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PubMed2002

Phage-displayed random peptide libraries in mice: toxicity after serial panning.

PURPOSE: In vivo screening of phage-displayed random peptide libraries (RPLs) has been used to identify peptide ligands to targets found on endothelial cells of blood vessels supplying specific tissues such as brain, kidney, and tumor tissue. Peptides that bind specifically to blood vessels supplying tumor tissue have been conjugated to cytotoxic agents and used to successfully eradicate tumors in a mouse model. With the ultimate goal of developing similar methods for treating human cancer, we describe an in vivo RPL screening process that, unlike previous in vivo experiments, does not harm the animal being screened. METHODS: RPLs were administered to FVB, BalbC, and tumor-bearing MRL/MpJ-fas(LPR) mice in a variety of dosing formats. Tumor nodules were excised 10 min following infusion and phage were amplified from the specimens. Phage were reinjected into the same animal within 48 h. This process was repeated twice for a total of three in vivo screens of mouse tumor tissue within the same animal. Mice were observed for systemic side effects, histopathologic damage, and presence of phage in organs. Peptide sequences were determined from several third-pan phage clones. RESULTS: Overall there was minimal toxicity from administration of single or repeat doses of RPLs. Amino acid consensus sequences were identified and some of the sequences were similar to those of peptide ligands that bind matrix metalloproteinases. CONCLUSIONS: Serial administration of an RPL is well tolerated and serial panning in individual mice leading to consensus sequence motifs is possible. Based on these preclinical data the Food and Drug Administration has approved the implementation of human clinical trials with this technique.

Amino Acid Sequence↗
PubMed1999

A series of 6- and 7-piperazinyl- and -piperidinylmethylbenzoxazinones with dopamine D4 antagonist activity: discovery of a potential atypical antipsychotic agent.

As part of a program to develop dopamine D4 antagonists for the treatment of schizophrenia, we discovered a series of 6- and 7-(phenylpiperazinyl)- and -(phenylpiperidinyl)methylbenzoxazinones through mass screening of our compound library. A structure-activity relationship SAR study was carried out involving substituents on the phenyl ring, and several selective D4 antagonists were identified. The 7-substituted benzoxazinones showed more activity in neurochemical and behavioral tests than the 6-substituted series. One of the most potent and selective compounds (26) was found to have potent activity in animal tests predictive of antipsychotic activity in humans after oral administration. This paper describes the SAR of the benzoxazinone series and the preclinical characterization of 26.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2006

A systematic review of the efficacy and safety of atypical antipsychotics in patients with psychological and behavioral symptoms of dementia.

Although the Food and Drug Administration (FDA) has not approved atypical antipsychotics for use in patients with dementia, they are commonly prescribed in this population. Recent concerns about increased risk of cerebrovascular events and mortality have led to warnings. A systematic review was conducted to assess the benefits and harms of atypical antipsychotics when used in patients with behavioral and psychological symptoms of dementia. Electronic searches (through March 2005) of the Cochrane Library, Medline, Embase, and PsycINFO were supplemented with hand searches of reference lists, dossiers submitted by pharmaceutical companies, and a review of the FDA Website and industry-sponsored results database. Using predetermined criteria, each study was assessed for inclusion, and data about study design, population, interventions, and outcomes were abstracted. An overall quality rating (good, fair, or poor) was assigned based on internal validity. The evidence for olanzapine and risperidone supports their effectiveness compared with placebo. Short-term adverse events were similar to placebo. Risperidone had no advantage over haloperidol on efficacy measures in the better-quality studies. Risperidone had an advantage over haloperidol on some measures of extrapyramidal symptoms. Evidence for the other atypical antipsychotics is too limited to assess efficacy and safety. Trials were short term and conducted in highly selected populations. The potential for increased risk of cerebrovascular adverse events and mortality is a serious concern. To make judgments about when the benefits of atypical antipsychotics outweigh the potential harms, clinicians need more information. Additional data from existing trials and more-complete reporting of trial results could provide this information.

Alzheimer Disease↗
PubMedDate not supplied

Design and implementation of a portal for the medical equipment market: MEDICOM.

