The enhancer of polycomb gene of Drosophila encodes a chromatin protein conserved in yeast and mammals

The Polycomb group of genes in Drosophila are homeotic switch gene regulators that maintain homeotic gene repression through a possible chromatin regulatory mechanism. The Enhancer of Polycomb (E(Pc)) gene of Drosophila is an unusual member of the Polycomb group. Most PcG genes have homeotic phenotypes and are required for repression of homeotic loci, but mutations in E(Pc) exhibit no homeotic transformations and have only a very weak effect on expression of Abd-B. However, mutations in E(Pc) are strong enhancers of mutations in many Polycomb group genes and are also strong suppressors of position-effect variegation, suggesting that E(Pc) may have a wider role in chromatin formation or gene regulation than other Polycomb group genes. E(Pc) was cloned by transposon tagging, and encodes a novel 2023 amino acid protein with regions enriched in glutamine, alanine and asparagine. E(Pc) is expressed ubiquitously in Drosophila embryogenesis. E(Pc) is a chromatin protein, binding to polytene chromosomes at about 100 sites, including the Antennapedia but not the Bithorax complex, 29% of which are shared with Polycomb-binding sites. Surprisingly, E(Pc) was not detected in the heterochromatic chromocenter. This result suggests that E(Pc) has a functional rather than structural role in heterochromatin formation and argues against the heterochromatin model for PcG function. Using homology cloning techniques, we identified a mouse homologue of E(Pc), termed Epc1, a yeast protein that we name EPL1, and as well as additional ESTs from Caenorhabditis elegans, mice and humans. Epc1 shares a long, highly conserved domain in its amino terminus with E(Pc) that is also conserved in yeast, C. elegans and humans. The occurrence of E(Pc) across such divergent species is unusual for both PcG proteins and for suppressors of position-effect variegation, and suggests that E(Pc) has an important role in the regulation of chromatin structure in eukaryotes.     

Early mortality after surgical repair of postinfarction ventricular septal rupture: importance of rupture location

BACKGROUND: The aim of this study was to identify factors influencing early outcome after surgical treatment of postinfarction ventricular septal rupture. We investigated the influence of proximal or distal rupture location. METHODS: Between 1980 and 1992 109 patients were treated surgically for ventricular septal rupture using a standardized technique. A division in time periods was made. The rupture was categorized according to its anterior or posterior site and proximal or distal location. RESULTS: The 30-day mortality rate was 27.5%. Multivariate logistic regression analysis identified preoperative shock (p = 0.0007) and right atrial oxygen saturation less than 60% (p = 0.021) as predictors for early death; the risk for early death declined over the time periods from 50% to 12.8% (p = 0.0007). Proximal ventricular septal rupture location (p = 0.0092) and interval between infarction and ventricular septal rupture less then 1 day (p = 0.034) were risk factors for the occurrence of preoperative shock. CONCLUSIONS: Proximal ventricular septal rupture location was the main determinant of preoperative cardiogenic shock, which in turn was the strongest predictor of early mortality. Over the time periods a decrease in early mortality was reached.     

Acute appendicitis following laparoscopic inguinal hernioplasty. Coincidence or complication?]

The Authors report two cases of renal leiomyosarcomas with atypical clinical features. Despite a malignant histological picture, nephron-sparing surgery was performed. The two patients are alive and disease-free at six years and fifteen months respectively. Specific radiologic findings, indications and rationale for conservative treatment are discussed.     

Crystal structure at 2.6-A resolution of human macrophage migration inhibitory factor

Macrophage migration inhibitory factor (MIF) was the first cytokine to be described, but for 30 years its role in the immune response remained enigmatic. In recent studies, MIF has been found to be a novel pituitary hormone and the first protein identified to be released from immune cells on glucocorticoid stimulation. Once secreted, MIF counterregulates the immunosuppressive effects of steroids and thus acts as a critical component of the immune system to control both local and systemic immune responses. We report herein the x-ray crystal structure of human MIF to 2.6 angstrom resolution. The protein is a trimer of identical subunits. Each monomer contains two antiparallel alpha-helices that pack against a four-stranded beta-sheet. The monomer has an additional two beta-strands that interact with the beta-sheets of adjacent subunits to form the interface between monomers. The three beta-sheets are arranged to form a barrel containing a solvent-accessible channel that runs through the center of the protein along a molecular 3-fold axis. Electrostatic potential maps reveal that the channel has a positive potential, suggesting that it binds negatively charged molecules. The elucidated structure for MIF is unique among cytokines or hormonal mediators, and suggests that this counterregulator of glucocorticoid action participates in novel ligand-receptor interactions.     

