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At least 523 records · Page 29Linked to original sources
PubMed2005

Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa Double A beta in human A betaPP transgenic mice.

Cerebral amyloid angiopathy (CAA) is a prominent pathological feature of Alzheimer's disease and related familial CAA disorders. However, the mechanisms that account for the cerebral vascular accumulation of amyloid beta-peptide (A beta) have not been defined. Recently, we reported novel transgenic mice (Tg-SwDI) expressing neuronally derived Swedish/Dutch/Iowa vasculotropic mutant human A beta precursor (A betaPP) that develop early-onset and robust accumulation of fibrillar cerebral microvascular A beta. Deficient clearance of Dutch/Iowa mutant A beta from brain across the capillary blood-brain barrier into the circulation may contribute to its potent cerebral accumulation. To further evaluate this theory, we generated a new transgenic mouse (Tg-Sw) that is nearly identical to Tg-SwDI, except lacking the Dutch/Iowa A beta mutations. Tg-Sw and Tg-SwDI mice expressed comparable levels of human A betaPP in brain and not in peripheral tissues. However, Tg-SwDI mice strongly accumulated Dutch/Iowa mutant A beta in brain, particularly in the cerebral microvasculature, whereas Tg-Sw mice exhibited no accumulations of wild-type A beta. Conversely, Tg-SwDI mice had no detectable Dutch/Iowa mutant A beta in plasma whereas Tg-Sw mice exhibited consistent levels of human wild-type A beta in plasma. Together, these findings suggest that while wild-type A beta is readily transported out of brain into plasma, Dutch/Iowa mutant A beta is deficient in this clearance process, likely contributing to its robust accumulation in the cerebral vasculature.

Age of Onset↗
PubMed2004

Discrete state analysis for interpretation of data from clinical trials.

OBJECTIVE: The objective of this study was to demonstrate a multivariate health state approach to analyzing complex disease data that allows projection of long-term outcomes using clustering, Markov modeling, and preference weights. SUBJECTS: We studied patients hospitalized 30 to 364 days with refractory schizophrenia at 15 Veterans Affairs medical centers. STUDY DESIGN: We conducted a randomized clinical trial comparing clozapine, an atypical antipsychotic, and haloperidol, a conventional antipsychotic. METHODS: Health status instruments measuring disease-related symptoms and drug side effects were administered in face-to-face interviews at baseline, 6 weeks, and quarterly follow-up intervals for 1 year. Cost data were derived from Veterans Affairs records supplemented by interviews. K-means clustering was used to identify a small number of health states for each instrument. Markov modeling was used to estimate long-term outcomes. RESULTS: Multivariate models with 7 and 6 states, respectively, were required to describe patterns of psychiatric symptoms and side effects (movement disorders). Clozapine increased the proportion of clients in states characterized by mild psychiatric symptoms and decreased the proportion with severe positive symptoms but showed no long-term benefit for negative symptoms. Clozapine dramatically increased the proportion of patients with no movement side effects and decreased incidences of mild akathisia. Effects on extrapyramidal symptoms and tardive dyskinesia were far less pronounced and slower to develop. Markov modeling confirms the consistency of these findings. CONCLUSIONS: Analyzing complex disease data using multivariate health state models allows a richer understanding of trial effects and projection of long-term outcomes. Although clozapine generates substantially fewer side effects than haloperidol, its impact on psychiatric aspects of schizophrenia is less robust and primarily involves positive symptoms.

Antipsychotic Agents↗
PubMed1997

Maintenance nortriptyline effects on electroencephalographic sleep in elderly patients with recurrent major depression: double-blind, placebo- and plasma-level-controlled evaluation.

