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PubMed2006

Pregabalin is effective against behavioral and electrographic seizures during alcohol withdrawal.

AIMS: Pregabalin has been shown to possess anticonvulsant, analgesic, and anxiolytic properties in a variety of testing situations. This study was designed to evaluate the ability of pregabalin to exert its anticonvulsant effects against behavioral and electrographic measures of CNS hyperexcitability associated with alcohol withdrawal in a mouse model of ethanol dependence. METHODS: Adult mice were chronically exposed to ethanol and, upon withdrawal, were tested for behavioral signs of seizure activity (handling-induced convulsions) or abnormalities in spontaneous EEG activity recorded from cortical and subcortical sites. RESULTS: Pregabalin (50-200 mg/kg) administered 1 and 4 h into withdrawal dose dependently reduced severity of handling-induced convulsions in comparison to vehicle-treated mice. Similarly, pregabalin reduced the frequency in which EEG activity was interrupted by trains of high-voltage synchronous activity in a dose-related fashion. Finally, pregabalin treatment of repeated withdrawals was effective in blocking the development of withdrawal sensitization observed in vehicle-treated mice. CONCLUSIONS: Collectively, these results suggest that pregabalin may be an effective therapeutic agent for medical management of alcohol detoxification.

Administration, Inhalation↗
PubMed1984

Interruption of a human nuclear sequence homologous to mitochondrial DNA by a member of the KpnI 1.8 kb family.

We reported that several DNA sequences homologous to mitochondrial DNA (mtDNA) are present in the human nuclear genome (Tsuzuki et al. (1983) Gene 25, 223-229). Detailed Southern blot analyses revealed that one of such sequences is interrupted by a repetitive sequence about 1.8 kb long, and that the insert is one member of the dispersed repeated DNA sequences of the KpnI 1.8 kb family. Nucleotide sequence analysis showed that the KpnI 1.8 kb DNA is flanked with imperfect 15-base pair (bp) direct repeats of mtDNA. This KpnI 1.8 kb DNA has an A-rich sequence at its 3'-end, and has a considerable homology with one of the published cDNA sequences homologous to one of the human KpnI families and also to one of the African green monkey KpnI families, KpnI-LS1. These structural features suggest that the KpnI 1.8 kb DNA is a movable element and is inserted within the mtDNA-like sequence by an RNA-mediated process.

Animals↗
PubMed2002

Selective REM sleep deprivation during daytime I. Time course of interventions and recovery sleep.

Although repeated selective rapid eye movement (REM) sleep deprivation by awakenings during nighttime has shown that the number of sleep interruptions required to prevent REM sleep increases within and across consecutive nights, the underlying regulatory processes remained unspecified. To assess the role of circadian and homeostatic factors in REM sleep regulation, REM sleep was selectively deprived in healthy young adult males during a daytime sleep episode (7-15 h) after a night without sleep. Circadian REM sleep propensity is known to be high in the early morning. The number of interventions required to prevent REM sleep increased from the first to the third 2-h interval by a factor of two and then leveled off. Only a minor REM sleep rebound (11.6%) occurred in the following undisturbed recovery night. It is concluded that the limited rise of interventions during selective daytime REM sleep deprivation may be due to the declining circadian REM sleep propensity, which may partly offset the homeostatic drive and the sleep-dependent disinhibition of REM sleep.

Adult↗
PubMed1998

Beta3 integrins are upregulated after vascular injury and modulate thrombospondin- and thrombin-induced proliferation of cultured smooth muscle cells.

BACKGROUND: Treatment with an antibody that binds beta3 integrins (abciximab; c7E3 Fab) at the time of coronary angioplasty decreases the need for repeat revascularization. Two potential mechanisms have been proposed to explain this effect: (1) inhibition of platelet aggregation or (2) interruption of ligand binding to beta3 integrins on the smooth muscle cell (SMC) surface. We examined the latter hypothesis by determining (1) if beta3 integrin expression is upregulated after vascular injury in the baboon, (2) if 7E3 binds beta3 integrins on cultured SMC, and (3) if beta3 integrin activation plays a role in proliferation of cultured SMC. METHODS AND RESULTS: Results demonstrated that immunostaining for beta3 integrins was present in the neointima 1 week after balloon withdrawal injury of baboon brachial arteries and that beta3 integrin expression colocalized with alpha-actin-positive cells. In contrast, staining for beta3 integrins was undetectable in contralateral uninjured brachial arteries. 7E3 bound to cultured human aortic SMC with an affinity (KD=3.3 nmol/L) similar to 7E3 binding to endothelial cells or platelets. Cotreatment with 7E3 partially inhibited thrombospondin-induced or alpha-thrombin-induced proliferation but not PDGF-induced or serum-induced proliferation. CONCLUSIONS: In summary, these studies demonstrate that vascular cell beta3 integrin expression is increased after injury, that 7E3 binds to cultured SMC with high affinity, and that beta3 activation is important for thrombospondin-induced or alpha-thrombin-induced proliferation. These results support the hypothesis that beta3 integrins play a role in SMC growth responses after balloon injury.