BACKGROUND: The MEDICOM (Medical Products Electronic Commerce) Portal provides the electronic means for medical-equipment manufacturers to communicate online with their customers while supporting the Purchasing Process and Post Market Surveillance. The Portal offers a powerful Internet-based search tool for finding medical products and manufacturers. Its main advantage is the fast, reliable and up-to-date retrieval of information while eliminating all unrelated content that a general-purpose search engine would retrieve. The Universal Medical Device Nomenclature System (UMDNS) registers all products. The Portal accepts end-user requests and generates a list of results containing text descriptions of devices, UMDNS attribute values, and links to manufacturer Web pages and online catalogues for access to more-detailed information. Device short descriptions are provided by the corresponding manufacturer. The Portal offers technical support for integration of the manufacturers Web sites with itself. The network of the Portal and the connected manufacturers sites is called the MEDICOM system. OBJECTIVES: To establish an environment hosting all the interactions of consumers (health care organizations and professionals) and providers (manufacturers, distributors, and resellers of medical devices). METHODS: The Portal provides the end-user interface, implements system management, and supports database compatibility. The Portal hosts information about the whole MEDICOM system (Common Database) and summarized descriptions of medical devices (Short Description Database); the manufacturers servers present extended descriptions. The Portal provides end-user profiling and registration, an efficient product-searching mechanism, bulletin boards, links to on-line libraries and standards, on-line information for the MEDICOM system, and special messages or advertisements from manufacturers. Platform independence and interoperability characterize the system design. Relational Database Management Systems are used for the system s databases. The end-user interface is implemented using HTML, Javascript, Java applets, and XML documents. Communication between the Portal and the manufacturers servers is implemented using a CORBA interface. Remote administration of the Portal is enabled by dynamically-generated HTML interfaces based on XML documents. A representative group of users evaluated the system. The aim of the evaluation was validation of the usability of all of MEDICOM s functionality. The evaluation procedure was based on ISO/IEC 9126 Information technology - Software product evaluation - Quality characteristics and guidelines for their use. RESULTS: The overall user evaluation of the MEDICOM system was very positive. The MEDICOM system was characterized as an innovative concept that brings significant added value to medical-equipment commerce. CONCLUSIONS: The eventual benefits of the MEDICOM system are (a) establishment of a worldwide-accessible marketplace between manufacturers and health care professionals that provides up-to-date and high-quality product information in an easy and friendly way and (b) enhancement of the efficiency of marketing procedures and after-sales support.

Advertising↗
PubMed1992

Secondary data on health-related subjects: major sources, uses, and limitations.

Although secondary data are generally neglected by nurses, they are useful for nurse researchers, practitioners, educators, administrators, and policy makers. Major sources of data on health-related subjects are medical records, administrative records, the census, vital statistics, surveys of the National Center for Health Statistics, social science archives, and nursing archives, each with its specific uses and limitations.

Archives↗
PubMed1995

Gonadotropin-releasing hormone receptor messenger ribonucleic acid expression in rat ovary.

Rat GnRH pituitary receptor complementary DNA was used to isolate a truncated clone from a rat corpus luteum complementary DNA library that proved to be identical in sequence to the rat anterior pituitary GnRH receptor. The distribution of the GnRH receptor messenger RNA (mRNA) was then determined in rat ovary using in situ hybridization. GnRH receptor expression was investigated in cyclic female rats and in hypophysectomized immature female rats treated with either recombinant human FSH or human menopausal gonadotropin. The expression of LH receptor mRNA was determined in serial sections as an index of the health and differentiation of the follicles. In cyclic animals, GnRH receptor mRNA was detected in granulosa cells at varying stages of follicular development and in the corpus luteum. Ovaries from hypophysectomized animals expressed GnRH receptor mRNA in the granulosa cells of most follicles. The administration of FSH or human menopausal gonadotropin to hypophysectomized animals altered the distribution of GnRH receptor mRNA. During antral development, the signal was most abundant in medium-sized follicles not expressing LH receptor mRNA and showing signs of follicular atresia. However, healthy preovulatory follicles also expressed GnRH receptor mRNA. We conclude that the expression of the GnRH receptor gene in granulosa cells is 1) individually regulated for each follicle, 2) persists in the corpus luteum, and 3) expressed in atretic follicles.

