Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Library Administration”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 829 records · Page 46Linked to original sources
PubMed2004

Intravenous immunoglobulin for suspected or subsequently proven infection in neonates.

BACKGROUND: Congenital and nosocomial infections are important causes of neonatal morbidity and mortality. Maternal transport of immunoglobulins to the fetus mainly occurs after 32 weeks gestation and endogenous synthesis does not begin until several months after birth. Administration of intravenous immunoglobulin provides IgG that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody dependent cytotoxicity, and improve neutrophilic chemo luminescence. Theoretically infectious morbidity and morbidity could be reduced by the administration of intravenous immunoglobulin. OBJECTIVES: To assess the effectiveness of intravenous immunoglobulin (IVIG) to reduce mortality/morbidity caused by suspected infection in newborn infants. In secondary analyses to assess the effectiveness of IVIG to reduce mortality/morbidity in those neonates who entered into the studies with suspected infection and who later were confirmed as being infected. SEARCH STRATEGY: MEDLINE, EMBASE and the Cochrane Library were searched in September 2003. The reference lists of identified RCTs, meta-analyses and personal files were searched. No language restrictions were applied. Unpublished information was requested from and obtained from five researchers (Erdem 1993; Gokalp 1994; Haque 1988; Mancilla-R 1992; Shenoi 1999). For this update no new trials were identified but additional information on one trial (Mancilla-R 1992) was obtained in February 2002. SELECTION CRITERIA: The criteria used to select studies for inclusion were: 1) DESIGN: RCT (including quasi-randomized trials) 2) Newborn infants (< 28 days old)3) INTERVENTION: IVIG for treatment of suspected (and in some infants subsequently proved) bacterial/fungal infection compared to placebo or no intervention. 4) At least one of the following outcomes was reported: mortality during initial hospital stay; length of hospital stay; side effects; psychomotor development/growth at follow up. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted information for the outcomes of interest and one researcher (AO) checked for any discrepancies and pooled the results. Typical Relative Risk (RR) and Risk Difference (RD) with 95% confidence intervals (CI) using the fixed effects model are reported for dichotomous outcomes and weighted mean difference (WMD) for continuous data. NNT were to be calculated for outcomes that showed a statistically significant reduction in RD. For this update we did not calculate the RD and the NNT for the subset of patients, who entered the trials with suspected sepsis and who were subsequently proven to have sepsis. Such estimates are meaningless as the clinician is unaware at the point of starting treatment, whether the infant will have proven sepsis or not. For this update we added the I(2) statistic. MAIN RESULTS: Five hundred fifty three neonates with suspected infection have been enrolled in RCTs to evaluate the effect of IVIG on neonatal outcomes. These studies were undertaken in seven countries. Six studies (n = 318) reported on the outcome of mortality for randomized patients with clinically suspected infection. The results showed a reduction in mortality following IVIG treatment [typical RR 0.63 (95% CI; 0.40, 1.00), RD -0.09 (95% CI; 0.00, -0.17) of borderline statistical significance. Treatment with IVIG (seven trials, n = 262) in cases of subsequently proven infection did result in a statistically significant reduction in mortality [typical RR 0.55 (95% CI; 0.31, 0.98)In spite of different geographical locations of the studies, differences in the mortality in the control groups (range 0% - 43.8%), the use of different IVIG preparations, and different dosing regimens, there was no statistically significant between-study heterogeneity for the outcome of mortality in the two analyses. I(2 )= 0%. REVIEWER'S CONCLUSIONS: The conclusions did not change in this updated review. There is insufficient evidence to support the routine administration of IVIG preparations investigated to date to prevent mortality in infants with gated to date to prevent mortality in infants with suspected or subsequently proved neonatal infection. Researchers should be encouraged to undertake well-designed trials to confirm or refute the effectiveness of IVIG to reduce adverse outcomes in neonates with suspected infection. Such a trial is currently ongoing in the UK and Australia (Brocklehurst 2001). The sample size is 5000 neonates and as of September 2003 more than 600 patients have been enrolled.

