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Biomedical subjects

J L Shenep

Publications and source records attributed to J L Shenep.

At least 19 recordsLinked to original sources
PubMed2001

Lactic acidosis: a metabolic complication of hematologic malignancies: case report and review of the literature.

BACKGROUND: Lactic acidosis (LA) associated with hematologic malignancies is rare, ominous, and generally occurs in adults. Its pathogenesis is poorly understood. METHODS: The authors present one case of childhood lymphoma and two cases of childhood leukemia associated with LA, and they review the available literature. Plasma concentrations of insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), and tumor necrosis factor (TNF)-alpha were retrospectively measured to elucidate the pathogenesis of LA. RESULTS: Lactic acidosis has been reported to date in 28 cases of lymphoma and 25 cases of leukemia, including the authors' cases. Ongoing rapid cellular proliferation was indicated in all leukemia cases. The liver was involved in 43 of the 53 cases, and hypoglycemia was present in 20. The acidosis improved only if the disease responded to chemotherapy. Remission was achieved in only five of the reported cases. In the authors' three cases, LA was associated with altered concentrations of IGFs, IGFBPs, and TNF-alpha, although causality was not established. CONCLUSIONS: Lactic acidosis in association with hematologic malignancies carries an extremely poor prognosis. Because cancer cells have a high rate of glycolysis and produce a large quantity of lactate, this condition may result from an imbalance between lactate production and hepatic lactate utilization. The authors speculate that the IGF system is involved in the pathophysiology of LA in these patients. Only chemotherapy so far has been effective in correcting the acute acidosis in a few patients; however, it has not necessarily improved ultimate outcome.

Acidosis, Lactic↗
PubMed2001

Bacillus cereus bacteremia and meningitis in immunocompromised children.

Two cases of Bacillus cereus meningitis in immunocompromised children at our hospital within a 2-month period prompted us to review B. cereus--related invasive disease. We identified 12 patients with B. cereus isolated in blood cultures from September 1988 through August 2000 at our institution. Three of these patients also had B. cereus isolated from CSF specimens; 1 additional patient had possible CNS involvement (33%, group A), whereas 8 patients had no evidence of CNS involvement (67%, group B). Patients in group A were more likely to have neutropenia at the onset of sepsis and were more likely to have an unfavorable outcome. They were also more likely to have received intrathecal chemotherapy in the week before the onset of their illness. Two patients from group A died. One survived with severe sequelae. The fourth patient had mild sequelae at follow-up. No sequelae or deaths occurred among patients in group B. In patients with unfavorable outcomes, the interval from the time of recognition of illness to irreversible damage or death was short, which demonstrates a need for increased awareness, early diagnosis, and more-effective therapy, particularly that which addresses B. cereus toxins.

Adolescent↗
PubMed2000

Oral cefixime is similar to continued intravenous antibiotics in the empirical treatment of febrile neutropenic children with cancer.

Empiric oral antibiotic therapy for febrile neutropenic cancer patients has been suggested as a means to decrease hospitalization, but the safety of this approach has not been adequately studied in children. We compared continued iv antibiotic therapy with switching treatment to orally administered cefixime in a group of selected febrile neutropenic children for whom blood cultures were sterile after 48 h of incubation. Two hundred episodes of febrile neutropenia were studied (156 patients), and 100 episodes were randomized to receive each treatment. Failure to respond to therapy was defined by documented or suspected bacterial infection, recurrent fever, or discontinuation of assigned therapy for any reason before neutropenia resolved. Rates of treatment failure were similar in the oral cefixime group (28%) and in the iv antibiotic group (27%; P=1.0). Results support the safety of oral cefixime therapy for low-risk febrile neutropenic children, a therapeutic approach that would facilitate earlier outpatient management and decrease the costs of treatment.

Administration, Oral↗
PubMed2000

Candidal meningitis in children with cancer.

