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PubMed2002

Ethical issues in the long-term management of progressive degenerative neuromuscular diseases.

Degenerative neuromuscular diseases are characterized by a gradual decline of motor function leading to respiratory collapse, while the patients retain consciousness and cognition. The ethical challenges of caring for such patients result from the need to implement various combinations of initiating, withholding, and withdrawing life-sustaining interventions. In caring for this population of patients physicians should adhere to the ethical principles of autonomy, beneficence, nonmaleficence, and justice. A central goal of care is to avoid a decisional impasse by anticipating end-of-life issues in discussion with patients and families. The evolution of these diseases is usually slow enough to allow ample patient education, and thus physicians should foster early and frank discussions and encourage the patient to set up advance directives, designate a durable power of attorney for health care, and plan end-of-life care. Competent patients have the right to accept or refuse life-sustaining therapies, and such requests should be honored. In delivering palliative care, adequate sedation and analgesia must be provided when needed. If a decision to withhold or withdraw life support is made, patient comfort and dignity are the ultimate objectives.

Journal Article↗

PubMed2004

Planning for the end of life: the views of older people about advance care statements.

Advance statements about medical care have been heralded by some as a solution to the problem of end of life decision making for people not able to participate in discussions about their care. Since death is now most likely to occur at the end of a long life, it is important to understand the views and values which older people express in relation to these. This paper reports on a study which used focus groups to explore older people's views about advance statements and the role these might play in end of life care decisions. Participants were 32 older people or their representatives who belonged to six diverse community groups in Sheffield, UK. Advance statements were understood primarily in terms of their potential to aid personal integrity and to help the families of older people by reducing the perceived 'burden' of their decision making. However, concerns were expressed about the perceived link between advance care statements and euthanasia, their future applicability, and the possibility that preferences for care may change. Participants also reported worries and difficulties related to thinking about and discussing death and dying. Trust between doctor and patient, built up over time, was perceived to be important in creating an environment in which the communication necessary to underpin advance care planning could take place. Lastly, participants did not perceive that during dying they would be ready necessarily to adhere to an advance statement and 'disengage' from their lives. We conclude that, rather than emphasising the completion of advance statements, it may be preferable to conceptualise advance care planning as a process of discussion and review between clinicians, patients and families.

Advance Directives↗

PubMed2006

Beyond consumer-driven health care: purchasers' expectations of all plans.

Skyrocketing health care costs and quality deficits can only be addressed through a broad approach of quality-based benefit design. Consumer-directed health plans that are built around better consumer information tools and support hold the promise of consumer engagement, but purchasers expect these features in all types of health plans. Regardless of plan type, simply shifting costs to consumers is a threat to access and adherence to evidence-based medicine. Comparative and interactive consumer information tools, coupled with provider performance transparency and payment reform, are needed to advance accountability and support consumers in getting the right care at the right time.

Consumer Behavior↗

PubMed1993

Complement receptors in shock and transplantation.

Over the last decade, elegant studies of the basic biologic characteristics of inflammation and tissue injury have implicated leukocyte-mediated vascular and tissue injury in the pathogenesis of a wide variety of immune and inflammatory clinical disorders, including allograft rejection, adult respiratory distress syndrome, and shock. Recognition of the importance of leukocyte adherence to the endothelium in the pathogenesis of these disorders, in combination with advances in cellular and molecular biology, have led to the development of novel therapeutic approaches to the treatment of immune and inflammatory disorders in which leukocytes contribute to vascular and tissue injury. Several of these promising new therapeutic approaches have focused on the complement system. Examples of this therapeutic approach include the use of monoclonal antibodies directed at leukocyte complement receptors and the administration of soluble complement receptors to inhibit the binding of leukocytes to the endothelium. Because of the biologic and significant potential clinical importance of these advances, in this review, we focus on the complement system and complement receptor-mediated tissue injury.

