What Does the Boxed Warning Tell Us? Safe Practice of Using Ferumoxytol as an MRI Contrast Agent.

BACKGROUND AND PURPOSE: Despite the label change and the FDA's boxed warning added to the Feraheme (ferumoxytol) label in March 2015, radiologists have shown increasing interest in using ferumoxytol as an MR imaging contrast agent as a supplement or alternative to gadolinium. The goals of this study were to provide information regarding ferumoxytol safety as an imaging agent in a single center and to assess how the Feraheme label change may affect this potential, currently off-label indication. MATERIALS AND METHODS: This retrospective study evaluated the overall frequency of ferumoxytol-related adverse events when used for CNS MR imaging. Patients with various CNS pathologies were enrolled in institutional review board-approved imaging studies. Ferumoxytol was administered as multiple rapid bolus injections. The risk of adverse events was correlated with demographic data/medical history. RESULTS: The safety of 671 ferumoxytol-enhanced MR studies in 331 patients was analyzed. No anaphylactic, life-threatening, or fatal (grade 4 or 5) adverse events were recorded. The overall proportion of ferumoxytol-related grade 1-3 adverse events was 10.6% (8.6% occurring within 48 hours), including hypertension (2.38%), nausea (1.64%), diarrhea (1.04%), and headache (1.04%). History of 1 or 2 allergies was associated with an increased risk of adverse events (14.61% versus 7.51% [no history]; P = .007). CONCLUSIONS: The frequency of mild ferumoxytol-related adverse events was comparable with literature results, and no serious adverse event was recorded. Although the recommendations in the boxed warning should be followed, serious adverse events appear to be rare, and with proper precautions, ferumoxytol may be a valuable MR imaging agent.

The selective PAC1 receptor agonist maxadilan inhibits neurogenic vasodilation and edema formation in the mouse skin.

We have earlier shown that PACAP-38 decreases neurogenic inflammation. However, there were no data on its receptorial mechanism and the involvement of its PAC1 and VPAC1/2 receptors (PAC1R, VPAC1/2R) in this inhibitory effect. Neurogenic inflammation in the mouse ear was induced by topical application of the Transient Receptor Potential Ankyrin 1 (TRPA1) receptor activator mustard oil (MO). Consequent neurogenic edema, vasodilation and plasma leakage were assessed by measuring ear thickness with engineer's micrometer, detecting tissue perfusion by laser Doppler scanning and Evans blue or indocyanine green extravasation by intravital videomicroscopy or fluorescence imaging, respectively. Myeloperoxidase activity, an indicator of neutrophil infiltration, was measured from the ear homogenates with spectrophotometry. The selective PAC1R agonist maxadilan, the VPAC1/2R agonist vasoactive intestinal polypeptide (VIP) or the vehicle were administered i.p. 15 min before MO. Substance P (SP) concentration of the ear was assessed by radioimmunoassay. Maxadilan significantly diminished MO-induced neurogenic edema, increase of vascular permeability and vasodilation. These inhibitory effects of maxadilan may be partially due to the decreased substance P (SP) levels. In contrast, inhibitory effect of VIP on ear swelling was moderate, without any effect on MO-induced plasma leakage or SP release, however, activation of VPAC1/2R inhibited the increased microcirculation caused by the early arteriolar vasodilation. Neither the PAC1R, nor the VPAC1/2R agonist influenced the MO-evoked increase in tissue myeloperoxidase activity. These results clearly show that PAC1R activation inhibits acute neurogenic arterial vasodilation and plasma protein leakage from the venules, while VPAC1/2R stimulation is only involved in the attenuation of vasodilation.

L-carnitine supplementation and adipokines in patients with end-stage renal disease on regular hemodialysis.

