$34 million neuropeptide deal.
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Drug Industry↗
Biomedical subjects
M Page
Publications and source records attributed to M Page.
Dysregulation of monocytic nuclear factor-kappa B by oxidized low-density lipoprotein.
Nuclear factor-kappa B (NF-kappa B)/Rel transcription factors may be involved in atherosclerosis, as is suggested by the presence of activated NF-kappa B in human atherosclerotic lesions. The aim of the present study was to investigate the effects of oxidized LDL (oxLDL) on the NF-kappa B system in human THP-1 monocytic cells as well as adherent monocytes. Our results demonstrate that short-term incubation of these cells with oxLDL activated p50/p65 containing NF-kappa B dimers and induced the expression of the target gene IL-8. This activation of NF-kappa B was inhibited by the antioxidant and H2O2 scavenger pyrrolidine dithiocarbamate and the proteasome inhibitor PSI. The oxLDL-induced NF-kappa B activation was accompanied by an initial depletion of I kappa B-alpha followed by a slight transient increase in the level of this inhibitor protein. In contrast, long-term treatment with oxLDL prevented the lipopolysaccharide-induced depletion of I kappa B-alpha, accompanied by an inhibition of both NF-kappa B activation and the expression of tumor necrosis factor-alpha and interleukin-1 beta genes. These observations provide additional evidence that oxLDL is a potent modulator of gene expression and suggest that (dys)regulation of NF-kappa B/Rel is likely to play an important role in atherogenesis.
Antioxidants↗
CBER status on reform initiatives: industry reactions and comments.
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Biological Products↗
[Equipments of quality control].
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Diagnostic Imaging↗
[Mammography. Still at the technological advant-guard].
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Female↗
Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion.
Nuclear factor-kappa B (NF-kappaB)/Rel transcription factors play an important role in the inducible regulation of a variety of genes involved in the inflammatory and proliferative responses of cells. The present study was designed to elucidate the implication of NF-kappaB/Rel in the pathogenesis of atherosclerosis. Activation of the dimeric NF-kappaB complex is regulated at a posttranslational level and requires the release of the inhibitor protein IkappaB. The newly developed mAb alpha-p65mAb recognizes the IkappaB binding region on the p65 (RelA) DNA binding subunit and therefore selectively reacts with p65 in activated NF-kappaB. Using immunofluorescence and immunohistochemical techniques, activated NF-kappaB was detected in the fibrotic-thickened intima/media and atheromatous areas of the atherosclerotic lesion. Activation of NF-kappaB was identified in smooth muscle cells, macrophages, and endothelial cells. Little or no activated NF-kappaB was detected in vessels lacking atherosclerosis. Electrophoretic mobility shift assays and colocalization of activated NF-kappaB with NF-kappaB target gene expression suggest functional implications for this transcription factor in the atherosclerotic lesion. This study demonstrates the presence of activated NF-kappaB in human atherosclerotic tissue for the first time. Atherosclerosis, characterized by features of chronic inflammation and proliferative processes, may be a paradigm for the involvement of NF-kappaB/Rel in chronic inflammatory disease.
Animals↗
Activation of methotrexate-phenylalanine by monoclonal antibody--carboxypeptidase A conjugate for the specific treatment of ovarian cancer in vitro.
Monoclonal antibody 4E3 directed against a glycosylated surface protein on human ovarian teratocarcinoma cells (CRL-1572 cell line) was conjugated to bovine carboxypeptidase A (CPA) using a 3400 Da polyethylene glycol chain bearing an N-hydroxysuccinimide group at both ends. The conjugate preparation was purified by fast protein liquid chromatography on a Superose 12/30 HR column. The 4E3-CPA conjugate was recovered in the third fraction by SDS-PAGE analysis. The specific binding of the 4E3-CPA conjugate to CRL-1572 cells was confirmed by a FACS analysis and the enzymatic activity of the conjugate remained while tested with hippuryl-L-phenylalanine. In vitro cytotoxic assays on CRL-1572 cells showed that the prodrug methotrexate-phenylalanine (MTX-Phe) alone was non-toxic (ID50 > 1000 ng ml-1) but was selectively converted to MTX when the cells were pretreated with 50 micrograms ml-1 4E3-CPA conjugate, which enhanced considerably the pharmacological activity of the prodrug with an ID50 of 70 ng ml-1. The co-culture assays with CRL-1572 and MRC-5 cells (human normal lung diploid fibroblast cell lines) demonstrated the specificity of the 4E3-CPA conjugate for the CRL-1572 cells since no cytotoxicity was observed on the MRC-5 cells. When both cell lines were mixed in ratios ranging from 1:10,000 to 1:5 (CRL-1572:MRC-5), the significant increase in the ID25 was correlated with the proportion of tumoral cells present in the cell inoculum. These results suggest that MTX-Phe combined with 4E3-CPA conjugate is a promising model for a more selective and localised anti-cancer chemotherapy based on the ADEPT concept.
