Biomedical subjects

T Roth

Publications and source records attributed to T Roth.

At least 73 records · Page 4Linked to original sources

PubMed1999

Repeated nocturnal sleep latencies in narcoleptic, sleepy and alert subjects.

OBJECTIVES: The purpose of this study was to assess nocturnal sleep latencies among narcoleptics. METHODS: Thirteen narcoleptics and matched sleepy and alert controls participated in this study. Subjects were awakened three times on each of two experimental nights. The latencies to sleep and rapid eye movement sleep were evaluated at the beginning of the night and following each experimental awakening. RESULTS: The alert group (AG) had a significantly longer mean nocturnal sleep latency than the narcoleptic (NG) and sleepy groups (SG). The sleep latencies at 23:00 and 01:10 h were significantly longer than the latencies at 03:10 and 05:10 h. The interaction between group and time of night demonstrated longer latencies at 23:00 and 03:10 h for the AG when compared to the SG and the NG. At 01:10 and 05:10 h all groups had comparable latencies. The number of subjects in the NG who had multiple sleep onset REM periods (SOREMPs) was significantly higher than in either the AG or the SG. CONCLUSIONS: Narcoleptics were found to have a heightened propensity to fall asleep and increased number of SOREMPs during nocturnal sleep opportunities. These characteristics are consistent with the daytime polysomnographic findings known in this patient population.

Adult↗

PubMed1999

Sleepiness and the reinforcing and subjective effects of methylphenidate.

On 4 days, 6 volunteers received 10 mg methylphenidate or placebo at 0900 after 4 or 8 hr time in bed (TIB) and then on 4 days after 4 or 8 hr TIB chose their preferred capsule. On sampling days, 4 hr TIB increased multiple sleep latency test (MSLT) scores and Fatigue scale scores on the Profile of Mood States (POMS). In both TIBs, the drug increased the MSLT and POMS Vigor and Tension scale scores. It reduced POMS Fatigue scores and improved divided attention performance to a greater extent after 4 versus 8 hr. Drug was chosen on 88% of days after 4 hr, but only 29% of days after 8 hr. Preference for the drug depends on sleepiness and is mediated by performance-enhancing and fatigue-altering effects.

Adult↗

PubMed1999

Reduction of fibronectin expression by intravitreal administration of antisense oligonucleotides.

We have investigated whether antisense oligonucleotides delivered intravitreally could reduce gene expression specifically in the retina. In this study, phosphorothioate antisense oligonucleotides targeted to fibronectin transcripts were coupled to a novel carrier and used to specifically reduce fibronectin (FN) expression in retinal vascular cells. Using confocal microscopy, fluorescence from fluorescein isothio-cyanate-labeled FN-oligonucleotides was detected in retinal vascular cells at 24 h postinjection and persisted until day 6 (the end point of this study). The fibronectin mRNA level was consistently decreased to 86.7% +/- 7.9% of control (p<0.05) at day 2, and 46.7% +/- 4.9% of control (p<0.01) at day 6. In contrast, the beta-actin mRNA level, an internal control, was unaltered in rat retinas that received FN-oligonucleotides. Fibronectin protein level at day 6 was also significantly reduced to 61.4% +/- 16% of control (p<0.01). No toxic effect resulting from the carrier was detected histologically. Thus, intravitreal delivery of antisense oligonucleotides to modulate abnormal gene expression in retinal diseases may be an effective approach for ocular gene therapy.

Animals↗

PubMed1999

New trends in insomnia management.

