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Biomedical subjects

Timothy Murphy

Publications and source records attributed to Timothy Murphy.

10 recordsLinked to original sources
PubMed2004

Effect of srtA and srtB gene expression on the virulence of Staphylococcus aureus in animal models of infection.

OBJECTIVE: The role that the surface proteins anchored by the srtA and srtB gene products play in the ability of Staphylococcus aureus bacteria to establish infection was investigated in several animal models. METHODS: Wild-type and corresponding mutants with deletions of the srtA and/or srtB genes were used in murine acute lethal infection, septic arthritis, kidney infection and rat endocarditis models. RESULTS: The LD(50) of the wild-type and srtB- knockout were comparable and approximately two- to four-fold lower than the required inoculum of the srtA- and srtA-B- strains. This difference was exhibited as a two-fold greater mortality at the highest inoculum. The wild-type strain established arthritic inflammation in over 90% of the animals with a maximum arthritic index of 6.5 by days 17-21. The srtB- knockout was able to cause inflammation in 70-80% of the mice, but with a lower index of 3.0. Both the srtA- and srtA-B- strains appeared to be less virulent in this model with arthritic indices of around 0.5 and only 20% of the animals with inflammation. Strains with the srtA mutation achieved statistically significant lower titres than wild-type in kidneys of mice after intravenous infection. Mean bacterial counts in cardiac vegetations were significantly higher for the wild-type and srtB- strain compared with the srtA- and srtA-B- strains. CONCLUSION: Results from this study substantiate the role of the srtA gene product in the establishment of infections and further studies are warranted to define and exploit this as a target for antimicrobial chemotherapy.

Aminoacyltransferases↗
PubMed2004

In vivo efficacy and pharmacokinetics of AC98-6446, a novel cyclic glycopeptide, in experimental infection models.

AC98-6446 is a novel semisynthetic derivative of a natural product related to the mannopeptimycins produced by Streptomyces hygroscopicus. Naturally occurring esterified mannopeptimycins exhibited excellent in vitro activity but only moderate in vivo efficacy against staphylococcal infection. The in vivo efficacy and pharmacokinetics of AC98-6446 were investigated in murine acute lethal, bacterial thigh and rat endocarditis infections. Pharmacokinetics were performed in mice, rats, monkeys, and dogs. Acute lethal infections were performed with several gram-positive isolates: Staphylococcus aureus (methicillin-susceptible and methicillin-resistant staphylococci), vancomycin-resistant Enterococcus faecalis, and penicillin-susceptible and -resistant Streptococcus pneumoniae. The 50% effective dose for all isolates tested ranged from 0.05 to 0.39 mg/kg of body weight after intravenous (i.v.) administration. Vancomycin was more than fivefold less efficacious against all of these same infections. Results of the thigh infection with S. aureus showed a static dose for AC98-6446 of 0.4 mg/kg by i.v. administration. Reduction of counts in the thigh of >2 log(10) CFU were achieved with doses of 1 mg/kg. i.v. administration of 3 mg/kg twice a day for 3 days resulted in a >3 log(10) reduction in bacterial counts of vancomycin-susceptible and -resistant E. faecalis in a rat endocarditis model. Pharmacokinetics of AC98-6446 showed an increase in exposure (area under the concentration-time curve) from mouse to dog species. The i.v. half-life (t(1/2)) increased threefold between rodents and the higher species dosed. Efficacy of AC98-6446 has been demonstrated in several models of infection with resistant gram-positive pathogens. This glycopeptide exhibited bactericidal activity in these models, resulting in efficacy at low doses with reduction in bacterial load.

Animals↗
PubMed2003

Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein.

Depsipeptide is in clinical trials for chronic lymphocytic leukemia (CLL) on the basis of earlier observations demonstrating selective in vitro activity in CLL. We sought to determine the relationship of histone H3 and H4 acetylation, inhibition of histone deacetylase, and apoptosis observed in CLL cells to justify a pharmacodynamic end point in these clinical trials. We demonstrate that in vitro depsipeptide induces histone H3 and H4 acetylation and histone deacetylase enzyme inhibition at concentrations corresponding to the LC50 (concentration producing 50% cell death) for cultured CLL cells (0.038 microM depsipeptide). The changes in histone acetylation are lysine specific, involving H4 K5, H4 K12, and H3 K9, and to a lesser extent H4 K8, but not H4 K16 or H3 K14. Depsipeptide-induced apoptosis is caspase dependent, selectively involving the tumor necrosis factor (TNF) receptor (extrinsic pathway) initiating caspase 8 and effector caspase 3. Activation of caspase 8 was accompanied by the down-regulation of cellular FLICE-inhibitory protein (c-FLIP, I-FLICE) without evidence of Fas (CD95) up-regulation. Changes in other apoptotic proteins, including Bcl-2, Bax, Mcl-1, and X-linked inhibitor of apoptosis (XIAP), were not observed. Our results demonstrate a relationship between target enzyme inhibition of histone deacetylase, histone H3 and H4 acetylation, and apoptosis involving the TNF-receptor pathway of apoptosis that is not used by other therapeutic agents in CLL. These data suggest use of histone H3 and H4 acetylation, inhibition of histone deacetylase, and down-regulation of FLIP as pharmacodynamic end points for further evaluation of this drug in patients.

