Citations

AbstractHigh-dose melphalan followed by stem cell transplantation (HDM-SCT) has become the treatment of choice for patients with immunoglobulin light chain amyloidosis (AL). Unfortunately, treatment mortality can be excessive in certain subpopulations. We have noted that patients who gained more than 2% body weight during mobilization had a poorer outcome following HDM-SCT. Excluding 2 patients for lack of weight record and denial of consent, 126 patients between July 1997 and June 2003 were retrospectively studied. Weight increased more than 2.0% during mobilization in 51.6% of the patients. Patients who accumulated more than 2.0% tended to have more proteinuria, more organs involved, lower serum albumin, more diuretic use, and dosage adjustment during mobilization. First-year mortality was significantly higher in those with more than 2% weight gain (33.9% versus 9.8%, P = .002). Multivariate analysis showed weight gain, glomerular filtration rate, and septal thickness to be independent predictors of first-year mortality. The increase in mortality was noted even after the excess weight was diuresed prior to conditioning. The impact on mortality dissipated after the first year. Weight gain during mobilization appears to be a new marker of adverse outcome following HDM-SCT. Better prognostication may improve the treatment mortality rate of these patients.

ABSTRACT Although electrical coupling along the arteriolar endothelium is central in arteriolar conducted response and in control of vascular resistance, little is known about the pathophysiological effect of hypoxia and reoxygenation (H/R) on this coupling. We examined this effect in a monolayer of cultured microvascular endothelial cells (ECs) derived from wild‐type (WT) or connexin (Cx)40 −/− mice (Cx40 is a key gap junction protein in ECs). To assess electrical coupling, we used a current injection technique and Bessel function model to compute the monolayer intercellular resistance. Hypoxia (0.1% O 2 , 1 h) followed by abrupt reoxygenation (5–90 min) reduced coupling (i.e., increased resistance) in WT but not in Cx40 −/− monolayer. H/R increased superoxide production and reduced protein kinase A (PKA) activity in both monolayers. Activation of PKA by 8‐bromo‐cAMP prevented the reduction in coupling. Preloading of the WT monolayer with the antioxidant ascorbate prevented reductions in both PKA activity and cell coupling. Inhibition of PKA with 6–22 amide during normoxia mimicked the reduction in coupling. Finally, hypoxia followed by slow reoxygenation caused no change in superoxide level, PKA activity, or coupling. Using intravital microscopy, we assessed the physiological relevance of these findings in terms of KCl‐induced conducted vasoconstriction in arterioles of WT mouse cremaster muscle in vivo. Ischemia (1 h) followed by abrupt reperfusion (15–30 min) reduced conduction. 8‐bromo‐cAMP prevented this reduction, while 6–22 amide mimicked this reduction in control nonischemic arterioles. We propose that abrupt reoxygenation reduces interendothelial electrical coupling via oxidant‐ and PKA‐dependent signaling that targets Cx40. We suggest that this mechanism contributes to compromised arteriolar function after H/R.

A recombinant measles virus (MV) expressing red fluorescent protein (MVDsRed1) was used to produce a persistently infected cell line (piNT2-MVDsRed1) from human neural precursor (NT2) cells. A similar cell line (piNT2-MVeGFP) was generated using a virus that expresses enhanced green fluorescent protein. Intracytoplasmic inclusions containing the viral nucleocapsid protein were evident in all cells and viral glycoproteins were present at the cell surface. Nevertheless, the cells did not release infectious virus nor did they fuse to generate syncytia. Uninfected NT2 cells express the MV receptor CD46 uniformly over their surface, whereas CD46 was present in cell surface aggregates in the piNT2 cells. There was no decrease in the overall amount of CD46 in piNT2 compared to NT2 cells. Cell-to-cell fusion was observed when piNT2 cells were overlaid onto confluent monolayers of MV receptor-positive cells, indicating that the viral glycoproteins were correctly folded and processed. Infectious virus was released from the underlying cells, indicating that persistence was not due to gross mutations in the virus genome. Persistently infected cells were superinfected with MV or canine distemper virus and cytopathic effects were not observed. However, mumps virus could readily infect the cells, indicating that superinfection immunity is not caused by general soluble antiviral factors. As MVeGFP and MVDsRed1 are antigenically indistinguishable but phenotypically distinct it was possible to use them to measure the degree of superinfection immunity in the absence of any cytopathic effect. Only small numbers of non-fusing green fluorescent piNT2-MVDsRed1 cells (1 : 300 000) were identified in which superinfecting MVeGFP entered, replicated and expressed its genes.