Chronic hemodialysis (HD) patients frequently encounter carnitine depletion, elevated adipose tissue-derived hormones/cytokines, that may contribute to accelerated arteriosclerosis. 10 non-diabetic HD patients were studied over 28 weeks. In the 12 weeks treatment period 1 g L-carnitine was given iv after each HD session. Measurements of plasma free- and acylcarnitines, insulin, leptin, adiponectin, resistin and ghrelin were performed at baseline, at weeks 2, 4, 8, 12 (treatment period) and at weeks 24-28 (post-treatment period). L-carnitine supplementation resulted in progressive increase of free- and acylcarnitine levels. Plasma levels of insulin, resistin, leptin and ghrelin remained at the already elevated baseline values. L-carnitine therapy induced a significant increase in plasma adiponectin from 20.2 ± 12.7 µg/ml (baseline) to 32.7 ± 20.2 µg/ml in week 2 (p<0.05) and 35.4 ± 19.6 µg/ml in week 12 (p < 0.03), which remained unchanged in the post-carnitine period. Plasma insulin levels correlated positively with leptin (r = 0.525, p<0.0001) and resistin (r = 0.284, p<0.005); adiponectin levels correlated inversely with leptin (r = -0.255, p<0.02) and resistin (r = -0.213, p<0.04) irrespective of carnitine status. Plasma levels of adipokines and related hormones are greatly elevated in patients on regular HD. L-carnitine administration further augmented the plasma levels of protective adiponectin, therefore it may have a role in preventing cardiovascular complications of uremia.

Identification of a VWF peptide antagonist that blocks platelet adhesion under high shear conditions by selectively inhibiting the VWF-collagen interaction.

BACKGROUND: Because the collagen-VWF-GPIb/IX/V axis plays an important role in thrombus formation, it represents a promising target for development of new antithrombotic agents. OBJECTIVES: We used phage display to identify potential small peptides that interfere with the VWF-collagen binding and might serve as lead products for the development of possible oral antithrombotic compounds. METHODS: A random linear heptamer peptide library was used to select VWF-binding peptides. RESULTS: We identified a phage clone, displaying the YDPWTPS sequence, further referred to as L7-phage, that bound to VWF in a specific and a dose-dependent manner. This L7-phage specifically inhibited the VWF-collagen interaction under both static and flow conditions. Epitope mapping using deletion mutants of VWF revealed that the L7-phage does not bind to the known collagen-binding A3 domain within VWF, but to the more carboxyterminal situated C domain. This inhibition was not due to steric hindrance of the A3 domain-collagen interaction by the L7-phage. Indeed, a tetrabranched multi-antigen peptide (MAP) presenting four copies of the peptide, but not the scrambled MAP, also inhibited VWF-collagen interaction under conditions of high shear stress at a concentration of 148 nmol L(-1). CONCLUSIONS: Based on these results, we conclude that we have identified the first peptide antagonist that binds to the VWF C domain and by this specifically inhibits the VWF binding to collagen, suppressing platelet adhesion and aggregation under high shear conditions. As a consequence, this peptide and its future derivates are potentially interesting antithrombotic agents.

[Comparison of the effectiveness and tolerability of the saccharosum-sennosid-B solution and sodium-picosulfate in preparation for colonoscopy. Prospective, multicenter, randomized study]. / A saccharosum + sennosid-B oldat és a Na-pikoszulfát effektivitásának és tolerálhatóságának összehasonlítása kolonoszkópos elókészítés során. Multicentrikus, prospektív, randomizált vizsgálat.

INTRODUCTION: The effectivity, evaluability of the colonoscopic procedure depends greatly on the preparation and the cleanliness of the colon. A large scale of laxatives used for colon preparation are also available in our country (phenolphtalein, Karlsbad-salt, saccharosum + sennosid-B solution, bisacodyl, powder mixtures). AIMS: The authors examined in 5 gastroenterology centres the tolerability and effectivity of two frequently used laxatives--saccharosum + sennosid-B solution and Na-picosulphate--during colonoscopic preparation in 157 patients. METHODS: Exclusion criteria were: severe anemia, renal insufficiency, cardiac failure, active ulcerative colitis and Crohn's disease, possible stenotising colonic process and hypersensibility to one of the compounds. The patients were randomised prospectively. In the case of the saccharosum + sennosid-B solution the colon preparation was performed according to the manufacturers prescriptions, in the case of the Na-pikosulfate the investigator's own procedure was used based on literature data. The tolerability of the preparation was assessed using a questionnaire. The investigators made their statements concerning the cleanliness of the different colon sections based on uniform criteria. RESULTS: Both methods showed good efficacy concerning the cleanliness of the colon. The patients considered the Na-picosulphate better tolerable--based on the questionnaire data. The authors consider the analysis of further laxatives to help improve the work of their fellow endoscopists.