Antibodies, Monoclonal↗
Testing plasma pools for markers of viral contamination: the UK experience.
The transmission of viral infections through the use of products derived from blood has emphasised the need for adequate validation of the production process, testing of materials used in production and quality control tests on the final product. Since the late 1980s, as part of its batch release procedures, NIBSC has tested for markers of viral infectivity plasma pools used in production of blood products used in the UK. As a result of testing over 9,000 pools, NIBSC has identified 9 pools contaminated with HBsAg and 2 pools containing antibodies to HIV-1. Since routine screening of plasma pools for anti-HCV was introduced in 1993, 8 pools out of the 4,000 tested have been found to contain antibodies to HCV. In addition, the release of 12 batches of blood products was withheld and it is known that further batches of material produced from the positive pools were not submitted for batch release. Studies involving assays of dilutions of known positive plasma samples indicated that there is considerable variation in the endpoint dilutions of antigen or antibody detected by test kits from different manufactures. The selection and validation of the kits used in such testing is therefore important. The usefulness of standardised low-level external controls in assays of plasma pools for markers of viral infection is discussed.
Antibodies, Viral↗
Intravenous carboplatin for recurrent gliomas. A dose-escalating phase II trial.
In a Phase II trial, 63 evaluable patients with recurrent glioma received i.v. infusions of carboplatin every 3 weeks beginning at a dose of 400 mg/m2. The dose was increased by 50 mg/m2 at each subsequent infusion until the maximum tolerated dose reached, as defined by a platelet count < 25,000/mm3 or an absolute neutrophil count (ANC) < 500/mm3. Treatment was then resumed at the previous dose level and continued until tumor progression occurred. There were 43 men and 20 women studied (mean age, 41 years; range, 6 months to 70.6 years). The combined response and stabilization rate was 29% for 31 patients with glioblastoma and 71.9% for 32 patients with other tumors; median time to tumor progression was 8.2 and 20.3 weeks and median survival was 25.9 and 58.3 weeks, respectively. Twenty patients had level 4 platelet toxicity and nine had level 4 ANC toxicity. Most tumors progressed before the maximum tolerated dose was reached. These results were not better than those from a previous trial of carboplatin at an initial dose of 350 mg/m2, which was escalated by 25 mg/ m2 after every two infusions. Therefore, an optimal dosing schedule was not achieved in this trial.
Adolescent↗
The chemistry and structure-activity relationships of C3-quaternary ammonium cephem antibiotics.
The observation of a broad spectrum of antibacterial activity for cefpirome and for cefepime highlighted the benefits of combining a C3-quaternary ammonium substituent with the (Z)-2-(2-aminothiazole-4-yl)-2-methoxyiminoacetamido side chain at C7. The quaternary nitrogen imparts beta-lactamase stability and improves both the cell penetration and the pharmacokinetic properties of these antibiotics. A variety of different quaternary ammonium substituents have been added, successive alterations in the groups attached to nitrogen have extended the activity of the fourth generation compounds. A number of different methods for attaching the quaternary ammonium group have been established, including the direct linkage to the C3-methylene, linkage via a C3-thiomethylene and also linkage via an alkenyl bridge. A number of different strategies have been developed for the preparation of these derivatives and these have been collated in this review. The beta-lactamase stability of fourth generation cephalosporins can be attributed to the formation of a transiently stable modified acyl-enzyme. The extent to which the modified acyl-enzyme contributes to the beta-lactamase stability is very much dependent on the leaving ability (nucleofugacity) of the C3-substituent. The influence of the quaternary ammonium substituents, on the formation of the modified acyl-enzyme, will be discussed.
Amines↗
The nurse's role in resuscitation decisions.
Cardiopulmonary resuscitation should be instituted only for the benefit of the patient. The patient's views should be sought where possible. Nurses have a responsibility to act as the patient's advocate if doctors fail to ascertain patients' views.
Aged↗
Cell-binding and growth-stimulating activities of the C-terminal part of human MGSA/Gro alpha.
The FITC-labeled C-terminal alpha-helix portion of human MGSA/gro alpha (MGSA 47-71) was shown, using flow cytometry, to bind to human melanoma cells Hs294t but not to non-melanoma cells. MGSA (47-71) is capable to induce specifically DNA synthesis of melanoma cells. These results indicate that the C-terminal portion of human MGSA is sufficient for its biological activity, thus raising questions about the importance of dimerization and of the N-terminal ELR box of the molecule which has been proposed.
Amino Acid Sequence↗
Fragmentation of therapeutic human immunoglobulin preparations.
