Psychosocial implications of learning amyloid PET results in an observational cohort.

INTRODUCTION: Information on the psychosocial impact of Alzheimer's disease (AD) biomarker testing in adults at risk of AD is needed to inform best practices for communicating biomarker results. METHODS: Ninety-nine cognitively unimpaired older adults learned amyloid positron emission tomography (PET) results (mean age = 72.0 ± 4.8, 95% White, 28% elevated amyloid). Linear mixed-effects regression models were used to test the main effects and interaction of PET result × time on psychosocial outcomes up to 6 months after learning results. RESULTS: A significant interaction of PET result × time was observed for concern about AD (ß = 0.28, p = 0.02) and intrusive thoughts and avoidance (ß = -0.82, p < 0.001). A main effect of PET result was observed for AD test-related distress (ß = 12.09, p < 0.001). DISCUSSION: Cognitively unimpaired adults learning elevated-amyloid PET results reported mildly intrusive thoughts/avoidance initially following disclosure, but these symptoms decreased over time. Concern about AD dementia and AD biomarker test-related distress remained higher in elevated-amyloid compared to non-elevated-amyloid participants. HIGHLIGHTS: Longitudinal assessment of psychosocial reactions after amyloid PET disclosure was conducted. Transient highly intrusive thoughts or avoidance after learning elevated amyloid results. Persistent test result-related distress after receiving elevated-amyloid results. There is increased concern about AD dementia after receiving elevated-amyloid results. Happiness and relief are experienced after receiving non-elevated-amyloid results.

A perpetual switching system in pulmonary capillaries.

Of the 300 billion capillaries in the human lung, a small fraction meet normal oxygen requirements at rest, with the remainder forming a large reserve. The maximum oxygen demands of the acute stress response require that the reserve capillaries are rapidly recruited. To remain primed for emergencies, the normal cardiac output must be parceled throughout the capillary bed to maintain low opening pressures. The flow-distributing system requires complex switching. Because the pulmonary microcirculation contains contractile machinery, one hypothesis posits an active switching system. The opposing hypothesis is based on passive switching that requires no regulation. Both hypotheses were tested ex vivo in canine lung lobes. The lobes were perfused first with autologous blood, and capillary switching patterns were recorded by videomicroscopy. Next, the vasculature of the lobes was saline flushed, fixed by glutaraldehyde perfusion, flushed again, and then reperfused with the original, unfixed blood. Flow patterns through the same capillaries were recorded again. The 16-min-long videos were divided into 4-s increments. Each capillary segment was recorded as being perfused if at least one red blood cell crossed the entire segment. Otherwise it was recorded as unperfused. These binary measurements were made manually for each segment during every 4 s throughout the 16-min recordings of the fresh and fixed capillaries (>60,000 measurements). Unexpectedly, the switching patterns did not change after fixation. We conclude that the pulmonary capillaries can remain primed for emergencies without requiring regulation: no detectors, no feedback loops, and no effectors-a rare system in biology. NEW & NOTEWORTHY The fluctuating flow patterns of red blood cells within the pulmonary capillary networks have been assumed to be actively controlled within the pulmonary microcirculation. Here we show that the capillary flow switching patterns in the same network are the same whether the lungs are fresh or fixed. This unexpected observation can be successfully explained by a new model of pulmonary capillary flow based on chaos theory and fractal mathematics.

The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation.

Human plasmacytoid dendritic cells (PDCs) can drive naive, allogeneic CD4(+)CD25(-) T cells to differentiate into CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). However, the intracellular mechanism or mechanisms underlying PDC-induced Treg generation are unknown. In this study, we show that human PDCs express high levels of IDO, an intracellular enzyme that catabolizes tryptophan degradation. Triggering of TLR 9 with CpG oligodeoxynucleotides activates PDCs to up-regulate surface expression of B7 ligands and HLA-DR Ag, but also significantly increases the expression of IDO and results in the generation of inducible Tregs from CD4(+)CD25(-) T cells with potent suppressor cell function. Blocking IDO activity with the pharmacologic inhibitor 1-methyl-D-tryptophan significantly abrogates PDC-driven inducible Treg generation and suppressor cell function. Adding kynurenine, the immediate downstream metabolite of tryptophan, bypasses the 1-methyl-D-tryptophan effect and restores PDC-driven Treg generation. Our results demonstrate that the IDO pathway is essential for PDC-driven Treg generation from CD4(+)CD25(-) T cells and implicate the generation of kynurenine pathway metabolites as the critical mediator of this process.

Blood flow switching among pulmonary capillaries is decreased during high hematocrit.

Pulmonary capillary perfusion within a single alveolar wall continually switches among segments, even when large-vessel hemodynamics are constant. The mechanism is unknown. We hypothesize that the continually varying size of plasma gaps between individual red blood cells affects the likelihood of capillary segment closure and the probability of cells changing directions at the next capillary junction. We assumed that an increase in hematocrit would decrease the average distance between red blood cells, thereby decreasing the switching at each capillary junction. To test this idea, we observed 26 individual alveolar capillary networks by using videomicroscopy of excised canine lung lobes that were perfused first at normal hematocrit (31-43%) and then at increased hematocrit (51-62%). The number of switches decreased by 38% during increased hematocrit (P < 0.01). These results support the idea that a substantial part of flow switching among pulmonary capillaries is caused by the particulate nature of blood passing through a complex network of tubes with continuously varying hematocrit.

Heterogeneous capillary recruitment among adjoining alveoli.

Pulmonary capillaries recruit when microvascular pressure is raised. The details of the relationship between recruitment and pressure, however, are controversial. There are data supporting 1). gradual homogeneous recruitment, 2). sudden and complete recruitment, and 3). heterogeneous recruitment. The present study was designed to determine whether alveolar capillary networks recruit in a variety of ways or whether one model predominates. In isolated, pump-perfused canine lung lobes, fields of six neighboring alveoli were recorded with video microscopy as pulmonary venous pressure was raised from 0 to 40 mmHg in 5-mmHg increments. The largest group of alveoli (42%) recruited gradually. Another group (33%) recruited suddenly (sheet flow). Half of the neighborhoods had at least one alveolus that paradoxically derecruited when pressure was increased, even though neighboring alveoli continued to recruit capillaries. At pulmonary venous pressures of 40 mmHg, 86% of the alveolar-capillary networks were not fully recruited. We conclude that the pattern of recruitment among neighboring alveoli is complex, is not homogeneous, and may not reach full recruitment, even under extreme pressures.

Pulmonary capillaries are recruited during pulsatile flow.

Capillaries recruit when pulmonary arterial pressure rises. The duration of increased pressure imposed in such experiments is usually on the order of minutes, although recent work shows that the recruitment response can occur in <4 s. In the present study, we investigate whether the brief pressure rise during cardiac systole can also cause recruitment and whether the recruitment is maintained during diastole. To study these basic aspects of pulmonary capillary hemodynamics, isolated dog lungs were pump perfused alternately by steady flow and pulsatile flow with the mean arterial and left atrial pressures held constant. Several direct measurements of capillary recruitment were made with videomicroscopy. The total number and total length of perfused capillaries increased significantly during pulsatile flow by 94 and 105%, respectively. Of the newly recruited capillaries, 92% were perfused by red blood cells throughout the pulsatile cycle. These data provide the first direct account of how the pulmonary capillaries respond to pulsatile flow by showing that capillaries are recruited during the systolic pulse and that, once open, the capillaries remain open throughout the pulsatile cycle.