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A novel assay for measurement of Hepatitis C virus (HCV) NS3 helicase activity was developed using Flashplate technology. This assay involves the use of a DNA duplex substrate and recombinant HCV NS3 produced in Escherichia coli. The DNA duplex consisted of a pair of oligonucleotides, one biotinylated, the other radiolabeled at their respective 5' termini. This DNA duplex was immobilized, via the biotin molecule, on the surface of a neutravidin-coated SMP103 Flashplate (NEN Life Science Products). Helicase activity results in the release of the radiolabeled oligonucleotide, which translates in signal reduction with respect to control wells. Biochemical characterization of the HCV NS3 helicase activity was performed using this assay. We demonstrated that the NS3-mediated unwinding is proportional to both the amount of DNA substrate in the well, and to the NS3 concentration in the reaction. Most of the NS3-mediated unwinding was achieved in the initial 60 min of incubation. As expected the reactions were ATP-dependent and found to be affected by the concentration of MgCl(2), MnCl(2), KCl, EDTA, and by pH. We found this assay to be highly reproducible since only slight variation was observed when a total of 68 helicase reactions were performed on one plate. Therefore, this Flashplate helicase assay is fast, convenient and reproducible. These criteria make it suitable for high throughput screening of potential NS3 helicase inhibitors.

Background: Few studies describe the end of life in very old people., Objectives: To characterize the last 6 months of life and dying in patients 80 years and older by describing demographic characteristics, functional state and quality of life, symptoms, preferences, use of life-sustaining treatments, satisfaction with care, and family burden., Design: A retrospective analysis for patients enrolled in a prospective cohort study., Setting: Four teaching hospitals who participated in the Hospitalized Elderly Longitudinal Project (HELP)., Subjects: 417 patients who died within 1 year of their enrollment hospitalization., Measurements: Chart reviews and interview data with patients and surrogates at several points in time. We constructed four observational time windows backward in time beginning with the patients' death., Results: Before hospitalization, two out of three patients reported fair quality of life, and patients averaged 2.4 impairments in activities of daily living. Seventy percent preferred comfort care on the third day of hospitalization. During the last month of life, three of five patients interviewed in the hospital and four of five interviewed out of the hospital preferred not to be resuscitated. At the time of death, four of five patients had a do not resuscitate (DNR) order and two of five had an order to withhold a ventilator. During the last month of life, one out of four patients reported severe pain., Conclusions: Patients reported increasing functional impairments and limited quality of life. The majority preferred comfort care. The number of patients in severe pain was substantial. Before death, the majority had measures in place to limit aggressive care.

Objectives: To review previously published findings about how patient age influenced patterns of care for seriously ill patients enrolled in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT)., Design: An observational prospective study., Setting: Five acute care hospitals., Participants: A total of 9105 seriously ill patients enrolled in SUPPORT., Measurements: The outcomes examined included patients' preferences for aggressive care, decision making regarding cardiopulmonary resuscitation and use of other life-sustaining treatments, hospital costs, intensity of resource use, and survival., Results: Although older patients preferred less aggressive care than younger patients, many older patients wanted cardiopulmonary resuscitation and care focused on life extension. Patients' families and healthcare providers underestimated older patients' desire for aggressive care. After adjustment for illness severity, comorbidity, baseline function, and patients' preferences for aggressive care, older age was associated with lower hospital costs and resource intensity and higher rates of decisions to withhold life-sustaining treatments. In adjusted analyses, older age was associated with a slight survival disadvantage. This survival disadvantage persisted, even after adjustment for aggressiveness of care, suggesting that the relation between age and survival is not accounted for by less aggressive treatment of older patients., Conclusions: Even after adjustment for patients' prognoses and care preferences, seriously ill hospitalized older patients were treated less aggressively than younger patients. SUPPORT cannot fully identify whether the relationship between older age and less aggressive treatment is better explained by the withholding of potentially beneficial treatments from older patients, or by the excessive provision of ineffective treatment to younger patients. However, the latter explanation is favored by the SUPPORT finding that less aggressive treatment for older patients does not contribute to the modest survival disadvantage associated with older age.

Background: The intervention in SUPPORT, the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments, was ineffective in changing communication, decision-making, and treatment patterns despite evidence that counseling and information were delivered as planned. The previous paper in this volume shows that modest alterations in the intervention design probably did not explain the lack of substantial effects., Objective: To explore the possibility that improved individual, patient-level decision-making is not the most effective strategy for improving end-of-life care and that improving routine practices may be more effective., Design: This paper reflects our efforts to synthesize findings from SUPPORT and other sources in order to explore our conceptual models, their consistency with the data, and their leverage for change., Results: Many of the assumptions underlying the model of improved decision-making are problematic. Furthermore, the results of SUPPORT suggest that implementing an effective intervention based on a normative model of shared decision-making can be quite difficult. Practice patterns and social expectations may be strong influences in shaping patients' courses of care. Innovations in system function, such as quality improvement or changing the financing incentives, may offer more powerful avenues for reform., Conclusions: SUPPORT's intervention may have failed to have an impact because strong psychological and social forces underlie present practices. System-level innovation and quality improvement in routine care may offer more powerful opportunities for improvement.

