"October, 2004" / Bibliography: leaves 118-154. / xii, 154 leaves : ill. (some col.), plates (col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, School of Molecular and Biomedical Sciences, Discipline of Microbiology and Immunology, 2005

The aims of this Thesis were to investigate early markers of neonatal sepsis and patient-factors affecting the pharmacokinetics and pharmacodynamics (PKPD) of aminoglycosides in the treatment of neonatal sepsis. A prospective cohort study of neonates commenced on gentamicin for suspected sepsis was performed between 1 July 2002 and 28 February 2007. Receiver operator characteristics (ROC) plots were used to assess potential markers of sepsis against culture positive sepsis. When sepsis was first suspected, the most promising tests were interleukin (IL) IL-12(p70) with an area under the curve (95% CI) for the ROC of 0.74 (0.63-0.86), and which (with a cut-off at 75 pg/mL) had a sensitivity (95% CI) of 28% (20-36%) and a specificity of 98% (96-100%). IL-10 had a sensitivity of 17% (10-23%) and a specificity of 99% (97-100%). Retrospective studies of neonates treated with gentamicin, amikacin and netilmicin for suspected sepsis were used to identify patient characteristics that affected aminoglycoside PKPD properties. Population PK modelling used NONMEM� v.5 to determine aminoglycoside clearance (CL) and volume of distribution (V). Logistic regression was used to examine the treatment outcome measures (serum peak and trough concentrations and ototoxicity). Simulations of new dosing regimens were undertaken for netilmicin and amikacin using MATLAB� The final gentamicin PK covariate model gave CL = 0.097 x (current weight/2)[1.3] x (postnatal age/7)[0.29] and V = 1.07 x (current weight/2)[0.8]+ (confirmed sepsis) x 0.13. A 10% increase in gentamicin V in neonates with sepsis was estimated. For amikacin, 17 (35%) of 49 episodes of confirmed sepsis met the treatment failure criteria from 12 (15%) individual patients. The final amikacin PK covariate model was CL = 0.23 x (current weight/2)[0.691] x (postmenstrual age/40)[3.23] and V = 0.957 x (current weight/2)[0.89]. PD analysis determined risk factors linked to hearing impairment in neonates treated with amikacin included: co-medication with vancomycin, high C-reactive protein concentration and low gestational age. Simulation of a new amikacin dosing regimen recommended: 15 mg/kg 36 hourly, 14 mg/kg 24 hourly, and 15 mg/kg 24 hourly, for neonates [less than or equal to] 28 weeks, 29 to 36 weeks, and [greater than or equal to] 37 postmenstrual age, respectively. For netilmicin, the final PK covariate model was CL = 0.192 x (current weight/2)[1.35] x (postmenstrual age/40)[1.03], V = 1.5 x (current weight/2)[0.3]. Simulation of a new optimal dosing regimen for netilmicin was: 5 mg/kg 36 hourly, 5 mg/kg 24 hourly, 6 mg/kg 24 hourly, and 7 mg/kg 24 hourly, for neonates [less than or equal to] 27, 28 to 30, 31 to 33, and [greater than or equal to] 34 weeks postmenstrual age, respectively. IV infusions representing gentamicin administration to neonates of 2.5 kg and 0.5 kg in the NICU setting (30 minutes gentamicin infusion then a 30 minute saline flush) showed the larger neonates received 80% of the drug within 60 minutes. This increased to 90-95% by 75 minutes. However, in extremely low birth weight neonates (0.5 kg), only 60% of the intended gentamicin dose was delivered by 60 minutes (70% by 75 minutes). In conclusion: IL-12(p70) and IL-10 were identified as promising diagnostic tests to confirm sepsis in neonates. Confirmed sepsis caused a 10% increase in V of gentamicin in neonates, suggesting larger initial dosages (mg/kg) are required for effective treatment of neonates with sepsis. Aminoglycoside clearance in neonates is predominantly affected by current weight, postmenstrual age or postnatal age. Adjusting netilmicin and amikacin doses based on current weight, and dosing interval based on both postmenstrual age and current weight improves drug efficacy. Identification of co-medication with vancomycin, low gestational age, and high C-reactive protein during treatment with amikacin increases risk of hearing impairment. The delivery of gentamicin administrated by IV infusion is substantially extended in extremely low birth weight neonates.

Recent advances in DNA vaccine technology has brought about a promising strategy for the control of viruses that contain surface membrane glycoproteins. This type of vaccine involves the intramuscular injection of a bacterial plasmid containing a gene encoding a viral protein. The strategy uses eukaryotic processing of the protein as would naturally occur during a viral infection. In this study, plasmid DNA encoding the glycoproteins of infectious hematopoietic necrosis virus (pcDNA3-IHNV-g), snakehead rhabdovirus (pcDNA3-SHRV-g), or spring viremia of carp virus (pcDNA3-SVCV-g) was injected into the skeletal muscle of rainbow trout fry. At 30 days post-vaccination, fish were challenged with IHNV. Protection against IHNV was observed among all DNA vaccinated groups. Fish injected with plasmid pcDNA3-IHNV-g, pcDNA3-SHRV-g, or pcDNA3-SVCV-g had relative survival rates of 93.2%, 98.3% and 94.9%, respectively. The mechanisms for the viral mediated resistance induced by these glycoprotein based DNA vaccines is unknown. A parallel study conducted by Dr. Carol Kim on the production of Mx proteins in these fish indicates that the observed protection might be a consequence of the stimulation of interferon. / Graduation date: 1999

Hookworm infection caused by Ancylostoma duodenale or Necator americanus is a significant global health threat, causing chronic anemia, malnutrition, developmental delay, enteritis, and increased susceptibility to non-parasitic diseases. One of the most prevalent of the neglected tropical diseases, hookworm infection affects almost 1 billion people worldwide, particularly in developing countries. Current methods for diagnosis and treatment of hookworm infection are largely the same as they have been for the past century. However, several recent advances in the molecular characterization of hookworm virulence factors now provide researchers with an improved understanding of disease pathogenesis, potential targets for treatment and novel antigens for vaccine development. In order to better understand hookworm pathophysiology and immunology in human populations, a comprehensive, cross-sectional immunoepidemiologic survey of approximately 200 villagers in a remote area of the Peruvian Amazon was conducted. Hookworm prevalence rates were found to approach 40% by microscopic diagnosis. Additionally, molecular speciation techniques showed that both A. duodenale and N. americanus are endemic to this region. Reagents from a laboratory model of hookworm disease were then utilized to characterize human immune responses to hookworm specific antigens. By studying the immunoepidemiology of an endemic community we have found that a laboratory strain of hookworm, Anyclostoma ceylanicum, is a useful tool for describing species specific immune responses to disease. This work lays the foundation for future development of improved hookworm diagnostic techniques by molecular and immunologic methods.

Diss.--Ulm--Universität, 2004. / Bibliogr. p. 163-188.

Thesis (M.S. )--Marshall University, 2009. / Title from document title page. Includes abstract. Document formatted into pages: contains 155 p. Includes bibliographical references p. 151-152.

Source: Dissertation Abstracts International, Volume: 70-03, Section: B, page: 1574. Adviser: Lu-Yu Hwang. Includes bibliographical references.

Thesis (M. Med. Sc.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 82-86).

Thèse d'exercice : Pharmacie : Université de Nantes : 2003. / Bibliogr. f. 113-119 [78 réf.].

Thèse de doctorat : Sciences de la vie et de la santé : Paris 12 : 2003. / Titre provenant de l'écran-titre.