Humans↗
PubMed2004

Intramuscular penicillin for the prevention of early onset group B streptococcal infection in newborn infants.

BACKGROUND: Early-onset group B streptococcal disease (EOGBSD) is the most frequent cause of serious infection in the newborn period. Current strategies used to prevent EOGBSD are focused upon maternal antibiotic prophylaxis to reduce transmission of GBS to the infant. Observational studies have suggested that the administration of intramuscular penicillin to the newborn immediately following delivery may be an effective strategy to reduce the incidence of EOGBSD. OBJECTIVES: To determine if the administration of intramuscular penicillin to newborns at birth is a safe and effective method to prevent morbidity and mortality from EOGBSD. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. This included searches of electronic databases: Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 1, 2004), and MEDLINE (1966 - Dec 2003); and previous reviews including cross references, expert informants and journal hand searching in the English language as well as conference and symposia proceedings published in Pediatric Research. SELECTION CRITERIA: Randomised trials in which intramuscular penicillin was administered as prophylaxis for EOGBSD within four hours of birth.Outcomes considered were EOGBSD, neonatal mortality, late-onset GBSD, neonatal sepsis, and other secondary outcomes such as neurodevelopmental status and length of hospital stay. DATA COLLECTION AND ANALYSIS: The search for and assessment of trials for inclusion, quality assessment and data extraction were undertaken independently by the reviewers. Meta-analysis was not undertaken as data from only one trial is included in this review. Data were analysed using relative risk (RR) with 95% confidence intervals (CI). MAIN RESULTS: One randomised controlled trial was included in this review. In this trial of 1187 infants of birthweight 501 to 2000 grams, there were no significant differences found for the outcomes of EOGBSD (RR 0.73; 95%CI 0.32, 1.62), or neonatal mortality (RR 0.78; 95% CI 0.55, 1.11). No other outcomes were able to be assessed. REVIEWERS' CONCLUSIONS: This review does not support the routine use of intramuscular penicillin to prevent EOGBSD in newborn infants. There is a discrepancy between this finding and the results of a number of larger non-randomised trials. Explanations for this are proposed. There is a need for this intervention to be tested as a component of the existing prevention strategies in widespread use.

Humans↗
PubMed2004

Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats.

Liver fibrosis is characterized by increased synthesis, and decreased degradation, of extracellular matrix (ECM) within the injured tissue. Decreased ECM degradation results, in part, from increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), which blocks matrix metalloproteinase (MMP) activity. TIMP-1 is also involved in promoting survival of activated hepatic stellate cells (HSCs), a major source of ECM. This study examined the effects of blocking TIMP-1 activity in a clinically relevant model of established liver fibrosis. Rats were treated with carbon tetrachloride (CCl(4)), or olive oil control, for 6 weeks; 24 days into the treatment, the rats were administered a neutralizing anti-TIMP-1 antibody derived from a fully human combinatorial antibody library (HuCAL), PBS, or an isotype control antibody. Livers from CCl(4)-treated rats exhibited substantial damage, including bridging fibrosis, inflammation, and extensive expression of smooth muscle alpha-actin (alpha-SMA). Compared to controls, rats administered anti-TIMP-1 showed a reduction in collagen accumulation by histological examination and hydroxyproline content. Administration of anti-TIMP-1 resulted in a marked decrease in alpha-SMA staining. Zymography analysis showed antibody treatment decreased the activity of MMP-2. In conclusion, administration of a TIMP-1 antibody attenuated CCl(4)-induced liver fibrosis and decreased HSC activation and MMP-2 activity.

Actins↗
PubMed2003

Salusins: newly identified bioactive peptides with hemodynamic and mitogenic activities.

