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The steady growth of managed care, combined with advances in both medical and computer science, has begun to transform the way health care providers treat patients. The evolution and rapidly expanding use of clinical pathways has become an important component of the modern health care system.
Monoclonal antibody (mAb) targeting to tumor antigen is an important therapeutic approach for the treatment of a variety of cancers. Both positive and negative co-stimulatory pathways are critical components for the control and fine-tuning fo immune responses and recently mAb targeting of lymphocyte co-stimulatory pathways has been investigated. With the development of agonistic and antagonistic mAbs, both positive and negative pathways can be regulated and the potent therapeutic efficacy of this method has been demonstrated in experimental models. With high affinity and selectivity, as well as humanization technology for mAbs, there is little doubt that this new approach alone, or in combination with other therapeutic modalities, will play an important role in immunotherapy for cancers in the near future.
A clinical pathway is a written sequence of clinical processes or events that guides a patient with a defined problem toward an expected outcome. Clinical pathways are tools to assist with the cost-effective management of clinical outcomes related to specific problems or disease processes. The primary obstacles to developing clinical pathways for wound care are the chronic natures of some wounds and the many variables that can delay healing. The pathway introduced in this article was modeled upon the three phases of tissue repair: inflammatory, proliferative, and maturation. This physiology-based model allows clinicians to identify and monitor outcomes based on observable and measurable clinical parameters. The pathway design, which also includes educational and behavioral outcomes, allows the clinician to individualize the expected timeframe for outcome achievement based on individual patient criteria and expert judgement. Integral to the pathway are the "4P's" which help standardize the clinical processes by wound type: Protocols, Policies, Procedures, and Patient education tools. Four categories into which variances are categorized based on the cause of the deviation from the norm are patient, process/system, practitioner, and planning/discharge. Additional research is warranted to support the value of this clinical pathway in the clinical arena.
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Examination of signal transduction pathways that modulate neuronal cell differentiation and protection against apoptosis has revealed a central role for the MAPK/Erk cascade. The activation of MAPK/Erk through the TrkA NGF signaling pathway is critical for growth and survival of neuronal cells. Here, we investigate the impact of HIV-1 Tat on the NGF-signaling pathway in SK-N-MC neuroblastoma cells. Expression of Tat decreased cell growth and induced apoptosis. Our results revealed dysregulation of various steps involved in the NGF pathway including suppression of MAPK, and inhibition of the promoter activity of Egr-1, a key pleiotropic mediator of the expression of genes involved in cell growth upon expression of Tat in SK-N-MC cells. Similarly, exposure of SK-N-MC to conditioned media derived from cells expressing Tat decreased phosphorylation of MAPK and reduced the level of Egr-1 protein expression in SK-N-MC cells. Furthermore, MAPK was able to phosphorylate Puralpha, a cellular protein that plays an important role in neuronal cell function and differentiation, and this was inhibited by Tat. The ability of Puralpha to interact with a GA/GC-rich sequence positioned upstream from the transcription start site of the Egr-1 promoter provided a rationale to examine Egr-1 expression. Expression of Tat decreased NGF-induced Egr-1 levels in SK-N-MC cells and reduced binding of Puralpha to the Egr-1 promoter. All of these observations support a model where the interplay between Tat and Puralpha dysregulates the NGF pathway including the MAPK/Erk network, resulting in reduced expression and activity of Egr-1 in neuronal cells.
The cAMP and ERK/MAP kinase (MAPK) signal transduction pathways are critical for hippocampus-dependent memory, a process that depends on CREB-mediated transcription. However, the extent of crosstalk between these pathways and the downstream CREB kinase activated during memory formation has not been elucidated. Here we report that PKA, MAPK, and MSK1, a CREB kinase, are coactivated in a subset of hippocampal CA1 pyramidal neurons following contextual fear conditioning. Activation of PKA, MAPK, MSK1, and CREB is absolutely dependent on Ca(2+)-stimulated adenylyl cyclase activity. We conclude that adenylyl cyclase activity supports the activation of MAPK, and that MSK1 is the major CREB kinase activated during training for contextual memory.
The retinoblastoma protein (pRb) pathway is critical in regulating the G1 phase of the cell cycle and it is frequently disrupted in human cancers. Components of the pRb pathway which are often altered in tumour progression include the INK4 cyclin-dependent kinase (CDK) inhibitors p16INK4a/ CDKN2A and p15INK4b/CDKN2B, CDK4, D-type cyclins and pRb. Several of these components were studied in a series of cultured melanoma cell lines in order to determine the frequency and spectrum of genetic alterations and to define targets for potential gene transfer studies. Also studied were the p16INK4a alternate transcript (p14ARF) and the p21(waf1) CDK inhibitor. The majority of the melanoma cell lines tested (13 out of 17; 76%) carried mutated (two), deleted (nine) or silenced (two) p16(INK4a). CDK4 was mutated or overexpressed in two melanoma cell lines with homozygously deleted CDKN2A and CDKN2B genes. This suggests that the selective growth advantages afforded by CDKN2A inactivation and CDK4 insensitivity are distinct and may involve the mediation of other CDK inhibitors or CDKs.
