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Amyloid beta-protein (Abeta) assemblies are thought to play primary roles in Alzheimer disease (AD). They are considered to acquire surface tertiary structures, not present in physiologic monomers, that are responsible for exerting toxicity, probably through abnormal interactions with their target(s). Therefore, Abeta assemblies having distinct surface tertiary structures should cause neurotoxicity through distinct mechanisms. Aiming to clarify the molecular basis of neuronal loss, which is a central phenotype in neurodegenerative diseases such as AD, we report here the selective immunoisolation of neurotoxic 10-15-nm spherical Abeta assemblies termed native amylospheroids (native ASPDs) from AD and dementia with Lewy bodies brains, using ASPD tertiary structure-dependent antibodies. In AD patients, the amount of native ASPDs was correlated with the pathologic severity of disease. Native ASPDs are anti-pan oligomer A11 antibody-negative, high mass (>100 kDa) assemblies that induce degeneration particularly of mature neurons, including those of human origin, in vitro. Importantly, their immunospecificity strongly suggests that native ASPDs have a distinct surface tertiary structure from other reported assemblies such as dimers, Abeta-derived diffusible ligands, and A11-positive assemblies. Only ASPD tertiary structure-dependent antibodies could block ASPD-induced neurodegeneration. ASPDs bind presynaptic target(s) on mature neurons and have a mode of toxicity different from those of other assemblies, which have been reported to exert their toxicity through binding postsynaptic targets and probably perturbing glutamatergic synaptic transmission. Thus, our findings indicate that native ASPDs with a distinct toxic surface induce neuronal loss through a different mechanism from other Abeta assemblies.

Amyloid beta-protein (Abeta) assemblies are thought to play primary roles in Alzheimer disease (AD). They are considered to acquire surface tertiary structures, not present in physiologic monomers, that are responsible for exerting toxicity, probably through abnormal interactions with their target(s). Therefore, Abeta assemblies having distinct surface tertiary structures should cause neurotoxicity through distinct mechanisms. Aiming to clarify the molecular basis of neuronal loss, which is a central phenotype in neurodegenerative diseases such as AD, we report here the selective immunoisolation of neurotoxic 10-15-nm spherical Abeta assemblies termed native amylospheroids (native ASPDs) from AD and dementia with Lewy bodies brains, using ASPD tertiary structure-dependent antibodies. In AD patients, the amount of native ASPDs was correlated with the pathologic severity of disease. Native ASPDs are anti-pan oligomer A11 antibody-negative, high mass (>100 kDa) assemblies that induce degeneration particularly of mature neurons, including those of human origin, in vitro. Importantly, their immunospecificity strongly suggests that native ASPDs have a distinct surface tertiary structure from other reported assemblies such as dimers, Abeta-derived diffusible ligands, and A11-positive assemblies. Only ASPD tertiary structure-dependent antibodies could block ASPD-induced neurodegeneration. ASPDs bind presynaptic target(s) on mature neurons and have a mode of toxicity different from those of other assemblies, which have been reported to exert their toxicity through binding postsynaptic targets and probably perturbing glutamatergic synaptic transmission. Thus, our findings indicate that native ASPDs with a distinct toxic surface induce neuronal loss through a different mechanism from other Abeta assemblies.

[beta]-Amyloid (A[beta]) acquires toxicity by self-aggregation. To identify and characterize the toxic form(s) of A[beta] aggregates, we examined in vitro aggregation conditions by using large quantities of homogenous, chemically synthesized A[[beta].sub.1-40] peptide. We found that slow rotation of A[[beta].sub.1-40] solution reproducibly gave self-aggregated A[[beta].sub.1-40] containing a stable and highly toxic moiety. Examination of the aggregates purified by glycerol-gradient centrifugation by atomic force microscopy and transmission electron microscopy revealed that the toxic moiety is a perfect sphere, which we call amylospheroid (ASPD). Other A[[beta].sub.1-40] aggregates, including fibrils, were nontoxic. Correlation studies between toxicity and sphere size indicate that 10- to 15-nm ASPD was highly toxic, whereas ASPD 10 nm also appeared to exist when A[[beta].sub.1-42] formed ASPD by slow rotation. However, A[[beta].sub.1-42]-ASPD formed more rapidly, killed neurons at lower concentrations, and showed [approximately equal to] 100-fold-higher toxicity than A[[beta].sub.1-40]-ASPD. The toxic ASPD was associated with SDS-resistant oligomeric bands in immunoblotting, which were absent in nontoxic ASPD. Because the formation of ASPD was not disturbed by pentapeptides that break [beta]-sheet interactions, A[beta] may form ASPD through a pathway that is at least partly distinct from that of fibril formation. Inhibition experiments with lithium suggest the involvement of tau protein kinase I/glycogen synthase kinase-3[beta] in the early stages of ASPD-induced neurodegeneration, Here we describe the identification and characterization of ASPD and discuss its possible role in the neurodegeneration in Alzheimer's disease.