Pharmacological management of insomnia is continually evolving. The introduction of non-benzodiazepine benzodiazepine receptor agonist hypnotics provides an opportunity to understand different patterns of pharmacological activity with mechanistic differences in receptor activity. The impact of insomnia on daytime functioning and long-term health and socioeconomic status has been recognized. Epidemiological studies indicate that insomnia is associated with increased absenteeism and healthcare costs (although the latter appear to be partly attributable to comorbid depression). It will thus be important to determine whether hypnotics, in addition to their effects on sleep, provide other benefits for the patient that are related to these parameters. The successful resolution of this issue will require the adoption of additional outcome measures, such as effects on quality of life and healthcare costs. Recognition that long-term hypnotic use is widespread among insomniacs has prompted proposals for alternative prescribing patterns. Although certain hypnotics appear to be free of tolerance on prolonged use, caution is required in the long-term use of any hypnotic because of the lack of systematic data on chronic efficacy and safety. Therefore, alternative administration schedules (e.g. intermittent and 'as required') are being investigated. These may have very different consequences in terms of abuse liability and patients' perceptions of efficacy, and thus permit a more effective and appropriate use of this drug class.

Antidepressive Agents↗

PubMed1999

Application of grounded theory to content definition: a case study.

Successful implementation of a clinical information system requires clinician involvement throughout the process of content definition and system development to ensure acceptance of the automated care process. In these times of downsizing, however, clinicians are not always able to participate fully in the dontent definition phase of system development and often become frustrated with their inability to obtain the patient information they need from the system. The qualitative research principles of grounded theory afford clinicians the opportunity to participate in content definition for information systems. This article presents a case study of the application of grounded theory to develop systematically the content definition for a clinical information system in preparation for implementation on four medical-surgical units.

Abstracting and Indexing↗

PubMed1998

The effects of REM sleep deprivation on the level of sleepiness/alertness.

STUDY OBJECTIVES: The purpose of this study was to evaluate the effects of acute REM deprivation on daytime sleepiness/alertness, as measured by the MSLT. PARTICIPANTS: Twenty-six healthy, normal volunteers (14 males and 12 females) participated in this study. Participating subjects were in good physical and psychological health and were asymptomatic as to sleep/wake complaints. INTERVENTIONS: Subjects spent 5 nights and 5 days in the laboratory. The first night and day were utilized for screening purposes. The remaining stay in the laboratory consisted of a baseline night and day, 2 deprivation nights and days, and a recovery night and day. Each night, a nocturnal polysomnogram was employed to monitor subjects' sleep. Each day, subjects underwent an MSLT to evaluate their sleepiness/alertness. Subjects were randomized into REM-deprivation (RD) and yoked-control (YC) groups. On deprivation nights, RD subjects were awakened each time they entered stage REM sleep, and the YC subjects were awakened concomitantly with the RD subjects, assuming they were not in stage REM sleep. RESULTS: The REM-deprived subjects did not demonstrate any changes in MSLT scores across experimental days. In contrast, the YC subjects documented significantly lower MSLT scores on deprivation days due to decreased total sleep time. CONCLUSION: The REM-deprivation procedure antagonized the effects of sleep loss on daytime sleepiness, resulting in increased alertness for RD subjects compared to YC subjects. The mechanism by which REM deprivation exerts its alerting effects is unknown and will require future research.

Adult↗

PubMed1998

Synthesis and in vitro efficacy of transferrin conjugates of the anticancer drug chlorambucil.

