Characterization and quantitation of the circulating forms of serum transferrin receptor using domain-specific antibodies

To characterize the nature of the immunoreactive transferrin receptor in human serum, antisera were developed to peptide sequences of the extracellular domain of human transferrin receptor between amino acids 107 and 120 and the intracellular domain between amino acids 40 and 54. Antisera against the extracellular domain exhibited reactivity against both purified intact receptor and immunopurified circulating receptor, whereas antisera against the intracellular domain reacted only with intact receptor. Using competitive binding enzyme-linked immunosorbent assays, transferrin receptor in ultracentrifuged sera from normal subjects and patients with sickle cell anemia could be detected with antisera against the extracellular but not the intracellular domain. When the pellet obtained by ultracentrifugation of these sera was assayed after solubilization in 1% teric (polyoxyethylene-9-lauryl ether), only 0.6% of total serum receptor was detected in normal subjects and 3.8% in subjects with sickle cell disease. Roughly equal amounts of this pelleted immunoactivity were detected with antibodies against the extracellular and intracellular domains. These results indicate that less than 1% of transferrin receptor in normal human sera is intact receptor consistent with an exosomal origin and that virtually all circulating transferrin receptor is in the form of a truncated extracellular domain.     

Assessing the Legacy of a Legislative Workgroup for Bidirectional Integration of Services

Across the USA, health care systems are recognizing the value of integrating behavioral health services and primary care. The Texas Legislature took a unique approach to integration, passing legislation creating a Workgroup to explore key issues, identify best practices, and recommend policy and practice changes. This article situates the Workgroup in a rapidly evolving policy environment, describing the passage of integrated health care legislation in Texas, the Integration of Health and Behavioral Health Services Workgroup that was created by the legislation, and the policy recommendations that emerged from the Workgroup. The article analyzes how the Workgroup process intersected with a changing policy environment in Texas and nationally, opening the door for essential collaboration and partnership. The Workgroup ultimately laid the groundwork for integration's key role in a comprehensive Medicaid transformation waiver designed to expand access, improve population health and satisfaction with treatment, while better managing costs.     

Trust in government and support for governmental regulation: the case of electronic health records

Background

This paper presents results from a public engagement effort in Nebraska, USA, which measured public opinions about governmental involvement in encouraging the use of electronic health records (EHRs).

Objective

We examine the role of trust in government in contributing to public support for government involvement in the development of EHR technologies. We hypothesize that trust in government will lead to support for federal and state governmental encouragement of the use of EHRs among doctors and insurance companies. Further, because individual experiences with health‐care professionals will reduce perceptions of risk, we expect that support for governmental involvement will be tempered by greater personal experience with the health‐care industry.

Design and Results

Examining a small survey of individuals on the issue, we find general support for both of our hypotheses. The findings suggest that trust in government does have a positive relationship with support for government involvement in the policy domain, but that the frequency of personal experiences with health‐care providers reduces the extent to which the public supports governmental involvement in the development of EHR technology.

Discussion and Conclusion

This inquiry contributes to our understanding of public attitudes towards government involvement in EHRs in the United States specifically and contributes to social science examining links between trust in government and support for governmental activity in the emerging policy domain regarding electronic health records systems.     

Repetition-related reductions in neural activity reveal component processes of mental simulation

In everyday life, people adaptively prepare for the future by simulating dynamic events about impending interactions with people, objects and locations. Previous research has consistently demonstrated that a distributed network of frontal–parietal–temporal brain regions supports this ubiquitous mental activity. Nonetheless, little is known about the manner in which specific regions of this network contribute to component features of future simulation. In two experiments, we used a functional magnetic resonance (fMR)-repetition suppression paradigm to demonstrate that distinct frontal–parietal–temporal regions are sensitive to processing the scenarios or what participants imagined was happening in an event (e.g. medial prefrontal, posterior cingulate, temporal–parietal and middle temporal cortices are sensitive to the scenarios associated with future social events), people (medial prefrontal cortex), objects (inferior frontal and premotor cortices) and locations (posterior cingulate/retrosplenial, parahippocampal and posterior parietal cortices) that typically constitute simulations of personal future events. This pattern of results demonstrates that the neural substrates of these component features of event simulations can be reliably identified in the context of a task that requires participants to simulate complex, everyday future experiences.     