Premature white babies appear to have benefitted more from surfactant therapy than premature black babies. Surfactant therapy was approved in 1990 to treat very-low-birth-weight babies with respiratory distress syndrome. After 1990, the mortality rate among these babies dropped 17%. However, the mortality rate among black babies remained the same while the rate in white babies dropped 41%. Black babies were just as likely to receive surfactant as white babies but they may have less need for it, since their lungs mature faster.

Infants born prematurely often suffer from lung problems such as respiratory distress syndrome that increase their risk of illness and death above that of full-term infants. Premature infants lack a substance called surfactant in the lungs which is essential for respiratory function. In the past decade, it was found that a surfactant derived from cows (bovine surfactant) could be given to these infants, and that this decreased the need for oxygen and ventilation (use of a breathing machine). Further studies found that a single dose given at birth reduced the severity of the symptoms of respiratory distress syndrome, but did not necessarily increase survival rates. This study examined if giving more than a single dose of the surfactant when disease persisted would increase survival rates in these infants. The study involved 798 infants born prematurely weighing between 600 and 1,750 grams (1.3 and 3.9 pounds) that developed respiratory distress syndrome within six hours after birth. The infants were randomly assigned to one of two groups; one was the control group (396 infants) and the other received an initial dose of the surfactant with repeated doses if needed (402 infants). Results showed that in the first 28 days after birth, 36 treated infants (9 percent) and 80 untreated infants (20 percent) died from respiratory distress syndrome. Deaths from all causes during this period were 74 (18 percent) in the treated group and 108 (27 percent) in the untreated group. Mean airway pressure and oxygenation values, measures of respiratory function, during the first 72 hours of life were significantly better in the treated than in the untreated infants. The treated infants also developed significantly fewer cases of pulmonary interstitial emphysema and of pulmonary air leaks than the untreated infants. These results indicate that multiple doses of bovine surfactant given to premature infants with respiratory distress syndrome can reduce the incidence of illness and death. (Consumer Summary produced by Reliance Medical Information, Inc.)

Background: Rates of retinopathy of prematurity (ROP) and ROP treatment vary between neonatal intensive care units (NICUs). Neonatal care practices, including oxygen saturation (SpO2) targets and criteria for the screening and treatment of ROP, are potential contributing factors to the variations. Objectives: To survey variations in SpO2 targets in 2015 (and whether there had been recent changes) and criteria for ROP screening and treatment across the networks of the International Network for Evaluating Outcomes in Neonates (iNeo). Methods: Online prepiloted questionnaires on treatment practices for preterm infants were sent to the directors of 390 NICUs in 10 collaborating iNeo networks. Nine questions were asked and the results were summarized and compared. Results: Overall, 329/390 (84%) NICUs responded, and a majority (60%) recently made changes in upper and lower SpO2 target limits, with the median set higher than previously by 2–3% in 8 of 10 networks. After the changes, fewer NICUs (15 vs. 28%) set an upper SpO2 target limit > 95% and fewer (3 vs. 5%) a lower limit < 85%. There were variations in ROP screening criteria, and only in the Swedish network did all NICUs follow a single guideline. The initial retinal examination was carried out by an ophthalmologist in all but 6 NICUs, and retinal photography was used in 20% but most commonly as an adjunct to indirect ophthalmoscopy. Conclusions: There is considerable variation in SpO2 targets and ROP screening and treatment criteria, both within networks and between countries. [ABSTRACT FROM AUTHOR]