Prospective Evaluation of Cognitive Health and Related Factors in Elderly at Risk for Developing Alzheimer's Dementia: A Longitudinal Cohort Study.

BACKGROUND: The CHARIOT PRO Main study is a prospective, non-interventional study evaluating cognitive trajectories in participants at the preclinical stage of Alzheimer's disease (AD) classified by risk levels for developing mild cognitive impairment due to AD (MCI-AD). OBJECTIVES: The study aimed to characterize factors and markers influencing cognitive and functional progression among individuals at-risk for developing MCI-AD, and examine data for more precise predictors of cognitive change, particularly in relation to APOE ε4 subgroup. DESIGN: This single-site study was conducted at the Imperial College London (ICL) in the United Kingdom. Participants 60 to 85 years of age were classified as high, medium (amnestic or non-amnestic) or low risk for developing MCI-AD based on RBANS z-scores. A series of clinical outcome assessments (COAs) on factors influencing baseline cognitive changes were collected in each of the instrument categories of cognition, lifestyle exposure, mood, and sleep. Data collection was planned to occur every 6 months for 48 months, however the median follow-up time was 18.1 months due to early termination of study by the sponsor. RESULTS: 987 participants were screened, among them 690 participants were actively followed-up post baseline, of whom 165 (23.9%) were APOE ε4 carriers; with at least one copy of the allele. The mean age was 68.73 years, 94.6% were white, 57.4% were female, and 34.8% had a Family History of Dementia with a somewhat larger percentage in the APOE ε4 carrier group (42.4%) compared to the non-carrier group (32.4%). Over half of the participants were married and 53% had a Bachelor's or higher degree. Most frequently, safety events typical for this population consisted of upper respiratory tract infection (10.4%), falls (5.2%), hypertension (3.5%) and back pain (3.0%). Conclusion (clinical relevance): AD-related measures collected during the CHARIOT PRO Main study will allow identification and evaluation of AD risk factors and markers associated with cognitive performance from the pre-clinical stage. Evaluating the psycho-biological characteristics of these pre-symptomatic individuals in relation to their natural neurocognitive trajectories will enhance current understanding on determinants of the initial signs of cognitive changes linked to AD.

Feasibility and Acceptability of an Online Positive Affect Intervention for Those Living with Comorbid HIV Depression.

Positive affect has unique beneficial effects on psychological and physical health, independent of the effects of negative affect. Interventions that explicitly target positive affect show promise for improving health outcomes in a number of chronic illnesses. In this article, we present pilot data on the acceptability and feasibility of an online intervention to increase positive affect in those living with comorbid human immunodeficiency virus (HIV) and depression. The intervention was rated both acceptable and feasible by participants. Six of nine participants completed the intervention and the subsequent follow-up assessment and a post-intervention phone call. We also present outcomes of planned comparisons of intervention effects on emotion, which indicate that positive affect increased significantly in the intervention group. Based upon results of the current study, future research should continue the development of positive affect interventions for people living with comorbid HIV and depression.

TCR-pMHC interactions: Two peptide repertoires-one signal.

The peptide (P) ligand seen by the TCR is presented by an MHC-encoded restricting element (R). Peptide is viewed from two perspectives, that of the TCR and that of R. The TCR looks at P using an anti-P site that is somatically generated and selected, whereas R looks at P using a binding site that is germline generated and selected. The two segments of P, the one viewed by the TCR, the other viewed by R divide P into two repertoires, Ptcr and Pr that are recognized independently but function cooperatively. The consequences of this for an understanding of TCR specificity and signalling as well as the role of differential processing are analysed. It is ironic that from the point of view of the immunologist, the TCR is highly polyreactive recognizing over a million peptides, whereas from the point of view of the immune system, the TCR is highly specific recognizing essentially only one epitope.

Somatic diversification of the B cell repertoire requires two cell subsets.

Evolution found itself in a Catch-22 situation when selecting for the somatically derived paratopic repertoire of the humoral immune system. The B cell BCR repertoire can only be somatically diversified from a substrate of paratopes that is encoded in the germline. In order for the cells expressing that substrate to also be a target of germline selection, their BCRs must, independently, be of selective value by being expressed in a functionally important way in each individual. A somatically derived repertoire scrambles this substrate so that its specificities are lost, making it unselectable in the germline. Consequently, evolution faced an incompatibility. Here, we explore what it takes to resolve it.

