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The frequency of ras (H-, K-, and N-ras) and c-myc oncogenes was investigated in multiple myeloma (MM). By means of the polymerase chain reaction (PCR)/oligonucleotide hybridization method, DNA from 56 tumor biopsies was analyzed for the presence of activating mutations involving codons 12 and 61 of the H-, K-, and N-ras genes and codon 13 of the N-ras gene. Mutations, involving the N- or K-ras genes, were detected in 18 of 56 (32%) cases of which 12/43 (27%) were at diagnosis and 6/13 (46%) were after treatment. In some cases, multiple mutations affecting different ras alleles were detected. Direct nucleotide sequence analysis of PCR products indicated that a more heterogeneous nature of the base pair changes than previously shown for other tumors along with a preferential involvement of N-ras codon 61. The heterogeneity of MM cases with respect to the presence of ras oncogenes prompted an analysis of possible correlations with different clinico-pathologic characteristics of MM from which a correlation between the presence of ras oncogenes and a partial or complete lack of response to therapy emerged. The frequency of activating rearrangements or mutations of the c-myc gene were studied by Southern blot analysis and PCR sequencing, respectively. However, contrary to previous reports involving mostly MM cell lines, no structural alterations of the c-myc gene were found. These results indicate that ras, but not c-myc, oncogenes are activated in vivo in MM cells, representing the first oncogene alteration that has been associated at appreciable frequency with this type of malignancy. While the mechanism of occurrence and biological role of ras activation in MM remains to be elucidated, the preliminary correlations observed in this study between the presence of ras oncogenes and poor therapeutic response suggest that further investigations of the possible prognostic significance of these alterations are necessary.

Among infants born at less than or equal to 34 weeks to women who have intact membranes and are initially afebrile, those exposed to AF bacteria or cytokines have more adverse neonatal outcomes than unexposed infants of similar birth weight.

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Previous studies demonstrated that high-frequency oscillatory ventilation (HFOV) begun at birth limits the development of alveolar proteinaceous edema in premature monkeys at risk for hyaline membrane disease (HMD). We hypothesized that exogenous surfactant combined with HFOV would lead to even further reductions in edema. Twenty Macaca nemestrina monkeys were delivered at 134 d gestation (term = 168 d) and treated with either HFOV or conventional mechanical ventilation (CMV) from the first breath; modified bovine surfactant (Survanta [beractant]) was introduced into the trachea over the first few minutes of life. These animals were compared with 20 animals treated with either CMV or HFOV but without surfactant. At 6 h the lung was rapidly frozen in situ during inflation for determination of the volume fraction of alveolar edema. The combined use of surfactant and HFOV from the first breath reduced alveolar proteinaceous edema (3 +/- 1%; mean +/- SEM) from that seen with CMV alone (27 +/- 3%, p < 0.0001), CMV after surfactant (21 +/- 3%, p < 0.0001), and HFOV alone (13 +/- 3%, p < 0.015). We conclude that the use of surfactant with HFOV after premature birth is superior to either surfactant or HFOV alone in reducing lung injury during the first few hours of life. We speculate that this reduction in lung injury may reduce the incidence or severity of bronchopulmonary dysplasia.

BackgroundMany older people in long-term care do not receive evidence-based diagnosis or management for heart failure; it is not known whether this can be achieved for this population. We initiated an onsite heart failure service, compared with ‘usual care’ with the aim of establishing the feasibility of accurate diagnosis and appropriate management.MethodsA pilot randomised controlled trial which randomised residents from 33 care facilities in North-East England with left ventricular systolic dysfunction (LVSD) to usual care or an onsite heart failure service. The primary outcome was the optimum prescription of angiotensin-converting enzyme inhibitors and beta-adrenergic antagonists at 6 months.ResultsOf 399 echocardiographically-screened residents aged 65–100 years, 30 subjects with LVSD were eligible; 28 (93%) consented and were randomised (HF service: 16; routine care: 12). Groups were similar at baseline; six month follow-up was completed for 25 patients (89%); 3 (11%) patients died. Results for the primary outcome were not statistically significant but there was a consistent pattern of increased drug use and titration to optimum dose in the intervention group (21% compared to 0% receiving routine care, p=0.250). Hospitalisation rates, quality of life and mortality at 6 months were similar between groups.ConclusionsThis study demonstrated the feasibility of an on-site heart failure service for older long-term care populations. Optimisation of medication appeared possible without adversely affecting quality of life; this questions clinicians’ concerns about adverse effects in this group. This has international implications for managing such patients. These methods should be replicated in a large-scale study to quantify the scale of benefit.Trial registrationISRCTN19781227 http://www.controlled-trials.com/ISRCTN19781227

