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PubMed2004

Mapping critical biological motifs and biosynthetic pathways of heparan sulfate.

Heparan sulfate (HS) interacts with numerous proteins at the cell surface and orchestrates myriad biological events. Unraveling the mechanisms of these events at the molecular level calls for the structural analysis of these negatively charged and highly heterogeneous biopolymers. However, HS is often available only in small quantities, and the task of structural analysis necessitates the use of ultra-sensitive methods, such as mass spectrometry. Sequence heterogeneity within HS chains required us to identify critical functional groups and their spacing to determine structure-function relationships for HS. We carried out structural analysis of HS isolated from wild type, 3-OST-1, 3-OST-3A, or 3-OST-5 sulfotransferase-transduced Chinese hamster ovary cells and also from various tissues. In the context of tissue-specific HS, the data allowed us to map the biosynthetic pathways responsible for the placement of critical groups. As a means of determining the distance between critical groups within a motif, we determined the spacing of the rare GlcNAc-GlcA disaccharide sequence in the completely desulfated re-N-sulfated porcine intestinal heparin. These disaccharides are biosynthetic regulatory markers for 3-OST-1 modification and the partial structure of the antithrombin III binding site. They occur only at the distance of hexasaccharide, octasaccharide, decasaccharide, or dodecasaccharide. Thus this approach allowed us to map both the biosynthetic pathways for generating critical functional groups and their spacing within HS. Our new strategy removes two obstacles to rapid progress in this field of research.

Animals↗
PubMed1998

Septocingulate and septohippocampal cholinergic pathways: involvement in working/episodic memory.

The contribution of the septohippocampal cholinergic pathway to performance of a working/episodic memory task was compared to that of the septocingulate cholinergic path. The septocingulate and septohippocampal cholinergic pathways were selectively destroyed in male Sprague-Dawley rats using site-specific injections of the anti-neuronal immunotoxin 192-IgG saporin into either the hippocampus or the cingulate cortex. 192-IgG-saporin selectively destroys cholinergic neurons and terminals that express the p75 neurotrophin receptor. Following extensive pre-operative training, working memory was assessed using a delayed nonmatch to sample eight arm radial maze task, with delays of 1, 4 and 8 h. The group with lesions of the septohippocampal cholinergic pathway displayed performance deficits on this task which were not related to length of delay. In contrast, the group with lesions of the septocingulate cholinergic pathway did display delay-dependent deficits which were observed at the 4- and 8-h delays, but not at the 1-h delay. These data suggest that the septocingulate cholinergic pathway is critically involved in working/episodic memory but that the septohippocampal cholinergic pathway is either not contributing to working/episodic memory per se or it is involved only at shorter delays.

Acetylcholinesterase↗
PubMed2002

Expression of G1-S modulators (p53, p16, p27, cyclin D1, Rb) and Smad4/Dpc4 in intrahepatic cholangiocarcinoma.

Aberrations of G1-S cell cycle arrest and TGF-beta/Smad pathway are critical events in human carcinogenesis. We studied alterations of both pathways by immunohistochemical staining for p53, p16, p27, cyclin D1, Rb and Smad4/Dpc4 in 42 intrahepatic cholangiocarcinomas (ICCs). Abnormal nuclear overexpression of p53 and cyclin D1 was noted in 15 (35.7%) and 26 (61.9%) cases, respectively. Total loss of p16, p27, Rb and Smad4 was detected in 15 (35.7%), 13 (31.0%), 5 (11.9%) and 19 (45.2%) cases, respectively. Forty cases (95.2%) showed aberrations of at least one of the pathways, of which 21 (50%) revealed abnormality in G1-S pathway only, 17 (40.5%) had abnormalities in both pathways and 2 (4.8%) had an abnormality in TGF-beta/Smad pathway only. Among the examined genes, loss of Smad4 was found to have a positive relationship with the pTNM stage (P < 0.05). The overall stage of the high-altered group (alterations in 2 to 5 of the genes, n = 29) was significantly higher than that of the low-altered group (alteration of one or no gene, n = 13) (P < 0.01). We also examined the expression of above genes in the accompanying biliary dysplasia and found out abnormal expression of p53, cyclin D1 or p16 in 7 out of 13 dysplastic lesions. Our data suggest that abnormal G1-S cell cycle and altered TGF-beta/Smad pathway are major events in cholangiocarcinogenesis. Moreover, there might be a possible cumulative effect of the alterations in the examined genes upon the clinical outcome of patients with resectable ICCs.

Adult↗
PubMed1990

Dystonia musculorum deformans: a 'critical phenomenon' model involving nigral dopaminergic and caudate pathways.