Background: The aim of the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments -- SUPPORT -- was to improve the care of seriously ill patients by improving decision-making for patients with life-threatening illnesses. Several theories have been proposed to explain why the SUPPORT intervention was unsuccessful at improving outcomes., Objective: To review and discuss explanations offered by others regarding why the SUPPORT intervention failed to have a discernible impact on its prespecified outcome measures., Design: A descriptive review of published articles and book chapters, with synthesis of data-based and conceptual insights., Methods: The Medline, Bioethicsline, and Ethx databases were searched for citations to SUPPORT articles between 1994 and the end of 1998. This search was supplemented by other published materials that had come to the authors' attention., Results: The critiques and explanations regarding the reasons the SUPPORT intervention did not improve outcomes were catalogued and organized into 11 major categories, the first 10 of which are explored in the present study: (1) the inception cohort was biased against an effect of the intervention, (2) the intervention was not implemented as designed, (3) the intervention failed because nurses were too readily ignored, (4) the intervention was too polite, (5) the intervention presented information ineffectively, (6) the intervention did not focus on primary care physicians, (7) the intervention falsely dichotomized do not resuscitate (DNR) decisions, (8) the intervention needed more years on site or an earlier start with each patient, (9) the intervention required more appropriate outcome measures, (10) the intervention was irrelevant because usual care is not seriously flawed, (11) the conceptual model behind SUPPORT was fundamentally flawed in aiming to improve individual, patient-level decision-making as the way to improve seriously ill, hospitalized patients' experiences., Conclusions: Although some of the critiques were found to raise important concerns, we conclude in each case that the explanation offered is inadequate to explain the failure of the intervention. We urge further reflection on the fundamental assumptions that informed the design of that intervention and refer the reader to a more comprehensive treatment of that issue in the companion paper in this volume.

Objective: To identify age group differences in care practices and outcomes for seriously ill hospitalized patients with malignancy., Design: Prospective cohort study (SUPPORT project)., Setting: Five United States teaching hospitals; data was gathered between 1989 and 1994., Subjects: Nine hundred twenty five older (age > or = 65 years), 983 middle aged (age = 45-64 years), and 274 younger (age = 18-44 years) hospitalized patients receiving care for non-small cell lung cancer, colon cancer metastasized to the liver, or multi-organ system failure associated with malignancy., Measurements: Care practices and patient outcomes were determined from hospital records. Length of survival was identified using the National Death Index. After adjusting for important variables, including severity of illness (i.e., SUPPORT model estimate for 2-month survival, cancer condition), hospital site, selection to intervention and sociodemographic variables, age group differences in care practices and outcomes were identified using general linear models., Results: Older patients with cancer had lower resource utilization during hospitalization (P < .04) and were less likely to receive cancer-related treatments (i.e., chemotherapy, platelet infusions, scheduled intravenous medications) than middle-aged and young-adult patients in the first week of hospitalization (P < or = .01). More care topics were discussed with older patients and their families then with younger patients and their families (P < .001). Length of stay and total hospital costs were lower for older and middle-aged patients than for younger patients. Although more older patients had discussions about transfer to hospice (P < .001), older patients were no more likely to be discharged with supportive care (inpatient hospice or home with home/ hospice care). Older patients died sooner than middle-aged patients (P < .01)., Conclusions: Patient age influenced care decisions and outcomes. Older patients (age > or = 65 years) received less aggressive care, had more discussions about care decisions, and died sooner than younger patients with cancer. Younger patients had longer stays, higher hospital costs, and greater probability of rehospitalization. Although well over half of patients died within 6 months of hospitalization, few patients in any age group were discharged with supportive care. Future studies should examine age differences in palliation, as well as acute care of cancer patients across inpatient and ambulatory care settings and should assess quality of care at the end of life.

Background: Despite concern about the high costs and the uncertain benefit of prolonged treatment in the intensive care unit (ICU), there has been little research examining decision-making and outcomes for patients with prolonged ICU stays., Objectives: To evaluate decision-making and outcomes for seriously ill patients with an ICU stay of at least 14 days., Design: A prospective cohort study., Setting: Five teaching hospitals., Participants: Seriously ill patients enrolled in the Study To Understand Prognoses and Preferences for Risks and Outcomes of Treatments (SUPPORT)., Measurement: Patients, their surrogate decision-makers, and their physicians were interviewed about prognosis, communication, and goals of medical care. Based on age, diagnoses, comorbid illnesses, and acute physiology data, the SUPPORT Prognostic Model provided estimates of 6-month survival on study days 1, 3, 7, and 14. Hospital costs were estimated from hospital billing data., Results: Of the 9105 patients enrolled in SUPPORT, 1494 (16%) had ICU stays of 14 days or longer. The median length of stay in an ICU was 4 days for the entire SUPPORT cohort and 35 days for patients who were treated in an ICU for 14 days or longer. Median hospital costs were $76,501 for patients who had ICU stays 14 days or longer and $10,916 for patients who did not have long ICU stays. Fifty-five percent of patients with long ICU stays had died by 6 months, and an additional 19% had substantial functional impairment. Among patients with ICU stays of at least 14 days, only 20% had estimates of 6-month survival that fell below 10% at any time during their hospitalization. For patients with long ICU stays, the mean predicted probability of 6-month survival was 0.46 on study Day 3 and 0.47 on study Day 14. Fewer than 40% of patients (or their surrogates) reported that their physicians had talked with them about their prognoses or preferences for life-sustaining treatment. Among the patients who preferred a palliative approach to care, only 29% thought that their care was consistent with that aim. Those who discussed their preferences for care with a physician were 1.9 times more likely to believe that treatment was in accord with their preferences for palliation (95% CI, 1.4-2.5), Conclusions: Prolonged ICU stays were expensive and were often followed by death or disability. Patients reported low rates of discussions with their physicians about their prognoses and preferences for life-sustaining treatments. Many preferred that care focus on palliation and believed that care was inconsistent with their preferences. Patients were more likely to receive care consistent with their preferences if they had discussed their care preferences with their physicians.

