Granulocyte/macrophage colony stimulating factor. A potent activation signal for mature macrophages and monocytes

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a well-characterized hematopoietic growth factor. Recently, using purified recombinant-derived material, we have found that GM-CSF is also a potent activator of mature functional macrophages. Thus, we have found that exogenous GM-CSF augments the primary plaque-forming response to sheep red blood cells and that this effect is due to upregulation of Ia antigen expression and interleukin 1 production by the macrophages. We also show that GM-CSF inhibits the replication of Trypanosoma cruzi in cultured peritoneal macrophages and causes an accelerated clearance of Salmonella typhimurium from the peritoneal cavity of mice. These data indicate that GM-CSF is a multifunctional molecule stimulating both hematopoiesis and mature macrophage function.     

Increased susceptibility to RSV infection by exposure to inhaled diesel engine emissions

Although epidemiologic data strongly suggest a role for inhaled environmental pollutants in modulating the susceptibility to respiratory infection in humans, the underlying cellular and molecular mechanisms have not been well studied in experimental systems. The current study assessed the impact of inhaled diesel engine emissions (DEE) on the host response in vivo to a common pediatric respiratory pathogen, respiratory syncytial virus (RSV). Using a relatively resistant mouse model of RSV infection, prior exposure to either 30 microg/m3 particulate matter (PM) or 1,000 microg/m3 PM of inhaled DEE (6 h/d for seven consecutive days) increased lung inflammation to RSV infection as compared with air-exposed RSV-infected C57Bl/6 mice. Inflammatory cells in bronchoalveolar lavage fluid were increased in a dose-dependent manner with regard to the level of DEE exposure, concomitant with increased levels of inflammatory mediators. Lung histology analysis indicated pronounced peribronchial and peribronchiolar inflammation concordant with the level of DEE exposure during infection. Mucous cell metaplasia was markedly increased in the airway epithelium of DEE-exposed mice following RSV infection. Interestingly, both airway and alveolar host defense and immunomodulatory proteins were attenuated during RSV infection by prior DEE exposure. DEE-induced changes in inflammatory and lung epithelial responses to infection were associated with increased RSV gene expression in the lungs following DEE exposure. These findings are consistent with the concept that DEE exposure modulates the lung host defense to respiratory viral infections and may alter the susceptibility to respiratory infections leading to increased lung disease.     

A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy

Background  

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder with monogenic mutations setting the stage for successful gene therapy treatment. We have completed a study that directly deals with the following key issues that can be directly adapted to a gene therapy clinical trial using rAAV considering the following criteria: 1) A regional vascular delivery approach that will protect the patient from widespread dissemination of virus; 2) an approach to potentially facilitate safe passage of the virus for efficient skeletal muscle transduction; 3) the use of viral doses to accommodate current limitations imposed by vector production methods; 4) and at the same time, achieve a clinically meaningful outcome by transducing multiple muscles in the lower limb to prolong ambulation.     

Effects of placentation on selected type A behaviors in adult males in the national heart,lung, and blood institute (NHLBI) twin study

A dermatoglyphic index derived from monozygotic (MZ) twins of known placental type was used to estimate placentation retrospectively in a sample of adult male MZ twins. Examination of behavioral test scores with respect to placentation showed that the within-pair difference of most measures of type A behavior was smaller in presumed monochorionic than presumed dichorionic pairs. Measures of cognitive function and hostility were not related to placental type. Intraclass correlations in the monochorionic subgroup of MZ twins were greater than the correlations reported for the full sample of MZ twins. The trends were strongest for the Adjective Check List scales taken at two different exams 5 years apart and, to a lesser extent, for the Framingham type A scale. Our results are most consistent with greater intrauterine environmental covariance in monochorionic MZ twins as an explanation for inflation of the MZ twin correlation relative to dizygotic (DZ) correlation reported for some type A measures.     

Specific immunization of mice against Leishmania mexicana amazonensis using solubilized promastigotes.