Acetylation↗
PubMed2003

Internet-based tele-audiometry system for the assessment of hearing: a pilot study.

The application of tele-audiology is in its infancy. Several systems have been developed to screen hearing, yet the application of real-time diagnostic audiology to a remote location is new. This paper describes a tele-audiometric system developed for the application of realtime diagnostic audiometry via the Internet. A pilot study evaluated 31 adult participants in a double-blind study of two different systems (i.e., conventional versus Internet-based) for assessing auditory thresholds. The threshold data show substantial agreement between the two systems. Mean thresholds varied by no more than 1.3 dB, well within established variability of audiometric testing. This pilot study demonstrated the feasibility of real-time Internet-based assessment of hearing. The system allows this remote assessment of hearing without an audiologist on site. Further investigation will assess of outcomes and costs.

Audiometry↗
PubMed2003

Guidelines for the reporting of renal artery revascularization in clinical trials.

Although the treatment of atherosclerotic renal artery stenosis with use of percutaneous angioplasty, stent placement, and surgical revascularization has gained widespread use, there exist few prospective randomized controlled trials (RCTs) comparing these techniques to each other or against the standard of medical management alone. To facilitate this process as well as help answer many important questions regarding the appropriate application of renal revascularization, well-designed and rigorously conducted trials are needed. These trials must have clearly defined goals and must be sufficiently sized and performed so as to withstand intensive outcomes assessment. Toward this end, this document provides guidelines and definitions for the design, conduct, evaluation, and reporting of renal artery revascularization RCTs. In addition, areas of critically necessary renal artery revascularization investigation are identified. It is hoped that this information will be valuable to the investigator wishing to conduct research in this important area.

Comment↗
PubMed2002

Kinetics of nitric oxide binding to R-state hemoglobin.

Despite earlier work indicating otherwise, some recent reports have suggested that nitric oxide (NO) binds to hemoglobin cooperatively. In particular, it has been suggested that, under physiological conditions, NO binds to the high-affinity R-state hemoglobin as much as 100 times faster than to the low-affinity T-state hemoglobin. This rapid NO binding could provide a means of preserving NO bioactivity. However, using a flash-flow photolysis technique, we have determined that the rate of NO binding to normal adult R-state hemoglobin is (2.1 +/- 0.1) x 10(7) (s(-1) M(-1)), which is essentially the same as that reported for T-state NO binding. (c)2002 Elsevier Science (USA).

Allosteric Regulation↗
PubMed2002

Guidelines for the reporting of renal artery revascularization in clinical trials.

Although the treatment of atherosclerotic renal artery stenosis with use of percutaneous angioplasty, stent placement, and surgical revascularization has gained widespread use, there exist few prospective randomized controlled trials (RCTs) comparing these techniques to each other or against the standard of medical management alone. To facilitate this process as well as help answer many important questions regarding the appropriate application of renal revascularization, well-designed and rigorously conducted trials are needed. These trials must have clearly defined goals and must be sufficiently sized and performed so as to withstand intensive outcomes assessment. Toward this end, this document provides guidelines and definitions for the design, conduct, evaluation, and reporting of renal artery revascularization RCTs. In addition, areas of critically necessary renal artery revascularization investigation are identified. It is hoped that this information will be valuable to the investigator wishing to conduct research in this important area.

Angioplasty, Balloon↗
PubMed2002

RFI-641, a potent respiratory syncytial virus inhibitor.

Human respiratory syncytial virus (RSV), a paramyxovirus, is a major cause of acute upper and lower respiratory tract infections in infants, young children, and adults. RFI-641 is a novel anti-RSV agent with potent in vitro and in vivo activity. RFI-641 is active against both RSV type A and B strains. The viral specificity and the large therapeutic window of RFI-641 (>100-fold) indicate that the antiviral activity of the compound is not due to adverse effects on normal cells. The potent in vitro activity of RFI-641 can be translated to efficacy in vivo: RFI-641 is efficacious when administered prophylactically by the intranasal route in mice, cotton rats, and African green monkeys. RFI-641 is also efficacious when administered therapeutically (24 h postinfection) in the monkey model. Mechanism of action studies indicate that RFI-641 blocks viral F protein-mediated fusion and cell syncytium formation.

Animals↗