Citations

Abstract Background: Objective methods to assess the adequacy of medication therapy for patients with advanced heart failure are lacking. Serial measurements of biomarkers might be beneficial. Therapy guided by N-terminal pro-B-type natriuretic peptide (NT-proBNP) might be helpful because NT-proBNP should be lowered by therapies that decrease endogenous BNP secretion. Methods: NT-proBNP and BNP were measured in a nonconsecutive patient cohort receiving clinically indicated intravenous nesiritide. Blood samples were drawn before, at 6 and 24 h during, and at 6 h after infusion. A reduction in NT-proBNP was defined as a decrease from baseline during infusion (“infusion responders”) of >3 SD of the variability of the assay measurement (∼20%). Patients with decreases >20% in both NT-pro BNP and BNP at 6 h post infusion were designated “biochemical responders”. Results: Forty patients [27 males; mean (SE) age, 68 (2) years; mean (SE) left ventricular ejection fraction, 25 (1.4)%] were studied. All patients improved clinically. Overall, the changes in NT-proBNP were a 18 (4.6)% [mean (SE)] and 19.8% (median) decrease from baseline at 24 h of infusion and a 22 (6.0)% and 17.8% decrease at 6 h post infusion (P <0.001 compared with baseline). In a large number of patients, decreases in NT-proBNP were, however, within the variability of the assay. Subgroup analysis showed that 22 of 40 patients were infusion responders with a >20% decrease from baseline in NT-proBNP during nesiritide infusion, whereas only 12 patients were biochemical responders with >20% decreases from baseline postinfusion for both NT-proBNP and BNP. Conclusions: In this study, many patients had decreased NT-proBNP and BNP values after therapy with nesiritide, but the majority of patients did not demonstrate biochemically significant decreases in analytes despite a clinical response. Until we know more about the responses of natriuretic peptides to therapies such as nesiritide, a strategy of monitoring NT-proBNP and BNP to guide therapy cannot be universally advocated.

There is a major deficiency in the end-of-life care offered to patients dying in the intensive care unit (ICU). Hypothesis: Hospitalized dying patients had informed discussions on endof-life and palliative care options before admission to ICU. Patients and methods: A descriptive non-interventional study was performed at a teaching hospital to examine if patients who died in hospital had informed discussions on end-of-life care before admission to ICU. The impact of these discussions on subsequent patient care: aggressive therapy in the ICU, the quality of palliation, use of hospice care services and utilization of hospital resources were examined. Data were collected from medical records for all hospital deaths over 24 months. Results: Of 252 hospital deaths, 196 (78%) were treated and subsequently 165 (65%) died in the ICU. Patients treated either in the ICU or general hospital wards had similar frequency of ultimately or rapidly fatal pre-existing disease (47% versus 62%, P: ns) and readmission to hospital within one year before death (43% versus 57%, P, ns). The median age (10-90% percentile) was slightly younger for the ICU than hospital wards patients: 73 (45-85) versus 76 (55-91) years, PB / 0.01. Of the 156 patients who were transferred to ICU from hospital wards: 136 (87%) were managed by house staff on teaching services and 20 (13%) were managed by attending staff hospitalists, PB / 0.01. None of those transferred to the ICU who subsequently died had discussion of palliation or end-of-life care as an alternative treatment. Of those who died who were treated on general wards, 14 (25%) patients had discussion of palliation as an alternative treatment option before death. Do-not-resuscitate decisions were made in 48% of cases two days before death. Patients who were treated in the ICU had more invasive tests performed on them and were less likely to have adequate pain control or referral to hospice care services than on a general ward. Median hospital charge was much higher for patients who received ICU versus general ward care ($33 252 versus $8549, PB / 0.001). Conclusions: Patients who died in the ICU did not have informed discussions of end-of-life or palliative care as an alternative treatment option before admission. The quality of end-of-life care was disrupted for patients with fatal pre-existing chronic disease who were admitted to the ICU before death. Lack of clinical experience, knowledge and competency with end-of-life care influenced admission of patients to ICU regardless of poor prognosis. Decisions regarding the pursuit of aggressive therapy versus palliative care must be addressed with patients by physicians who are competent and experienced in end-of-life care as this will have a profound impact on both the quality of care delivered and effective use of limited hospital resources.

ABSTRACTThe subgroup A to E avian sarcoma and leukosis viruses (ASLVs) are highly related and are thought to have evolved from a common ancestor. These viruses use distinct cell surface proteins as receptors to gain entry into avian cells. Chickens have evolved resistance to infection by the ASLVs. We have identified the mutations responsible for the block to virus entry in chicken lines resistant to infection by subgroup A ASLVs [ASLV(A)]. Thetvagenetic locus determines the susceptibility of chicken cells to ASLV(A) viruses. In quail, the ASLV(A) susceptibility alleletvasencodes two forms of the Tva receptor; these proteins are translated from alternatively spliced mRNAs. The normal cellular function of the Tva receptor is unknown; however, the extracellular domain contains a 40-amino-acid, cysteine-rich region that is homologous to the ligand binding region of the low-density lipoprotein receptor (LDLR) proteins. The chickentvascDNAs had not yet been fully characterized; we cloned the chickentvacDNAs from two lines of subgroup A-susceptible chickens, line H6 and line 0. Two types of chickentvascDNAs were obtained. These cDNAs encode a longer and shorter form of the Tva receptor homologous to the Tva forms in quail. Two different defects were identified in cDNAs cloned from two different ASLV(A)-resistant inbred chickens, line C and line 72. Line Ctvarcontains a single base pair substitution, resulting in a cysteine-to-tryptophan change in the LDLR-like region of Tva. This mutation drastically reduces the binding affinity of TvaRfor the ASLV(A) envelope glycoproteins. Line 72tvar2contains a 4-bp insertion in exon 1 that causes a change in the reading frame, which blocks expression of the Tva receptor.

