Aerosolized lipopolysaccharide increases pulmonary clearance of 99mTc-DTPA in rabbits.

Bacterial endotoxins alter the permeability of endothelium, but little is known of their effect on epithelium. We exposed specific pathogen-free rabbits to aerosolized Pseudomonas aeruginosa LPS or saline and performed serial measurements of RL, Cdyn, BP, WBC count and differential, and platelet counts. Pulmonary 99mTc-DTPA half-life was measured 4, 6, or 8 h after exposure. The animals were sacrificed and BAL performed. Background and PMA-stimulated superoxide production was measured from individual AM using electrooptical determination of reduction of NBT. Lung tissue was processed for light microscopy and ratio of wet to dry weight. 99mTc-DTPA half-life was significantly shorter in LPS-exposed animals at 6 h (p < 0.05) and 8 h (p < 0.001). There were no differences in Cdyn, RL, BP, WBC, differential, platelet, or BAL cell count at any time between groups. No histologic changes or differences in lung wet to dry weight ratios were found. PMA-stimulated AM superoxide production was significantly increased (p < 0.01) in LPS-exposed animals. This effect was time dependent and could be duplicated in AM from control animals following a 4-h incubation with LPS, lavage fluid from LPS-exposed animals, or recombinant murine TNF. These results demonstrate that aerosolized Pseudomonas LPS increases pulmonary epithelial permeability and primes AM superoxide production.     

The effect of hemodialysis and C5a des arg on neutrophil subpopulations

Alterations in neutrophil subpopulations during human hemodialysis or following injection of C5a des arg into rabbits were studied. Whereas baseline peripheral blood neutrophils contained approximately 80% of cells that formed rosettes with IgG-sensitized erythrocytes, neutrophils harvested at the granulocyte nadir (20 min after initiating hemodialysis or the injection of C5a des arg) were markedly depleted of this population. This was seen in a change in ratio of rosette-forming neutrophils (RFN) to non-rosette-forming neutrophils (non-RFN) from 4:1 at 0 time to 1:2 at 20 min. Since non-RFN are less active in assays of adherence and chemotaxis, these alterations in circulating neutrophil populations were reflected in abnormal functional capacity of neutrophils harvested at 20 min. To study the mechanism of RFN depletion, we investigated the ability of C5a des arg to aggregate various human neutrophil suspensions. Unfractionated neutrophils and RFN demonstrated prompt in vitro aggregation in response to C5a des arg, whereas this activated complement fragment induced little aggregation in a population enriched for non-RFN. These results may explain the alterations in neutrophil adherence, chemotaxis, phagocytosis, and bactericidal activity, which have been reported to accompany clinical disorders characterized by in vivo complement activation (i.e., hemodialysis or gram-negative sepsis).     

Fear of falling in older women: a longitudinal study of incidence, persistence, and predictors

OBJECTIVES: To determine longitudinal predictors of incident and persistent fear of falling (FOF) in older women. DESIGN: Longitudinal study. SETTING: Clinical research center based at a university hospital. PARTICIPANTS: One thousand two hundred eighty-two community-dwelling women aged 70 to 85. MEASUREMENTS: FOF at baseline and after 3 years of follow-up; a range of baseline demographic and clinical variables, including mobility, balance, and depression. RESULTS: FOF was present in 418 subjects (33%) at baseline, developed in 30% of women who had been free of the symptom at baseline, and was reported by a total of 46% of the sample after 3 years of follow-up. In cross-sectional multivariable analysis, baseline FOF was independently associated with a range of variables, including living alone, obesity, cognitive impairment, depression, and impairments in balance and mobility. Baseline predictors of FOF that persisted after 3 years were similar, whereas obesity and slower timed up and go test scores predicted new-onset FOF. CONCLUSION: FOF in older women is a common and persistent complaint that is caused mainly by impairments of balance and mobility. A range of social, psychological, and physical risk factors for disability are associated with persistence of FOF. These results imply that early intervention may be important for the prevention of persistent FOF.     