Animals↗
PubMed2003

Inhaled versus systemic corticosteroids for the treatment of chronic lung disease in ventilated very low birth weight preterm infants.

BACKGROUND: Chronic lung disease (CLD) remains a serious and common problem among very low birth weight infants despite the use of antenatal steroids and postnatal surfactant therapy to decrease the incidence and severity of respiratory distress syndrome. Corticosteroids have been widely used to treat or prevent CLD due to their anti-inflammatory properties. However, the use of systemic steroids has been associated with serious short and long term adverse effects. Administration of corticosteroids topically through the respiratory tract might result in beneficial effects on the pulmonary system with fewer undesirable systemic side effects. OBJECTIVES: To compare the effectiveness of inhaled versus systemic corticosteroids administered to ventilator dependent preterm neonates with birth weight </= 1500 grams or gestational age </= 32 weeks after two weeks of life for the treatment of evolving CLD. 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 for Pediatric Research/Pediatric Academic Societies' Annual Meetings. SELECTION CRITERIA: Randomized or quasi-randomized trials comparing inhaled versus systemic corticosteroid therapy (irrespective of the dose and duration of therapy) starting after the first two weeks of life in ventilator dependent very low birth weight preterm neonates. DATA COLLECTION AND ANALYSIS: Data were extracted 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. 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 statistically significant, number needed to treat (NNT) was calculated. MAIN RESULTS: Five trials comparing inhaled versus systemic corticosteroids in the treatment of CLD were identified. Two trials were excluded as both included non ventilator dependent patients. One trial is awaiting assessment and clarification of published data. Two trials qualified for inclusion in this review. Halliday et al (Halliday 2001a) randomized infants < 72 hours, while Suchomski et al (Suchomski 2002) randomized at 12-21 days. Although the steroids were commenced after the first 2 weeks of life in both the trials, the outcomes were measured over different time periods, from the age at randomization in each trial, making it inappropriate to combine results. In neither trial was there a statistically significant difference between the groups in the incidence of CLD at 36 weeks CGA amongst all randomized infants. The estimates for the trial by Halliday et al (Halliday 2001a) were RR 1.10 (95% CI 0.82, 1.47), RD 0.03 (95% CI -0.08, 0.15); number of infants (n) = 292 and for the trial by Suchomski et al (Suchomski 2002) RR 0.90 (95% CI 0.79, 1.02), RD -0.10 (95% CI -0.22, 0.02; n = 78 ). There were no statistically significant differences between the groups in either trial for oxygen dependency at 28 days, death by 28 days or 36 weeks, the combined outcome of death or CLD by 28 days or 36 weeks CGA, duration of intubation, duration of oxygen dependence, or adverse effects. Information on the long term neurodevelopmental outcomes was not available. REVIEWER'S CONCLUSIONS: This review found no evidence that inhaled corticosteroids confer net advantages over systemic corticosteroids in the management of ventilator dependent preterm infants. Neither inhaled steroids, nor systemic steroids, can be recommended as standard treatment for ventilated preterm infants. There was no evidence of difference in effectiveness or side-effect profiles for inhaled versus systemic steroids. A better delivery system guaranteeing selective delivery of inhaled steroids to the alveoli might result in beneficial clinical effects without increasing side-effects. To resolve this issue, studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. The long term effects of inhaled steroids, with particular attention to neurodevelopmental outcome, should be addressed in future studies.

Administration, Inhalation↗
PubMed2001

Integration of mass spectrometry into early-phase discovery and development of central nervous system agents.