Abstract The present study tests the intuition that successful aging in men is marked by: 1) impaired feedforward by endogenous LH concentrations (con) of testosterone (Te) secretion (sec); and/or 2) attenuated feedback by unmanipulated Te con of LH sec. The goal was to assess both implicit linkages analytically without disrupting normal pathway coupling. This strategy required: 1) assay of paired LH and Te con sampled every 10 min for 24 h in 13 older (O) (ages 60–78 yr) and 13 young (Y) (ages 18–30 yr) men; 2) deconvolution-based estimation of LH and Te sec rates; 3) lag-specific cross-correlation analyses of the relationships between LH and Te con and sec; and 4) statistical contrasts by age stratum. Salient outcomes were: 1) O and Y men maintain comparable LH con drive of Te sec, viz maximal r = +0.51 and r = +0.52, respectively, at an optimal time lag of 50 min (both P < 0.001 against random LH and Te associations); 2) elderly subjects exhibit reduced Te con inhibition of LH sec [minimal r = −0.008 (O) vs. r = −0.10 (Y), P < 0.01 at a time lag of 40 min]; 3) mean (24-h) LH con do not differ by age; and 4) molar Te/sex hormone-binding globulin con are lower in the elderly than in Y individuals (P < 0.01). In conclusion, noninvasive analyses predict that attenuation of endogenous Te feedback restraint on the hypothalamo-pituitary unit may be an early biological marker of adaptive changes in the GnRH-LH-Te ensemble axis in the healthy O male.

Background— Coronary bypass surgery (CABG) and angioplasty (PTCA) have been compared in several randomized trials, but data about long-term economic and quality-of-life outcomes are limited. Methods and Results— Cost and quality-of-life data were collected prospectively from 934 patients who were randomized in the Bypass Angioplasty Revascularization Investigation (BARI) and followed up for 10 to12 years. CABG had 53% higher costs initially, but the gap closed to <5% during the first 2 years; after 12 years, the mean cumulative cost of CABG patients was $123 000 versus $120 750 for PTCA, yielding a cost-effectiveness ratio of $14 300/life-year added. CABG patients experienced significantly greater improvement in their physical functioning for the first 3 years but not in later follow-up. Recurrent angina substantially reduced all quality-of-life measures throughout follow-up. Cumulative costs were significantly higher among patients with diabetes, heart failure, and comorbid conditions and among women; costs also were increased by angina, by the number of revascularization procedures, and among patients who died. Conclusion— Early differences between CABG and PTCA in costs and quality of life were no longer significant at 10 to 12 years of follow-up. CABG was cost-effective as compared with PTCA for multivessel disease.

The mechanisms underlying CD4+ T cell depletion in human immunodeficiency virus (HIV) infection are not well understood. Comparative studies of lymphoid tissues, where the vast majority of T cells reside, and peripheral blood can potentially illuminate the pathogenesis of HIV-associated disease. Here, we studied the effect of HIV infection on the activation and depletion of defined subsets of CD4+ and CD8+ T cells in the blood, gastrointestinal (GI) tract, and lymph node (LN). We also measured HIV-specific T cell frequencies in LNs and blood, and LN collagen deposition to define architectural changes associated with chronic inflammation. The major findings to emerge are the following: the GI tract has the most substantial CD4+ T cell depletion at all stages of HIV disease; this depletion occurs preferentially within CCR5+ CD4+ T cells; HIV-associated immune activation results in abnormal accumulation of effector-type T cells within LNs; HIV-specific T cells in LNs do not account for all effector T cells; and T cell activation in LNs is associated with abnormal collagen deposition. Taken together, these findings define the nature and extent of CD4+ T cell depletion in lymphoid tissue and point to mechanisms of profound depletion of specific T cell subsets related to elimination of CCR5+ CD4+ T cell targets and disruption of T cell homeostasis that accompanies chronic immune activation.

Objective. Sexual behavior in children can cause uncertainty in the clinician because of the relationship between sexual abuse and sexual behavior. Consequently, it is important to understand normative childhood sexual behavior. Design. Sexual behavior in 1114 2- to 12-year-old children was rated by primary female caregivers. These children were screened for the absence of sexual abuse. A 38-item scale assessing a broad range of sexual behavior (Child Sexual Behavior Inventory, Third Version) was administered along with the Child Behavior Checklist and a questionnaire assessing family stress, family sexuality, social maturity of the child, maternal attitudes regarding child sexuality, and hours in day care. Results. Sexual behavior was related to the child's age, maternal education, family sexuality, family stress, family violence, and hours/week in day care. Frequencies of sexual behaviors for 2- to 5-, 6- to 9-, and 10- to 12-year-old boys and girls are presented. Conclusions. A broad range of sexual behaviors are exhibited by children who there is no reason to believe have been sexually abused. Their relative frequency is similar to two earlier studies, and this reinforces the validity of these results.