Removal of dissolved brown algal phlorotannins using insoluble polyvinylpolypyrrolidone (PVPP).

Tannins, a large and diverse group of phenolic secondary metabolites, are common in terrestrial plants and marine brown algae. It is sometimes desirable to remove the tannins from plant or algal extracts, e.g., when isolating enzymes and nucleic acids, when using certain colorimetric methods to quantify the tannin content, or to create reliable controls when using tannins in experimental studies. Insoluble polyvinylpolypyrrolidone (PVPP) can be used to specifically remove tannins from solution. In the present study, we evaluated the effect of different factors (amount of PVPP, number of PVPP treatments, type of solvent, pH, and incubation time) on the PVPP removal of dissolved brown algal phlorotannins. Our results imply that there is a limited amount of phlorotannins that can bind to a given amount of PVPP, and that it is preferable to use low quantities of PVPP repeatedly, compared to using fewer treatments with a high amount of PVPP. Furthermore, we found no consistent effect on the removal of phlorotannins due to solvent type (acetone, methanol, distilled water or filtered seawater). There was a slight decrease in the amount of phlorotannins removed from extracts with increasing pH when repeatedly treated with PVPP. All phlorotannins were removed from extracts with pH < or = 6.2, and 89% of the initial phlorotannin content was removed at pH 9.7. These results are compared with previous methodological studies on tannin removal with PVPP. Furthermore, the implications of phlorotannin removal in analytical and ecological investigations are discussed.

(9Z)-capsanthin-5,6-epoxide, a new carotenoid from the fruits of Asparagus falcatus.

From the fruits of Asparagus falcatus a novel minor (Z)-carotenoid has been isolated and, on the basis of spectral data interpretation, characterized as (9Z)-capsanthin-5,6-epoxide [(9Z,3S,5R,6S,3'S,5'R)-5,6-epoxy-3,3'-dihydroxy-5,6-dihydro-beta,kappa-caroten-6'-one, (1)]. In addition, seven other (Z)-carotenoids [namely, (9Z)-, (9'Z)-, (13Z)-, and (13'Z)-capsanthins, (9Z)- and (13Z)-capsorubins, and (9Z)-violaxanthin], which have been previously described from other plants, were isolated and identified.

Effects of endomorphin-1 on open-field behavior and on the hypothalamic-pituitary-adrenal system.

The effects of endomorphin-1 (EM1) on behavioral responses and on the hypothalamic-pituitary-adrenal system were investigated in mice. Locomotor activity was measured in an "open-field" apparatus, with parallel recording of the numbers of rearings and groomings. Different doses of the peptide (250 ng to 5 microg) were administered to the animals intracerebroventricularly 30 min before the tests. EM1 caused significant increases in the locomotor activity and the number of rearings. The effect of EM1 on the basal corticosterone secretion was also investigated. At a dose of 5 microg, the peptide significantly increased plasma corticosterone level. The corticotropin-releasing hormone (CRH) antagonist alpha-helical CRH9-41, applied 30 min prior to EM1 administration, completely abolished the increases in both locomotion and the number of rearings and attenuated the corticosterone release evoked by EM1. These results suggest that the EM1 -induced increases in locomotion and rearing activity as well as the pituitary-adrenal activation are mediated by CRH.

Carotenoid composition in the fruits of red paprika (Capsicum annuum var. lycopersiciforme rubrum) during ripening; biosynthesis of carotenoids in red paprika.