Objectives: The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT) represents one of the largest and most comprehensive efforts to describe patient preferences in seriously ill patients, and to evaluate how effectively patient preferences are communicated. Our objective was to review findings from SUPPORT describing the communication of seriously ill patients' preferences for end-of-life care., Methods: We identified published reports from SUPPORT describing patient preferences and the communication of those preferences. We abstracted findings that addressed each of the following questions: What patient characteristics predict patient preferences for end of life care? How well do physicians, nurses, and surrogates understand their patients' preferences, and what variables are correlated with this understanding? Does increasing the documentation of existing advance directives result in care more consistent with patients' preferences?, Results: Patients who are older, have cancer, are women, believe their prognoses are poor, and are more dependent in ADL function are less likely to want CPR. However, there is considerable variability and geographic variation in these preferences. Physician, nurse, and surrogate understanding of their patient's preferences is only moderately better than chance. Most patients do not discuss their preferences with their physicians, and only about half of patients who do not wish to receive CPR receive DNR orders. Factors other than the patients' preferences and prognoses, including the patient's age, the physician's specialty, and the geographic site of care were strong determinants of whether DNR orders were written. In SUPPORT patients, there was no evidence that increasing the rates of documentation of advance directives results in care that is more consistent with patients' preferences., Conclusions: SUPPORT documents that physicians and surrogates are often unaware of seriously ill patients' preferences. The care provided to patients is often not consistent with their preferences and is often associated with factors other than preferences or prognoses. Improving these deficiencies in end-of-life care may require systematic change rather than simple interventions.

Background: The dying experience of patients with acute respiratory failure (ARF) or multiple organ system failure with sepsis (MOSF) has not been described., Objectives: To describe patients dying from ARF or MOSF, including demographic characteristics, baseline function and quality of life, symptoms, preferences, use of life-sustaining treatments, satisfaction with care, and family burden., Design: A multicenter prospective study., Setting: Five US teaching hospitals, in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT)., Participants: A total of 1295 adults who died during hospitalization for ARF or MOSF., Measurements: Chart reviews and interviews with patients and surrogates., Results: SUPPORT enrolled 2956 patients with ARF or MOSF, and 44% died during enrollment hospitalization. Quality of life before hospitalization was reported as fair by 87% of patients. The mean number of impairments in their baseline activities of daily living was 1.6. At the time of death, 79% had a DNR order and 31% had an order to withhold ventilator support. The average time from the DNR order to death was 2 days. Dying patients spent an average of 9 days on a ventilator. Surrogates indicated that one out of four patients died with severe pain and one out of three with severe confusion. Families of 42% of the patients who died reported one or more substantial burden., Conclusions: Patients in this study reported substantial functional impairments and reduced quality of life. Limitations to aggressive treatments were usually implemented only when death was imminent. Family impact and physical and emotional suffering were substantial.

Background: We sought to describe the resuscitation preferences of patients hospitalized with an exacerbation of severe congestive heart failure, perceptions of those preferences by their physicians, and the stability of the preferences., Methods and Results: Of 936 patients in this study, 215 (23%) explicitly stated that they did not want to be resuscitated. Significant correlates of not wanting to be resuscitated included older age, perception of a worse prognosis, poorer functional status, and higher income. The physician's perception of the patient's preference disagreed with the patient's actual preference in 24% of the cases overall. Only 25% of the patients reported discussing resuscitation preferences with their physician, but discussion of preferences was not significantly associated with higher agreement between the patient and physician. Of the 600 patients who responded to the resuscitation question again 2 months later, 19% had changed their preferences, including 14% of those who initially wanted resuscitation (69 of 480) and 40% of those who initially did not (48 of 120). The physician's perception of the patient's hospital resuscitation preference was correct for 84% of patients who had a stable preference and 68% of those who did not., Conclusions: Almost one quarter of patients hospitalized with severe heart failure expressed a preference not to be resuscitated. The physician's perception of the patient's preference was not accurate in about one quarter of the cases. but communication was not associated with greater agreement between the patient and the physician. A substantial proportion of patients who did not want to be resuscitated changed their minds within 2 months of discharge.

