Audit-guided action can improve the compliance with thromboembolic prophylaxis prescribing to hospitalized, acutely ill older adults.
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Acute Disease↗
Biomedical subjects
S Timmons
Publications and source records attributed to S Timmons.
Resistance to computerized care planning systems by qualified nurses working in the UK NHS.
OBJECTIVE: This study investigated whether computerized systems, designed to produce detailed plans for the nursing care of inpatients, were resisted by the nurses who were expected to use them. METHODS: Qualitative study, using semi-structured interviews with nurses working in the UK National Health Service. RESULTS AND CONCLUSIONS: Resistance took the form of 'resistive compliance,' and this resistance is analyzed and explained. Resistance can best be understood in terms of the culture of nursing. This implies that the design and implementation of computerized systems in health care should take these factors into account.
Attitude of Health Personnel↗
New onset seizures in the elderly: aetiology and prognosis.
Late onset epilepsy is increasing in incidence. These patients often have significant underlying morbidity. This retrospective study in a tertiary referral centre identified 68 patients aged 65 years or older, with new onset seizures over a four-year period. 81% of patients (n = 55) were followed up at an average of 2.7 years post diagnosis. 38% of patients had evidence of cerebrovascular disease (CT visualised focal infarction, haemorrhage or small vessel ischaemia in 32%, clinical diagnosis with normal CT brain in 6%). No patient was found to have a space-occupying lesion. Of the 55 patients followed up, 45% of these had died at a mean age of 82 years old and 1.9 years post diagnosis (range 12 hours to 5 years). Three patients died as a direct result of seizures (trauma and sepsis). 14 patients died of clearly unrelated causes. Eight patients died from underlying vascular disease or Alzheimer's dementia. Patients who died during follow-up were on average 3.4 years older at the time of diagnosis than survivors (p< 0.05). Patients with atrial fibrillation at the time of diagnosis, had increased mortality (relative risk 2.53; 95% C.I. 1.19 - 5.36), but they were older than those without atrial fibrillation. At the time of follow up, 92% of those taking anti-convulsants were maintained seizure free on anticonvulsant monotherapy.
Age Factors↗
Use of the Internet by patients: not a threat to nursing, but an opportunity?
The Internet poses numerous challenges for health care professionals. A significant one is the way in which patients, clients and carers now have access to large amounts of unfiltered, specialized health information, much of which was, hitherto, solely the province of the professionals. The specific problems that this poses, in terms of the effect that it might have on the therapeutic relationship, are discussed, along with some of the proposed solutions, such as the National Electronic Library for Health initiative and NHS Direct Online. Since this change is inevitable, it is recommended that nurses should seek to build on their role as educators of patients and carers. One of the ways in which they can do this is by guiding patients' and carers' use of the Internet, and helping them to evaluate the information that they find.
Humans↗
Blunt cerebrovascular injuries: diagnosis and treatment.