The early-phase discovery and development of useful central nervous system (CNS) agents present ample opportunities to exploit mass spectrometry and provide detailed compound/mixture characterization, or to make the process faster and/or more economic. Neuropeptide FF antagonists and centrally active thyrotropin-releasing hormone analogues were used as specific examples in this work. We evaluated the characterization of focused libraries of peptide derivatives by electrospray ionization, tandem mass spectrometry and liquid chromatography/tandem mass spectrometry on a quadrupole ion trap and nanoelectrospray on a Fourier transform ion cyclotron resonance mass spectrometer. Immobilized artificial-membrane chromatography was employed as a model to predict/rank new agents against lead compounds for their potential to reach the central nervous system in pharmacologically significant amounts. Measuring brain concentrations in rodents after the intravenous administration of test compounds was used as an in vivo approach, and we took advantage of microdialysis sampling that furnished samples without interfering tissue matrix and afforded the estimation of extracellular concentrations in a localized part of the brain. Overall, making atmospheric-pressure ionization mass spectrometry an integral part of the process has played a major role in increasing throughput, selectivity, specificity and detection sensitivity and thereby providing useful information about the extent or mechanism of transport and metabolic activation/inactivation in early-phase discovery and development of CNS agents.

Animals↗
PubMed2003

Skeletal muscle disorders associated with selenium deficiency in humans.

Skeletal muscle disorders manifested by muscle pain, fatigue, proximal weakness, and serum creatine kinase (CK) elevation have been reported in patients with selenium deficiency. The object of this report was to review the conditions in which selenium deficiency is associated with human skeletal muscle disorders and to evaluate the importance of mitochondrial alterations in these disorders. A systematic literature review using the Medline database and Cochrane Library provided 38 relevant articles. The main conditions associated with selenium deficiency fell into three categories: (1) insufficient selenium intake in low soil-selenium areas; (2) parenteral or enteral nutrition, or malabsorption; and (3) chronic conditions associated with oxidative stress, such as chronic alcohol abuse and human immunodeficiency virus (HIV) infection. In low soil-selenium areas, reversibility of muscle symptoms was similar after selenium supplementation and placebo administration, suggesting a role for other factors in the development of disease. In parenteral or enteral nutrition, or malabsorption, muscle symptoms improved after selenium supplementation in 18 of 19 patients (median delay: 4 weeks). The reason that only a minority of selenium-deficient patients present with skeletal muscle disorders is unclear and is possibly related to cofactors, such as viral infections and drugs. Prospective studies of selenium-deficient myopathies would be useful in critically ill patients, alcohol abusers, and HIV-infected patients.

Adult↗
PubMed1991

Molecular cloning of cDNA for the B beta subunit of Xenopus fibrinogen, the product of a coordinately-regulated gene family.

Fibrinogen, the principal blood-clotting protein, is made up of three different subunits synthesized in the liver. In vitro administration of glucocorticoids to liver cells from the frog Xenopus laevis causes a dramatic increase in fibrinogen synthesis. Investigations of molecular mechanisms underlying this hormonal stimulation at the mRNA level require cDNA clones complementary to the mRNAs coding for the three fibrinogen subunits, called A alpha, B beta, and gamma. We describe here the isolation and characterization of cDNA clones for the B beta subunit of Xenopus fibrinogen. cDNA libraries in both plasmid (pBR322) and phage (lambda gt10) cloning vectors were constructed from frog liver mRNA and screened with a rat B beta cDNA. Clones thus isolated hybridized to two Xenopus liver mRNAs 2500 and 1800 bases long, the previously-determined sizes for B beta mRNAs. The identity of the plasmid clone B beta-27 was confirmed by hybridization-selection of complementary mRNA which translated in vitro into the B beta polypeptide, as determined by size and susceptibility to thrombin cleavage. lambda/B beta 10, a clone representing nearly all of the 2500-base B beta mRNA, was isolated from the phage cDNA library. The 3'-end of this clone includes a polyadenylation signal about 20 residues upstream of a stretch of 34 adenosine residues, which probably represents the 3'-poly(A) tail of the messenger RNA. lambda/B beta 10 lacks only 20 nucleotides of full-length B beta mRNA at the 5'-end and there is one major start site of transcription. The 2500-base B beta mRNA has a 700-base extension at the 3'-end that is not present in the 1800-base mRNA. The Xenopus laevis genome contains two or three genes for the B beta fibrinogen subunit. Using the cDNA clone as a probe, B beta mRNA was shown to be induced at least 20-fold by glucocorticoid treatment of purified parenchymal cells of Xenopus liver maintained in primary culture.

Animals↗
PubMed1997

Immunocontraception in rodents: a review of the development of a sperm-based immunocontraceptive vaccine for the grey squirrel (Sciurus carolinensis).