The discovery of endogenous bioactive peptides has typically required a lengthy identification process. Computer-assisted analysis of cDNA and genomic DNA sequence information can markedly shorten the process. A bioinformatic analysis of full-length, enriched human cDNA libraries searching for previously unidentified bioactive peptides resulted in the identification and characterization of two related peptides of 28 and 20 amino acids, which we designated salusin-alpha and salusin-beta. Salusins are translated from an alternatively spliced mRNA of TOR2A, a gene encoding a protein of the torsion dystonia family. Intravenous administration of salusin-alpha or salusin-beta to rats causes rapid, profound hypotension and bradycardia. Salusins increase intracellular Ca2+, upregulate a variety of genes and induce cell mitogenesis. Salusin-beta stimulates the release of arginine-vasopressin from rat pituitary. Expression of TOR2A mRNA and its splicing into preprosalusin are ubiquitous, and immunoreactive salusin-alpha and salusin-beta are detected in many human tissues, plasma and urine, suggesting that salusins are endocrine and/or paracrine factors.

Adenosine Triphosphatases↗
PubMed2003

Characterization and cDNA cloning of a clofibrate-inducible microsomal epoxide hydrolase in Drosophila melanogaster.

In order to understand the roles of the epoxide hydrolases (EHs) in xenobiotic biotransformation in insects, we examined the induction of EHs by exogenous compounds in Drosophila melanogaster third instar larvae. Among the chemicals tested, clofibrate, a phenoxyacetate hypolipidermics drug, increased EH activity towards cis-stilbene oxide approximately twofold in larval whole-body homogenates. The same dose of clofibrate also induced glutathione S-transferase activity. The effect of clofibrate on EH induction was dose-dependent and the highest activity occurred with a 10% clofibrate application. Three other substrates conventionally used in EH assays (trans-stilbene oxide, trans-diphenylpropene oxide and juvenile hormone III) were poorly hydrolysed by larval homogenates, with or without clofibrate administration. Because the increased EH activity was localized predominantly in the microsomal fraction, we synthesized degenerate oligonucleotide primers with sequences corresponding to conserved regions of known microsome EHs from mammals and insects in order to isolate the gene. The 1597 bp putative cDNA of D. melanogaster microsomal EH (DmEH) obtained from a larval cDNA library encoded 463 amino acids in an open reading frame. Northern blot analysis showed that the transcription of DmEH was increased in larvae within 5 h of clofibrate treatment. Recombinant DmEH expressed in baculovirus hydrolysed cis-stilbene oxide (23 nmol.min-1.mg protein-1) and was located mainly in the microsomal fraction of virus-infected Sf9 cells. There was no detectable EH activity toward juvenile hormone III. These observations suggest that DmEH is involved in xenobiotic biotransformation, but not in juvenile hormone metabolism, in D. melanogaster.

Amino Acid Sequence↗
PubMedDate not supplied

Quality of life assessment of randomized controlled trials.

AIMS AND BACKGROUND: According to the USA Food and Drug Administration, quality of life (QOL) and/or survival are a priority for new anticancer drug approval. This study was performed to review approaches to QOL in randomized controlled clinical trials (RCCTs) and to survey the use of such measures in trials. MATERIAL AND METHODS: A literature survey was carried out using the Medline/Medscape, Embase, Cochrane Library, and Ovid databases. Included in the survey were all publications in the set period (from 1966 to June 2005) with "quality of life" in the title or in the abstract in the field of "randomized, controlled clinical trials". Each trial was evaluated according to the level of importance of QOL as a measure of outcome (primary, important and secondary) and was analyzed using the quality scoring system reported by Nicolucci et al. with some items regarding QOL. RESULTS: Four hundred and five RCCT articles in the oncology setting were found. Fifty-six of the 405 (13.8%) publications had QOL as primary end point. The overall quality score of these trials ranged from 40% to 100%, with a median overall score of 80%. The overall score was correlated with the year of publication (P = 0.007), the type of journal (P = 0.05), the presence of a biostatistician among the authors (P = 0.001), and the number of participating institutions (P = 0.009). CONCLUSIONS: More attention to QOL in all components of RCCTs (design, choice of instruments, data management and processing) is required from both clinicians and statisticians.

Humans↗
PubMed2000

Practical aspects to realize data transfer between a patient administration mastersystem and clinical subsystems using ProtoGen/HL7.

At the Medizinische Einrichtungen Bonn the module IS-H of SAP R/3 is used for patient administration. All clinical subsystems will be provided with patient data using HL7 2.3 messages. These messages are generated from HCM messages a proprietary format of IS-H by means of a communication server. Interface application for subsystems which are not capable of processing HL7 messages are written using the open source C++ class library ProtoGen/HL7. First experiences and remaining problems are discussed.

