Comparison of neural histomorphology in tail tips from pigs docked using clippers or cautery iron.

Tail docking of pigs is commonly performed to reduce the incidence of unwanted tail-biting behaviour. Two docking methods are commonly used: blunt trauma cutting (i.e. using side clippers), or cutting and concurrent cauterisation using a hot cautery iron. A potential consequence of tail amputation is the development of neuromas at the docking site. Neuromas have been linked to neuropathic pain, which can influence the longer-term welfare of affected individuals. To determine whether method of tail docking influences the extent of neuroma formation, 75 pigs were allocated to one of three treatments at birth: tail docked using clippers; tail docked using cautery iron; tail left intact. Tail docking was performed at 2 days of age and pigs were kept under conventional conditions until slaughter at 21 weeks of age. Tails were removed following slaughter and subjected to histological examination. Nerve histomorphology was scored according to the following scale: 1=discrete well-organised nerve bundles; 2=moderate neural proliferation and disorganisation affecting more than half of the circumference of the tail; 3=marked neural proliferation to form almost continuous disorganised bundles or non-continuous enlarged bundles compressing the surrounding connective tissue. Scores of 2 or 3 indicated neuroma formation. Scores were higher in docked pigs than undocked pigs (P<0.001), but did not differ between pigs docked using clippers and those docked using cautery (P=0.23). The results indicate that tail docking using either clippers or cautery results in neuroma formation, thus having the potential to affect long-term pig welfare.

Palliative oncology: identity, progress, and the path ahead.

Palliative care is a rapidly growing subspecialty of medicine entailing expert and active assessment, evaluation and treatment of the physical, psychological, social and spiritual needs of patients and families with serious illnesses. It provides an added layer of support to the patient's regular medical care. As cancer is detected earlier and its treatments improve, palliative care is increasingly playing a vital role in the oncology population. Because of these advances in oncology, the role of palliative care services for such patients is actively evolving. Herein, we will highlight emerging paradigms in palliative care and attempt to delineate key education, research and policy areas that lie ahead for the field of palliative oncology. Despite the critical need for improving multi-faceted and multi-specialty symptom management and patient-physician communication, we will focus on the interface between palliative care and oncology specialists, a relationship that can lead to better overall patient care on all of these levels.

How prevalent are hospital-based palliative care programs? Status report and future directions.

In the United States, the majority of deaths occur in the hospital but the dying process there is at best unsatisfactory and more likely inadequate for both patients and caregivers. The development of hospital-based palliative care programs (HBPCPs) can vastly improve inpatient end-of-life care. This study is the first to examine the prevalence and characteristics of HBPCPs in the United States, thus providing a snapshot of the characteristics of these HBPCPs. It also serves as a baseline and benchmark against which future development and patterns of HBPCPs can be compared. Phase 1: Data were obtained from the American Hospital Association (AHA) 1998 Annual Survey, on the existence of end-of-life care (EOLC) and pain management (PM) services in U.S. hospitals. Phase 2: A focused survey further assessed programs in Phase 1 and was sent to all registered hospitals that responded affirmatively to the AHA survey questions as having either a PM service, an EOLC service, or both. In phase 1, 1,751 (36%) hospitals reported having a PM service and 719 (15%) had an EOLC service, for a total of 2,015 unique hospitals that had one or both. For Phase 2, 1,120 of 2,015 responded (56%). Of these, 337 (30%) hospitals reported having an HBPCP, and another 228 (20.4%) had plans to establish one. HBPCPs are most commonly structured as inpatient consultation service and hospital-based hospice. They tend to be based in oncology, general medicine, and geriatrics. We also assessed reasons for consultation, patient characteristics, and future development needs. These findings can help guide future funding, educational, and programming efforts in hospital-based palliative care.

Self-reported symptom experience of critically ill cancer patients receiving intensive care.

