Doctor of Philosophy

dissertationWe present a method for absolutely quantifying pharmacokinetic parameters in dynamic contrast-enhanced (DCE)-MRI. This method, known as alternating mini-mization with model (AMM), involves jointly estimating the arterial input function (AIF) and pharmacokinetic parameters from a characteristic set of measured tissue concentration curves. By blindly estimating the AIF, problems associated with AIF measurement in pharmacokinetic modeling, such as signal saturation, flow and partial volume eff ects, and small arterial lumens can be ignored. The blind estimation method described here introduces a novel functional form for the AIF, which serves to simplify the estimation process and reduce the deleterious e ffects of noise on the deconvolution process. Computer simulations were undertaken to assess the performance of the estimation process as a function of the input tissue curves. A con fidence metric for the estimation quality, based on a linear combination of the SNR and diversity of the input curves, is presented. This con fidence metric is then used to allow for localizing the region from which input curves are drawn. Local blood supply to any particular region can then be blindly estimated, along with some measure of con fidence for that estimation. Methods for evaluating the utility of the blind estimation algorithm on clinical data are presented, along with preliminary results on quantifying tissue parameters in soft-tissue sarcomas. The AMM method is applied to in vivo data from both cardiac perfusion and breast cancer scans. The cardiac scans were conducted using a dual-bolus protocol, which provides a measure of truth for the AIF. Twenty data sets were processed with this method, and pharmacokinetic parameter values derived from the blind AIF were compared with those derived from the dual-bolus measured AIF. For seventeen of the twenty datasets there were no statistically signifi cant differences in Ktrans estimates. The cardiac AMM method presented here provides a way to quantify perfusion of myocardial tissue with a single injection of contrast agent and without a special pulse sequence. The resulting parameters are similar to those given by the dual bolus method. The breast cancer scans were processed with the AMM method and the results were compared to an analysis done with the semiquantitative DCE-MRI scans. The e ffects of the temporal sampling rate of the data on the AMM method are examined. The ability of the AMM-derived parameters to distinguish benign and malignant tumors is compared to more conventional methods

Development and performance of the Fast Neutron Imaging Telescope for SNM detection

FNIT (the Fast Neutron Imaging Telescope), a detector with both imaging and energy measurement capabilities, sensitive to neutrons in the range 0.8-20 MeV, was initially conceived to study solar neutrons as a candidate design for the Inner Heliosphere Sentinel (IHS) spacecraft of NASA\u27s Solar Sentinels program and successively reconfigured to locate fission neutron sources. By accurately identifying the position of the source with imaging techniques and reconstructing the Watt spectrum of fission neutrons, FNIT can detect samples of special nuclear material (SNM), including heavily shielded and masked ones. The detection principle is based on multiple elastic neutron-proton scatterings in organic scintillators. By reconstructing n-p event locations and sequence and measuring the recoil proton energies, the direction and energy spectrum of the primary neutron flux can be determined and neutron sources identified. We describe the design of the FNIT prototype and present its energy reconstruction and imaging performance, assessed by exposing FNIT to a neutron beam and to a Pu fission neutron source

Role of Amoxicillin Serum Levels for Successful Prophylaxis of Experimental Endocarditis Due to Tolerant Streptococci

The importance of amoxicillin serum profiles for successful prophylaxis of experimental endocarditis in rats was assessed. Animals with catheter-induced vegetations were challenged intravenously with large inocula of Streptococcus sanguis and received one of the following amoxicillin dosages: single or multiple bolus injection of 40 mg/kg; 40 mg/kg administered as a continuous infusion over 12 h; or either 9 or 18 mg/kg administered over 12 or 24 h, respectively. The regimen producing a single transient high peak serum level failed to prevent experimental endocarditis; in contrast, a second injection 6 h after the first resulted in successful prophylaxis. Likewise, the three regimens of continuous, relatively low-dose regimens prevented infections. Thus, the most important parameter for successful prophylaxis was the duration of inhibitory concentration of the drug in the serum. The total dose of antibiotic, the peak serum levels, or the area-under-the-curve values were not predictive of successful prophylaxi