Data Collection↗
PubMed2006

Tumor specific phage particles promote tumor regression in a mouse melanoma model.

Within cancer research, phage display libraries have been widely used for the identification of tumor targeting peptides and antibodies. Additionally, phages are known to be highly immunogenic; therefore we evaluated the immunotherapeutic potential of tumor specific phages to treat established solid tumors in a mouse model of melanoma. We developed two tumor specific phages, one derived from a peptide phage display library and one Fab expressing phage with known specificity, for the treatment of mice bearing palpable B16-F10 or B16/A2K(b) tumors. Therapy in B16-F10 tumor bearing mice with tumor specific phages was superior to treatment with non-tumor specific phages and lead to delayed tumor growth and increased survival. In B16/A2K(b )tumor bearing mice, therapy with tumor specific phages resulted in complete tumor regression and long-term survival in 50% of the mice. Histological analysis of tumors undergoing treatment with tumor specific phages revealed that phage administration induced a massive infiltration of polymorphonuclear neutrophils. Furthermore, phages induced secretion of IL-12 (p70) and IFN-gamma as measured in mouse splenocyte culture supernatants. These results demonstrate a novel, immunotherapeutic cancer treatment showing that tumor specific phages can promote regression of established tumors by recruitment of inflammatory cells and induction of Th1 cytokines.

Animals↗
PubMed2001

Alpha-1 proteinase inhibitor (a1PI) for preventing chronic lung disease in preterm infants.

BACKGROUND: Inflammation of the pulmonary parenchyma is one of the important mechanisms implicated in development of chronic lung disease (CLD) in preterm neonates. Release of enzymes and other anti - oxidants following cell damage is considered to be responsible for the damage to lung tissue. Various strategies have been attempted to counteract enzymatic damage to pulmonary parenchyma and to prevent CLD. OBJECTIVES: This review examines the effectiveness of alpha 1 proteinase inhibitor (a1PI) for the prevention of CLD defined as requirement of supplemental oxygen at 36 weeks post menstrual age (PMA) in preterm neonates. SEARCH STRATEGY: A literature search was performed using the following databases: MEDLINE (1966 - February 2001), EMBASE (1980 -February 2001), CINAHL (1982 - February 2001), Cochrane Controlled Trials Register (Issue 1, 2001 of Cochrane Library) and abstracts from the annual meetings of the Society of Pediatric Research, American Pediatric Society and Pediatric Academic Societies published in Pediatric Research (1991-2000). No language restrictions were applied. SELECTION CRITERIA: Selection criteria applied to the clinical trials were: 1. The population had to be preterm neonates 2. The intervention had to be administration of a1PI compared to placebo or no treatment within the first week of life 3. The eligible studies had to include any of the following outcomes: a. prevention of CLD b. reduction in duration of assisted ventilation c. reduction in the duration of oxygen requirement d. reduction in the need for systemic antiinflammatory therapy e. reduction in mortality or f. reduction in long term adverse neurological sequelae. 4. The trial had to be randomized or quasi-randomized. DATA COLLECTION AND ANALYSIS: The methodological quality of the trials was assessed using the information provided in the studies and by personal communication with the authors. Data on relevant outcomes were extracted and the effect size was estimated and reported as pooled relative risk (RR), risk difference (RD) and weighted mean difference (WMD) as appropriate. Two strategies were used for analysis : 1. Comparison of 60 mg/kg/dose of a1PI administered for 4 days in first 2 weeks after birth, versus placebo and 2. Comparison of any dose of a1PI administered in first 2 weeks after birth, versus placebo. MAIN RESULTS: Two eligible studies were identified. The methodological qualities of identified studies were good. One study randomized infants to either placebo, or a1PI 60 mg/kg/dose for four doses while in the second study the same investigators explored the efficacy of different dose regimens of a1PI compared to placebo. There was no statistically significant difference in the development of CLD at 36 weeks PMA amongst all randomized infants. For 60 mg/kg/dose for four doses of a1PI compared to placebo the pooled RR was 0.64 [95% CI 0.35, 1.18] and RD was -0.10 [95% CI -0.23, 0.03] while for any doses of a1PI the pooled RR was 0.79 [95% CI 0.44, 1.41], RD was -0.05 [95% CI -0.17, 0.06]. There was a trend towards reduced risk of development of oxygen dependency at 28 days postnatal age, pooled RR 0.81 [95% CI 0.64, 1.01], RD -0.14 [95% CI -0.29, 0.00] for 60 mg/kg/dose for four doses of a1PI compared to placebo. The pooled RR was statistically significant, RR 0.80 [95% CI 0.65, 0.98], RD -0.15 (95 % CI -0.29, -0.01) when any doses of a1PI were combined. The number of patients needed to treat (NNT) with a1PI to prevent one infant developing oxygen dependency at 28 weeks was 7. The benefits of short-term outcomes did not remain for long-term outcomes such as CLD and/or death at 36 weeks post menstrual age (pooled RR 0.84 [95% CI 0.53, 1.34], RD -0.06 [95% CI -0.20, 0.09] for 60 mg/kg/dose and pooled RR 0.95 [95% CI 0.61, 1.49], RD -0.02 [95% CI -0.15, 0.12] for any dose) or risk of development of long term neurodevelopmental abnormalities (pooled RR 1.29 [95% CI 0.43, 3.90], RD 0.03 [95% CI -0.11, 0.18]). In addition, no statistically significant difference was noted in other respiratory parameters such as duration of oxygen requirement or respiratory support. REVIEWER'S CONCLUSIONS: Prophylactic administration of a1PI did not reduce the risk of CLD at 36 weeks or long term adverse developmental outcomes in preterm neonates.