One strategy for improving the selectivity and toxicity profile of antitumor agents is to design drug carrier systems employing soluble macromolecules or carrier proteins. Thus, five maleimide derivatives of chlorambucil were bound to thiolated human serum transferrin which differ in the stability of the chemical link between drug and spacer. The maleimide ester derivatives 1 and 2 were prepared by reacting 2-hydroxyethylmaleimide or 3-maleimidophenol with the carboxyl group of chlorambucil, and the carboxylic hydrazone derivatives 5-7 were obtained through reaction of 2-maleimidoacetaldehyde, 3-maleimidoacetophenone, or 3-maleimidobenzaldehyde with the carboxylic acid hydrazide derivative of chlorambucil. The alkylating activity of transferrin-bound chlorambucil was determined with the aid of 4-(4-nitrobenzyl)pyridine (NBP) demonstrating that on average 3 equivalents were protein-bound. Evaluation of the cytotoxicity of free chlorambucil and the respective transferrin conjugates in the MCF7 mammary carcinoma and MOLT4 leukemia cell line employing a propidium iodide fluorescence assay demonstrated that the conjugates in which chlorambucil was bound to transferrin through non-acid-sensitive linkers, i.e., an ester or benzaldehyde carboxylic hydrazone bond, were not, on the whole, as active as chlorambucil. In contrast, the two conjugates in which chlorambucil was bound to transferrin through acid-sensitive carboxylic hydrazone bonds were as active as or more active than chlorambucil in both cell lines. Especially, the conjugate in which chlorambucil was bound to transferrin through an acetaldehyde carboxylic hydrazone bond exhibited IC50 values which were approximately 3-18-fold lower than those of chlorambucil. Preliminary toxicity studies in mice showed that this conjugate can be administered at higher doses in comparison to unbound chlorambucil. The structure-activity relationships of the transferrin conjugates are discussed with respect to their pH-dependent acid sensitivity, their serum stability, and their cytotoxicity.

Animals↗

PubMed1998

Epidemiology of alcohol and medication as aids to sleep in early adulthood.

STUDY OBJECTIVES: In a representative sample of adults 18-45 years of age, this study addressed three questions about the use of sleep aids in the general population: (1) what are the past-year prevalences of the use of alcohol, over-the-counter medication and prescription medication to facilitate sleep? (2) among those who use these substances for sleep problems, what are the patterns of use? and (3) are there social factors, independent of sleep characteristics, that increase the likelihood of alcohol and medication use to aid sleep? DESIGN: The 1996 Detroit Area Survey was a random-digit-dial, computer-assisted survey of a representative sample of 2,181 adults ages 18-45 in the Detroit primary metropolitan statistical area. Eligible household response rate was 86.8%. RESULTS: In the general population, use of alcohol and medication as sleep aids in the past year was found to be fairly common: 13% used alcohol, 18% used medications and 5% used both. The prevalence of any substance use to aid sleep was 26%. The duration of use was short for the majority of users, less than 1 week. However, duration of use was greater for the majority of those using prescription sleep aids. A substantial minority of users report regular use lasting longer than 1 month: 15%, 9%, and 36% for alcohol, OTC medications, and prescription medications, respectively. Both sociodemographic and sleep characteristics were associated with alcohol and medication use to aid sleep. Difficulty falling asleep was the factor most strongly associated with use of substances to improve sleep. Sex, race/ethnicity, work shift, marital status and education were also significantly associated with one or more types of sleep aid use adjusting for difficulty falling asleep.

Adolescent↗

PubMed1998

Albumin conjugates of the anticancer drug chlorambucil: synthesis, characterization, and in vitro efficacy.

In our efforts to improve the selectivity and toxicity profile of antitumor agents, four maleimide derivatives of chlorambucil (1-4) were bound to thiolated human serum albumin which differ in the stability of the chemical link between drug and spacer. 1 is an aliphatic maleimide ester derivative of chlorambucil, whereas 2-4 are acetaldehyde, acetophenone, and benzaldehyde carboxylic hydrazone derivatives. HPLC stability studies at pH 5.0 with the related model compounds 5, 7, 8, and 9, in which chlorambucil was substituted by 4-phenylbutyric acid, demonstrated that the carboxylic hydrazone derivatives have acid-sensitive properties; the acid lability of 7 was particular prominent with a half-life of only a few hours. The alkylating activity of albumin-bound chlorambucil was determined with the aid of 4-(4-nitrobenzyl)-pyridine (NBP), demonstrating that on average three equivalents were protein-bound. Evaluation of the cytotoxicity of free chlorambucil and the respective albumin conjugates in the MCF7 mamma carcinoma and MOLT4 leukemia cell line employing a propidium iodide fluorescence assay demonstrated that the conjugate in which chlorambucil was bound to albumin through an ester bond was not as active as chlorambucil. In contrast, the conjugates in which chlorambucil was bound to albumin through carboxylic hydrazone bonds were as or more active than chlorambucil in both cell lines. In particular, the conjugate in which chlorambucil was bound to albumin through an acetaldehyde carboxylic hydrazone bond exhibited IC50 values which were approximately 4-fold (MCF7) to 13-fold (MOLT4) lower than those of chlorambucil. Preliminary toxicity studies in mice showed that this conjugate can be administered at higher doses in comparison to unbound chlorambucil.

