Immunoprophylaxis and immunotherapy of gram-negative sepsis and shock with antibodies to core glycolipids and lipid a of bacterial lipopolysaccharides

Conclusions The results obtained by numerous investigators reveal the ability of antibodies to cross-reactive LPS antigens to protect against infections caused by various gram-negative pathogens and their endotoxins. Based upon experimental and clinical experience, one could postulate that these antibodies are a promising approach for the prophylaxis and therapy of sepsis. The recognition of high-risk patients would allow early start of combined therapy with appropriate immune preparations and antibiotics, which along with life-supporting measures (corticosteroids, electrolyte and nutrition infusions, etc.), would be a useful tool in the treatment of gram-negative sepsis and endotoxin shock.     

Retrosternal (intrathoracic) goitre--diagnosis and surgical treatment

For a period of 12 years (1987-1998) 2033 patients underwent surgical treatment of the thyroids in the surgical clinics of the Higher Medical Institute in Plovdiv. Retrosternal or intrathoracic goitre was found in 29 patients (p +/- Sp = 1.43 +/- 0.26%). Of these, seven were males and 22 females all aged 32 to 76 years. Twenty two of the patients were euthyroid and seven hyperthyroid (75.9 +/- 7.9% and 24.1 +/- 7.8%, respectively). Compression of adjacent organs was detected in 19 of the patients (65.5 +/- 8.8%) (P < 0.05). X-ray, ultrasonography, scintigraphy (gamma-chamber), computed tomography, and in cases of voice disorders, direct laryngoscopy were used in making the diagnosis. All patients underwent surgical treatment. Cervical collar incision was suitable in 27 patients and in one patient longitudinal sternotomy was used and in other, who had deep posterior mediastinal goitre, Hart's method of combined thoracotomy and cervicotomy was required. The weight of the resected glands varied from 50 to 1500 g. The results obtained are discussed in terms of the incidence, type, and site of the retrosternal (intrathoracic) goitre, capabilities of the contemporary methods of diagnostics, surgical necessities, surgical approach and compared with literature data.     

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.     

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.     

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

The PI3K/mTOR signaling cascade is fundamental in T‐cell activation and fate decisions. We showed the distinct regulation of PI3K/mTOR in regulatory and effector T‐cells and proposed the potential therapeutic benefit of targeting this pathway to control the balance between effector and regulatory T‐cell activities. Substantial adverse effects in long‐term clinical usage of rapamycin suggest the use of alternative treatments in restraining effector T‐cell function in transplant patients. We hypothesize that dual PI3K/mTOR inhibitors may represent an immunosuppressant alternative. Here we show that dual PI3K/mTOR PI‐103 and PKI‐587 inhibitors interfered IL‐2‐dependent responses in T‐cells. However, in contrast to the inhibitory effects in non‐Treg T‐cell proliferation and effector functions, dual inhibitors increased the differentiation, preferential expansion, and suppressor activity of iTregs. Rapamycin, PI‐103, and PKI‐587 targeted different signaling events and induced different metabolic patterns in primary T‐cells. Similar to rapamycin, in vivo administration of PI‐103 and PKI‐587 controlled effectively the immunological response against allogeneic skin graft. These results characterize specific regulatory mechanisms of dual PI3K/mTOR inhibitors in T‐cells and support their potential as a novel therapeutic option in transplantation.