Antibodies, Monoclonal↗

PubMed2005

Focusing of gene expression as the basis of stem cell differentiation.

In a prior report (Stem Cells Dev 14(4):354-366, 2005), we employed two-dimensional gel electrophoresis followed by advanced proteomics and the Database for Annotation, Visualization and Integrated Discovery (DAVID) to compare the protein expression profiles of mesenchymal stem cells to that of fully differentiated osteoblasts. These data were reported to advance technical approaches to define the basis of differentiation, but also led us to suggest that osteogenic differentiation of stem cells may result from the focusing of gene expression in functional clusters (e.g., calcium-regulated signaling proteins or adherence proteins) rather than simply from the induced expression of new genes, as many have assumed. Here, we have employed these analytical techniques to compare protein expression by mesenchymal stem cells directly with that of cells derived from them after induced osteogenic differentiation. Our results support the concept of gene focusing as the basis of differentiation. Specifically, induced differentiation results in a decrease in the number of mesenchymal cell markers and calcium-mediated signaling molecules expressed by their differentiated progeny. This effect was seen in parallel to increased expression of specific extracellular matrix (ECM) molecules and their receptors. These results strongly imply that changes in the ECM have a direct impact on stem cell differentiation, and that osteogenic differentiation of stem cells directed by matrix clues results from focusing of the expression of genes involved in Ca2+-dependent signaling pathways.

Calcium Signaling↗

PubMed1984

Survival after extended resection for locally advanced carcinomas of the colon and rectum.

Two hundred and fifty five patients were treated surgically for adenocarcinoma of the colon or rectum on the Surgical Unit at Westminster Hospital in the years 1962-78. After 13 patients had been excluded on the grounds of inadequate data, 57 of the remaining 242 had tumours which, at laparotomy, were firmly adherent to neighbouring organs or the abdominal wall. These 'locally advanced' tumours were treated by an extended en-bloc resection of the tumour and neighbouring organs. The operative mortality after extended resections was higher than after standard resections, but subsequent survival did not differ significantly from survival after standard excisions for tumours of the same Dukes' stage. Histological examination of the neighbouring organs included in the extended resections confirmed direct tumour spread in only 33%.

Adenocarcinoma↗

PubMed2002

Strategies for culturally effective end-of-life care.

As a result of profound worldwide demographic change, physicians will increasingly care for patients from cultural backgrounds other than their own. Differences in beliefs, values, and traditional health care practices are of particular relevance at the end of life. Health care providers and patients and families may not have shared understandings of the meaning of illness or death and may not agree on the best strategies to plan for the end of life or to alleviate pain and suffering. Good end-of-life care may be complicated by disagreements between physicians and patients, difficult interactions, or decisions the physician does not understand. Challenges may result from cultural differences between the patient's background and traditional medical practice. Values so ingrained in physicians as to be unquestioned may be alien to patients from different backgrounds. Physicians need to be sensitive to cultural differences and to develop the skills necessary to work with patients from diverse backgrounds. Community and cultural ties provide a source of great comfort as patients and families prepare for death. This paper describes two cases that raise issues about cross-cultural end-of-life practice and suggests strategies for negotiating common problems. Physicians should assess the cultural background of each patient and inquire about values that may affect care at the end of life. They should become aware of the specific beliefs and practices of the populations they serve, always remembering to inquire whether an individual patient adheres to these cultural beliefs. Attention to cultural difference enables the physician to provide comprehensive and compassionate palliative care at the end of life.

Advance Directives↗

PubMed2005

Protrusion force transmission of amoeboid cells crawling on soft biological tissue.

