Biomedical subjects
T Darville
Publications and source records attributed to T Darville.
A role for interleukin-6 in host defense against murine Chlamydia trachomatis infection.
Interleukin-6-deficient (IL-6(-/-)) knockout mice had significantly increased Chlamydia trachomatis levels in lung tissue and increased mortality compared to B6129F2/J controls early after intranasal infection. Gamma interferon production and chlamydia-specific antibody levels were consistent with a decreased but reversible Th1-like response in IL-6(-/-) mice. IL-6 is needed for an optimal early host response to this infection.
Respiratory syncytial virus.
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Prevention of perinatal transmission of HIV in Arkansas.
In 1994, the Centers for Disease Control and Prevention (CDC) recommended zidovudine (ZDV) prophylaxis to reduce perinatal transmission of HIV. Caregivers at the University of Arkansas for Medical Sciences (UAMS) instituted a program of universal voluntary HIV testing of pregnant females combined with maternal education regarding ZDV prophylaxis in October 1994. Since that time, 7 of 39 (18%) infants referred to Arkansas Children's Hospital (ACH) for evaluation of perinatal HIV exposure have been infected compared to 21 of 53 (40%) referred prior to October 1994, (p = 0.042). Unfortunately, of the 39 infants referred to ACH after October 1994, 21 were born to HIV-infected mothers who did not comply with prophylaxis. Fifteen of these mothers were not offered intravenous ZDV during delivery; five have children infected with HIV. These data indicate the need for increased efforts by health officials in Arkansas to institute nationally recommended methods of prevention of perinatal HIV.
Intravenous immunoglobulin inhibits staphylococcal toxin-induced human mononuclear phagocyte tumor necrosis factor alpha production.
Intravenous gamma immunoglobulin (IVIG) is used as therapy in superantigen-mediated disease, yet its mode of action is not clear. Pooled immunoglobulin G contains high concentrations of staphylococcal exotoxin (SE)-specific antibodies which inhibit the in vitro activation of T cells. However, SE and streptococcal exotoxins are potent stimulators of monocytes as well. Monocytes exposed to SE in vitro release large amounts of tumor necrosis factor alpha (TNF-alpha). The purpose of the present study was to determine if SE-specific antibodies in IVIG can inhibit the activation of monocytes by SE. We examined the in vitro effect of IVIG on the ability of staphylococcal exotoxin A (SEA) and staphylococcal exotoxin B (SEB) to stimulate release of TNF-alpha from human mononuclear phagocytes (MO). Pretreatment of SEA with 0.1 mg of IVIG per ml resulted in a slight decrease of SEA-induced TNF-alpha secretion by MO. In contrast, pretreatment of SEB with 0.1 mg of IVIG per ml resulted in significant (greater than 50%) inhibition of SEB-induced TNF-alpha secretion at 24, 48, 72, and 96 h (P < 0.05 for TNF-alpha levels induced by SEB alone versus SEB pretreated with IVIG at all time points). Enzyme-linked immunosorbent assay and Western immunoblotting assays of the IVIG revealed high concentrations of antibodies against SEB and lower concentrations of antibodies to SEA. These data indicate that IVIG can act in a toxin-specific manner to decrease the MO TNF-alpha response to superantigens. Such inhibition may be one mechanism by which IVIG exerts an immunoregulatory role in superantigen-mediated disease.
Mouse strain-dependent variation in the course and outcome of chlamydial genital tract infection is associated with differences in host response.
Whether there is a pathogenic or protective outcome to chlamydial infection may be defined by the host response. We infected C57BL/6 (C57) and C3H/HeN (C3H) mice with the human biovar of Chlamydia trachomatis, serovar E, and, in select experiments, with the mouse pneumonitis agent of C. trachomatis (MoPn). We compared the courses of infection, histopathology, and host responses that resulted from these infections. The duration of infection with either chlamydial biovar was significantly increased in the C3H strain of mice. The intensity of infection was examined in mice infected with serovar E, and it was significantly increased in the C3H strain. Histopathology revealed the incidence of severe hydrosalpinx to be significantly greater in C3H mice than in C57 mice. In contrast, severe distention of the uterine horns was observed in all infected C57 mice compared to none of the C3H mice infected with serovar E and only 25% of those infected with MoPn. Acute inflammation was significantly increased in the uterine horns of C57 mice compared to that of C3H mice. Examination of antigen-specific responses revealed qualitatively similar responses in the two strains. Determination of gamma interferon- versus interleukin 4- producing cells revealed the predominance of a Th1 response in both strains. Serum enzyme-linked immunosorbent assays for immunoglobulin G1 (IgG1) and IgG2a revealed a predominance of IgG2a antibody in both strains, although the levels of antibody were significantly greater in C3H mice. Lymphocyte proliferation studies revealed increased proliferation in the iliac nodes of both strains at 1 to 3 weeks after infection. Because of the early eradication of infection observed in the C57 strain, we explored the relative production of tumor necrosis factor alpha (TNF-alpha) in the two strains. TNF-alpha levels were significantly increased in the genital tract secretions of C57 mice compared to that of C3H mice during the first week of infection. Increased TNF-alpha may be beneficial to the host by leading to earlier eradication of infection, thereby preventing infection of the oviduct and thus the major disease sequelae associated with chlamydial infection of the genital tract.