OBJECTIVE: To characterize the symptom experience of a cohort of intensive care unit (ICU) patients at high risk for hospital death. DESIGN: Prospective analysis of patients with a present or past diagnosis of cancer who were consecutively admitted to a medical ICU during an 8-month period. SETTING: Academic, university-affiliated, tertiary-care, urban medical center. PATIENTS: One hundred cancer patients treated in a medical ICU. INTERVENTION: Assessment of symptoms. MEASUREMENTS: Patients' self-reports of symptoms using the Edmonton Symptom Assessment Scale (ESAS), and ratings of pain or discomfort associated with ICU diagnostic/therapeutic procedures and of stress associated with conditions in the ICU. MAIN RESULTS: Hospital mortality for the group was 56%. Fifty patients had the capacity to respond to the ESAS, among whom 100% provided symptom reports. Between 55% and 75% of ESAS responders reported experiencing pain, discomfort, anxiety, sleep disturbance, or unsatisfied hunger or thirst that they rated as moderate or severe, whereas depression and dyspnea at these levels were reported by approximately 40% and 33% of responders, respectively. Significant pain, discomfort, or both were associated with common ICU procedures, but most procedure-related symptoms were controlled adequately for a majority of patients. Inability to communicate, sleep disruption, and limitations on visiting were particularly stressful among ICU conditions studied. CONCLUSIONS: Among critically ill cancer patients, multiple distressing symptoms were common in the ICU, often at significant levels of severity. Symptom assessment may suggest more effective strategies for symptom control and may direct decisions about appropriate use of ICU therapies.

Pescadillo, a novel cell cycle regulatory protein abnormally expressed in malignant cells.

Using a culture model of glial tumorigenesis, we identified a novel gene that was up-regulated in malignant mouse astrocytes following the loss of p53. The gene represents the murine homologue of pescadillo, an uncharacterized gene that is essential for embryonic development in zebrafish. Pescadillo is a strongly conserved gene containing unique structural motifs such as a BRCA1 C-terminal domain, clusters of acidic amino acids and consensus motifs for post-translational modification by SUMO-1. Pescadillo displayed a distinct spatial and temporal pattern of gene expression during brain development, being detected in neural progenitor cells and postmitotic neurons. Although it is not expressed in differentiated astrocytes in vivo, the pescadillo protein is dramatically elevated in malignant human astrocytomas. Yeast strains harboring temperature-sensitive mutations in the pescadillo gene were arrested in either G(1) or G(2) when grown in nonpermissive conditions, demonstrating that pescadillo is an essential gene in yeast and is required for cell cycle progression. Consistent with the latter finding, DNA synthesis was only observed in mammalian cells expressing the pescadillo protein. These results suggest that pescadillo plays a crucial role in cell proliferation and may be necessary for oncogenic transformation and tumor progression.

Complementary and alternative medicine in the management of pain, dyspnea, and nausea and vomiting near the end of life. A systematic review.

To review the evidence for efficacy of complementary and alternative medicine (CAM) modalities in treating pain, dyspnea, and nausea and vomiting in patients near the end of life, original articles were evaluated following a search through MEDLINE, CancerLIT, AIDSLINE, PsycLIT, CINAHL, and Social Work Abstracts databases. Search terms included alternative medicine, palliative care, pain, dyspnea, and nausea. Two independent reviewers extracted data, including study design, subjects, sample size, age, response rate, CAM modality, and outcomes. The efficacy of a CAM modality was evaluated in 21 studies of symptomatic adult patients with incurable conditions. Of these, only 12 were directly accessed via literature searching. Eleven were randomized controlled trials, two were non-randomized controlled trials, and eight were case series. Acupuncture, transcutaneous electrical nerve stimulation, supportive group therapy, self-hypnosis, and massage therapy may provide pain relief in cancer pain or in dying patients. Relaxation/imagery can improve oral mucositis pain. Patients with severe chronic obstructive pulmonary disease may benefit from the use of acupuncture, acupressure, and muscle relaxation with breathing retraining to relieve dyspnea. Because of publication bias, trials on CAM modalities may not be found on routine literature searches. Despite the paucity of controlled trials, there are data to support the use of some CAM modalities in terminally ill patients. This review generated evidence-based recommendations and identified areas for future research.

Palliative care consultations: how do they impact the care of hospitalized patients?

