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PubMed2006

Synthesis and pharmacological profile of an orally-active growth hormone secretagogue, SM-130686.

Hypothalamic hormones physiologically regulate pulsatile release of growth hormone (GH) from the anterior pituitary gland. Since the discovery of these hormones in the 1970s, several new chemically synthesized peptidyl and non-peptidyl derivatives have been proved to stimulate and amplify GH secretion, and this series of molecules has been named the growth hormone secretagogues (GHSs). One of these compounds led to the discovery of a GPCR-type receptor for GHSs (GHS-R), and subsequently the endogenous ligand for the receptor has been identified, and is referred to as ghrelin. The identification of GHSs as physiological regulators of GH secretion encouraged us to examine our GHSs pharmacologically. We previously reported that novel oxindole derivatives have been identified as GHS-R agonists from our internal chemical library. Among these derivatives, (+)-6-carbamoyl-3-(2-chlorophenyl)-(2-diethylaminoethyl)-4-trifluoromethyloxindole (SM-130686, 37S) was found to have potent activity in vitro with a good pharmacokinetic profile in rats (bioavailability of 28%). In this article, we review the synthesis and pharmacological evaluation of SM-130686. SM-130686 binds specifically to GHS-R and increases the Ca(2+) concentration in Chinese hamster ovary cells expressing recombinant GHS-R. Maximal enhancement of the intracellular Ca(2+) concentration induced by SM-130686 treatment was approximately 55% that induced by ghrelin, suggesting that SM-130686 may be a partial GHS-R agonist. Also, in in vivo studies, oral administration of SM-130686 increased body length and fat-free mass gain. We compare the pharmacological profile of SM-130686 with other GHSs, including GHRH and ghrelin, and discuss the therapeutic usefulness of GHSs against several disorders, as well as for treatment of GH deficiency.

Administration, Oral↗
PubMed1999

Thrombotic thrombocytopenic purpura and autoimmunity: a tale of shadows and suspects.

BACKGROUND AND OBJECTIVE: The key pathogenic feature of TTP is the formation of platelet aggregates within the microcirculation; however, the etiology of such aggregates has been elusive for years. A large amount of evidence points to an abnormal interaction between damaged vascular endothelium and platelets, although the cause of the primary microvascular endothelial cell injury is seldom clear. The autoimmune hypothesis often recurs, and this is based on a number of observations: the claimed superiority of plasma-exchange over plasma infusion, the anecdotal report of the presence of immunocomplexes and autoantibodies in TTP patients, the efficacy of the administration of corticosteroids and other immunosuppressant agents, and the concomitant occurrence of TTP in association with autoimmune diseases, especially systemic lupus erythematosus (SLE). This review will focus on the complex relationships between TTP and humoral autoimmunity; in particular, similarities and differences between TTP, SLE and antiphospholipid (aPL) antibodies syndrome, as well as the putative role of several other antibodies directed towards endothelial cells and/or platelets, including the recently discovered anti-CD36 antibodies and antivWF-cleaving metalloprotease, will be discussed. DESIGN AND METHODS: The authors have been involved in the study and treatment of TTP and autoimmune diseases for years; furthermore, the PubMed data base of the National Library of Congress has been extensively searched using the Internet. CONCLUSIONS: Although over the years evidence has increased in favor of the autoimmune hypothesis for TTP etiopathogenesis, TTP should not yet be considered an autoimmune disease. Autoantibodies should be regarded as only one of the many different insults which can trigger microvascular thrombosis even though the autoimmune theory of the pathogenesis of TTP is gaining more and more strength. As far as concerns the relationship between TTP, SLE and aPL antibodies-related disorders, these diseases should be distinguished on the basis of both different clinical presentations and accurate antibody screening, although this approach should definitely not delay the prompt start of treatment.

ADAM Proteins↗
PubMed1988

Integrated Academic Information Management Systems (IAIMS). Part III. Implementation of integrated information services. Library/computer center partnership.