The changes in the carotenoid pigments of the Capsicum annuum var. lycopersiciforme rubrum during maturation have been investigated quantitatively by means of a HPLC technique. In all of the chromatograms, 40 peaks were detected; 34 carotenoids were identified. The total carotenoid content of the ripe fruits was about 1.3 g/100 g of dry weight, of which capsanthin constituted 37%, zeaxanthin was 8%, cucurbitaxanthin A was 7%, capsorubin constituted 3.2%, and beta-carotene accounted for 9%. The remainder was composed of capsanthin 5,6-epoxide, capsanthin 3,6-epoxide, 5,6-diepikarpoxanthin, violaxanthin, antheraxanthin, beta-cryptoxanthin, and several cis isomers and furanoid oxides. The possible biosynthetic routes for the formation of minor carotenoids containing 3,5,6-trihydroxy-beta-, 3,6-epoxy-beta-, and 6-hydroxy-gamma-end groups are described.

[Carotenoid contents of herbal teas]. / Gyógyteafüvek karotinoid tartalmának vizsgálata.

Carotenoid composition of 14 herbal tea consumed by Herbaria was investigated by HPLC method. The main components were lutein (36-49%) cis-luteins (2-20%) and beta-carotene (3-25%). alpha- and beta-cryptoxanthin, alpha-carotene and some 5,6-epoxy-carotenoids (neoxanthin, violaxanthin, antheraxanthin) were detected. The chlorophyll content was also measured.

Deltorphin II analogues with 6-hydroxy-2-aminotetralin-2-carboxylic acid in position 1.

Two approaches to the design of very active and highly selective delta opioid peptides were used to obtain new deltorphin analogues with altered hydrophobic and stereoelectronic properties. Deltorphin II analogues were synthesized with the substitution of Ile instead of Val at positions 5 and 6 in the address domain and 6-hydroxy-2-aminotetralin-2-carboxylic acid (Hat) instead of Tyr(1) in the message domain. In the radioreceptor-binding studies, in which type-specific tritiated opioid ligands were used, (R)- and (S)-Hat-deltorphins exhibited similar K(i) values, revealing high delta selectivity. The peptides displayed agonist properties in the in vitro bioassay, with IC(50) values in the subnanomolar range in the mouse vas deferens assay and in the micromolar or higher range in the guinea pig ileum assay, again demonstrating a high selectivity toward delta receptors. The agonist property of the new ligands was confirmed by means of [(35)S]GTPgammaS-binding experiments in membranes of the rat frontal cortex.

Intrarenal distribution of the colonic H,K-ATPase mRNA in rabbit.

BACKGROUND: Evidence suggests that the colonic H,K-ATPase isoform is expressed in the kidney and that a mRNA species highly homologous to the rat and guinea pig HKalpha2 is expressed in the cortical collecting duct (CCD) of the rabbit. The goals of this study were to determine if this mRNA is the rabbit homologue of HKalpha2 or a novel isoform and to determine intrarenal distribution of the HKalpha2 mRNA in rabbit. METHODS: 5'-RACE and Dye Deoxy Terminator chemistry were used to determine the full-length sequence of the rabbit HKalpha2 mRNA. The intrarenal distribution of HKalpha2 mRNA was determined in microdissected nephron segments, connecting tubule (CNT), and CCD cells isolated by immunodissection, as well as in the three cell types of the CCD. Principal cells and alpha- and beta-intercalated cells were isolated by fluorescence-activated cell sorting. HKalpha2 mRNA levels were determined by quantitative reverse transcription-polymerase chain reaction (RT-PCR) or single-nephron RT-PCR (SN-RTPCR). RESULTS: The full-length sequence of the rabbit kidney HKalpha2 mRNA was determined. This transcript is identical to the one expressed in rabbit distal colon. In microdissected nephron segments, strong HKalpha2 amplicons were present in the CNT, CCD, and outer medullary collecting duct (OMCD), whereas no signal was detected in the proximal tubule, distal convoluted tubule, think ascending limb, and inner medullary collecting duct. Roughly comparable levels of HKalpha2 mRNA were present in all three CCD cell types, and the highest levels were observed in a subpopulation most likely corresponding to CNT cells. CONCLUSIONS: These results suggest that the HKalpha2 mRNA is expressed in rabbit collecting duct is identical in size and sequence to the one expressed in rabbit distal colon. HKalpha2 mRNA in the rabbit kidney is selectively expressed in the CNT, CCD, and OMCD, and all three collecting duct subtypes express its mRNA.

