Measuring health outcomes. Measuring quality of life is important.
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Humans↗
Biomedical subjects
K Rose
Publications and source records attributed to K Rose.
Effects of nonlinear synapses on the performance of multilayer neural networks.
The problems arising from the use of nonlinear multipliers in multilayer neural network synapse structures are discussed. The errors arising from the neglect of nonlinearities are shown and the effect of training in eliminating these errors is discussed. A method for predicting the final errors resulting from nonlinearities is described. Our approximate results are compared with the results from circuit simulations of an actual multiplier circuit.
Neural Networks, Computer↗
Preparation of a trivalent antigen-binding construct using polyoxime chemistry: improved biodistribution and potential for therapeutic application.
In an attempt to improve the pharmacokinetic behavior of an antitumor radioimmunoconjugate, we have prepared a trivalent antigen-binding construct formed from three Fab' fragments derived from the parent murine monoclonal antibody (MAb) 35 directed against the carcinoembryonic antigen. The construct was generated by a novel approach using polyoxime chemistry. This approach leads to a homogeneous construct, as judged by SDS-PAGE and by mass spectrometry, which was found to retain full immunoreactivity. A comparison of the monovalent, divalent, and trivalent F(ab')n materials in vitro revealed the expected trend of increasing association constant with increasing valency. The in vivo biodistribution of the 125I-labeled trivalent construct was studied in xenograft-bearing nude mice. Absolute tumor accumulation seen with the trivalent construct (10.8% injected dose/g) was lower than that seen with the intact MAb35 (15.2% injected dose/g). This finding and the more rapid loss of activity from tumor are presumably the consequence of the quicker blood clearance of the trivalent material. However, the construct showed tumor:blood ratios up to 10-fold higher than those seen for the parent antibody, and ratios of tumor:normal tissue accumulation were generally greatly improved. These improvements were achieved despite only modest reduction in maximum tumor accumulation when compared to the parent MAb35, and this augurs well for an improved potential for this novel construct as an agent for radioimmunotherapy and radioimmunoscintigraphy.
Animals↗
Media enquiries and nurses.
In this article, the legal and professional implications surrounding 'confidentiality' and in particular confidentiality with regards to dealing with media enquiries are considered; and professional and legal responsibilities and problem areas for nurses are outlined. The use of specific policies which give instruction on dealing with media enquiries is also discussed.
Confidentiality↗
Effects of antibiotics on epithelial ion transport in the rabbit distal colon in-vitro.
One side-effect of the therapeutic use of antimicrobial agents is respiratory paralysis as a result of inhibition of skeletal neuromuscular transmission; cholinergic neuro-effector motor transmission in the gastrointestinal tract is inhibited by the same classes of antimicrobial agent. Study of the effects of several classes of antibiotic compound on intestinal motility has suggested that antibiotic-induced alterations of intestinal motility may be related to the onset of diarrhoea or the development of antibiotic-associated colitis. These compounds may, however, also initiate or exacerbate diarrhoea by altering control of epithelial function, a possibility that has not previously been rigorously investigated. This series of experiments investigated the effect of six antibiotics on rabbit distal colonic epithelial ion transport. Of all the antibiotics studied, only ampicillin was without effect. Clindamycin, erythromycin, gentamicin and lincomycin, each reduced the response of the epithelium to electrical field stimulation. In addition, the lincosamides clindamycin and lincomycin reduced basal short circuit current and the epithelial response to acetylcholine. Vancomycin had no effect on the response to electrical field stimulation or acetylcholine but enhanced the secretory action of prostaglandin E2. These data suggest that, in addition to their ability to alter intestinal motility, a number of potential antibiotic interactions with the epithelium and its innervation may contribute to the pathogenesis of antibiotic-associated diarrhoea and colitis.
Acetylcholine↗
Intragastric pH and serum gastrin during administration of different doses of pantoprazole in healthy subjects.
