Murine model of pulmonary anthrax: kinetics of dissemination, histopathology, and mouse strain susceptibility

Bioweapons are most often designed for delivery to the lung, although this route is not the usual portal of entry for many of the pathogens in the natural environment. Vaccines and therapeutics that are efficacious for natural routes of infection may not be effective against the pulmonary route. Pulmonary models are needed to investigate the importance of specific bacterial genes in virulence, to identify components of the host immune system that are important in providing innate and acquired protection, and for testing diagnostic and therapeutic strategies. This report describes the characteristics of host and Bacillus anthracis interactions in a murine pulmonary-infection model. The infective dose varied depending on the route and method of inoculation. The germination process in the lung began within 1 h of inoculation into the lung, although growth within the lung was limited. B. anthracis was found in the lung-associated lymph nodes approximately 5 h after infection. Minimal pneumonitis was associated with the lung infection, but significant systemic pathology was noted after dissemination. Infected mice typically succumbed to infection approximately 3 to 4 days after inoculation. The 50% lethal doses differed among inbred strains of mice, but within a given mouse strain, neither the age nor the sex of the mice influenced susceptibility to B. anthracis.     

Peptide-based approaches to treat asthma, arthritis, other autoimmune diseases and pathologies of the central nervous system

In this review we focus on peptide- and peptidomimetic-based approaches that target autoimmune diseases and some pathologies of the central nervous system. Special attention is given to asthma, allergic rhinitis, osteoarthritis, and Alzheimer's disease, but other related pathologies are also reviewed, although to a lesser degree. Among others, drugs like Diacerhein and its active form Rhein, Pralnacasan, Anakinra (Kineret), Omalizumab, an antibody "BION-1", directed against the common beta-chain of cytokine receptors, are described below as well as attempts to target beta-amyloid peptide aggregation. Parts of the review are also dedicated to targeting of pathologic conditions in the brain and in other tissues with peptides as well as methods to deliver larger molecules through the "blood--brain barrier" by exploring receptor-mediated transport, or elsewhere in the body by using peptides as carriers through cellular membranes. In addition to highlighting current developments in the field, we also propose, for future drug targets, the components of the inflammasome protein complex, which is believed to initiate the activation of caspase- 1 dependent signaling events, as well as other pathways that signal inflammation. Thus we discuss the possibility of targeting inflammasome components for negative or positive modulation of an inflammatory response.     

Centrilobular histopathologic changes in liver transplant biopsies

We evaluated centrilobular histologic changes seen on post-orthotopic liver transplantation (OLT) biopsies to refine the pathologic diagnosis by systematic study of morphologic and clinical data with possible identification of prognostic criteria. A total of 110 biopsies with zone 3 pathology from 59 patients were reviewed and correlated with clinical findings. Within the first 6 months post-OLT (group I), 39 of 47 patients had combinations of centrilobular hepatocytic dropout, ballooning, and cholestasis on single or multiple biopsies attributed to perioperative ischemic/perfusion injury; 12 of 39 patients with all 3 features present had increased incidence of biliary complications and sepsis and decreased 1-year patient and graft survival; 17 of 39 patients with 2 of the 3 features had increased biliary complications but not decreased 1-year survival; and the remaining 8 of 47 patients had central venulitis associated with acute cellular rejection. After 6 months post-OLT (group II), 14 patients, including 2 from group I, had biopsies with centrilobular pathology; 8 of 14 had central venulitis related to rejection (acute, 4; chronic, 4), and fibrosis was seen in 8 (rejection, 6; cardiac problems, 2). In conclusion, combinations of centrilobular hepatocytic ballooning, dropout, and cholestasis are seen in association with reversible or irreversible ischemic/perfusion damage in the early post-OLT period. The presence of all 3 features is associated with a poor outcome. Central venulitis as a feature of acute/chronic rejection is seen at any time post-OLT and is not a predictor of poor graft/patient survival.     

Persistent organochlorines, sedentary occupation, obesity and human male subfertility

BACKGROUND: Studies have suggested that the quality of human semen has been declining over recent decades, presumably because of lifestyle or environmental factors. METHODS: Polychlorinated biphenyls and organochlorine pesticides were analysed in the plasma of 25 men with poor semen quality, 20 men with normal semen quality and idiopathic subfertility and 27 men with normal semen quality and female factor subfertility. Samples of seminal fluid were also analysed to assess the relationship between the levels in blood and semen. RESULTS: The results indicate no difference in the levels of organochlorines between the groups. The levels of organochlorines in seminal fluid were proportional to the levels in plasma, but approximately 40 times lower. Men with poor semen quality were three times more likely to be obese than men with normal semen quality. There was also a significant negative correlation between semen quality parameters and body mass index among men with normal semen quality. The prevalence of sedentary work was lowest among men with the best semen quality. CONCLUSIONS: Poor semen quality was found to be associated with sedentary work and obesity but not with plasma levels of persistent organochlorines. More research is needed to assess whether sedentary lifestyle and obesity are causal factors in the decline of semen quality.     