Chronic Disease↗
PubMed2007

A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice.

Peptidic mimics of the gut hormone glucagon-like peptide (GLP) 1, exemplified by the recently approved drug exenatide, show promise as therapies for type 2 diabetes. Such "incretin mimetics" regulate glucose appearance in the plasma and can restore glucose-stimulated insulin secretion without excess risk of hypoglycemia. The need for injection, which may limit the use of peptidic GLP-1 receptor (GLP-1R) agonists, has driven largely unsuccessful efforts to find smaller molecules. The failure to identify orally effective agonists has instead promoted the indirect approach of inhibiting the GLP-1-degrading enzyme dipeptidyl peptidase IV. Here we report a nonpeptidic GLP-1R agonist with sufficient activity to evoke effects in whole animals, including antidiabetic efficacy in db/db mice. Two substituted cyclobutanes (S4P and Boc5) were developed after screening a compound library against a cell line stably cotransfected with GLP-1R and a cAMP-responsive reporter. Each bound to GLP-1R and increased intracellular cAMP. Agonist effects were blocked by the GLP-1R antagonist exendin(9-39). Boc5 amplified glucose-stimulated insulin secretion in isolated rat islets. Both i.p. and oral administration of Boc5 dose-dependently inhibited food intake in mice, an effect that could be blocked by pretreatment with exendin(9-39). Daily injections of Boc5 into db/db mice reduced HbA1c to nondiabetic values, an effect not observed in ad libitum-fed or pair-fed diabetic controls. Thus, Boc5 behaved as a full GLP-1 mimetic in vitro and in vivo. The chemical genus represented by Boc5 may prompt the exploration of orally available GLP-1R agonists with potential utility in diabetes and obesity.

Acute Disease↗
PubMed1995

Rat CYP1B1: an adrenal cytochrome P450 that exhibits sex-dependent expression in livers and kidneys of TCDD-treated animals.

