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Biomedical subjects

K Johnson

Publications and source records attributed to K Johnson.

At least 37 records · Page 2Linked to original sources
PubMed2001

The Trauma Symptom Checklist for Young Children (TSCYC): reliability and association with abuse exposure in a multi-site study.

OBJECTIVE: The Trauma Symptom Checklist for Young Children (TSCYC) is a 90-item caretaker-report measure of children's trauma- and abuse-related symptomatology. It contains two reporter validity scales and eight clinical scales [Post-traumatic Stress-Intrusion (PTS-I), Post-traumatic Stress-Avoidance (PTS-AV), Post-traumatic Stress-Arousal (PTS-AR), Post-traumatic Stress-Total (PTS-TOT), Sexual Concerns (SC), Dissociation (DIS), Anxiety (ANX), Depression (DEP), and Anger/Aggression (ANG)], as well as an item assessing hours per week of caretaker contact with the child. This paper introduces the TSCYC and describes its psychometric properties in a multisite validity study. METHOD: A total of 219 TSCYCs administered by six clinician/researchers across the United States were analyzed for scale reliability and association with several types of childhood maltreatment. RESULTS: The TSCYC clinical scales have good reliability and are associated with exposure to childhood sexual abuse, physical abuse, and witnessing domestic violence. The PTS-I, PTS-AV, PTS-AR, and PTS-TOT scales were most predictive, followed by SC in the case of sexual abuse and DIS in the case of physical abuse. There were a small number of age, sex, and race effects on TSCYC scores. CONCLUSIONS: The TSCYC appears to have reasonable psychometric characteristics, and correlates as expected with various types of trauma exposure. Subject to continued validation and the development of general population norms, its use as a clinical measure is supported.

Anger↗
PubMed2001

NF-kappaB is involved in the survival of cerebellar granule neurons: association of IkappaBbeta [correction of Ikappabeta] phosphorylation with cell survival.

The NF-kappaB transcription factor consists of dimeric complexes belonging to the Rel family, which include p50, p52, p65 (RelA), RelB and c-Rel. NF-kappaB activity is tightly controlled by IkappaB proteins which bind to NF-kappaB preventing its translocation to the nucleus. Activation of NF-kappaB is most often mediated by IkappaB degradation, which permits NF-kappaB to enter the nucleus. We investigated the role of NF-kappaB in the survival of cerebellar granule neurons. We found that survival of these neurons in high potassium medium is blocked by three separate inhibitors of NF-kappaB activity: SN-50, N-tosyl-L-phenylalanine chloromethyl ketone and pyrrolidinedithiocarbamate, indicating that NF-kappaB is required for neuronal survival. Gel-shift assays reveal three complexes that bind to the NF-kappaB binding site in high potassium medium. Switching these cultures to low potassium medium, a stimulus that leads to apoptotic death, causes a reduction in the level of the largest complex, which contains p65. Overexpression of p65 by transfection inhibits low potassium-induced apoptosis, whereas overexpression of IkappaBalpha promotes apoptosis even in high potassium medium. Surprisingly, however, neither the level of endogenous p65 nor that of IkappaBalpha and IkappaBbeta is altered by low potassium treatment. Similarly, no changes are seen in the nuclear or cytoplasmic levels of p50, p52, RelB and c-Rel. Phosphorylation of p65, which can lead to its activation, is unchanged. Phosphorylation of IkappaBbeta is, however, reduced by low potassium treatment. Besides being necessary for high potassium-mediated neuronal survival, NF-kappaB is also involved in the survival-promoting effects of IGF-1 and cAMP as judged by the ability of SN-50 to inhibit the actions of these survival factors and the ability of these factors to inhibit the low potassium-induced alterations in the DNA-binding activity of NF-kappaB. Taken together, our results show that NF-kappaB may represent a point of convergence in the signaling pathways activated by different survival factors and that uncommon mechanisms might be involved in NF-kappaB-mediated survival of cerebellar granule neurons.

Animals↗
PubMed2001

Prevention of ventilator-induced lung injury with partial liquid ventilation.