Candidal meningitis is a rare disease that is seen most frequently in neonates, neurosurgical patients, and the immunocompromised host. We describe a series of 12 children with cancer (all of whom had leukemia) who had candidal meningitis develop. Univariate analysis revealed that duration of fever, antibiotic therapy, and profound neutropenia and use of total parenteral nutrition were significantly associated (P<.05) with candidal meningitis in children with cancer, compared with matched control subjects. Only duration of profound neutropenia (P=.08) and use of total parenteral nutrition (P=.06) approached significance in the multivariate analysis. One species of Candida, Candida tropicalis, was responsible for 11 of the 12 cases, indicating increased pathogenicity of this organism in CNS disease. The cases were invariably fatal, supporting aggressive treatment of candidal meningitis in immunocompromised patients and further study of the prevention, diagnosis, and management of C. tropicalis meningitis.

Antifungal Agents↗
PubMed2000

Group B streptococcal beta-hemolysin induces nitric oxide production in murine macrophages.

Group B streptococcus (GBS) is the leading cause of sepsis in neonates. Nitric oxide (NO) release plays a role in the hypotension that characterizes septic shock. To examine the role of the GBS beta-hemolysin in NO production, the murine macrophage line RAW 264. 7 was exposed to a wild-type (WT) GBS isolate and to hyperhemolytic (HH) and nonhemolytic (NH) transposon mutants derived from that isolate. After activation of macrophages by the WT strain, the HH mutant, or cell-free extracts of beta-hemolysin, nitrite release into the supernatant increased >10-fold and inducible NO synthase (iNOS) levels in cell lysates increased up to 10-fold compared with treatment with the NH mutant or extracts from that mutant. Hemolysin-induced NO production was dependent on protein tyrosine kinases and NF-kappaB, but not on extracellular signal-related kinase-1/2-mitogen-activated kinases or protein kinase A. These results indicate that GBS beta-hemolysin induces murine macrophage iNOS via intracellular pathways similar to those that mediate lipopolysaccharide-induced iNOS activation.

Animals↗
PubMed2000

Viridans-group streptococcal infections in immunocompromised hosts.

Viridans streptococci, a diverse group of streptococcal species, are important causes of sepsis and pneumonia in the neutropenic host and sepsis and meningitis in the neonate. The oral mucosa is the most common portal of entry. Among the factors that predispose to development of viridans streptococcal sepsis are: profound neutropenia; mucositis, especially oral mucositis; cytarabine (Ara-C) therapy, which seems to have an effect beyond its association with mucositis; young age; and trimethoprim-sulphamethoxazole or quinolone administration. Fever is usually more than 39 degrees C and prolonged for several days even though blood cultures are typically negative after 24 h of therapy. The majority of patients recover uneventfully if appropriate therapy is initiated early. However, fulminant septic shock may occasional occur at onset. Delayed shock 2 or 3 days after presentation may also occur despite administration of microbiologically effective antibiotics. In severe cases, adult respiratory distress syndrome may be manifested two or three days after the initial bacteremia. There is considerable variability among institutions, but the median death rate associated with viridans streptococcal sepsis is about 10%. Local susceptibility patterns should be used to guide initial therapy for suspected viridans streptococcal infections. Some isolates of viridans streptococci are resistant to penicillins and cephalosporins, in which case vancomycin is preferred. Recurrence during subsequent neutropenic episodes is not unusual.

Anti-Bacterial Agents↗
PubMed2000

Single-dose pharmacokinetics and safety of the oral antiviral compound adefovir dipivoxil in children infected with human immunodeficiency virus type 1. The Pediatrics AIDS Clinical Trials Group.

The acyclic phosphonate analog adefovir is a potent inhibitor of retroviruses, including human immunodeficiency virus (HIV) type 1, and, unlike some antiviral nucleosides, does not require the initial phosphorylation step for its activity. Two oral dosages of the adefovir prodrug adefovir dipivoxil were evaluated in a phase I study with children with HIV infection. A total of 14 patients were stratified into age groups ranging from 6 months to 18 years of age. Eight patients received 1.5 mg of adefovir dipivoxil per kg of body weight, and six patients received 3.0 mg of adefovir dipivoxil per kg. Serum samples were obtained at intervals during the 8 h postdosing and were analyzed for adefovir concentrations. Patients were monitored for adverse effects. All samples collected resulted in quantifiable levels of adefovir (lower limit of quantitation, 25 ng/ml) from each patient. The areas under the concentration-versus-time curves (AUCs) were similar (P = 0.85) for the 1.5- and 3.0-mg/kg doses, while the apparent oral clearance (CL/F) was significantly higher (P = 0.05) for the 3-mg/kg dose. Pharmacokinetic parameters differed by patient age. In comparing those children older and younger than the median age of 5.1 years, AUC (P = 0.03), maximum concentration of drug in serum (P = 0.004), and the concentration at 8 h postdosing (P = 0.02) were significantly lower for the younger children. There were no significant differences for apparent volume of distribution and CL/F normalized to body surface area, but there was a suggestive difference in half-life (P = 0.07) among the subjects in the older and younger age groups. No significant adverse events were encountered. These data provide the basis for a multidose phase II study of adefovir dipivoxil in HIV-infected infants and children.