The broad spectrum of biological responses associated with exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is believed to be due to the alteration in expression of TCDD-inducible genes. The aim of this study was to investigate the effects of TCDD on the in vivo tissue-specific expression of the recently identified TCDD-inducible cytochrome P450 CYP1B1 [Sutter et al. (1994) J. Biol. Chem., 269, 13092-13099] in Sprague-Dawley rats. We cloned the 5.0 kb rat homolog of CYP1B1 from a TCDD-treated rat liver cDNA library and showed that the rat and human CYP1B1 predicted amino acid sequences are 80% identical. RNA hybridization analysis showed that CYP1B1 is constitutively expressed in the adrenal glands and also in the testes of untreated rats. This tissue distribution suggests that CYP1B1 may be a physiological steroid hydroxylase. Seventy-two hours post-administration of 25 micrograms/kg body wt TCDD by gavage, steady-state levels of the 5.1 kb CYP1B1 RNA were increased > 50-fold in liver, and to a lesser extent in kidneys, lung, heart and ovaries. Average CYP1B1 RNA levels were significantly higher in the kidneys and livers of TCDD-treated females than in those from similarly treated males. In contrast, no significant sex-difference was observed in the levels of CYP1A1 in these tissues in TCDD-treated animals. In Sprague-Dawley rats, TCDD is a more potent hepatocarcinogen in females than in males. The induction of CYP1B1 in TCDD rat liver may be a contributing factor to the carcinogenic action of this persistent environmental pollutant.

Adrenal Glands↗
PubMed2002

A novel short-chain alcohol dehydrogenase from rats with retinol dehydrogenase activity, cyclically expressed in uterine epithelium.

Retinoic acid is necessary for the maintenance of many lining epithelia of the body, such as the epithelium of the luminal surface of the uterus. Administration of estrogen to prepubertal rats induces in these epithelial cells the ability to synthesize retinoic acid from retinol, coincident with the appearance of cellular retinoic acid-binding protein, type two, which is normally present in these cells only at estrus in the mature, cycling animal. Here, we report the isolation, from a cDNA library prepared from uterine mRNA collected at the estrous stage and from a rat mammary adenocarcinoma cell line, of a cDNA that encodes a novel retinol dehydrogenase. A member of the short-chain alcohol dehydrogenase family, the encoded enzyme was capable of metabolizing retinol to retinal when expressed in cells after transfection of its cDNA. When cotransfected with the cDNA of human aldehyde 6, a known retinaldehyde dehydrogenase, the transfected cells synthesized retinoic acid from retinol. Immunohistochemical analysis revealed that the protein was present in the uterine lining epithelium of the mature animal only at estrus, coincident with the presence of cellular retinol-binding protein and cellular retinoic acid-binding protein, type two. Consequently, this novel short-chain alcohol dehydrogenase is an excellent candidate for the retinol dehydrogenase that catalyzes the first step in retinoic acid biosynthesis that occurs in uterine epithelial cells.

Adenocarcinoma↗
PubMedDate not supplied

[Neurotoxic effects induced by the topical administration of cycloplegics. A case report and review of the literature].

INTRODUCTION: We report a patient who developed an acute confusional state with hallucinations after exposure to cycloplejic eye drops, and review the current literature regarding neurotoxicity due to this type of eye drops. CASE REPORT: A 61 year-old man who developed in two occasions confusion, disorientation and vivid visual hallucinations following exposure to a cyclopejic eye drop containing atropine 2%, scopolamine 0.5% and phenylephrine 4%. We performed a literature search regarding neurological complications of cycloplegic eye drops using the PubMed Database and the services of the Virtual Library 'Agencia Lain Entralgo'. The clinical features of all reports in which the original document was obtained are analyzed and summarized. We have summarized the clinical features of 29 patients with neurotoxicity due to cyclopentolate, 19 to atropine, 18 to scopolamine, 7 to homatropine, and 2 to tropicamide. Our patient should be the fourth reported in Spain, being the offending drug in the four cases the same eye drop. The most commonly reported symptoms are visual hallucinations, behavioral disorders/acute psychosis, alterations of consciousness/confusion, restlessness/hyperactivity, ataxia and speech disorders. Many of the patients reported are children and elder. There have been reported some fatal cases, specially related with atropine. CONCLUSIONS: Neurotoxicity related with anticholinergic effects of cycloplegic agents is not infrequent, although it is not well known in our setting; and can cause death in some cases. Exposure to these drugs should be taken in account in the differential diagnosis of acute confusional syndromes.