Male reproductive effects of solvent and fuel exposure during aircraft maintenance.

Few studies have addressed the effects of mixed, low-level exposures to complex mixtures on a man's reproductive potential. In this prospective study, each subject was evaluated before first exposure and at 15 and 30 weeks after exposures had begun. A total of 50 men working on aircraft maintenance at an Air Force installation were included in the study. In addition, eight unexposed men were concurrently sampled. Industrial hygiene (IH) sampling and expired breath samples were collected for jet fuel as measured by total napthas, benzene--a component of jet fuel, 1,1,1-trichloroethane, methyl ethyl ketone, xylenes, toluene, and methylene chloride. Sperm production, structure, and function (sperm concentration, sperm motion, viability, morphology, morphometrics, and stability of sperm chromatin) were evaluated. Exposures were low. All mean IH measures were below 6 ppm, which is less than 10% of the Occupational Safety and Health Administration standard for all chemicals except benzene. Sheet metal workers had the highest mean breath levels for both total solvents (24 ppb) and fuels (28.3 ppb). For most sperm measures, mean values remained in the normal range throughout the 30 weeks of exposure. When jobs were analyzed by exposure groups, some adverse changes were observed. The paint shop group had a significant decline in motility of 19.5% at 30 weeks. Internal dose measures, however, did not show a significant association with spermatogenic changes.

Labeled trimethyllysine load depletes unlabeled carnitine in premature infants without evidence of incorporation.

6-N-Trimethyl-[d9]-L-lysine (dTML), the labeled form of a mammalian carnitine precursor, was administered to two groups of premature infants. Although the urinary output of dTML significantly increased in the low-dose-treated group (100 micromol/day), this amount did not affect the urinary output or plasma levels of carnitine and carnitine esters. In the second group of infants, after administration of 500 micromol dTML the plasma-free carnitine concentration increased (from 9.95 +/- 0.63 to 12.9 +/- 0.87 nmol/ml, p > 0.05) with a significant increase in the urinary excretion of free carnitine on the day of dTML administration and on the posttreatment day (from 4.79 +/- 1.36 to 9.85 +/- 1.18 and to 17.5 +/- 2.31 micromol/day, respectively). Analysis of urine using fast atom bombardment mass spectrometry (FAB-MS) revealed only the presence of the dTML in the urine of the newborns; no change was detected in the relative abundance of any other carnitine precursor. Surprisingly, in the second group, which received the higher dose of dTML supplement, only the signal intensity of the unlabeled carnitine increased after dTML administration; no new peak appeared in the urine that would correspond to the de novo synthesized carnitine containing the stable isotope-labeled trimethyl group of dTML. Thus, the FAB-MS analysis clearly demonstrated that contrary to the likely prediction, the 270% extra free carnitine output was a consequence of a dose-dependent dTML-induced depletion of the free carnitine reserves from the newborns. The absence of the incorporation of the label from dTML into carnitine strongly suggests that circulating TML is not the precursor of carnitine in premature infants.

Expression of colonic H-K-ATPase mRNA in cortical collecting duct: regulation by acid/base balance.