Giving Context to Non-self-marker Theories of Immune Responsiveness.

In 2001, long ago by modern standards, Matzinger changed the emphasis of her Danger theory from one that downplayed the self-non-self discrimination to one that concerned itself with the regulation of effector class. This gave her theory a measure of validity that the other non-self-marker theorists have yet to confront. However, precision and clarity are still lacking.

A Commentary on a Workshop 'To Reveal the Foundational Concepts of Immune Regulation' (i.e. Tolerance).

A summary of the workshop with its laudatory goal 'to reveal the foundational concepts in immunology' was recently published in SJI with an invitation to outsiders to comment. In the end, a foundational concept is one upon which we can all agree. This requires debate and meaningful experimentation. The goal of this commentary is to provide some of that. Most of immunology is description of an observation (i.e. a fact). However, what ties all the facts together as a discipline is theory or conceptualization that gives a general context to observation and predicts the next step. This is what is meant by 'foundational concepts'.

Are Proactive and Reactive Aggression Meaningful Distinctions in Adolescents? A Variable- and Person-Based Approach.

This study was designed to examine whether proactive and reactive aggression are meaningful distinctions at the variable- and person-based level, and to determine their associated behavioral profiles. Data from 587 adolescents (mean age 15.6; 71.6 % male) from clinical samples of four different sites with differing levels of aggression problems were analyzed. A multi-level Latent Class Analysis (LCA) was conducted to identify classes of individuals (person-based) with similar aggression profiles based on factor scores (variable-based) of the Reactive Proactive Questionnaire (RPQ) scored by self-report. Associations were examined between aggression factors and classes, and externalizing and internalizing problem behavior scales by parent report (CBCL) and self-report (YSR). Factor-analyses yielded a three factor solution: 1) proactive aggression, 2) reactive aggression due to internal frustration, and 3) reactive aggression due to external provocation. All three factors showed moderate to high correlations. Four classes were detected that mainly differed quantitatively (no 'proactive-only' class present), yet also qualitatively when age was taken into account, with reactive aggression becoming more severe with age in the highest affected class yet diminishing with age in the other classes. Findings were robust across the four samples. Multiple regression analyses showed that 'reactive aggression due to internal frustration' was the strongest predictor of YSR and CBCL internalizing problems. However, results showed moderate to high overlap between all three factors. Aggressive behavior can be distinguished psychometrically into three factors in a clinical sample, with some differential associations. However, the clinical relevance of these findings is challenged by the person-based analysis showing proactive and reactive aggression are mainly driven by aggression severity.

Contemplating Bretscher's View that the Tritope Model is 'Implausible'.

There is, at present, only two models of the TCR structure-function relationship. These are referred to here as the Standard (Centric) model and the Tritope model. While I have argued that the Standard model is untenable and proposed the Tritope to replace it, Bretscher has argued that the Tritope model is 'implausible' and throws his support for the Standard model. This essay analyses the implausibility argument concluding that it is unfounded.

Simple method for correct enumeration of Staphylococcus aureus.

Optical density (OD) measurement is applied universally to estimate cell numbers of microorganisms growing in liquid cultures. It is a fast and reliable method but is based on the assumption that the bacteria grow as single cells of equal size and that the cells are dispersed evenly in the liquid culture. When grown in such liquid cultures, the human pathogen Staphylococcus aureus is characterized by its aggregation of single cells into clusters of variable size. Here, we show that aggregation during growth in the laboratory standard medium tryptic soy broth (TSB) is common among clinical and laboratory S. aureus isolates and that aggregation may introduce significant bias when applying standard enumeration methods on S. aureus growing in laboratory batch cultures. We provide a simple and efficient sonication procedure, which can be applied prior to optical density measurements to give an accurate estimate of cellular numbers in liquid cultures of S. aureus regardless of the aggregation level of the given strain. We further show that the sonication procedure is applicable for accurate determination of cell numbers using agar plate counting of aggregating strains.

Thoughts on Positive Selection in Thymus.