In Escherichia coli the release factor 1 protein (RF1) recognizes and terminates translation at UAG and UAA codons. Using the technique of ColEl plasmid integration in polA strains, we have mapped the cloned gene for RF1 to 27 min on the E. coli chromosome. This is the same location as that of the uar gene in which temperature-sensitive mutations increase the suppresgion of UAG and UAA alleles. In this study we proved that the uar mutation lies in the gene for RF1 by (i) complementation of the uar phenotype with plasmids carrying the RF1 gene and by (ii) cloning the uar allele onto the RF1 plasmid by mneans of homologous recombination. In addition, complententation and P1 mapping data suggest that sueB is also a mutation in the same position as the RF1 gene. We propose that the gene for RF1 be named prA after protein release factor.In vitro studies have shown that protein release factors are essential to the process of translational termination (2). In Escherichia coli release factor 1 (RF1) recognizes UAA and UAG codons, while release factor 2 (RF2) responds to the UAA and UGA terminators. The mechanisms whereby RF1 and RF2 execute their functions are not well known, but it is reasonable to believe that they compete with aminoacyl tRNAs for recognition of the nonsense triplets. In a previous report we described the isolation of mutants by selection for increased misreading of a particular UAG allele (15). One mutant, which proved to be temperature sensitive for growth, also misread UAA codons and increased the efficiency of UAA and UAG nonsense suppressors. This mutant carries the uar allele, which was named for its affect on UAA and UAG codons.In another study we reported the cloning of the wild-type gene for RF1 into the multicopy plasmid YRp7 (18). Here we describe the mapping, by plasmid integration, of the cloned RF1 gene to the same position as the uar mutation. We also show that the uar mutation was complemented by the multicopy plasmid carrying RF1. Moreover, by using homologous recombination between the RF1 plasmid and the chromosomal uar mutation, it proved possible to clone the uar gene and to confirm that the uar mutation is indeed an allele of the gene for RF1.

Aims Morphine is shown to relieve chronic breathlessness in chronic obstructive pulmonary disease. There are no definitive data in people with heart failure. We aimed to determine the effectiveness and cost-effectiveness of 12 weeks morphine therapy for the relief of chronic breathlessness in people with chronic heart failure compared with placebo. Methods and results Parallel group, double-blind, randomized, placebo-controlled, phase III trial of 20 mg daily oral modified release morphine was conducted in 13 sites in England and Scotland: hospital/community cardiology or palliative care outpatients. The primary analysis compared between-group numerical rating scale average breathlessness/24 hours at week 4 using a covariance pattern linear mixed model. Secondary outcomes included treatment-emergent harms (worse or new). The trial closed early due to slow recruitment, randomizing 45 participants [average age 72 (range 39-89) years; 84% men; 98% New York Heart Association class III]. For the primary analysis, the adjusted mean difference was 0.26 (95% confidence interval, À0.86 to 1.37) in favour of placebo. All other breathlessness measures improved in both groups (week 4 change-from-baseline) but by more in those assigned to morphine. Neither group was excessively drowsy at baseline or week 4. There were no betweengroup differences in quality of life (Kansas) or cognition (Montreal) at any time point. There was no exercise-related desaturation and no change between baseline and week 4 in either group. There was no change in vital signs at week 4. The natriuretic peptide measures fell in both groups but by more in the morphine group [morphine 2169 (1092, 3851) pg/mL vs. placebo 2851 (1694, 5437)] pg/mL. There was no excess serious adverse events in the morphine group. Treatment-emergent harms during the first week were more common in the morphine group; all apart from 1 were ≤ grade 2. ConclusionsWe could not answer our primary objectives due to inadequate power. However, we provide novel placebocontrolled medium-term benefit and safety data useful for clinical practice and future trial design. Morphine should only be prescribed in this population when other measures are unhelpful and with early management of side effects.