Sternal pain after rigid fixation: a pilot study of randomization rigid vs conventional wire closure.

Objective: Rigid sternal fixation may provide better sternal closure than conventional sternal wire closure. We performed a prospective randomized study to investigate if rigid closure reduces postoperative sternal pain. Methods: Patients undergoing CABG ± valve surgery between July 2011 and January 2012 were prospectively randomized into conventional wire closure (group C) or rigid fixation using sternal plates (group R). Pain scores were determined at 6 AM using a numeric rating scale (0 no pain, 5 moderate pain, 10 worst possible pain). Narcotic pain medication requirement from day 1 to 5 was collected and converted into intravenous morphine equivalent. Results: Among the total of 26 patients, 11 patients were in Group R (10 male and 1 female, age 67 ± 8.0) and 15 patients were in Group C (13 male and 2 female, age 66 ± 9.9). Preoperative risk factors and procedure were identical between the two groups. Pain scores were not significantly different between 2 groups. Narcotic requirement was smaller in group R (15.7 mg intravenous morphine equivalent in group R in day 1vs 18.4 mg intravenous morphine equivalent in day 1 in group C in day 1, 13.1 mg vs 12.5 mg in day 2, 9.4 mg vs 10.5 mg in day 3, 6.9 mg vs 7.7 mg in day 4, and 6.2 mg vs 6.9 mg in day 5) than group C. Total iv narcotic given over 5 days was 24 ± 41 mg in group R and 34 mg ± 54 mg in group C (p=0.60). Conclusion: Randomized data rom this ongoing study showed a trend of fewer narcotic requirement especially intravenous narcotics in group R than in group C. Implications: Rigid fixation may potentially improve immediate sternal pain after open heart surgery. Less narcotic requirement potentially facilitate early return to the daily activity

Peptide mimics of a conserved H5N1 avian influenza virus neutralization site

A panel of 52 murine monoclonal antibodies was found to recognize antigenic determinants that had been conserved among till major genetic subgroups of the I ON I avian influenza virus prevalent since 1997. We screened a phage display library for peptides recognized by one such antibody (8H5). We analysed the specificity of 8H5 for reactive peptides presented as fusion proteins of HBc (hepatitis B core protein) and HEV (hepatitis E virus) structural protein, p239. This was then related to the specificity of the native HA (haemagglutinin) molecule by virtue of the capacity of fusion proteins to compete for 8H5 binding with different strains of H5N1 virus and the reactivity of antisera generated against fusion proteins to bind native HA molecules, and to inhibit haemagglutination and arrest infection by the virus. Nine reactive peptides of different amino acid sequences were identified, six of which were also reactive with the antibody in association with HBc and four were in association with p239. Binding occurred with the dimeric form of the four p239-fusion proteins and one of the HBc-fusion proteins, but not with the monomeric form. The HBc-fusion proteins blocked 8H5 binding with four strains of H5N1 influenza virus. Mouse antisera generated against fusion proteins bound to HA molecules, but did not inhibit haemagglutination or arrest H5N1 infection. Our findings indicate that 8H5 recognizes discontinuous sites presented by secondary and possibly higher structural orders ol'the peptides in spatially favourable positions for binding with the antibody, and that the peptides partially mimic the native 8H5 epitopes oil file H5N1 virus.Science and Technology Foundation of Fujian Province [2008Y0059, F2006BA101B06]; Key Project of Chinese Ministry of Education [1081157]; Foundation front Ministry of Science and Technology [2005DC105006

Broad Cross-Protection against H5N1 Avian Influenza Virus Infection by Means of Monoclonal Antibodies that Map to Conserved Viral Epitopes

Background. Passive immunization with human H5 antisera or H5-specific monoclonal antibodies (MAbs) has potential as an effective treatment for acute H5N1 influenza virus infection, but its efficacy against antigenically diverse H5N1 viruses is unconfirmed. Methods. Cross-protection against antigenically diverse H5N1 strains with H5-specific MAbs, generated by successive immunization of antigenically distinct strains, was evaluated in mice. Results. A panel of 52 broadly cross-reactive H5 specific MAbs were generated and characterized. One of these MAbs, 13D4, has been demonstrated to protect mice against lethal challenge by 4 H5N1 strains representing the current major genetic populations, clades 1, 2.1, 2.2, and 2.3, even at a stage of infection when H5N1 virus has disseminated beyond the pulmonary system. Complete neutralization of virus in lung tissue of infected animals was observed 24 h after treatment with 13D4. Mapping of this MAb with escape mutants showed it to bind to 2 conserved, possibly critical, sites of H5N1 hemagglutinin, 152 and 182. Conclusion. Generation of broadly cross-protective MAbs against H5N1 influenza virus may be optimized by selecting MAbs that target conserved sites in hemagglutinin. H5 MAbs such as 13D4 may prove to have therapeutic value in controlling infection due to current and future H5N1 variants.National Key Technology R&D Program of China [2004BA519A73, 2006BAI01B06]; National Natural Science Foundation of China [30640017]; Science and Technology Project of Fujian Province in China [2005Y020]; Area of Excellence Scheme of the University Grants Committee [AoE/M-12/06]; Council of the Hong Kong SAR Government [RGC7619/07M]; Li Ka Shing Foundation

