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Biomedical subjects

E Fox

Publications and source records attributed to E Fox.

At least 19 recordsLinked to original sources
PubMed2001

Plasma pharmacokinetics and cerebrospinal fluid penetration of hypericin in nonhuman primates.

UNLABELLED: Hypericin, a polycyclic aromatic dianthroquinone, is a natural pigment derived from the plant Hypericum perforatum (St John's Wort). The compound has been synthesized and shown to inhibit the growth of malignant glioma cell lines in vitro via inhibition of protein kinase C. Oral hypericin has entered clinical trials in adults with recurrent malignant glioma. PURPOSE: The present study was performed to characterize the plasma pharmacokinetics (PK) and cerebrospinal fluid (CSF) penetration of hypericin in nonhuman primates. METHODS: Hypericin was administered as an intravenous bolus dose of 2 mg/kg (n = 3) or 5 mg/kg (n = 1). Plasma and CSF (ventricular or lumbar) were sampled prior to administration and at frequent intervals for up to 50 h after administration of the drug. Hypericin concentrations in plasma and CSF were determined using a specific reverse-phase HPLC assay. RESULTS: Mean peak plasma concentration of hypericin following the 2 mg/kg dose was 142 +/- 45 microM. Elimination of hypericin from plasma was biexponential, with an average alpha half-life of 2.8 +/- 0.3 h and average terminal half-life of 26 +/- 14 h. CONCLUSIONS: The 2 mg/kg dose in the nonhuman primate was sufficient to maintain plasma concentrations above 10 microM (the in vitro concentration required for growth inhibition of human glioma cell lines) for up to 12 h. No hypericin was detected in the CSF of any animal (lower limit of detection 0.1 microM); the CSF penetration is therefore less than 1%. A severe dose-limiting photosensitivity skin rash was seen at the 5 mg/kg dose level.

Animals↗
PubMed2001

Functional analysis of patient-derived mutations in the Fanconi anemia gene, FANCG/XRCC9.

OBJECTIVE: Fanconi anemia (FA) is an autosomal-recessive cancer susceptibility syndrome with seven complementation groups. Six of the FA genes have been cloned (corresponding to subtypes A, C, D2, E, F, and G) and the encoded proteins interact in a common pathway. Patient-derived mutations in FA genes have been helpful in delineating functional domains of FA proteins. The purpose of this work was to subtype FA patient-derived cell lines in our repository and to identify FA gene mutations. METHODS: We subtyped 62 FA patients as type A, G, C, or non-ACG by using a combination of retroviral gene transfer and immunoblot analysis. Among these FA patients, we identified six FA-G patients for further analysis. We used a strategy involving amplification of FANCG/XRCC9 exons and direct sequencing to identify novel FANCG mutations in cell lines derived from these FA-G patients. We functionally analyzed FANCG mutant alleles by transducing the corresponding cDNAs into a known FA-G indicator cell line and scoring correction of MMC sensitivity. RESULTS: Our results demonstrate a wide range of mutations in the FANCG gene (splice, nonsense, and missense mutations). Based on this mutational screen, a carboxy terminal functional domain of the FANCG protein appears to be required for complementation of FA-G cells and for normal assembly of the FANCA/FANCG/FANCC protein complex. CONCLUSION: The identification of patient-derived mutant alleles of FA genes can provide important insights to the function of FA proteins. FA subtyping is also a necessary precondition for gene therapy.

Adolescent↗
PubMed2001

Probe calibration in transient microdialysis in vivo.

PURPOSE: We examine the theoretical basis for calibrating microdialysis probes in vivo for pharmacokinetic experiments in which the extracellular analyte concentrations vary in time. METHODS: A software package, MICRODIAL. was used to simulate microdialysis for illustrative transient situations with linear concentration dependence. RESULTS: For a constant distant extracellular analyte concentration. the calibration factor (extraction fraction, Ed) exhibits a mass transfer transient associated with the development of spatial concentration profiles within the tissue and the probe. Processes clearing the analyte from the extracellular fluid (ECF) strongly influence the rapidity of approach to steady-state and affect the magnitude of the steady-state calibration factor, Ess(d). For situations in which the distant ECF concentration varies in time as a result of exchange with the plasma compartment, different time profiles of the distant ECF and plasma concentrations yield different transient E(d). For the linear, transient cases examined, the area-under-the-curve (AUC 0-infinity) time integral of the distant ECF concentration was found to be proportional to the outflow dialysate concentration-time integral with Ess(d) being the proportionality constant. CONCLUSIONS: The options for calibrating microdialysis probes in solid tissues appear limited under non-steady state conditions; however, AUC integrals for linear systems may be determined by continuous microdialysis sampling and steady-state probe calibration approaches.

