The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines.

Farnesyl transferase inhibitors (FTIs) target signal-transduction pathways responsible for the proliferation and survival of hematologic malignancies, including acute myelogenous leukemias (AML). Lonafarnib has been shown to be a potent inhibitor of Pgp-mediated drug efflux. On the basis of these findings, we examined the Pgp-inhibitory properties of tipifarnib and assessed its activity when combined with anthracyclines. The effects of tipifarnib on cell proliferation, induction of apoptosis and inhibition of Pgp-mediated anthracycline efflux were analyzed in two human leukemia cell lines overexpressing Pgp (CCRF-CEM and KG1a). Measurement of residual daunorubicin (DNR)-mediated fluorescence after incubation with DNR and tipifarnib demonstrated that tipifarnib significantly inhibited DNR efflux in CCRF-CEM with an IC(50) value less than 0.5 microM. Proliferation and apoptosis assays after exposure to DNR in the presence or absence of tipifarnib demonstrated synergistic inhibition of cellular proliferation, and induction of apoptosis with the combination of tipifarnib and DNR. Similar data was obtained with an enantiomer of tipifarnib that possesses no FTI activity. Incubation with tipifarnib and DNR did not interfere with inhibition of the post-translational processing of HDJ-2. These data suggest that tipifarnib possesses Pgp-inhibitory activity in addition to its FTI activity. In high risk and refractory patients these properties may be exploited as a dual targeting mechanism in the therapy of AML.     

Localized monocyte chemotactic protein-1 production correlates with T cell infiltration of synovium in patients with psoriatic arthritis

OBJECTIVE: To examine normal and psoriatic skin and synovial tissue from patients with psoriatic arthritis (PsA) for evidence of monocyte chemotactic protein-1 (MCP-1) mediated T cell chemotaxis. METHODS: Peripheral blood (PB), synovial fluid (SF), normal and psoriatic skin, and synovial biopsies were obtained from patients with PsA (n = 19) and compared to samples from normal (n = 5) and disease (n = 5) controls (NC, DC). Immune cell populations in PB and SF samples were assessed by immunofluorescent labeling and flow cytometry, levels of soluble MCP-1 were determined by quantitative ELISA, and immunohistochemistry was used to detect T cell subsets and macrophages and MCP-1 protein in frozen skin and synovial tissue sections. RESULTS: CD8+ but not CD4+ T cells were elevated in SF compared to PB, and the majority of these cells expressed CD45RO. Plasma MCP-1 levels in PsA were elevated relative to NC. MCP-1 levels were significantly higher than paired plasma samples in patients with recent onset (< 6 mo) synovitis (n = 10). A positive correlation was observed between synovial T cell numbers and MCP-1 levels in SF. MCP-1 protein was present in all tissues examined, but most intense expression was observed in synovium. CONCLUSION: Elevated concentrations of MCP-1 concomitant with memory T cell infiltration in PsA SF suggests that MCP-1 mediated chemotaxis is involved in the recruitment of T lymphocytes into the synovial compartment of patients with PsA.     

Thrombosis in patients with connective tissue diseases treated with specific cyclooxygenase 2 inhibitors. A report of four cases

Specific inhibitors of cyclooxygenase 2 (COX-2) have been approved for the treatment of osteoarthritis and rheumatoid arthritis. Unlike nonsteroidal anti-inflammatory drugs, specific COX-2 inhibitors do not inhibit platelet activation. However, these agents significantly reduce systemic production of prostacyclin. As a result, theoretical concerns have been raised that specific COX-2 inhibitors could shift the hemostatic balance toward a prothrombotic state. Patients with connective tissue diseases (CTD), who may be predisposed to vasculopathy and thrombosis, often have arthritis or pain syndromes requiring treatment with antiinflammatory agents. Herein we describe 4 patients with CTD who developed ischemic complications after receiving celecoxib. All patients had a history of Raynaud's phenomenon, as well as elevated anticardiolipin antibodies, lupus anticoagulant, or a history compatible with antiphospholipid syndrome. It was possible to measure a urinary metabolite of thromboxane A2 in 2 of the patients as an indicator of in vivo platelet activation, and this was markedly elevated in both. In addition, the patients had evidence of ongoing inflammation as indicated by elevated erythrocyte sedimentation rate, hypocomplementemia, and/or elevated levels of anti-DNA antibodies. The findings in these 4 patients suggest that COX-2 inhibitor-treated patients with diseases that predispose to thrombosis should be monitored carefully for this complication.     

Risk of enteric infection associated with child day care

Pediatricians may advise parents that diarrhea is a frequent occurrence among infants and toddlers in day care and that diarrhea is usually mild and self-limited. A child newly enrolled in a day-care facility is at a particularly high risk for developing a diarrheal illness within the first month after enrollment, but the risk has been found to decrease as children remain in the same setting. Children who have diarrhea, fever, or vomiting of infectious origin should be isolated from well children. Infants and toddlers may return to the day-care environment when their diarrhea subsides and they are feeling well. Transmission of enteric infection from the child attending day-care center to other members of the family is possible; therefore, family members should also routinely practice good hygiene. Child-care providers should enforce written guidelines that establish hygienic practices and outline the management of ill children. Parents should be encouraged to read these policies and observe practices within the child-care setting before deciding to enroll their child in any care setting. The National Standards for out-of-home child care scheduled for release in 1991 will be important reading and a comprehensive reference for pediatricians who choose to be a child health consultant to one or more day-care facilities.     