Fascin,an actin-bundling protein,modulates colonic epithelial cell invasiveness and differentiation in vitro

In epithelial tissue, cell-matrix and cell-cell adhesive interactions have important roles in the normal organization and stabilization of the cell layer. The malignant conversion of epithelial cells involves alterations in the expression and function of these adhesion systems that enable a switch to a migratory phenotype in tumor invasion and metastasis. Fascin is an actin-crosslinking protein that is found in the core actin bundles of cell-surface spikes and projections that are implicated in cell motility. We demonstrate that fascin is not detectable in normal colonic epithelium, but is dramatically up-regulated in colorectal adenocarcinoma. To test the hypothesis that fascin could participate in tumor invasive behavior, we developed a cell culture model to examine the effect of fascin expression on the adhesive interactions, invasiveness, and differentiation of colonic epithelial cells. We report marked effects on the organization of cell-surface protrusions, actin cytoskeleton, and focal adhesions in the absence of alterations in the protein levels of the major components of these structures. These effects correlate with alterations in cell movements on two-dimensional matrix, and increased invasiveness in three-dimensional matrix. The cells also show increased proliferation and decreased capacity for normal glandular differentiation in collagen gels. We propose that up-regulation of fascin, by promoting the formation of protrusive, actin-based, cell-motility structures, could be a significant component in the acquisition of invasive phenotype in colonic carcinoma.     

A design study for a 'spiral staircase' ionization chamber for the quality control of electron beams

In order to verify that the energies of electron beams used for external beam therapy remain constant, IPEM 81 recommends a constancy check based on the ratio of ionization chamber measurements at two depths along the central axis. Such measurements for a range of electron energies can be a time consuming process. The purpose of this study was to design a device that would use several ion chambers simultaneously to measure electron depth dose curves, and hence the electron energy. A design was developed for a device consisting of ten independent ionization chambers, shaped and arranged in a solid phantom like the steps of a spiral staircase, the axis of the staircase being coincident with the axis of the electron beam. Measurements were carried out to test the design of individual chambers and to optimize the radius of the spiral and both the depth intervals and the lateral spacing between adjacent chambers. For ranges of electron energy from 6-12 MeV and 12-20 MeV the radii of the spirals needed were found to be 36.5 mm and 30.9 mm, the angular separations between edges of the chambers were 52 degrees and 30 degrees and chamber depths were found to be 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 mm and 20, 40, 45, 50, 55, 60, 65, 70, 75, 80 mm, respectively.     

Dysmorphic features and learning disability in an adult male with pure partial trisomy 17q24-q25 due to a terminal duplication

We describe an adult male with severe learning disability, epilepsy, and dysmorphic features. Cytogenetic studies demonstrated a terminal duplication of the long arm of chromosome 17, resulting in partial trisomy 17q24-q25. Our patient shows some of the characteristic features of the distal 17q phenotype, but in addition has more unusual features such as epilepsy, sensorineural hearing loss, and long fingers and overlapping toes. We suggest that these features occur with terminal duplications of 17q.     

Cytogenetic and loss of heterozygosity studies in ependymomas, pilocytic astrocytomas, and oligodendrogliomas.

Cytogenetic and/or loss of heterozygosity studies were performed on 13 ependymomas, 11 pilocytic astrocytomas, and 18 oligodendrogliomas. Loss of chromosome 22 was the most frequent genetic abnormality among the ependymomas. We found no consistent genetic abnormality in pilocytic astrocytomas. The most common genetic abnormality in oligodendrogliomas was loss of a portion of chromosome 19. Each informative oligodendroglioma had loss of alleles mapped to the long arm (q) of chromosome 19. One oligodendroglioma had an apparent homozygous deletion of the D19S8 locus. Our results, when combined with those in the literature, indicate that chromosomes 9, 11, and 22 may harbor genes important for the pathogenesis of ependymomas and that 19q probably harbors a gene important for the pathogenesis of oligodendrogliomas.