BACKGROUND: Blunt cerebrovascular injuries (BCVIs), once thought to be rare, have been recognized with increasing frequency in recent years. An incidence of 0.33% for carotid artery injury (CAI) was noted from our institution, with 24% stroke-related mortality. Vertebral artery injury (VAI) has been thought both rare and of questionable significance. Incidence, associated injury patterns, and outcomes were examined during a period of aggressive screening (four-vessel angiography). METHODS: Patients with BCVI were identified from the registry of a Level I trauma center over a 5-year period (1995-1999). RESULTS: One hundred thirty-nine BCVIs were identified in 96 patients: 75 were CAIs (14 bilateral), 64 were VAIs (14 bilateral), and 15 patients had both CAI and VAI. The incidence of CAI was 0.5% of all blunt trauma admissions, significantly higher than our earlier experience (p < 0.0002), whereas that for VAI was 0.4%. Thirty-four percent of CAIs were diagnosed because of ischemic changes and 38% because of injury pattern (neck, Horner syndrome, basilar skull fracture); only 12% of VAIs were diagnosed because of posterior circulation ischemia, with 64% because of injury pattern (cervical spine, soft tissue, facial fracture). Stroke-related mortality for CAI was 13%, and that for VAI was 4%. Forty-three of the 75 CAIs were treated (anticoagulation/antiplatelet) before development of ischemia. Thirty-nine of the 50 VAI patients were treated before development of ischemia. Stroke rate for CAI was 31% (hemiplegia/hemiparesis) and for VAI was 14% (brain stem dysfunction). Stroke rate for treated vessels (heparin, antiplatelet therapy) with CAI was 6.8% compared with 64% in untreated vessels (p < 0.001). Treated patients with VAI had a stroke rate of 2.6%, whereas untreated patients developed stroke 54% of the time. CONCLUSION: Increased awareness and aggressive screening have resulted in significantly increased incidence of diagnosis of CAI, with associated lower stroke-related mortality. VAIs have been noted with similar incidence, and though the stroke rate is lower with VAI, stroke outcomes are generally catastrophic. Anticoagulation therapy is effective for both varieties of BCVI.
Adult↗
Peptide-directed suppression of a pro-inflammatory cytokine response.
Signal-dependent nuclear translocation of transcription factor nuclear factor kappaB (NF-kappaB) is required for the activation of downstream target genes encoding the mediators of immune and inflammatory responses. To inhibit this inducible signaling to the nucleus, we designed a cyclic peptide (cSN50) containing a cell-permeable motif and a cyclized form of the nuclear localization sequence for the p50-NF-kappaB1 subunit of NF-kappaB. When delivered into cultured macrophages treated with the pro-inflammatory agonist lipopolysaccharide, cSN50 was a more efficient inhibitor of NF-kappaB nuclear import than its linear analog. When delivered into mice challenged with lipopolysaccharide, cSN50 potently blocked the production of proinflammatory cytokines (tumor necrosis factor alpha and interferon gamma) and significantly reduced the lethality associated with ensuing endotoxic shock. Based on specificity studies conducted with a mutated form of cSN50, a functional nuclear localization motif is required for this protective effect. Taken together, our findings demonstrate effective targeting of a cell-permeable peptide that attenuates cytokine signaling in vivo. This new class of biological response modifiers may be applicable to the control of systemic inflammatory reactions.
Amino Acid Sequence↗
Backstage in the theatre.
Observations undertaken in the operating theatre suggested that the social environment, and certain forms of staff behaviour could be explained using the space analysis developed by Erving Goffman (1969) in The Presentation of Self in Everyday Life. In the study reported in this paper the theatre department was found to be a strongly 'backstage' area. However, it was also found that there were limits to this analysis, and these are explained within this article. Some practical suggestions as to how this analysis might be helpful in the management of health care institutions and the education of health care professionals are made.
Attitude of Health Personnel↗
IkappaB kinase complex is an intracellular target for endotoxic lipopolysaccharide in human monocytic cells.
Endotoxic lipopolysaccharide (LPS) is a proinflammatory agonist produced by gram-negative bacteria and a contributor to the majority of the 400,000 septic shock cases recorded annually in US hospitals. The primary target cells for LPS are monocytes and macrophages. Their response consists of massive production of proinflammatory cytokines, reactive oxygen- and nitrogen-intermediates, procoagulants, and cell adhesion molecules. In turn, expression of these LPS-responsive factors contributes to collapse of the circulatory system, to disseminated intravascular coagulation, and to a 30% mortality rate. A common intracellular mechanism responsible for the expression of septic shock genes in monocytes and macrophages involves the activation of NF-kappaB. This transcription factor is regulated by a family of structurally related inhibitors including IkappaBalpha, IkappaBbeta, and IkappaBepsilon, which trap NF-kappaB in the cytoplasm. In this report, the investigators show that LPS derived from different gram-negative bacteria activates cytokine-responsive IkappaB kinases containing catalytic subunits termed IKKalpha (IKK1) and IKKbeta (IKK2). The kinetics of IKKalpha and IKKbeta activation in LPS-stimulated human monocytic cells differ from that recorded on their stimulation with tumor necrosis factor-alpha, thereby implying a distinct activation mechanism. LPS-activated IKK complexes phosphorylate all 3 inhibitors of NF-kappaB: IkappaBalpha, IkappaBbeta, and IkappaBepsilon. Moreover, LPS activates IKKbeta preferentially, relative to IKKalpha. Thus, IKK complex constitutes the main intracellular target for LPS-induced NF-kappaB signaling to the nucleus in human monocytic cells to activate genes responsible for septic shock.