Decreased segregation of brain systems across the healthy adult lifespan

Healthy aging has been associated with decreased specialization in brain function. This characterization has focused largely on describing age-accompanied differences in specialization at the level of neurons and brain areas. We expand this work to describe systems-level differences in specialization in a healthy adult lifespan sample (n = 210; 20–89 y). A graph-theoretic framework is used to guide analysis of functional MRI resting-state data and describe systems-level differences in connectivity of individual brain networks. Young adults’ brain systems exhibit a balance of within- and between-system correlations that is characteristic of segregated and specialized organization. Increasing age is accompanied by decreasing segregation of brain systems. Compared with systems involved in the processing of sensory input and motor output, systems mediating “associative” operations exhibit a distinct pattern of reductions in segregation across the adult lifespan. Of particular importance, the magnitude of association system segregation is predictive of long-term memory function, independent of an individual’s age.Healthy adult aging is characterized by a progressive degradation of brain structure and function associated with gradual changes in cognition (see reviews in refs. 1, 2). Among the age-accompanied functional changes, one prominent observation is a reduction in the specificity with which distinct neural structures mediate particular processing roles [i.e., a reduction in functional specialization, or “dedifferentiation” (3)]. A reduction in functional specificity has been observed across multiple spatial scales of brain organization, ranging from the firing patterns of single neurons (e.g., refs. 4, 5) to the evoked activity of individual brain areas (6–10). (For additional discussion see ref. 11.)Despite the compelling evidence for age-accompanied reductions in functional specialization across numerous brain areas, the relationship between neural specialization and cognition generally is weak. This likely is related to the fact that broad cognitive domains such as “long-term memory” and “executive control” are mediated by distributed and interacting brain systems, each consisting of multiple interacting brain areas. Thus, relating functional specialization in a single brain area to general measures of cognition likely will be unsuccessful. Such an argument is consistent with the view that severe impairment in cognitive function due to injury or insult typically is a consequence of damage to multiple brain locations (e.g., refs. 12, 13). Based on these considerations, it seems plausible that the cognitive decline evident even in healthy older adults may be related to decreased functional integrity at a systems level of organization. The present report approaches healthy aging from this systems-level perspective in an effort to relate systems-related functional specialization to age-accompanied differences in cognition.Before proceeding, it is important to clarify the meaning of system. The term “system” often is used in relation to brain organization when referring to any group of areas that subserve common processing roles. For example, the visual system comprises brain areas primarily defined by their role in processing visual stimuli (e.g., ref. 14), and the frontal–parietal task control system consists of brain areas involved mainly in adaptive task control (15). Identifying distinct brain systems and defining their functional roles by examining how their constituent areas are modulated by experimental testing or are impaired by brain damage is not an easy endeavor; systems of brain areas typically mediate processing roles that span multiple stimulus and task demands. This reality makes assessing changes in the functional specialization of systems across cohorts of individuals extremely challenging.An alternative formal and complementary approach to defining a brain system involves understanding how brain areas relate to one another via their patterns of shared functional or anatomical relationships in the context of a large-scale network (16, 17). Like many other complex networks, brain networks may be analyzed as a graph of connected or interacting elements. When a brain network graph represents the interaction of areas, one prominent feature is the presence of subsets of areas that are highly interactive with one another and less interactive with other subsets of areas. This pattern of organization reflects the presence of distinct “modules” or “communities” (e.g., ref. 18). Importantly, numerous connectivity-defined human brain modules have been shown to overlap closely with functional systems as defined by other methods of assessing information processing [e.g., task-evoked activity, lesion-mapping (19, 20)]. The close correspondence between differing methods of system identification provides a basis for using connectivity to understand the organization of brain systems and how they may differ with age.Modular brain networks are characterized by a fine balance of dense within-system relationships among brain areas (nodes) that have highly related processing roles, as well as sparser (but not necessarily absent) relationships between areas in systems with divergent processing roles. This pattern of system segregation facilitates communication among brain areas that may be distributed anatomically but nevertheless are in the service of related sets of processing operations, and simultaneously reinforces the functional specialization of systems that perform different sets of processing operations (21). Importantly, segregated systems can communicate with one another via the presence of the sparser connections between them. As such, any deviation in the patterns of within- and between-system connectivity may be considered evidence for a change in the system’s specialization. Furthermore, if aging is associated with changes in functional specialization at the level of brain systems, this may be revealed by examining the differences in patterns of within- and between-system areal connectivity across age.We use functional connectivity, as measured by blood oxygen-level–dependent (BOLD) functional MRI (fMRI) during rest [resting-state functional correlations (RSFCs), see ref. 22], to assess age-related differences in the organization of brain systems. Changes in RSFC patterns between sets of areas have been observed following extensive directed training (23–25), and differences in RSFC patterns also have been reported in cross-sectional comparisons spanning from childhood to older age (e.g., refs. 26–29). The extant data suggest that RSFCs are malleable and reflect sensitivity to a history of coactivation: changes in the processing roles of areas may be characterized by changes in their RSFCs with other areas (for discussion, see ref. 17). This feature makes RSFCs particularly useful in assessing differences in the organization and specialization of brain systems.In the present study, the age-accompanied differences in the functional specialization of brain systems are revealed by examining patterns of within- and between-system areal RSFCs in a large healthy adult lifespan sample (n = 210; age range, 20–89 y). The inclusion of subjects distributed across each decade of adulthood not only allows us to assess how older and younger adults differ in their organization of brain systems, but also provides insight as to whether there is a critical stage of the adult lifespan when differences in system organization may appear. Previous reports attempted to address related questions by examining end points of the adult aging spectrum, focusing on the organization within specific systems (e.g., refs. 26, 28, 30), or using area nodes that are not representative of functional areas [e.g., structural parcels (31–34)]. The latter feature likely contributes to the inconsistent findings observed in the relationship between summary network measures and age groups (e.g., refs. 31, 35 vs. refs. 30, 36). In addition to examining age-related differences in system organization developed from a biologically plausible cortical parcellation of the human brain network, we also relate systems-level differences in organization to differences in general measures of cognitive ability. To foreshadow the results that follow, we report that aging is associated with differences in patterns of connectivity within and between brain systems, that these differences are not uniform across all systems, and that the segregation of brain systems has a direct relationship to measures of cognitive ability independent of age.