We applied a colloidal force microscopy technique to measure the spreading and retraction forces generated by protrusions (pseudopodia) of vegetative amoeboid cells (Dictyostelium discoideum) adhering on soft tissue analogues composed of 2-mm thick hydrogels of hyaluronic acid exhibiting Young's moduli between 10 and 200 Pa. Local shear deformations of the polymer films evoked by magnetic tweezers and by cellular protrusions were determined by analyzing the deflections of colloidal beads randomly deposited on the surface of the polymer cushions, which enabled us to measure forces generated by advancing ("pushing" forces) and retracting ("pulling" forces) protrusions in a direct way. We found that the maximum amplitudes generated by the advancing protrusions (pushes) decrease with increasing stiffness of the HA substrate while the amplitudes of the retractions do not show such a dependence. The maximum forces transmitted by the advancing and retracting protrusions increase with increasing stiffness of the HA films (from 0.02 to 1 nN for the case of pushing). The protrusions spread or retract with constant velocities which are higher for retractions (100 nm s(-1)) than for spreadings (50 nm s(-1)) and are not significantly influenced by the substrate rigidity. We provide evidence that elastic equilibrium during protrusion formation and retraction is maintained by local elastic dipole fields generated at the rim of the protrusions. A model of protrusion force transmission by coupling of growing actin gel in the cytoplasm of the protrusions to cell surface receptors through talin clutches is proposed.

Animals↗

PubMed2003

[Intravenous myocardial contrast echocardiography; recent advances].

Until quite recently, contrast echocardiography for myocardial perfusion imaging has required the invasive direct injection of contrast agent into the coronary artery. Recent advances in ultrasonic technology and contrast agents have enabled myocardial contrast echocardiography with intra-venous injection of contrast agent in the clinical setting. This noninvasive technique has made the following clinical applications; left ventricular opacification, determination of the endocardium, enhancement of the Doppler flow signals, and detection of myocardial perfusion. Furthermore, in the near future, local drug delivery and pathology-specific targeted adherence of contrast agent may be added to the applications for the treatment. Intravenous myocardial contrast echocardiography is expected to have wide-ranging clinical potential.

Contrast Media↗

PubMed1999

A Phase I study of active immunotherapy with carcinoembryonic antigen peptide (CAP-1)-pulsed, autologous human cultured dendritic cells in patients with metastatic malignancies expressing carcinoembryonic antigen.

Dendritic cells (DCs), antigen-presenting cells capable of priming naive T cells to specific antigens in an HLA-restricted fashion, have been demonstrated to induce protective T cell-mediated immunity in tumor-bearing animals. We performed this study to test the safety, feasibility, and clinical response of immunizations with in vitro-generated DCs, loaded with an HLA-A2-restricted peptide fragment of the tumor antigen carcinoembryonic antigen (CEA), for the treatment of patients with advanced CEA-expressing malignancies. Cell preparations enriched for autologous DCs were generated from the patients' plastic adherent peripheral blood mononuclear cells in serum-free media supplemented with granulocyte macrophage colony-stimulating factor and interleukin-4. Within the cell preparation, 66% of the cells expressed the phenotype typical for DCs (CD86high, HLA-DRhigh, and CD14low). The DCs were loaded with the CEA peptide CAP-1 and cryopreserved. Groups of three to six patients received four weekly or biweekly i.v. infusions of the CAP-1-loaded DC in escalating dose levels of 1 x 10(7), 3 x 10(7), and 1 x 10(8) cells/dose. A subset of the patients in the last group also received intradermal injections of 1 x 10(6) DCs. There were no toxicities directly referable to the treatments. One patient had a minor response, and one had stable disease. Skin punch biopsy at DC injection sites demonstrated pleomorphic infiltrates in the three patients evaluated. We conclude that it is feasible and safe to generate and administer large numbers of previously cryopreserved DCs loaded with CAP-1 peptide to patients with advanced malignancies.

Adult↗

PubMed2002

Unpacking cultural factors in adaptation to type 2 diabetes mellitus.

