Approximately 17 papers from the Division of Infectious Diseases were published, or are in press, in peer-reviewed journals during 2003-2004. Five publications are highlighted below.

Publication Highlights

Changes in thrombolytic and inflammatory markers after initiation of indinavir- or amprenavir-based antiretroviral therapy. Young EM, Considine RV, Sattler FR, Deeg MA, Buchanan TA, Degawa-Yamauchi M, Shankar SS, Edmondson- Melançon H, Hernandez J, Dubé MP. Cardiovasc Toxicol 4: 179-86, 2004.

HIV-infected subjects who have lipodystrophy and insulin resistance on prolonged antiretroviral therapy have elevated levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) antigens, markers of impaired thrombolysis that are associated with hyperinsulinemia and increased cardiovascular risk. We studied HIV-infected, protease inhibitor (PI)- naive adults treated with indinavir (N=11) or amprenavir (N=14) plus two nucleoside reverse transcriptase inhibitors enrolled in two prospective trials. Antiretroviral and immune responses were similar in both studies. Over 8 weeks, indinavir was associated with decreased insulin sensitivity while amprenavir was not. Levels of tPA antigen declined by ~25% with both treatments (p<0.05 for each); levels of PAI-1 antigen did not change. Levels of soluble tumor necrosis factor-alpha receptor II (sTNFr2) correlated positively with tPA antigen (r=0.33, p=0.02), and mean (±SD) plasma concentrations of this inflammatory marker also declined (4.44±1.11 ng/mL pre-therapy, 3.75±1.21 post-therapy, p=0.007). Short-term improvement in markers of impaired thrombolysis and increased vascular risk can occur during PI-based antiretroviral therapy, perhaps as a consequence of improvement in HIV-related inflammation. This improvement occurred irrespective of the PI-induced insulin resistance seen with indinavir.

Laboratory monitoring in pediatric acute osteomyelitis and septic arthritis. Khachatourians AG, Patzakis MJ, Roidis N, Holtom PD. Clin Orthop Rel Res 409:186-194, 2003.

The purpose of the current study was to determine the usefulness of erythrocyte sedimentation rate and C-reactive protein in pediatric bone and joint infections treated with and without surgery. The medical records of 50 patients admitted for acute osteomyelitis, septic arthritis, or both were reviewed retrospectively. There were 22 patients with septic arthritis, 20 with osteomyelitis, and eight with osteomyelitis with adjacent septic arthritis. There were 25 patients each in the surgical and nonsurgical groups. There was a statistically significant difference between the two groups regarding mean days to peak and normalization of erythrocyte sedimentation rate values and normalization of C-reactive protein values. Statistically significant differences were revealed for the mean days to normalization of erythrocyte sedimentation rate and C-reactive protein values among the patients with a diagnosis of osteomyelitis, septic arthritis, or both. The mean days to peak and normalization for erythrocyte sedimentation rate and C-reactive protein were twice as long in the surgical group as compared with the nonsurgical group. Complete recovery was achieved in all patients. This information should help clinicians in the diagnosis and treatment of children having surgery for acute osteomyelitis and septic arthritis.

Negative pressure dressings as an alternative technique for the treatment of infected wounds. Wongworawat MD, Schnall SB, Holtom PD, Moon C, Schiller F. Clin Orthop Rel Res 414:45-48, 2003.

Coverage of wounds caused by infection and subsequent treatment often are variable because of the location of the wound and wound size. Although much research has been done to expand the indications of negative pressure wound treatment systems, little investigation has been done to quantify the reduction of wound size for vacuum-assisted closure treatment in the presence of infection. In this series, 14 patients who had wounds caused by infections were treated with the vacuum-assisted wound closure system. All wounds were greater than 20 cm2. The duration of treatment averaged 10 days (range, 2-27 days), and the initial wound size averaged 70 cm2 (range, 22.5-288 cm2). After the course of treatment, the final wound size averaged 39 cm2 (range, 10-147 cm2). The average wound size reduction was 43%. This method seems to enhance the rapidity of wound reduction, and because it is a closed system of treatment, it has the added benefit of minimizing exposure of staff and other patients to communicable diseases. Vacuum-assisted wound closure systems add another option in the care of musculoskeletal infections.