Algorithms↗
PubMed2001

Inhibitory effects of repeating color and shape: inhibition of return or repetition blindness?

There is a current debate regarding whether attention is influenced by stimulus attributes other than location. The present article replicates and extends previous findings that repeating the nonspatial attribute of color leads to a delay in target detection (M. B. Law, J. Pratt, & R. A. Abrams, 1995). Repetition disadvantage effects were found for the stimulus attributes of both color and shape, as well as for location. However, the nonspatial repetition disadvantage disappeared if the stimuli were presented in peripheral locations (Experiments 3a, 3b, and 4) or the cue was presented for 50 ms (Experiment 6). Moreover, the magnitude of the repetition disadvantage tended to decline as the cue-target stimulus-onset asynchrony increased (Experiments 5a, 5b, and 6). These results suggest that a repetition blindness mechanism may underlie the repetition disadvantage effects of nonspatial features, rather than an inhibition of return mechanism.

Adolescent↗
PubMed2001

Validity of pulp-to-palm distance as a measure of finger flexion.

This study investigated the validity of pulp-to-palm distance measures as clinical indicators of finger flexion capacity. Pulp-to-palm distance and goniometry of the metacarpophalangeal, proximal interphalangeal and distal interphalangeal joints were measured by a single tester in 50 patients with abnormal digital flexion using a computerized hand assessment system. The correlation between pulp-to-palm distance measurements and total finger flexion measures obtained by goniometry, was moderate (r=-0.46 and -0.51). This indicates that the measures are not interchangeable. The relationship between an upper extremity disability score (DASH) and restricted motion was stronger for the goniometric measurements (r=0.45, P<0.01) than for the pulp-to-palm distance measurements (r<0.30, P>0.01). Both types of range of motion measurements were able to discriminate between minimal and substantial upper extremity disability. Further methodological evaluation is required to support the use of pulp-to-palm distance measures as an outcome indicator.

Adult↗
PubMed2001

Do threatening stimuli draw or hold visual attention in subclinical anxiety?

Biases in information processing undoubtedly play an important role in the maintenance of emotion and emotional disorders. In an attentional cueing paradigm, threat words and angry faces had no advantage over positive or neutral words (or faces) in attracting attention to their own location, even for people who were highly state-anxious. In contrast, the presence of threatening cues (words and faces) had a strong impact on the disengagement of attention. When a threat cue was presented and a target subsequently presented in another location, high state-anxious individuals took longer to detect the target relative to when either a positive or a neutral cue was presented. It is concluded that threat-related stimuli affect attentional dwell time and the disengage component of attention, leaving the question of whether threat stimuli affect the shift component of attention open to debate.

Adolescent↗
PubMed2000

Transmitral Doppler: a new transthoracic contrast method for patent foramen ovale detection and quantification.

OBJECTIVES: This study compared a new transthoracic echocardiographic (TTE) method for detection of right to left bubble passage, transmitral Doppler (TMD), against two-dimensional (2D) TTE contrast study and the gold standard, of transesophageal echocardiography (TEE), and assessed its utility in quantitative assessment of patent foramen ovales (PFO). BACKGROUND: Current TTE methods are relatively insensitive in PFO detection and do not allow quantitative assessment of right to left shunt. METHODS: In 44 patients (59 years, range 34 to 76 years) saline contrast and color Doppler studies were performed in three conditions--TTE TMD, TTE 2D and TEE. Bubble transit on the TMD was measured semiquantitatively by a visual bubble score and objectively by integrating the acoustic power within the mitral velocity envelope. RESULTS: By TEE it was determined that 17 patients (39%) had PFOs; 16 had right to left contrast passage, and only 1 had left to right flow by color Doppler. Against TEE contrast study, the sensitivity of TMD and 2D contrast studies were 100% and 75%, respectively, with specificity of 96% and 100%. Greater than 10 bubbles on a single beat of the resting contrast TMD identified patients with a maximum resting TEE PFO opening diameter >2 mm with 78% sensitivity and 100% specificity. There was a strong correlation (r2 = 0.72, p<0.01) between the TMD acoustic power and PFO opening diameter. CONCLUSIONS: Transmitral Doppler is a sensitive and specific method for TTE PFO detection that allows quantification of right to left bubble passage and may obviate the need for TEE in many patients after stroke.