OBJECTIVE AND DESIGN: The effect of increasing doses of pantoprazole, a newly developed proton pump inhibitor, given at once daily doses of 40, 80 and 120 mg, on intragastric pH and serum gastrin profiles was studied in 15 healthy subjects in a randomized, double-blind, crossover study and compared to recordings without therapy. Measurements of intragastric pH and serum gastrin were performed on the 7th day of treatment by continuous pH recording and radioimmunoassay in blood samples obtained in 1-h intervals, respectively. RESULTS: Pantoprazole significantly increased gastric pH above basal at all pantoprazole doses studied: median 24-h pH rose from 1.2 without therapy to 3.4, 3.3 and 3.6 at 40, 80 and 120 mg daily, respectively. The corresponding integrated 24-h gastrin output was 1632, 2338 and 2248 pg/ml x 24 h compared to 575 pg/ml x 24 h without pantoprazole. There was no interindividual correlation between values of 24-h median pH and 24-h gastrin output at any pantoprazole dose studied. However, fasting gastrin levels closely correlated with 24-h gastrin output (r = 0.789; P < 0.0001). The acid inhibitory effect was significantly (P < 0.01) augmented in Helicobacter pylori positive subjects. CONCLUSION: It is concluded that pantoprazole is an effective inhibitor of gastric acid secretion. Increasing a single pantoprazole dose above 40 mg does not lead to increased median pH elevation. The individual extent of acid inhibition does not predict the magnitude of gastrin elevation. Acid inhibition appears more efficient in Helicobacter pylori positive subjects.
2-Pyridinylmethylsulfinylbenzimidazoles↗
Regulation of rat hepatic sulfotransferase gene expression by glucocorticoid hormones.
Because hormones have been implicated in the molecular regulation of the sulfotransferase multigene family, the effects of glucocorticoid and antiglucocorticoid hormones on rat hepatic hydroxysteroid sulfotransferase-a and aryl sulfotransferase IV gene expression were investigated in vivo and in primary rat hepatocyte culture. Adult male Sprague-Dawley rats were treated for three consecutive days with 2% Tween-20 vehicle, or 100 mg/kg of dexamethasone, betamethasone, hydrocortisone, or triamcinolone acetonide. Betamethasone and triamcinolone acetonide significantly increased hepatic aryl sulfotransferase IV mRNA to levels that were approximately 252% and approximately 452% of control, respectively. Dexamethasone significantly increased hydroxysteroid sulfotransferase-a mRNA and protein to levels that were approximately 150% and approximately 316% of control, respectively. In contrast, in vivo treatment with hydroxysteroid sulfotransferase-a substrate dehydroepiandrosterone significantly decreased hydroxysteroid sulfotransferase-a mRNA levels (by approximately 55% relative to control). To determine if glucocorticoid mediated changes in sulfotransferase expression occurred as a result of direct effects on the hepatocyte, studies were performed in primary rat hepatocyte culture. Triamcinolone acetonide and betamethasone increased sulfotransferase mRNA expression in hepatocyte culture and hydrocortisone proved to be a less effective inducer. Effects of glucocorticoids on sulfotransferase gene expression were compared with glucocorticoid effects on tyrosine aminotransferase expression, a gene known to be regulated by a classical glucocorticoid receptor-mediated mechanism. Dexamethasone produced maximal increases in aryl sulfotransferase IV and tyrosine aminotransferase mRNA levels when added to culture medium at a concentration of 10(-7) M, whereas hydroxysteroid sulfotransferase-a mRNA levels continued to increase through a dexamethasone concentration of 10(-5) M. Treatment of hepatocytes with the antiglucocorticoid RU-486 (10(-5) M) inhibited dexamethasone-stimulated aryl sulfotransferase and tyrosine amino-transferase mRNA expression by approximately 48% and approximately 35%, respectively, but had less effect on hydroxysteroid sulfotransferase mRNA expression. These results suggest that glucocorticoids regulate rat hepatic aryl sulfotransferase IV and hydroxysteroid sulfotransferase-a via classical glucocorticoid receptor-mediated and non-classical mechanisms, respectively.
