Ehrlich II –2nd World Conference on Magic Bullets



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Pivotal Evaluation of the Accuracy of a Diagnostic Biomarker: the PRoBE Study Design
PEPE MS1, FENG Z1, JANES H1, BOSSUYT P2, POTTER J.
1Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, USA, 2Department of Clinical Epidemiology, Academic Medical Center, Amsterdam, the Netherlands
Background: The Early Detection Research Network (EDRN), NCI funded and investigator driven, has the mission to evaluate biomarkers for their clinical utilities in cancer risk prediction, diagnosis, early detection, and prognosis. Abundant cancer biomarkers reported in literature yet few are used in clinics. Therefore, the emphasis of the EDRN is biomarker validation. Although schema for a phased approach to development exists and guidelines are available for study reporting, a coherent and comprehensive set of guideline for a definitive biomarker validation study design have not been delineated.

Methods: We proposed PRoBE study design, Prospective specimen collection and Retrospective Blinded Evaluation, for pivotal definitive evaluation of the accuracy of a classification biomarker. A detailed formulation of all aspects of the design is provided. Four tables itemize aspects that relate to (i) the Clinical Context; (ii) Performance Criteria; (iii) the Biomarker test; and (iv) Study power and termination. Alternative designs and strategies were contrasted to illustrate the merit of PRoBE design.

Results: The ideas are applied to studies of biomarkers the intended use of which is for disease diagnosis, screening, or prognosis. Two EDRN validation studies (breast cancer and prostate cancer) were used as examples to elucidate PRoBE design.

Conclusion: Common biases that pervade the biomarker research literature would be eliminated if these rigorous standards were followed closely. We urge the adoption of the design as standard of practice for pivotal evaluation of the classification accuracy of biomarkers.

Locked and Boweled Over: Infections Down the Line



FENNELL JP1, CORMICAN M1 and LYNCH M2
1National University of Ireland Galway, Galway, Ireland, 2Mater Misericordiae University Hospital, Dublin, Ireland
Background: Patients who are dependent on total parenteral nutrition (TPN) commonly suffer from recurring central venous catheter related infections (CVCRI) from gram positive organisms. As more CVCRI occur, the available sites for central venous catheter placement diminish. We report a case where linezolid lock therapy was used to prevent CVCRI and prolong the life of the line.

Methods: A linezolid lock solution was prepared by the hospital pharmacy and a new bag was used daily. The patient was trained to administer it himself using aseptic technique. He availed of the 16 h when the line was free and instilled 3 ml of a 2 g linezolid l21 solution (without heparin) into the lumen after 8 h of nocturnal total parenteral nutrition. He was monitored routinely by regular blood culture, line swabbing and testing of platelet levels and inflammatory markers.

Results: In the 21 months prior to linezolid lock prophylaxis, the patient had 18 admissions for CVC-related infections, 28 positive blood cultures and eight CVC changes. He had spent 180 of the preceding 632 days in hospital. In 7 months of linezolid lock prophylaxis, he had one line change and one admission for 7 days due to CVC-related infection and a deep vein thrombosis in the common and external iliac veins. The patient had 44.3 infections per 1000 days (28 line infections in 632 days) prior to lock prophylaxis and 4.5 infections per 1000 days (one infection in the subsequent 221 days) during prophylaxis. The mean time to infection increased from 22.57 to 221 days when linezolid lock prophylaxis was used.

Conclusion: While use of linezolid lock prophylaxis is not suitable for routine prevention of CVCRI, linezolid appears to be an effective method of prolonging the life of a central line in TPN dependent patients when other sites are not available.


Smoking, Streptococci and Sputum
FENNELL JP1, GREINER B2, CORCORAN GD3, CRYAN B3
1UHG, Galway, Ireland, 2 UCC, Cork, Ireland, 3 Cork University Hospital, Cork, Ireland

Background: Smoking is estimated to cause 5 million deaths a year. The contribution of smoking to infection is less well defined than cancer and cardiovascular disease but has been shown in respiratory diseases such as influenza, tuberculosis, Legionnaire’s, S pneumoniae and other infections such as otitis media, H. pylori and human papillomavirus. In 2004, Ireland became the first country to institute a ban on smoking in the work place. This provided an exceptional opportunity to examine the effects of the ban on the epidemiology of respiratory pathogens.