Animals↗

PubMed1998

Transferrin conjugates of doxorubicin: synthesis, characterization, cellular uptake, and in vitro efficacy.

One strategy for improving the antitumor selectivity and toxicity profile of antitumor agents is to design drug carrier systems employing suitable carrier proteins. Thus, thiolated human serum transferrin was conjugated with four maleimide derivatives of doxorubicin that differed in the stability of the chemical link between drug and spacer. Of the maleimide derivatives, 3-maleimidobenzoic or 4-maleimidophenylacetic acid was bound to the 3'-amino position of doxorubicin through a benzoyl or phenylacetyl amide bond, and 3-maleimidobenzoic acid hydrazide or 4-maleimidophenylacetic acid hydrazide was bound to the 13-keto position through a benzoyl hydrazone or phenylacetyl hydrazone bond. The acid-sensitive transferrin conjugates prepared with the carboxylic hydrazone doxorubicin derivatives exhibited an inhibitory efficacy in the MDA-MB-468 breast cancer cell line and U937 leukemia cell line comparable to that of the free drug (employing the BrdU (5-bromo-2'-deoxyuridine) incorporation assay and tritiated thymidine incorporation assay, respectively, IC50 approximately 0.1-1 mM), whereas conjugates with the amide derivatives showed no activity. Furthermore, antiproliferative activity of the most active transferrin conjugate (i.e. the conjugate containing a benzoyl hydrazone link) was demonstrated in the LXFL 529 lung carcinoma cell line employing a sulforhodamine B assay. In contrast to in vitro studies in tumor cells, cell culture experiments performed with human endothelial cells (HUVEC) showed that the acid-sensitive transferrin conjugates of doxorubicin were significantly less active than free doxorubicin (IC50 values approximately 10-40 higher by the BrdU incorporation assay), indicating selectivity of the doxorubicin-transferrin conjugates for tumor cells. Fluorescence microscopy studies in the MDA-MB-468 breast cancer cell showed that free doxorubicin accumulates in the cell nucleus, whereas doxorubicin of the transferrin conjugates is found localized primarily in the cytoplasm. The differences in the intracellular distribution between transferrin-doxorubicin conjugates and doxorubicin were confirmed by laser scanning confocal microscopy in LXFL 529 cells after a 24 h incubation that revealed an uptake and mode of action other than intercalation with DNA. The relationship between stability, cellular uptake, and cytotoxicity of the conjugates is discussed.

Chromatography, High Pressure Liquid↗

PubMed1998

Daytime CPAP titration: a viable alternative for patients with severe obstructive sleep apnea.

OBJECTIVE: Continuous positive airway pressure (CPAP) is the treatment of choice for patients diagnosed with severe obstructive sleep apnea (OSA). The implementation of CPAP therapy has traditionally been based on full-night titration studies or split-night protocols. This study compared a group of patients who received a regular nocturnal CPAP titration with patients who received a daytime CPAP titration. The objective of the study was to determine if daytime CPAP titration is a viable alternative for the implementation of CPAP treatment in patients with severe OSA. STUDY DESIGN: Fourteen patients (13 men and one woman) received a daytime CPAP titration (day group). The day group was matched to 18 patients (17 men and one woman) who were titrated under a full-night regular nocturnal study (night group). Eligible patients were those with severe OSA (respiratory event index > 40). The groups were matched by age, sex, and body mass index. RESULTS: Daytime and nocturnal CPAP titration studies yielded sufficient amounts of rapid eye movement (REM) and non-REM sleep to help determine CPAP settings. Importantly, the diurnal and nocturnal CPAP titrations resulted in comparable therapeutic pressures as well as comparable resolution of sleep-disordered breathing. After 1 week of treatment, the groups exhibited similar CPAP use and comparable improvements in subjective sleepiness as indicated by their increase in sleep/wake activity inventory scores. CONCLUSIONS: Daytime CPAP titration studies may be a viable alternative for the efficient and expedient implementation of CPAP therapy among some patients with severe OSA.