Administration, Topical↗
PubMed2005

Combinatorial design of nonsymmetrical cyclic urea inhibitors of aspartic protease of HIV-1.

The aspartic protease (PR) of the human immunodeficiency virus type 1 (HIV-1) is an important target for the design of specific antiviral agents dedicated to treatment of HIV-1 infection. We have employed computer-assisted combinatorial chemistry methods to design a small focused virtual library of nonsymmetrically substituted cyclic urea inhibitors of the PR. Nonsymmetrical compounds with decreased peptidic character were namely found to inhibit the PR with comparable inhibition potencies as their C2-pseudosymmetric counterparts and to possess superior pharmacokinetic properties. To generate the virtual library of fully nonsymmetrical cyclic urea analogs, diverse reagents were selected from databases of available chemicals with characteristics similar to those of the building blocks of known potent PR inhibitors. The X-ray structure of the protease-inhibitor complex PR-XV-638 was used as the receptor model in the structure-based focusing and in silico screening of the virtual library. A target-specific LUDI-type scoring function, parameterized for a QSAR training set of known cyclic urea inhibitors and validated on a set of compounds not included into the training set, was used to predict the inhibition constants (Ki) of the generated analogs toward the HIV-1 PR. The fragments most frequently occurring in the analogs with the highest predicted inhibition potencies (Ki*<10 pM) were then selected to constitute a highly focused library subset containing novel nonsymmetrical cyclic ureas with predicted Ki*s 1 order of magnitude lower than the most potent known cyclic urea inhibitors. ADME properties calculated for the most promising analogs suggested that the cyclic ureas are endowed with a wide range of favorable pharmacokinetic properties, which may favor the discovery of a potent orally administrable antiviral drug.

Combinatorial Chemistry Techniques↗
PubMed1991

Interleukin-1 gene expression in rabbit vascular tissue in vivo.

Cultured human vascular endothelial and smooth muscle cells express interleukin-1 (IL-1) genes when exposed to bacterial lipopolysaccharides (LPS) and a variety of inflammatory mediators. Local production of IL-1 may contribute to the pathogenesis of various vascular diseases. Therefore the ability of intact vascular tissue to accumulate IL-1 mRNA and synthesize de novo biologically active IL-1 protein was examined. Escherichia coli LPS (10 micrograms/kg) was administered intravenously to adult rabbits and total RNA was isolated from aortic tissue at various times after LPS injection. In saline-injected rabbits, RNA extracted from the thoracic aorta contained little or no IL-1 message detected by Northern analysis using IL-1 alpha and beta cDNA probes cloned from an LPS-stimulated rabbit splenic macrophage library. Lipopolysaccharide treatment promptly induced transient accumulation of mRNA for IL-1 alpha and IL-1 beta within the aorta (maximal 1-hour after injection). Short-term organoid cultures of rabbit aorta exposed to LPS in vitro synthesized immunoprecipitable IL-1 alpha protein. Extracts of aortic tissue excised 1.5 to 3.0 hours after intravenous LPS administration contained immunoreactive and biologically active IL-1 alpha. Anti-rabbit IL-1 alpha antibody neutralized the biologic activity (more than 90%). Microscopic and immunohistochemical studies did not disclose adherent or infiltrating macrophages in rabbit aorta at the time of maximal IL-1 mRNA accumulation after LPS administration (1.5 hours), indicating that intrinsic vascular wall cells rather than mononuclear phagocytes probably account for the IL-1 activity induced by LPS. In addition, aortic tissue from rabbits fed an atherogenic diet showed an enhanced ability to accumulate IL-1 alpha and beta mRNA and produce immunodetectable protein in response to LPS administration. These studies demonstrate inducible IL-1 gene expression in rabbit vascular tissue in vivo and support a local role for this cytokine in vascular pathophysiology.

Animals↗
PubMed2000

Antibiotics for preterm labour with intact membranes.

