Cationic antimicrobial peptides (AMPs) are present in many organisms and can kill a broad range of microorganisms by membrane permeabilization. Consequently short cationic peptides may serve as a new generation of antibiotics, especially in light of the alarming increase in microbial resistance to the conventional antibiotics. Membrane pore-forming peptides and known AMPs share a similar mechanism of action in lipid bilayers in vitro. In an effort to develop a novel strategy to screen for new peptide antibiotics, we used combinatorial chemistry and high-throughput screening. We selected potent pore-forming peptides from a combinatorial library of 16,000 putative short, cationic amphipathic beta-strand peptides of 9-15 residues using our screening assay. We selected 10 water-soluble potent pore-forming peptides, less than 0.1% of library population. These pore-forming peptides were soluble in buffer but bind strongly to lipid vesicles and induce rapid transient leakage of encapsulated contents. All of the peptides were beta-sheets in membranes. We found that these peptides release the contents of liposomes in all-or-none leakage mechanism. These pore-forming peptides have potent, broad-spectrum antimicrobial activity ranging from 2 to 4 muM minimum sterilization concentrations (MSC). But they have little lytic activity against erythrocytes or living human cells. In an attempt to select AMPs directly from the library, we developed a bioassay, and compared the results with the liposome-based screening assay. We found that the bioassay may allow us to screen for species-specific peptides while the vesicle-based assay gives broad-spectrum AMPs. Here, we propose that a rational combinatorial design coupled with a function-based screening assay is a powerful method to select peptides that are not only potent membrane-active, but also broad-spectrum antibiotics / acase@tulane.edu

<p>This work investigates phantom and subject positioning as well as collecting data with a variety of angular sampling and acquisition trajectories. The overall goal of this work has been to utilize the dedicated, breast SPECT-CT system to acquire the best possible images. A large portion of this work has been to apply corrections to the system for quantitative imaging. The system has been shown to provide high quality images with minimal out-of-field signal contribution. Additionally, the quantification procedure has been shown to be within 10% of the known activity concentration present at the time of imaging for both VAOR and PROJSINE trajectories.</p> / Dissertation

Gap junction channels connect the cytoplasms of adjacent cells and provide a pathway for the exchange of materials between cells. The nature of the materials exchanged is determined by the biophysical characteristics of the channels. The functional gap junction channel is composed of paired hemichannels (connexons) from each cell. Connexons are hexamers of protein subunits called connexins (Cx). Of the 15 connexin genes found in the mammalian genome, the products of only two, Cx40 and Cx43 have been localized in vascular smooth muscle cells (SMC) (1;2). We have been interested in identifying the role of gap junctions in cardiac rhythmic activity and vascular function. Like many other cell types, mammalian heart and blood vessels express multiple gap junction connexins (3). These connexins may form heteromeric channels. A7r5 cells, a cell line derived from embryonic rat aortic smooth muscle cells, provide a good model because they express both connexins 40 and 43. From the previous studies in this laboratory, Moore and Burt reported the presence of channels with a wide range of unitary conductance with major peaks at 75, 110 and 145 pS. One explanation for the wide range of unitary conductance could be the presence of heteromeric Cx40 and Cx43 channels. Thus, the goal of this study was to investigate gating behaviors of gap junction channels in A7r5 cells to determine whether heteromeric Cx40/43 channels are formed. I will demonstrate that Cx40 and Cx43 form heteromeric channels with unique unitary conductances, voltage-dependent gating properties and enhanced sensitivity to halothane induced closure.

Using Monte Carlo techniques, the 18 MV accelerators CL2300 and CL21EX, 8 physical wedges and the enhanced dynamic wedge have been modeled and validated. The simulated PDDs, profiles, output factors and wedge factors are in good agreement with measured values. These models have been applied in the dose calculation of lung cancer patients to investigate the effect of tissue heterogeneity by comparing with the CADplan treatment planning system with and without heterogeneity correction. Plan I and plan II for 8 patients have been re-calculated with the Monte Carlo method. On average, the mean PTV dose calculated with the Monte Carlo method is 2.4% higher than that calculated with CADplan without correction but 2.5% lower than that with EqTAR correction. The Monte Carlo method predicts 13% higher mean lung dose than CADplan without heterogeneity correction. Because of this difference, the risk of radiation pneumonitis based on available NTCP models will be underestimated. A relationship of mean lung dose between two types of dose algorithms can be used to correct this underestimation.

This study involves the measurement of the neutron equivalent dose ( NED) and the induced activity produced from medical linear accelerators. For the NED, various parameters such as the profile, field effects and energy responses were studied. The NED in a Solid Water(TM) phantom was measured and a new quantity, the neutron equivalent dose tissue-air ratio (NTAR), was defined and determined. Neutron production for electron beams was also measured. For the induced activity, comparisons were carried out between different linacs, fields and dose rates. The half life and activation saturation were also studied. A mathematical model of induced activity was developed to explain the experimental results. Room surveys of NED and induced activity were performed in and around a high energy linear accelerator room. Unwanted doses from photoneutrons and induced activity to the high energy linear accelerator radiotherapy staff and patient were estimated.