Animals↗
Drug administration made safer.
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Drug Delivery Systems↗
1H NMR structural study of free and template-linked antigenic peptide representing the C-terminal region of the heavy chain of influenza virus hemagglutinin.
A 12 kDa template-assembled molecule, incorporating four oxime-linked synthetic peptides representing residues 306-328 of influenza virus hemagglutinin (HA), has been analysed by 1H NMR spectroscopy. The molecule (referred to as the 'tetraoxime') is of interest because it has been shown to elicit a better immune response than the free, monomeric peptide not only in the production of antibodies crossreactive with HA but also in its ability to elicit CD4+ T helper cells. We describe here an NMR structural analysis of (i) the unlinked template molecule and (ii) the free peptide and show that their conformations are not affected upon assembly of the tetraoxime. Our results suggest that the increased immune response observed for the tetraoxime may be due to its greater size and valency compared to that of the free peptide rather than being due to any induced structural effects.
Amino Acid Sequence↗
Phospholipase D signaling is essential for meiosis.
Phospholipid metabolism plays an important role in cellular regulation by generating second messengers for signal transduction. Many stimuli activate a phospholipase D, which catalyzes the hydrolysis of phosphatidylcholine, producing phosphatidic acid and choline. Here we report that the yeast SP014 gene, which is essential for meiosis [Honigberg, S. M., Conicella, C. & Esposito, R. E. (1992) Genetics 130, 703-716], encodes a phospholipase D. SP014 RNA and protein activity are induced during late meiotic prophase, and the enzyme has properties similar to mammalian phosphatidylinositol 4,5-bisphosphate-regulated phospholipase D. Characterization of an unusual allele of SP014 defines regions of the protein important for enzyme catalysis and regulation. These results implicate phospholipase D signaling in regulating cellular differentiation.
Alleles↗
Human ADP-ribosylation factor-activated phosphatidylcholine-specific phospholipase D defines a new and highly conserved gene family.
Activation of phosphatidylcholine-specific phospholipase D (PLD) has been implicated as a critical step in numerous cellular pathways, including signal transduction, membrane trafficking, and the regulation of mitosis. We report here the identification of the first human PLD cDNA, which defines a new and highly conserved gene family. Characterization of recombinant human PLD1 reveals that it is membrane-associated, selective for phosphatidylcholine, stimulated by phosphatidylinositol 4,5-bisphosphate, activated by the monomeric G-protein ADP-ribosylation factor-1, and inhibited by oleate. PLD1 likely encodes the gene product responsible for the most widely studied endogenous PLD activity.
ADP-Ribosylation Factors↗
Isolation and characterization of a cyclic hydroxamic acid from a pollen extract, which inhibits cancerous cell growth in vitro.
One fraction, designated FV-7, in the water soluble ingredient of the pollen extract Cernilton was found to be inhibitory to the growth of a prostate cancer cell line. Characterization of FV-7 by high-resolution mass spectrometry and nuclear magnetic resonance identified the fraction as hydroxamic acid, 2,4-dihydroxy-2H-1,4-benzoxazin-3(4H)-one (DIBOA). To confirm this further, we synthesized an authentic sample of DIBOA and found subsequently that the synthetic DIBOA was structurally indistinguishable from FV-7. Furthermore, in a separate experiment we compared the in vitro effects of FV-7 and DIBOA on the growth of a prostate cancer cell line and found that in both cases the effect was inhibitory and that the inhibition curves obtained for both compounds were virtually identical.
Antineoplastic Agents, Phytogenic↗
Expression of two new protein isoforms of the neurofibromatosis type 1 gene product, neurofibromin, in muscle tissues.