Inflammation and fibrogenesis are the two determinants of the progression of renal fibrosis, the common pathway leading to end-stage renal disease. The p38 mitogen-activated protein kinase (MAPK) and transforming growth factor (TGF)-beta1/Smad signaling pathways play critical roles in inflammation and fibrogenesis, respectively. The present study examined the beneficial renoprotective effect of combination therapy using the p38 MAPK pathway inhibitor (SB203580) and a TGF-beta receptor I (ALK5) inhibitor (ALK5I) in a mouse model of adriamycin (ADR) nephrosis. The p38 MAPK and TGF-beta1/Smad2 signaling pathways were activated in ADR-induced nephropathy in a sequential time course manner. Two weeks after ADR injection, the combined administration of SB203580 (1 mg/kg/24 hours) and ALK5I (1 mg/kg/24 hours) markedly reduced p38 MAPK and Smad2 activities. Moreover, the co-administration of SB203580 and ALK5I to ADR-injected mice resulted in a down-regulation of total and active TGF-beta1 production, reduced myofibroblast accumulation, and decreased expression of collagen type IV and fibronectin. In these mice, retardation in the development of glomerulosclerosis and interstitial fibrosis was observed. In conclusion, although p38 MAPK and TGF-beta1/Smad signaling pathways are distinct they coordinate the progression of renal fibrosis in ADR nephrosis. The co-administration of a p38 MAPK inhibitor and an ALK5 inhibitor may have potential applications in the treatment of renal fibrosis.
The integrated stress response to tissue trauma is crucial for the maintenance of homeostasis. An exaggerated or prolonged response may be detrimental in compromised patients. Knowledge of the involved afferent pathways will suggest therapeutic interventions that may modulate the intensity of the stress response. Described are these concepts as they relate to perioperative medicine.
BACKGROUND: At Stanford University Hospital, attempts to improve the case management program led to the development of clinical paths, a multidisciplinary case management tool. Successful design and implementation of clinical paths depend on physician leadership. However, since physicians are trained to function independently and to treat each clinical problem as unique, they tend to resist attempts to have them follow clinical paths. Strategies to get physicians who perform the same clinical procedure to agree with each other on a sequence of common interventions had to be developed. Clinical paths define the expected processes of care and therefore allow for the introduction of continuous quality improvement (CQI) into the clinical arena. A structure had to be developed for the effective use of pathways in a CQI framework, and physicians had to be encouraged to function as CQI leaders. EXAMPLE: Description of the design of a perioperative knee arthroplasty pathway demonstrates the steps needed for successful physician involvement in pathway design and its integration into clinical CQI. CONCLUSIONS: With sensitive facilitation, physicians can become productive leaders of the design of clinical paths, and when they learn the benefits of improved efficiency, outcomes, and costs their involvement becomes self-sustaining. A quality improvement group led by physicians to develop the pathway after implementation can mark the beginning of clinical CQI implementation.
A recent study at the Prince of Wales Hospital (PoW) compared health outcomes and user satisfaction for conventional clinical pathways with a shortened pathway incorporating day of surgery admission (DOSA), early discharge and post acute care domiciliary visits for two high volume, elective surgical procedures (herniorrhaphy and laparoscopic cholecystectomy). This paper quantifies cost differences between the control and intervention groups for nursing salaries and wages, other ward costs, pathology and imaging. The study verified and measured the lower resource use that accompanies a significant reduction in length of stay (LOS). Costs of pre- and post-operative domiciliary visits were calculated and offset against savings generated by the re-engineered clinical pathway. Average costs per separation were at least $239 (herniorrhaphy) and $265 (laparoscopic cholecystectomy) lower for those on the DOSA pathway with domiciliary post acute care.
As in many developed nations, health care consumers in Singapore are demanding better (and more costly) services. At the operational level, one way to address consumers' demands while ensuring cost-effectiveness is through the implementation of a clinical pathway program. This paper provides an overview of the program at Changi General Hospital (CGH), a regional general acute care hospital in the Republic of Singapore. The paper highlights the problems encountered during the planning, developing and implementing phases. It concludes by predicting what the future might hold for clinical pathways in Singapore and the South East Asian Region.
Integrated care pathways (ICPs) are multiprofessional documents designed to enable the implementation of evidence-based care and support the practical delivery of clinical governance. However, the implementation of care pathways is resource intensive and few evaluations have been conducted with respect to these areas or to the efficacy of care pathways to change practice and improve outcomes in care. This project sought to address these issues and the report outlines the approach taken by a palliative care team in South Wales, UK, to implement a care pathway for the dying throughout a district general hospital and six community hospitals. Dying can be a complex area of care and changing practice can be challenging, therefore a PRINCE Project management approach was taken and a full-time project nurse employed for the life of the project. This paper describes the strategies used to approach implementing a care pathway and provides a template for other teams who may embark on similar projects. At the end of the project, the care pathway was successfully implemented and provided demonstrable outcomes of care for those dying from cancer and nonmalignant diseases. Strikingly, a large number of patients dying from nonmalignant disease were cared for via the pathway, which was not expected.
In the UK, managed care is beginning to be recognized as a cost effective, quality-driven system which can be used to structure patient care. This article examines the potential use of managed care pathways in mental health services, focusing on clients with schizophrenia. The strengths of managed care include the effective coordination of healthcare resources, the clear accountable audit of mental health practice and the re-engineering of mental health practice to improve patient outcomes. Problems in designing representative care pathways and encouraging healthcare providers to implement care pathways are some of the disadvantages of this system.