Adult↗
PubMed2000

The role of perceptual load in negative priming.

Negative priming (NP) effects from irrelevant distractors were assessed as a function of perceptual load in the processing of prime targets. Participants searched for a target letter among a varying number of nontarget letters in the center of the display and ignored an irrelevant peripheral distractor. NP from this distractor was found to depend on the relevant search set size, decreasing as this set size was increased. The authors conclude that exhausting attention in relevant processing reduces irrelevant processing (e.g., N. Lavie, 1995), leaving less distractor processing to produce NP. This conclusion is consistent with recent reactive inhibition views for NP (e.g., G. Houghton, S. P. Tipper, B. Weaver, & D. I. Shore, 1996).

Attention↗
PubMed2000

Target selection difficulty, negative priming, and aging.

It has been recently suggested that the presence of identity negative priming effects in old adults could occur when there is substantial processing of the distracting information in a selective attention task (J. M. Kieley & A. A. Hartley, 1997). In three experiments, using a letter identification task, it was found that making target selection more difficult increased the magnitude of the negative priming effect to a similar extent in both young and old adults. Moreover, the size of the negative priming effect did not differ between young and elderly participants. These results are discussed with respect to the issue of age-related deficits in the mechanisms underlying negative priming.

Adolescent↗
PubMed2000

Rethinking fundamental assumptions: SUPPORT's implications for future reform. Study to Understand Prognoses and Preferences and Risks of Treatment.

BACKGROUND: The intervention in SUPPORT, the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments, was ineffective in changing communication, decision-making, and treatment patterns despite evidence that counseling and information were delivered as planned. The previous paper in this volume shows that modest alterations in the intervention design probably did not explain the lack of substantial effects. OBJECTIVE: To explore the possibility that improved individual, patient-level decision-making is not the most effective strategy for improving end-of-life care and that improving routine practices may be more effective. DESIGN: This paper reflects our efforts to synthesize findings from SUPPORT and other sources in order to explore our conceptual models, their consistency with the data, and their leverage for change. RESULTS: Many of the assumptions underlying the model of improved decision-making are problematic. Furthermore, the results of SUPPORT suggest that implementing an effective intervention based on a normative model of shared decision-making can be quite difficult. Practice patterns and social expectations may be strong influences in shaping patients' courses of care. Innovations in system function, such as quality improvement or changing the financing incentives, may offer more powerful avenues for reform. CONCLUSIONS: SUPPORT's intervention may have failed to have an impact because strong psychological and social forces underlie present practices. System-level innovation and quality improvement in routine care may offer more powerful opportunities for improvement.

Decision Making↗
PubMed2000

Patients who want their family and physician to make resuscitation decisions for them: observations from SUPPORT and HELP. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment. Hospitalized Elderly Longitudinal Project.

OBJECTIVE: To determine the extent to which older or seriously ill inpatients would prefer to have their family and physician make resuscitation decisions for them rather than having their own stated preferences followed if they were unable to decide themselves. DESIGN: Analysis of existing data from the Hospitalized Elderly Longitudinal Project (HELP) and the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment (SUPPORT). SETTING: Five teaching hospitals in the United States. PARTICIPANTS: 2203 seriously ill adult inpatients (SUPPORT) and 1226 older inpatients (HELP) who expressed preferences about resuscitation and about advance decision-making. MEASURES: We used a logistic regression model to determine which factors predicted preferences for family and physician decision-making. RESULTS: Of the 513 HELP patients in this analysis, 363 (70.8%) would prefer to have their family and physician make resuscitation decisions for them whereas 29.2% would prefer to have their own stated preferences followed if they were to lose decision-making capacity. Of the 646 SUPPORT patients, 504 (78.0%) would prefer to have their family and physician decide and 22.0% would prefer to have their advance preferences followed. Independent predictors of preference for family and physician decision-making included not wanting to be resuscitated and having a surrogate decision-maker. CONCLUSIONS: Most inpatients who are older or have serious illnesses would not want their stated resuscitation preferences followed if they were to lose decision-making capacity. Most patients in both groups would prefer that their family and physician make resuscitation decisions for them. These results underscore the need to understand resuscitation preferences within a broader context of patient values.

Activities of Daily Living↗
PubMed2000

Pretransfusion testing without serologic crossmatch: approaches to ensure patient safety.