Our aim was to contrast the effects of maintenance nortriptyline and placebo on electroencephalographic sleep measures in elderly recurrent depressives who survived 1-year without recurrence of depression. Patients on nortriptyline took longer to fall asleep and did not maintain sleep better than patients on placebo; however, maintenance nortriptyline was associated with more delta-wave production and higher delta-wave density in the first non-REM (NREM) period relative to the second. Nortriptyline levels were positively but weakly related to all-night delta-wave production during maintenance (accounting for 6.6% of the variance in delta-wave counts). Total phasic REM activity increased 100% under chronic nortriptyline relative to placebo, with a robust increase in the rate of REM activity generation across the night. Effective long-term pharmacotherapy of recurrent major depression is associated with enhancement in the rate of delta-wave production in the first NREM period (i.e., delta sleep ratio) and of REM activity throughout the night.

Aged↗
PubMed2004

Pretreatment neurophysiological and clinical characteristics of placebo responders in treatment trials for major depression.

RATIONALE: High placebo response rates are a confound in treatment trials for major depressive disorder (MDD). A method for prospective identification of placebo responders could enhance the efficiency of clinical trials. OBJECTIVE: The objective was to identify the neurophysiological, symptomatic, and cognitive characteristics of subjects who were likely to respond to placebo in clinical trials for MDD. METHODS: Fifty-one subjects with MDD were treated in clinical trials with either fluoxetine ( n=24) or venlafaxine ( n=27) versus placebo. All subjects underwent pretreatment assessment with quantitative electroencephalographic (QEEG) power and cordance, as well as symptom ratings and neuropsychological testing. After a 1-week single-blind placebo lead-in, subjects were randomized to double-blind placebo controlled treatment with a medication or placebo. At the end of 8 weeks, the blind was broken and treatment response assessed. Response was defined by a final Hamilton Depression Rating Scale score of </=10. RESULTS: Of the medication-treated and placebo-treated subjects, 52% (13/25) and 38% (10/26) responded. Placebo responders had lower pretreatment frontocentral cordance in the theta frequency band than all other subjects ( P<0.006) and medication responders in particular ( P<0.004). Placebo responders also had faster cognitive processing time, as assessed by neuropsychological testing, and lower reporting of late insomnia ( P<0.03). Exploratory examination of a multiple variable model for predicting placebo response was conducted using logistic regression, in which these three pretreatment measures accurately identified 97.6% of eventual placebo responders. CONCLUSIONS: These findings suggest that combined clinical, neurophysiological, and cognitive assessments of prospective subjects for clinical trials may be useful for identifying MDD subjects who are likely to show robust response to placebo. Prospective validation of these results in a larger, independent sample of subjects is necessary to establish the reliability and usefulness of this method for prospective identification of placebo responders.

Adult↗
PubMed2004

Functional characterization of a human histone gene cluster duplication.

Histones are the major protein component of nucleosomes, and de novo histone synthesis is essential for packaging newly replicated DNA into chromatin. As a result, histone gene expression is exquisitely and functionally coupled with DNA replication. Vastly divergent organisms such as yeast, fly and human all demonstrate the phylogenetically conserved propensity to maintain clustering of histone genes at one or more genomic loci. Although specific mechanisms are unclear, clustering is presumed to be important for common stringent transcriptional control of these genes at the G1/S phase transition. In this study, we describe a genomic duplication of the human histone gene cluster located at chromosome 1q21, which effectively doubles the previously known size and gene number of that cluster. The duplication persists in all examined tissues and cell lines, and the duplicated genes are transcriptionally active. Levels of messenger RNAs for duplicated histone H4 genes are high relative to those for non-duplicated H4 genes. Our data suggest that transcriptionally robust histone H4 genes may have been preferentially duplicated during evolution.

Amino Acid Sequence↗
PubMed2004

Experimental demonstration of single photon nonlocality.

In this Letter we experimentally implement a single photon Bell test based on the ideas of S. Tan et al. [Phys. Rev. Lett. 66, 252 (1991)]] and L. Hardy [Phys. Rev. Lett. 73, 2279 (1994)]]. A double homodyne measurement is used to measure correlations in the Fock space spanned by zero and one photons. Local oscillators used in the correlation measurement are distributed to two observers by copropagating it in an orthogonal polarization mode. This method eliminates the need for interferometrical stability in the setup, consequently making it a robust and scalable method.

