Case report: Increased viral receptor expression associated with high viral load and severe pneumonia in a young patient infected with 2009 H1N1 influenza a with no pre-existing conditions

A case of unusually high severity of influenza pneumonia leading to acute respiratory distress syndrome and death was investigated. This was a previously a healthy 28-year-old man with no underlying conditions, admitted to a hospital during the first wave of influenza pandemic in Thailand in July 2009. He had experienced high fever and influenza-like illness for 5 days before coming to the hospital. He developed acute respiratory distress syndrome and expired on day 7 after admission. In comparison to three other cases of influenza pneumonia in the same outbreak with known risk factors for severe influenza, such as pregnancy and diabetes mellitus, a much higher viral load was detected in the lungs of this patient despite antiviral treatment. In agreement with the high viral load, the lung specimens from this patient, but not the other three patients, showed a high expression of α-2,6-linked sialic acid by lectin staining. The gene responsible for the synthesis of this sialic acid was also found to be upregulated. The data indicated overexpression of the viral receptor as a potential mechanism for severe disease in some patients.     

Percutaneous transvenous mitral commissurotomy via left femoral vein approach--exploring an unusual approach for left atrial entry

Percutaneous transvenous mitral commissurotomy (PTMC) using Inoue technique through a right femoral vein approach (RFVA) is well established. Left femoral vein approach (LFVA) is traditionally contraindicated because of certain technical issues. We report a case of PTMC successfully done through this unusual approach, which should be reserved exclusively for cases with right femoral vein occlusion. It also opens up the avenue for other interventions requiring a septal puncture, left atrial entry and use of bulky devices.     

Drug resistance: Still a daunting challenge to the successful treatment of AML

Resistance to chemotherapy remains a challenging issue for patients and their physicians. P-glycoprotein (Pgp, MDR1, ABCB1), as well as a family of structurally and functionally related proteins, are plasma membrane transporters able to efflux a variety of substrates from the cell cytoplasm, including chemotherapeutic agents. The discovery of ABCB1 made available a potential target for pharmacologic down-regulation of efflux-mediated chemotherapy resistance. In patients with acute myeloid leukemia (AML), a neoplasm characterized by proliferation of poorly differentiated myeloid progenitor cells, leukemic cells often express ABCB1 at high levels, which may lead to the development of resistance to chemotherapy. Thus, AML seemed to be a likely cancer for which the addition of drug efflux inhibitors to the chemotherapeutic regimen would improve outcomes in patients. Despite this rational hypothesis, the majority of clinical trials evaluating this strategy have failed to reach a positive endpoint, most recently the Eastern Cooperative Oncology Group E3999 trial. Here we review data suggesting the importance of ABCB1 in AML, address the failure of clinical trials to support a therapeutic strategy aimed at modulating ABCB1-mediated resistance, and consider the type of research that should be conducted in this field going forward.     

Cloned cDNA of A/swine/Iowa/15/1930 internal genes as a candidate backbone for reverse genetics vaccine against influenza A viruses

Reverse genetics viruses for influenza vaccine production usually utilize the internal genes of the egg-adapted A/Puerto Rico/8/34 (PR8) strain. This egg-adapted strain provides high production yield in embryonated eggs but does not necessarily give the best yield in mammalian cell culture. In order to generate a reverse genetics viral backbone that is well-adapted to high growth in mammalian cell culture, a swine influenza isolate A/swine/Iowa/15/30 (H1N1) (rg1930) that was shown to give high yield in Madin-Darby canine kidney (MDCK) cells was used as the internal gene donor for reverse genetics plasmids. In this report, the internal genes from rg1930 were used for construction of reverse genetics viruses carrying a cleavage site-modified hemagglutinin (HA) gene and neuraminidase (NA) gene from a highly pathogenic H5N1 virus. The resulting virus (rg1930H5N1) was low pathogenic in vivo. Inactivated rg1930H5N1 vaccine completely protected chickens from morbidity and mortality after challenge with highly pathogenic H5N1. Protective immunity was obtained when chickens were immunized with an inactivated vaccine consisting of at least 2(9) HA units of the rg1930H5N1 virus. In comparison to the PR8-based reverse genetics viruses carrying the same HA and NA genes from an H5N1 virus, rg1930 based viruses yielded higher viral titers in MDCK and Vero cells. In addition, the reverse genetics derived H3N2 and H5N2 viruses with the rg1930 backbone replicated in MDCK cells better than the cognate viruses with the rgPR8 backbone. It is concluded that this newly established reverse genetics backbone system could serve as a candidate for a master donor strain for development of inactivated influenza vaccines in cell-based systems.