Hepatitis with Fibrin-Ring Granulomas

Abstract : We describe a 66-year-old woman hospitalized with fever, fatigue and hepatopathy. In her medical history arterial hypertension (treated with propranolol and lisinopril), diabetes mellitus type 2 (no treatment before admission) and a gout arthropathy were noted wherefore a therapy with allopurinol 300 mg per day has been started 4 months before. Liver biopsy revealed fibrin-ring granulomas, compatible with allopurinolinduced hepatitis. Because of persistence of high fever after stopping allopurinol, steroids (1 mg/kg) were started. Under this treatment, she developed pancytopenia and fever. The bone marrow aspiration revealed Leishmania infantum. A second liver biopsy showed amastigotes and a disappearance of the granulomas. The history revealed a travel to Malta 2 years earlier. Despite adequate treatment with liposomal amphotericin B the patient deteriorated and finally died in septic shoc

Highly effective regimen for decolonization of methicillin-resistant Staphylococcus aureus carriers

OBJECTIVE: To evaluate the efficacy of a standardized regimen for decolonization of methicillin-resistant Staphylococcus aureus (MRSA) carriers and to identify factors influencing decolonization treatment failure. DESIGN: Prospective cohort study from January 2002 to April 2007, with a mean follow-up period of 36 months. SETTING: University hospital with 750 beds and 27,000 admissions/year. PATIENTS: Of 94 consecutive hospitalized patients with MRSA colonization or infection, 32 were excluded because of spontaneous loss of MRSA, contraindications, death, or refusal to participate. In 62 patients, decolonization treatment was completed. At least 6 body sites were screened for MRSA (including by use of rectal swabs) before the start of treatment. INTERVENTIONS: Standardized decolonization treatment consisted of mupirocin nasal ointment, chlorhexidine mouth rinse, and full-body wash with chlorhexidine soap for 5 days. Intestinal and urinary-tract colonization were treated with oral vancomycin and cotrimoxazole, respectively. Vaginal colonization was treated with povidone-iodine or, alternatively, with chlorhexidine ovula or octenidine solution. Other antibiotics were added to the regimen if treatment failed. Successful decolonization was considered to have been achieved if results were negative for 3 consecutive sets of cultures of more than 6 screening sites. RESULTS: The mean age (+/- standard deviation [SD]) age of the 62 patients was 66.2 +/- 19 years. The most frequent locations of MRSA colonization were the nose (42 patients [68%]), the throat (33 [53%]), perianal area (33 [53%]), rectum (36 [58%]), and inguinal area (30 [49%]). Decolonization was completed in 87% of patients after a mean (+/-SD) of 2.1 +/- 1.8 decolonization cycles (range, 1-10 cycles). Sixty-five percent of patients ultimately required peroral antibiotic treatment (vancomycin, 52%; cotrimoxazole, 27%; rifampin and fusidic acid, 18%). Decolonization was successful in 54 (87%) of the patie in the intent-to-treat analysis and in 51 (98%) of 52 patients in the on-treatment analysis. CONCLUSION: This standardized regimen for MRSA decolonization was highly effective in patients who completed the full decolonization treatment course

Highly Effective Regimen for Decolonization of Methicillin-Resistant Staphylococcus aureus Carriers

Objective. To evaluate the efficacy of a standardized regimen for decolonization of methicillin-resistant Staphylococcus aureus (MRSA) carriers and to identify factors influencing decolonization treatment failure. Design. Prospective cohort study from January 2002 to April 2007, with a mean follow-up period of 36 months. Setting. University hospital with 750 beds and 27,000 admissions/year. Patients. Of 94 consecutive hospitalized patients with MRSA colonization or infection, 32 were excluded because of spontaneous loss of MRSA, contraindications, death, or refusal to participate. In 62 patients, decolonization treatment was completed. At least 6 body sites were screened for MRSA (including by use of rectal swabs) before the start of treatment. Interventions. Standardized decolonization treatment consisted of mupirocin nasal ointment, chlorhexidine mouth rinse, and full-body wash with chlorhexidine soap for 5 days. Intestinal and urinary-tract colonization were treated with oral vancomycin and cotrimoxazole, respectively. Vaginal colonization was treated with povidone-iodine or, alternatively, with chlorhexidine ovula or octenidine solution. Other antibiotics were added to the regimen if treatment failed. Successful decolonization was considered to have been achieved if results were negative for 3 consecutive sets of cultures of more than 6 screening sites. Results. The mean age (± standard deviation [SD]) age of the 62 patients was 66.2 ± 19 years. The most frequent locations of MRSA colonization were the nose (42 patients [68%]), the throat (33 [53%]), perianal area (33 [53%]), rectum (36 [58%]), and inguinal area (30 [49%]). Decolonization was completed in 87% of patients after a mean (±SD) of 2.1 ± 1.8 decolonization cycles (range, 1-10 cycles). Sixty-five percent of patients ultimately required peroral antibiotic treatment (vancomycin, 52%; cotrimoxazole, 27%; rifampin and fusidic acid, 18%). Decolonization was successful in 54 (87%) of the patients in the intent-to-treat analysis and in 51 (98%) of 52 patients in the on-treatment analysis. Conclusion. This standardized regimen for MRSA decolonization was highly effective in patients who completed the full decolonization treatment cours