The neurofibromatosis type 1 (NF1) gene encodes a tumor suppressor protein, termed neurofibromin, which is expressed predominantly in neurons, Schwann cells, oligodendrocytes, and leukocytes. There are at least three isoforms of neurofibromin produced by the alternative use of exons 23a and 48a. Previously we described the identification of an NF1 mRNA isoform containing an additional 54 nucleotides from exon 48a (type 3 NF1) in human skeletal, cardiac and smooth muscle tissues by reverse-transcribed (RT)-PCR. To extend our initial observations, we have produced high titer chicken IgY antibodies which specifically recognize this muscle-specific neurofibromin isoform. An NF1 cDNA was generated containing human exon 48a sequences and expressed as a fusion protein in bacteria. The muscle-specific neurofibromin antibodies detected this exon 48a fusion protein by Western immunoblotting. Immunoprecipitation using these type 3 neurofibromin antibodies also specifically detected a 250 kDa protein in human and rat muscle tissues. Type 3 neurofibromin was found in rat heart and muscle, but not in liver brain, kidney or spleen with levels of expression declining after postnatal day 7. Expression of total NF1 RNA during rat embryonic development was detected at high levels in E15 heart, tongue, and limb bud. In addition, using type 2 neurofibromin-specific antibodies, the existence of a fourth isoform of neurofibromin (type 4 neurofibromin) containing both exon 23a and 48a sequences was demonstrated in rat heart muscle tissues. The identification of two muscle-specific isoforms of neurofibromin expands our definition of this important tumor suppressor protein and suggests additional roles for neurofibromin in muscle development and differentiation.
Amino Acid Sequence↗
Loss of neurofibromatosis type I (NF1) gene expression in pheochromocytomas from patients without NF1.
The neurofibromatosis type 1 (NF1) gene encodes a tumor-suppressor protein termed neurofibromin, which, in adults, is expressed predominantly in neurons, Schwann cells, and the adrenal medulla. Loss of NF1 gene expression has been reported in Schwann cell tumors (neurofibrosarcomas) from patients with NF1 as well as in malignant melanomas and neuroblastomas from patients without NF1. Previously, we demonstrated the lack of neurofibromin expression in six pheochromocytomas from patients with NF1, supporting the idea that neurofibromin might be an essential regulator of cell growth in these cells. To determine whether NF1 gene expression is similarly altered in pheochromocytomas from patients without NF1, we examined 20 pheochromocytomas for the presence of NF1 RNA and neurofibromin by reverse-transcribed polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. Reduced or absent NF1 gene expression was documented in 7 of these 20 tumors (35%) including 1 of 4 sporadic tumors, 3 of 10 tumors from patients with multiple endocrine neoplasia (MEN) 2A, 2 of 4 tumors from patients with MEN2B, and 1 of 2 tumors from patients with von Hippel-Lindau syndrome. In addition, most of these tumors expressed predominantly the type 1 NF1 isoform (75% type 1 NF1 isoform expression) as opposed to other neural crest-derived tissues such as adrenal gland and Schwann cells, which express predominantly type 2 NF1. This type 1 isoform predominance was also observed in the rat pheochromocytoma PC12 cell line, suggesting that this change in isoform expression may be associated with the genesis of these tumors.(ABSTRACT TRUNCATED AT 250 WORDS)
Base Sequence↗
A synthetic peptide-based polyoxime vaccine construct of high purity and activity.
An artificial protein containing four copies of a peptide comprising the C-terminal 23 residues of influenza virus hemagglutinin was constructed using oxime chemistry and compared with two tetrameric multiple antigenic peptide (MAP) constructions of the same peptide displayed either radially or linearly which were made by conventional techniques. The tetra-oxime was much more homogeneous yielding a single peak on reversed phase HLPC and the correct mass spectrum. In addition, the tetra-oxime was found to be recognized by anti-peptide antibodies, to stimulate at low concentrations a T-cell clone and also to elicit in mice high titres of antibodies which were able to recognize native virus. The modular polyoxime approach, which permits artificial proteins to be assembled rapidly, in high yield and in high purity, is expected to lead to an increase in the use of artificial proteins in vaccine technology.