Blastomycosis in children.
Infections due to Blastomyces dermatitidis are not commonly encountered in children and adolescents. Knowledge of the diagnosis and treatment of this disease is largely based upon experience with adult patients. We recently reviewed our experience with blastomycosis to evaluate the difficulties in diagnosis and treatment of this disease in the pediatric population. Ten patients with blastomycosis were identified during our review, and five had pulmonary disease alone. Of these five patients, four required open-lung biopsy for diagnosis, even though three had previously undergone bronchoalveolar lavage. The response to treatment with the oral azole antifungal agents (ketoconazole, fluconazole, and itraconazole) was limited, and the agent with the greatest success remains amphotericin B. Until more data are available, amphotericin B should be used for complicated and life-threatening cases of blastomycosis. If oral azole agents are used for non-life-threatening cases, patients should be followed closely, and if clinical deterioration occurs or serum levels of medications are not adequate, then amphotericin B should be substituted for the oral azole agent.
Tumor necrosis factor alpha activity in genital tract secretions of guinea pigs infected with chlamydiae.
Previous studies using the guinea pig model of chlamydial genital infection demonstrated that primary infection is associated with a marked acute inflammatory response early on, while chronic inflammation appears later, at a time when the level of infection is reduced. Challenge infections result primarily in a chronic inflammatory response. The stimuli that initiate inflammation and lead to tissue damage have not been defined. We investigated the possibility that tumor necrosis factors (TNFs) play a role in the inflammatory response to chlamydial genital tract infection. Cytotoxicity assays for TNF were performed on genital tract secretions collected from female guinea pigs during infection with the Chlamydia psittaci agent of guinea pig inclusion conjunctivitis. During the early days of primary infection, high levels of TNF-alpha were detected in genital tract secretions from inbred S2 strain and outbred Hartley strain guinea pigs. Significantly lower levels of TNF-alpha were detected in secretions from both strains during challenge infection. In general, the intensity of the TNF-alpha response was proportional to the intensity of infection. High TNF-alpha levels were present during primary infection at a time of marked neutrophil influx. Thus, TNF-alpha may play an important role in the response to primary chlamydial genital tract infection.
Recent advances in pediatric HIV.
Pediatric human immunodeficiency virus (HIV) infection is a disease of mother-to-infant transmission. The World Health Organization estimates there will be ten million HIV-infected children by the end of this century. It is now thought that both intrauterine and intrapartum transmission of HIV occurs. Infants infected in utero develop clinical signs and symptoms at an earlier age than those who are infected at the time of delivery. We describe two cases that demonstrate early-onset and late-onset pediatric HIV disease, respectively. Recently, it was determined that perinatal transmission of HIV can be significantly reduced by the administration of the antiretroviral drug, zidovudine (ZDV), to HIV-positive pregnant women and their newborns, making HIV screening of pregnant women more desirable than ever. A program of universal voluntary HIV testing for pregnant women has been successfully implemented at the University of Arkansas for Medical Sciences. Details of this program are described herein.
Impact of immunization against Haemophilus influenzae type b (HIB) on the incidence of HIB meningitis treated at Arkansas Children's Hospital.
