Tracheoesophageal fistula after blunt chest trauma.

Tracheoesophageal fistula is a very rare but potentially life-threatening complication of blunt chest trauma. Prior reviews have revealed that the victims were all young men involved in deceleration or crush injuries. Of those involved in motor vehicle accidents, most were thrown against the steering wheel. Herein, we review the world literature on this injury and include our own report of 1 of the few cases of traumatic tracheoesophageal fistula involving a female victim. In this case, the victim was an unrestrained driver thrown against an air bag.

A role for lipoxygenase metabolites of arachidonic acid in porcine ovulation.

Prostaglandins, products of arachidonic acid via the cyclooxygenase pathway, are essential to the porcine ovulatory process in that inhibition of their synthesis results in ovulation failure. Studies in the rat have shown that ovulation is also preceded by a rise in three ovarian hydroxyeicosatetraenoic acids, products of the lipoxygenase pathway, and inhibition of this pathway also inhibits ovulation. Experiments were designed, using a pregnant mare serum gonadotropin/human chorionic gonadotropin (hCG)-treated prepuberal gilt model, to measure pre-ovulatory changes in follicular fluid concentrations of 15-hydroxyeicosatetraenoic acid (15-HETE), and to compare the effects of indomethacin and nordihydroguaiaretic acid (NDGA) on ovulation in the pig and on 15-HETE and prostaglandin F2 alpha synthesis both in vivo and in vitro. Follicular fluid concentrations of 15-HETE were elevated significantly just prior to the expected time of ovulation (40 h after hCG). When indomethacin (10 mg) was injected into the ovarian stalk at 24 h after hCG, follicular fluid concentrations of both 15-HETE and prostaglandin F2 alpha were lower (P < 0.01) than controls at 40 h and ovulation rate was suppressed (P < 0.01). When NDGA (5 mg) was administered in the same manner, ovulation rate was suppressed (P < 0.01), but the levels of 15-HETE and prostaglandin F2 alpha were not altered. Synthesis of 15-HETE by cultured granulosa and theca interna cells was reduced by the presence of NDGA (1 mg/ml), whereas indomethacin (100 ng/ml) lowered 15-HETE production in theca interna cells only. These results clearly demonstrate that indomethacin can block the lipoxygenase as well as the cyclooxygenase pathways, depending on the dose used, and suggest that lipoxygenase metabolites of arachidonic acid are involved in the ovulatory process in the pig.

A role for IFN-lambda1 in multiple myeloma B cell growth.

Multiple myeloma (MM) is a progressive disease that results from dysregulated proliferation of plasma cells. Although, causative factors such as genetic events and altered expression of anti-apoptotic factors have been described in a number of patients, the mechanistic details that drive myeloma development and continued growth of malignant cells remain largely undefined. Numerous growth factors, including interleukin (IL)-6, Insulin-like growth factor-1 and IL-10 have been shown to promote growth of MM cells suggesting a significant role for cytokines in this disease. Interferon (IFN)-lambda1 is a new member of the Class II cytokine family that, similar to IFN-alpha, has been shown to mediate viral immunity. In light of data supporting a role for cytokines in myeloma, we investigated the significance of IFN-lambda1 on myeloma cell biology. Our studies show for the first time that myeloma cells bind to soluble IFN-lambda1, and that IFN-lambda1 induces myeloma cell growth and protects against dexamethasone-induced cell death. Our data also show that IFN-lambda1 induces phosphorylation of STAT1, STAT3 and Erk. Taken together, our results suggest that IFN-lambda1 may regulate myeloma cell biology and could prove to be therapeutically important.

Characterization of the role of the human granulocyte-macrophage colony-stimulating factor receptor alpha subunit in the activation of JAK2 and STAT5.