Information technologies are changing the traditional role of the library from that of a repository of information to that of an aggressive provider of information services utilizing electronic methods. In many cases, the library cannot realistically achieve this transformation independently but must work with the computer center to reach its objectives. Various models of the integration of libraries and computer centers are thus emerging. At the University of Maryland at Baltimore the Health Sciences Library and the Information Resources Management Division have developed a partnership based on functional relationships without changing the organizational structure. Strategic planning for an Integrated Academic Information Management System (IAIMS) acted as a catalyst in the process. The authors present the evolution of the partnership and discuss current projects being developed jointly by the two units.

Academic Medical Centers↗
PubMed1999

Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption.

Calcium is a major component of the mineral phase of bone and serves as a key intracellular second messenger. Postnatally, all bodily calcium must be absorbed from the diet through the intestine. Here we report the properties of a calcium transport protein (CaT1) cloned from rat duodenum using an expression cloning strategy in Xenopus laevis oocytes, which likely plays a key role in the intestinal uptake of calcium. CaT1 shows homology (75% amino acid sequence identity) to the apical calcium channel ECaC recently cloned from vitamin D-responsive cells of rabbit kidney and is structurally related to the capsaicin receptor and the TRP family of ion channels. Based on Northern analysis of rat tissues, a 3-kilobase CaT1 transcript is present in rat duodenum, proximal jejunum, cecum, and colon, and a 6.5-kilobase transcript is present in brain, thymus, and adrenal gland. In situ hybridization revealed strong CaT1 mRNA expression in enterocytes of duodenum, proximal jejunum, and cecum. No signals were detected in kidney, heart, liver, lung, spleen, and skeletal muscle. When expressed in Xenopus oocytes, CaT1 mediates saturable Ca(2+) uptake with a Michaelis constant of 0.44 mM. Transport of Ca(2+) by CaT1 is electrogenic, voltage-dependent, and exhibits a charge/Ca(2+) uptake ratio close to 2:1, indicating that CaT1-mediated Ca(2+) influx is not coupled to other ions. CaT1 activity is pH-sensitive, exhibiting significant inhibition by low pH. CaT1 is also permeant to Sr(2+) and Ba(2+) (but not Mg(2+)), although the currents evoked by Sr(2+) and Ba(2+) are much smaller than those evoked by Ca(2+). The trivalent cations Gd(3+) and La(3+) and the divalent cations Cu(2+), Pb(2+), Cd(2+), Co(2+), and Ni(2+) (each at 100 microM) do not evoke currents themselves, but inhibit CaT1-mediated Ca(2+) transport. Fe(3+), Fe(2+), Mn(2+), and Zn(2+) have no significant effects at 100 microM on CaT1-mediated Ca(2+) transport. CaT1 mRNA levels are not responsive to 1,25-dihydroxyvitamin D(3) administration or to calcium deficiency. Our studies strongly suggest that CaT1 provides the principal mechanism for Ca(2+) entry into enterocytes as part of the transcellular pathway of calcium absorption in the intestine.

Amino Acid Sequence↗
PubMed2004

Practice parameter: treatment of postherpetic neuralgia: an evidence-based report of the Quality Standards Subcommittee of the American Academy of Neurology.

A systematic review of the literature on postherpetic neuralgia was performed. The authors identified studies using the National Library of Medicine's Medline database and Cochrane Library database. The authors determined absolute reduction rate, number needed to treat (NNT), 95% CI for NNT, and number needed to harm (NNH) for successful therapies of postherpetic neuralgia. Tricyclic antidepressants, gabapentin, pregabalin, opioids, and lidocaine patch were found to be effective in reducing the pain of postherpetic neuralgia.

Acupuncture Analgesia↗
PubMed1997

Identification and characterization of a novel human cortistatin-like peptide.