BACKGROUND: Race and ethnicity are used as predictors of outcome in health services research. Often, however, race and ethnicity serve merely as proxies for the resources, values, beliefs, and behaviors (ie, ecology and culture) that are assumed to correlate with them. "Unpacking" proxy variables-directly measuring the variables believed to underlie them-would provide a more reliable and more interpretable way of looking at group differences. OBJECTIVE: To assess the use of a measure of ecocultural domains that is correlated with ethnicity in accounting for variance in adherence, quality of life, clinical outcomes, and service utilization. DESIGN: A cross-sectional observational study. PARTICIPANTS: Twenty-six Hispanic and 29 non-Hispanic white VA primary care patients with type 2 diabetes mellitus. MEASURES: The independent variables were patient ethnicity and a summed score of ecocultural domains representing patient adaptation to illness. The outcomes were adherence to treatment, health-related quality of life, clinical indicators of disease management, and utilization of urgent health care services. RESULTS: Patient adaptation was correlated with ethnicity and accounted for more variance in all outcomes than did ethnicity. The unique variance accounted for by adaptation was small to moderate, whereas that accounted for by ethnicity was negligible. CONCLUSIONS: It is possible to identify and measure ecocultural domains that better account for variation in important health services outcomes for patients with type 2 diabetes than does ethnicity. Going beyond the study of ethnic differences alone and measuring the correlated factors that play a role in disease management can advance understanding of the phenomena involved in this variation and provide better direction for service design and delivery.

Adaptation, Psychological↗

PubMed1985

Sacrococcygeal chordoma: magnetic resonance imaging and computed tomography.

Magnetic resonance imaging (MRI) was compared to computed tomography (CT) in four cases of sacrococcygeal chordoma. Both techniques yielded important anatomic information and represented important advances over early radiologic imaging methods. MRI provides superior contrast with surrounding soft tissues because of the prolonged T1 and T2 times of the tumors. This was especially important in a case of recurrent chordoma. The direct sagittal images obtained by MRI were valuable in determining the extent of lesions. Either MRI or direct CT coronal images were needed for the demonstration of tumor involving the sacral nerve roots. It was not possible to reliably distinguish between tumor adherent to bowel wall and bowel wall invasion by either technique. It is concluded that MRI is at least equal to CT for demonstration of these lesions and seems likely to become the imaging method of choice.

Adult↗

PubMed2002

Ethical issues in geriatric medicine: a unique problematic?

It is commonly believed that geriatric medicine generates a distinctive set of ethical problems. Implicated are such issues as resource allocation, competence and consent, advance directives, medical futility and deliberate death. It is also argued that it would be unjust to allow the elderly to compete with younger populations for expensive and scarce healthcare resources because the elderly "have already lived," and that treating them the same as these other populations would diminish the available resources unfairly, prolong a life of inevitably failing health and result in increased health care expenditures. In fact, however, this perception of ethical uniqueness is mistaken. Differences in medical conditions, demographics and aetiology should not be allowed to obscure the fact that ethical issues in geriatric medicine are essentially the same as those faced in any other area of health care, and that the solutions that are adopted in the geriatric context must be consistent with the ethical principles that are followed elsewhere. The paper argues that the root of the mistaken perception lies in the abandonment of the Hippocratic mandate of medicine and in an unreflective adherence to the belief that medical advances are inevitably beneficial. It is suggested that a return to patient-centred medicine and the use of ethics impact analyses before introducing medical advances may be ethically appropriate.

Aged↗

PubMed2006

Physicians' decisions to withhold and withdraw life-sustaining treatment.

