How do CTL control virus infections? Evidence for prelytic halt of herpes simplex.

Cytotoxic T lymphocytes (CTL) induce in target cells a rapid, prelytic fragmentation of target cell DNA, accompanied by apoptosis. In contrast, complement and (with a few exceptions) chemical and physical means of inducing cytolysis induce necrosis, without DNA fragmentation. The function of the unusual DNA fragmentation induced by CTL remains to be elucidated. The major recognized function of CTL is in halting virus infections. Earlier, we proposed that CTL might halt virus infections prelytically, by fragmenting viral and cellular nucleic acids, and that in this case, cytolysis per se might be a less important function of CTL. We report here experiments designed to detect prelytic halt of virus replication. We employed in vivo-like conditions: fibroblast targets (difficult to lyse) were infected with herpes simplex virus (HSV), then incubated at low E/T cell ratios overnight. At the highest E/T ratios which produced less than 10% CTL-induced lysis, plaque-forming unit yield was reduced by about 50%. At higher E/T ratios which lysed 1/6 to 1/3 of the infected target cells, 3/4 to 9/10 of the virus production was prevented. The discrepancy between the level of lysis and the reduction in virus yield is evidence for significant CTL-induced prelytic halt of HSV replication. At present, it is unclear whether the antiviral effect observed involves an activity of CTL distinct from their lytic ability, such as their DNA fragmenting ability.     

Red blood cell methotrexate and folate levels in children with acute lymphoblastic leukemia undergoing therapy: a Pediatric Oncology Group pilot study

Summary We enrolled children with acute lymphoblastic leukemia (ALL) in a Pediatric Oncology Group (POG) pilot study to monitor erythrocyte (RBC) methotrexate (MTX) and folate (F) levels before and during treatment. The mean value for RBCF at diagnosis was 0.86±0.46 nmol/ml RBC in the 214 patients who achieved remission and 1.21±0.74 nmol/ml RBC in the 10 patients who did not (P=0.020). Folate levels tended to increase during remission induction, but they dropped following an intensive consolidation with methotrexate to levels that were sustained throughout chemotherapy treatment. Methotrexate levels reached mean values of approximately 0.15 nmol/ml RBC at the end of an intensive methotrexate consolidation, then fell to levels that were sustained throughout maintenance therapy. There was a weak correlation between improved event-free survival and higher RBCMTX levels after consolidation, but no correlation was found between improved survival and the level of RBCMTX or RBCF during maintenance therapy. A larger study with more complete data is needed to determine whether RBCMTX or RBCF might be useful in predicting event-free survival in patients with ALL.This work was supported in part by grants from the National Cancer Institute and the National Institute of Health (CA-30969, CA-28476, CA29139, CA-159-89, and CA-33587)     

Correlation of pre-treatment transurethral resection and prognosis in patients with stage C carcinoma of the prostate treated with definitive radiotherapy--RTOG experience

Four hundred and ninety-four patients with clinical Stage C carcinoma of the prostate, who were entered onto a phase III RTOG study, have been analyzed as to the potential effect of the pre-treatment transurethral resection (TUR) of the tumor. Treatment consisted of definitive irradiation to the prostate (6500-7000 cGy) and regional lymphatics (4500-5000 cGy). A total of 202 patients underwent pre-treatment TUR. This population was compared with the remaining 292 patients as to the rate of locoregional failure, incidence of distant metastases, disease-free survival, and survival. The TUR population fared significantly worse for all four end-points. To account for uneven distribution of recognized prognostic factors the results were then adjusted using stratified Mantel-Haenszel tests. The stratification process resulted in a reduced level of significance in the differences between the two populations. However, a trend toward a higher incidence of distant metastases could be observed within most strata. The trend was most pronounced in subpopulations characterized by Gleason score 6-7 and normal serum acid phosphatase (SAP). For the population characterized by Gleason score 6-10 and normal SAP, the differences in the incidence of distant metastases retained statistical significance. Whether these findings are secondary to tumor dissemination during TUR or are due to incompletely identified selection biases remains to be demonstrated in future (prospective) studies.     

O6-Methylguanine methyltransferase activity is increased in rat tissues by ionising radiation

The effect of whole body ionising radiation from a linear acceleratoron rat tissue O⁶-methylguanine (O⁶-meG) methyl-transferase (MT)activity has been assessed using an assay which measures thetransfer of ³H-radioactivity from ³H-methylated substrate DNAto protein. The maximal effect occurred 2 days after a 1 kraddose, at which time activity in liver extracts was increased5-fold in two different rat strains. Activity in lung and kidneywas increased 4- and 2-fold, respectively. Similar degrees ofenhancement were found in these three tissues using an h.p.l.c.method for measuring MT activity. The increase in activity wasreflected in an increased capacity to repair O⁶-meG producedin liver DNA by administration of [¹⁴C]dimethylnitrosamine (DMN):this effect was dose dependent, being detectable after 30 radsand maximal after 600 rads. Incorporation of labelled breakdownproducts of the DMN into adenine in DNA increased as the doseradiation increased suggesting an inhibition of DNA synthesis.The implications of these results for the mechanism of enhancingO⁶-meG repair are discussed.     

Patient participation in pressure injury prevention: giving patient's a voice

Pressure injuries burden patients and healthcare organisations, with some preventative practices having little impact on prevalence reduction. Patient participation in care may be an effective pressure injury prevention strategy, yet patient preferences are unknown. The aim of this interpretive study was to describe patients' perceptions of their current and future role in pressure injury prevention. Semi‐structured interviews were conducted with 20 adult inpatients recruited from four medical units, at two Australian metropolitan hospitals. Interview data were analysed using content analysis, with three categories emerging: ‘experiencing pressure injuries’; ‘participating in pressure injury prevention’; and ‘resourcing pressure injury prevention and treatment’. These categories reflect the complex nature of participants’ pressure injury experience. The findings suggest participants gather pressure injury knowledge from first‐hand and vicarious experience; knowledge they bring to hospital. Most participants preferred a proactive pressure injury prevention role. Many identified barriers in the healthcare environment that impeded their participation and affected their experience of pressure injuries and pressure injury prevention. If patient participation as a pressure injury prevention strategy is to be considered, nurses and organisations need to view patients as partners.