In physical systems, a 'critical phenomenon' is a macroscopic occurrence which arises from a change in the relative magnitudes of two or more physical influences whose action is expressed purely in microscopic terms. This concept is potentially valuable in describing the clinical symptomatology of dystonia musculorum deformans (DMD) and other movement disorders. The lateral inhibitory network of Spiny I caudate cells and the profuse neostriatal projection of dopaminergic neurons from the substantia nigra are proposed as anatomic substrates for two short-range neostriatal influences whose interaction contributes to the onset and progression of global dystonic spasm in DMD. Such spasm may be explainable as a critical phenomenon, suggesting new directions for research into the etiology and treatment of this disorder.

Caudate Nucleus↗
PubMed2003

Comparison of the visceral antinociceptive effects of spinally administered MPV-2426 (fadolmidine) and clonidine in the rat.

BACKGROUND: The authors determined the visceral antinociceptive effect induced by MPV-2426 (fadolmidine), a selective alpha 2 -adrenoceptor agonist, in rats with and without inflammation of the colon. They also determined whether the sympathetic nervous system or intact descending pathways are critical for the alpha 2 -adrenoceptor-induced visceral antinociception. METHODS: Spinal neuronal responses evoked by colorectal distension were recorded in pentobarbitone-anesthetized rats. MPV-2426 was administered onto the spinal cord. Clonidine was used as a reference alpha 2 -adrenoceptor agonist. Inflammation of the colon was induced by turpentine. Sympathectomy was induced by 6-hydroxydopamine. A midthoracic transection of the spinal cord was performed to study the role of descending pathways. RESULTS: Spinal administration of MPV-2426 produced a dose-dependent attenuation of responses evoked by colorectal distension, and this effect was of the same percentual magnitude in inflamed as in noninflamed animals. Clonidine and MPV-2426 induced equipotent visceral antinociception. The effect by spinally administered MPV-2426 was enhanced by a chemical sympathectomy but not influenced by spinal transection. CONCLUSIONS: Spinally administered MPV-2426 produces a dose-dependent visceral antinociception as well in animals with an inflammation of the colon as in controls. The visceral antinociceptive effect induced by spinal MPV-2426 is equipotent to that of spinal clonidine. An intact sympathetic nervous system or intact brainstem-spinal pathway is not critical for the MPV-2426-induced visceral antinociception.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Application of a prototype process for developing a tube gastrostomy clinical pathway.

The development and implementation of clinical pathways as a managed care tool have been widely embraced as principal components of the healthcare industry's drive to reform costly, inconsistent, and often uncontrolled delivery of services. Clinical pathways are not new to healthcare; however, the lack of a defined and systematic process for pathway development has hindered organizational efforts to develop and implement clinical pathways. A multidisciplinary clinical pathway process prototype was identified as a means for effectively defining and linking care and outcomes for patients requiring tube gastrostomy placement at a large military medical facility. This article presents the prototype process for developing a clinical pathway with a practical application to illustrate the process and provides a process template for potential use by others interested in developing multidisciplinary clinical pathways.

Critical Pathways↗
PubMedDate not supplied

Functional health pattern assessment on-line. Lessons learned.

Assessment of patient care needs is the foundation for planning patient care and documenting the nursing process to enhance the nurse's ability to coordinate care, plan discharges effectively, and provide appropriate patient/family education. An on-line assessment module in the hospital clinical information system was implemented. This module uses Gordon's Functional Health Pattern Assessment as the foundation for the professional nursing documentation system in this academic, health science center. The article provides a description of the design of the pathways for the on-line assessment, analysis of the design, benefits of using the on-line assessment, and lessons learned from the design and implementation of the pathways.

Activities of Daily Living↗
PubMed2004

Developing and piloting a structured, stepped approach to patient education.

The DESMOND initiative aims to provide patients with Type 2 diabetes with ongoing education about their condition from the point of diagnosis. The programme is in the process of developing a structured education curriculum that, combined with clinical management, will offer an integrated care pathway to patients.

Critical Pathways↗
PubMed2000

Development and implementation of a clinical pathway programme in an acute care general hospital in Singapore.

A critical or clinical pathway defines the optimal care process, sequencing and timing of interventions by doctors, nurses and other health care professionals for a particular diagnosis or procedure. Clinical pathways are developed through collaborative efforts of clinicians, case managers, nurses, pharmacists, physiotherapists and other allied health care professionals with the aim of improving the quality of patient care, while minimizing cost to the patient. The use of clinical pathways has increased over the past decade in the USA, the UK, Australia, and many other developed countries. However, its use in the developing nations and Asia has been sporadic. To the author's knowledge, there is to date, no published literature on the use and impact of clinical pathways on the quality and cost of patient care in the Asian health care setting. This paper provides a qualitative account of the development and implementation of a clinical pathway programme (using the example of patients with uncomplicated acute myocardial infarction) in an acute care general hospital in Singapore. The paper concludes that clinical pathways, when implemented in the context of an acute care hospital, can result in improvements in the care delivery process.

Cost-Benefit Analysis↗