The impact of early standard therapy on dyspnoea in patients with acute heart failure: the URGENT-dyspnoea study.

AIMS: The vast majority of acute heart failure (AHF) trials to date have targeted dyspnoea. However, they enrolled patients relatively late and did not standardize their methods of dyspnoea measurement. URGENT Dyspnoea was designed to determine changes in dyspnoea in response to initial, standard therapy in patients presenting with AHF using a standardized approach. METHODS AND RESULTS: URGENT Dyspnoea was an international, multi-centre, observational cohort study of AHF patients managed conventionally and enrolled within 1 h of first hospital medical evaluation. Patient-assessed dyspnoea was recorded in the sitting position at baseline and at 6 hours by Likert and visual analog scales. Less symptomatic patients were placed supine to determine whether this provoked worsening dyspnoea (orthopnoea). Of the 524 patients with AHF, the mean age was 68 years, 43% were women, and 83% received intravenous diuretics. On a 5-point Likert scale, dyspnoea improvement was reported by 76% of patients after 6 h of standard therapy. Supine positioning (orthopnoea test) led to worse dyspnoea in 47% of patients compared to sitting upright. CONCLUSION: When sitting upright, dyspnoea in the sitting position improves rapidly and substantially in patients with AHF after administration of conventional therapy, mainly intra-venous diuretics. However, many patients remain orthopnoeic. Improving the methodology of clinical trials in AHF by standardizing the conditions under which dyspnoea is assessed could enhance their ability to identify effective treatments. Relief of orthopnoea is clinically valuable and may represent a useful goal for clinical trials.

Detection of human mammary tumor virus proteins in human breast cancer cells.

Mouse mammary tumor virus (MMTV) has been proven to induce mammary cancer in mice. MMTV-like env gene sequences have been detected in one-third of the human breast tumors studied. The whole proviral structure with 95% homology to MMTV was found in two human breast tumors and was designated as human mammary tumor virus (HMTV). HMTV viral particles with betaretroviral features have been isolated. In addition, a retrovirus called human betaretrovirus (HBRV), homologous to the mentioned retroviruses, has been isolated from tissues of patients with primary biliary cirrhosis. In this report, the expression of HMTV envelope (Env) and capsid (Ca) was detected in 10 primary cultures of human breast cancer containing HMTV sequences (MSSM) by Western blot and fluorescence activated cell sorting (FACS), using a panel of antibodies against HMTV Env, HBRV Env and Ca and the MMTV Env Gp36 and Ca P27 proteins. By contrast, HMTV proteins did not react with antibody against the MMTV Env Gp52 protein. All the antibodies detected MMTV proteins with exception of two out of four monoclonal antibodies against HMTV Env. Approximately 13% of the MSSM cells showed HMTV protein expression by FACS analysis. This report shows the expression of HMTV proteins for the first time in human breast cancer cells using a panel of antibodies against HMTV, HBRV and MMTV proteins. This should be taken into consideration when MMTV antibodies are used to detect HMTV proteins in human tissues.

Characterization of viral particles isolated from primary cultures of human breast cancer cells.

The association of human breast cancer with sequences similar to the mouse mammary tumor virus (MMTV) has been shown, but convincing evidence for the presence of viral particles in breast tumors has been lacking. We have described the complete proviral structure of a retrovirus in human breast cancer. This provirus, designated as human mammary tumor virus (HMTV), was 95% homologous to MMTV and revealed features of a replication-competent virus. We have therefore investigated the production of viral particles in primary cultures of human breast cancer (MSSM). Cells isolated from ascites or pleural effusions of patients with metastatic breast cancer contained viral sequences in their DNA, expressed Env protein, and showed retroviral particles by electron microscopy. Viral particles from culture media exhibited morphologic features of beta-retroviruses sedimenting at buoyant densities of 1.12 to 1.18 g/mL in sucrose gradients and showed reverse transcriptase activity. cDNA sequences from virion RNA were synthesized, amplified, and sequenced and all the virion genes were detected and 70% of the virion RNA was sequenced. The sequence homologies were, respectively, 85% to 95% compared with the MMTV and HMTV proviruses we have previously described. These results clearly show that breast cancer cells in primary cultures produced HMTV viral particles that are similar to the mouse virus and which may play a role in human breast cancer pathogenesis.