Expressed sequence tags (ESTs) that showed significant homology to rat cortistatin (CST) were found in a human fetal brain cDNA library. A protein coded by the cDNA showed 55% identity to rat preprocortistatin in amino acid. Similarly in the generation of mature peptides from rat preprocortistatin, it was expected that cleavage at dibasic amino acids in the C-terminal portion of the coded protein might produce at least two different sizes of mature peptides with 29 and 17 amino acid residues, respectively. We chemically synthesized the predicted mature peptide with 17 amino acid residues (hCS-17) and examined its biological activities. It bound to all human somatostatin receptor (SSTR) subtypes in almost the same manner as rat CST-14. It also inhibited cAMP production induced by forskolin through SSTRs. Administration of hCS-17 to the cerebral ventricle showed flattening of cortical and hippocampal electroencephalograms in rats. These results indicate that a bioactive peptide encoded by the cDNA is a human counterpart corresponding to rat CST.

Amino Acid Sequence↗
PubMedDate not supplied

Identification of the epidural space: is loss of resistance to air a safe technique? A review of the complications related to the use of air.

BACKGROUND AND OBJECTIVES: The major determinant of successful epidural anesthesia is the localization of the epidural space. The manual loss of resistance technique is widely used by anesthesiologists in identifying the epidural space. Should air or saline be used in detecting the point of loss of resistance? No consensus exists as to which technique is superior, and individual providers currently use the technique with which they are most comfortable. The incidence of adverse effects associated with the use of epidural air is unknown and may be underreported as the effects may be unrecognized or considered trivial. The authors comprehensively review the complications of epidural air from published reports. METHODS: Using the appropriate key words, the authors searched the Medline (National Library of Congress) scientific data bank from 1966 to 1995, for case reports of epidural complications. RESULTS: There are few prospective, controlled, double-blinded studies comparing the relative merits of using air versus saline for the loss of resistance technique of epidural placement. There are, however, numerous case reports. Complications associated with the use of air for the loss of resistance technique included pneumocephalus, spinal cord and nerve root compression, retroperitoneal air, subcutaneous emphysema, and venous air embolism. Additionally, inadequate analgesia and paresthesia have been associated with the loss of resistance technique using air. Transient and permanent neurologic sequelae have been attributed to some of the complications. The simultaneous administration of nitrous oxide and positive. Pressure ventilation has also been reported to expand localized collections of air, resulting in heightened symptoms. CONCLUSIONS: The potential complications associated with the use of air for identifying the epidural space with the loss of resistance technique may outweigh the benefits. The use of saline to identify the epidural space may help to reduce the incidence of these complications.

Adult↗
PubMed1994

Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection.

The cultured T-cell line TIL1200, established from the tumor-infiltrating lymphocytes (TILs) of a patient with advanced metastatic melanoma, recognized an antigen on most HLA-A2+ melanomas and on all HLA-A2+ cultured neonatal melanocytes in an HLA-A2 restricted manner but not on other types of tissues or cell lines tested. A cDNA encoding an antigen recognized by TIL1200 was isolated by screening an HLA-A2+ breast cancer cell line transfected with an expression cDNA library prepared from an HLA-A2+ melanoma cell line. The nucleotide and amino acid sequences of this cDNA were almost identical to the genes encoding glycoprotein gp100 or Pmel17 previously registered in the GenBank. Expression of this gene was restricted to melanoma and melanocyte cell lines and retina but was not expressed on other fresh or cultured normal tissues or other types of tumor tested. The cell line transfected with this cDNA also expressed antigen recognized by the melanoma-specific antibody HMB45 that bound to gp100. A synthetic 10-amino acid peptide derived from gp100 was recognized by TIL1200 in the context of HLA-A2.1. Since the administration of TIL1200 plus interleukin 2 resulted in regression of metastatic cancer in the autologous patient, gp100 is a possible tumor rejection antigen and may be useful for the development of immunotherapies for patients with melanoma.

Adult↗
PubMed1988

Reciprocal regulation of sex-dependent expression of testosterone 15 alpha-hydroxylase (P-450(15 alpha)) in liver and kidney of male mice by androgen. Evidence for a single gene.