Journal Article↗
PubMed2001

Characterization of the iron transporter DMT1 (NRAMP2/DCT1) in red blood cells of normal and anemic mk/mk mice.

Divalent metal transporter 1 (DMT1) is the major transferrin-independent iron uptake system at the apical pole of intestinal cells, but it may also transport iron across the membrane of acidified endosomes in peripheral tissues. Iron transport and expression of the 2 isoforms of DMT1 was studied in erythroid cells that consume large quantities of iron for biosynthesis of hemoglobin. In mk/mk mice that express a loss-of-function mutant variant of DMT1, reticulocytes have a decreased cellular iron uptake and iron incorporation into heme. Interestingly, iron release from transferrin inside the endosome is normal in mk/mk reticulocytes, suggesting a subsequent defect in Fe(++) transport across the endosomal membrane. Studies by immunoblotting using membrane fractions from peripheral blood or spleen from normal mice where reticulocytosis was induced by erythropoietin (EPO) or phenylhydrazine (PHZ) treatment suggest that DMT1 is coexpressed with transferrin receptor (TfR) in erythroid cells. Coexpression of DMT1 and TfR in reticulocytes was also detected by double immunofluorescence and confocal microscopy. Experiments with isoform-specific anti-DMT1 antiserum strongly suggest that it is the non-iron-response element containing isoform II of DMT1 that is predominantly expressed by the erythroid cells. As opposed to wild-type reticulocytes, mk/mk reticulocytes express little if any DMT1, despite robust expression of TfR, suggesting a possible effect of the mutation on stability and targeting of DMT1 isoform II in these cells. Together, these results provide further evidence that DMT1 plays a central role in iron acquisition via the transferrin cycle in erythroid cells.

Anemia↗
PubMed2000

A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities.

BACKGROUND: Controversy persists about the use of right unilateral (RUL) and bilateral (BL) electroconvulsive therapy (ECT). While RUL ECT results in less severe short-term and long-term cognitive effects, there is concern that it is less efficacious than BL ECT. METHODS: In a double-blind study, 80 depressed patients were randomized to RULECT, with electrical dosages 50%, 150%, or 500% above the seizure threshold, or BL ECT, with an electrical dosage 150% above the threshold. Depression severity and cognitive functioning were assessed before, during, immediately after, and 2 months after ECT. Compared with baseline, responders had at least a 60% reduction in symptom scores 1 week after ECT, and were monitored for relapse for 1 year. RESULTS: High-dosage RUL and BL ECT were equivalent in response rate (65%) and approximately twice as effective as low-dosage (35%) or moderate-dosage (30%) unilateral ECT. During the week after the randomized phase, BL ECT resulted in greater impairment than any dosage of unilateral ECT in several measures of anterograde and retrograde memory. Two months after ECT, retrograde amnestic deficits were greatest among patients treated with BL ECT. Thirty-three (53%) of the 62 patients who responded to ECT relapsed, without treatment group differences. The relapse rate was greater in patients who had not responded to adequate pharmacotherapy prior to ECT and who had more severe depressive symptoms after ECT. CONCLUSION: Right unilateral ECT at high dosage is as effective as a robust form of BL ECT, but produces less severe and persistent cognitive effects.

Amnesia↗
PubMed2002

Dopamine agonist effects on startle and sensorimotor gating in normal male subjects: time course studies.