Electron arc therapy is the treatment of choice for tumours involving large curved surfaces. At the Montreal General Hospital a unique approach to the electron arc therapy was developed in 1986 and has been used clinically ever since. The approach is based on the concept of the characteristic angle beta. / We measured radial percentage depth doses in a polystyrene cylindrical phantom irradiated with electron arc beams having angles beta in the range from 5$ sp circ$ to 100$ sp circ,$ for 9 MeV, 12 MeV, 15 MeV, and 18 MeV electron beam energies. We showed that the characteristic angle-$ beta$ concept can be extended to the beams with nominal energy of 18 MeV. The validity of the empirical relationship, relating the doses in two beams with different energies, was confirmed. A linear relationship between the angle $ beta$ and the depth of dose maximum, the depth of the 85% depth dose, and the depth of the 50% depth dose, was established. The surface dose dependence on the angle $ beta$ was also determined and the bremsstrahlung contamination in the electron arc therapy studied.

An algorithm for optimization of numerous modulated beam weights has been developed. This algorithm employs a penalty function theorem and a simulated annealing (SA) routine to model a large-scale constrained optimization problem incorporating dose and dose volume constraints in reflecting the goal of inverse treatment planning by sparing sufficient healthy tissues while delivering a necessary tumorcidal dose. The convergence property of the dose-volume SA algorithm is investigated for validation. Its performance is also evaluated by comparing the algorithm with a gradient technique minimizing the same dose-volume objective function that incorporates the target dose objectives and organ dose-volume constraints by the penalty functions. The comparison shows that the objective function exhibits a global valley in which multiple local minima with similar outcomes in terms of the function values, the dose-volume histograms, and the dose distributions exist. Thus, the gradient algorithm is preferred for this optimization approach due to its fast efficiency.

Recently, an important role has been attributed to endothelin-1 (ET-1), a potent vasoconstrictor and a mitogenic factor. The prostate and the vascular endothelium, including that of the penis, are known to produce ET-1. Furthermore, it has been shown that there are two receptor subtypes in the penis, ETa and ETb. Radiation treatment is known to cause an increase in ET-1 and may be a fundamental cause of radiation-associated impotence (RAI). / The aim of the present study was to evaluate the role of ET-1 in RAI. In the first part of our study, rats were divided into groups according to a different radiation dose. A ET-1 time course in tissue and serum was established. Markedly higher ET-1 levels were found in a high radiation dose compared with a lower dose and in the control group. / In the second part of the study, rats underwent evaluation of erectile function after radiation therapy. Subsequently, rats were given an antagonist of ETa (BQ-123) to assess whether the erectile response could be potentiated. Our results show that the use of this specific antagonist results in an improved erectile activity in a rat animal model. (Abstract shortened by UMI.)

X-ray mammography is currently the modality of choice for breast cancer screening. However, X-ray mammography cannot provide a positive diagnosis for cancer. A novel, dedicated breast imaging modality has been developed based on the principles of Positron Emission Tomography (PET). The Positron Emission Mammography (PEM) system is a sensitive, high resolution ($ sp sim2$ mm) breast scanner. PEM detects increased cell metabolism (indicating the presence of cancer) by imaging the distribution of tumour-specific metabolic radiotracers. The accurate co-registration of metabolic and X-ray breast images is important for localizing and characterizing suspicious lesions. Traditionally, registration between different imaging modalities has been difficult. PEM simplifies the image registration process by acquiring an X-ray image and a metabolic image consecutively, without moving the breast between scans. The PEM detectors are integrated into a conventional mammography unit and a co-registration tool has been developed. By providing metabolic information about a suspicious breast lesion, the number of invasive biopsy procedures (currently used to diagnose breast cancer) can be reduced.

An isocentric teletherapy cobalt unit provides a viable alternative to an isocentric linac as a radiation source for radiosurgery. An isocentric cobalt unit was evaluated for its potential use in radiosurgery in three areas: (1) the physical properties of its radiosurgical beams, (2) the quality of radiosurgical dose distributions obtained with 4 to 10 non-coplanar arcs, and (3) the accuracy with which the radiosurgical dose can be delivered. In each of these areas the 10 MV beam of a linear accelerator served as a standard for comparison. / The difference between the 80%--20% penumbras of the radiosurgical fields of the cobalt-60 and 10 MV photon beams is remarkably small, with the cobalt-60 beam penumbras on the average only about 0.7 mm larger than those of the linac beam. Differences between the cobalt-60 and 10 MV plans in terms of dose homogeneity within the target volume and conformity of the prescribed isodose volume to the target volume are also minimal, and therefore of limited clinical significance. Moreover, measured obtained isodose distributions of a radiosurgical procedure performed on the isocentric cobalt unit agreed with calculated distributions to within the +/-1 mm spatial and +/-5% numerical dose tolerances which are generally accepted in radiosurgery. The viability of isocentric cobalt units for radiosurgery would be of particular interest for centers in developing counties where cobalt units, because of their relatively low costs, provide the only megavoltage source of radiation for radiotherapy, and could easily and inexpensively be modified for radiosurgery.