Any analysis of the mechanism of signalling during positive selection in the thymus is dependent on one's model of the TCR-ligand interaction. To date, thinking about mechanism has been dominated by what might be termed the Standard (or Centric) model, which is based on analogy between the BCR and the TCR. As the present analysis is an independent rationalized view of the TCR-ligand interactions, it permits a more balanced view of positive selection. The goal here was to explore this alternative to the Standard model.

Thoughts engendered by Bretscher's Two-step, Two-signal model for a peripheral self-non-self discrimination and the origin of primer effector T helpers.

There are three questions under re-examination here that have been inspired by Bretscher's 'Two-step, Two-signal' model. First, what is the nature of the steps required in order for antigen-responsive cells to become effectors? Second, how does the immune system get started? Third and the most troublesome, what is the mechanism that relates the delivery of the two signals? To answer the first question, Bretscher proposes a pathway that I will place in another context by comparing it with what had been envisaged under the Associative Recognition of Antigen (ARA) model. The second question, how does the immune system gets started, is crucial to our understanding of the self-non-self discrimination. This problem boils down to, what is the origin of the first effector T helper (eTh) cells required to activate all antigen-responsive cells including the T helpers themselves (the primer problem)? To deal with this question, I proposed an antigen-independent pathway to primer eTh. Bretscher presents us with an antigen-dependent pathway to primer eTh. As competing models are precious in clarifying thinking and in guiding experimentation, I felt it important to reanalyse the two models and look for ways to decide between them. The third question deals with the requirement for and the mechanism of associative (linked) recognition of antigen (ARA). The concept of ARA is so compelling at both the experimental and theoretical levels that to save it, a new perspective will be introduced.

Fear conditioning, persistence of disruptive behavior and psychopathic traits: an fMRI study.

Children diagnosed with Disruptive Behavior Disorders (DBD), especially those with psychopathic traits, are at risk of developing persistent and severe antisocial behavior. Deficient fear conditioning may be a key mechanism underlying persistence, and has been associated with altered regional brain function in adult antisocial populations. In this study, we investigated the associations between the neural correlates of fear conditioning, persistence of childhood-onset DBD during adolescence and psychopathic traits. From a cohort of children arrested before the age of 12 years, participants who were diagnosed with Oppositional Defiant Disorder or Conduct Disorder in previous waves (mean age of onset 6.5 years, s.d. 3.2) were reassessed at mean age 17.6 years (s.d. 1.4) and categorized as persistent (n=25) or desistent (n=25) DBD. Using the Youth Psychopathic Traits Inventory and functional magnetic resonance imaging during a fear conditioning task, these subgroups were compared with 26 matched healthy controls from the same cohort. Both persistent and desistent DBD subgroups were found to show higher activation in fear processing-related brain areas during fear conditioning compared with healthy controls. In addition, regression analyses revealed that impulsive-irresponsible and grandiose-manipulative psychopathic traits were associated with higher activation, whereas callous-unemotional psychopathic traits were related to lower activation in fear-related areas. Finally, the association between neural activation and DBD subgroup membership was mediated by impulsive-irresponsible psychopathic traits. These results provide evidence for heterogeneity in the neurobiological mechanisms underlying psychopathic traits and antisocial behavior and, as such, underscore the need to develop personalized interventions.

Challenging the Tritope Model of T cell receptor structure-function relationships with classical data on 'super' and 'allo-MHC' antigens.

The response of the immune system to allo-MHC-encoded antigens and Mls 'superantigens' has been experimentally analysed in detail, but the data have not been coupled to a theoretical framework. It should therefore be instructive to see how well the newly proposed Tritope Model of TCR structure-function relationships deals with the signalling interactions between the TCR and the above antigens. We will pay heed to William Bateson's admonition, 'treasure the exceptions', by showing how a meaningful theory interrogates the data with the same validity that the data interrogate the theory. The concordances, as well as the contradictions, with the Tritope Model are a test of its heuristic value.

Meanderings into the regulation of effector class by the immune system: derivation of the trauma model.