RATIONALE: Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is deficient in schizophrenia and in rodents treated with dopamine (DA) agonists. Reduced PPI is reported in normal humans treated with direct or indirect DA agonists. To facilitate future studies, we assessed the time course of DA agonist effects on PPI in humans, for both direct (bromocriptine: 1.25, 2.5 mg; pergolide: 0.025, 0.1 mg) and indirect DA agonists (amphetamine: 20 mg; amantadine: 200 mg) ( n=6-10/dose). METHODS: Baseline (no drug) levels of acoustic and tactile startle, as well as uni- and cross-modal PPI, were assessed in 63 normal adult males. Seven to ten days later, subjects were tested in five sessions over 3.5 h after ingestion of placebo or active drug in a double-blind design. RESULTS: Expected drug effects were observed in both autonomic (for example, increased heart rate and blood pressure with amphetamine), somatic (for example, "queasiness" with direct DA agonists), and psychological measures (for example, "happiness", less "drowsiness" with amphetamine). Drugs increased (bromocriptine) or decreased (amantadine) startle magnitude, and caused either no change or modest, time-dependent effects on PPI. Amantadine increased PPI over the test session, a pattern not observed with other DA agonists or placebo. No consistent effects on PPI were observed with either bromocriptine, pergolide, or amphetamine. Drug effects on startle did not consistently correlate with self-assessment measures. CONCLUSIONS: Despite evidence of "bioactivity", under the specific experimental conditions of this study, neither direct nor indirect DA agonists had robust effects on startle or PPI. In some cases (for example, amantadine), a time course was identified that will facilitate future studies of DA agonist effects on PPI in humans.

Adolescent↗
PubMed2001

Cost-effectiveness of gatifloxacin vs ceftriaxone with a macrolide for the treatment of community-acquired pneumonia.

STUDY OBJECTIVE: To determine the cost-effectiveness of sequential IV to oral gatifloxacin therapy vs IV ceftriaxone with or without IV erythromycin to oral clarithromycin therapy to treat community-acquired pneumonia (CAP) patients requiring hospitalization. PATIENTS: Two hundred eighty-three patients enrolled in a randomized, double-blind, clinical trial were eligible for inclusion in the cost-effectiveness analysis. METHODS: Data collected included patient demographics, clinical and microbiological outcomes, length of stay (LOS), and antibiotic-related LOS (LOSAR). Costs evaluated include drug acquisition (level 1); plus costs of preparation, dispensing, and administration, treating adverse events, and clinical failures (level 2); plus hospital per diem costs (level 3). Robustness of economic findings was tested using sensitivity analyses. RESULTS: Two hundred three patients were clinically and economically evaluable (98 receiving gatifloxacin and 105 receiving ceftriaxone). IV erythromycin was administered to 35 patients in the ceftriaxone-treated group. Oral conversion was achieved in 98% of patients in each group. Clinical cure and microbiological eradication rates did not differ statistically (98% and 97% with gatifloxacin vs 92% and 92% with ceftriaxone, respectively). Overall, neither geometric mean LOS nor LOSAR differed significantly (4.2 days and 4.1 days with gatifloxacin vs 4.9 days and 4.9 days with ceftriaxone, respectively). Treatment failures in the ceftriaxone group contributed to a mean incremental increase in LOSAR of 1.09 days and increased mean cost per patient. The geometric mean costs per patient (level 3) were $5,109 for gatifloxacin and $6,164 for ceftriaxone (p = 0.011). The cost-effectiveness ratios (mean cost per expected success) were $5,236:1 and $7,047:1 for gatifloxacin and ceftriaxone, respectively. CONCLUSIONS: Gatifloxacin monotherapy for CAP patients requiring hospitalization is clinically effective and provides an economic advantage compared to the regimen of ceftriaxone with or without erythromycin IV with a switch to oral clarithromycin.

Adolescent↗
PubMed1999

Neurophysiologic predictors of treatment response to fluoxetine in major depression.