Testosterone 15 alpha-hydroxylase activities and its mRNA levels are higher in kidneys than in livers from male 129/J mice. Castration of 129/J male mice resulted in repression of P-450(15 alpha) in kidney, but increased it in liver. Two types of cDNA (p15 alpha-29 (Type I) and -15 (Type II)) encoding P-450(15 alpha) were previously cloned from 129/J female livers (Burkhart, B.A., Harada, N., and Negishi, M. (1985) J. Biol. Chem. 260, 15357-15361). With the use of p15 alpha-29 as a probe, Type I and II P-450(15 alpha) cDNAs were isolated from libraries of 129/J kidney poly(A)+ RNA. The nucleotide sequences of the cDNAs showed that Type I and II cDNAs from liver and kidney were identical and shared 98.3% similarity. The deduced amino acid sequence from a full-length Type I cDNA indicated that Type I P-450(15 alpha) consists of 494 amino acids with a molecular weight of 56,594. Nine amino acid substitutions were found in the Type II clone in 432 amino acids overlapping Type I. Type I cDNA clones accounted for approximately 90% P-450(15 alpha) clones isolated from a male kidney library, whereas approximately 90% of cDNA clones in a female kidney library were Type II. Liver cDNA libraries from males and females contained similar ratios of Type I and II. Effects of castration on Type I and II mRNAs were determined by Southern hybridization of a 32P-labeled ClaI-ClaI fragment from p15 alpha-29 to cDNAs synthesized from kidney and liver poly(A)+ RNAs prepared from sham-operated, castrated 129/J mice. The double-stranded cDNAs were digested with ClaI and PstI prior to gel electrophoresis to create the diagnostic restriction fragments specific for Type I or II. Castration resulted in decreased levels of Type I mRNA in male kidney. In male liver, only Type I mRNA rose significantly in response to castration. Testosterone administration returned the Type I mRNA to normal levels in castrated mice. It therefore appears that the high levels of P-450(15 alpha) in male kidney were due to androgen-dependent induction of Type I mRNA. Both Types I and II were repressed in male liver, which results in decreased levels of P-450(15 alpha). Androgen was responsible for the repression and expression of Type I in liver and kidney, but not Type II.

Amino Acid Sequence↗
PubMed1997

Human UGT2B7 catalyzes morphine glucuronidation.

A human UDP-glucuronosyltransferase (UGT) catalyzing the glucuronidation of morphine has been identified. A full length cDNA was isolated from a human liver cDNA library and found to be identical to the UGT2B7 form having a tyrosine at position 288. This cDNA was transfected into HK 293 cells, and stable expression was achieved. Cell homogenates and membrane preparations from HK 293 cells expressing UGT2B7 catalyzed the glucuronidation of morphine and other clinically significant opioid agonists, antagonists, and partial agonists. UGT2B7 catalyzed morphine glucuronidation at the 3- and 6-hydroxy positions and also mediated the formation of codeine-6-glucuronide from codeine. This represents the first demonstration of a UGT capable of catalyzing the glucuronidation of both the 3- and 6-positions of opioids. Since humans excrete morphine-3-glucuronide and morphine-6-glucuronide after morphine administration, it is likely that UGT2B7 is a major isoform in humans responsible for the metabolism of this important drug and its surrogates.

Cell Line↗
PubMed2003

Inhaled versus systemic corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates.