The strategy for developing contraceptive vaccines for wild rodents will depend on the species. In rats and mice, high all-year birth rates, high levels of dispersal and promiscous mating systems suggest that, if immunocontraception was used alone, > 90% of the population would have to sterilized to achieve the desired control. In Britain, the grey squirrel (Sciurus carolinensis) may be a better candidate to investigate the feasibility of a contraceptive vaccine in rodents. This introduced species is a seasonal breeder with a much lower population turnover than rats or mice. As well as causing damage to woodland, it has ousted the native red squirrel (S. valgaris) from most of the UK. A human and selective method for the control of grey squirrels is therefore highly desirable. Numerous sperm-specific antigens have been identified on rodent spermatozoa. Monoclonal antibodies to particular components block sperm-egg interactions in laboratory animals and cross-react with grey squirrel spermatozoa. In vitro fertilization assays indicate that squirrel sperm-egg binding may be inhibited also. Currently, a cDNA library obtained from grey squirrel testis is being screened to identify genes encoding specific sperm antigens involved in fertilization. Methods of enhancing immunogenicity after oral immunization using microparticle carriers and immune-stimulating complexes are currently under investigation.

Administration, Oral↗
PubMed1994

Heat shock enhances the amount of prenylated Dnaj protein at membranes of glyoxysomes.

Proteins similar to the bacterial Dnaj protein have been implicated as molecular chaperones in different compartments of eukaryots. A plant equivalent is now described in tissues of dark-grown cucumber seedlings. Using a cucumber Dnaj protein produced by expression in bacteria, we raised polyclonal antibodies against the protein and used them for localization studies. In etiolated cucumber seedlings, both cotyledons and hypocotyledons were found to contain Dnaj proteins. Cell fractionation of etiolated cotyledons showed that Dnaj proteins were detectable mainly in the postnuclear cell fraction after sedimentation at 10,000 x g, and in the microsomes. Following subfractionation by sucrose density gradient centrifugation and analysis by immunoblotting, a 53-kDa protein was attributed to the glyoxysomal fraction and an 80-kDa protein to the mitochondrial fraction. The glyoxysomal Dnaj protein behaved as a membrane-bound form. Upon heat shock, a slight increase in the content of the glyoxysomal Dnaj protein was found. When glyoxysomes were treated with protease and subsequently isolated by gradient centrifugation, virtually all immunologically detectable Dnaj protein was removed. Administration of radiolabelled mevalonic acid to cotyledons and isolation of glyoxysomes yielded labelled Dnaj protein which remained membrane bound during the purification of glyoxysomal membranes by floatation in a density gradient.

Cell Fractionation↗
PubMed1992

Molecular cloning and analysis of in vivo expression of murine P-selectin.

P-selectin (CD62) is a rapidly inducible cell surface adhesion molecule that is expressed on platelets and endothelial cells and mediates their interaction with leukocytes. In vitro studies have suggested that this receptor may play an important role in hemostasis and in inflammatory response to tissue injury. We report the molecular cloning and sequencing of murine cDNA for P-selectin. The lectin, epidermal growth factor (EGF)-like, transmembrane, and cytoplasmic domains are highly conserved between mouse and human, with an overall amino acid identity of 79%. To further investigate the biology of this adhesion molecule in vivo, we analyzed mRNA levels for P-selectin in mice after injection with endotoxin. Northern blot data indicate that the cellular response in vivo includes a rapid increase in the level of mRNA, presumably for new synthesis of P-selectin. The increase in mRNA is maximal at 4 hours, and turnover is relatively rapid, with levels of RNA having decreased substantially by 6 hours following stimulation with endotoxin. After administration of endotoxin, the highest levels of mRNA expression were detected in liver, lung, kidney, and heart.

3T3 Cells↗
PubMed2002

Antibiotics for trachoma.