The TRAIL to cancer therapy: hindrances and potential solutions

Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. Resistance to apoptosis is a hallmark of virtually all malignancies. Despite being a cause of pathological conditions, apoptosis could be a promising target in cancer treatment. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of TNF cytokine superfamily. It is a potent anti-cancer agent owing to its specific targeting towards cancerous cells, while sparing normal cells, to induce apoptosis. However, resistance occurs either intrinsically or after multiple treatments which may explain why cancer therapy fails. This review summarizes the apoptotic mechanisms via extrinsic and intrinsic apoptotic pathways, as well as the apoptotic resistance mechanisms. It also reviews the current clinically tested recombinant human TRAIL (rhTRAIL) and TRAIL receptor agonists (TRAs) against TRAIL-Receptors, TRAIL-R1 and TRAIL-R2, in which the outcomes of the clinical trials have not been satisfactory. Finally, this review discusses the current strategies in overcoming resistance to TRAIL-induced apoptosis in pre-clinical and clinical settings

Peptide mimics of a conserved H5N1 avian influenza virus neutralization site

A panel of 52 murine monoclonal antibodies was found to recognize antigenic determinants that had been conserved among all major genetic subgroups of the H5N1 avian influenza virus prevalent since 1997. We screened a phage display library for peptides recognized by one such antibody (8H5). We analysed the specificity of 8H5 for reactive peptides presented as fusion proteins of HBc (hepatitis B core protein) and HEV (hepatitis E virus) structural protein, p239. This was then related to the specificity of the native HA (haemagglutinin) molecule by virtue of the capacity of fusion proteins to compete for 8H5 binding with different strains of H5N1 virus and the reactivity of antisera generated against fusion proteins to bind native HA molecules, and to inhibit haemagglutination and arrest infection by the virus. Nine reactive peptides of different amino acid sequences were identified, six of which were also reactive with the antibody in association with HBc and four were in association with p239. Binding occurred with the dimeric form of the four p239-fusion proteins and one of the HBc-fusion proteins, but not with the monomeric form. The HBc-fusion proteins blocked 8H5 binding with four strains of H5N1 influenza virus. Mouse antisera generated against fusion proteins bound to HA molecules, but did not inhibit haemagglutination or arrest H5N1 infection. Our findings indicate that 8H5 recognizes discontinuous sites presented by secondary and possibly higher structural orders of the peptides in spatially favourable positions for binding with the antibody, and that the peptides partially mimic the native 8H5 epitopes on the H5N1 virus. © The Authors Journal compilation.link_to_OA_fulltex

Peptide mimics of a conserved H5N1 avian influenza virus neutralization site

A panel of 52 murine monoclonal antibodies was found to recognize antigenic determinants that had been conserved among all major genetic subgroups of the H5N1 avian influenza virus prevalent since 1997. We screened a phage display library for peptides recognized by one such antibody (8H5). We analysed the specificity of 8H5 for reactive peptides presented as fusion proteins of HBc (hepatitis B core protein) and HEV (hepatitis E virus) structural protein, p239. This was then related to the specificity of the native HA (haemagglutinin) molecule by virtue of the capacity of fusion proteins to compete for 8H5 binding with different strains of H5N1 virus and the reactivity of antisera generated against fusion proteins to bind native HA molecules, and to inhibit haemagglutination and arrest infection by the virus. Nine reactive peptides of different amino acid sequences were identified, six of which were also reactive with the antibody in association with HBc and four were in association with p239. Binding occurred with the dimeric form of the four p239-fusion proteins and one of the HBc-fusion proteins, but not with the monomeric form. The HBc-fusion proteins blocked 8H5 binding with four strains of H5N1 influenza virus. Mouse antisera generated against fusion proteins bound to HA molecules, but did not inhibit haemagglutination or arrest H5N1 infection. Our findings indicate that 8H5 recognizes discontinuous sites presented by secondary and possibly higher structural orders of the peptides in spatially favourable positions for binding with the antibody, and that the peptides partially mimic the native 8H5 epitopes on the H5N1 virus. © The Authors Journal compilation.link_to_OA_fulltex