Pegylated megakaryocyte growth and development factor abrogates the lethal thrombocytopenia associated with carboplatin and irradiation in mice.

Megakaryocyte growth and development factor (MGDF) is a potent inducer of megakaryopoiesis in vitro and thrombopoiesis in vivo. The effects of MGDF appear to be lineage-selective, making this cytokine an ideal candidate for use in alleviating clinically relevant thrombocytopenias. This report describes a murine model of life-threatening thrombocytopenia that results from the combination treatment of carboplatin and sublethal irradiation. Mortality of this regimen is 94% and is associated with widespread internal bleeding. The daily administration of pegylated recombinant human MGDF (PEG-rMGDF) significantly reduced mortality (to < 15%) and ameliorated the depth and duration of thrombocytopenia. The severity of leucopenia and anemia was also reduced, although it was not clear whether these effects were direct. Platelets generated in response to PEG-rMGDF were morphologically indistinguishable from normal platelets. PEG-rMGDF administered in combination with murine granulocyte colony-stimulating factor completely prevented mortality and further reduced leukopenia and thrombocytopenia. These data support the concept that PEG-rMGDF may be useful to treat iatrogenic thrombocytopenias.

Sustained and distinctive patterns of gene activation in synovial fibroblasts and whole synovial tissue obtained from inflammatory synovitis.

Fibroblastoid synovial lining cells isolated from rheumatoid and other chronic inflammatory synovial tissue exhibit distinctive and sustained alterations in serial culture not commonly found in similarly cultured cells from osteoarthritic synovium. These are demonstrable using a multi-gene dot blot assay by labelling reverse transcribed fibroblast cDNA which is hybridized to plasmids containing relevant target gene inserts. Cultured synovial fibroblastoid cells from patients with chronic inflammatory synovitis expressed significantly higher levels of stromelysin, vimentin and TIMP-1 mRNA and lower levels of c-myc compared to cells isolated from osteoarthritis synovium although with considerable variation. Early fetal synovial lining cells were similar to cells from osteoarthritis synovium but vimentin expression was higher. Marked differences in patterns of gene expression between cell lines persisted through 10 serial passages over 6-8 months. In whole synovia, the average level of mRNA for stromelysin, vimentin, IL-4, IL-6, TIMP-1, cathepsin D, gelatinase, TGF alpha, c-fms and DR beta were preferentially expressed in inflammatory tissue while c-myc expression was higher in osteoarthritis synovium. Inflammatory synovium also expressed TNF alpha, IL-1 alpha, IL-1 beta, IL-2, c-sis, tissue plasminogen activator, CSF-1, and GM-CSF. This pattern resembles, in part, that found in cultured inflammatory fibroblasts but, in addition, gene products apparently reflecting the presence of activated monocytes and lymphocytes were detected. These results provide evidence that profiles of certain gene activation in cells from patients with inflammatory synovitis differ from those with non-inflammatory disease and suggest that the fibroblastoid cells are responsible for a considerable proportion of the altered phenotypic expression pattern in whole tissue. Furthermore, this modulated pattern of gene activation appears to be an intrinsic pro-inflammatory characteristic of the fibroblastoid cells initiated in response to chronic inflammation and persists for a prolonged period in the absence of other inflammatory cells.

Metabolic derangements in children requiring parenteral nutrition.

Intravenous alimentation is routinely used in many hospitalized pediatric patients, however, there are few reports of the nature and frequency of metabolic complications. In order to assess the frequency and nature of metabolic complications all children receiving parenteral nutrition from January 1, 1982 to December 31, 1982 were prospectively enrolled in the study. Data collection began with the institution of parenteral nutrition. Serum electrolytes, minerals, liver function tests, and renal function tests were followed weekly. A total of 201 patients received parenteral nutrition for 5378 days. Nutrition was delivered to 146 patients (4980 patient days) via a central line and 55 patients via a peripheral line (398 patient days). The sepsis rate was 3.7% in central lines used only for parenteral and 4.8% in multipurpose central lines. In general, complications were fewer in the patients supported peripherally. In patients supported centrally, hypoalbuminemia was the most commonly found abnormality followed by hypocalcemia, hypophosphatemia and hypomagnesemia, reflecting a malnourished state. One-third of the patients had abnormal liver function tests, and in half of those factors causing liver dysfunction other than parenteral nutrition were present. Abnormal renal function tests occurred in 10% of the patients. Thus, a high incidence of metabolic complications occurred in association with parenteral nutrition. Most were present during the initiation of parenteral nutrition, suggesting an abnormal metabolic state was present prior to the institution of parenteral nutrition. The frequency of low serum albumin and minerals is consistent with previous publications of the prevalence of malnutrition in hospitalized patients.