BACKGROUND: Chronic lung disease (CLD) remains an important cause of mortality and morbidity in preterm infants despite the administration of antenatal corticosteroids, surfactant replacement therapy and other advances in neonatal intensive care. There is increasing evidence from cellular and biochemical research that inflammation plays an important role in the pathogenesis of CLD. Thus, interventions aimed at reducing or modulating the inflammatory process may reduce the incidence or severity of CLD. Theoretically, the use of inhaled corticosteroids may allow for beneficial effects on the pulmonary system without concomitant high systemic concentrations and less risk of adverse effects. OBJECTIVES: To compare the effectiveness of inhaled versus systemic corticosteroids, started within the first two weeks of life, in preventing CLD in ventilated very low birth weight infants. SEARCH STRATEGY: Randomized and quasi-randomized trials were identified by searching the Cochrane Controlled Trials Register (The Cochrane Library, Issue 3, 2002), MEDLINE (1966 - September 2002), EMBASE (1980 - September 2002), CINAHL (1982 - September 2002), reference lists of published trials and abstracts published in Pediatric Research (1990 - April 2002) from the Society of Pediatric Research/ Pediatric Academic Society's annual meetings. SELECTION CRITERIA: Randomized or quasi-randomized clinical trials comparing inhaled versus systemic corticosteroid therapy (regardless of the dose and duration of therapy), started in first two weeks of life in very low birth weight preterm infants receiving assisted ventilation. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including CLD at 28 days or 36 weeks corrected gestational age (CGA), mortality, combined outcome of death or CLD at 28 days or 36 weeks CGA, other pulmonary outcomes and adverse effects were evaluated. All data were analyzed using RevMan 4.1. When appropriate, meta-analysis was performed using relative risk (RR), risk difference (RD), and weighted mean difference (WMD) along with their 95% confidence intervals (CI). If RD was significant, number needed to treat (NNT) or number needed to harm (NNH) was calculated. MAIN RESULTS: Two trials qualified for inclusion in this review. There was an increase in the incidence of CLD at 36 weeks CGA in the inhaled steroid group amongst all randomized infants, which was of borderline statistical significance: [RR 1.45 (95% CI 0.99, 2.11); RD 0.11 (95% CI 0.00, 0.21), p = 0.05, 1 trial and n = 278]. There was no statistically significant difference in the incidence of CLD at 36 weeks amongst all survivors [RR 1.34 (95% CI 0.94, 1.90); RD 0.11(95% CI -0.02, 0.24), 1 trial and n = 206]. There were no statistically significant differences for oxygen dependency at 28 days (2 trials and n = 294), death by 28 days (2 trials and n = 294) or 36 weeks (2 trials and n = 294) and the combined outcome of death or CLD by 28 days (2 trials and n = 294) or 36 weeks CGA (1 trial and n = 278). The duration of mechanical ventilation was statistically significantly longer in the inhaled as compared to the systemic steroid group (WMD 3.89 days, 95% CI 0.24, 7.55; 2 trials and n = 294). The duration of supplemental oxygen was statistically significantly longer in the inhaled as compared to the systemic steroid group (WMD 11.10 days, 95% CI 1.97, 20.22; 2 trials and n = 294). There was a significantly lower incidence of hyperglycemia in the group receiving inhaled steroids (RR 0.52, 95% CI 0.39,0.71; RD -0.25, 95% CI -0.37, -0.14; 1 trial and n = 278). The NNT was 4.0 (95% CI 2.7, 7.14) to avoid one infant experiencing hyperglycemia. There was a statistically significant increase in the rate of patent ductus arteriosus (RR 1.64, 95% CI 1.23, 2.17; RD 0.21, 95% CI 0.10, 0.33; 1 trial and n = 278) in the group receiving inhaled steroids. The NNH was 4.8, 95% CI 3, 10. There were decreases of borderline statistical significance in the incidences of gastrointestinal hemorrhage and gastrointestinal perforation in the inhaled as compared to systemic steroid group: for gastrointestinal hemorrhage, RR 0.40, 95% CI 0.16, 1.02; RD -0.06, 95% CI -0.12, 0.00, p = 0.05 (1 trial and n = 278); for gastrointestinal perforation, RR 0.16, 95% CI 0.02, 1.29; RD -0.04, 95% CI -0.07, 0.00, p = 0.05 (1 trial and n = 278). The incidence of other side effects was not statistically significantly different in the two groups. No information was available on long term neurodevelopmental outcomes. REVIEWER'S CONCLUSIONS: This review found no evidence that early inhaled steroids confer important advantages over systemic steroids in the management of ventilator dependent preterm infants. Neither inhaled steroids, nor systemic steroids, can be recommended as a part of standard practice for ventilated preterm infants. Because they might have fewer adverse effects than systemic steroids, further randomized controlled trials of inhaled steroids are needed which address risk/benefit ratio of different delivery techniques, dosing schedules and long term effects, with particular attention to neurodevelopmental outcome.