BACKGROUND: Few data are available about physicians' decisions in regard to withholding or withdrawing life-sustaining measures. We therefore studied internists' views on this subject. METHODS: We surveyed 1000 generalist and subspecialist internists about their views on withholding or withdrawing life-sustaining treatment. Thirty-two hypothetical cases were included. The effect of the demographic data on withholding or withdrawing treatment was analyzed via analysis of covariance and multiple logistic regression. RESULTS: Of 1000 internists, 407 (41%) completed and returned surveys. A majority of respondents (51%) were willing to withhold or withdraw treatment in all 32 scenarios; 49% were unwilling to withhold or withdraw in at least 1 scenario. Respondents were likely to withhold treatment in 14 of 16 scenarios compared with 13.7 of 16 scenarios for withdrawing treatments (P<.001). Respondents withheld or withdrew feeding tubes in 6.6 of 8 scenarios (P<.001) and antibiotics in 6.7 of 8 scenarios (P = .001) compared with ventilators (7.1 of 8 scenarios) and dialysis (7.3 of 8 scenarios). Respondents were less likely to withhold or withdraw treatments in nonterminally ill (12.9 of 16 scenarios) (P = .02) and alert patients (13.2 of 16 scenarios) (P<.001) compared with terminally ill patients (14.9 of 16 scenarios) and patients with dementia (14.5 of 16 scenarios). CONCLUSIONS: A large percentage of internists would be unwilling to adhere to some of patients' wishes to withhold or withdraw life-sustaining treatment. The clinical scenario and type of treatment affect internists' decisions about whether they would withhold or withdraw such treatment.

Advance Directives↗

PubMed2003

Treatment of Crohn's Disease of Inflammatory, Stenotic, and Fistulizing Phenotypes.

The heterogeneous nature of Crohn's disease (CD) is reflected in the diversity of treatment options available for individual patients. The stratification of CD patients into more homogeneous groups based on disease location and disease behavior may provide clinicians with a more focused approach to therapeutic decision-making. Uncomplicated disease behaviors are typically treated medically. When complications arise and patterns of disease become more aggressive, combined medical and surgical approaches are often necessary and yield favorable results. The surgical management of CD can be as complex as the disease itself, and should involve a surgeon who professes a special expertise in inflammatory bowel disease. Progress in our understanding of the role of the interaction between the environment and the immune system in disease development has led to major advancements in the area of CD therapeutics. Current therapies target the various elements of the inflammatory cascade implicated in the pathogenesis of CD. The anti-inflammatory properties of the pharmacologic therapies presented in this review vary from actions that are extremely broad to those that are cellular or cytokine specific. Maximizing the efficacy of CD-directed therapies while minimizing their toxicity remains the principal objective in developing management strategies for CD patients. Maintaining good quality of life and maximizing adherence to therapies are also important considerations. Despite the various therapeutic options available for CD patients, chosen therapies should be based on the overall treatment goal for individual patients. Therapeutics can be broadly categorized as induction therapies (goal to treat active disease) and maintenance therapies (goal to prevent relapse of disease).

Journal Article↗

PubMed2005

Adhesion-dependent and contractile ring-independent equatorial furrowing during cytokinesis in mammalian cells.

Myosin II-dependent contraction of the contractile ring drives equatorial furrowing during cytokinesis in animal cells. Nonetheless, myosin II-null cells of the cellular slime mold Dictyostelium divide efficiently when adhering to substrates by making use of polar traction forces. Here, we show that in the presence of 30 microM blebbistatin, a potent myosin II inhibitor, normal rat kidney (NRK) cells adhering to fibronectin-coated surfaces formed equatorial furrows and divided in a manner strikingly similar to myosin II-null Dictyostelium cells. Such blebbistatin-resistant cytokinesis was absent in partially detached NRK cells and was disrupted in adherent cells if the advance of their polar lamellipodia was disturbed by neighboring cells. Y-27632 (40 microM), which inhibits Rho-kinase, was similar to 30 microM blebbistatin in that it inhibited cytokinesis of partially detached NRK cells but only prolonged furrow ingression in attached cells. In the presence of 100 microM blebbistatin, most NRK cells that initiated anaphase formed tight furrows, although scission never occurred. Adherent HT1080 fibrosarcoma cells also formed equatorial furrows efficiently in the presence of 100 microM blebbistatin. These results provide direct evidence for adhesion-dependent, contractile ring-independent equatorial furrowing in mammalian cells and demonstrate the importance of substrate adhesion for cytokinesis.