The newly available Haemophilus influenzae type b (HIB) protein conjugate vaccines are efficacious among study populations in which a high proportion of infants and children are vaccinated. In this retrospective study, we show the impact of the availability of HIB conjugate vaccines on the incidence of HIB meningitis at Arkansas Children's Hospital (ACH) in Little Rock. The Arkansas State Health Department estimates that only 43% of children in the state younger than 2 years of age have received the appropriate vaccinations. From 1985 through 1987, 27.3 +/- 4 HIB meningitis cases per year were treated at ACH. Although an HIB conjugate vaccine was licensed for 18-month-old children in December 1987, the incidence of HIB meningitis treated at ACH did not decrease significantly; there were 19.0 +/- 2 cases per year from 1988 through 1990. In December 1990, an HIB conjugate vaccine was licensed for use in infants beginning at 2 months of age. From that time through August 1992, there were five cases of HIB meningitis treated at ACH, representing a significant decrease over previous years. Four of these cases occurred in unimmunized infants younger than 6 months of age. The availability of HIB conjugate vaccines for infants has resulted in a dramatic decrease in the number of cases of HIB meningitis treated at ACH, despite a relatively low proportion of infants and children who are receiving vaccination.
The cephalosporin antibiotics.
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Intravenous immunoglobulin modulates human mononuclear phagocyte tumor necrosis factor-alpha production in vitro.
Mononuclear phagocytes (MO) secrete tumor necrosis factor-alpha (TNF) in response to inflammatory stimuli, most notably the bacterial product lipopolysaccharide (LPS). Cross-linking of MO Fc receptors also induces TNF release. Immunoglobulin for i.v. use is currently being investigated for the treatment and prophylaxis of neonatal sepsis and for the treatment of various syndromes of autoimmune dysfunction in children and adults. We examined the in vitro effect of immunoglobulin-gamma (IgG) on neonatal (cord blood) monocyte and adult MO TNF production. Kinetic studies were performed on MO incubated with IgG alone and on MO preincubated with IgG and stimulated with interferon-gamma/LPS. Incubation of MO in IgG (1-25 g/L) for 2, 6, and 24 h did not stimulate TNF secretion or production. However, enhanced TNF secretion was detected in MO preincubated in IgG and subsequently stimulated with interferon-gamma/LPS. TNF secretion by cord blood monocytes was increasingly enhanced by preincubation for 6 h with 1, 10, and 25 g/L IgG (2413.1 +/- 1389.4, p < 0.05; 4070.4 +/- 3069.2, p < 0.005; and 6383.7 +/- 2982.2, p < 0.005 versus 1215 +/- 575.9 ng/L, respectively, in cells preincubated in medium alone). Significant enhancement was also detected in cord blood monocytes preincubated in IgG for 2 h. TNF secretion by adult MO was similarly enhanced (6082.0 +/- 1732.8, p < 0.05; 7158.8 +/- 3938.2, p < 0.05; and 7302.7 +/- 3451.4, p < 0.05 versus 3353.2 +/- 2946.7 ng/L for 1, 10, and 25 g/L IgG, respectively, versus preincubation in medium alone). In additional experiments performed with Fc, Fab, and F(ab')2 fragments, only F(ab')2 fragments yielded positive results.(ABSTRACT TRUNCATED AT 250 WORDS)
Diagnosis, care and management of the pediatric HIV/AIDS patient in Arkansas.
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Safety profile and efficacy of cefotaxime for the treatment of hospitalized children.
Cefotaxime has been used to treat serious bacterial infections in children since 1982. With the predominant use of cephalosporins in pediatrics, reports of adverse effects of certain compounds have increased. A retrospective review is presented of 2,243 cases of children receiving therapy with cefotaxime in order to evaluate the safety profile and efficacy of cefotaxime in the treatment of serious infections in hospitalized children. Overall, 57 (2.5%) children experienced adverse reactions. These included local reactions in 6 (0.3%), rash in 28 (1.2%), diarrhea in 15 (0.97%), vomiting in 10 (0.7%), abdominal pain in 1 (0.1%), headache in 3 (0.4%), and drug fever in 1 (0.1%). No cases of hemolytic anemia, bleeding, or hyperbilirubinemia were found. Efficacy of treatment for different disease categories ranged from 90.5% to 100%. The percentage of children in any treatment group with a particular laboratory abnormality following initiation of cefotaxime therapy ranged from 0% to 2.6%, and rates of superinfection with bacteria or Candida were 0.4% to 1.7%. Cefotaxime has the distinct advantage of high rates of efficacy and low rates of complications and superinfection among children hospitalized for serious infections.
Detection of Haemophilus influenzae type B antigen in cerebrospinal fluid after immunization.
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