In addition to the gastric isoform of H-K-ATPase, the colonic isoform is also expressed in the kidney, but its intrarenal localization and exact function are not known. The goal of this study was to determine whether the colonic H-K-ATPase is expressed in the rabbit cortical collecting duct (CCD) and whether it is regulated by changes in acid/base balance. With quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) with RNA isolated from immunodissected rabbit CCD cells and degenerate oligonucleotide primers, a PCR product of the predicted size (approximately 430 bp) was amplified. The amplified DNA was further characterized by nested PCR and sequencing. Direct sequencing of the 434-bp PCR product revealed 83% identity at the nucleotide level and an 80.4% identity at the deduced amino acid level to the rat colonic H-K-ATPase. With the same primers and cDNA originating from rabbit distal colon, a DNA fragment with a size and nucleotide sequence identical to that originating from CCD cells was amplified. Furthermore, using PCR screening, we isolated and sequenced a 1.5-kb cDNA clone from a rabbit CCD library. The predicted amino acid sequence of the protein encoded by this cDNA is 85 and 82% identical to the corresponding regions of the guinea pig and rat colonic H-K-ATPase, respectively, and 70% identical to the H-K-ATPase recently cloned from Bufo marinus, whereas it shows only 45 and 42% homology to the rat Na-K-ATPase alpha 1-subunit and the rat gastric H-K-ATPase, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression cloning of the aldosterone target cell-specific 11 beta-hydroxysteroid dehydrogenase from rabbit collecting duct cells.

11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) is thought to confer aldosterone specificity to mineralocorticoid target cells by protecting the mineralocorticoid receptor from occupancy by endogenous glucocorticoids. We have recently described a novel isoform of 11-OHSD in the renal aldosterone target cells (11 beta-OHSD/CD) that differs from the previously characterized isoform (11 beta-OHSD-1). Unlike 11-OHSD-1, the collecting duct enzyme catalyzes irreversible dehydrogenation, has a very high affinity for its substrate, and is tissue-specific. We report here the isolation, sequence, and characterization of a complementary DNA (cDNA) encoding the rabbit collecting duct 11 beta-OHSD/CD or 11 beta-OHSD type 2. The cDNA, isolated using expression screening in Xenopus oocytes, is 1.9 kilobases in length and encodes a protein of 406 amino acids with a predicted molecular mass of 44,130 daltons. The cloned enzyme has a Michaelis constant (Km) for corticosterone of 6.6 +/- 3 nM, catalyzes exclusively dehydrogenation, and uses only NAD as cofactor. The cloned enzyme shows 85% and 75% amino acid identity to the recently cloned human type 2 11 beta-OHSD and sheep kidney 11 beta-OHSD, respectively, whereas the overall homology to rat liver 11 beta-OHSD-1 is less than 20% The messenger RNA for this 11 beta-OHSD is expressed at very high levels in the renal collecting duct and at much lower levels in the colon. The intrarenal distribution was determined by reverse-transcription polymerase chain reaction in isolated nephron segments or cell types. The messenger RNA is present only in aldosterone target cells within the kidney, at highest levels in principal cells, at lower levels in intercalated cells, and in inner medullary cells. These data suggest that the 11 beta-OHSD cDNA from rabbit collecting duct cells encodes the enzyme that confers aldosterone selectivity to mineralocorticoid target cells.

Blood glutathione peroxidase enzyme activity as an index of selenium release from Permasel in ewes.

Ten Merino ewes were given a single Permasel pellet (containing 5% of elementary selenium) orally and examined for the release of selenium in the reticulum by determining glutathione enzyme activity of the whole blood haemolysate over a period of 12 months. As compared to the controls, the treated ewes exhibited a significant elevation in glutathione peroxidase activity for 8 months, indicating an acceptable persistence of the product tested.

[Clavicle fracture in the newborn]. / Ujszülöttek kulcscsonttörése.

The authors have found 244 clavicle fractures during 4131 vaginal delivery (5.91%). Both clavicles of three newborns have fractured. The incidence of fracture had relation to weight of newborns, to weakness of pains and to vacuum extraction. The Apgar score of the newborns with fractured clavicle was not less, than one of newborns with unbroken clavicle. None of 704 newborns from cesarean section, and none of 52 newborns, who was born out of the hospital had fracture of the clavicle. The cause of fracture is the violent hurry of delivery, the drawing of the head before birth of shoulders. One of 244 injured newborns had permanent brachial plexus palsy. Late complication was not found. Between the injured newborns was more frequent the jaundice requiring phototherapy.