Perinatal cocaine effects on neonatal stress behavior and performance on the Brazelton Scale

Fifty-two newborns were assessed for the effects of maternal cocaine use on their performance on the Brazelton Neonatal Behavior Assessment Scale and on their stress behaviors during the Brazelton as tapped by the Neonatal Stress Scale. The cocaine-exposed newborns experienced more obstetric complications, had smaller head circumferences, showed more limited habituation abilities on the Brazelton Scale, and exhibited more stress behaviors than control newborns.     

The influence of spontaneous accelerations of fetal heart rate on umbilical artery velocity waveforms

For clinical interpretation of Doppler waveforms, it is important to establish the extent to which fetal heart rate changes affect the umbilical artery velocity waveform. Umbilical artery waveforms were measured with continuous wave ultrasonography during spontaneous accelerations of the fetal heart rate in 20 uncomplicated, near-term pregnancies. On average, an acceleration of 20 beats/min of fetal heart rate within an individual was associated with a reduction in the systolic/diastolic velocity ratio of 0.25. There was, however, considerable variability in the response, and in six patients the systolic/diastolic ratio actually increased with heart rate. We conclude that fetal heart accelerations within the normal range cause only small and variable changes in the systolic/diastolic ratio.     

Empowering communities to remove the pump handle. An emerging role in epidemiology

PURPOSE: The epidemiologist's role in relation to the populations they study needs to be reconsidered in order to maximize the contribution of epidemiology to public health, and to balance science with social responsibility.METHODS: Historical analysis and a case study of community-based, collaborative epidemiology conducted in Eastern Virginia as the basis for identifying and improving child health outcomes.RESULTS: The origins of epidemiology in Snow's work on cholera provides a dynamic model of etiologic research combined with community intervention to prevent disease. While in past decades, epidemiology was excessively objectivist and focused on identifying individual-level risk factors, epidemiologists are now reclaiming a vital role in community health promotion. Yet the historic role of the epidemiologist, whether as the white knight who saves the community from an epidemic, or alternatively, as the remote scientist who studies populations but bears no responsibility for improving their health, is no longer viable. The emerging role is that of collaborator, a scientist working in partnership with communities. In Eastern Virginia, academic epidemiologists work closely with diverse community-based coalitions to assess child health needs, prioritize health problems, design and enact interventions, and monitor health outcomes. Diagnostic studies of child health outcomes, published in peer-reviewed journals and in community reports, have identified serious health needs in Eastern Virginia, e.g., under-immunization, attention deficit hyperactivity disorder, asthma, and adverse perinatal health indicators. Epidemiologic research is being used to guide interventions planned and enacted by the community, with evidence of improved outcomes in certain indicators.CONCLUSIONS: A vitally important, emerging role for epidemiologists in the 21(st) century is to empower communities to identify and effectively address their own health needs. Epidemiologic data not only evaluates health status, but should be used to guide community action.     

A comparison of herpes simplex virus specific antibodies found in human milk and serum.

It is not known if milk antibody protects infants from herpes simplex virus (HSV) infection. As a first step to test this hypothesis, anti-HSV antibodies were studied in human milk. Paired serum and milk samples were analyzed for anti-HSV antibodies by ELISA, Western blot analysis (WBA), neutralization (NT) plaque assay, and antibody-dependent cellular cytotoxicity (ADCC) assay. Nineteen of the 20 serum samples showed anti-HSV activity by ELISA and ADCC, and 18 showed activity by WBA and NT. We found a significant association between the immunoassays for detection of anti-HSV antibodies in sera. Fewer of the human milk samples showed anti-HSV activity; only one milk sample was positive by ELISA and one by NT assay, four by ADCC and 12 by WBA. The milk sample from the seronegative donor was also negative. We found a poor association of antibody titers in human milk and serum antibody titers using ELISA, NT, and ADCC assays. There was a significant (p = 0.022) association between serum and milk results using WBA. Among the four assays, WBA was the most sensitive for antibody detection. It will be used in an on-going prospective study to determine the role of anti-HSV antibody in the protection against HSV infections in infants.     

Cardiac electromechanical dissociation in the hypoxic fetal sheep may have clinical implications.

OBJECTIVES: Our purpose was to determine the sequence of fetal cardiac electrical and mechanical events associated with acute hypoxic acidemia and to correlate those events with terminal fetal heart rate patterns preceding fetal death. STUDY DESIGN: Eight acutely catheterized fetal sheep were rendered hypoxic by placental embolization with microspheres until fetal death occurred. The fetal electrocardiogram, Doppler cardiogram, left ventricular and aortic pressures, and fetal heart rate were continuously recorded. RESULTS: All eight fetuses showed a terminal bradycardia consisting of two phases: an initial phase of falling ventricular pressures, culminating in mechanical asystole, and a subsequent phase after asystole during which the electrocardiographic signal persisted for an average duration of 15.2 +/- 8.7 minutes (range 3.1 to 32.4) and triggered a Hewlett-Packard 8040A monitor to show a heart rate pattern. CONCLUSIONS: The phenomenon of cardiac electromechanical dissociation may be occurring during similar terminal bradycardias that are observed in human labor and explains the delivery of a fresh stillbirth in spite of the recording of an electrocardiographic signal from a scalp electrode.