Development of the fast neutron imaging telescope

We report on the development of a next generation neutron telescope, with imaging and energy measurement capabilities, sensitive to neutrons in the 2-20 MeV energy range. The Fast Neutron Imaging Telescope (FNIT) was initially conceived to study solar neutrons as a candidate instrument for the Inner Heliosphere Sentinels (IHS) program under formulation at NASA. This detector is now being adapted to locate Special Nuclear Material (SNM) for homeland security purposes by detecting fission neutrons and reconstructing the image of their source. In either case, the detection principle is based on multiple elastic neutron-proton scatterings in organic scintillator. By reconstructing the scattering coordinates and measuring the recoil proton energy, the direction and energy of each neutron can be determined and discrete neutron sources identified. We describe the performance of the FNIT prototype, report on the current status of R&D efforts and present the results of recent laboratory measurements

Atmospheric neutron measurements with the SONTRAC science model

–The SOlar Neutron TRACking (SONTRAC) telescope was originally developed to measure the energy spectrum and incident direction of neutrons produced in solar flares, in the energy range 20 - 250 MeV. While developed primarily for solar physics, the SONTRAC detector may be employed in virtually any application requiring both energy measurement and imaging capabilities. The SONTRAC Science Model (SM) is presently being operated at the University of New Hampshire (UNH) as a ground-based instrument to investigate the energy spectrum, zenith and azimuth angle dependence of the cosmic-ray induced sea-level atmospheric neutron flux. SONTRAC measurements are based on the non-relativistic double scatter of neutrons off ambient protons within a block of scintillating fibers. Using the n-p elastic double-scatter technique, it is possible to uniquely determine the neutron’s energy and direction on an event-by-event basis. The 3D SM consists of a cube of orthogonal plastic scintillating fiber layers with 5 cm sides, read out by two CCD cameras. Two orthogonal imaging chains allow full 3D reconstruction of scattered proton tracks

Advanced characterization and simulation of SONNE: a fast neutron spectrometer for Solar Probe Plus

SONNE, the SOlar NeutroN Experiment proposed for Solar Probe Plus, is designed to measure solar neutrons from 1-20 MeV and solar gammas from 0.5-10 MeV. SONNE is a double scatter instrument that employs imaging to maximize its signal-to-noise ratio by rejecting neutral particles from non-solar directions. Under the assumption of quiescent or episodic small-flare activity, one can constrain the energy content and power dissipation by fast ions in the low corona. Although the spectrum of protons and ions produced by nanoflaring activity is unknown, we estimate the signal in neutrons and γ−rays that would be present within thirty solar radii, constrained by earlier measurements at 1 AU. Laboratory results and simulations will be presented illustrating the instrument sensitivity and resolving power

Antibiotic treatment of experimental endocarditis due to methicillin-resistant Staphylococcus epidermidis.

The natural history and treatment of experimental endocarditis due to heterogeneous and homogeneous methicillin-resistant Staphylococcus epidermidis was investigated. Amoxicillin/clavulanate or vancomycin were administered for 3 days via a computerized pump to mimic human drug kinetics in animals. After challenge with the minimum inoculum producing 90% of infections (ID90), bacteria in the vegetations grew logarithmically for 16 h. Then, bacterial densities stabilized (at approximately 10(8) cfu/g) and growth rates sharply declined. Both regimens cured > or = 60% of endocarditis (due to heterogeneous or homogeneous bacteria) when started 12-16 h after infection, although the bacterial densities in the vegetations had increased by 20 times in between. In contrast, treatment started after 24 h failed in most animals, while bacterial densities had not increased any more. Thus, while both regimens were equivalent, the therapeutic outcome was best predicted by growth rates in the vegetations, not by bacterial densities. These observations highlight the importance of phenotypic tolerance developing in vivo