Methods: The numbers of samples positive for S. pneumoniae, H. influenzae and M. catarrhalis isolated from community sputum samples were analysed for a year before and after the smoking ban. Samples from those under 18 were excluded. We obtained monthly smoking prevalence data covering the same period as the clinical data (April 2003 to March 2005) for the Munster area from the Office of Tobacco Control. Data was weighted according to the age and gender distribution of the general population. The before and after totals for each organism were compared as a proportion of the total sputum samples using the chi2 test. Separate logistic regression models were built for each organism under observation simultaneously adjusting for age group, gender and seasonality.

Results: 1089 and 1095 sputum samples were cultured from the community in the year before and after the smoking ban respectively. There was no significant difference between males and females for any of the organisms studied. The number of isolates of normal oral flora increased from 581 (53%) samples to 623 (57%). There was a non significant reduction in levels of all three organisms during the smoking ban. Interestingly, both H influenzae and S pneumoniae were reduced by the same amount (1.7%). The change in S pneumoniae isolation rates approached significance (p = 0.065). On adjusting for the effects of age and gender in a logistic regression model the odds ratio (OR=0.746) for S pneumoniae before versus after the ban became statistically significant (p =0.048).

Conclusions: This study showed a significant difference between S. pneumoniae subgroup samples before and after the smoking ban. Smoking is a risk factor for S. pneumoniae colonisation and infection. This is the first time that a population reduction in smoking has been shown to reduce community pneumococcal levels.



Structure-Activity Relationships of Some 1,4-Dihydropyridine (DHP) Derivatives Evaluated by Interactions with the Physical Properties of Synthetic Lipid Bilayers and Rat Liver Mitochondrial Bioenergetics
FERNANDES MAS1, PEREIRA SPS1, JURADO AS1, VIDEIRA RA2, CUSTÓDIO JBA1, SANTOS MA1, MORENO AJM1, DUBURS G3, VICENTE JAF1
1Univ. Coimbra, Coimbra, Portugal; 2Esc. Sup. Tecnol. Viseu, Viseu, Portugal; 3Latv. Inst. Org. Synth., Riga, Latvia.
Background: Studies of chemical–biological interactions, particularly, the influence of minor changes of substituent structure, play a major role in the understanding of drug’s structure-activity, drug’s development and therapeutic success. Aim: to correlate the length of the alkoxyl chain in positions 3 and 5 of the DHP ring of four DHP derivatives (OSI-1210, OSI-1211, OSI-1212, and OSI-3802) with their actions on the physical properties of synthetic lipid bilayers and mitochondrial bioenergetics.

Methods: Biophysical studies were performed by differential scanning calorimetry (DSC) using multilamellar vesicles of dimyristoyl-phosphatidylcholine (DMPC). Rat liver mitochondrial bioenergetics was evaluated by measuring respiratory activities with oxygen and tetraphenylphosphonium (TPP+) electrodes. All the experiments were performed using four different DMPC and mitochondrial preparations. One-way ANOVA test, followed by the posthoc Tukey test, was used for statistical analysis.

Results: At low concentrations (≤ 30 µM), OSI-3802, like its analogue OSI-1212, reduced the phase transition temperature (Tm), the cooperative unit size and the enthalpy associated with the phase transition of DMPC bilayers. A good correlation was established between the effects of 200 µM OSI-1210, OSI-1211, OSI-1212,and OSI-3802 on the respiratory control (RCR) of rat liver mitochondria and on the enthalpy change (∆H) for the endothermic profile of DMPC vesicles at 0.2 drug/DMPC molar ratio.

Conclusion: 1) The changes induced by these 1,4-dihydropyridine derivatives on both mitochondrial function and lipid bilayers biophysics are strongly related to the length of the alkoxyl chain in positions 3 and 5 of the DHP ring. 2) This experimental strategy is a good in vitro tool to evaluate structure-activity of related compounds, contributing to their synthesis amelioration.

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