Androgen therapy improves muscle mass and strength but not muscle quality: Results from two studies. Schroeder ET, Terk M, Sattler FR. Am J Physiol: Endocrinol Metab 285:E16-E24, 2003.

The relationship of strength to muscle area was used to assess change in muscle quality after anabolic interventions. Study No.1: asymptomatic HIV positive men (39±9 years) were randomized to receive nandrolone decanoate (600mg/week) with or without resistance training. Study No.2: older healthy men (72±5 years) were randomized to oxandrolone (20mg/day) or placebo. Maximum voluntary strength was determined by the 1-repetition method (1-RM) method for leg press, leg flexion and leg extension, and cross-sectional area of leg muscles by MRI. From study weeks 0-to-12, muscle quality was unchanged with nandrolone, oxandrolone, or oxandrolone placebo, respectively for total thigh muscles (1.23±0.012 vs 1.27±0.29 kg/cm2; 9.0±1.1 vs 8.9±1.2 N/cm2; 8.9±1.2 vs 8.9±1.9 N/cm2) and hamstrings (0.41±0.08 vs 0.43±0.07 kg/cm2; 0.90±0.14 vs 0.95±0.016 N/cm2; 0.94±0.23 vs 0.93±0.21 N/cm2). Whereas, lower-extremity 1-RM strength increased several fold greater with resistance training plus nandrolone (51-63% increases) than with nandrolone alone (4.7-16%), despite similar increases in muscle area. Therefore, muscle quality increased from 1.13±0.17-to-1.51±0.18 kg/cm2 (+36±19%; p<0.001) for total thigh muscle, 0.37±0.10-to -0.53±0.08 kg/cm2 (+49±39%; p<0.001) for hamstrings, and 0.73±0.19-to-1.07±0.16 kg/cm2 (+55±36%; p<0.001) for quadriceps. Thus, androgen therapy alone did not improve muscle quality but the addition of resistance training to nandrolone produced substantive improvements.

Special Basic Research Activities

Brenda E. Jones, M.D.
Dr. Jones has developed collaboration relationships with faculty in the Department of Preventive Medicine and Division of Gastrointestinal and Liver Diseases at USC. As a result, her future studies will include the use of a novel system to quantify levels of gamma interferon for the diagnosis of latent tuberculosis infection and studies to determine the genetic susceptibility and risks for isoniazid hepatotoxicity (ie., pharmacogenomics).

Robert A. Larsen, M.D.
Dr. Larsen continues his laboratory work on correlative studies involving a murine model of cryptococcal disease and an in vitro system to test fungal susceptibility.

Fred Sattler, M.D.
Dr. Sattler continued with the second year of his R01 study as principal investigator to assess “Hormonal Regulators of Muscle and Metabolism in Aging”. This study is investigating the effects of restoring testosterone and growth hormone individually and the combination to youthful levels on synthesis of myofibrillar proteins actin and myosin, muscle protein breakdown via activation of the ubiquitin-proteasome system, quantification of satellite cell activation, and the effects of the local regulators IGF-1, IGFBP-4 and myostatin on net protein balance.

Special Clinical Research Activities

P. Jan Geiseler, M.D.
Antiretroviral therapy. Dr. Geiseler continued his work with antiretroviral therapy utilizing new antiviral compounds in clinical trials in HIV-infected patients.

Paul D. Holtom, M. D.
Bone and soft tissue infections. Dr. Holtom continued his collaboration with Drs. Michael Patzakis, Ed McPherson and others in the Department of Orthopedic Surgery, to study the pathogenesis and treatment of infections in total joint arthroplasties. The Group is currently conducting several therapeutic trials with special emphasis on the pharmacodynamics of the elution of antibiotics from PMMA beads and spacers.