The high-affinity human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (GMR) consists of an alpha (GMRalpha) and a common beta (betac) subunit. The intracellular domain of betac has been extensively characterized and has been shown to be critical for the activation of both the JAK/STAT and MAP kinase pathways. The function of the intracellular domain of GMRalpha, however, is not as well characterized. To determine the role of this domain in GMR signaling, an extensive structure-function analysis was performed. Truncation mutants alpha362, alpha371, and alpha375 were generated, as well as the site-directed mutants alphaVQVQ and alphaVVVV. Although alpha375beta, alphaVQNQbeta, and alphaVVVVbeta stimulated proliferation in response to human GM-CSF, the truncation mutants alpha362beta and alpha371beta were incapable of transducing a proliferative signal. In addition, both alpha371 and alphaVVVV were expressed at markedly reduced levels, indicating the importance of residues 372 to 374 for proper protein expression. More importantly, we show that GMRalpha plays a direct role in the activation of the JAK/STAT pathway, and electrophoretic mobility shift assays (EMSA) indicate that both GMRalpha and betac play a role in determining the STAT5 DNA binding complex activated by the GMR. Thus, the intracellular domain of the human GMRalpha is important for activation of the JAK/STAT pathway and protein stabilization.

Predicting clinical outcome in the elderly renal transplant recipient.

BACKGROUND: The purpose of this study was to evaluate graft and patient survival in first-time kidney transplant recipients 60 years old or older, and to identify pretransplant risk factors that predict clinical outcome. METHODS: We reviewed the clinical course of 206 recipients, 60 years old or older, of first kidney transplants at the University of Minnesota. Patient and graft survival were compared with 1640 patients aged 18 to 59 transplanted during the same time period. Regression analysis was performed to identify risk factors that predicted a poor outcome. RESULTS: In patients 60 years old or older, graft survival at one and five years was 86 and 60%, and patient survival at one and five years was 90 and 68%, respectively. Graft and patient survival were decreased compared with recipients aged 18 to 59, but were similar when censored for patient death as a cause of graft loss. A pretransplant history of nonskin malignancy and vascular disease and a current smoking history were risk factors for decreased graft and patient survival. To determine the potential impact of screening for low-risk patients, we evaluated graft and patient survival in patients age > or =60 without these risk factors versus those with one or more risk factors. In the absence of risk factors, both graft and patient survival were significantly improved compared with patients with these risk factors and were equivalent to that of patients aged 18 to 59. CONCLUSIONS: Renal transplantation is a safe and effective therapy for the older renal failure patient. In the absence of identified risk factors, graft survival is equivalent to that seen in younger patients.

Conserved amino acids in the human granulocyte-macrophage colony-stimulating factor receptor-binding subunit essential for tyrosine phosphorylation and proliferation.

A superfamily of growth factor and cytokine receptors has recently been identified, which is characterized by four spatially conserved cysteine residues and a tryptophan-serine motif (WSXWS) in the extracellular domain and proline-rich cytoplasmic domain. The high-affinity human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor, hGM-CSFR, consists of two subunits, alpha (hGM-CSFR alpha), which is required for ligand binding, and beta (hGM-CSFR beta), which is required for signal transduction. Both the alpha and beta subunits are members of the cytokine receptor superfamily. In this study, we analyzed mutations in the conserved amino acids of the alpha subunit to determine their function in signal transduction, as assayed by tyrosine phosphorylation and proliferation. Disruption of either of the conserved disulfide bonds in the extracellular domain abolishes low-affinity binding but not binding to a preformed heterodimeric complex with the beta-chain. Cells expressing receptors with mutations in cysteines 2 or 3 grew as well as cells expressing wild-type receptors in human GM-CSF (hGM-CSF) and phosphorylated the same proteins on tyrosine residues, although the level of phosphorylation may be attenuated; cysteine 3 appears to be required for generation of the true high-affinity binding site. The WSXWS motif and the cytoplasmic domain are required for function of the human GM-CSF receptor, as stable cell lines expressing receptors with these mutations were unable to proliferate continuously in hGM-CSF. Surprisingly, no function for the conserved proline-rich region of the cytoplasmic domain could be ascertained from these studies; cells expressing these receptors were indistinguishable from wild-type in both binding and functional assays.