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To inform earlier identification of intensive care unit (ICU) patients needing palliative care, we examined factors associated with in-hospital death among ICU patients (N=260) receiving palliative care consultations at a 542-bed tertiary care hospital (2005-2009). High pre-consultation length of stay (LOS, ≥7 days) (adjusted odds ratio (aOR)=5.0, 95% confidence interval (95% CI)=2.5-9.9, P<.01) and consultations for assistance with plan of care (aOR=11.6, 95% CI=5.6-23.9, P<.01) were independently associated with in-hospital death. Patients with both consultation for plan of care and high pre-consult LOS had the highest odds of in-hospital death (aOR=36.3, 95% CI=14.9-88.5, P<.001), followed by patients with consultation for plan of care and shorter pre-consult LOS (aOR=9.8, 95% CI=4.3-22.1, P<.001), and patients with long pre-consult LOS but no consultation for plan of care (aOR=4.7, 95% CI=1.8-12.4, P=.002). Our findings suggest that ICU patients who require assistance with plan of care need to be identified early to optimize end-of-life care and avoid in-hospital death.

Background: Despite palliative care implementation, most deaths still occur in hospitals., Objectives: To identify factors associated with in-hospital death among elderly patients receiving palliative care, by site of consultation., Design: Prospective observational study., Setting/subjects: All inpatients aged 65 years and older receiving pain and palliative care consultations in a 533-bed acute tertiary care hospital in Honolulu, Hawaii, from January 2005 through December 2009., Measurements: During consultation, demographics, diagnoses, consultation site (intensive care unit [ICU], non-ICU medical, non-ICU surgical, and rehabilitation floors), consultation indication (assistance with establishing goals of care versus pain and/or symptom management), Karnofsky scores, length of stay (LOS), discharge disposition, and in-hospital death were collected. Multiple logistic regression analyses examined factors associated with in-hospital death., Results: Of 1630 elderly inpatients receiving palliative care, 305 (19%) died in-hospital. In-hospital death among non-ICU medical patients was associated with needing consultation to assist with plan of care (odds ratio [OR]=1.89, 95% confidence interval [CI]=1.27-2.80). Likelihood of in-hospital death increased 2% for each additional hospital day before consultation (OR=1.02, 95% CI=1.01-1.03). Among elderly ICU patients, likelihood of in-hospital death increased 8% for each additional hospital day before consultation (OR=1.08, 95% CI=1.01-1.16)., Conclusion: Among elderly non-ICU medical patients receiving palliative care consultations, the need for a consultation to assist with plan of care was associated with in-hospital death, while length of stay prior to consultation was important among both elderly ICU and non-ICU medical patients. Elderly hospitalized patients may benefit from earlier identification and palliative care consultation for assistance with plan of care to avoid in-hospital death.

Hypothesis: The unique toxic and adverse effects of meperidine hydrochloride have prompted a number of expert panels convened by national health care policy organizations to recommend that meperidine not be used in older patients. We hypothesized that the prescription of meperidine was less likely to reflect these recommendations in older surgical patients than in older medical patients. The current study examined the use of meperidine in 2 urban hospitals as 1 quality indicator of the care of older adults, measuring the prevalence of its use and characteristics of the patients to whom it is administered., Design: Retrospective analysis., Setting: Two urban hospitals: a large private tertiary care teaching hospital and a smaller academically affiliated Veterans Affairs medical center., Patients: Patients 65 years or older and hospitalized on medical and surgical services between February 19, 2001, and February 14, 2003., Main Outcome Measures: Patient demographics, medication administration, and department of admitting physician., Results: Meperidine was administered to approximately 1 in 8 older surgical patients at both institutions. Surgical patients were more likely than medical patients to receive a dose of meperidine (hospital A, 12.2% vs 4.3%, P<.001; hospital B, 12.9% vs 1.9%, P<.001). Of those administered meperidine, surgical patients were also more likely than medical patients to receive multiple doses (hospital A, 86.0% vs 65.5%, P = .045; hospital B, 73.8% vs 48.4%, P = .02)., Conclusions: Contrary to national recommendations, meperidine continues to be administered to many hospitalized older adults, particularly those on surgical services. Several alternatives to meperidine exist that provide equal or better pain relief with fewer toxic effects. Hospitals and, in particular, departments of surgery should address this cause of preventable morbidity in this vulnerable population.