Abciximab↗
PubMedDate not supplied

Convulsive action of flunarizine in rabbits.

High doses of an anticonvulsant agent, flunarizine, given singly or repeatedly produce convulsions in rabbits. Albino rabbits were more vulnerable than mongrel ones. The flunarizine-induced convulsions are interrupted by diazepam.

Animals↗
PubMed1994

[Diagnosis and treatment of inflammatory infiltrates of the abdominal cavity in Crohn disease].

An infiltrate in the abdominal cavity in Crohn's disease does not hinder successful drug therapy in most cases. A positive effect (regression or a marked decrease in the size of the infiltrate) is achieved in 80% of patients, mostly in those with a moderately or mildly severe form of the disease in which a sufficiently prolonged, 10-12-week course of antiinflammatory treatment can be conducted. Combination of prednisolone with azathioprine and antibiotics is most justified. The prednisolone dose is determined by the severity and activity of the disease rather than by the infiltrate. Antibiotics are necessary only in high fever and treatment with them may be limited to 10-14 days in the absence of septicemia. Interrupted seasonal courses of sulfasalazine therapy may fail to prevent exacerbation and, consequently, recurrent infiltrates. These respond readily to repeated drug therapy and do not expand the indications for surgery. Operations were performed on 14 patients, in 11 of them the infiltrate did not recur again.

Abdomen↗
PubMed1994

[Transstadial transmission of Francisella tularensis by Ixodes ricinus ticks infected during the nymphal stage].

The degree of infection of nymphs of Ixodes ricinus which finished their feeding on experimentally infected mice on the day of their death from tularaemia represented more than 10(7) cells of Francisella tularensis per tick after feeding. The high degree of positivity was preserved in ticks also during one month of metamorphosis. Transstadial transmission of the agent from the stage of nymph to the stage of imago was confirmed in adults either by cultivation or by experiments attempting to transmit the infection to white mice, even after more than a year after infection of nymphs or more than a year after metamorphosis. Some of the ticks which did not transmit the infection while feeding were found to be positive subsequently. Results of quantitative examination of the degree of infection indicate also the possibility of reproduction of the agent in imagines after feeding on hosts. Incompletely engorged nymphs which fed repeatedly on mice after being collected from their host dead from tularaemia, were able to transmit the infection during interrupted feeding. Further possibilities of transmission were indicated by findings of consumption of infected ticks by hosts or by elimination of F. tularensis in faeces of infected nymphs and adults.

Animals↗
PubMed1975

[Test methods for surgical hand disinfection (author's transl)].

As exemplified by a test preparation, methods for assessing the effect of hand disinfection on the resident flora are put up for discussion. The test of a method for hand disinfection must make allowance for conditions prevailing in practice. Accordingly, the following steps should be taken into consideration: A. Single use 1. Immediate disinfecting effect 2. Duration of the disinfecting effect B. Repeated use 3. Course of the initial colony count 4. Immediate disinfecting effect 5. Behaviour of colony count after interruption of the disinfecting method applied. For the purpose of comparing the total count, as with all other disinfecting methods, the colony count must be determined by fractional collection methods; to this end, Traub's procedure may be modified, possibly using the plastic bag method described by Gaschen. A careful statistical evaluation with appropriate transformation of the results is indispensable.

Bacteria↗
PubMed2004

Regional and transient ischemia/reperfusion injury in the liver improves therapeutic efficacy of allogeneic intraportal hepatocyte transplantation in low-density lipoprotein receptor deficient Watanabe rabbits.