Adult↗

PubMed1998

Electrophysiological assessment (The Multiple Sleep Latency Test) of the biphasic effects of ethanol in humans.

The Multiple Sleep Latency Test (MSLT) was used to assess the effects of ethanol at the peak and descending phases of the breath ethanol curve. Ethanol (0.75 g/kg) was administered (at 0900 hr) to 8 healthy, normal-sleeping men, aged 21 to 45 years old after 8 hr of sleep the previous night. MSLTs were conducted and breath ethanol concentrations (BrECs) were measured at 15, 45, 75, 105, 225, and 345 min after drinking was completed. Subjective measures were administered immediately before each sleep latency test. BrECs over the first 75 min (tests 1 to 3) peaked and differed from all subsequent tests (tests 4 to 6) over which BrECs declined. Sleep latency and subjective measures were averaged over tests 1 to 3 and 4 to 6. There was a significant increase in mean sleep latency relative to placebo for tests 1 to 3 and a significant reduction for tests 4 to 6. The subjective measure of stimulation sedation, the Biphasic Alcohol Effects Scale, showed lessened sedation after ethanol versus placebo on tests 1 to 3, compared with tests 4 to 6. This study confirmed the presence of a biphasic ethanol effect using an electrophysiological method (MSLT), showing increased physiological alertness on the peak phase of the BrEC curve and increased sedation on the descending phase. Relative to the effects observed on the MSLT with other low-dose stimulant drugs, the stimulatory effect of ethanol was mild.

Adult↗

PubMed1997

Synthesis and biological activity of novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 2-Aryl-substituted benzimidazoles.

The development of new nonnucleoside inhibitors of human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) active against the drug-induced mutations in RT continues to be a very important goal of AIDS research. We used a known inhibitor of HIV-1 RT, 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-alpha]benzimidazole (TZB), as the lead structure for drug design with the objective of making more potent inhibitors against both wild-type (WT) and variant RTs. A series of structurally related 1,2-substituted benzimidazoles was synthesized and evaluated for their ability to inhibit in vitro polymerization by HIV-1 WT RT. A structure-activity study was carried out for the series of compounds to determine the optimum groups for substitution of the benzimidazole ring at the N1 and C2 positions. The best inhibitor, 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimida zole (35), has an IC50 = 200 nM against HIV-1 WT RT in an in vitro enzyme assay. Cytoprotection assays utilizing HIV-infected MT-4 cells revealed that 35 had strong antiviral activity (EC50 = 440 nM) against wild-type virus while retaining broad activity against many clinically observed HIV-1 strains resistant to nonnucleoside inhibitors. Overall, the activity of 35 against wild-type and resistant strains with amino acid substitution in RT is 4-fold or greater than that of TZB and is comparable to that of other nonnucleoside inhibitors currently undergoing clinical trials, most of which do not have the capacity to inhibit the variant forms of the enzyme.

Anti-HIV Agents↗

PubMed1997

Characterization of the human homologue of RAD54: a gene located on chromosome 1p32 at a region of high loss of heterozygosity in breast tumors.