Successful immunization of highly susceptible BALB/c mice against progressive infection by Leishmania mexicana amazonensis, using whole solubilized promastigotes was achieved. The best immunization schedule consisted of three weekly injections of 5 X 10(7) parasite equivalents. Intravenous was superior to intraperitoneal or subcutaneous immunization. Protection persisted for up to 2 months after immunization, and beneficial effects could be observed in long-term follow-up (24 weeks after infection). Immunized mice exhibited marked reduction in primary lesion size, as well as reduction of the number of parasites in the spleen, and developed less metastases. High titres of specific anti-L. m. amazonensis IgG antibodies resulted from immunization, but titres did not correlate with protection. Groups with widely differing pre-infection antibody titres were equally protected, and similar antibody titres resulted in different levels of protection. Immunization alone did not induce significant serum interferon-gamma levels and specific delayed-type hypersensitivity (DTH) reactions, but resulted in the persistence of positive (DTH) reactions after infection, at a time when infected control animals had suppressed responses. Resistance to leishmaniasis appears to depend on cell mediated immune mechanisms, and the possibility of immunization with a solubilized antigen without adjuvant is intriguing and opens new perspectives in this area.     

Extraskeletal myxoid chondrosarcoma: multimodal diagnosis and identification of a new cytogenetic subgroup characterized by t(9;17)(q22;q11)

Extraskeletal myxoid chondrosarcoma is a rare malignant soft tissue tumour that can be difficult to diagnose correctly, especially preoperatively. We describe four cases of extraskeletal myxoid chondrosarcoma of the extremities diagnosed by a multimodal approach. The cytological examination of fine-needle aspirates showed small and round, mildly pleomorphic cells lying in sheets and cords, but also dispersed within a myxoid and metachromatic intercellular substance. Histological, electron microscopic and immunocytochemical examination also yielded findings compatible with the diagnosis of extraskeletal myxoid chondrosarcoma. Cytogenetic analysis demonstrated a t(9;22)(q22;q12) in two tumours and a t(9;17)(q22;q11) in the third and fourth. The translocation t(9;22)(q22;q12) has been described repeatedly in extraskeletal myxoid chondrosarcoma but never in other tumours; hence, the detection of this pathognomonic chromosome abnormality in short-term cultured cells from fine-needle aspirates verified the diagnosis in two of the cases. The t(9;17)(q22;q11) found in the last two cases probably represents a new cytogenetic subgroup of extraskeletal myxoid chondrosarcoma as it, too, is unknown in other contexts. The multimodal approach taken in these four cases enabled a definite diagnosis of a rare malignant tumour whose cytological and histological features alone are usually not sufficiently distinct to rule out other differential diagnostic possibilities. Received: 16 March 1999 / Accepted: 1 June 1999     

Isolation of rhinoviruses and coronaviruses from 38 colds in adults

Nasal washings were collected from 27 normal adults during 38 naturally acquired colds. The washings were exhaustively tested using tissue cultures, organ cultures and electron microscopy. Washings yielding no identifiable agent were inoculated into human volunteers, and further specimens obtained from the latter were examined by the same techniques in vitro. Viruses were identified in association with 25 of the original 38 colds (65.7%). Fifteen were rhinoviruses (39.5%), seven coronaviruses (18.4%), two were para-influenza viruses, and one was influenza virus. Use of organ cultures and of volunteers significantly increased the isolation rate. No agent was cultivated from the remaining 13 specimens, although tests in volunteers showed that cold-producing agents were present in five of them (13%). Three specimens gave doubtful results in volunteers, and five others, all collected within a period of six weeks in December and January, apparently contained no infectious agent.     

Extreme resistance to Potato leafroll virus in potato cv. Russet Burbank mediated by the viral replicase gene

High levels of field resistance to Potato leafroll virus (PLRV; Genus: Polerovirus; Family: Luteoviridae) were achieved by expression of the unmodified, full-length PLRV replicase gene in potato plants cv. Russet Burbank. A high degree of resistance was also achieved, but less frequently, by expression of a truncated construct of the replicase gene. In limited testing, neither miss-frame nor antisense constructs of the replicase gene conferred resistance. The degree of resistance expressed among different transformant lines ranged from near immunity to full susceptibility. Resistance to the Colorado potato beetle (Leptinotarsa decemlineata Say) was combined with resistance to PLRV by expression of the cry3A insect control protein gene from Bacillus thuringiensis var. tenebrionis in combination with the unmodified, full-length, viral replicase gene. Resistance was expressed as a reduced incidence of infection detectable by foliage symptoms or serological tests. Reduced incidence of infection was not associated with a decrease in virus antigen concentration in the few plants of resistant lines that became infected. Virus was not detected in the foliage of symptomless plants but was detected in progeny plants produced from the tubers of inoculated but symptomless test plants of some resistant lines. The resistance was effective under natural exposure and against plant-to-plant spread of PLRV by the aphid vector, Myzus persicae Sulzer. Three of the resistant lines selected in these studies were released and are now in commercial production.