To provide a detailed description of the recommendations of a Palliative Care Service (PCS) and to describe the impact of these recommendations on the care of terminally ill patients in an academic medical center, we describe data from all consecutive patients referred by their attending physicians to the PCS of an academic teaching hospital over a 15-month period. All patients were seen within 24 hours of consultation request. Data were collected prospectively on the day of discharge or death. Attention was focused on six recommendations and their implementation: 1) discussion about prognosis and goals of care; 2) pursuing documentation of advance directives; 3) discussion about foregoing specific treatments and/or diagnostic interventions; 4) family and patient support; 5) discharge planning; and 6) symptom management. Over a 15-month period, we collected data on 325 patients. The most frequent diagnoses were cancer, dementia, and HIV disease. The patients were followed for a mean of 7.6 days. The average number of recommendations was 4.2 per patient and 91% of the recommendations were implemented (3.8 per patient). Recommendations increased to 5.3 per patient and the implementation rate increased to 97% (5.1 per patient) for the 44 patients transferred to the Palliative Care Unit (PCU). PCS consultations result in multiple recommendations with a very high implementation rate. The number of recommendations and the high implementation rate suggest a strong need for palliative care services within acute care hospitals.

Delirium on hospital admission in aged hip fracture patients: prediction of mortality and 2-year functional outcomes.

BACKGROUND: Hip fracture patients are at increased risk of confusion or delirium due to the trauma associated with the injury and the rapid progression to hospitalization and surgery, in addition to the pain and loss of function experienced. Hip fracture patients who develop delirium may require longer hospital stays, are more often discharged to long-term care, and have a generally poor prognosis for returning home or regaining function in activities of daily living (ADL). METHODS: The present study examines the impact of delirium present on hospital admission in a sample of 682 non-demented, aged hip fracture patients residing in the community at the time of their fracture. In-hospital assessments designed to assess both prefracture and postfracture functioning, as well as follow-up interviews at 2, 6, 12, 18, and 24 months postfracture, were obtained from participants. RESULTS: Analyses indicate that baseline or admission delirium is an important prognostic predictor of poor long-term outcomes in persons without known cognitive impairment, after controlling for age, gender, race, comorbidity, and functional status. Delirium at admission (i.e., prior to surgery) was associated with poorer functioning in physical, cognitive, and affective domains at 6 months postfracture and slower rates of recovery. Impairment and delays in recovery may be further exacerbated by increased depressive symptoms in confused patients over time. Delirium on hospital admission was not a significant predictor of mortality after adjustment for confounding factors. CONCLUSIONS: The present findings further emphasize the significance of immediate detection and treatment of delirium in hip fracture patients to ameliorate the short and long-term effects of acute confusion on functional outcomes.

Development. p73--guilt by association?

It has been assumed that the new members of the p53 protein family, p63 and p73, would have the same job as p53, namely, forcing cells to die if they or their DNA is damaged. Now, as Morrison and Kinoshita explain in their Perspective, one particular form of p73 has been found to be a survival factor rather than a death factor for sympathetic neurons during development (Pozniak et al.).

Absence of p53: no effect in a transgenic mouse model of familial amyotrophic lateral sclerosis.

Familial amyotrophic lateral sclerosis (ALS) has been linked in some families to dominantly inherited mutations in the gene encoding copper-zinc superoxide dismutase 1 (Cu-Zn SOD1). Transgenic mice expressing a mutant human Cu-Zn SOD1 (G93A) develop a dominantly inherited adult-onset paralytic disorder that replicates many of the clinical and pathological features of familial ALS. Increased p53 immunoreactivity has been reported in the motor cortex and spinal ventral horns of postmortem tissue from ALS patients. The nuclear phosphoprotein p53 is an important regulator of cellular proliferation, and increasing evidence supports the role of p53 in regulating cellular apoptosis. To assess the role of p53-mediated apoptosis in amyotrophic lateral sclerosis, mice deficient in both p53 alleles (p53-/-) were crossed with transgenic mice expressing the G93A mutant (G93A+), creating novel transgenic knockout mice. The animals (p53 +/+G93A+, p53+/-G93A+, p53-/-G93A+) were examined at regular intervals for cage activity, upper and lower extremity strength, and mortality. At 120 days from birth mice from each genotype were sacrificed, and L2-L3 anterior horn motor neurons were counted. There was no significant difference in time to onset of behavioral decline, mortality, or motor neuron degeneration between the different genotypes. Despite evidence that p53 plays an important role after acute neuronal injury, the current study suggests that p53 is not significantly involved in cell death in the G93A+ transgenic mouse model of familial ALS.

p38 MAP kinase mediates bax translocation in nitric oxide-induced apoptosis in neurons.