A search of the Human Genome Sciences database of expressed sequence-tagged DNA fragments, for sequences containing homology to known yeast DNA recombination and repair genes, yielded a cDNA fragment with high homology to RAD54. Here we describe the complete cDNA sequence and the characterization of the genomic locus coding for the human homologue of the yeast RAD54 gene (hRAD54). The yeast RAD54 belongs to the RAD52 epistasis group and appears to be involved in both DNA recombination and repair. The hRAD54 gene maps to chromosome 1p32 in a region of frequent loss of heterozygosity in breast tumors and encodes a protein of M(r) 93,000 that displays 52% identity to the yeast RAD54 protein. The hRAD54 protein sequence additionally contains all seven of the consensus segments of a superfamily of proteins with presumed or proven DNA helicase activity. Mutations in genes with consensus helicase homology have been found in cancer-prone syndromes such as xeroderma pigmentosum and Bloom syndrome as well as Werner's syndrome, in which patients age prematurely, and the X-linked mental retardation with alpha-thalassemia syndrome, ATR-X. We have examined the hRAD54 gene in several breast tumors and breast tumor cell lines and, although the gene region appears to be deleted in several tumors, at present we have found no coding sequence mutations.

Amino Acid Sequence↗

PubMed1997

[Laser angioplasty and recanalization].

Percutaneous transluminal coronary balloon angioplasty (PTCA) still is the most frequently applied interventional technique for treatment of coronary artery disease. Plastic deformation of the obstructive plaque with creation of splits, intimal tears and dissections is the main mechanism of PTCA for lumen widening. As a result, acute complications due to flow limiting dissections and acute vessel closure can unpredictably occur resulting in myocardial infarction, urgent bypass surgery and death. Furthermore, long-term success of PTCA is limited by restenosis. In order to overcome these limitations of PTCA, alternative interventional techniques were developed, which instead of deforming the obstructive plaque ablate this tissue. These techniques include high and low speed rotational angioplasty, directional atherectomy, the transluminal extraction catheter, ultrasound angioplasty and laser (Light Amplification by Stimulated Emission of Radiation) angioplasty. 308 nm XeCl excimer laser angioplasty today is the laser technique of choice for clinical application. This pulsed laser requires direct contact to the obstructive plaque. It creates fast (< 200 microseconds) expanding gas bubbles which induce plaque ablation. Main indications for 308 nm XeCl excimer laser angioplasty are diffuse and long coronary lesions and total coronary occlusions. Despite promising initial results this technique showed no better acute and long-term results in comparison to PTCA for the treatment of these types of lesions ("Amsterdam-Rotterdam" Study, "Excimer Rotational Balloon Angioplasty Comparison" Study). As a result, this interventional technique was rarely applied for patient treatment. More recently, the concept of plaque ablation by 308 nm XeCl excimer laser angioplasty was renewed for the treatment of in-stent restenosis. This indication is being investigated in the "Laser Angioplasty of Restenosed Stents" trial. First results document the practicability and safety of this approach. Long-term results are awaited. With ongoing miniaturization, laser guidewires were developed for the recanalization of chronic total occlusions. The randomized multicenter "Total Occlusion Trial with Angioplasty assisted by Laser guidewire "Study documented a success rate of laser wire recanalization in up to 66% in contrast to 47.5% for mechanical wires only. Long-term results are still awaited. Technical and procedural progress including saline flush during laser application, homogeneous light distribution and the concept of smooth laser ablation is pushed foreward to make excimer laser angioplasty safer, more predictable and more effective.

Angioplasty, Balloon, Coronary↗

PubMed1997

Cytoskeletal changes induced by excess extracellular matrix impair endothelial cell replication.