BACKGROUND/AIMS: Hepatocyte transplantation has the potential to become an alternative to organ transplantation for the treatment of hereditary liver disease. Currently used hepatocyte transplantation techniques are often not sufficient for phenotypic correction. In a pre-clinical model we investigated the effect of regional transient ischemia reperfusion injury and repeated infusions of allogeneic hepatocytes on LDL cholesterol levels in LDL receptor deficient hyperlipidemic Watanabe rabbits. METHODS: A catheter was surgically inserted into the inferior mesenteric vein. Blood supply to the right liver lobe was transiently interrupted. Nine infusions of 2.5x10(7) adult allogeneic hepatocytes from white New Zealand rabbits were applied over a period of 2 months. RESULTS: Compared to pretreatment levels LDL cholesterol decreased significantly in Watanabe rabbits with transient ischemia reperfusion injury and repeated hepatocyte transplantation (-42+/-3%). Repeated hepatocyte transplantation without transient ischemia reperfusion injury decreased LDL cholesterol levels only moderately (-11+/-4%). LDL receptor messenger RNA and proteins were detected in hepatocyte transplanted liver but not in the liver of sham treated animals. CONCLUSIONS: Our data indicate that transient ischemia reperfusion injury of the recipient liver is safe and significantly improves the therapeutic efficacy of allogeneic hepatocyte transplantation in hyperlipidemic rabbits with congenital LDL receptor deficiency.

Animals↗
PubMed1977

Localization of single-chain interruptions in bacteriophage T5 DNA. II. Electrophoretic studies.

Upon denaturation, T5 DNA yields a large number of discrete, single-chain fragments that can be resolved by agarose gel electrophoresis. The positions of the more prominent of these fragments in the T5 duplex were determined by analyzing their sensitivity to digestion with lambda exonuclease and their distribution among EcoRI fragments of T5 DNA. These experiments also provide firm evidence concerning the polarity of the strands in T5 DNA. An analogous study was carried out on the fragments produced by treating exonuclease III-degraded T5 DNA with the single-strand-specific SI endonuclease. This procedure yielded over 40 discrete duplex fragments that could be resolved with considerable precision by agarose gel electrophoresis. The positions of most of these fragments were determined by analyzing EcoRI fragments of T5st(+) and T5st(0) DNA. Over 20 sites where single-chain interruptions can occur in T5 DNA were identified, and the distribution of interruptions within the terminal repetition was shown to be identical at both ends of the molecule. A precise value for the size of the terminal repetition in T5 DNA was obtained by analyzing SI endonuclease digests of ligase-repaired, circular T5 DNA in agarose gels. The repeated segment represented 8.3% of the T5st(+) DNA. The results of this study also provide information concerning the properties of lambda exonuclease. Hydrolysis by this enzyme was not terminated when single-chain interruptions were encountered either in the strand being degraded or in the complementary strand.

Base Sequence↗
PubMed2026

Population-scale disease-associated tandem repeat analysis reveals locus and ancestry-specific insights.

Tandem repeat (TR) expansions, including short TRs (motifs ≤6 bp) and variable number TRs (motifs >6 bp), underlie many monogenic disorders, with variable length and sequence influencing pathogenicity, penetrance, severity, and onset. Accurate genotype-phenotype correlation and disease prevalence estimation require characterization beyond repeat length. Here we present a population-scale analysis of 66 disease-associated TR loci using long-read assemblies from 2530 diverse haplotypes from 1265 unaffected donors. Integrating repeat length, motif composition, local ancestry, linkage disequilibrium, and phylogenetic analyses, we reveal extensive locus-, population-, and allele-specific variation shaping disease risk. Up to 8.5% of individuals carry expansions above established pathogenic thresholds, many containing interrupting motifs or sequence structures that attenuate pathogenicity. After excluding alleles from loci with uncertain disease association, non-pathogenic interrupted expansions, and carrier states inconsistent with inheritance patterns, ~4% carried expansions predicted to confer disease risk, largely at adult-onset loci with reduced penetrance. Ancestry-resolved analyses uncover population-specific TR architectures contributing to epidemiological disparities in repeat expansion disorders. Phylogenetic analyses identify conserved ancestral alleles and loci with recent instability. We describe variable linkage disequilibrium patterns and recombination signatures around specific disease-associated TR loci. Our findings emphasize integrating sequence, ancestry, and evolutionary context to understand the complex landscape of disease-associated TRs.