Nitric oxide is a chemical messenger implicated in neuronal damage associated with ischemia, neurodegenerative disease, and excitotoxicity. Excitotoxic injury leads to increased NO formation, as well as stimulation of the p38 mitogen-activated protein (MAP) kinase in neurons. In the present study, we determined if NO-induced cell death in neurons was dependent on p38 MAP kinase activity. Sodium nitroprusside (SNP), an NO donor, elevated caspase activity and induced death in human SH-SY5Y neuroblastoma cells and primary cultures of cortical neurons. Concomitant treatment with SB203580, a p38 MAP kinase inhibitor, diminished caspase induction and protected SH-SY5Y cells and primary cultures of cortical neurons from NO-induced cell death, whereas the caspase inhibitor zVAD-fmk did not provide significant protection. A role for p38 MAP kinase was further substantiated by the observation that SB203580 blocked translocation of the cell death activator, Bax, from the cytosol to the mitochondria after treatment with SNP. Moreover, expressing a constitutively active form of MKK3, a direct activator of p38 MAP kinase promoted Bax translocation and cell death in the absence of SNP. Bax-deficient cortical neurons were resistant to SNP, further demonstrating the necessity of Bax in this mode of cell death. These results demonstrate that p38 MAP kinase activity plays a critical role in NO-mediated cell death in neurons by stimulating Bax translocation to the mitochondria, thereby activating the cell death pathway.

The cause of delirium in patients with hip fracture.

OBJECTIVES: To ascertain the most common causes of delirium, to establish the initiation and timing of delirium, and to determine the duration of delirium in patients with hip fracture. METHODS: Five hundred seventy-one (88%) of 650 patients with hip fracture admitted to 4 New York City hospitals were prospectively interviewed on a daily basis, 5 days a week, with the Confusion Assessment Method for the presence of delirium. The patients were enrolled within 48 hours of admission. Their medical charts and the data collected by the study staff were reviewed and summarized. Two of us (R.S.M. and A.L.S.) reviewed the case summaries independently and assigned a cause based on a previously developed classification system, estimated the onset of the delirious episode, and determined whether the delirium had cleared, improved, or persisted at discharge. Subsequently, discrepancies in cause, timing of initiation, and mental status on discharge between the 2 physicians reviewers were discussed until consensus was reached. RESULTS: The prevalence of delirium was 9.5% (54/ 571; 95% confidence interval, 7.0-11.9). Seven percent of episodes were assigned a definite cause, 20% a probable cause, 11% a possible cause, and 61% were attributable to 1 or more comorbid conditions. Twenty-eight (53%) of 54 subjects developed delirium after surgery. The delirium had cleared or improved in 40 (74%) of 54 subjects at the time of discharge. CONCLUSIONS: Delirium in patients with hip fracture appears to be a different syndrome from that observed in patients who are otherwise medically ill; it also appears to follow a different clinical course. These results have important implications for the management of delirium in patients with hip fracture.

Survival in end-stage dementia following acute illness.

CONTEXT: Little is known about the prognosis of acutely ill patients with end-stage dementia or about the type of care that these patients receive. If their prognosis is poor, then emphasis should be placed on palliative care for these patients rather than on curative interventions. OBJECTIVES: To examine survival for patients with end-stage dementia following hospitalization for hip fracture or pneumonia and to compare their care with that of cognitively intact older adults. DESIGN: Prospective cohort study with 6 months of follow-up. SETTING AND PATIENTS: Patients aged 70 years or older who were hospitalized with hip fracture (cognitively intact, n=59; with end-stage dementia, n=38) or pneumonia (cognitively intact, n=39; with end-stage dementia, n=80) in a large hospital in New York, NY, between September 1, 1996, and March 1, 1998. MAIN OUTCOME MEASURES: Mortality, treatments directed at symptoms, and application of distressing and painful procedures in cognitively intact patients vs those with end-stage dementia. RESULTS: Six-month mortality for patients with end-stage dementia and pneumonia was 53% (95% confidence interval [CI], 41%-64%) compared with 13% (95% CI, 4%-27%) for cognitively intact patients (adjusted hazard ratio, 4.6; 95% CI, 1.8-11.8). Six-month mortality for patients with end-stage dementia and hip fracture was 55% (95% CI, 42%-75%) compared with 12% (95% CI, 5%-24%) for cognitively intact patients (adjusted hazard ratio, 5.8; 95% CI, 1.7-20.4). Patients with end-stage dementia received as many burdensome procedures as cognitively intact patients and only 8 (7%) of 118 patients with end-stage dementia had a documented decision made to forego a life-sustaining treatment other than cardiopulmonary resuscitation. Only 24% of patients with end-stage dementia and hip fracture received a standing order for analgesics. CONCLUSIONS: In this study, patients with advanced dementia and hip fracture or pneumonia had a very poor prognosis. Given the limited life expectancy of patients with end-stage dementia following these illnesses and the burdens associated with their treatment, increased attention should be focused on efforts to enhance comfort in this patient population. JAMA. 2000;284:47-52

