beta-amyloid peptide (Abeta) is the primary constituent of senile plaques, a defining feature of Alzheimer's disease. Aggregated Abeta is toxic to neurons, but the mechanism of toxicity remains unproven. One proposal is that Abeta toxicity results from relatively nonspecific Abeta-membrane interactions. We hypothesized that Abeta perturbs membrane structure as a function of the aggregation state of Abeta. Toward exploring this hypothesis, Abeta aggregate size and hydrophobicity were characterized using dynamic and static light scattering and 1,1-bis(4-anilino)naphthalene-5,5-disulfonic acid (bis-ANS) fluorescence. The effect of Abeta aggregation state on the membrane fluidity of unilamellar liposomes was assessed by monitoring the anisotropy of the membrane-embedded fluorescent dye, 1,6-diphenyl-1,3,5-hexatriene (DPH). Unaggregated Abeta at pH 7 did not bind bis-ANS and had little to no effect on membrane fluidity. More significantly, Abeta aggregated at pH 6 or 7 decreased membrane fluidity in a time- and dose-dependent manner. Aggregation rate and surface hydrophobicity were considerably greater for Abeta aggregated at pH 6 than at neutral pH and were strongly correlated with the extent of decrease in membrane fluidity. Prolonged (7 days) Abeta aggregation resulted in a return to near-baseline levels in both bis-ANS fluorescence and DPH anisotropy at pH 7 but not at pH 6. The addition of gangliosides to the liposomes significantly increased the DPH anisotropy response. Hence, self-association of Abeta monomers into aggregates exposes hydrophobic sites and induces a decrease in membrane fluidity. Abeta aggregate-induced changes in membrane physical properties may have deleterious consequences on cellular functioning.

BACKGROUND AND OBJECTIVES: Children with medical complexity (CMC) account for disproportionately high hospital use, and it is unknown if hospitalizations may be prevented. Our objective was to summarize evidence from (1) studies characterizing potentially preventable hospitalizations in CMC and (2) interventions aiming to reduce such hospitalizations. METHODS:Our data sources include Medline, Cochrane Central Register of Controlled Trials, Web of Science, and Cumulative Index to Nursing and Allied Health Literature databases from their originations, and hand search of article bibliographies. Observational studies (n = 13) characterized potentially preventable hospitalizations, and experimental studies (n = 4) evaluated the efficacy of interventions to reduce them. Data were extracted on patient and family characteristics, medical complexity and preventable hospitalization indicators, hospitalization rates, costs, and days. Results of interventions were summarized by their effect on changes in hospital use. RESULTS:Preventable hospitalizations were measured in 3 ways: ambulatory care sensitive conditions, readmissions, or investigator-defined criteria. Postsurgical patients, those with neurologic disorders, and those with medical devices had higher preventable hospitalization rates, as did those with public insurance and nonwhite race/ethnicity. Passive smoke exposure, nonadherence to medications, and lack of follow-up after discharge were additional risks. Hospitalizations for ambulatory care sensitive conditions were less common in more complex patients. Patients receiving home visits, care coordination, chronic care-management, and continuity across settings had fewer preventable hospitalizations.CONCLUSIONS: There were a limited number of published studies. Measures for CMC and preventable hospitalizations were heterogeneous. Risk of bias was moderate due primarily to limited controlled experimental designs. Reductions in hospital use among CMC might be possible. Strategies should target primary drivers of preventable hospitalizations.

beta-Amyloid peptide (A beta) is the primary constituent of senile plaques, a defining feature of Alzheimer's disease. Aggregated A beta is toxic to neurons, but the mechanism of toxicity is uncertain. One hypothesis is that interactions between A beta aggregates and cell membranes mediate A beta toxicity. Previously, we described a positive correlation between the A beta aggregation state and surface hydrophobicity, and the ability of the peptide to decrease fluidity in the center of the membrane bilayer [Kremer, J. J., et al. (2000) Biochemistry 39, 10309--10318]. In this work, we report that A beta aggregates increased the steady-state anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) embedded in the hydrophobic center of the membrane in phospholipids with anionic, cationic, and zwitterionic headgroups, suggesting that specific charge--charge interactions are not required for A beta--membrane interactions. A beta did not affect the fluorescence lifetime of DPH, indicating that the increase in anisotropy is due to increased ordering of the phospholipid acyl chains rather than changes in water penetration into the bilayer interior. A beta aggregates affected membrane fluidity above, but not below, the lipid phase-transition temperature and did not alter the temperature or enthalpy of the phospholipid phase transition. A beta induced little to no change in membrane structure or water penetration near the bilayer surface. Overall, these results suggest that exposed hydrophobic patches on the A beta aggregates interact with the hydrophobic core of the lipid bilayer, leading to a reduction in membrane fluidity. Decreases in membrane fluidity could hamper functioning of cell surface receptors and ion channel proteins; such decreases have been associated with cellular toxicity.

clinicaltrials.gov Identifier: NCT00632775.

Background National guidelines recommend 10 days of antibiotics for children with community-acquired pneumonia (CAP), acknowledging that the outcomes of children hospitalized with CAP who receive shorter durations of therapy have not been evaluated. Methods We conducted a comparative effectiveness study of children aged ≥6 months hospitalized at The Johns Hopkins Hospital who received short-course (5–7 days) vs prolonged-course (8–14 days) antibiotic therapy for uncomplicated CAP between 2012 and 2018 using an inverse probability of treatment weighted propensity score analysis. Inclusion was limited to children with clinical and radiographic criteria consistent with CAP, as adjudicated by 2 infectious diseases physicians. Children with tracheostomies; healthcare-associated, hospital-acquired, or ventilator-associated pneumonia; loculated or moderate to large pleural effusion or pulmonary abscess; intensive care unit stay >48 hours; cystic fibrosis/bronchiectasis; severe immunosuppression; or unusual pathogens were excluded. The primary outcome was treatment failure, a composite of unanticipated emergency department visits, outpatient visits, hospital readmissions, or death (all determined to be likely attributable to bacterial pneumonia) within 30 days after completing antibiotic therapy. Results Four hundred and thirty-nine patients met eligibility criteria; 168 (38%) patients received short-course therapy (median, 6 days) and 271 (62%) received prolonged-course therapy (median, 10 days). Four percent of children experienced treatment failure, with no differences observed between patients who received short-course vs prolonged-course antibiotic therapy (odds ratio, 0.48; 95% confidence interval, .18–1.30). Conclusions A short course of antibiotic therapy (approximately 5 days) does not increase the odds of 30-day treatment failure compared with longer courses for hospitalized children with uncomplicated CAP.