Administration, Inhalation↗
PubMed1996

Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction.

Melanocortin peptides are reported to antagonize opiate dependence and tolerance, but the neural substrates underlying these actions are unknown. In this study, we characterize the rat melanocortin-4 receptor (MC4-R) and demonstrate that this receptor is regulated by opiate administration. The rat MC4-R is 95% identical to the human MC4-R, and the potency of melanocortin peptides to stimulate cAMP production is similar in these two species homologs (alpha-melanocyte-stimulating hormone = adrenocorticotropic hormone > gamma-melanocyte-stimulating hormone). Expression of MC4-R mRNA was found to be enriched in the striatum, nucleus accumbens, and periaque-ductal gray, all of which are regions implicated in the behavioral effects of opiates. In contrast, MC1-, MC3-, and MC5-R are expressed at very low or undetectable levels in these brain regions. Chronic administration of morphine (5 days) resulted in a time-dependent down-regulation of MC4-R mRNA expression in the striatum and periaqueductal gray. Expression of MC4-R mRNA was also decreased in the nucleus accumbens/ olfactory tubercle, but this effect was observed after 1 or 3 days of morphine treatment. In the striatum, the reduction of MC4-R mRNA was accompanied by a concomitant decrease in melanocortin receptor levels, shown by quantitative radioligand binding and autoradiography. In contrast, morphine administration did not influence levels of MC4-R mRNA in several other brain regions, including frontal cortex, olfactory bulb, hypothalamus, and ventral tegmentum/substantia nigra. In light of previous findings that melanocortins antagonize opiate self-administration, analgesic tolerance, and physical dependence, we hypothesize that decreased melanocortin function, via down-regulation of MC4-R expression, may contribute to the development of these opiate-induced behaviors.

Animals↗
PubMed2005

Botulinum toxin type A therapy for cervical dystonia.

BACKGROUND: Cervical dystonia is characterized by involuntary posturing of the head and frequently is associated with neck pain. Disability and social withdrawal are common. In recent years, Botulinum toxin Type A (BtA) has become the first line therapy. However its true efficacy, in particular the potential effect size, is still unclear. OBJECTIVES: To determine whether botulinum toxin (BtA) is an effective and safe treatment for cervical dystonia. SEARCH STRATEGY: We searched the Cochrane Movement Disorders Group trials register (June 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2003, MEDLINE (1977 to June 2003), EMBASE (1977 to June 2003) and reference lists of articles. We also contacted drug manufacturers and researchers in the field. SELECTION CRITERIA: Randomised studies comparing BtA with placebo in adults with cervical dystonia. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: We found thirteen high quality eligible studies. They were short term (6 to 16 weeks). Eight trials, enrolling 361 patients, used the BtA formulation Botox(r) and five, enrolling 319 patients, used the BtA formulation Dysport. The dose and technique of administration varied significantly between studies.Meta-analysis showed statistically and clinically significant improvements on objective rating scales: (Peto OR 4.31; 95% confidence interval (CI) 2.68 to 6.94) and subjective rating scales (Peto OR 6.58; 95% CI 4.55 to 9.54); and for pain relief in subjective scales (Peto OR 11.92; 95% CI 6.32 to 22.5). However, for many of the outcomes, we could use data from only a few studies. Only adverse events clearly associated with the mechanism of action of BtA were more frequent in the treatment group. These included neck weakness, dysphagia, dry mouth/sore throat and voice changes/hoarseness. Sub-group and sensitivity analyses showed a clear dose-response relationship for subjective and objective benefit and for frequency and severity of adverse events. Indirect comparisons between trials that used Dysport against placebo and trials that used Botox against placebo showed no significant differences between Dysport and Botox in terms of benefits or adverse events. AUTHORS' CONCLUSIONS: A single injection cycle of BtA is effective and safe for treating cervical dystonia. Enriched trials (using patients previously treated with BtA), suggest that further injection cycles continue to work for most patients.