Platelet glycoproteins IIb and IIIa as a calcium channel in liposomes

Human platelet membrane glycoproteins IIb and IIIa (GPIIb and IIIa) were incorporated into phospholipid vesicles by the reverse-phase technique to assess the ability of GPIIb and IIIa to function as a Ca2+ channel. Movement of Ca2+ across the lipid bilayer was quantitated by injection of proteoliposomes with encapsulated Fura-2 into Ca2+ buffers and measurement of Fura-2 fluorescence as an indicator of Ca2+ influx. Reciprocally, to assess the function of proteins in an inside-out orientation, Ca2+-loaded vesicles were injected into Ca2+-free buffer and Ca2+ efflux monitored by a calcium electrode. Incorporation of the IIb-IIIa complex produced significant facilitation of Ca2+ movement across the lipid bilayer. No net transmembrane Ca2+ movement was seen with dissociated IIb and IIIa. Movement of Ca2+ was proportional to the transmembrane Ca2+ gradient. Ca2+ movement into the vesicles was inversely proportional to extravesicular NaCl from 25 to 150 mmol/L, analogous to several studies in the intact platelet. Adenosine triphosphate had no effect on Ca2+ movement into or out of the vesicles. Specific inhibition of a Ca2+ shift into the vesicles was seen with M148, a monoclonal antibody to IIb/IIIa, while no inhibition was observed with a panel of other anti-IIb/IIIa monoclonal antibodies. This suggests that a specific site on the complex or orientation of the complex is essential for calcium channel function. These data demonstrate that the GPIIb/IIIa complex can serve as a passive Ca2+ channel across a phospholipid bilayer and has the potential to play a role in Ca2+ flux across the platelet plasma membrane.     

Mobilizing stem cells from normal donors: is it possible to improve upon G-CSF?

Currently, granulocyte colony stimulating factor (G-CSF) remains the standard mobilizing agent for peripheral blood stem cell (PBSC) donors, allowing the safe collection of adequate PBSCs from the vast majority of donors. However, G-CSF mobilization can be associated with some significant side effects and requires a multi-day dosing regimen. The other cytokine approved for stem cell mobilization, granulocyte-macrophage colony stimulating factor (GM-CSF), alters graft composition and may reduce the development of graft-versus-host disease, but a significant minority of donors fails to provide sufficient CD34+ cells with GM-CSF and some experience unacceptable toxicity. AMD3100 is a promising new mobilizing agent, which may have several advantages over G-CSF for donor mobilization. As it is a direct antagonist of the interaction between the chemokine stromal-derived factor-1 and its receptor CXCR4, AMD3100 mobilizes PBSCs within hours rather than days. It is also well tolerated, with no significant side effects reported in any of the clinical trials to date. Studies of autologous and allogeneic transplantation of AMD3100 mobilized grafts have demonstrated prompt and stable engraftment. Here, we review the current state of stem cell mobilization in normal donors and discuss novel strategies for donor stem cell mobilization.     

Chronic heart failure in the community: missed diagnosis and missed opportunities

BACKGROUND: The aim of this study was to determine the incidence of congestive heart failure (CHF) in patients discharged from a hospital without a diagnosis of CHF who were admitted with shortness of breath and had a low left ventricular ejection fraction (LVEF). CHF is a devastating disease in terms of financial cost, prevalence, and effect on morbidity and mortality. The true incidence rate is not known because of reliance on discharge records and death certificates, and because diagnosis remains a clinical judgment. METHODS AND RESULTS: CHF was diagnosed by the Framingham criteria. We retrospectively reviewed the records of 225 randomly selected patients admitted with a complaint of shortness of breath and discharged without a diagnosis of CHF (group 1). We compared group 1 with patients admitted at the same time with a diagnosis of CHF and of similar age and LVEF (group 2). In group 1, 100 patients had a low LVEF (< or =40%) and 51% met criteria for CHF that had been missed. Readmission rate was high (42%). Mortality at 12 months was 18%. Rate of cardiomegaly on x-ray films was similar in groups 1 and 2 (64.6% v 64.4%, respectively). Third heart sound (39% v 10%; P <.001) and heart rate > 120 beats/min (41.7% v 12.5%; P <.001) were significantly more frequent in group 1. By contrast, signs and symptoms suggestive of fluid overload were more frequent in group 2. CONCLUSIONS: Many patients admitted with shortness of breath and low LVEF have CHF but are not diagnosed. Physicians are more likely to miss CHF in patients presenting without signs of fluid overload even when third heart sound is present with resting tachycardia. A missed diagnosis of CHF is associated with a high readmission rate, multiple admissions, and a mortality rate comparable to that of patients with newly diagnosed CHF.