Cells, Cultured↗
The implications of the Data Protection Acts for theatre nurses.
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Attitude of Health Personnel↗
Preparation of functionally active cell-permeable peptides by single-step ligation of two peptide modules.
Noninvasive cellular import of synthetic peptides can be accomplished by incorporating a hydrophobic, membrane-permeable sequence (MPS). Herein, we describe a facile method that expedites synthesis of biologically active, cell-permeable peptides by site-specific ligation of two free peptide modules: one bearing a functional sequence and the second bearing a MPS. A nonpeptide thiazolidino linkage between the two modules is produced by ligation of the COOH-terminal aldehyde on the MPS and the NH2-terminal 1, 2-amino thiol moiety on the functional sequence. This thiazolidine ligation approach is performed with stoichiometric amounts of fully unprotected MPS and functional peptide in an aqueous buffered solution, eliminating the need for additional chemical manipulation and purification prior to use in bioassays. Two different MPSs were interchangeably combined with two different functional sequences to generate two sets of hybrid peptides. One set of hybrid peptides, carrying the cytoplasmic cell adhesion regulatory domain of the human integrin beta3, inhibited adhesion of human erythroleukemia cells to fibrinogen-coated surfaces. A second set of hybrid peptides, carrying the nuclear localization sequence of the transcription factor NF-kappaB, inhibited nuclear import of transcription factors NF-kappaB, activator protein 1, and nuclear factor of activated T cells in agonist-stimulated Jurkat T lymphocytes. In each assay, these nonamide bond hybrids were found to be functionally comparable to peptides prepared by the conventional method. Cumulatively, this new ligation approach provides an easy and rapid method for engineering of functional, cell-permeable peptides and demonstrates the potential for synthesis of cell-permeable peptide libraries designed to block intracellular protein-protein interactions.
Amino Acid Sequence↗
An international health and nursing informatics module for distance education.
This paper describes why a module about health and nursing informatics is a necessary component for nursing education. Several developments in society and health care force health providers to manage the large amount of health data adequately. A module about health and nursing informatics was developed in international cooperation by three schools of nursing from Germany, The Netherlands and the UK. The content and learning activities of the realized example module for distance learning are described. Future plans include making this course material available in different languages on the World Wide Web.
Computer-Assisted Instruction↗
Identification of a functionally important sequence in the cytoplasmic tail of integrin beta 3 by using cell-permeable peptide analogs.