Botulinum Toxins, Type A↗
PubMed2000

Recent developments in receptor-selective retinoids.

Natural (all trans-retinoic acid, RA) and synthetic retinoids exhibit potent anti-proliferative, normalization of differentiation and anti-inflammatory activities which appear to account for their therapeutic effects in acne, psoriasis, photoaging, precancerous lesions and established cancers. Although RA has shown considerable promise in dermatologic indications, certain side effects have restricted its use as a choice of agent for chronic administration. Systematic synthesis of receptor-selective retinoids has resulted in two topical drugs, Tazorac/Zorac (tazarotene) and Differin (adapalene). Tazorac is indicated for psoriasis and acne and Differin gel for the treatment of acne. These drugs bind to the retinoic acid receptor (RAR) family members. Various RAR subtype-specific and function-selective retinoids have been synthesized. These retinoids, which are in various stages of pre-clinical development for the treatment of cancers, psoriasis and as an antidote to Accutane-mediated mucocutaneous toxicity, will also be discussed in this review. Discovery of another retinoid receptor, retinoid X receptor (RXR), revealed that RXR-specific retinoids already existed in retinoid chemical libraries. Structure activity relationship studies based upon binding and transactivation assays led to the synthesis of RXR-specific ligands with high affinities for RXR subtypes. These compounds were found to be effective in the treatment of hyperglycemia in animal models of type II diabetes. The discovery of novel retinoids along with an increased understanding of the biological functions and mechanisms of action of retinoid receptors are likely to result in improved treatments for existing responsive indications and identification of new retinoid therapeutic targets.

Adapalene↗
PubMed1995

HPCC and the National Information Infrastructure: an overview.

The National Information Infrastructure (NII) or "information superhighway" is a high-priority federal initiative to combine communications networks, computers, databases, and consumer electronics to deliver information services to all U.S. citizens. The NII will be used to improve government and social services while cutting administrative costs. Operated by the private sector, the NII will rely on advanced technologies developed under the direction of the federal High Performance Computing and Communications (HPCC) Program. These include computing systems capable of performing trillions of operations (teraops) per second and networks capable of transmitting billions of bits (gigabits) per second. Among other activities, the HPCC Program supports the national supercomputer research centers, the federal portion of the Internet, and the development of interface software, such as Mosaic, that facilitates access to network information services. Health care has been identified as a critical demonstration area for HPCC technology and an important application area for the NII. As an HPCC participant, the National Library of Medicine (NLM) assists hospitals and medical centers to connect to the Internet through projects directed by the Regional Medical Libraries and through an Internet Connections Program cosponsored by the National Science Foundation. In addition to using the Internet to provide enhanced access to its own information services, NLM sponsors health-related applications of HPCC technology. Examples include the "Visible Human" project and recently awarded contracts for test-bed networks to share patient data and medical images, telemedicine projects to provide consultation and medical care to patients in rural areas, and advanced computer simulations of human anatomy for training in "virtual surgery."

Computer Communication Networks↗
PubMed1983

Androgen regulation of prostatic binding protein messenger RNA studied by using cloned complementary DNA.