AbstractThe clinical efficacy of evaluating genetic anomalies in metaphase cells versus interphase nuclei for multiple myeloma (MM) is poorly understood. Therefore, survival for 154 patients with newly diagnosed untreated MM was compared with results from analysis of metaphase and interphase cells. Metaphases were studied by conventional cytogenetics and fluorescent-labeled DNA probes (fluorescence in situ hybridization [FISH]), whereas inter-phase nuclei were evaluated only by FISH. All FISH studies were done using DNA probes to detect t(4;14)(p16;q32), t(11;14)(q13;q32), t(14;16)(q32;q23), del(17) (p13.1), and chromosome 13 anomalies. Metaphases were abnormal by cytogenetics and/or metaphase FISH in 61 (40%) patients. Abnormal interphase nuclei were observed in 133 (86%) patients, including each patient with abnormal metaphases. FISH was a necessary adjunct to cytogenetics to detect t(4;14) and t(14;16) in metaphase cells. Patient survival was especially poor for patients with greater than 50% abnormal interphase nuclei, although this result was more likely due to level of plasma cells than specific chromosome anomalies. For metaphase data, patients with t(4;14), t(14;16), del(17) (p13.1), and/or chromosome 13 anomalies (primarily monosomy 13) had poor survival. A different outcome was observed for interphase data as patients with t(4;14) or t(14;16) had poor survival, whereas patients with chromosome 13 anomalies had intermediate survival: interphase FISH did not substitute for metaphase analysis.

Background— Sympathetic and parasympathetic systems are considered the principal rapidly reacting systems that control heart rate. Methods and Results— We propose a symbolic analysis series to quantify the prevalence of sympathetic or parasympathetic cardiac modulation. This analysis decomposes the heart rate variability series in patterns lasting 3 beats and classifies them into 3 categories: nonvariable, variable, and very variable patterns referred to as 0V, 1V, and 2V patterns. First, we applied this method to experimental and pharmacological conditions characterized by sympathetic activation (tilt test, handgrip, nitroprusside, and high-dose atropine administration) or parasympathetic activation (phenylephrine and low-dose atropine administration) in 60 healthy subjects. An increase in sympathetic modulation and a vagal withdrawal elicited a significant increase in 0V patterns and a decrease in 2V patterns, whereas parasympathetic dominance induced the opposite, reflecting a reciprocal sympathovagal balance. The second part of the study considered a series of 300 beats before the onset of major arrhythmic events in patients with an implantable cardioverter-defibrillator. Symbolic analysis detected an increase in the percentage of 0V patterns before the onset of major arrhythmias compared with baseline (41.6±3.9% and 24.4±2.9%, respectively; P <0.01), indicating a sympathetic prevalence. On the other hand, the 2V patterns did not decrease before major arrhythmias, suggesting the presence of nonreciprocal autonomic modulations. Conclusions— Symbolic analysis of 3 beat sequences takes into account the different time course of sympathetic and parasympathetic cardiac modulations and seems appropriate for elucidating the neural pathophysiological mechanisms occurring during the short periods that precede acute cardiac events.

Abstract Bortezomib, a potent and reversible proteasome inhibitor, affects the myeloma cell and its microenvironment, resulting in down-regulation of growth and survival signaling pathways and durable responses in patients with relapsed and refractory myeloma. Potential associations between baseline parameters and outcomes with bortezomib were explored in 202 patients who received bortezomib 1.3 mg/m2 twice weekly for 2 weeks every 3 weeks for up to 8 cycles in a phase 2 trial. Using European Group for Blood and Marrow Transplantation criteria, the response rate (complete or partial response) to bortezomib alone was 27% and was not associated with sex, race, performance status, isotype, chromosome 13 deletion, number or type of previous therapies, or concentration of hemoglobin or β2-microglobulin. By multivariate analysis, factors associated with lower response were being age 65 or older versus younger than 65 (19% vs 32%; P &lt; .05) and plasma-cell infiltration in bone marrow greater than 50% versus 50% or less (20% vs 35%; P &lt; .05). Factors that may be indicative of tumor burden (bone marrow plasma-cell infiltration greater than 50%, hypoalbuminemia, thrombocytopenia) were predictive of overall survival. Chromosome 13 deletion and elevated β2-microglobulin, generally considered poor prognostic factors, were not predictive of poor outcome with bortezomib in this study.

Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patients with neurodegenerative diseases and have been implicated in mediating neuronal death and cognitive deficits. Here, we found that mice expressing a repressible human tau variant developed progressive age-related NFTs, neuronal loss, and behavioral impairments. After the suppression of transgenic tau, memory function recovered, and neuron numbers stabilized, but to our surprise, NFTs continued to accumulate. Thus, NFTs are not sufficient to cause cognitive decline or neuronal death in this model of tauopathy.

The National Cancer Institute’s Cancer Patient Education Network (CPEN) is composed of cancer education leaders from National Cancer Institute (NCI)-designated comprehensive and clinical cancer centers throughout the United States. Despite this commonality, the role and responsibilities of CPEN members vary across institutions. In an effort to further understand the common-alties and variances among the membership, the authors undertook a research project addressing salary and budget issues across NCI-designated cancer centers. The purpose of this study was to benchmark salaries and budgets of cancer educators at NCI-designated cancer centers; provide information to support a competitive salary range based on benchmarking with peers responsible for cancer patient education; and glean information on CPEN membership, roles, education levels, and job functions. This article highlights lessons learned and offers suggestions for using this information in a broader capacity for other cancer patient educators and patient educators in general.