BACKGROUND AND OBJECTIVES: A crossmatch is usual in pretransfusion testing, but we eliminated it at our tertiary care university hospital. In place of the crossmatch, we have introduced a system where, if an antibody screen is negative, two technologists confirm the ABO of the same patient sample, and we release blood of the patient's type without a serologic or electronic crossmatch. MATERIALS AND METHODS: In 65,628 samples received for pretransfusion testing, we studied the effect of common errors that occur from the time of receipt of a sample until release of the blood unit, in order to decide if elimination of the serologic crossmatch would affect patient safety. All sample labels were inspected for acceptability. RESULTS: A total of 1,082 (1.64%) samples were rejected for mislabeling. Discordance in patient ABO typing results between two technologists was 0.43%. Such discrepancies were resolved before the release of blood units. No donor unit mislabeling or unit release errors were detected. CONCLUSION: Elimination of the crossmatch for red cell antibody-negative patients is safe provided a system of error detection is used. This enhances patient care through the quicker release of blood, increased laboratory efficiency and decreased costs.

ABO Blood-Group System↗
PubMed1999

Evaluation of prognostic criteria for determining hospice eligibility in patients with advanced lung, heart, or liver disease. SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments.

CONTEXT: Many individuals involved with care of the dying advocate expanding access to hospice care for persons with advanced lung, heart, or liver disease. However, to be eligible, these patients generally must have a prognosis for survival of less than 6 months. OBJECTIVE: To test the ability of currently available criteria to identify a population with a survival prognosis of 6 months or less among seriously ill hospitalized patients with 1 of 3 commonly fatal chronic diseases. DESIGN: Validation study using data from the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT) phase 1 (June 1989-June 1991) and phase 2 (January 1992-January 1994), with a 6-month follow-up. SETTING AND PATIENTS: Consecutive sample of 2607 seriously ill patients from 5 US medical centers who were hospitalized with chronic obstructive pulmonary disease, congestive heart failure, or end-stage liver disease, and who survived to hospital discharge. MAIN OUTCOME MEASURES: Descriptive and operating characteristics of 5 general and 2 disease-specific clinical criteria for identifying patients with a survival prognosis of 6 months or less, and 3 sets of combination criteria (broad, intermediate, and narrow inclusion) aimed at providing low, medium, and high thresholds for hospice eligibility based on National Hospice Organization guidelines. RESULTS: Seventy-five percent of the sample survived more than 6 months after hospital discharge; 44% expressed a preference for palliative care. Broad inclusion criteria identified 923 patients eligible for hospice care, of whom 70% survived longer than 6 months. Intermediate inclusion criteria identified 300 patients, of whom 65% survived longer than 6 months. Narrow inclusion criteria identified 19 patients, of whom 53% survived longer than 6 months. Sensitivities and specificities of the combination criteria were 41.7% and 66.7% (broad inclusion), 16.2% and 90.1 % (intermediate inclusion), and 1.4% and 99.5% (narrow inclusion), respectively. CONCLUSIONS: These data indicate that for seriously ill hospitalized patients with advanced chronic obstructive pulmonary disease, congestive heart failure, or end-stage liver disease, recommended clinical prediction criteria are not effective in identifying a population with a survival prognosis of 6 months or less.

Adult↗
PubMed1999

Lipid mediated gene delivery in the adult rat brain: quantitative analysis of expression.

Gene transfer into the adult brain is potentially an attractive alternative to commonly employed transgenic approaches. DNA-lipid complexes have been used to obtain brain gene transfer, but data are sparse to indicate to what extent this results in significant expression of functional protein. Here, an expression construct encoding the functional reporter, chloramphenicol-acetyl-transferase (CAT), was complexed to a novel biodegradable lipid, and delivered into the rat brain. CAT-activity was assayed in tissue extracts to allow a precise quantitation of functional enzyme protein. Following bilateral intraventricular (i.c.v.) injection, robust enzyme activity was found in all brain regions studied, peaking at 4 weeks. Other routes of administration, e.g. intra-parenchymal injection or chronic infusion of complexes, resulted in marginal or no activity. Presence of CAT mRNA and plasmid DNA in tissue extracts was confirmed at 4 weeks post i.c.v. administration. In agreement with previous studies, labelled lipid-DNA complexes were mainly found in the ventricular ependyma. Present data support the feasibility of lipid mediated brain gene transfer, and outline some of its anatomical and temporal limitations.

Animals↗
PubMed1999

In vivo studies of gene expression via transient transgenesis using lipid-DNA delivery.