Brenda E. Jones, M.D.
Natural history and treatment of tuberculosis. Dr. Jones is the USC principal investigator of a 10-year contract (September 1999- 2009) sponsored by the Centers for Disease Control and Prevention (TBTC). The USC study site, which includes Los Angeles County TB Control, is one of 27 international study sites. The purpose of the Consortium is to address the research needs for the treatment and prevention of tuberculosis. A high priority of research is for improved treatment of latent tuberculosis infection. An important secondary goal of the Consortium is to contribute to the global control of tuberculosis in HIV-infected persons. In October 2003, Drs. Jones (PI) and Patricio Escalante (Co-Investigator - Pulmonary Department) were awarded a five-year NIH subcontract with UCSD to establish a National TB Curriculum Center (NTCC). The NTCC will coordinate the activities of a multidisciplinary team to develop and implement curriculum, using state-of- the-art technology for education. The Consortium consists of 23 partner schools, of which USC is one of the five coordinating centers.

Robert A. Larsen, M.D.
Most of Dr. Larsen’s research is directed toward the understanding of central nervous system infections. His other investigations include study of viral, fungal and bacterial pathogens.

Fungal Infections. Dr. Larsen is a member of the NIH-sponsored Bacterial and Mycoses Study Group (BAMSG). The BAMSG has initiated a trial of amphotericin B plus fluconazole in persons with AIDS and cryptococcal meningitis. Dr. Larsen is a co-chair of this study being conducted in the USA and Thailand. The NIH-sponsored Adult AIDS Cooperative Trials Group (AACTG) is also developing an international study of AIDS-associated cryptococcal meningitis with high doses of fluconazole. Dr. Larsen is the domestic (USA) vice-chair of this study to be conducted in the USA, Peru, Brazil and South Africa. Both trial concepts were proposed by Dr. Larsen and based on prior clinical studies he has conducted.

Viral Infections. The NIH-sponsored Collaborative Anti-Viral Study Group which conducts clinical trials in West Nile encephalitis and Herpes simplex encephalitis invited Dr. Larsen and USC to join in the multi-centered group. Now in its 7th year, the NIHsponsored California NeuroAIDS Tissue Network (CNTN) continues to evaluate the impact of the AIDS virus (HIV) on the central nervous system.

Bacterial Infections. As a subproject of the California NeuroAIDS Tissue Network (CNTN), Dr. Larsen has started an evaluation of syphilis on persons co-infected with HIV. A novel diagnostic approach to identify central nervous system infection with syphilis is being tested with samples collected as part of the CNTN program.

Other activities. Dr. Larsen is the local principal investigator for the California Collaborative Treatment Group (CCTG), a state supported research program in HIV. The principal activity of the CCTG over the last year has been associated with HIV prevention activities among HIV positive persons. Dr. Larsen also served as a site investigator of a Center for Disease Control and Prevention (CDC) study of clinic and drug adherence in persons with HIV infection receiving highly active anti-retroviral drug therapy.

Mary Ann Leal, M.D.
Clinical Research. Dr. Leal continued to collaborate and support the investigator initiated clinical mycology studies being conducted by Dr. Larsen. She continued as an active member of the AIDS Clinical Trial Group (ACTG) Unit at USC and assisted Dr. Squires in the clinical aspects of studies being performed at the USC Unit.

James W. Mosley, M.D.
Blood borne viral infections. Dr. Mosley’s primary research activity is the re-evaluation of specimens from the 1970s Transfusiontransmitted Viruses Study. Dr. Mosley and co-workers completed a paper on the amount of HCV in a donor’s blood necessary to transmit the infection to his recipient. They examined characteristics of the virus in the donor (level of viremia, extent of ALT elevation, and genotype/subtype) in relation to the host infection. The course of the acute infection in the recipient was determined entirely by the host, which included even the size of the inoculum. The paper was published in the October issue of Transfusion (Transfusion 43(10):1433-41, 2003). Using the same 94 blood recipients, Dr. Mosley and co-workers have been examining the course of the acute illness in relation to the length of the latent (incubation) period, ALT elevations, occurrence of symptoms, and genotype. The paper entitled Viral and host factors in early hepatitis C virus infection by James W. Mosley, Eva A. Operskalski, and others is presently under review by Hepatology. The present effort is focused upon the immediate postacute phase in an effort to determine predictors of long-term outcome. He is cooperating with Dr. Leonard Seeff at NIH to relate the early course immediately after the acute phase to a long-term follow-up (>10 years) carried out by Dr. Seeff.