Integrins are major two-way signaling receptors responsible for the attachment of cells to the extracellular matrix and for cell-cell interactions that underlie immune responses, tumor metastasis, and progression of atherosclerosis and thrombosis. We report the structure-function analysis of the cytoplasmic tail of integrin beta 3 (glycoprotein IIla) based on the cellular import of synthetic peptide analogs of this region. Among the four overlapping cell-permeable peptides, only the peptide carrying residues 747-762 of the carboxyl-terminal segment of integrin beta 3 inhibited adhesion of human erythroleukemia (HEL) cells and of human endothelial cells (ECV) 304 to immobilized fibrinogen mediated by integrin beta 3 heterodimers, alpha IIb beta 3, and alpha v beta 3, respectively. Inhibition of adhesion was integrin-specific because the cell-permeable beta 3 peptide (residues 747-762) did not inhibit adhesion of human fibroblasts mediated by integrin beta 1 heterodimers. Conversely, a cell-permeable peptide representing homologous portion of the integrin beta 1 cytoplasmic tail (residues 788-803) inhibited adhesion of human fibroblasts, whereas it was without effect on adhesion of HEL or ECV 304 cells. The cell-permeable integrin beta 3 peptide (residues 747-762) carrying a known loss-of-function mutation (Ser752Pro) responsible for the genetic disorder Glanzmann thrombasthenia Paris I did not inhibit cell adhesion of HEL or ECV 304 cells, whereas the beta 3 peptide carrying a Ser752Ala mutation was inhibitory. Although Ser752 is not essential, Tyr747 and Tyr759 form a functionally active tandem because conservative mutations Tyr747Phe or Tyr759Phe resulted in a nonfunctional cell permeable integrin beta 3 peptide. We propose that the carboxyl-terminal segment of the integrin beta 3 cytoplasmic tail spanning residues 747-762 constitutes a major intracellular cell adhesion regulatory domain (CARD) that modulates the interaction of integrin beta 3-expressing cells with immobilized fibrinogen. Import of cell-permeable peptides carrying this domain results in inhibition "from within" of the adhesive function of these integrins.
Amino Acid Sequence↗
Mouse Col18a1 is expressed in a tissue-specific manner as three alternative variants and is localized in basement membrane zones.
We have isolated overlapping cDNAs encoding the N-terminal non-triple-helical region of mouse alpha 1(XVIII) collagen and shown that three different variants of alpha 1(XVIII) collagen exist. Each of the three variants shows characteristic tissue-specific expression patterns. Immunohistochemical studies show positive staining for alpha 1(XVIII) collagen along the basement membrane zones of vessels in the intestinal villi, the choroid plexus, skin, liver, and kidney. Thus, we conclude that alpha 1(XVIII) collagen may interact (directly or indirectly) with components in basement membrane zones or on the basal surface of endothelial/epithelial cells.
Alternative Splicing↗
Isolation and sequencing of cDNAs for proteins with multiple domains of Gly-Xaa-Yaa repeats identify a distinct family of collagenous proteins.
We have isolated overlapping mouse cDNAs encoding a collagenous polypeptide that we have designated alpha 1(XVIII) collagen. Nucleotide sequence analysis shows that alpha 1(XVIII) collagen contains 10 triple-helical domains separated and flanked by non-triple-helical regions. Within the non-triple-helical regions, there are several Ser-Gly-containing sequences that conform to consensus sequences for glycosaminoglycan attachment sites in proteoglycan core proteins. Northern blots show that alpha 1(XVIII) transcripts are present in multiple organs, with the highest levels in liver, lung, and kidney. We have also isolated overlapping cDNAs encoding human alpha 1(XV) collagen, and their sequence extends a published partial alpha 1(XV) sequence to the 3' end. Comparison of the alpha 1(XV) and alpha 1(XVIII) sequences reveals a striking similarity in the lengths of the six most carboxyl-terminal triple-helical domains. In addition, within the carboxyl non-triple-helical domain NC1 of the two chains, a region of 177 amino acid residues shows about 60% identity at the amino acid level. We suggest, therefore, that alpha 1(XV) and alpha 1(XVIII) collagens are structurally related. Their structure is different from that of other known collagen types. We conclude that they belong to a subfamily of extracellular matrix proteins and we suggest the designation multiplexins (for protein with multiple triple-helix domains and interruptions) for members of this subfamily.
Amino Acid Sequence↗
Cloning of cDNA and genomic DNA encoding human type XVIII collagen and localization of the alpha 1(XVIII) collagen gene to mouse chromosome 10 and human chromosome 21.