Amides↗

PubMed2005

Early glycoprotein IIb/IIIa inhibitor use for non-ST-segment elevation acute coronary syndrome: patient selection and associated treatment patterns.

OBJECTIVES: The authors analyzed contemporary use of glycoprotein (GP) IIb/IIIa inhibitors in patients with non-ST-segment elevation acute coronary syndrome (NSTE ACS) to determine patient selection patterns with early (<24 hours) GP IIb/IIIa inhibitor use and the relationship between GP IIb/IIIa inhibitor therapy and use of other guidelines-recommended therapies for NSTE ACS. METHODS: Using the CRUSADE Quality Improvement Initiative database, patient characteristics, in-hospital treatments, and outcomes for 65,424 patients with ischemic chest pain of <24 hours' duration and either positive cardiac markers or ischemic electrocardiographic changes were analyzed. Data were collected from 443 U.S. hospitals from January 2001 to June 2003. RESULTS: Only 35% of eligible patients received GP IIb/IIIa inhibitors <24 hours after hospital admission. Approximately one third of patients received GP IIb/IIIa inhibitors in the emergency department, one third in the coronary care unit, and one third in the catheterization laboratory. Admission to a cardiologist's care was the most significant associated factor with early GP IIb/IIIa inhibitor use, along with elevated cardiac markers or ST-segment deviation. Patients at high risk for adverse cardiac events due to advanced age, congestive heart failure, or female gender were less likely to receive early GP IIb/IIIa inhibitor therapy. Patients who received early GP IIb/IIIa inhibitor therapy were more likely to receive other guidelines-recommended therapies. CONCLUSIONS: Despite the American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommendations, early GP IIb/IIIa inhibitor therapy remains underutilized in patients with NSTE ACS and administration of early GP IIb/IIIa inhibitors is directed toward lower-risk patients. Early GP IIb/IIIa inhibitor therapy is associated with improved overall adherence to the ACC/AHA guidelines.

Acute Disease↗

PubMed1989

The role of arterial wall injury in atherogenesis and arterial thrombogenesis.

Accumulating mainly experimental evidence from research of the last 3 decades shows that many types of arterial wall injury can accelerate and intensify the development of atherosclerosis in arteries exposed to chronic hyperlipemia by increasing the permeability of their endothelium for plasma lipoproteins, proteins and several types of smooth muscle mitogens (including soluble platelet-derived growth factor). Of the numerous artery-injuring agents studied experimentally today only those that can be proven to operate in humans at concentrations and durations of action that injure animal arteries can be accepted as capable of playing a role in human atherogenesis. Seven such groups of agents can be recognized at present: blood turbulence, hypertension, certain viruses, metabolic disturbances (including hyperlipemia), certain immune insults, exogenous chemicals, and obstruction of adventitial lymphatics. Most of the above agents cause various degenerative changes in individual endothelial cells or open interendothelial junctions, and they seem to promote the penetration of plasma macromolecules into the wall in 3 different ways: directly through the altered endothelial cytoplasm, through opened interendothelial junctions or through transport in the cytoplasm of immigrating monocytes. None of the commonly occurring injury agents produce complete endothelial denudation of wide areas of the arterial cylinders. New findings from the transmission electron microscopic study of step-serial sections of human arteries obtained under conditions minimizing artificial endothelial loss indicate that endothelial denudation accompanied by platelet adherence and aggregation does not occur over early myoproliferative lesions but occasionally develops over small areas of advanced plaques with mostly necrotic or damaged caps and is, therefore, not an initiating event but a late complication of atherosclerosis. Light microscopic serial section studies of human thrombosed vessels in several centers reveal that thrombogenesis in most human atherosclerotic arteries is initiated by a severe structural injury of the cap of advanced plaques that leads to a microscopic break of the plaque surface through which some blood can enter the plaque interior before it is sealed by a thrombus.

Arteries↗