This article describes a simple method for rating the patient-clinician interaction from the perspective of the older adult patient, with the goal of improving patient outcomes. A measure for rating the quality of an interaction with a patient who is bothered by a problem is called the Functional Education Index or FNXEI. Usually, sicker patients are known to be less satisfied with their medical care. What is unique about the FNXEI is that it is not affected by a patient's overall health, giving clinicians an accurate account of their interactions with patients. Considering this, the FNXEI becomes a useful tool for improving care because it has face validity and specificity about the type of care clinicians are providing for their older adult patients.

The vertebral cervical syndrome is a clinical entity defined as a dysfunction of the cranio-cervical junction of traumatic or non traumatic cause. The authors report on asthenopic disorders occurring in such a syndrome. The fusion amplitude and the accommodation power were reduced in all patients and were a cause of delayed job recurrence. The treatment of fusion was long, painful and, in some cases, not successful. A depressive status associated with a prolonged job interruption were bad prognosis factors. A differential diagnosis has to be made with the so-called insurance neurotic reaction.

We recently reported that previously activated T cells, irrespective of the nature of the first stimulus they encountered, are unable to respond to Staphylococcal enterotoxin B (SEB), nor to soluble anti-CD3 monoclonal antibody (mAb) presented by splenic antigen-presenting cells (APC). Such previously activated T cells are, however, fully capable of responding to plate-bound anti-CD3 plus splenic APC. These data suggest differential integration of the T-cell receptor (TCR) and co-stimulatory signalling pathways in naive versus antigen-experienced T cells. Consistent with this hypothesis, anti-CD28 mAb restores the proliferative capacity of resting ex vivo CD45RBlo CD4+ T cells (representing previously activated T cells) to both soluble anti-CD3 mAb and SEB. Interestingly, mAb-mediated engagement of cytotoxic T-lymphocyte antigen-4 (CTLA-4) completely negates the rescue effects mediated by anti-CD28 mAb in CD45RBlo cells. Nevertheless, the non-responsiveness of CD45RBlo CD4+ T cells cannot be reversed by anti-CTLA-4 Fab fragments, indicating that it is not related to negative regulatory effects of CTLA-4 engagement itself. Interestingly, the addition of interleukin-2 (IL-2) restores the proliferative capacity of CD45RBlo CD4+ T cells to SEB and soluble anti-CD3 mAb. Moreover, when rescued by IL-2, the cells are less susceptible to the negative regulatory effects of CTLA-4 engagement. Together, these findings suggest that the non-responsiveness of CD45RBlo CD4+ T cells to certain stimuli may be related to inadequate TCR signalling, primarily affecting IL-2 production.

Objective: To evaluate the pain experience of very old hospitalized patients during and up to 1 year after hospitalization. To understand the relationship of level of pain to demographic, psychological, and illness-related variables., Design: Prospective cohort study., Setting: Four teaching hospitals., Participants: 1266 patients at least 80 years of age in the Hospitalized Elderly Longitudinal Project (HELP)., Measurements: Pain interviews during hospitalization and 2 and 6 months later. Ordinal logistic regression was used to study the association of variables with level of pain., Results: Interviews about symptoms were available for 806 (64.6% of survivors) patients during hospitalization, 614 (57.9% of survivors) at 2-months, and 416 (48.0% of survivors) at 12 months; of these, 45.8, 49.8 and 53.6%, respectively, reported pain, and 12.9% of those with pain during hospitalization were dissatisfied with its control. Multivariable analysis revealed that study hospital, admission diagnosis, depressed mood, alertness, and level of activity 2 weeks before admission were associated with pain during hospitalization, and pain reported during hospitalization, study site, patient level of activity 2 weeks before hospital admission, and patient education were associated with pain 2 months later., Conclusions: Frequency of pain among very old hospitalized patients and at follow-up is similar to that reported for other hospitalized patients. Further studies of strategies to better control pain during and after hospitalization in very old patients are needed. These studies will have to adjust for other variables associated with pain in the oldest-old.

Objective: To evaluate patients' willingness to live permanently in a nursing home and surrogate and physician understanding of that preference., Design: Evaluation of cross-sectional interview data from a cohort study., Setting: Five academic medical centers., Participants: Seriously ill hospitalized adults enrolled in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT)., Measurements: Patients' willingness to live permanently in a nursing home was measured on a 5-point scale ranging from "very willing" to "rather die." Ordinal logistic regression was used to identify patient demographic and clinical characteristics associated with this preference. Surrogate and physician perceptions of patient preferences were compared with patients' responses, and factors associated independently with surrogate and physician understanding of patient preference were identified., Results: Of 9105 patients, 3262 (36%) provided responses to the study question: 7% were "very willing" to live permanently in a nursing home, 19% "somewhat willing," 11% "somewhat unwilling," 26% "very unwilling," and 30% would "rather die." Older age was associated independently with less willingness to live permanently in a nursing home (odds ratio [OR] = .90 per decade; 95% confidence interval [CI]: 0.85, 0.96). Patients with more education (OR = 1.03 per year; 95% CI: 1.00, 1.05) and more disabilities (OR = 1.05 per disability; 95% CI: 1.01, 1.09), and black patients (OR = 1.46 compared with white patients; 95% CI: 1.20, 1.76) were more willing to live in a nursing home. Surrogates understood 61% of patients' nursing home preferences but identified only 35% of patients who were willing to live permanently in a nursing home. Physicians identified 18% of patients willing to live permanently in a nursing home., Conclusion: Patient attitudes about living permanently in a nursing home can be elicited, cannot be reliably predicted from demographic and clinical variables, and are frequently misunderstood by surrogates and physicians. Elicitation of patient preferences regarding permanent nursing home placement should be explored before patients become unable to participate in decision making in order to enhance the concordance of patient preference with the way they spend the end of their lives.