Types XV and XVIII collagen belong to a unique and novel subclass of the collagen superfamily for which we have proposed the name the MULTIPLEXIN family. Members of this class contain polypeptides with multiple triple-helical domains separated and flanked by non-triple-helical regions. In this paper, we report the isolation of human cDNAs and genomic DNAs encoding the alpha 1(XVIII) collagen chain. Utilizing a genomic clone as probe, we have mapped the COL18A1 gene to chromosome 21q22.3 by fluorescence in situ hybridization. In addition, using an interspecific backcross panel, we have shown that the murine Col18a1 locus is on chromosome 10, close to the loci for Col6a1 and Col6a2.
Amino Acid Sequence↗
A beta-turn is present in the 392-411 segment of the human fibrinogen gamma-chain. Effects of structural changes in this segment on affinity to antibody 4A5.
The interaction between fibrinogen gamma-peptide 392-411, LTIGEGQQHHLGGAKQAGDV, and monoclonal antibody 4A5, an antibody with a high affinity for both for the peptide and native fibrinogen, is being studied as a model for peptide-antibody interaction. Two-dimensional NMR studies of the free peptide at pH 5.2 indicated the presence of a significant population, about 60%, of type II beta-turn, spanning residues Gln407-Asp410. At pH 2.7, little, if any, turn structure is present. The D-Ala409 analog, which, for steric reasons, would be expected to preserve the beta-turn, and the L-Ala409 analog, which would not be expected to have this conformational feature, were synthesized, and NMR studies confirmed the respective structural predictions. The affinity of the D-Ala analog for antibody 4A5 is even greater than that displayed by native gamma 392-411, while the affinity of the L-Ala analog is less than one-tenth that of the native peptide. Both conformational and steric effects involving residues 407-410 may be important in recognition by antibody 4A5. Since gamma 392-411 includes a platelet receptor binding locus of fibrinogen, and this and related peptides are inhibitors of platelet aggregation, the D-Ala409 and L-Ala409 analogs were tested for platelet binding. Neither of the analogs displays any measurable platelet binding, indicating that the recognition requirements for the platelet receptor differ considerably from those for antibody 4A5.
Amino Acid Sequence↗
Binding of fibrinogen and von Willebrand factor to platelet glycoprotein IIb-IIIa complex.
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Amino Acid Sequence↗
A modified Arg-Asp-Val (RDV) peptide derived during the synthesis of Arg-Glu-Asp-Val (REDV), a tetrapeptide derived from an alternatively spliced site in fibronectin, inhibits the binding of fibrinogen, fibronectin, von Willebrand factor and vitronectin to activated platelets.
Characterization of a side-product obtained during the synthesis of Arg-Glu-Asp-Val (REDV) with inhibitory activity in thrombin-activated platelet aggregation was carried out. The semipreparative column fractionation of REDV peptide was rechromatographed on an analytical HPLC column and revealed two peaks which were re-tested for inhibitory activity. Using amino acid analysis with sequencing and fast atom bombardment mass spectrometry (FABMS), the first peak was determined to be REDV with molecular mass of 517 Da, and the second peak was determined to be a modified RDV with a mass of 608 Da. The modified RDV peptide inhibited thrombin-induced platelet aggregation with an IC50 of 200 microM, and complete inhibition occurred at 600 microM. However, the REDV peptide did not inhibit platelet aggregation up to 1 mM concentration. The modified RDV peptide eluted platelet glycoprotein IIb-IIIa complex that had been bound to GRGDSP-agarose. These studies show that the modified RDV peptide interacts with the platelet glycoprotein IIb-IIIa complex. Based on the collision-induced dissociation (CID) mass spectral data analysis, the modified RDV peptide has been characterized to contain an N-terminus blocking group on the Arg residue. The origin of this blocking group is presumed to have originated from decomposition products of the phenylacetamidomethyl (PAM) resin used in the solid-phase synthesis of the target peptide Arg-Glu-Asp-Val.
Amino Acid Sequence↗