The construction of a double-stranded cDNA library using rat prostatic poly(A)RNA and pBR322/kappa 1776 system and the isolation of three prostatic binding protein (PBP) cDNA clones are described. These cDNA clones were characterized and identified by in situ hybridization, mRNA selection-translation and immuno-precipitation as coding for the three subunit components, C1, C2, and C3, of PBP. These clones were used in hybridization experiments with prostatic poly(A)RNA to determine the effect of testosterone on the levels of PBP-mRNA. The results showed that synthesis of these mRNAs varied in response to either androgen withdrawal or replacement. Accumulation of PBP-mRNAs coding for C2 and C3 components occurred 1 hr after androgen administration to castrated rat, whereas the mRNA coding for the C1 component did not appear until 4 hr after androgen replacement. Quantitation of PBP-mRNA sequences in nuclear and polysomal poly(A)RNAs showed that they did not vary coordinately in response to androgen withdrawal. These results indicate differential regulation of PBP genes and suggest possible multiple levels of androgen control of PBP synthesis.

Animals↗
PubMed2002

Genetic toxicology: web resources.

Genetic toxicology is the scientific discipline dealing with the effects of chemical, physical and biological agents on the heredity of living organisms. The Internet offers a wide range of online digital resources for the field of Genetic Toxicology. The history of genetic toxicology and electronic data collections are reviewed. Web-based resources at US National Library of Medicine (NLM), including MEDLINE, PUBMED, Gateway, Entrez, and TOXNET, are discussed. Search strategies and Medical Subject Headings (MeSH) are reviewed in the context of genetic toxicology. The TOXNET group of databases are discussed with emphasis on those databases with genetic toxicology content including GENE-TOX, TOXLINE, Hazardous Substances Data Bank, Integrated Risk Information System, and Chemical Carcinogenesis Research Information System. Location of chemical information including chemical structure and linkage to health and regulatory information using CHEMIDPLUS at NLM and other databases is reviewed. Various government agencies have active genetic toxicology research programs or use genetic toxicology data to assist fulfilling the agency's mission. Online resources at the US Food and Drug Administration (FDA), the US Environmental Protection Agency (EPA), the National Institutes of Environmental Health Sciences, and the National Toxicology Program (NTP) are outlined. Much of the genetic toxicology for pharmaceuticals, industrial chemicals and pesticides that is performed in the world is regulatory-driven. Regulatory web resources are presented for the laws mandating testing, guidelines on study design, Good Laboratory Practice (GLP) regulations, and requirements for electronic data collection and reporting. The Internet provides a range of other supporting resources to the field of genetic toxicology. The web links for key professional societies and journals in genetic toxicology are listed. Distance education, educational media resources, and job placement services are also available online in the field of genetic toxicology. As molecular biology and computational tools improve, new areas within genetic toxicology such as structural activity relationship analysis, mutational spectra databases and toxicogenomics, now have resources online as well.

Animals↗
PubMed1995

Cloning and expression of glucocorticoid-induced genes in fetal rat lung fibroblasts. Transforming growth factor-beta 3.

Glucocorticoids have been shown to accelerate fetal lung type II cell maturation, and this effect appears, in part, to be mediated via fibroblasts. To identify glucocorticoid induced genes in fetal lung fibroblasts, we screened a cDNA library from cortisol-treated fetal lung fibroblasts with a subtracted cDNA probe which was enriched for sequences specific for cortisol-treated fetal lung fibroblasts. Fifty-seven clones were isolated from the cDNA library. One cDNA represented approximately 30% of the 57 clones. Analysis of DNA sequence homology suggested that this cDNA encodes the rat transforming growth factor-beta 3 (TGF beta 3). We found that TGF beta 3 mRNA was expressed in fetal lung fibroblasts but not epithelial cells. Expression of message in fetal lung fibroblasts was developmentally regulated. TGF beta 3 mRNA levels were low during the pseudoglandular stage (day 18), peaked during the early canalicular stage of lung development (day 19), then fell again at days 20 and 21 (term = 22 days). Exposure of fetal lung fibroblasts to cortisol increased TGF beta 3 mRNA expression in a time- and dose-dependent manner. Maternal administration of dexamethasone also enhanced mRNA expression of TGF beta 3 in fetal lung fibroblasts. These data suggest that glucocorticoids may mediate their stimulatory effect on lung maturation by inducing TGF beta 3 expression in fetal lung fibroblasts.

Amino Acid Sequence↗