Humans↗
PubMed2002

Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection.

Potent antiretroviral therapy (ART) suppresses HIV-1 viral replication and results in decreased morbidity and mortality. However, prolonged treatment is associated with drug-induced toxicity, emergence of drug-resistant viral strains, and financial constraints. Structured therapeutic interruptions (STIs) have been proposed as a strategy that could boost HIV-specific immunity, through controlled exposure to autologous virus over limited time periods, and subsequently control viral replication in the absence of ART. Here, we analyzed the impact of repeated STIs on virological and immunological parameters in a large prospective STI study. We show that: (i) the plateau virus load (VL) reached after STIs correlated with pretreatment VL, the amount of viral recrudescence during the treatment interruptions, and the off-treatment viral rebound rate; (ii) the magnitude and the breadth of the HIV-specific CD8(+) T lymphocyte response, despite marked interpatient variability, increased overall with STI. However, the quantity and quality of the post-STI response was comparable to the response observed before any therapy; (iii) individuals with strong and broad HIV-specific CD8(+) T lymphocyte responses at baseline retained these characteristics during and after STI; (iv) the increase in HIV-specific CD8(+) T lymphocyte frequencies induced by STI was not correlated with decreased viral set point after STI; and (v) HIV-specific CD4(+) T lymphocyte responses increased with STI, but were subsequently maintained only in patients with low pretreatment and plateau VLs. Overall, these data indicate that STI-induced quantitative boosting of HIV-specific cellular immunity was not associated with substantial change in viral replication and that STI was largely restoring pretherapy CD8(+) T cell responses in patients with established infection.

Anti-HIV Agents↗
PubMed1985

Influence of repeated APF applications on long-term remineralization of initial lesions in bovine enamel.

Initial lesions in bovine enamel were remineralized in vitro for periods lasting from one hour to two weeks; in some cases, remineralization was interrupted daily for a ten-minute APF application. After two weeks, surface coatings appeared on APF-treated specimens; SEM and TEM observations, including selected area and micro-electron diffraction, indicated both a layered structure within these coatings, and the predominance of calcium fluoride single crystals, ranging from 0.1 to 1.0 micrometer in size. Using double (45 Ca and 32 P) labeled remineralizing solutions, we obtained depth profiles of deposited labeled calcium and phosphate; these indicated that repeated APF applications prevented inward penetration of calcium and phosphate and limited the deposition of these ions to an outer surface region corresponding to the surface coating. These phenomena are explained in terms of the composition and apparent reactivity of the coating.

Acidulated Phosphate Fluoride↗
PubMed1984

Non-random loss of uninterrupted ribosomal DNA repeating units upon induction of a bobbed mutation.

To investigate the physical organization of ribosomal RNA genes of two bobbed (bb) loci carried by the Dp(1;f)122 free duplication, a wild type and a deleted one derived from it, genomic DNAs from XXNO-/Dp122bb+ and XXNO-/Dp122bb adult females were analyzed by restriction enzyme digestions. We found that in the bb mutant there was a loss of uninterrupted genes, while genes interrupted by type I and type II insertions remained apparently unchanged. This is an indication that at least in this wild type bb+ locus, carried by the 122 free duplication, the different repeating units are not distributed randomly. In fact, after digestion of the rDNA carried by the bb+ duplication with the enzyme BamHI that cuts only in type I insertions, we have obtained long uncleaved fragments of DNA containing uninterrupted genes.

Animals↗
PubMed1997

Repeatability of methacholine challenges in 2- to 4-year-old children with asthma, using a new technique for quantitative delivery of aerosol.