The role of p53 in neuronal cell death.

The p53 tumor suppressor gene is a sequence-specific transcription factor that activates the expression of genes engaged in promoting growth arrest or cell death in response to genotoxic stress. A possible role for p53-related modulation of neuronal viability has been suggested by the finding that p53 expression is elevated in damaged neurons in acute models of injury such as ischemia and epilepsy and in brain tissue samples derived from patients with chronic neurodegenerative diseases. Moreover, the absence of p53 has been shown to protect neurons from a wide variety of acute toxic insults. Signal transduction pathways associated with p53-induced cell death are being unraveled and suggest that intervention may prove fruitful in maintaining neuronal viability and restoring function following cytopathic insults.

Localization of fibroblast growth factor-2 (basic FGF) and FGF receptor-1 in adult human kidney.

BACKGROUND: The expression pattern of fibroblast growth factor-2 (FGF-2; basic FGF), a pleiotrophic growth factor, as well as one of its receptors (FGFR1), in the kidney is highly controversial. METHODS: Using an approach that combines multiple antibodies for immunohistochemistry and correlative in situ hybridization, we assessed the intrarenal expression of both FGF-2 and FGFR1 in 13 specimens of adult kidney removed during tumor nephrectomy. RESULTS: The FGF-2 expression pattern in the kidneys as detected by immunohistochemistry was variable and depended on the antibody used. The most consistent expression of FGF-2 protein was demonstrated in glomerular parietal epithelial cells, tubular cells (mainly of the distal nephron), as well as arterial endothelial cells. These locations also corresponded to areas of FGF-2 mRNA expression. Additionally, by immunohistochemistry, FGF-2 protein was detected in arterial smooth muscle cells and occasional podocytes. The expression of FGFR1 protein and mRNA was most consistently present in tubular cells of the distal nephron and in vascular smooth muscle cells. In situ hybridization, but not immunohistochemistry, also suggested FGFR1 expression in cells that could not be precisely identified within the glomerular tuft as well as some interstitial cells. CONCLUSION: These data suggest potential autocrine and paracrine pathways within the FGF-2 system, particularly within the vascular walls and in the distal nephron, and thereby provide information for further mechanistic understanding of the role of the FGF-2 system in human renal disease.

Suppression of glioblastoma cell growth following antisense oligonucleotide-mediated inhibition of fibroblast growth factor receptor expression.

Astrocytes exhibit significant changes in fibroblast growth factor receptor (FGFR) gene expression during malignant progression. These changes include induction of FGFR1 and concomitant loss of FGFR2 expression. The induction of FGFR1 is believed to endow malignant astrocytes with a selective growth advantage. Glioblastoma (the most malignant form of astrocytoma) cell lines, which exhibit the same pattern of FGFR gene expression as glioblastoma biopsies, were used to evaluate the contribution of FGFR1 expression to glioblastoma cell growth. Addition of phosphorothioate-modified antisense oligonucleotides complementary to the initiation site or the alpha exon of the FGFR1 gene suppressed growth of human glioblastoma-derived cell lines. Reverse antisense controls or antisense oligonucleotide complementary to FGFR2 had no effect on proliferation. Consistent with its growth-suppressive effect, FGFR1 antisense oligonucleotides markedly reduced expression of both FGFR1 mRNA and high-affinity bFGF binding sites, whereas FGFR1 reverse antisense control oligonucleotide had no effect. Antisense oligonucleotide targeted to the alpha exon of the FGFR1 gene suppressed alpha and beta alternatively spliced FGFR1 mRNA isoforms but did not alter the expression of related FGFR family members. Fluorescein-labeled antisense and reverse control oligonucleotides demonstrated cellular uptake and nuclear accumulation. These results indicate that alterations in FGFR expression may contribute to malignant proliferation in human astrocytomas. These findings also illustrate the high degree of selectivity that can be obtained with antisense oligonucleotides, a property that is essential for employing these reagents therapeutically.