BACKGROUND: Trachoma is the world's leading cause of preventable blindness. In 1997 the World Health Organization launched an initiative on trachoma control based on the 'SAFE' strategy (surgery, antibiotics, facial cleanliness and environmental improvement). OBJECTIVES: The aim of this review is to assess the evidence supporting the antibiotic arm of the SAFE strategy by assessing the effects of antibiotics on both active trachoma (primary objective) and on Chlamydia trachomatis infection of the conjunctiva (secondary objective). SEARCH STRATEGY: We searched The Cochrane Controlled Trials Register - CENTRAL/CCTR, which contains the Cochrane Eyes and Vision Group specialised register (Cochrane Library Issue 3, 2001), MEDLINE (1966 to August 2001), and EMBASE (1980 to September 2001). We used the Science Citation Index to look for articles that cited the included studies. We searched the reference lists of identified articles and we contacted authors and experts for details of further relevant studies. SELECTION CRITERIA: We included only randomised trials that satisfied either of two criteria: (a) trials in which topical or oral administration of an antibiotic was compared to placebo or no treatment in people with trachoma, (b) trials in which a topical antibiotic was compared with an oral antibiotic in people with trachoma. A subdivision of particular interest was of trials in which topical tetracycline/chlortetracycline was compared with oral azithromycin, as these are the two World Health Organization recommended treatments. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. We contacted investigators for missing data. MAIN RESULTS: We found 15 studies that randomised a total of 8678 participants. For both outcomes (active trachoma and laboratory evidence of infection) the results of the chi-square tests suggested that there was significant statistical heterogeneity among the trials. There was also marked clinical heterogeneity. No summary statistics were calculated and we therefore present a narrative summary of the results. For the comparisons of oral or topical antibiotic against placebo/no treatment, the data are consistent with there being no effect of antibiotics but are suggestive of a lowering of the point prevalence of relative risk of both active disease and laboratory evidence of infection at three and 12 months after treatment. For the comparison of oral against topical antibiotics the results suggest that oral treatment is neither more nor less effective than topical treatment. REVIEWER'S CONCLUSIONS: There is some evidence that antibiotics reduce active trachoma but results are not consistent and cannot be pooled.

Anti-Bacterial Agents↗
PubMed2005

Antibiotics for trachoma.

BACKGROUND: Trachoma is the world's leading cause of preventable blindness. In 1997 the World Health Organization launched an initiative on trachoma control based on the 'SAFE' strategy (surgery, antibiotics, facial cleanliness and environmental improvement). OBJECTIVES: To assess the evidence supporting the antibiotic arm of the SAFE strategy by assessing the effects of antibiotics on both active trachoma (primary objective) and on Chlamydia trachomatis infection of the conjunctiva (secondary objective). SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials - CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to February 2005), and EMBASE (1980 to February 2005). We used the Science Citation Index to look for articles that cited the included studies. We searched the reference lists of identified articles and we contacted authors and experts for details of further relevant studies. SELECTION CRITERIA: We included only randomised trials that satisfied either of two criteria: (a) trials in which topical or oral administration of an antibiotic was compared to placebo or no treatment in people with trachoma, (b) trials in which a topical antibiotic was compared with an oral antibiotic in people with trachoma. A subdivision of particular interest was of trials in which topical tetracycline/chlortetracycline was compared with oral azithromycin, as these are the two World Health Organization recommended treatments. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted investigators for missing data. MAIN RESULTS: We found 15 studies that randomised a total of 8678 participants. For both outcomes (active trachoma and laboratory evidence of infection) the results of the chi squared tests suggested that there was significant statistical heterogeneity among the trials. There was also marked clinical heterogeneity. No summary statistics were calculated and we therefore present a narrative summary of the results. For the comparisons of oral or topical antibiotic against placebo/no treatment, the data are consistent with there being no effect of antibiotics but are suggestive of a lowering of the point prevalence of relative risk of both active disease and laboratory evidence of infection at three and 12 months after treatment. For the comparison of oral against topical antibiotics the results suggest that oral treatment is neither more nor less effective than topical treatment. AUTHORS' CONCLUSIONS: There is some evidence that antibiotics reduce active trachoma but results are not consistent and cannot be pooled.

Administration, Oral↗
PubMed2005

Direct in vitro selection of a 2'-O-methyl aptamer to VEGF.