Objectives: Although complications occur with long-term steroid usage in elderly Crohn's disease patients, there is little information on their short-term risk. This study was designed to assess that risk., Method: We reviewed admissions from 1984 to 1995 and found 115 patients over age 50 yr with a confirmed flare of Crohn's disease. Of this group, 55 patients were treated with steroids. We studied potential complications including hypertension (blood pressure > or = 160/90), hyperglycemia (glucose > 200 mg/dl), hypokalemia (K < 3.5 meq/l), mental status changes, nosocomial infections, and heart failure., Results: The mean age was 67 yr (50-90), and 64% were women. There were no differences in baseline characteristics between patients treated with steroids and those not treated with steroids. The relative risk for developing complications are as follows: hypertension 1.46 (95% confidence interval (CI) = 1.09-1.95), hyperglycemia, 1.53 (95% CI = 0.54-4.32), hypokalemia, 1.59 (95% CI = 1.06-2.37), mental status changes, 7.64 (95% CI = 0.97-60.1), nosocomial infection, 1.09 (95% CI = 0.37-3.18), and congestive heart failure, 1.09 (95% CI = 0.16-7.48). Multivariate analyses adjusting for age, severity index, and number of comorbid conditions demonstrated similar findings to the unadjusted analyses. Analyses stratified by patient age demonstrated a similar risk of steroid associated complications for patients < 65 and > or = 65 yr of age., Conclusion: Crohn's disease patients over age 50 yr treated with steroids are at significantly increased risk for developing hypertension and hypokalemia and at increased risk for developing mental status changes, but such steroid-effects were not more pronounced with advancing age.

Memory T cells are considered to be less dependent on costimulation and to respond more vigorously to TCR triggering compared to their naive counterparts. We and others, however, observed that memory CD4 T cells display nonresponsiveness to a variety of stimuli, including superantigens and soluble anti-CD3. We now report that CD28-derived costimulation can revert the nonresponsive state of antigen-exposed CD4 T cells. Interestingly, the rescuing effect of CD28 can be completely negated by CTLA-4 engagement. The malfunction of memory T cells is related to increased cell death; the viability can be restored by CD28 engagement and is negatively regulated by CTLA-4 engagement. Importantly, it has been reported that antigen-exposed T cells express lower levels of the anti-apoptotic mediator Bcl-2. In addition, CD28 costimulation was reported to upregulate the expression levels of Bcl-xL. We therefore examined the possible role of Bcl-2 family proteins in the nonresponsiveness of antigen-exposed CD4 T cells, and determined whether CTLA-4, in analogy to CD28, mediates its negative regulatory effects via the Bcl-2 family of apoptotic mediators. Our data indicate that neither the nonresponsiveness nor the susceptibility to CTLA-4 of antigen-experienced CD4 T cells are related to the expression levels of Bcl-2 or Bax. The rescuing effects of CD28, however, may be related to increased Bcl-xL levels. Addition of IL-2 normalizes the nonresponsiveness of memory CD4 T cells and renders these cells resistant to the negative effects of CTLA-4 engagement. Impaired IL-2 production is therefore likely to be the cause of the malfunction and CTLA-4 susceptibility of memory CD4 T cells.

Objective: To determine the effect of age on hospital resource use for seriously ill adults, and to explore whether age-related differences in resource use are explained by patients' severity of illness and preferences for life-extending care., Study Design: Prospective cohort study., Setting: Five geographically diverse academic acute care medical centers participating in the SUPPORT Project., Patients: A total of 4301 hospitalized adults with at least one of nine serious illnesses associated with an average 6-month mortality of 50%., Measurements: Resource utilization was measured using a modified version of the Therapeutic Intervention Scoring System (TISS); the performance of three invasive procedures (major surgery, dialysis, and right heart catheter placement); and estimated hospital costs., Results: The median patient age was 65; 43% were female, and 48% died within 6 months. After adjustment for severity of illness, prior functional status, and study site, when compared with patients younger than 50, patients 80 years or older were less likely to undergo major surgery (adjusted odds ratio .46), dialysis (.19), and right heart catheter placement (.59) and had median TISS scores and estimated hospital costs that were 3.4 points and $ 71.61 lower, respectively. These differences persisted after further adjustment for patients' preferences for life-extending care., Conclusions: Compared with similar younger patients, seriously ill older patients receive fewer invasive procedures and hospital care that is less resource-intensive and less costly. This preferential allocation of hospital services to younger patients is not based on differences in patients' severity of illness or general preferences for life-extending care.

