasmic domain of G- CSF-R is not only crucial for proliferative signaling and activation of JAK2 and STATs, but is also required for activation of the p21ras route, which occurs via the membrane-distal region of G-CSF-R.     

Subclinical peritonitis due to perforated sigmoid diverticulitis 14 years after heart-lung transplantation

Acute complicated diverticulitis, particularly with colon perforation, is a rare but serious condition in transplant recipients with high morbidity and mortality. Neither acute diverticulitis nor colon perforation has been reported in young heart-lung grafted patients. A case of subclinical peritonitis due to perforated acute sigmoid diverticulitis 14 years after heart-lung transplantation is reported. A 26-year-old woman, who received heart-lung transplantation 14 years ago, presented with vague abdominal pain. Physical examination was normal. Blood tests revealed leukocytosis. Abdominal X-ray showed air-fluid levels while CT demonstrated peritonitis due to perforated sigmoid diverticulitis. Sigmoidectomy and end-colostomy （Hartmann＇s procedure） were performed. Histopathology confirmed perforated acute sigmoid diverticulitis. The patient was discharged on the 8th postoperative day after an uneventful postoperative course. This is the first report of acute diverticulitis resulting in colon perforation in a young heart-lung transplanted patient. Clinical presentation, even in peritonitis, may be atypical due to the masking effects of immunosuppression. A high index of suspicion, urgent aggressive diagnostic investigation of even vague abdominal symptoms, adjustment of immunosuppression, broad-spectrum antibiotics, and immediate surgical treatment are critical. Moreover, strategies to reduce the risk of this complication should be implemented. Pretransplantation colon screening, prophylactic pretransplantation sigmoid resection in patients with diverticulosis, and elective surgical intervention in patients with nonoperatively treated acute diverticulitis after transplantation deserve consideration and further studies.     

Liver histology in ICU patients dying from sepsis：A clinico-pathological study

AIM：To determine end-stage pathologic changes in the liver of septic patients dying in the intensive care unit.
METHODS： Needle liver biopsies obtained immediately after death from 15 consecutive patients with sepsis and no underlying liver disease were subjected to routine histological examination. Liver function tests and clinical monitoring measurements were also recorded.
RESULTS： Liver biochemistries were increased in the majority of patients before death. Histology of liver biopsy specimens showed portal inflammation in 73.3%, centrilobular necrosis in 80%, lobular inflammation in 66.7%, hepatocellular apoptosis in 66.6% and cholangitis/cholangiolitis in 20% of patients. Mixed hepatitic/ cholestatic type of liver injury was observed in 6/15 （40%） patients and hepatitc in 9/15 （60%）. Steatosis was observed in 11/15 （73.3%） patients affecting 5%-80% of liver parenchyma. Among the histological features, the presence of portal inflammation in liver biopsy was associated with increased hospitalization in the ICU prior death （P = 0.026）.
CONCLUSION： Features of hepatitis and steatosis arethe main histological findings in the liver in the majority of patients dying from sepsis.     

p38 MAPK对嗜酸性粒细胞和支气管上皮细胞共培养时细胞因子释放的调控作用

目的 了解嗜酸性粒细胞和支气管上皮细胞相互作用诱导细胞因子释放的p38 MAPK信号转导通路.方法 用CD16磁珠抗体分离外周血中嗜酸性粒细胞,以嗜酸性粒细胞和支气管上皮细胞(BEAS-2B)接触共培养为实验模型,观察SB 203580对细胞培养上清液中细胞因子浓度的影响.细胞因子浓度采用ELISA和流式细胞微珠方法测定.结果 SB 203580能够有效抑制BEAS-2B细胞释放IL-6、IL-8(P＜0.05)和嗜酸性粒细胞释放IL-8(P＜0.01).SB 203580对嗜酸性粒细胞与BEAS-2B细胞接触共培养诱导的IL-6、IL-8和IP-10释放具有显著抑制作用(P＜0.001).结论 嗜酸性粒细胞、BEAS-2B细胞单独或相互作用时均通过p38 MAPK信号转导通路释放细胞因子.     

HLA-DR antigen and bax protein expression in patients with primary non-Hodgkin's gastric lymphoma

Primary gastric lymphoma represents a rare gastrointestinal malignancy with an unclear prognosis. The aim of this study was to determine the prognostic significance of HLA-DR antigen and bax expression in patients with primary non-Hodgkin's gastric lymphoma. We immunohistochemically studied bax protein and HLA-DR antigen expression in 36 B-cell, MALT-type primary gastric lymphoma patients diagnosed and treated in our department from 1990 to 1995. Ten non-malignant gastric tissue specimens were used as benign controls. Clinicopathological and survival data were correlated with the staining results. HLA-DR antigen expression was observed in 33 gastric lymphoma patients (91.7%). Positive bax staining was found in 24 gastric lymphomas (66.7%) and in none of the benign cases studied. In the univariate analysis, those gastric lymphoma patients who expressed HLA-DR antigen in more than 15% of their tumor cells, presented a significantly improved 5-year survival rate (75% vs. 37.5%, p = 0.04). Furthermore, gastric lymphoma patients who were bax(+)/HLA-DR(+) had a statistically better overall survival compared to those who were bax(-)/HLA-DR(-) (82.4% vs. 25%, p = 0.01). HLA-DR antigen expression was associated with a favorable clinical outcome. Its expression improved the predictive value of bax protein expression in non-Hodgkin's gastric lymphoma patients. The combined use of these markers permits the identification of a high-risk group of patients that may benefit from a more aggressive therapeutic approach.