Adenine↗
PubMed1999

Aspergillosis in children with cancer: A 34-year experience.

A retrospective review of medical records, microbiology and pathology laboratory records, and nosocomial infection surveillance data was undertaken to describe the experience with culture-documented aspergillus infection in pediatric cancer patients at our facility. Sixty-six patients were identified from a 34-year period. The most common underlying diagnosis was leukemia. Risk factors included neutropenia, immunosuppression, and prior antibiotic therapy. On the basis of clinical presentation, 23 patients were believed to have disseminated disease and 43 to have localized disease. The lung was the most frequently affected organ. Despite aggressive medical and surgical management, overall mortality was 85% within the first year after diagnosis. Patients who presented with disease in sites other than the lungs fared better than patients with initial pulmonary involvement (P=.0014). Aspergillosis continues to be associated with poor outcome. Development of improved medical and adjuvant therapies, including surgery, is warranted.

Adolescent↗
PubMed1999

Pneumolysin, a protein toxin of Streptococcus pneumoniae, induces nitric oxide production from macrophages.

Nitric oxide (NO) production by inducible NO synthase (iNOS) during inflammation is an essential element of antimicrobial immunity but can also contribute to host-induced tissue damage. Under conditions of bacterial sepsis, large amounts of NO are produced, causing hypotension, a critical pathological feature of septic shock. In sepsis caused by gram-positive organisms, the bacterial factors contributing to host NO production are poorly characterized. We show that a soluble toxin of Streptococcus pneumoniae, pneumolysin (Pln), is a key component initiating NO production from macrophages. In contrast to wild-type bacteria, a mutant of S. pneumoniae lacking Pln failed to elicit NO production from murine macrophages. Purified recombinant Pln induced NO production at low concentrations and independently of exogenous gamma interferon (IFN-gamma) priming of RAW 264.7 macrophages. However, IFN-gamma was essential for Pln-induced NO production, since primary macrophages from mice lacking the IFN-gamma receptor or interferon regulatory factor 1, a transcription factor essential for iNOS expression, failed to produce NO when stimulated with Pln. In addition, Pln acts as an agonist of tumor necrosis factor alpha and interleukin 6 production in macrophages. The properties of Pln, previously identified as a pore-forming hemolysin, also include a role as a general inflammatory agonist.

Animals↗
PubMed1999

A phase I study of abacavir (1592U89) alone and in combination with other antiretroviral agents in infants and children with human immunodeficiency virus infection. AIDS Clinical Trials Group 330 Team.

OBJECTIVES: To evaluate the pharmacokinetic features, safety, and tolerance of abacavir, given alone and in combination with other nucleoside antiretroviral agents, in symptomatic human immunodeficiency virus (HIV)-infected children. METHODS: HIV-infected children discontinued prior antiretroviral therapy and were given abacavir orally, 4 mg/kg every 12 hours for 6 weeks, followed by 8 mg/kg every 12 hours for 6 weeks (n = 39); or 8 mg/kg every 12 hours for 12 weeks (n = 8). Children then were randomized to receive a second nucleoside antiretroviral agent (zidovudine, stavudine, didanosine, or lamivudine), plus abacavir. Pharmacokinetics, safety, tolerance, CD4(+) lymphocyte counts, and plasma HIV RNA concentrations were evaluated. RESULTS: At a dose of 8 mg/kg every 12 hours, area under the plasma concentration-versus-time curves and plasma half-life values were comparable with those reported for adults receiving abacavir at a dose of 300 mg twice daily. One case each of hypersensitivity reaction and peripheral neuropathy occurred during abacavir monotherapy. Three children experienced neutropenia while receiving abacavir in combination with another antiretroviral agent. Mean CD4(+) lymphocyte count and plasma HIV RNA concentration did not change when prior antiretroviral therapy was changed to abacavir monotherapy. CONCLUSIONS: Abacavir therapy is associated with good short-term tolerance and safety in HIV-infected children. Phase III studies are in progress to assess the antiviral activity of abacavir in children and adults.