Background: The aim of this study was to verify the presence and stability across life of the positive/negative distinction in early-onset schizophrenia (EO-SZ) through a longitudinal factor analysis of the schizophrenic dimensions, and to identify the factors predicting several indices of long-term outcome for EO-SZ., Method: Forty children consecutively referred for DSM-III-R schizophrenia (SZ) in a specific catchment area comprised the sample., Results: Across a 14.8-year follow-up, longitudinal factor analysis identified two separate factors corresponding to the positive and negative symptom dimensions. We also observed that: the GAS rated over the last three years of adult illness and the severity of negative symptoms during the stabilised interepisode intervals in adulthood were the indices of adult outcome that were most easily predicted; and the best childhood predictors of adult outcome were premorbid functioning and severity of positive and negative symptoms during acute episodes., Conclusions: The presence of premorbid non-psychotic behaviour disturbances (NPBD) and premorbid developmental problems was not related to severity of outcome, in contrast to the former variables.

Background: Little is known about the long-term outcome of schizophrenia that has its onset during childhood and early adolescence (early-onset schizophrenia, or EO-SZ). Whether or not EO-SZ is an aetiologically separate form of schizophrenia (SZ) is unresolved., Method: The study was a 14.8-year follow-up, using methods such as systematic sampling, evaluation of possible non-respondent bias, consensus best-estimate diagnoses (DSM-III-R) made independently in childhood and adulthood, measures of positive and negative dimensions, of non-psychotic behaviour disturbances (NPBD) and of developmental problems before the appearance of SZ., Results: There was high stability of EO-SZ (n = 40) diagnoses (mean onset at 14.0 years) until adulthood (mean age at follow-up 28.8 years) but a lower stability of positive and negative schizophrenic dimensions. There was a poor outcome of EO-SZ, a strong over-representation of males but few gender differences, and no effect of age of onset on clinical features and outcome., Conclusions: EO-SZ taken as a whole shows no qualitative differences to adult-onset SZ. However, a distinction through the onset of preschizophrenic developmental problems or NPBD might be a way to investigate heterogeneity within EO-SZ.

Objective: To examine the association between patient race and hospital resource use., Design: Prospective cohort study., Setting: Five geographically diverse teaching hospitals., Patients: Patients were 9,105 hospitalized adults with one of nine illnesses associated with an average 6-month mortality of 50%., Measurements and Main Results: Measures of resource use included: a modified version of the Therapeutic Intervention Scoring System (TISS); performance of any of five procedures (operation, dialysis, pulmonary artery catheterization, endoscopy, and bronchoscopy); and hospital charges, adjusted by the Medicare cost-to-charge ratio per cost center at each participating hospital. The median patient age was 65; 79% were white, 16% African-American, 3% Hispanic, and 2% other races; 47% died within 6 months. After adjusting for other sociodemographic factors, severity of illness, functional status, and study site, African-Americans were less likely to receive any of five procedures on study day 1 and 3 (adjusted odds ratio [OR] 0.70; 95% confidence interval [CI] 0.60, 0.81). In addition, African-Americans had lower TISS scores on study day 1 and 3 (OR -1.8; 95% CI-1.3, -2.4) and lower estimated costs of hospitalization (OR (-)$2,805; 95% CI (-)$1,672, (-)$3,883). Results were similar after adjustment for patients' preferences and physicians' prognostic estimates. Differences in resource use were less marked after adjusting for the specialty of the attending physician but remained significant. In a subset analysis, cardiologists were less likely to care for African-Americans with congestive heart failure (p < .001), and cardiologists used more resources (p < .001). After adjustment for other sociodemographic factors, severity of illness, functional status, and study site, survival was slightly better for African-American patients (hazard ratio 0.91; 95% CI 0.84, 0.98) than for white or other race patients., Conclusions: Seriously ill African-Americans received less resource-intensive care than other patients after adjustment for other sociodemographic factors and for severity of illness. Some of these differences may be due to differential use of subspecialists. The observed differences in resource use were not associated with a survival advantage for white or other race patients.

We recently described an mAb (MTS23) reactive with a membrane Ag expressed on a subset of thymic medullary stromal cells. This Ag is also constitutively expressed at high levels on peripheral B cells, macrophages, and thymic and splenic dendritic cells of C57BL/6 mice. A number of stromal cell lines derived from thymus and bone marrow also stain with MTS23, but thymocytes and peripheral T cells only weakly express the Ag detected by MTS23. Here we show that the molecule detected by MTS23 is a member of the Ly-6 family of phosphatidylinositol-anchored membrane proteins. Treatment of stromal cells with phosphatidylinositol-phospholipase C before staining completely abolished expression. Using transient expression of 293T cells and a cDNA library of a stromal cell line cloned into the pEF-BOS vector, a cDNA encoding the MTS23-target Ag was isolated. Partial sequencing and restriction enzyme mapping revealed that it represents the Ly-6A/E protein. While the physiologic significance of the presence of Ly-6 molecules on stromal cells is not clear, it has been known for some time that, at least in lymphocytes, cellular activation events can be induced upon Ly-6 engagement. We now demonstrate that Ly-6 also functions as a signal transduction molecule on stromal cells, in that granulocyte-macrophage CSF can be produced by a variety of stromal cell lines upon mAb-mediated cross-linking of Ly-6. Together with the dramatic up-regulation of Ly-6 expression on stromal cells upon IFN-gamma treatment, this is the first indication of a biologic function of an Ly-6 gene product on nonhemopoietic cells. The results suggest that Ly-6 may play a role in the cross-talk between lymphocyte precursors and stromal cells.