The pathway of immune system behaviour can be divided into three modules, each with its own logic and database. The modules are related in that they feed sequentially into each other for function. The modules are (1) the generation of the recognitive repertoire; (2) the sorting of the repertoire by purging it of anti-self; and (3) the coupling of the residue, anti-nonself, appropriately to the biodestructive and ridding effector functions. While both the generation and sorting of the repertoire have been intensively investigated and are well understood in terms of firm theoretical frameworks, the understanding of Module 3, the regulation of effector class, is patchy. This essay is an attempt to define the elements required for an understanding of Module 3 and that leads us to propose the Trauma Model.

Musings about regulation by T-suppressors: a response to the commentary by Kristofor Ellestad on 'Meanderings into the regulation of effector class by the immune system: derivation of the trauma model'.

Any discussion of the regulation of effector class must include feedback control on the magnitude of the response. The induced effector activities are biodestructive and ridding. They are, in and of themselves, unspecific with respect to self and nonself. Consequently all responses include some level of innocent bystander pathology. The regulation of magnitude is essential to keeping this level of pathology at an evolutionarily acceptable level. This is my postulated role of suppressor T-cells, more popularly referred to as Treg. In order to perform this function they must be somatically selected to be anti-nonself like all other T/B-cells. If correct, any role that they might play in determining normal tolerance is excluded. As the commentary of Ellestad illustrates, their function to regulate autoimmunity is the consensus view today and, therefore, this competing concept and my analysis of suggested papers should invite a wide ranging debate.

Mesangial cells initiate compensatory tubular cell hypertrophy.

Unilateral nephrectomy results in compensatory renal growth, in which both the size and the functional capacity of the remaining kidney are increased. The functional adaptation to the removal of the contralateral kidney consists mostly of an increase in the glomerular filtration rate of the remaining kidney, and hypertrophy of cells comprising the nephron, mainly of the proximal tubular cells. Although the phenomenon of single kidney hypertrophy has been known for the past thousand years and despite intensive research over the past century, the mechanism of this process still remains unclear. The present article reviews the role of mesangial cells in compensatory renal hypertrophy.

On the critique by Colin Anderson of 'A reply to Dembic: on an end to the beginning of mis-understanding the immune response'.

My proposal of a set of postulates that can be used to guide computer modeling has understandably met with significant criticism at two levels, semantic and conceptual. The major source of contention is my assumption that the sorting of the paratopic repertoire is both necessary and sufficient to explain the evolutionarily selected mechanism for the self-nonself discrimination. While 'necessary' is agreed upon, 'sufficient' is debatable as this commentary illustrates. My essay is in defense of 'sufficiency'.

A reply to Dembic: on an end to the beginning of misunderstanding the immune response.

We all agree that dealing with the complexity and volume of the data necessitates the use of computer modelling. This in turn requires a heuristic conceptual framework to guide this modelling. The first attempt to do this by Cohn has been criticized by Dembic as being severely lacking. This commentary deals with his criticism of the framework to show why Cohn's postulates, in fact, remain unchallenged.

A rationalized set of default postulates that permit a coherent description of the immune system amenable to computer modeling.

This discussion delineates and rationalizes a set of postulates that permit a coherent understanding of immune function. Although analytical tools such as mathematics and computer modeling have become very popular, simulation and data mining in the absence of a conceptual framework cannot increase understanding. The goal of this essay is to provide the foundation for a discussion that has as its goal the formulation of an agreed upon set of default postulates. Such a set is required to guide the algorithms needed to analyze complex immune behavior.

On 'Credo 2004' as viewed under the 'development-context' model of Colin Anderson.

In analysing the Zinkernagel and Hengartner's 'Credo 2004,' Anderson introduces his 'development-context model' for the immunity-tolerance discrimination. He compares this model with the 'geographical model of Credo 2004' and our 'time-based two-signal model'. The discussion here deals with the advantages and limitations of the Anderson model considered largely at the level of principle. A meaningful discussion requires that we agree on the principle which separates the pathway of the effector output into two decision steps, the sorting of the repertoire and the regulation of effector class. The mechanism for the sorting of the repertoire is what might be referred to as the Self-Nonself discrimination. The black box approach, antigen-in, effector response-out, is what is referred to as the immunity-tolerance discrimination which includes the sorting of the repertoire. If this point of principle is accepted then we are left with a 'time-based two signal default model'.