Eva A. Operskalski, Ph.D.
Blood borne viral infections, pediatric and maternal HIV, and HIV vaccine preparedness. Dr. Operskalski’s principal activity during academic year 2003-2004 was development and implementation, as Principal Investigator of an HIV vaccine family and community preparedness pilot study, a collaborative approach to HIV vaccine preparedness, sponsored by the Pediatric AIDS Clinical Trials Group. She continued to serve as Clinical Research Manager for the LAC+USC Maternal Child and Adolescent HIV Management and Research Center. She is co-investigator on a recently funded grant (Dr. Andrea Kovacs, Principal Investigator) to evaluate the relationship of HCV infection with progression of HIV and response to highly active anti-retroviral therapy (HAART) in women. She also worked with Dr. James W. Mosley in the re-evaluation of specimens from the 1970s Transfusiontransmitted Viruses Study to investigate the association of viral load in anti-HCV-reactive donors and infectivity for their recipients; viral and host factors in early hepatitis C virus (HCV) infection; and, course and resolution of acute hepatitis C virus (HCV) infection among transfusion recipients: course and resolution.

Fred R. Sattler, M.D.
Metabolic abnormalities in HIV infection and aging. Dr. Sattler continued his scientific leadership in the NIAID AIDS Clinical Trials Group studies that evaluate pathophysiology and management of HIV associated weight loss, changes in body fat and metabolic complications. He serves as a chair, co-chair, vice-chair, or protocol team member for a number of studies including ACTG 313, 329, 392, 892, 5079, 5112, 5116, 5124 and 5125 which are either actively accruing study subjects or were recently completed (ACTG 313, 329, 392, 892) and the results are being analyzed for preparation of manuscripts and submission of abstracts to scientific meetings. As an outgrowth of studies of AIDS muscle wasting, Dr. Sattler conducted investigator-initiated pilot studies in the USC GCRC to evaluate the effects of anabolic androgens in elderly subjects with loss of skeletal muscle mass (sarcopenia) and muscle strength and thus at risk for frailty and who have gains in central fat and are at risk for the metabolic syndrome. These studies have demonstrated dose dependent improvements in muscle mass, maximal voluntary strength, and leg power, which are necessary constituents for physical function, independence, and quality of life during aging. In addition, study subjects have had a dose related decrease in total and central fat that appear to be sustained for at least 3 months after androgen therapy is discontinued. Based on the results of these studies which have been presented in at the Endocrine Society meetings, Dr. Sattler obtained commitments from Genentech, Tap, Solvay pharmaceutical companies to supply rhGH, leuprolide acetate, and a new, more physiologic formulation of testosterone to study the interactions of the growth hormone/IGF-1 and androgen axes in regulating muscle and adipose tissue in elderly persons. These activities culminated in his being funded by the National Institutes of Aging as PI to conduct a multicenter four-year study to evaluate the effects of restoring these hormonal axes to youthful levels on net anabolic protein balance. The translational effects of these interventions as measured by body composition (DEXA and total body water analysis by stable isotope biology), anthropometry, skeletal muscle strength, power, and physical function, maximal ventilatory capacity, and aerobic endurance are being measured in the USC GCRC.

Kathleen E. Squires, M.D.
HIV natural history and treatment of HIV in women. Dr. Squires is principal investigator of the USC funded ACTU sponsored by the Division of AIDS of NIAID. She is a member of the Women’s Health Committee and is interested in all aspects of HIV pathogenesis and its treatment. She is currently chair of ACTG 5029 and principal investigator for several of local ACTG trials. In addition, she is the local principal investigator for a new CCTG study examining, in a controlled manner, measures to improve adherence to anti-HIV medications. Dr. Squires also participates in the Women’s Interagency HIV Study (PI, Dr. Alexandra Levine), which is a natural history study of HIV infection in women sponsored by the National Institutes of Health because of her special interest in the natural history and other clinical aspects of HIV in women. She is the HIV clinical trials consultant for the National Institutes of Health sponsored Adolescent Trials Network.