Treatment with antidepressants is marked by heterogeneity of response; predicting individual response to any given agent remains problematic. Neuroimaging studies suggest that response is accompanied by physiologic changes in cerebral energy utilization, but have not provided useful markers at pretreatment baseline. Using quantitative EEG (QEEG) techniques, we investigated pretreatment neurophysiologic features to identify responders and non-responders to fluoxetine. In a double-masked study, 24 adult subjects with current major depression of the unipolar type were studied over 8 weeks while receiving fluoxetine (20 mg QD) or placebo. Neurophysiology was assessed with QEEG cordance, a measure reflecting cerebral energy utilization. Response was determined with rating scales and clinical interview. Subjects were divided into discordant and concordant groups based upon the number of electrodes exhibiting discordance. The concordant group had a more robust response than the discordant group, judged by lower final Hamilton Depression (HAM-D) mean score (8.0+/-7.5 vs. 19.6+/-4.7, P = 0.01) and final Beck Depression Inventory (BDI) mean score (14.0+/-9.4 vs. 27.8+/-3.7, P = 0.015), and by faster reduction in symptoms (HAM-D: 14.0+/-5.0 vs. 23.8+/-4.1, P = 0.004 at 1 week). Groups did not differ on pretreatment clinical or historical features. Response to placebo was not predicted by this physiologic measure. We conclude that cordance distinguishes depressed adults who will respond to treatment with fluoxetine from those who will not. This measure detects a propensity to respond to fluoxetine and may indicate a more general responsiveness to antidepressants.

Adult↗
PubMed1995

Mood, major depression, and fluoxetine response in cigarette smokers.

OBJECTIVE: Two smoking cessation studies provided venues to 1) look for differences in affective symptoms between cigarette smokers with and without a history of major depression or other psychiatric diagnoses who were not currently depressed and 2) evaluate the efficacy of fluoxetine in ameliorating affective symptoms in smokers with a history of major depression but not currently depressed. METHOD: Part I: Three hundred sixty-eight smokers who enrolled in a smoking cessation treatment study completed baseline self-rating scales. The relationship between the scale scores and a history of major depression and other psychiatric diagnoses was examined. Part II: Thirty-nine smokers with a history of major depression were enrolled in a randomized, double-blind study that examined the utility of fluoxetine as an aid to smoking cessation. Self-rated scales were compared at baseline and after 3 weeks of medication treatment before the attempt to quit. RESULTS: A history of major depression had significant main effects across all scale scores; subjects with such a history rated themselves as more symptomatic. The effects of other psychiatric diagnoses were neither as pervasive nor as robust. There were no differences in baseline scores between the fluoxetine- and placebo-treated groups and no change within the placebo group after 3 weeks. There was significant improvement from baseline in several subscale scores for the group treated with fluoxetine. However, comparison of the score changes for the placebo and fluoxetine groups did not show a statistically significant difference, which limited the ability to conclude that active treatment was better than placebo. CONCLUSIONS: Subjects with a history of major depression, but without current affective illness, reported themselves to be more symptomatic than those without such-a history. Furthermore, in a group of smokers with a history of major depression, affective symptoms, without concurrent syndromal illness, may be ameliorated by treatment with fluoxetine.

Adult↗
PubMed1989

A prospective evaluation of optimal sampling theory in the determination of the steady-state pharmacokinetics of piperacillin in febrile neutropenic cancer patients.

We examined the use of optimal sampling theory in the determination of the pharmacokinetics of piperacillin in febrile, neutropenic cancer patients. Patients were studied prospectively as part of a randomized, double-blind clinical trial of piperacillin and amikacin versus imipenem and placebo. The results from the analysis of 5 optimal samples were compared with those derived from 15 concentration determinations (10 samples, with the 5 optimal samples assayed in duplicate). The use of a standard least-squares estimator as opposed to a bayesian estimator, with normal prior distributions placed on beta and serum clearance, was also examined. Finally, the use of duplicate determinations in improving the precision of parameter estimation was studied. Plasma concentrations obtained at time points determined by optimal sampling theory, when analyzed with a bayesian estimator, produced estimates of pharmacokinetic parameter values that were in good agreement with those derived from the 15-determination set. Duplicate assay did not improve the precision of parameter estimation. Estimation of plasma clearance was quite robust, irrespective of the estimator used, probably because this evaluation was performed at steady state. Optimal sampling theory is a promising technique that can be employed to determine patient-specific estimates of pharmacokinetic parameter values in target populations.