To elucidate the parameters that lead to superantigen induced non-responsiveness, an in vitro model for studying primary and secondary responses to the bacterial superantigen staphylococcal enterotoxin B (SEB) was established. Upon re-activation with SEB, in vitro SEB primed T cells show an early proliferative response that 'quenches' in time and is severely impaired 3 days after re-stimulation. Despite their overall impaired proliferative capacity and IL-2 production, these T cells are able to produce IFN-gamma and to up-regulate activation markers CD69 and IL-2R alpha upon re-stimulation with SEB, demonstrating that SEB non-responsiveness is not absolute. Rather, it reflects the inability to mount an ongoing proliferative response upon re-stimulation with SEB. Our results also demonstrate that SEB-induced non-responsiveness is not simply the result of presentation in the absence of co-stimulation, since presentation of SEB on highly purified dendritic cells during the primary response did not prevent the induction of non-responsiveness. As previously shown, SEB induces a Th1 phenotype in responding CD4+ T cells. Skewing towards a Th2 phenotype by adding IL-4 and antibodies to IFN-gamma did not prevent the induction of non-responsiveness by SEB. Interestingly, T cells pretreated with plate-bound anti-CD3 epsilon and anti-V beta 8 were also non-responsive to SEB re-stimulation. Thus, non-responsiveness to SEB (defined here as inability to produce IL-2 and proliferate) seems to reflect an intrinsic inability of previously activated T cells to respond to SEB, probably reflecting differences in signal transduction pathways used by naive versus previously activated T cells.

Objective: To develop and validate a simple prognostic scoring system to identify patients in nontraumatic coma at high risk for poor outcomes using data available early in the hospital course., Design: Prospective cohort study., Setting: Five geographically diverse academic medical centers., Patients: A total of 596 patients in nontraumatic coma enrolled in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT), including 247 in the model derivation set and 349 in the model validation set., Main Outcome Measures: Death and severe disability by 2 months., Main Results: For the 596 patients studied (median age, 67 years; 52% female), the primary cause of coma was cardiac arrest in 31% and cerebral infarction or intracerebral hemorrhage in 36%. At 2 months 69% had died, 20% had survived with known severe disability, 8% were known to have survived without severe disability, and 3% survived with unknown functional status. Five clinical variables available on day 3 after enrollment were associated independently with 2-month mortality: abnormal brain stem response (adjusted odds ratio [OR] = 3.2; 95% confidence interval [CI], 1.3 to 8.1), absent verbal response (OR = 4.6; 95% CI, 1.8 to 11.7), absent withdrawal response to pain (OR = 4.3; 95% CI, 1.7 to 10.8), creatinine level greater than or equal to 132.6 mumol/L (1.5 mg/dL) (OR = 4.5; 95% CI, 1.8 to 11.0), and age of 70 years or older (OR = 5.1; 95% CI, 2.2 to 12.2). Mortality at 2 months for patients with four or five of these risk factors was 97% (58/60; 95% CI, 88% to 100%) in the validation set. Brain stem and motor responses best predicted death or severe disability by 2 months. For patients with either an abnormal brain stem response or absent motor response to pain, the rate of death or severe disability at 2 months was 96% (185/193; 95% CI, 92% to 98%) in the validation set., Conclusions: Five readily available clinical variables identify a large subgroup of patients in nontraumatic coma at high risk for poor outcomes. This risk stratification approach offers physicians, patients, and patients' families information that may prove useful in patient care decisions and resource allocation.

Two dideoxynucleosides, 2',3'-dideoxy-beta-L-cytidine and 2',3'-dideoxy-beta-L-5-flurocytidine, containing unnatural L-configuration in their sugar moieties, were synthesized and assayed for antiviral activities. Both compounds were shown to possess potent anti-human immunodeficiency virus type 1 and antihepatitis B virus activities, while demonstrating no anti-herpes simplex viruses 1 and 2 activity. These two compounds exhibited in vitro cellular toxicities for several leukocytic cell lines and were shown to inhibit phytohemagglutinin-stimulated human peripheral blood mononuclear leukocyte proliferations. At inhibitory concentrations, both compounds caused accumulations of cells in the S phase. While demonstrating no obvious morphological toxicity in vivo in mice at concentrations of 75 and 150 mg/kg, 2',3'-dideoxy-beta-L-5-fluorocytidine- treated animals were shown to have considerable increases in CD4/CD8 double positive T lymphocyte population in their blood circulation.

A framework that has been found useful in research on young adults, Deci and Ryan's self-determination theory [1, 2], is suggested as a promising direction for research on motivation in later life. The theory proposes the existence of four types of motivation (intrinsic, self-determined extrinsic, nonself-determined extrinsic, and amotivation) which are assumed to have varying consequences for adaptation and well-being. A previously published French measure of motivational styles which is known to be reliable and valid was translated into English and was tested on seventy-seven nursing home residents (aged 60 to 98 years). It was found that the four motivational styles can be reliably measured; that the intercorrelations between the motivational styles are consistent with theoretical predictions; and that the four types of motivation are related to other important aspects of the lives of elderly people in a theoretically meaningful manner. Suggestions are made for further research using self-determination theory and the present scales.