Anti-telomerase therapy suppressed glioma proliferation.

In order to determine if telomerase activity contributes to the growth of glioma cells, we constructed an anti-telomerase vector to suppress telomerase expression in glioma cells. The human telomerase (hTR)-antisense vector showed a significant suppression effect. However it did not appear to induce cell death as a stable population of cells survived more than two months following transfection. These results provide evidence that reagents aimed at inhibiting telomerase may represent a useful strategy for suppressing the growth of glioma cells. In addition to telomerase, another mechanism would also maintain telomere length, thus supporting continuous cell proliferation.

Contribution of p53-dependent caspase activation to neuronal cell death declines with neuronal maturation.

Caspases play a pivotal role in neuronal cell death during development and after trophic factor withdrawal. However, the mechanisms regulating caspase activity and the role played by caspase activation in response to neuronal injury is poorly understood. The tumor suppressor gene p53 has been implicated in the loss of neuronal viability caused by excitotoxic and DNA damaging agents. In the present study we determined if p53-mediated neuronal cell death required caspase activation. DNA damage increased caspase activity in both cultured embryonic telencephalic and postnatal cortical neurons in a p53-dependent manner. Caspase inhibitors protected embryonic telencephalic neurons, but not postnatal cortical neurons, from DNA damage-induced cell death as measured by direct cell counting and annexin V staining. In marked contrast to the caspase inhibitors, an inhibitor of the DNA repair enzyme, poly(ADP-ribose) polymerase, conferred significant protection from genotoxic and excitotoxic cell death on postnatal cortical neurons but had no effect on embryonic neurons. Glutamate-mediated excitotoxicity in postnatal neurons was not associated with measurable changes in caspase activity, consistent with the failure of caspase inhibitors to prevent cell death under these conditions. Moreover, adenovirus-mediated overexpression of p53 killed embryonic and postnatal neurons without activating caspases. Thus, p53-mediated neuronal cell death may occur via both caspase-dependent and caspase-independent pathways. These results demonstrate that p53 is required for caspase activation in response to some forms of neuronal injury. However, the relative importance of caspase activation in neurons depends on the developmental status of the cell and the specific nature of the death stimulus.

Mechanisms of hypoxia-induced endothelial cell death. Role of p53 in apoptosis.

Endothelial cell death may contribute to tissue injury from ischemia. Little is known, however, about the characteristics of endothelial cell death in response to hypoxia. Using an in vitro model, we found that human umbilical vein endothelial cells were resistant to hypoxia-induced cell death with only a 2% reduction in viability at 24 h and 45% reduction in viability at 48 h. Overexpression of a mutant, IkappaBalpha, via adenoviral vector did not potentiate cell death in hypoxia, indicating that nuclear factor-kappaB activation was not involved in cytoprotection. Cell death in hypoxia was determined to be apoptotic by 3' labeling of DNA using terminal deoxynucleotidyl transferase staining and reversibility of cell death with a caspase inhibitor. Exposure of endothelial cells to hypoxia did not alter levels of proapoptotic and antiapoptotic Bcl-2 family members Bax and Bcl-XL by immunoblot analysis. In contrast, changes in p53 protein levels correlated with the induction of apoptosis in hypoxic endothelial cells. Inhibition of the proteasome increased p53 protein levels and accelerated cell death in hypoxia. Overexpression of p53 by adenoviral transduction was sufficient to initiate apoptosis of normoxic endothelial cells. These data provide a framework for the study of factors regulating endothelial cell survival and death in hypoxia.