Thickening of basement membranes is an early and characteristic feature of diabetic vessels, but its consequences on the properties of vascular cells remain undefined. We investigated whether and how excess extracellular matrix (ECM) alters the replication of vascular endothelial cells in vitro. To test the effects of endogenous excess matrix, human umbilical vein endothelial cells (HUVEC) were plated on ECM produced under culture conditions (high ambient glucose) that increase ECM synthesis. Four of six HUVEC isolates plated on such ECM yielded a lower cell number (68 +/- 18%) than cells plated on control ECM. Growth inhibition was observed in HUVEC cultured on elevated concentrations (10 and 50 microg/ml) of exogenous fibronectin, when compared with HUVEC plated on tissue culture plastic or 0.25, 1.0, and 5.0 microg/ml fibronectin; the decreased replication was attributable to delayed transit through the G1 phase of the cell cycle. HUVEC grown on both 1 and 10 microg/ml fibronectin exhibited a modest upregulation of the fibronectin-specific integrin receptor alpha5beta1, and increased attachment to fibronectin substratum. However, unique to the HUVEC plated on growth-inhibitory concentrations of fibronectin was a redistribution in situ of integrins and vinculin to form more numerous focal adhesions, and an increased polymerization of cytoskeletal actin to form stress fibers. Concentrations (0.01 microg/ml) of cytochalasin D intended to prevent excess actin polymerization prevented the growth inhibition. Thus, excess ECM hampers endothelial cell replication in vitro through increased cell-ECM adhesion and attendant cytoskeletal rearrangements. These phenotypic changes provide probes to test whether cell-ECM interactions are altered in diabetic vessels in a direction that may compromise orderly endothelial cell renewal and its antithrombogenic function.

Actins↗

PubMed1997

Proliferative effect of high glucose is modulated by antisense oligonucleotides against fibronectin in rat endothelial cells.

Increased synthesis of fibronectin is associated with the development of basement membrane thickening-a characteristic lesion of diabetic microangiopathy, and it may affect the function of vascular cells. Because antisense technology offers the possibility to modulate specific gene expression, we investigated the effect of antisense phosphorothioate oligonucleotides directed against fibronectin mRNA on fibronectin synthesis and cell proliferation in a cell line derived from rat microvascular endothelium and cultured under high (30 mmol/l) glucose conditions. The rat endothelial cells grown in high glucose medium for 5.6 +/- 1.3 days exhibited increased cell proliferation compared to control cells grown in 5 mmol/l glucose (149% of control, p = 0.006). Fibronectin protein and mRNA levels (determined by Western blotting and reverse transcription-polymerase chain reaction) were also increased to 157%, p = 0.012 and 178%, p = 0.034 of control, respectively. However, when cells grown in high glucose medium were transfected with 0.4 mmol/l fibronectin-antisense phosphorothioate oligonucleotides in the presence of cationic liposomes, the cell number, fibronectin protein, and mRNA levels decreased compared to untransfected cells grown in high glucose medium to 102, 69, and 107% of control, respectively. This study shows that fibronectin antisense oligonucleotides targeted to the translation initiation site of the fibronectin transcript specifically reduce fibronectin synthesis in rat endothelial cells and the proliferative effect of high glucose concentrations.

Animals↗

PubMed1997

Hypnotic self administration: forced-choice versus single-choice.

Twenty-four men and women with insomnia, age 21-50 years, self administered hypnotics under a single-choice with placebo, single-choice with triazolam (0.25 mg), or forced-choice of placebo versus triazolam (0.25 mg) paradigm. Subjects received 4- sampling nights of placebo or triazolam in the single-choice conditions or 2 nights of each in the forced-choice condition. Then on 7 choice nights they could self administer a capsule, or not, in the single-choice conditions, or were required to choose one of two color-coded capsules in the forced-choice condition. In the single-choice conditions, subjects chose placebo 80% of nights and triazolam 77% of nights, while in the forced-choice condition triazolam was chosen on 86% of nights. Thus, the self administration of triazolam did not vary significantly between single or forced choice conditions, but that of placebo did. Placebo rate was high when it was the only alternative, but low when competing with triazolam. On sampling nights, compared to placebo, triazolam produced a significant increase in total sleep time, a reduction in latency to sleep, wake after sleep onset, and percentage stage 1 sleep. Triazolam, relative to placebo, also improved mood in the morning on some sampling nights. For subjects choosing capsules < 100% of opportunities (n = 14), on nights a capsule was chosen versus nights none was chosen (regardless of whether placebo or triazolam was the choice), self-ratings 30 min before bedtime on the Profile of Mood States vigor scale were significantly higher.

Adult↗