Adolescent↗
PubMed1998

Pneumococci stimulate the production of the inducible nitric oxide synthase and nitric oxide by murine macrophages.

The role of nitric oxide (NO) in the pathophysiology of gram-positive sepsis is uncertain. In inflammatory conditions, high-output NO production is catalyzed by the enzyme inducible nitric oxide synthase (iNOS). The ability of 2 strains of pneumococci, pneumococcal cell wall preparations, and purified pneumococcal capsule (Pnu-Imune 23) to trigger the production of iNOS protein and NO in RAW 264.7 murine macrophages was tested. Live pneumococci, oxacillin-killed pneumococci, and pneumococcal cell wall preparations stimulated the production of iNOS and NO by RAW 264.7 cells in the presence, but not the absence, of low concentrations of recombinant murine interferon-gamma. In contrast, purified pneumococcal capsule induced little or no iNOS or NO production by these cells. Thus, pneumococci stimulate high-output NO production by murine macrophages. The potential role of NO in the pathogenesis of pneumococcal sepsis deserves further study.

Animals↗
PubMed1998

Successful medical therapy for deeply invasive facial infection due to Pythium insidiosum in a child.

Pythiosis occurs in animals and humans who encounter aquatic habitats that harbor Pythium insidiosum. Drug therapy for deeply invasive infections with this organism has been ineffective in humans and animals; patients have been cured only by radical surgical debridement. A 2-year-old boy developed periorbital cellulitis unresponsive to antibiotic and antifungal therapy. The cellulitis extended to the nasopharynx, compromising the airway and necessitating a gastrostomy for feeding. P. insidiosum was isolated from surgical biopsy specimens of the affected tissue. On the basis of in vitro susceptibility studies of the isolate, the patient was treated with a combination of terbinafine and itraconazole. The infection resolved over a period of a few months. The patient remained well 1.5 years after completing a 1-year course of therapy. Cure of deep P. insidiosum infection is feasible with drug therapy.

Anti-Infective Agents↗
PubMed1997

Viridans streptococcal isolates from patients with septic shock induce tumor necrosis factor-alpha production by murine macrophages.

Viridans streptococci are an important cause of bacteremia and septic shock in neutropenic patients, especially patients receiving chemotherapeutic agents that induce severe mucositis. The mechanisms by which viridans streptococci cause septic shock are unclear. We hypothesized that septic shock due to viridans streptococci is attributable to host cytokine production. Three clinical isolates of viridans streptococci were evaluated for their ability to induce production of tumor necrosis factor-alpha (TNF-alpha) by RAW 264.7 murine macrophages. These three strains of viridans streptococci induced TNF-alpha in a dose-dependent fashion, and the kinetics of TNF-alpha induction were similar to those observed with a clinical isolate of Escherichia coli.

Animals↗
PubMed1997

1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Infectious Diseases Society of America.

This is the first in a series of practice guidelines commissioned by the Infectious Diseases Society of America through its Practice Guidelines Committee. The purpose of these guidelines is to provide assistance to clinicians when making decisions on treating the conditions specified in each guideline. The targeted providers are internists, pediatricians, and family practitioners. The targeted patients and setting for the fever and neutropenia guideline are hospitalized individuals with neutropenia secondary to cancer chemotherapy. Panel members represented experts in adult and pediatric infectious diseases and oncology. The guidelines are evidence-based. A standard ranking system was used for the strength of the recommendations and the quality of the evidence cited in the literature reviewed. The document has been subjected to external review by peer reviewers as well as by the Practice Guidelines Committee and was approved by the IDSA Council. An executive summary, algorithms, and tables highlight the major recommendations. The guideline will be listed on the IDSA home page at http://www.idsociety.org.

Adult↗