Matrix metalloproteinases contribute to the blood-brain barrier disruption during bacterial meningitis

In this study, we investigated the involvement of matrix metalloproteinases (MMPs) in the pathophysiology of bacterial meningitis. By using an enzyme immunoassay, high concentrations of MMP-9 were detected in the cerebrospinal fluid (CSF) of adult patients with bacterial meningitis but not in controls, and in patients with Guillain-Barré syndrome. Moreover, we observed significantly elevated concentrations of the tissue inhibitor of metalloproteinase-1 (TIMP-1) in the CSF of patients with bacterial meningitis, compared with controls. In a rat model of meningococcal meningitis, intracisternal injection of heat-killed meningococci caused a disruption of the blood-brain barrier (BBB), an increase in intracranial pressure, and CSF pleocytosis paralleled by the occurrence of MMP-9 activity in the CSF 6 hours after meningococcal challenge. The MMP inhibitor batimastat (BB-94) significantly reduced the BBB disruption and the increase in intracranial pressure irrespective of the time of batimastat administration (15 minutes before and 3 hours after meningococcal challenge) but failed to significantly reduce CSF white blood cell counts. In conclusion, our results suggest that MMPs are involved in the alterations of BBB permeability during experimental meningococcal meningitis.     

Donor factors affecting outcome after pancreas transplantation

In this study, we demonstrated that Px grafts from donors older than 45 years are associated with an increased risk of developing poor glycemic control and premature loss of Px function. Previous studies corroborate our finding that age of the donor is the principal donor characteristic impacting postoperative Px survival. Whereas prior studies also implicated hyperamylasemia as a factor which contributes adversely to outcome, we were unable to demonstrate a significant influence of donor hyperamylasemia on long-term graft survival, although it did correlate with the degree of immediate postoperative pancreatitis and with the need for oral hypoglycemic agents. Similarly, elevated blood glucoses in the donor, which can be a result of many other factors unrelated to the quality of the graft, did not predict a poor outcome in the recipient. NHB donor pancreata did as well as HB pancreata with regards to all postoperative functional parameters. A marginally increased risk of developing major complications was associated with older donors. Despite the frequent use of non-ideal donors, including older and NHB donors, excellent overall Px graft survival can be achieved. Although the quality of the pancreas graft was not directly addressed in this study, we believe irrespective of hyperglycemia or hyperamylasemia, subjective assessment of organ quality by an experienced transplant surgeon is the most important determinant of suitability.     

Osteoporosis after orchiectomy for prostate cancer

PURPOSE: The possibility of increased osteoporosis and osteoporotic fractures following therapeutic orchiectomy in men with prostate cancer was investigated. MATERIALS AND METHODS: A total of 235 men with nonstage A prostate cancer diagnosed between 1983 and 1990 was analyzed for therapeutic orchiectomy, other osteoporotic risk factors and subsequent hospital treatment for osteoporotic fractures. The 17 castrated men alive in 1995 were interviewed, and femoral neck bone mineral density was compared to that of 23 controls of similar age. RESULTS: Risk factors for osteoporosis, including smoking, slender habitus and atrophic testes, were common among men treated with orchiectomy. Of the men in the study cohort 10 had osteoporotic fractures: 8 of 59 treated with and 2 of 176 without orchiectomy (13.6 versus 1.1%, p < 0.001). First fracture cumulative incidence rates 7 years after castration or diagnosis were 28 and 1%, respectively (p < 0.001). Osteoporotic fractures were much more common than pathological fractures or those due to major trauma (1 each). Bone mineral density averaged 0.91, 0.84, 0.79 and 0.66 gm./cm.2 in 9 controls without prostate cancer, 14 men with prostate cancer before orchiectomy, 9 men at 9 to 60 and 8 men at 60 to 115 months after orchiectomy, respectively. Of the 16 men surviving for longer than 60 months after orchiectomy 6 had osteoporotic fractures, as did 5 of 6 and 5 of 7 with a bone mineral density of less than 0.70 gm./cm.2 and less than 75% of normal for age, respectively. CONCLUSIONS: Orchiectomy for prostate cancer is frequently followed by severe osteoporosis, some of which had developed before castration. Appropriate therapy should be identified that does not diminish the antitumorigenic effectiveness of androgen ablation.