Amino Acid Sequence↗
Haemoglobin Tunis-Bizerte: a new alpha 1 globin 129 Leu-->Pro unstable variant with thalassaemic phenotype.
A Leu-->Pro substitution at position 129 of the alpha 1 globin gene was detected in three members of a Tunisian family by sequencing the whole alpha 2 and alpha 1 DNA. The mutation was verified by dot-blot allele-specific hybridization as well as by digestion of PCR and RT-PCR products with Nci I, since the alpha 1(129) T-->C mutation creates an additional recognition site for the above-mentioned enzyme. The alpha 1(129)(H12)Leu-->Pro substitution disturbs helix H resulting in alpha-thal trait most probably because the unstable alpha-globin chain variant cannot form alpha beta dimers. A search for the abnormal Hb and for the abnormal alpha globin chain by isoelectric focusing, carboxymethyl cellulose chromatography and electrospray ionization mass spectrometry was negative. In the heterozygous state, the alpha 1(129)(H12) Leu-->Pro variant is manifested by microcytosis (MCV approximately 73 fl), whereas in the homozygous state there is moderate anaemia with marked microcytosis (Hb 11.6 g/dl, MCV 65 fl).
Adolescent↗
Pantoprazole is superior to ranitidine in the treatment of acute gastric ulcer.
BACKGROUND: Pantoprazole is a newly developed gastric H+/K(+)-adenosine triphosphatase inhibitor with a potent and long-acting inhibitory effect on gastric acid secretion. METHODS: In a double-blind multicenter study with 28 centers in Germany, pantoprazole (40 mg before breakfast) was compared with ranitidine (300 mg at bedtime) with regard to healing rates, time until healing, symptom relief, and tolerability. A total of 248 outpatients with benign gastric ulcer were included. RESULTS: The healing rates after 2, 4, and 8 weeks were 37%, 87%, and 97%, respectively, in the pantoprazole and 19%, 58%, and 80% in the ranitidine group. The differences between the two groups were significant at 2 weeks (p < 0.01), 4 weeks (p < 0.001), and 8 weeks (p < 0.001; Cochran/Mantel-Haenszel method). Ulcer healing proceeded significantly faster with pantoprazole (p < 0.001; Uleman's U-test). Both treatments were well tolerated. CONCLUSIONS: Pantoprazole appears to be superior to ranitidine in gastric ulcer healing.
2-Pyridinylmethylsulfinylbenzimidazoles↗
Characterization of two post-translationally processed forms of human serum retinol-binding protein: altered ratios in chronic renal failure.
Retinol-binding protein (RBP) is the specific blood carrier for the transport of retinol (vitamin A) to target tissues. As the kidney is involved in RBP metabolism, the analysis of RBP species in the serum of patients with chronic renal failure (CRF) was used as a model to study possible RBP alterations. SDS-PAGE-immunoblotting analysis of normal and CRF sera shows a doublet of RBP bands (band A and band B) near 21 kDa. Mass spectrometric analysis of purified RBPs from CRF and normal sera revealed the presence not only of full-length RBP (183 residues, migrating in band A) but also two forms of RBP differing from the native form by the loss of C-terminal Leu (i.e., RBP1 (residues 1-182), migrating in band A also) and the loss of C-terminal Leu-Leu (i.e., RBP2 (residues 1-181), migrating in band B). Interestingly, RBP2 was considerably increased in the serum of CRF, whereas it was low in normal sera. In healthy retinol target-tissues and in cultured HepG2 cells, RBP2 levels were significantly and variably present compared to RBP and RBP1. We propose that these post-translationally modified forms of RBP occur in cells and that after their release into the blood circulation RBP2 is cleared by the kidney in healthy individuals but accumulates in the serum of CRF patients. RBP2 may have an important physiological role in retinol transport and/or recycling.
Amino Acid Sequence↗