BACKGROUND/PURPOSE: Pulmonary injury from mechanical ventilation has been attributed to application of excess alveolar pressure (barotrauma) or volume (volutrauma). The authors questioned whether partial liquid ventilation (gas ventilation of the perfluorocarbon filled lung, PLV) would reduce ventilator-induced lung injury. METHODS: A tracheostomy tube and carotid artery catheter were placed in anesthetized Sprague-Dawley rats (500 +/- 50 g). Bovine serum albumin (BSA) labeled with Iodine (I) 125 was administered intraarterially. Ventilation with tidal volume (TV) of 5 mL/kg was initiated. The rats were then selected randomly to a 30-minute experimental period of one of the following ventilation protocols: continued atraumatic gas ventilation (GV, TV, 5 mL/kg; n = 10); atraumatic gas ventilation combined with intratracheal administration of 10 mL/kg perfluorocarbon (GV-PLV, TV, 5 mL/kg, n = 10); barotrauma (BT, peak inspiratory pressure [PIP], 45 cm H(2)O; n = 10); barotrauma with PLV (BT-PLV, PIP, 45 cm H(2)O; n = 8); volutrauma (VT, TV, 30 mL/kg; n = 8); or volutrauma with PLV (VT-PLV, TV, 30 mL/kg; n = 10). Animals were killed and the amount of radiolabeled BSA in both lungs was measured and normalized to the counts in 1 mL of blood from that animal (injury index). Data were analyzed by analysis of variance (ANOVA) with post-hoc t test comparison between groups. RESULTS: There was a significant difference in the (125)I-BSA injury index when all groups were compared (P <.001 by ANOVA). Post-hoc analysis showed a significant decrease in the injury index when comparing BT versus BT-PLV (P =.024) and VT versus VT-PLV (P =.014). CONCLUSION: (125)I-BSA leak produced during high-pressure or high-volume mechanical ventilation is reduced by partial liquid ventilation.

Analysis of Variance↗
PubMed2001

MAPS: a microarray project system for gene expression experiment information and data validation.

SUMMARY: MAPS is a MicroArray Project System for management and interpretation of microarray gene expression experiment information and data. Microarray project information is organized to track experiments and results that are: (1) validated by performing analysis on stored replicate gene expression data; and (2) queried according to the biological classifications of genes deposited on microarray chips.

Computer Communication Networks↗
PubMed2001

Drosophila-raf acts to elaborate dorsoventral pattern in the ectoderm of developing embryos.

In the early Drosophila embryo the activity of the EGF-receptor (Egfr) is required to instruct cells to adopt a ventral neuroectodermal fate. Using a gain-of-function mutation we showed that D-raf acts to transmit this and other late-acting embryonic Egfr signals. A novel role for D-raf was also identified in lateral cell development using partial loss-of-function D-raf mutations. Thus, we provide evidence that zygotic D-raf acts to specify cell fates in two distinct pathways that generate dorsoventral pattern within the ectoderm. These functional requirements for D-raf activity occur subsequent to its maternal role in organizing the anterioposterior axis. The consequences of eliminating key D-raf regulatory domains and specific serine residues in the transmission of Egfr and lateral epidermal signals were also addressed here.

Animals↗
PubMed2001

Unexpected effects of a heterozygous dnmt1 null mutation on age-dependent DNA hypomethylation and autoimmunity.

DNA methylation modifies gene expression. Methylation patterns are established during ontogeny, but they change with aging, usually with a net decrease in methylation. The significance of this change in T cells is unknown, but it could contribute to autoimmunity, senescence, or both. We examined the effects of a null mutation in DNA methyltransferase 1 (Dnmt1), a gene maintaining DNA methylation patterns, on immune aging. Whereas aged control mice developed hypomethylated DNA, autoimmunity, and signs of immune senescence as predicted, the knockout mice surprisingly increased DNA methylation and developed signs of autoimmunity and senescence more slowly. To identify potential mechanisms, we compared transcripts of DNA methyltransferase and methylcytosine binding protein family members in control and knockout mice. MeCP2, a methylcytosine binding protein involved in gene suppression and chromatin inactivation, was the only transcript differentially expressed between old knockout mice and controls, and thus it is a candidate for a gene product mediating these effects.

Aging↗
PubMed2001

New technologies in the assessment of hemodynamic parameters.

Pulmonary artery catheter (PAC) use has led to major advances in the assessment of hemodynamics. Since its introduction three decades ago, features have been added to the PAC to enhance its hemodynamic monitoring capabilities. In addition, newer technologies have been proposed to replace the PAC. This article discusses three features that enhance the PAC--measures of mixed venous oxyhemoglobin, right ventricular ejection fraction, and continuous cardiac output--and two newer technologies--esophageal Doppler and exhaled carbon dioxide measurements. The article describes current and future applications of hemodynamic monitoring.

Blood Gas Analysis↗
PubMed2001

Reliability of information collected by proxy in family studies of Alzheimer's disease.

The study evaluated the reliability of data obtained from proxy informants. The index subjects in this study were 81 nondemented participants in the Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) study. These index subjects and 159 proxy informants, identified by the index subjects, participated in the study. The kappa statistic with multiple raters per subject (for dichotomous variables) and the intraclass correlation coefficient (for continuous variables) were used to measure reliability. Among proxy respondents who provided answers, there was excellent agreement between proxy responses and the responses of the index subjects (0.7 < or = kappa < or =0.9), with the exception of questions about head injury (kappa = 0.4). A large proportion (>90%) of the proxy informants in this study were able to provide information on most items. Higher nonresponse rates (as high as 30%) were observed for medication history and women's health questions. This study supports the reliability of proxy responses for most categories of questions that are elicited in typical epidemiological studies, including the MIRAGE study.