Objective: LCME has recently required that all graduating medical students learn about end-of-life care. This program describes the design and integration into an existing geriatrics clerkship of a palliative care module that teaches the foundations of end-of-life and palliative care to medical students., Description: Faculty experts in geriatrics met during a series of weekly meetings in 1999 to design a mandatory four-week-long clinical clerkship in geriatrics. Since the palliative care program is based within the geriatrics department, faculty members with interest and expertise in both geriatrics and palliative care were invited to design a palliative care module that can be integrated into the clerkship. Since LCME does not specify details of what students must learn about end-of-life care, and our goal is to educate and prepare students for any chosen specialty, we wanted to design a basic core curriculum in palliative care that would be useful to any graduating student. After reviewing potential palliative care topics, and given limited curriculum time, we condensed the medical student core curriculum to the following sessions: (1) Systematic Pain Assessment Management, (2) Management of Distressing Symptoms, (3) Communicating Bad News, and (4) Advance Directives. We developed PowerPoint presentations, teaching case vignettes, and a set of reference articles, which can be distributed to students as well as to help faculty teachers prepare for the sessions. Teaching sessions occur in small groups, using case discussions and interactive lectures. Sessions 3 and 4 are co-facilitated by palliative care physicians and ethicists, who use role-plays, reflections, and discussions to teach the topics. At the end of the clerkship, students practice these communication skills with videotaped standardized patient encounters, and debrief with faculty members about their performances and ways to improve their communication skills., Discussion: Palliative care sessions are welcomed by the students, who traditionally have not received much teaching in this area. Even though students have learned about mechanisms regulating pain and other symptoms in the past, they have not learned to assess or treat symptoms in a systematic way. Students often have good questions about the decision-making, legal, and ethical issues that emerge for patients near the end of life. Thus, co-facilitation of physicians with ethicists presents both the practical clinical and the theoretical perspectives, and provides a good model for team teaching. In terms of teaching style, students are more involved and participatory when teachers use case vignettes as compared with slide presentations, even if they are case-based. When using role-plays to teach students how to communicate bad news, we found that students need to feel safe in that environment, need to know they can call for time out when necessary, and want to have seen one done before they are asked to do one.

Background: Patients often are rotated from other opioids to methadone when side effects occur before satisfactory analgesia is achieved. Various strategies have been proposed to estimate safe and effective starting doses of methadone when rotating from morphine and hydromorphone; however, there are no guidelines for estimating safe and effective starting doses of methadone when rotating from fentanyl., Methods: The authors prospectively observed 18 consecutive patients experiencing chronic pain from cancer who underwent opioid rotation from intravenous patient-controlled analgesia (PCA) with fentanyl to intravenous PCA with methadone. Patients were switched from fentanyl to methadone because of uncontrolled pain associated with sedation or confusion. A conversion ratio of 25 microg/hour of fentanyl to 0.1 mg/hour of methadone was used to calculate the initial dose of methadone in all patients., Results: Mean pain scores decreased from 8.1 to 4.8 on Day 1 after the switch and to 3.22 on Day 4 after the switch. Mean sedation scores were 1.5 before the switch and 0.44 and 0.16 on Days 1 and 4, respectively. Among the 6 patients who experienced confusion while on fentanyl before the switch, 5 improved within 2 days of the switch. None of the patients experienced toxicity from methadone., Conclusions: On the basis of this preliminary study, the authors suggest that when switching from intravenous fentanyl to methadone a conversion ratio of 25 microg/hour of fentanyl to 0.1 mg/hour of methadone may be safe and effective., (Copyright 2001 American Cancer Society.)

Although the GH3 line of somatolactotropic rat pituitary cells has proven useful for many regulation studies, the absence of functional D2 receptors on these cells long prevented their use in studies of dopaminergic action. However, it is now possible to employ GH3 cells expressing recombinant D2 receptors for such investigations. We have investigated both the level at which expression of functional D2 receptors in GH3 cells is blocked, and the cellular pathways employed by the major pituitary D2 receptor isoform, D2A, to inhibit prolactin (PRL) gene transcription. In run-off transcription assays with nuclei from either parental GH3 cells or a GH3 cell line stably expressing a D2A expression vector, Pit-1 gene transcription was detectable in either cell line, but only the latter cell line yielded detectable D2 receptor transcription, implying that the block in D2 receptor expression by GH3 cells is transcriptional. Further investigations employed GH3 cells transiently co-transfected with a D2A expression vector plus a rat PRL promoter construct (-1957)PRL-CAT. Pertussis toxin blocked repression by quinpirole, a D2 agonist, of PRL-CAT activity, demonstrating that this action is mediated by a pertussis toxin-sensitive G protein. The observations that neither of two agents expected to raise intracellular Ca2+, Bay K8644 or thyrotropin-releasing hormone, prevented quinpirole repression of PRL-CAT activity, and that the repressive effects on this construct of quinpirole and the Ca2+ channel antagonist were independent, suggested that regulation of intracellular Ca2+ levels does not play a major role in D2A-mediated repression of the PRL promoter.(ABSTRACT TRUNCATED AT 250 WORDS)