Adolescent↗
PubMed2000

Intravenous infusion of 4-AP in chronic spinal cord injured subjects.

STUDY DESIGN: A prospective double blind cross over trial of intravenous 4-Aminopyridine (4-AP). OBJECTIVE: To determine the efficacy of this drug in the treatment of spinal cord injured (SCI) patients for neurologic impairment, pain and spasticity. SETTING: The post anesthesia care unit (PACU) of a tertiary care acute hospital. METHODS: Twelve paraplegic patients were enrolled in a double blind cross over intravenous trial of 4-Aminopyridine (4-AP). Thirty milligrams of 4-AP or placebo were administered over a 2 h period. Patients were serially examined during and after the infusion clinically for pain, sensorimotor function, hypertonicity and motor control using electromyography (EMG). Samples of blood and cerebrospinal fluid (CSF) were also analyzed at similar intervals. RESULTS: Despite penetration of 4-AP into the CSF, no significant differences were noted in the clinical and EMG parameters at the times measured. Individual changes in sensory function were reported by some patients in both the placebo and 4-AP trials, however mean values were not robust. Frequently, patients complained of unpleasant symptoms during the 4-AP infusion. CONCLUSION: The intravenous route may not be the best way to administer this drug as no short term benefits were observed.

4-Aminopyridine↗
PubMed1997

Effect size of efficacy measures comparing divalproex, lithium and placebo in acute mania.

Effect size (ES) is a statistical concept that can be used to improve the interpretation of results from psychopharmacological studies. ES may aid interpretation of results when sample size is unbalanced or small or when units or levels of baseline measures differ across items. Usually, an investigator can define a threshold value for a clinically meaningful ES based on published data and clinical judgment or by resorting to conventions, e.g., a medium ES = 0.5 S.D., which can usually be discerned by the trained clinician. In the present study, we apply ES analysis to results from a study comparing the effectiveness of divalproex (DIVAL), lithium (LI), and placebo (PLA) in hospitalized, acutely manic patients. One hundred seventy-six patients were randomly assigned to DIVAL, LI, or PLA in a 2:1:2 ratio, with drug administered in a double-blind, parallel group design for 21 days. The primary efficacy measure was the Mania Rating Scale from the Schedule for Affective Disorders and Schizophrenia, composed of the Manic Syndrome Score (MSS) from items that are relatively specific to the manic state, and the Behavior and Ideation Score (BIS), which reflects severe but nonspecific psychopathology. Improvement of the MSS after 5 days of treatment was difficult to interpret based on percentage change (DIVAL = 19%, LI = 13.5%, PLA = 8.5%). However, the corresponding effect sizes of 0.79, 0.55, and 0.35 indicated a medium to marked ES for DIVAL, a medium ES for LI, and a small ES for PLA at this early point in treatment. Similarly, the ES for change on the MSS at the end of treatment indicated a large, readily observable improvement with both DIVAL (ES = 1.01) and LI (ES = 0.79) vs. an ES of 0.37 for PLA. ES analysis also indicated that the BIS is a less robust indicator of change to either drug. The ES at the end of treatment for the BIS was 0.67 for DIVAL-, 0.62 for LI-, and 0.25 for PLA-treated patients.

Adolescent↗
PubMed2002

Robust G1 checkpoint arrest in budding yeast: dependence on DNA damage signaling and repair.