Aptamers (protein binding oligonucleotides) have potential as a new class of targeted therapeutics. For applications requiring chronic systemic administration, aptamers must achieve high-affinity target binding while simultaneously retaining high in vivo stability, tolerability, and ease of chemical synthesis. To this end, we describe a method for generating aptamers composed entirely of 2'-O-methyl nucleotides (mRmY). We present conditions under which 2'-O-methyl transcripts can be generated directly and use these conditions to select a fully 2'-O-methyl aptamer from a library of 3 x 10(15) unique 2'-O-methyl transcripts. This aptamer, ARC245, is 23 nucleotides in length, binds to vascular endothelial growth factor (VEGF) with a Kd of 2 nM, and inhibits VEGF activity in cellular assays. Notably, ARC245 is so stable that degradation cannot be detected after 96 hr in plasma at 37 degrees C or after autoclaving at 125 degrees C. We believe ARC245 has considerable potential as an antiangiogenesis therapeutic.

Angiogenesis Inhibitors↗
PubMed2002

Evidence for calcium-sensing receptor mediated stanniocalcin secretion in fish.

The secretion of parathyroid hormone (PTH) and calcitonin (CT) in mammals are both tightly regulated by the prevailing levels of extracellular ionic calcium (Ca(2+)). And, it is now widely recognized that both of these Ca(2+) effects are mediated exclusively through a seven transmembrane calcium sensing receptor or CaR. As in the case of PTH and CT, the secretion of stanniocalcin (STC) in fish is tightly regulated by the levels of extracellular Ca(2+). Fish STC functions as an anti-hypercalcemic hormone such that a rise in extracellular Ca(2+) above the physiological set-point of approximately 1.2 mM provokes an immediate secretory response. Whether or not Ca(2+)-regulated STC secretion in fishes is mediated by similar type of receptor has never been addressed. Here, we have found that Ca(2+)-stimulated STC secretion in salmon is mimicked by CaR mimetics, pharmacological agents that increase the sensitivity of the CaR to calcium. NPS 467, a small organic molecule that acts as a positive allosteric modulator of the CaR and alters calciotropic hormone secretion in mammals, was examined for effects on serum levels of STC in trout. The IP administration of NPS R-467 had time and dose-dependent stimulatory effects on STC secretion that were indistinguishable from those of Ca(2+) loading. The effects of NPS 467 were stereospecific and had no effects on serum CT. NPS 467 induced STC release was also manifested by a downstream physiological response; the inhibition of gill calcium transport. A cDNA clone was amplified from a fish corpuscle of Stannius cDNA library with high homology to the human CaR. RT-PCR revealed that this transcript was also present in gill, kidney, pancreas, brain, muscle and spleen. These findings suggest that Ca(2+)-stimulated STC secretion in fishes is mediated by a calcium ion-sensing receptor similar to that in mammals.

Aniline Compounds↗
PubMed2004

Intravenous and indocyanine green angiography.

BACKGROUND: Indocyanine green angiography (ICGA) is an adjunct procedure to intravenous sodium fluorescein angiography (IVFA) for evaluation of disorders of the retina. It has particular application when choroidal pathology is implicated or suspected. Indocyanine green (ICG) dye has been used in the medical field since 1956, when it was approved by the Federal Drug Administration for imaging cardiac and hepatic circulations. Indocyanine green is a well-tolerated, tricarbocyanine dye with a molecular weight of 775 daltons that absorbs light at 790 to 805 nm and has a peak emission at 835 nm. While the substance gives off 4% the fluorescence of sodium fluorescein, its spectral properties allow it to be visualized through ocular pigments, blood, and serous fluids. METHODS: Using search engines and library resources, clinically relevant ICGA studies were reviewed for their purpose, description, outcome, clinical importance, and compared and contrasted to IVFA. RESULTS: Information is presented that represents the current modalities of ICGA. CONCLUSION: ICGA still remains an adjunct therapy to traditional IVFA. However, as the technology improves--allowing easier recording and visualization of ICG angiograms--and as more studies are conducted on the best use of the information obtained from ICGA, this technique may emerge as an important diagnostic tool in the fight to prevent the severe vision loss associated with the various retinal disorders mentioned.

Choroid Diseases↗