Aged↗
PubMed2001

Glatiramer acetate induces a Th2-biased response and crossreactivity with myelin basic protein in patients with MS.

Glatiromer acetate (GA) is an approved treatment for multiple sclerosis (MS). The proposed mechanism of action is the induction of GA-specific T cells characterized by protective anti-inflammatory Th2 response. We tested this hypothesis in 11 MS patients treated with GA from 1-19 months. Interferon-gamma and IL-5 (markers of Th1 and Th2 responses respectively) were assayed by ELISA in GA-specific T-cell lines (TCL) supernatants. Th1/Th2 bias was defined based on the ratio of IFN-gamma/IL-5 secretion. Fifty-eight pre-treatment and 75 on-treatment GA-specific TCL were generated. On-treatment mean IL-5 levels in GA-TCL increased significantly, whereas those for IFN-gamma were markedly reduced. Consequently, the ratio of IFN-gamma IL-5 also shifted in favor of a Th2 response. The percentage of GA-TCL classified as Th1 was decreased, whereas those classified as Th2 increased on-treatment as compared to pre-treatment. Some GA-specific TCL, (approximately 25%) generated during treatment secreted predominantly IL-5 in response to MBP and the immunodominant MBP peptide 83-99, indicating that these crossreactive antigens can act as partial agonists for GA-reactive TCL. These results strongly suggest that the mechanism of action of GA in MS involves the induction of crossreactive GA-specific T cells with a predominant Th2 cytokine profile.

Cell Line↗
PubMed2001

Autoreactive murine Th1 and Th2 cells kill syngeneic macrophages and induce autoantibodies.

D10 cells, a cloned Th2 line, become autoreactive following treatment with DNA methylation inhibitors like 5-azacytidine (5-azaC), and induce anti-DNA antibodies if injected into unirradiated syngenic mice. The mechanism by which the autoreactive cells break tolerance is unknown. To further define effector functions required, we asked if 5-azaC-treated Th1 cells could also induce autoimmunity. AE7 cells, a cloned Th1 line, were treated with 5-azaC and shown to become autoreactive and induce anti-DNA antibodies in vivo. Comparison of effector mechanisms demonstrated that the two cell lines secreted a distinct repertoire of cytokines, and that only killing of syngeneic Mø was common to both AE7 and D10 cells. This suggests that Mø killing may be an early step in the induction of anti-DNA antibodies, providing antigenic nucleosomes and decreasing clearance of apoptotic material. Secretion of cytokines promoting B cell differentiation may play a role, but no one cytokine is required.

Animals↗
PubMed2001

Surrogate markers of antitumor responses: in vitro activation of T cells by autologous tumor peptides.

The increasing ability to augment antitumor immunity in model systems has led to increased numbers of clinical trials. However, progress in detecting immune responses by patients against autologous tumors has been slow. Although a considerable number of tumor antigens, as well as peptides derived from them, and the MHC determinants together with which they are presented have been identified for melanoma, this is not so for the majority of solid tumors. Furthermore, tumor cells themselves are poor stimulators of immunity. Thus, approaches that do not depend upon defined antigens or using tumor cells as stimulators would be desirable. To attempt to measure immune responses in these situations, we tested whether total peptides, prepared from autologous tumor tissue, stimulated cytokine release by T cells. Peripheral blood mononuclear cells (PBMCs) were mixed with antigen-presenting cells (APCs), pulsed with tumor peptides, and tested in the ELISPOT assay for IFN-gamma secretion. Few spots were obtained when PBMCs were cultured with unpulsed APCs or in wells with peptide-pulsed APC alone. In contrast, a strong response was seen when PBMCs were cultured with APCs that had been pulsed with autologous total tumor peptides. This system should help to identify those immunotherapeutic approaches that induce responses against tumor cells in vivo. Because different cytokine profiles are associated with distinct arms of the immune response, testing in the ELISPOT assay may also help us understand the mechanisms responsible.

Antigen-Presenting Cells↗
PubMed2001

Recent rheumatoid arthritis clinical trials using radiographic endpoints--updated research agenda.

Recent randomized controlled trials of traditional and newly developed therapies provide evidence that we have interventions that potentially slow or prevent structural damage in active rheumatoid arthritis, as measured using radiography. These trials also provide a unique opportunity for exploratory data analysis to generate hypotheses apropos the pathogenesis and determinants of radiographic progression and functional disability; they also facilitate further study of the methodological issues regarding imaging measurement.