Although most eukaryotes can arrest in G1 after ionizing radiation, the existence or significance of a G1 checkpoint in S. cerevisiae has been challenged. Previous studies of G1 response to chemical mutagens, X-ray or UV irradiation indicate that the delay before replication is transient and may reflect a strong intra-S-phase checkpoint. We examined the yeast response to double-stranded breaks in G1 using gamma irradiation. G1 irradiation induces repair foci on chromosome spreads and a Rad53 band shift characteristic of activation, which suggest an active DNA damage response. Consistent with a G1 arrest, bud emergence, spindle pole duplication and DNA replication are each delayed in a dose-dependent manner. Sensitivity to mating pheromone is prolonged to over 18 hours when G1 cells are lethally gamma or UV irradiated. Strikingly, G1 delay is the predominant response to continuous gamma irradiation at a dose that confers no loss of viability but delays cell division. Like the G2/M checkpoint, G1 delay is completely dependent on both RAD9 and RAD24 epistasis groups but independent of POL(epsilon). Lethally irradiated rad9 mutants rapidly exit G1 but perform a slow S phase, whereas rad17 and rad24 mutants are completely arrest deficient. Distinct from gamma irradiation, G1 arrest after UV is RAD14 dependent, suggesting that DNA damage processing is required for checkpoint activation. Therefore, as in the yeast G2/M checkpoint response, free DNA ends and/or single-stranded DNA are necessary and sufficient to induce a bona fide G1 checkpoint arrest.

Cell Cycle Proteins↗
PubMed2006

An iontophoretic fentanyl patient-activated analgesic delivery system for postoperative pain: a double-blind, placebo-controlled trial.

An iontophoretic fentanyl HCl patient-activated transdermal system (fentanyl HCl PATS) is under development for the treatment of acute postoperative pain. The fentanyl HCl PATS is a needle-free, credit card-sized, preprogrammed system that is applied to the patient's upper outer arm or chest. The fentanyl HCl PATS was demonstrated to be superior to placebo in a previous trial; however, the randomization scheme used and the lack of control of entry pain level may have contributed to the lack of robust findings. We compared the fentanyl HCl PATS with placebo for acute postoperative pain management in a larger trial that addressed the limitations of the previous study. Adult patients admitted to the postanesthesia care unit after major surgery were titrated to comfort with opioids and randomized 1:1 to receive the fentanyl HCl PATS 40 microg or placebo for 24 hours. Supplemental IV fentanyl was available to patients upon request in both treatment groups for the first 3 hours after enrollment. The primary efficacy end-point was the percentage of patients who discontinued participation in the study because of inadequate analgesia. Pain intensity scores, patient global assessments (PGA), and investigator global assessments (IGA) were collected. Four-hundred-eighty-four patients (PATS, n = 244; placebo, n = 240) were enrolled. Fewer patients receiving the fentanyl HCl PATS discontinued because of inadequate analgesia compared with placebo (28.7% versus 60.0%; P < 0.0001). Mean last pain intensity scores were 3.5 and 5.4 for the fentanyl HCl PATS and placebo groups, respectively. Patients (73.4%, PGA) and investigators (72.1%, IGA) considered the fentanyl HCl PATS a good or excellent method of pain control. Treatment-related adverse events were similar between groups. This study demonstrated the superiority of the iontophoretic fentanyl HCl PATS over placebo for acute postoperative pain management.

Analgesia, Patient-Controlled↗
PubMed2004

Identification of a novel enhancer of brain expression near the apoE gene cluster by comparative genomics.

Comparative analysis of the human and mouse genomic sequences downstream of the apolipoprotein E gene (APOE) revealed a highly conserved element with previously undefined function. In reporter gene transfection studies, this element which is located approximately 42 kb distal to APOE was found to have silencer activity in a subset of cell lines examined. Analysis of transgenic mice containing a fusion construct linking this distal 631 bp conserved element to a reporter gene comprised of the human APOE gene with its proximal promoter resulted in robust brain expression of the transgenic human apoE mRNA in three independent transgenic lines, supporting the identification of a novel brain controlling region (BCR). Further studies using immunohistochemistry revealed widespread human apoE localization throughout the brains of the BCR-apoE transgenic mice with prominent expression in the cortex and diencephalon. In addition, double-label immunofluorescence performed on brain sections and cultures of primary cortical cells localized human apoE protein to cortical neurons and microglia. These studies demonstrate that comparative sequence analysis is a successful strategy to predict candidate regulatory regions in vivo, although they do not imply that this element controls apoE expression physiologically.

Animals↗