The transcription factor Pit-1 has been shown to be important for both the developmental and homeostatic regulation of expression of the PRL and GH genes in pituitary cells. However, little is known about possible covalent modifications in Pit-1 that might mediate its transactivational properties. Previous studies showing that Pit-1 is a phosphorylation substrate for either protein kinase A or C, or their cellular inducers, led us to investigate whether phosphorylation of Pit-1 is required for its function in either basal or induced cellular activity of either the PRL or GH promoters. The transactivational properties of wild type Pit-1 were compared with those of Pit-1(A3), mutated in the three known phosphorylation sites. At saturating levels of Pit-1 expression vectors, activation of transient basal expression in HeLa cells of constructs (-1957)PRL-CAT or (-244)GH-CAT by RSV-Pit-1(A3) was, respectively, about 50% and 65% as strong as by RSV-Pit-1. Hence, phosphorylation at the sites mutated in Pit-1(A3) is not critically required for basal transactivation of either promoter but may modulate this activity. RSV-Pit-1 and RSV-Pit-1(A3) were equally effective in mediating estrogen receptor stimulation of (-1957)PRL-CAT expression in HeLa cells, thus revealing no phosphorylation requirement for the prerequisite for Pit-1 in estrogen receptor action on the PRL estrogen response element.(ABSTRACT TRUNCATED AT 250 WORDS)

Nerve growth factor (NGF) plays a critical role in the development and survival of neurons in the peripheral nervous system. Following treatment with NGF but not epidermal growth factor, rat pheochromocytoma (PC12) cells undergo neural differentiation. We have cloned a nervous system-specific mRNA, NGF33.1, that is rapidly and relatively selectively induced by treatment of PC12 cells with NGF and basic fibroblast growth factor in comparison with epidermal growth factor. Analysis of the nucleic acid and predicted amino acid sequences of the NGF33.1 cDNA clone suggested that this clone corresponded to the NGF-inducible mRNA called VGF (A. Levi, J. D. Eldridge, and B. M. Paterson, Science 229:393-395, 1985; R. Possenti, J. D. Eldridge, B. M. Paterson, A. Grasso, and A. Levi, EMBO J. 8:2217-2223, 1989). We have used the NGF33.1 cDNA clone to isolate and characterize the VGF gene, and in this paper we report the complete sequence of the VGF gene, including 853 bases of 5' flank revealed TATAA and CCAAT elements, several GC boxes, and a consensus cyclic AMP response element-binding protein binding site. The VGF promoter contains sequences homologous to other NGF-inducible, neuronal promoters. We further show that VGF mRNA is induced in PC12 cells to a greater extent by depolarization and by phorbol-12-myristate-13-acetate treatment than by 8-bromo-cyclic AMP treatment. By Northern (RNA) and RNase protection analysis, VGF mRNA is detectable in embryonic and postnatal central and peripheral nervous tissues but not in a number of nonneural tissues. In the cascade of events which ultimately leads to the neural differentiation of NGF-treated PC12 cells, the VGF gene encodes the most rapidly and selectively regulated, nervous-system specific mRNA yet identified.