Objective: Advocates for health care reform and others claim that significant savings could be achieved if "futile" care were eliminated. Our objective was to provide an initial estimate of the effects of a public policy that would preclude futile life-sustaining treatments, defined as those employed despite < or = 1% chance of surviving for 2 months., Design: Simulation using data from an observational cohort study., Setting: Five academic medical centers., Patients: Seriously ill hospitalized adults enrolled in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment (SUPPORT)., Methods: We examined the impact of prognosis-based futility guidelines on survival and hospital length of stay on a cohort of seriously ill adults. We calculated the number of days of hospitalization that would not be used if, on the third study day, life-sustaining treatment had been stopped or not initiated for subjects with estimated 2-month survival probability of < or = 1%., Results: Of the 4301 patients, 115 (2.7%) had an estimated chance of 2-month survival of < or = 1%. All but one of these 115 subjects died within 6 months. Almost 86% died within 5 days of prognosis. At the time of death, 92 subjects (80.0%) had had no attempt at resuscitation; 35 (30.4%) had had a life-sustaining mechanical ventilator withdrawn. A Do-Not-Resuscitate order was written either before (n = 61) or within 5 days (n = 18) of reaching this prognosis for 68.6% of the patients. These 115 subjects had total hospital charges of $8.8 million. By forgoing or withdrawing life-sustaining treatment in accord with a strict 1% futility guideline, 199 of 1,688 hospital days (10.8%) would be forgone, with estimated savings of $1.2 million in hospital charges. Nearly 75% of the savings in hospital days would have resulted from stopping treatment for 12 patients, six of whom were under 51 years old, and one of whom lived 10 months., Conclusions: Patients at a high risk of dying can be identified prospectively. Implementation of a strict, prognosis-based futility guideline on the third day of a serious illness would result in modest savings.

Two enzyme immunoassays which measure anti-group B streptococcal type III capsular carbohydrate IgG antibodies were compared. One utilised poly-L-lysine conjugated coating antigen while the other used tyraminated coating antigen. Both carbohydrate antigens appeared to be antigenically identical but the poly-L-lysine based assay gave significantly lower values for some sera. Sera were identified which had low and high avidity anti-group B streptococcal type III IgG antibodies by the thiocyanate elution method. These antibodies gave results on a dilution range of coating concentrations consistent with their relative avidity. Comparison of dilution ranges of the two conjugates used for coating suggests that the poly-L-lysine conjugate coats with a ten-fold lower efficiency than the tyramine conjugate and therefore detects only higher avidity antibodies. Four fractions containing different relative avidities of affinity-purified IgG were produced from a single serum. These fractions behaved in the same manner as sera containing antibodies of different avidities. The results of this study suggest that the method of polysaccharide conjugation in enzyme immunoassays may affect the antigen concentration on the solid phase and thence the detection of antibodies of various avidities.

We describe a psychosocial intervention program designed to enhance coping with the stress associated with HIV infection. The NUCARE intervention program is based on six components of coping including: cognitive reframing, problem-solving, relaxation, goal setting, social support and use of resources and services. The rationale and development of the intervention is discussed and practical case examples illustrating the benefits of each component are presented.

The frequency, nature, context, and caregivers' reactions to aggressive behavior in 213 dementia patients residing in the community was studied. Aggression was reported in 57.2% of the patients and in 10.6% of the caregivers. Predictors of patient aggression were greater frequency of behavior and memory problems, premorbid aggression, and a more troubled premorbid social relationship between patient and caregiver. Patient aggression predicted the decision to discontinue home care.

We have isolated drug-resistant variants from adenovirus-transformed rat cells that had concomitantly lost their transformed phenotype. Our aim was to determine the reason for reversion, to attempt retransformation with 5-azacytidine (5-AzaC) and to study the mechanism of retransformation. Of the three cell lines studied, one (G4F) had lost the integrated E1a genes, whereas the other two (G2a and G5) failed to synthesize E1a RNA or proteins. Incubation of these cell lines with 3 microM-5-AzaC for 2 days, followed by passaging in the absence of drug, gave rise to transformed foci in all of the cell lines. The efficiency of transformation was typical of each cell line. Surprisingly, retransformation was not accompanied by the reappearance of detectable levels of E1a gene activity in the G2aAza and G5Aza cell lines. In search of a mechanistic explanation for the loss of gene activity in the revertants and its reappearance in the retransformants, we examined the state of methylation of the E1a gene region in these cells. Neither the E1a promoter nor its upstream region was methylated in the revertants or the 5-AzaC retransformants. These results suggest that E1a transcription was suppressed by mechanisms other than DNA methylation and that 5-AzaC could retransform these cells without lifting the E1a-suppressed state.

Eighty-one black-handed tamarins from the Tucurui region were tested for human type ABO blood groups by salivary inhibition tests. Eleven belonged to the A group, 45 to B, and 25 to AB. The serum samples were tested for the presence of agglutinins having specificities like those of humans. The ABO system appeared to be polymorphic, with three alleles occurring at the following frequencies: A = 0.26, B = 0.66, and O = 0.08. The observed distribution fitted the expected on the basis of Hardy-Weinberg equilibrium.