Arthritis, Rheumatoid↗
PubMed2001

Robustness and generalizability of smallest detectable difference in radiological progression.

The smallest detectable difference (SDD) reflects that component of a measure statistically attributable to error from the measurement process itself. As such it is an irreducible component of the inherent variability in measurements in clinical trials and will affect their design, whether randomized or observational. Even though the application of the SDD concept to assaying radiographs in rheumatoid arthritis is relatively new and not well understood, systematic work on the influences of radiographic SDD can be done. This report describes the effects of a number of clinical aspects of the disease and operational aspects of trials on the values of the SDD of radiographic progression data. We show that if conditions affecting SDD are known and kept constant across datasets, the SDD of radiological progression from one study may be generalizable to other studies. However, if any one condition varies, the SDD is distinctly unrobust and cannot be generalized to other studies.

Arthritis, Rheumatoid↗
PubMed2001

A proposal for developing a large patient population cohort for longterm safety monitoring in rheumatoid arthritis. OMERACT Drug Safety Working Party.

This paper proposes the creation of an objectively acquired reference database to more accurately characterize the incidence and longterm risk of relatively infrequent, but serious, adverse events. Such a database would be maintained longitudinally to provide for ongoing comparison with new rheumatologic drug safety databases collecting the occurrences and treatments of rare events. We propose the establishment of product-specific registries to prospectively follow a cohort of patients with rheumatoid arthritis (RA) who receive newly approved therapies. In addition, a database is required of a much larger cohort of RA patients treated with multiple second line agents of sufficient size to enable case-controlled determinations of the relative incidence of rare but serious events in the treated (registry) versus the larger disease population. The number of patients necessary for agent-specific registries and a larger patient population adequate to supply a matched case-control cohort will depend upon estimates of the detectability of an increased incidence over background. We suggest a system to carry out this proposal that will involve an umbrella organization, responsible for establishment of this large patient cohort, envisioned to be drawn from around the world.

Adverse Drug Reaction Reporting Systems↗
PubMed2001

Phase I trial of 96-hour continuous infusion of dexrazoxane in patients with advanced malignancies.

Dexrazoxane is a bidentate chelator of divalent cations. Pretreatment with short infusions of dexrazoxane prior to bolus doxorubicin has been shown to lessen the incidence and severity of anthracycline-associated cardiac toxicity. However, because of rapid, diffusion-mediated cellular uptake and the short plasma half-life of dexrazoxane, combined with prolonged cellular retention of doxorubicin, dexrazoxane may be more effective when administered as a continuous infusion. Thus, a Phase I pharmacokinetic trial of a 96-h infusion of dexrazoxane was performed. Dexrazoxane doses were escalated in cohorts of 3 to 6 patients per dose level. All patients received granulocyte-colony stimulating factor at a dose of 5 microg/kg/day starting 24 h after completion of the dexrazoxane infusion. Plasma samples were collected and analyzed for dexrazoxane by high-performance liquid chromatography. Urine collections were performed at baseline and during the infusion to determine the renal clearance of dexrazoxane and the excretion rate of divalent cations. Twenty-two patients were enrolled at doses ranging from 125 to 250 mg/m(2)/day. Grade 3 and 4 toxicities included grade 4 thrombocytopenia in 2 patients treated at 250 mg/m(2)/day, grade 3 thrombocytopenia and grade 4 nausea and vomiting in 1 patient treated at 221 mg/m(2)/day, grade 4 diarrhea and grade 3 nausea and vomiting in 1 patient treated at 221 mg/m(2)/day, and grade 3 hypertension in 1 patient treated at 166.25 mg/m(2)/day. Steady-state dexrazoxane levels ranged from 496 microg/l (2.2 microM) to 1639 microg/l (7.4 microM). Dexrazoxane plasma CL(ss) and elimination t(1/2) were 7.2 +/- 1.6 l/h/m(2) and 2.0 +/- 0.8 h, respectively. The mean percentage of administered dexrazoxane recovered in the urine at steady state was 30% (range, 10-66%). Urinary iron and zinc excretion during the dexrazoxane infusion increased in 12 of 18 and 19 of 19 patients by a median of 3.7- and 2.4-fold, respectively. These results suggest that dexrazoxane as a 96-h infusion can be safely administered with granulocyte-colony stimulating factor at doses that achieve plasma levels that have been demonstrated previously to inhibit topoisomerase II activity and to induce apoptosis in vitro. Additional studies will be required to determine whether the combination of continuous infusions of dexrazoxane and doxorubicin would provide enhanced cardioprotection compared with the currently recommended bolus or short infusion schedules.

Aged↗