BACKGROUND: There may be a link between infection and preterm birth. OBJECTIVES: Since rupture of the membranes is an important factor in the progression of preterm labour, it is important to see if antibiotics are of any benefit prior to membrane rupture. The objective of this review was to assess the effects of antibiotics administered to women in preterm labour with intact membranes, on maternal and neonatal outcomes. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register and reference lists of articles. We contacted experts in the field. SELECTION CRITERIA: Randomised trials which compared antibiotic treatment with placebo or no treatment for women in preterm labour (between 20 and 36 weeks gestation) with intact membranes. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted independently by two reviewers. Study authors were contacted for missing data. MAIN RESULTS: Meta-analysis of the ten included trials demonstrated a statistically significant prolongation of pregnancy associated with the use of antibiotics (5. 4 days, 95% confidence interval (CI) 0.9- 9.8 days). Antibiotic treatment was also associated with a statistically significant reduction in maternal infection (odds ratio (OR) 0.59, 95% CI 0.36, 0.97) and neonatal necrotising enterocolitis (OR 0.33, 95% CI 0.13, 0.88). No statistically significant effect was detected on the neonatal outcomes of respiratory distress syndrome and neonatal sepsis, although there was a trend towards the latter (OR 0.67, 95% CI 0.42, 1.07). An increase in perinatal mortality was observed in the group receiving antibiotics (OR 3.36, 95% CI 1.21, 9.32). REVIEWER'S CONCLUSIONS: Although a prolongation in time to delivery and a trend towards a reduction in neonatal sepsis was detected, this review fails to demonstrate a clear overall benefit from antibiotic treatment for preterm labour with intact membranes on neonatal outcomes and raises concerns about increased perinatal mortality for those who received antibiotics. This treatment cannot therefore be currently recommended for routine practice. Further research is required to identify a subgroup of women (and their babies) who are more likely to experience benefit from antibiotic treatment for preterm labour prior to membrane rupture, and to identify which antibiotic or combination of antibiotics is most effective. The results of the ongoing ORACLE trial should help resolve some of the uncertainties revealed by this review.

Anti-Bacterial Agents↗
PubMed2004

Manipulation of alternative splicing by a newly developed inhibitor of Clks.

The regulation of splice site usage provides a versatile mechanism for controlling gene expression and for the generation of proteome diversity, playing an essential role in many biological processes. The importance of alternative splicing is further illustrated by the increasing number of human diseases that have been attributed to mis-splicing events. Appropriate spatial and temporal generation of splicing variants demands that alternative splicing be subjected to extensive regulation, similar to transcriptional control. The Clk (Cdc2-like kinase) family has been implicated in splicing control and consists of at least four members. Through extensive screening of a chemical library, we found that a benzothiazole compound, TG003, had a potent inhibitory effect on the activity of Clk1/Sty. TG003 inhibited SF2/ASF-dependent splicing of beta-globin pre-mRNA in vitro by suppression of Clk-mediated phosphorylation. This drug also suppressed serine/arginine-rich protein phosphorylation, dissociation of nuclear speckles, and Clk1/Sty-dependent alternative splicing in mammalian cells. Consistently, administration of TG003 rescued the embryonic defects induced by excessive Clk activity in Xenopus. Thus, TG003, a novel inhibitor of Clk family will be a valuable tool to dissect the regulatory mechanisms involving serine/arginine-rich protein phosphorylation signaling pathways in vivo, and may be applicable for the therapeutic manipulation of abnormal splicing.

Alternative Splicing↗
PubMed2005

Ganglioside GM1-binding peptides as adjuvants of antigens inoculated by the intranasal route.

Forty-five GM1-binding peptides were identified using phage-displayed peptides libraries of random peptides. Most have a motif containing a hydrophobic amino acid followed by a serine (S). Based on a GM1-binding assays, two of these GM1-binding peptides (named 15 and 40) were chosen to investigate its immunostimulatory properties when chemically coupled to antigens. Mice intra-nasally (i.n.) vaccinated with some of these complexes developed a better local and systemic antibody response than mice i.n. vaccinated with the respective uncoupled antigens. The efficiency of the complex GM1-binding peptide-antigen strongly depends on the composition and structure of both of the components of the complex.

Adjuvants, Immunologic↗