To determine the repeatability of bronchial responsiveness in awake young children, two methacholine challenge tests were performed on separate days in 16 children with stable asthma (mean age, 3 3/4 years). Methacholine was administered using a new method for quantitative delivery of aerosol that eliminates the effect of dilution of the aerosol by entrainment of air and enables quantitative delivery of aerosol according to body weight. Respiratory function was monitored by measurement of respiratory resistance by the interrupter technique (Rint), respiratory resistance and reactance at 5 Hz (Rrs5, Xrs5) by the impulse oscillation technique, transcutaneous measurements of oxygen (PtcO2), and specific airway resistance (sRaw). Repeatability was evaluated by determining the provocative dose that caused a defined percentage of change relative to baseline (PD%: Rint PD30, Rrs5 PD30, Xrs5 PD80, PtcO2 PD10, and sRaw PD80. Repeatability was estimated from the difference between the PD% obtained at the time of the two tests. Using the numeric value of these differences, the repeatability of Xrs5 PD60, PtcO2 PD10, and sRaw PD50 was [mean (SD)]: [0.8 (0.5)] [0.5 (0.4)] and [0.7 (0.6)] doubling doses, respectively. Rint PD30 and Rrs5 PD30 proved to be less reproducible: [1.2 (1)] and [1.6 (0.9)] doubling doses, respectively. The new method of aerosol delivery offers a means of standardizing the bronchoconstrictor stimulus, and the results show that estimates of bronchial responsiveness in young children can be obtained reproducibly within one doubling dose of methacholine.

Aerosols↗
PubMed1994

Basal components of the transcription apparatus (RNA polymerase II, TATA-binding protein) contain activation domains: is the repetitive C-terminal domain (CTD) of RNA polymerase II a "portable enhancer domain"?

Regions rich in serine, threonine, and proline residues can be found in transcriptional activation domains, as well as in the N-terminal parts of mammalian TATA-binding proteins, where they are interrupted by polyglutamine stretches. Likewise, the C-terminal domain of the largest subunit of RNA polymerase II contains multiple repeats of the consensus heptapeptide sequence YSPTSPS. To test directly for possible activation functions, we fused the GAL4 DNA-binding domain to the N-terminal domain of human TBP or subdomains of it, and to the C-terminal domain (CTD) of mouse RNA polymerase II or synthetic polymers of a CTD consensus repeat. We found that these chimeric proteins were able to activate transcription when bound to a GAL4 site in front of the TATA box, a function characteristic of transcription factors. However, while subdomains of TBP functioned only from a position close to the TATA box ("promoter" position), multiple repeats of the CTD consensus sequence were also able to mediate transcriptional activation from a remote ("enhancer") position. Our findings suggest that a region of TBP that is unique to mammals functionally cooperates with "proximal" activation domains of promoter-bound transcription factors. They also imply that the C-terminal domain of RNA polymerase II includes a function that is otherwise confined to remote activation domains of enhancer-bound transcription factors. We suggest that the CTD of RNA polymerase II contains a "portable" remote activation domain that may also facilitate chromatin opening within the transcription unit.

Amino Acid Sequence↗
PubMed1999

Folyt1, a new member of the hAT family, is active in the genome of the plant pathogen Fusarium oxysporum.

An active transposable element, Folyt1, has been isolated from the tomato pathogen Fusarium oxysporum f. sp. lycopersici as an insertion sequence within the coding region of the nitrate reductase gene (nit 1) in two independent mutants (CO66 and CO108). Folyt1 was 2615 bp in length and contained 9-bp imperfect inverted terminal repeats (ITRs) and 8 bp duplicated at the target site upon insertion. The element contained a long open reading frame interrupted by a single putative intron. The predicted amino acid sequence showed similarity to conserved domains of transposases from hobo, Ac, and Tam3 elements, which belong to the hAT family. The excision frequency of Folyt1 was determined to be less than 10(-5) in both mutants. These events restored the nit 1 wild-type allele without leaving footprints in all the revertants of strain CO66. Nevertheless, some revertants of strain CO108 showed a point mutation footprint at the target sequence. Expression of the Folyt1 transposase was detected by Northern analysis as a 2.1-kb transcript. The element exists in about 10 copies per genome in F. oxysporum f. sp. lycopersici and appears to be widely distributed among different formae speciales of F. oxysporum.

Amino Acid Sequence↗
PubMed2000

[Acardius or "twin-reversed arterial prefusion" sequence. Report of four cases and review of current therapeutic possibilities].

We describe four cases of acardius (one of hemiacardius, two of holoacardius acephalus, and one of the holacardius amorphus) and present the current range of therapeutic possibilities: control of amniotic fluid by repeated amniocentesis or indomethacin therapy, administration of digoxin to the mother, selective preterm delivery of the acardiac twin by hysterotomy, interruption of the anastomoses by injection of thrombogenic coils, sclerosing agents, umbilical cord ligation, fetoscopic laser coagulation, and thermocoagulation.

Abnormalities, Multiple↗