As the sequencing of the human genome proceeds, the need for a new screen for in vivo function is becoming apparent. Many investigators are turning to various transgenic models as a means of studying function. However, these approaches are very time consuming, with a transgene-expressing mouse model often taking months to establish. We have developed an efficient system for delivering genes in vivo, which allows the gene product to be studied as early as 24 h after introduction into the mouse model. The delivery system employs a novel cationic lipid, 1-[2-(9-(Z)-octadecenoyloxy)ethyl]-2-(8-(Z)-heptadecenyl)-3- (hydroxyethyl)imidazolinium chloride (DOTIM), and a neutral lipid, cholesterol, complexed with an expression vector containing the reporter gene chloramphenicol acetyl transferase (CAT). After a single intravenous injection of these complexes, several tissues were seen to express the transgene. High, persistent expression in the vascular endothelial cells in the mouse lung was obtained. Delivery of DNA in vivo has been evaluated by quantitative polymerase chain reaction and protein expression by CAT activity assays. In vivo studies showed reproducible expression in more than 500 mice injected via the tail vein. An early peak of expression was followed by lower, but sustained, expression for > 50 days. Transgene expression of CAT could also be identified by immunohistochemistry staining in mouse lung and appeared to be located within the capillaries. The pattern of in vivo expression could be modulated and targeted to specific organs by altering the lipid-DNA formulation. New expression vectors with altered introns and polyadenylation sites further improved expression. The expression reported here may be sufficient in magnitude, duration, and flexibility to be an attractive alternative, in some cases, to establishing transgenic animals by stable gene transfer.

Animals↗
PubMed1999

Incorporating palliative care into critical care education: principles, challenges, and opportunities.

OBJECTIVE: To identify the goals and methods for medical education about end-of-life care in the intensive care unit (ICU). DATA SOURCES AND STUDY SELECTION: A status report on palliative care, a summary report of recent research on palliative care education, articles in the medical literature on end-of-life care and critical care, and expert opinion were considered. DATA EXTRACTION: A working group, including specialists in critical care, palliative care, medical ethics, consumer advocacy, and communications, was convened at the "Medical Education for Care Near the End of Life National Consensus Conference." A modified nominal group process was used to develop a consensus. DATA SYNTHESIS: In the ICU, life and death decisions are often made in a crisis mode or in the face of uncertainty, and may necessitate the withholding and withdrawal of life-supporting technologies. Because critical illness often diminishes the capacity of patients to make decisions, clinicians must often make decisions in conjunction with surrogates, rather than with patients. Discontinuity of care can threaten trusting relationships, and cultural diversity can have a particularly powerful impact on choices for care. In the face of these realities, it is possible and appropriate to give compassionate palliative care to dying patients and their families in the ICU. CONCLUSIONS: Teaching care of the dying in the ICU should emphasize the following: a) the goals of care should guide the use of technology; b) understanding of prognostication and treatment withholding and withdrawal is essential; c) effective communication and trusting relationships are crucial to good care; d) cultural differences should be acknowledged and respected; and e) the delivery of excellent palliative care is appropriate and necessary when patients die in the ICU.

Attitude to Death↗
PubMed1999

SDQR migrations in Caenorhabditis elegans are controlled by multiple guidance cues and changing responses to netrin UNC-6.

The netrin guidance cue, UNC-6, and the netrin receptors, UNC-5 and UNC-40, guide SDQR cell and axon migrations in C. elegans. In wild-type larvae, SDQR migrations are away from ventral UNC-6-expressing cells, suggesting that UNC-6 repels SDQR. In unc-6 null larvae, SDQR migrations are towards the ventral midline, indicating a response to other guidance cues that directs the migrations ventrally. Although ectopic UNC-6 expression dorsal to the SDQR cell body would be predicted to cause ventral SDQR migrations in unc-6 null larvae, in fact, more migrations are directed dorsally, suggesting that SDQR is not always repelled from the dorsal source of UNC-6. UNC-5 is required for dorsal SDQR migrations, but not for the ventral migrations in unc-6 null larvae. UNC-40 appears to moderate both the response to UNC-6 and to the other cues. Our results show that SDQR responds to multiple guidance cues and they suggest that, besides UNC-6, other factors influence whether an UNC-6 responsive cell migrates toward or away from an UNC-6 source in vivo. We propose that multiple signals elicited by the guidance cues are integrated and interpreted by SDQR and that the response to UNC-6 can change depending on the combination of cues encountered during migration. These responses determine the final dorsoventral position of the SDQR cell and axon.

Animals↗