In an attempt to further clarify the mechanism of the maintenance of the antihypertensive effect of beta-adrenoceptor antagonists, the effects of four antagonists with different ancillary properties (acebutolol, atenolol, pindolol, and propranolol) on systemic and renal hemodynamics, body fluid volumes, hormones, and lymphocyte beta-adrenoceptor density were studied in four groups of 10 hypertensive patients. The patients were observed for 3 weeks during active treatment and for 2 weeks after withdrawal of treatment. At the end of the 3-week treatment period, the four drugs had an equal antihypertensive effect (fall in mean arterial pressure, 10-13%). Although renin activity was suppressed (60-70%) by all four drugs, changes in renin or pretreatment values of renin levels were not correlated with the fall in blood pressure. The drugs had no effect on plasma catecholamine concentrations or body fluid volumes. Despite similar antihypertensive effects among the four drugs, the changes in flow and resistance underlying the fall in blood pressure differed considerably. With pindolol, the fall in blood pressure was associated with a fall in vascular resistance (26 +/- 6%), whereas with propranolol, it was predominantly associated with a fall in cardiac output (11 +/- 7%). No significant changes in vascular resistance or cardiac output occurred with atenolol or acebutolol. The changes in renal blood flow and renal vascular resistance occurred in parallel with the changes in cardiac output and systemic vascular resistance. Plasma epinephrine concentration and pretreatment cardiac chronotropic responsiveness to isoproterenol appeared to be inversely correlated with lymphocyte beta-adrenoceptor density (Bmax) (r = -0.41 and -0.43, respectively). With pindolol, Bmax decreased maximally by 39 +/- 6%, and with propranolol, it increased by 51 +/- 17%. With both drugs, significant changes in Bmax were already present 24 hours after treatment. Furthermore, 1 week after withdrawal of treatment with pindolol, Bmax was still down-regulated, and cardiac chronotropic responsiveness was still decreased, whereas 1 week after withdrawal of propranolol, Bmax was still up-regulated, and cardiac chronotropic responsiveness was still increased. No changes in Bmax occurred with the beta 1-selective antagonists acebutolol and atenolol. Thus, despite an equal antihypertensive effect, the four beta-adrenoceptor antagonists appear to have dissimilar effects on cardiac output, renal blood flow, and lymphocyte beta-adrenoceptors. Changes in cardiac output, the circulating blood volume, or angiotensin-mediated vasoconstriction are factors unlikely to be crucial for the antihypertensive effect of beta-adrenoceptor antagonists. Therefore, interference with vasoconstrictor nerve activity through blockade of either central or peripheral prejunctional beta-adrenoceptors could be an alternative explanation of their blood pressure-lowering potential.

Most antibodies known to interact with beta-adrenergic receptors do not exhibit subtype selectivity, nor do they provide quantitative immunoprecipitation. A monoclonal antibody, G27.1 raised against a synthetic peptide corresponding to the C-terminus of the beta 2-adrenergic receptor of hamster, is selective for the beta 2 subtype. G27.1 provides nearly quantitative immunoprecipitation of the beta 2-adrenergic receptor from hamster lung that has been photoaffinity-labeled and solubilized with sodium dodecyl sulfate. Immunoprecipitation is completely blocked by nanomolar concentrations of the immunizing peptide. This antibody interacts with beta 2-adrenergic receptors from three rodent species, but not with those from humans. When C6 glioma cells, which contain both beta 1- and beta 2-adrenergic receptors, are photoaffinity-labeled in the absence or presence of subtype-selective antagonists, subtype-selective photoaffinity-labeling results. G27.1 can immunoprecipitate beta 2-, but not beta 1-, adrenergic receptors from these cells. Similar results were obtained following subtype-selective photoaffinity-labeling of membranes from rat cerebellum and cerebral cortex. The beta-adrenergic receptors from C6 glioma cells and rat cerebral cortex exist as a mixture of two molecular weight species. These species differ in glycosylation, as shown by endoglycosidase F digestion of crude and immunoprecipitated receptors.

Acebutolol is a relatively new beta-adrenoceptor blocking antagonist, possessing both beta 1-adrenoceptor selectivity and partial agonist activity (PAA). Its acute (24 h, 400 mg, twice daily) and long-term effects (3 weeks) on systemic and renal hemodynamics, body fluid volumes, hormones, and beta-adrenoceptor density on lymphocytes were studied in a single-blind placebo-controlled trial, in 10 hypertensive patients. The initial response to acebutolol (1-2 h) was a fall in heart rate (HR) (-9.6 +/- 2.7%), cardiac output (-16.0 +/- 3%), and stroke volume (SV) (-10.7 +/- 0.2%), and an increase in systemic vascular resistance (SVR) (18.0 +/- 3.9%). Mean arterial pressure (MAP) began to fall 2-3 h after dosing in parallel with a decrease in SVR. At the end of the acute study, MAP and SVR were decreased by 18.1 +/- 2.7% and 15.6 +/- 5.6%, respectively. By that time, HR and SV had returned to control values despite blockade of beta-adrenoceptors. After 3 weeks of treatment (mean dose of acebutolol 480 mg twice daily), the fall in MAP was 10.1 +/- 2.7% and HR was decreased by 13.0 +/- 2.3%. Renal blood flow and glomerular filtration rate did not change. Acute and long-term treatment had no effect on the density of lymphocyte-membrane beta-adrenoceptors. This could be explained by acebutolol's beta 1 selectivity or, alternatively, this could be due to the drug's PAA.