Some commercial batches of human therapeutic immunoglobulins (Ig) have been found to show evidence of molecular fragmentation when examined by molecular sizing methodologies including sodium dodecyl sulphate polyacrylamide gel electrophoresis [SDS-PAGE] and size exclusion high performance liquid chromatography (SE-HPLC). These batches all demonstrated impaired immunobiological activity (efficacy) as assessed by Fc function measured using a rubella haemolytic assay and as such are likely to be subpotent for therapeutic use. Fragmented Igs were characterized by the presence of at least three protein bands and peaks additional to monomeric IgG. Incubation of Igs with blood enzymes (plasmin and kallikrein) reproduced the fragmentation patterns observed for intrinsically degraded batches, suggesting that fragmentation occurred by contamination with these proteases from the source material (human blood) during manufacture. Intravenous Igs (IVIG) were found to be more susceptible to proteolysis than intramuscular Igs, probably as a consequence of the post-fractionation processing that some IVIGs receive which may induce molecular alterations, allowing enzyme access and fragmentation. Two of the products examined were found to be relatively resistant to proteolysis and both were formulated by processes that limit enzyme activity. These processes were inclusion of an enzyme inhibitor, alpha 2-macroglobulin, and formulation at acidic pH. Enzyme carry-over into the final product is a likely cause of Ig fragmentation, and reduction in levels of such contamination should lead to improvements in product stability and efficacy.
Chemical Phenomena↗
Physiological studies of gastro-oesophageal reflux and airway protective responses in the young animal and human infant.
1. The mechanisms that underlie the Sudden Infant Death Syndrome (SIDS) must explain its two unique features; age at death and death during apparent sleep. 2. The occurrence of gastro-oesophageal reflux (GOR) during active sleep in infants presenting with apparent life threatening episodes (ALTE) and their similar age distribution to SIDS infants, suggested that reflux could be a cause of asphyxia. 3. Sleep related GOR was found to be a physiological and not a pathological event in normal, healthy term infants. 4. In healthy term infants, those infants that were formula-fed (who have a higher incidence of SIDS) had significantly longer oesophageal clearance times for acid reflux and significantly more active sleep compared with breast fed infants. 5. In very preterm infants (who are at increased risk for SIDS), both the frequency and duration of reflux during active sleep was significantly less at term equivalent age compared with healthy term infants, suggesting additional factors must operate to promote an ALTE. 6. One mechanism which may explain the pathogenesis of GOR could be that the reflux reaches the level of the pharynx and this, in turn, stimulates laryngeal receptors to produce apnoea. 7. Simulated reflux to the level of the pharynx in the sleeping piglet evoked airway protective responses, namely swallow, arousal and occasionally expectoration, but neither apnoea nor oxygen desaturation. 8. In the same piglets treated with pentobarbitone sodium, swallowing was impaired and arousal depressed. Simulated reflux to the pharynx produced significant apnoea and oxygen desaturation and death in two of five piglets.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Developmental maturation of gastro-oesophageal reflux in preterm infants.
The frequency and duration of gastro-oesophageal reflux were examined in 40 preterm infants and compared with a previously published healthy cohort of 74 term infants. Selection required that the infants were born between 24 and 32 weeks' gestation, had a normal head ultrasound and were studied at term post-menstrual age. Multi-channel pen recordings of sleep state, movement, breathing and acid reflux were made. In term and preterm infants the frequency and duration of reflux were greatest in active sleep, rare in quiet sleep and significantly less in preterm than term infants in wakefulness and active sleep (p < 0.05). The fewer and shorter episodes in preterm infants could not be explained by sleep state movement, gestational or postnatal age, days intubated, days on oxygen or the lowest pH of reflux episodes.
Age Factors↗
Mechanisms of airway protection after pharyngeal fluid infusion in healthy sleeping piglets.
The airway protective mechanisms evoked after infusion of fluids into the pharynx were examined in the intact and healthy newborn piglet during sleep. Thirteen healthy normothermic piglets (3-6 days of age) were examined on 4 consecutive days during sleep. The fluids infused (0.05-1.5 ml) were 0.9% saline, distilled water, and HCl (pH 3 and pH 2). Respiratory rate, heart rate, oxygen saturation (SaO2), swallowing, and arousal were compared pre- and postinfusion during active (AS) and quiet sleep (QS) for each test fluid. The most common response in AS and QS was swallowing (90%) and then arousal (24%); however, no apnea occurred, and respiratory rate and SaO2 were always maintained. A significant difference occurred between HCl infusions of pH 2 and pH 3; at pH 2, the frequency of swallows and latency to the first swallow were reduced (P < 0.05) and the frequency of arousal was reduced in AS compared with that in QS (P < 0.01). Airway protection after pharyngeal fluid stimulation is achieved primarily by swallowing and arousal, without any effect on respiratory rate and SaO2. Attenuation of protective mechanisms occurred, however, when the infusate was at pH 2.
Animals↗
The role of diet in coronary heart disease.
The causal factors of CHD are numerous, with diet playing a significant role in progression. As CHD is a chronic, progressive disease, a preventive rather than a palliative approach is indicated. Although health promotion initiatives pledge support for a preventive approach, resources have not followed government rhetoric. Research suggests nurses' knowledge of the dietary factors involved in CHD is poor.
Coronary Disease↗